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 .
Election/Restrictions
Applicant’s election of species (A) deep brain region as target site, (B) Huntington’s disease as neurodegenerative disorder, (C) therapeutic agent as viral vector, (D) molecular weight of the therapeutic agent greater or equal to 140-160 kDa, and (E) size of the therapeutic agent greater than 0 and less than 10 mm in the reply filed on July 2, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 7, 11, and 13-15 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-6, 8-10, 12, and 16-20 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit to U.S. Provisional Application No. 63/418,733 filed October 24, 2022.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 24, 2023, March 28, 2024, September 18, 2024, and January 17, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Claim Objections
Claim 1 are objected to because of the following informalities:
Claim 1 uses an acronym without first defining what they represent in the independent claims: LiFUS. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
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.
Claims 1-6, 8-10, 12, and 16-20 are 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.
The term “proximate” in claims 1 and 19 is a relative term which renders the claim indefinite. The term “proximate” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. According to the specification, the microbubbles are administered intravenously (pg 15), and there appears to be a disconnect between proximate to a brain target site and intravenous administration. If the claims are referring to where the microbubbles ultimately localize prior to sonication, the claims do not clearly say so.
The term “about” in claims 1, 3, 12, 16, and 19 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 3 and 19 are limited to an ultrasound delivery device parameter comprising a cavitation response of about 0.5 Volts second. It is unclear whether the cavitation response has the unit of 0.5 Volts second or the ultrasound delivery device parameter is set to 0.5 Volts second. Both interpretations are reasonable and materially different. Amend the claim to indicate clearly what comprises cavitation response and the device parameters. It is noted that “cavitation response” does not appear in the specification, whereas “cavitation signal” does [0018].
The term “variably” in claim 10 renders the claim indefinite because the claim does not specify what aspect of microbubble administration is variable. For example, is the variation in timing relative to LiFUS sonication or amount? Although claims are interpreted in light of the specification, essential limitations cannot be imported from the specification.
Claims 2, 4-6, 8-9, 12, and 16-18, 20 are included in this rejection for being dependent on a rejected claim and for failing to cure the indefiniteness.
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.
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.
Claims 1-2, 4-5, 9, 12, 16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rezai et al, published April 28, 2020 (instant PTO-892).
The claims are drawn to a method of improving a neurodegenerative disorder in a human patient, the method comprising steps of administering microbubbles, applying a low-intensity focused ultrasound sonication, and introducing a therapeutic agent.
Rezai et al teaches that LiFUS mediated oscillation of intravenously administered microbubbles promotes blood brain barrier (BBB) opening for the noninvasive targeted delivery of medications, immunotherapy, gene therapy, or stem cells into deep brain structures (pg 9181, para 1). In an animal model of Alzheimer’s disease, this technique was successfully used to administer antibodies and reduce amyloid-beta plaque (pg 9180, column 1, para 1 and Rezai et al reference 6), as required by claim 9. In the method of Rezai et al, the microbubbles are administered simultaneously with the LiFUS in patients with Alzheimer’s disease (pg 9180, column 1, para 2), as in claims 1 and 19. The LiFUS is administered to humans at 220 kHz (pg 9181, column 2, para 2), as in the limitation drawn to an ultrasound delivery device parameter comprising a frequency between 0.1 MHz and 3 MHz of instant claim 1 and between 0.1 Mhz and 10 Mhz of instant claim 19. The treatment of Rezai et al is targeted to the hippocampus (pg 9181, column 2, para 2), a deep brain region, which reads on the target site of instant claims 1 and 19 and the deep brain region of claim 4.
In Rezai et al, the presence of amyloid-beta plaques in the target area was confirmed (pg 9181, column 2, para 1), as in instant claim 2. The LiFUS of Rezai et al is administered at two to five targets (pg 9181, column 2, para 2), as in instant claim 5.
