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 .
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 (i.e., changing from AIA to pre-AIA ) 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.
Withdrawn Objections
The objections to the claims are withdrawn in response to the amendments.
Priority
The present application claims benefit under 35 U.S.C. 119(e) to provisional application 63/435,449 filed on 12/27/2022 and to provisional application 63/418,733 filed on 10/24/2022.
Claim Interpretation
Claim 1 recites the new limitation “…and mitigating the likelihood of the human patient of developing the neurodegenerative disorder”.
The specification fails to disclose an active step of “mitigating the likelihood of the human patient of developing the neurodegenerative disorder”. Instead, the specification discloses that “[i]n an aspect, a method of mitigating a likelihood of a human patient developing a neurodegenerative disorder is provided. Such a method can comprise applying a LiFUS sonication via an ultrasound delivery device to a target site of the human patient's brain. The method can further comprise detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter. The method can further include determining the likelihood of a human patient developing a neurodegenerative disorder based on the detection. The method can then include delivering a therapeutic agent to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder” (para. 7). The specification suggests that the steps of applying, detecting, determining, and delivering of claim 1 fulfill the embodiment of mitigating of the likelihood of developing the neurodegenerative disorder. Therefore, the “mitigating” step in claim 1 is hereby interpreted as an inherent step that follows the previous steps, and not necessarily required to be expressly taught in the prior art in order to address the claim over the art.
Maintained Rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims recite “[a] method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder comprising:…human patient's brain; detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter; determining the likelihood of the human patient of developing a neurodegenerative disorder based on the detection”.
The natural relationship to which the claims are directed (i.e., the relation between presence of a biomarker and likelihood of a human patient of developing a neurodegenerative disorder) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring presence of a biomarker and the likelihood of developing a neurodegenerative disorder.
The correlation between biomarker and neurodegenerative disorder is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that biomarkers based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter are elevated to different extents in neurodegenerative disorders vs. in disorders not affecting the nervous system.
Claim 2 recites “wherein the biomarker of the neurodegenerative disorder is a beta-amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder”. Claim 2 limits the biomarker used in the natural correlation, thus claim 2 is also directed to at least one judicial exception.
Claim 3 recites “wherein determining the likelihood of a human patient of developing a neurodegenerative disorder comprises determining the likelihood of the human patient of developing chronic traumatic encephalopathy (CTE)”. Claim 3 limits the neurodegenerative disorder used in the natural correlation, thus claim 3 is also directed to at least one judicial exception.
Claims 5-6 merely limit the neurodegenerative disease to which the natural correlation is directed to, thus claims 5-6 are also directed to at least one judicial exception.
Step 2A, Prong 2
The claims also recite “applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the human patient's brain…delivering a viral vector to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder; and mitigating the likelihood of the human patient of developing the neurodegenerative disorder”. Claim 4 further recites “applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the viral vector and/or applying a LiFUS sonication”.
These “sonication…delivering a viral vector…mitigating” and “applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the therapeutic agent and/or applying a LiFUS sonication” steps are insufficient to integrate the judicial exception as they are not limited to a particular treatment.
The recited steps of “sonication…delivering a viral vector…mitigating…applying an additional focused ultrasound neuromodulation signal” are recited at a high level of generality and are not limited to a particular treatment. Such highly generalized treatment limitations – which do not require any specific treatment for the neurodegenerative disorder – do not amount to sufficient practical application to provide patentability. Although a claim limitation can integrate a judicial exception by applying or using the judicial exception(s) to effect a particular treatment or prophylaxis for a disease or medical condition, in this case no specific or particular treatment is set forth.
The level of generality in the instant claims stands in contrast to the treatment claims found patent-eligible in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018) and Natural Alternatives Int’l v. Creative Compounds LLC, 2017 WL 1216226 (Fed. Cir. Mar. 15, 2019). The claims at issue in Vanda recited administering a specific drug (iloperidone) at specific dosage ranges based on a patient’s genotype. Vanda, 887 F.3d at 1135. Accordingly, the court found that although the inventors recognized the relationships between iloperidone, a patient’s genotype, and QTc prolongation, what they claimed is “an application of that relationship,” i.e., “‘a new way of using an existing drug’ that is safer for patients because it reduces the risk of QTc prolongation.” Id. (quoting Mayo, 566 U.S. at 87). The Federal Circuit characterized the Vanda claims as being directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.” Id. at 1136. Similarly, the Federal Circuit found that the claims in Natural Alternatives “contain specific elements that clearly establish they are doing more than simply reciting a natural law,” such as specifying a patient population, particular results to be obtained, specific compounds to be administered to achieve the claimed results, and dosages via an “effective” limitation. Natural Alternatives, 4-5.