Rezai teaches that the method can be used to administer antibodies (pg 9180, column 1, para 1). Monoclonal antibodies have a molecular weight of approximately 150 kDa, with dimensions of 14.2 nm × 8.2 nm × 3.8 nm, as evidenced by Jovcevska & Muyldermans (see instant PTO-892), as in the molecular weight and size limitations of the therapeutic agent of instant claims 12 and 16, respectively.
Rezai et al teaches the detection of hemorrhage after each treatment, suggesting that parameters would be adjusted to minimize bleeding, as in instant claim 17.
Regarding the limitation of claim 20 drawn to applying a neuromodulation signal during or after introducing the therapeutic agents or applying a LiFUS sonication, Rezai et al teaches the coupling of FUS with targeted delivery of medications (page 9181, column 1, para 2). The specification discloses that “[n]on-limiting examples of neuromodulation include ultrasound including focused ultrasound” [0047]. As the claim is given its broadest reasonable interpretation in light of the specification, the LiFUS sonication used on the hippocampus of the Alzheimer’s human patients inherently provides a neuromodulation signal to a brain region during a LiFUS sonication.
Because Rezai et al teaches the safe and temporary opening of the BBB of deep brain structures in humans and expressly contemplates the translation of targeted delivery of agents for use in humans (pg 9181), Rezai et al teaches the method of improving a neurodegenerative disorder in a human patient in claims 1, 9, and 19. Although Rezai et al does not perform the administration of a therapeutic in humans, it teaches that the method applied to rodents was effective to reduce metrics of Alzheimer’s disease (pg 9180, col 1, para 1). Therefore, it would have bene obvious to one of ordinary skill in the art at the time of the invention to apply the treatment method of Rezai et al to a human patient because these patients were identified as suitable for clinical translation based on studies in animal suffering from the same disease. The treatment of humans with a therapeutic would have been an obvious extension of the teachings of Rezai et al, as limiting a known treatment method from an animal model to the intended patient population would be the predictable use of the prior art method according to its known purpose, see MPEP 2143(I)D.
Claims 1-5, 9-10, 12, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rezai et al, as applied to claims 1-2, 4-5, 9, 12, 16, and 19-20 above, and further in view of D’Haese et al, published October 7, 2020 (instant PTO-892).
The teachings of Rezai et al are discussed above. Rezai does not teach the ultrasound delivery device parameters of claim 3 or the variable administration of microbubbles in claims 10 and 18.
D’Haese teaches a method of opening the BBB using FUS in patients with Alzheimer’s disease (abstract), with a sonication range of power of 4-11.5 W for 90 sec (pg 3, column 1, para 0), as in the parameters of instant claim 3. D’Haese also teaches that sonication power and parameter are tailored to each subject to achieve a 50-60% of cavitation thresholds to open the BBB (pg 3, column 1, para 0), demonstrating that D’Haese recognizes sonication power as a result-effect variable. Although the parameter of claim 3 does not overlap with the parameter taught by D’Haese, power is a result-effective variable, and, absent evidence to the contrary, identification of the setting of 20-60 W could be readily determined by routine optimization via methods known in the art.
D’Haese teaches a max microbubble dose of 20 ml/kg (pg 3, column 1, para 0), demonstrating that D’Haese recognizes microbubble dose as a result-effective variable. One would adjust the dose of microbubbles to achieve the desired BBB opening, as in the variably administered microbubbles of claim 10 and the adjustment of microbubble dose of claim 18.
Given that Rezai et al teaches a method for the safe and temporary opening of the BBB of deep brain structures in humans and the targeted delivery of agents for use in humans, and further given that D’Haese teaches the claimed parameters for FUS treatment, it would have been obvious to one of ordinary skill in the art to apply the FUS settings of D’Haese in the method of Rezai et al and the results would have been reasonably predictable. Such comprises the use of a known technique to improve a similar method in the same way, see MPEP 2143.I(C).