In contrast to the claims in Vanda and Natural Alternatives, the present claims do not specify a particular result to be obtained, a compound to be administered to achieve a claimed result, or any specific dosage of a specific compound.
Rather, “a viral vector”, “mitigating” and “neuromodulation signal” do not limit the claims to a particular therapeutic treatment; instead, the effect of the treatment limitations “is simply to tell doctors to apply the law somehow when treating their patients.” Mayo, 566 U.S. at 81-82.
Here, the claimed viral vector, the mitigating and neuromodulation steps are instead merely an instruction to “apply” the exception in a generic way. Thus, the viral vector, mitigating and neuromodulation steps do not integrate the judicial exception into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of “applying a LiFUS sonication via an ultrasound delivery device to a target site of the human patient's brain…delivering a viral vector to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder…mitigating the likelihood of the human patient of developing the neurodegenerative disorder”, and “applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the viral vector and/or applying a LiFUS sonication” do not add significantly more to the judicial exception(s).
In this case, it was well-understood, routine and conventional to apply a LiFUS sonication via an ultrasound delivery device to a target site of the human patient’s brain, delivering a therapeutic agent to the target site of the human patient’s brain and apply an additional focused ultrasound neuromodulation signal via an ultrasound device during or after introducing the therapeutic agent and/or applying a LiFUS sonication and mitigating the likelihood of the human patient of developing the neurodegenerative disorder. See for example Rezai et al. Proceedings of the National Academy of Sciences of the United States of America, April 28, 2020, Vol. 117, No. 17 (April 28, 2020), pp. 9180-9182 Cite No. U of PTO 892 4/30/2026 ("Rezai").
Rezai teaches applying a LiFUS sonication via an ultrasound delivery device to a target site of the human patient's brain (“Participants underwent MR-guided, low-intensity FUS treatment at 220 kHz (ExAblate Neuro Type 2; INSIGHTEC) directed to the hippocampus” page 9181 col. 2 para. 3); delivering a therapeutic agent to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder; and mitigating the likelihood of the human patient of developing the neurodegenerative disorder (“FUS provides a noninvasive method for time-limited, precise, and large BBB opening, providing an exciting opportunity for research coupling FUS with targeted delivery of medications, immunotherapy, gene therapy, or stem cells into various complex and deep brain structures, including the hippocampus” page 9181 col. 1 para. 2). Rezai suggests applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the therapeutic agent and/or applying a LiFUS sonication (“Fig. 1. Ultrasound beams travel transcranially to the target. Low-intensity (220 kHz) ultrasound energy beams interact with i.v. administered microbubbles. Subsequent oscillation of the microbubbles and acoustic cavitation cause transient opening of tight junctions in capillaries and open the BBB” page 9181, “coupling FUS with targeted delivery of medications” page 9181 col. 1 para. 2).
See also, Sadik et al. (FR 3108853 A1)-Cite No. N of PTO 892 4/30/2026 (“Sadik”). Sadik suggests that applying a LiFUS sonication via an ultrasound delivery device to a target site of the human patient's brain and applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after applying a LiFUS sonication is well-understood, routine and conventional in the art (“For example, US Pat. No. 7,896,821 is known relating to a method and an apparatus allowing reversible rupture of the blood-brain barrier using low-intensity focused ultrasound. We also know the application WO 2011/057028 relating to a method and a device for modulating cerebral activity in humans using ultrasound” page 3 para. 4). Sadik further teaches applying a LiFUS sonication via an ultrasound delivery device to a target site of the human patient's brain and delivering a therapeutic agent to the target site of the human patient's brain (“none of the devices of the prior art has been used for the administration of anti-TNF-alpha for the treatment of diseases of the central nervous system” page 3 para. 3, “said at least two ultrasound transducers are configured to deliver ultrasound at a low frequency” page 8 para. 2 “improving the bioavailability of anti-inflammatory mediator agents in a subject. For this purpose, the method is configured to deliver focused ultrasound to at least one specific site of a subject's brain to selectively and reversibly disrupt the blood-brain barrier” page 8 para. 5).
Furthermore, delivering a viral vector to the target site also appears to be well-understood, routine and conventional.
See for example, Kaplitt et al. (WO 2020198686 A1)-Cite No. 2 of IDS 10/24/2023 (“Kaplitt”). Kaplitt teaches “that transitory BBB disruption using MRgFUS can be a safe and
efficient method for site-specific delivery of viral vectors to the brain, raising the potential for non-invasive focal human gene therapy for neurological disorders” (page 3 lines 9-11).
See also Hsu et al. PLoS ONE 8(2): e57682. doi:10.1371/journal.pone.0057682 (“Hsu”). Hsu teaches “Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound” (Title). Hsu further teaches “that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (16109 vg/g) can successfully penetrate the BBB-opened brain regions to express GFP” (Abstract).
In view of the above evidence, the claimed steps of “applying a LiFUS sonication via an ultrasound delivery device to a target site of the human patient's brain…delivering a viral vector to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder…mitigating the likelihood of the human patient of developing the neurodegenerative disorder”, and “applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the viral vector and/or applying a LiFUS sonication” do not add any feature that is more than well-understood, purely conventional, or routine in the field of diagnostics and medical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
New Rejection
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.
Claims 1-2 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Rezai et al. Proceedings of the National Academy of Sciences of the United States of America, April 28, 2020, Vol. 117, No. 17 (April 28, 2020), pp. 9180-9182 ("Rezai")-Cite No. U of PTO 892 4/30/2026 in view of Hsu et al. PLoS ONE 8(2): e57682. doi:10.1371/journal.pone.0057682 (“Hsu”).
Regarding claim 1, Rezai teaches “Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound” (Title). Rezai further suggests a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder (“Animal studies have demonstrated safe and reversible BBB opening as well as reduction of amyloid- beta plaque, neurogenesis, and improvement of memory. Additionally, this technology enables targeted noninvasive delivery of genetic vectors and cells” page 9180 col. 1 para. 1) comprising: applying a low-intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the human patient's brain (“Participants underwent MR-guided, low-intensity FUS treatment at 220 kHz (ExAblate Neuro Type 2; INSIGHTEC) directed to the hippocampus” page 9181 col. 2 para. 3); detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter; determining the likelihood of the human patient developing a neurodegenerative disorder based on the detection (“Participant eligibility criteria included the presence of early AD diagnosed with the National Institute of Aging – Alzheimer’s Association (NIA-AA)criteria(14), 18F-florbetaben PET scan consistent with AD and the presence of amyloid-beta plaques in the target” page 9181 col. 2 para. 2); delivering a viral vector to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder ; and mitigating the likelihood of the human patient of developing the neurodegenerative disorder (page 9180 col. 1 para. 1, “FUS provides a noninvasive method for time-limited, precise, and large BBB opening, providing an exciting opportunity for research coupling FUS with targeted delivery of medications, immunotherapy, gene therapy, or stem cells into various complex and deep brain structures, including the hippocampus” page 9181 col. 1 para. 2). Rezai further shows “MRI evidence of BBB opening and closure in six [human] subjects” (page 9182 Fig. 2). Rezai further teaches that “[t]he hippocampus is critical in the pathogenesis of Alzheimer’s disease (AD), epilepsy, and depression(1). Patients with these disorders have significant unmet needs, driving efforts to develop treatments to address hippocampal pathology and dysfunction” (page 9180 col. 1 para. 1). Rezai further teaches that the hippocampus is an “important therapeutic target given the significant damage and atrophy in AD, their crucial role in memory and learning, and their involvement in the pathology of conditions like epilepsy and depression” (page 9181 col. 1 para. 1).
Rezai fails to teach the method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder in a single embodiment, i.e. there is some picking and choosing involved in order to arrive at the claimed method. Rezai teaches in page 9180 col. 1 para. 1 that LiFUS coupled with microbubbles enables the mitigation of a likelihood of an animal patient of developing a neurodegenerative disorder. And in page 9181 col. 1 para. 2 Rezai suggests the method being applied to humans.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the method of mitigating a likelihood of developing a neurodegenerative disorder taught by Rezai to humans because Rezai teaches that humans with Alzheimer’s disease, i.e. a neurodegenerative disorder, have significant unmet treatment needs, thereby motivating a person having ordinary skill in the art to try applying the method to humans in order to address the unmet needs of these patients. A person having ordinary skill in the art would have had a reasonable expectation of success because Rezai shows data proving that using LiFUS and microbubbles enables selective blood-brain barrier disruption in humans. Therefore one would expect success when using LiFUS and microbubbles as a targeted drug delivery method in humans, thereby mitigating a likelihood of a human patient of developing a neurodegenerative disorder.