Claims 1-2, 4-6, 9, 12, 16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rezai et al, as applied to claims 1-2, 4-5, 9, 12, 16, and 19-20 above, and further in view of Lin et al, published January 30, 2019 (instant PTO-892).
Lin teaches focused-ultrasound for opening the blood brain barrier in a mouse model of Huntington’s disease and the delivery of GDNF for improving HD associated motor impairment (abstract).
Given that Rezai et al teaches a method for the safe and temporary opening of the BBB of deep brain structures in humans and the targeted delivery of agents for use in humans, and further given that Lin et al teaches a method for opening the blood brain barrier and administration of a therapeutic agent in an animal model of Hungtinton’s disease, it would have been obvious to one of ordinary skill in the art to apply the method of Rezai et al in a patient with Huntington’s disease; such would require application of a known technique to a known method to yield predictable results, see MPEP 2143.I. The motivation to do some comes from Lin et al, which teaches that opening of the BBB using FUS is non-invasive and preferable to invasive approaches using direct local delivery of therapeutics to the CNS using a catheter or needle (pg 133, column 1, para 1).
Claims 1-2, 4-5, 8-9, 12, 16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rezai et al, as applied to claims 1-2, 4-5, 9, 12, 16, and 19-20 above, and further in view of Wang et al, published online November 6, 2014 (instant PTO-892).
The teachings of Rezai et al are discussed above. Rezai et al does not teach the method wherein the therapeutic agent is a viral vector.
Wang et al teaches a method using focused ultra-sound facilitated recombinant adeno-associated virus delivery in the brain (abstract).
Given that Rezai et al teaches a method for the safe and temporary opening of the BBB of deep brain structures in humans and the targeted delivery of gene therapy into deep brain structures in humans, and further given that Wang et al teaches the delivery of the viral vector rAAV for the treatment of an animal model of Parkinson’s disease, it would have been obvious to one of ordinary skill in the art to substitute the viral vector of Wang et al for the gene therapy of Rezai et al and have a reasonable expectation of success. The motivation to do so comes from Wang et al, which teaches that rAAV administration to the brain is limited by the presence of the BBB; therapeutic ultrasound circumvents this obstacle, allowing for the neuron specific expression of genes in neurons (pg 104).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8-10, 12, and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of U.S. Patent No. 12,467,932 in view of D’Haese et al, Lin et al, and Wang et al. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a method for improving a neurodegenerative disease comprising application of focused ultrasound sonication to a target and introducing a therapeutic agent.
Claims 1-20 of ‘932 is drawn to a method of improving a neurodegenerative disorder by administration microbubbles, applying focused ultrasound sonication, providing a therapy, and determining changes in tau protein or other biomarker of neurodegenerative disease, as in instant claims 1-2, 4-6, 9-10, 17-19. The LiFUS sonication parameters comprise changing frequency of the sonication, changing the dose of microbubbles, and changing timing of microbubble administration, as in instant claims 3-5 and 10. Claim 20 of ‘932 is drawn to further comprising a neuromodulation signal, as in instant claim 20.
D’Haese teaches a method of opening the BBB using FUS in patients with Alzheimer’s disease (abstract), with a sonication range of power of 4-11.5 W for 90 sec (pg 3, column 1, para 0), as in the parameters of instant claim 3. D’Haese also teaches that sonication power and parameter are tailored to each subject to achieve a 50-60% of cavitation thresholds to open the BBB (pg 3, column 1, para 0), demonstrating that D’Haese recognizes sonication power as a result-effect variable. Although the parameter of claim 3 does not overlap with the parameter taught by D’Haese, power is a result-effective variable, and, absent evidence to the contrary, identification of the setting of 20-60 W could be readily determined by routine optimization via methods known in the art.
D’Haese teaches a max microbubble dose of 20 ml/kg (pg 3, column 1, para 0), demonstrating that D’Haese recognizes microbubble dose as a result-effective variable. One would adjust the dose of microbubbles to achieve the desired BBB opening, as in the variably administered microbubbles of claim 10 and the adjustment of microbubble dose of claim 18.