Although suggested by Rezai “targeted delivery of…gene therapy” (page 9181 col. 1 para. 2), Rezai fails to explicitly teach “viral vector”.
Hsu teaches “Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound” (Title). Hsu suggests a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder ( “[i]n this study we showed transduction of astrocytes by AAV2-GFP delivered through FUS-BBB opening. Astrocytes have traditionally been considered to be merely neuronal supporter cells, but recent studies demonstrated that they also contribute to the pathogenesis of neurodegenerative disorders[51,52]. To date, attempts to target transgenes to glial cell populations by varying cellular promoters have resulted in limited transduction only [52,53]. Since most reports of AAV viral-vector CNS delivery have been of neuron transduction [11,54,55], AAV2-GFP may be a useful tool for efficient astrocytes transduction to treat neurodegenerative diseases” page 7 col. 1 para. 2) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the patient's brain and delivering a viral vector to the target site of the patient’s brain, thereby mitigating the likelihood of developing the neurodegenerative disorder (Title, “30 mL of viral vectors with the titer of 1×109 viral genomes per gram (vg/g) of treated animal were bolus injected through the same PE-10 catheter and immediately followed a 0.3 mL/kg microbubbles bolus injection (SonoVue SF6-coated ultrasound microbubbles, mean diameter 2–5 mm, 2.5 mg/kg, Bracco Diagnostics Inc., Milan, Italy; 0.03 mL/kg for clinical diagnostic application) mixed with 20 mL of saline…With a 10-second delay, ultrasonic energy was delivered to the brain transcranially using a spherically focused transducer (Imasonics, Besancon, France; diameter = 60 mm, radius of curvature = 80 mm, frequency=1.5 MHz; negative peak pressure when considering mouse skull insert loss was measured; the measured half-maximum pressure amplitude diameter and length of the produced focal spot were 2 and 10 mm, respectively; detailed FUS field calibration please see the Supporting Information). Burst-mode ultrasound with burst length 10 ms, pulse-repetition frequency (PRF) 1 Hz, and duration 120 seconds was used. The input electric power was 3–8 W (monitored by a RF-power meter (Bird model 4421, USA); corresponding acoustic pressure amplitude of 0.44–0.7 MPa)” page 2 col. 2 para. 2 and page 7 col. 1 para. 2)). Hsu further teaches that using viral vectors for mitigating a likelihood of developing a neurodegenerative disorder is safe and effective (“we found that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (16109 vg/g) can successfully penetrate the BBB-opened brain regions to express GFP. We show that MRI monitoring of BBB-opening could serve as an indicator of the scale and distribution of AAV transduction. Transduction peaked at 3 weeks and neurons and astrocytes were affected. This novel, noninvasive delivery approach could significantly broaden the application of AAV-viral-vector-based genes for treatment of CNS diseases” Abstract, “the given viral vector in this study should be of no safety concern, and there should be highly possible to further improve the gene expression rate and transduction distribution when higher titer of viral vector is employed” page 6 col. 1 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Rezai to rely on the viral vector taught by Hsu because Hsu suggests this enables safe and effective treatment of neurodegenerative diseases and Rezai is interested in mitigating a likelihood of developing a neurodegenerative disorder. A person having ordinary skill in the art would have had a reasonable expectation of success because both Rezai and Hsu teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain.
Regarding claim 2, Rezai in view of Hsu teach the method of claim 1 as discussed above.
Rezai in view of Hsu further teach wherein the biomarker of the neurodegenerative disorder is a beta-amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder (“Participant eligibility criteria included the presence of early AD diagnosed with the National Institute of Aging – Alzheimer’s Association (NIA-AA)criteria(14), 18F-florbetaben PET scan consistent with AD and the presence of amyloid-beta plaques in the target” page 9181 col. 2 para. 2 of Rezai).