Lin teaches focused-ultrasound for opening the blood brain barrier in a mouse model of Huntington’s disease and the delivery of GDNF for improving HD associated motor impairment (abstract), as in claim 6.
Wang et al teaches a method using focused ultra-sound facilitated recombinant adeno-associated virus delivery in the brain (abstract), as in claim 8.
Given that the claims of ‘932 teach a method for the opening of the BBB of deep brain structures in humans and the targeted delivery of therapy into the brain in humans, and further given that D’Haese teaches the parameters for application of focused ultrasound, Lin teaches treatment of motor impairment in Huntington’s disease model mice, and Wang et al teaches the delivery of the viral vector rAAV for the treatment of an animal model of Parkinson’s disease, it would have been obvious to one of ordinary skill to modify the method of ‘932 and have a reasonable expectation of successfully applying the claimed method for improving neurodegenerative disease. Such would amount to combining prior elements according to known methods to yield predictable results (see MPEP 2143).
Claims 1-6, 8-10, 12, and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-16 of U.S. Patent No. 12,366,583 in view of D’Haese et al, Lin et al, and Wang et al. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a method for improving a neurodegenerative disease comprising application of focused ultrasound sonication to a target and introducing a therapeutic agent.
Claims 1-16 of ‘583 is drawn to a method of improving a neurodegenerative disorder by administration microbubbles, applying focused ultrasound sonication, providing a therapy, and determining changes in tau protein or other biomarker of neurodegenerative disease, as in instant claims 1-2, 4-6, 9-10, 17-19. The LiFUS sonication parameters comprise changing frequency of the sonication, changing the dose of microbubbles, and changing timing of microbubble administration, as in instant claims 3-5 and 10. Claim 16 of ‘583 is drawn to further comprising a neuromodulation signal, as in instant claim 20.
D’Haese teaches a method of opening the BBB using FUS in patients with Alzheimer’s disease (abstract), with a sonication range of power of 4-11.5 W for 90 sec (pg 3, column 1, para 0), as in the parameters of instant claim 3. D’Haese also teaches that sonication power and parameter are tailored to each subject to achieve a 50-60% of cavitation thresholds to open the BBB (pg 3, column 1, para 0), demonstrating that D’Haese recognizes sonication power as a result-effect variable. Although the parameter of claim 3 does not overlap with the parameter taught by D’Haese, power is a result-effective variable, and, absent evidence to the contrary, identification of the setting of 20-60 W could be readily determined by routine optimization via methods known in the art.
D’Haese teaches a max microbubble dose of 20 ml/kg (pg 3, column 1, para 0), demonstrating that D’Haese recognizes microbubble dose as a result-effective variable. One would adjust the dose of microbubbles to achieve the desired BBB opening, as in the variably administered microbubbles of claim 10 and the adjustment of microbubble dose of claim 18.
Lin teaches focused-ultrasound for opening the blood brain barrier in a mouse model of Huntington’s disease and the delivery of GDNF for improving HD associated motor impairment (abstract), as in claim 6.
Wang et al teaches a method using focused ultra-sound facilitated recombinant adeno-associated virus delivery in the brain (abstract), as in claim 8.
Given that the claims of ‘932 teach a method for the opening of the BBB of deep brain structures in humans and the targeted delivery of therapy into the brain in humans, and further given that D’Haese teaches the parameters for application of focused ultrasound, Lin teaches treatment of motor impairment in Huntington’s disease model mice, and Wang et al teaches the delivery of the viral vector rAAV for the treatment of an animal model of Parkinson’s disease, it would have been obvious to one of ordinary skill to modify the method of ‘583 and have a reasonable expectation of successfully applying the claimed method for improving neurodegenerative disease. Such would amount to combining prior elements according to known methods to yield predictable results (see MPEP 2143).
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
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