Regarding claim 4, Rezai in view of Hsu teach the method of claim 1 as discussed above.
Rezai in view of Hsu suggest applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the viral vector and/or applying a LiFUS sonication (“Fig. 1. Ultrasound beams travel transcranially to the target. Low-intensity (220 kHz) ultrasound energy beams interact with i.v. administered microbubbles. Subsequent oscillation of the microbubbles and acoustic cavitation cause transient opening of tight junctions in capillaries and open the BBB” page 9181, “coupling FUS with targeted delivery of medications” page 9181 col. 1 para. 2 of Rezai). Note that the specification discloses that “[n]on-limiting examples of neuromodulation include ultrasound including focused ultrasound” (para. 47). Therefore, using the broadest reasonable interpretation of the claim as recited 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. Also, given that Rezai suggests targeted drug delivery using LiFUS (“coupling FUS with targeted delivery of medications” page 9181 col. 1 para. 2), Rezai suggests applying a neuromodulation signal to a brain region during or after introducing the therapeutic agent.
Regarding claim 5, Rezai in view of Hsu teach the method of claim 1 as discussed above.
Rezai in view of Hsu further teach wherein the neurodegenerative disorder is Alzheimer’s disease (Title and Abstract of Rezai).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Rezai in view of Hsu as applied to claim 1 above, and further in view of Reddi et al. Neural Regen Res 17(10):2166-2171 Date of web publication: February 28, 2022 https://doi.org/10.4103/1673-5374.335824 -Cite No. V of PTO 892 4/30/2026 ("Reddi").
Regarding claim 3, Rezai in view of Hsu teach the method of claim 1 as discussed above,
Rezai in view of Hsu fail to teach wherein determining the likelihood of a human patient developing a neurodegenerative disorder comprises determining the likelihood of the human patient developing chronic traumatic encephalopathy (CTE).
Reddi teaches “[s]tatus of precision medicine approaches to traumatic brain injury” (Title). Reddi further teaches that “chronic traumatic encephalopathy (CTE)…[is] a neurodegenerative condition linked to repeated TBIs” (page 2167 col. 1 para. 5). Reddi further teaches detecting the presence of a biomarker of at least one neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter and determining the likelihood of the human patient developing a neurodegenerative disorder based on the detection, wherein the neurodegenerative disorder is CTE or Alzheimer’s disease (“Another completed study used the tau PET ligand [F-18] FDDNP to investigate the same question, and consistent with other neuropathological theories of injury, they found that tau pathology is seen in subcortical, limbic, and cortical areas in a different pattern from the neurodegenerative changes that are seen in Alzheimer’s disease (Barrio et al., 2015). Notably, they were able to compare the findings from one of their subject’s in vivo imaging to the postmortem brain analysis, to confirm that the [F-18] FDDNP-PET binding levels were correlated with tau deposition in the postmortem brain, suggesting that this ligand may be effective at diagnosing CTE in vivo (Omalu et al., 2018). These results highlight the use of tau as a potential biomarker that can be used for both diagnostic purposes, as well as a target for personalized treatment approaches in higher risk individuals, such as APOE4 carriers, who may have an elevated tau burden after TBI” page 2169 col. 1 para. 1). Reddi further suggests that there is a need for methods to determine the likelihood of a human patient of developing CTE, for example for diagnosing CTE in retired NFL players (“determine the risk stratification of people who have sustained a TBI. There have been 44 clinical trials registered involving the investigation of tau in TBI. Of the 11 of these that have been completed, 4 have posted results. The first of the completed studies reporting results was done in retired National Football League (NFL) players who had clinical symptoms that were consistent with a diagnosis of CTE (the diagnosis of which can only currently be made postmortem) in an attempt to find a PET tracer that could assist in making the CTE diagnosis in vivo” page 2169 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Rezai in view of Hsu to include CTE in the determining step taught by Reddi because Reddi suggests that there is a need for methods to determine the likelihood of retired NFL players of developing CTE and Rezai in view of Hsu is interested in developing methods of mitigating a likelihood of a human patient of developing a neurodegenerative disorder. Therefore, it would have been obvious to include CTE in order to address the current need. Furthermore, both Rezai in view of Hsu and Reddi teach imaging the human brain with PET ligand [F-18] for determining the likelihood of developing Alzheimer’s. Reddi simply includes CTE in the determining step. Therefore, a person having ordinary skill in the art would have found it obvious to include CTE in the determining step of Rezai. A person having ordinary skill in the art would have had a reasonable expectation of success because both Rezai in view of Hsu and Reddi teach imaging the human brain with PET ligand [F-18] for determining the likelihood of developing Alzheimer’s.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezai in view of Hsu as applied to claim 1 above, and further in view of Burgess et al. Journal of Controlled Release 163 (2012) 125–129 http://dx.doi.org/10.1016/j.jconrel.2012.08.012 ("Burgess").
Regarding claim 6, Rezai in view of Hsu teach the method of claim 1 as discussed above.
Rezai in view of Hsu fail to teach wherein the neurodegenerative disorder is Hungtington’s Disease.
Burgess teaches that Hungtington’s disease is a serious neurodegenerative disorder, causing progressive neuronal disfunction and cell death “leading to the involuntary movements,
cognitive dysfunction, and behavioral changes characteristic of HD” (page 125 col. 1 para. 1). Burgess further suggests a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder, wherein the neurodegenerative disorder is Huntington’s disease (“RNA interference is a promising strategy for the treatment of Huntington's disease (HD) as it can specifically decrease the expression of the mutant Huntingtin protein (Htt)” Abstract) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the patient's brain and delivering a therapeutic agent to the target site of the patient’s brain, thereby mitigating the likelihood of developing the neurodegenerative disorder (“Non-invasive delivery of siRNA through the blood–brain barrier (BBB) would be a significant advantage for translating this therapy to HD patients. Focused ultrasound (FUS), combined with intravascular delivery of microbubble contrast agent, was
used to locally and transiently disrupt the BBB in the right striatum of adult rats. 48 h following treatment with siRNA… We demonstrate that FUS can non-invasively deliver siRNA-Htt directly to the striatum leading to a significant reduction of Htt expression in a dose dependent manner. Furthermore, we show that reduction of Htt with siRNA-Htt was greater when the extent of BBB disruption was increased. This study demonstrates that siRNA treatment for knockdown of mutant Htt is feasible without the surgical intervention previously required for direct delivery to the brain” Abstract). Burgess further suggests that there is a need for methods of mitigating the likelihood of a human patient of developing Huntington’s disease (“no current treatment” page 125 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Rezai in view of Hsu to rely on the neurodegenerative disorder being Huntington’s Disease taught by Burgess because Burgess teaches that there is a need for methods to mitigate the likelihood of developing Hungtington’s Disease and Rezai in view of Hsu are interested in methods of mitigating the likelihood of developing neurodegenerative disorders. Therefore, it would have been obvious to apply the method taught by Rezai in view of Hsu to Huntington’s Disease and help these patients. A person having ordinary skill in the art would have had a reasonable expectation of success because both Rezai in view of Hsu and Burgess teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain for mitigating a likelihood of developing a neurodegenerative disorder.
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 1-2 and 4-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12467932 B2 in view of Hsu.
Regarding claims 1-2 and 4-5, U.S. Patent No. 12467932 B2 recites a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder (“[a] method of improving a neurodegenerative disorder in a human patient suffering therefrom” claim 1) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the human patient's brain (“comprising:...applying a focused ultrasound (FUS) sonication via an ultrasound delivery device to the target site” claim 1); detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter, wherein the biomarker of the neurodegenerative disorder is a beta-amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder; determining the likelihood of the human patient of developing a neurodegenerative disorder based on the detection; delivering a therapeutic agent to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder, and mitigating the likelihood of the human patient of developing the neurodegenerative disorder (“based on at least one feedback parameter comprising at least one or more of an imaging parameter; an acoustic microbubble vibration analysis; an optical parameter; a bodily fluid parameter; or a physiological or anatomical parameter; and introducing a therapeutic agent to the target site before, during, or after application of the FUS sonication” claim 1, “wherein the determining step comprises determining one or more regions of the human patient's brain having a beta amyloid protein, a tau protein, Alpha synuclein, lysosomal enzymes, markers of amyloid and tau pathology, neurofilament light chain and other biomarkers detected in blood, CSF, brain, and other tissues and body fluids, and/or another biomarker of the neurodegenerative disorder” claim 2). U.S. Patent No. 12467932 B2 further recites applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the therapeutic agent and/or applying the LiFUS sonication (“adjusting the dose of the LiFUS sonication” claim 5).
U.S. Patent No. 12467932 B2 fails to recite viral vector and wherein the neurodegenerative disorder is Alzheimer’s Disease.
Hsu teaches “Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound” (Title). Hsu suggests a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder (page 7 col. 1 para. 2) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the patient's brain and delivering a viral vector to the target site of the patient’s brain, thereby mitigating the likelihood of developing the neurodegenerative disorder (Title, page 2 col. 2 para. 2 and page 7 col. 1 para. 2). Hsu further teaches that using viral vectors for mitigating a likelihood of developing a neurodegenerative disorder is safe and effective (Abstract, page 6 col. 1 para. 2). Hsu further suggests wherein the neurodegenerative disorder is Alzheimer’s Disease (“AAV serotype 2 (AAV2) vectors have been most intensively studied for the treatment of various diseases, and in clinical trials for Canavan’s [2], Batten’s [3], Parkinson’s [4], and Alzheimer’s diseases” page 1 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12467932 B2 to rely on the viral vector for mitigating the likelihood of developing Alzheimer’s Disease taught by Hsu because Hsu suggests this enables safe and effective treatment of Alzheimer’s and U.S. Patent No. 12467932 B2 is interested in mitigating a likelihood of developing a neurodegenerative disorder. Therefore, it would have been obvious to apply the technique of Hsu to the base method of mitigating a likelihood of developing neurodegenerative disorders taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12467932 B2 and Hsu teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain.
Claim 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12467932 B2 in view of Hsu as applied to claim 1 above, and further in view of Reddi.
Regarding claim 3, U.S. Patent No. 12467932 B2 in view of Hsu address the method of claim 1 as discussed above.
U.S. Patent No. 12467932 B2 in view of Hsu fail to recite determining the likelihood of the human patient developing chronic traumatic encephalopathy (CTE)
Reddi teaches “[s]tatus of precision medicine approaches to traumatic brain injury” (Title). Reddi further teaches that “chronic traumatic encephalopathy (CTE)…[is] a neurodegenerative condition linked to repeated TBIs” (page 2167 col. 1 para. 5). Reddi further teaches detecting the presence of a biomarker of at least one neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter and determining the likelihood of the human patient developing a neurodegenerative disorder based on the detection, wherein the neurodegenerative disorder is CTE ( page 2169 col. 1 para. 1). Reddi further suggests that there is a need for methods to determine the likelihood of a human patient of developing CTE, for example for diagnosing CTE in retired NFL players (page 2169 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12467932 B2 in view of Hsu to include CTE in the determining step taught by Reddi because Reddi suggests that there is a need for methods to determine the likelihood of retired NFL players of developing CTE and U.S. Patent No. 12467932 B2 in view of Hsu is interested in developing methods of mitigating a likelihood of a human patient of developing a neurodegenerative disorder. Therefore it would have been obvious to include CTE in order to address the current need. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12467932 B2 in view of Hsu and Reddi teach methods comprising determining the likelihood of developing a neurodegenerative disorder.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12467932 B2 in view of Hsu as applied to claim 1 above, and further in view of Burgess.
Regarding claim 6, U.S. Patent No. 12467932 B2in view of Hsu address the method of claim 1 as discussed above.
U.S. Patent No. 12467932 B2 in view of Hsu fail to recite wherein the neurodegenerative disorder is Hungtington’s Disease.
Burgess teaches that Hungtington’s disease is a serious neurodegenerative disorder, causing progressive neuronal disfunction and cell death “leading to the involuntary movements,
cognitive dysfunction, and behavioral changes characteristic of HD” (page 125 col. 1 para. 1). Burgess further suggests a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder, wherein the neurodegenerative disorder is Huntington’s disease comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the patient's brain and delivering a therapeutic agent to the target site of the patient’s brain, thereby mitigating the likelihood of developing the neurodegenerative disorder (Abstract). Burgess further suggests that there is a need for methods of mitigating the likelihood of a human patient of developing Huntington’s disease (page 125 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12467932 B2 in view of Hsu to rely on the neurodegenerative disorder being Huntington’s Disease taught by Burgess because Burgess teaches that there is a need for methods to mitigate the likelihood of developing Hungtington’s Disease and U.S. Patent No. 12467932 B2 in view of Hsu are interested in methods of mitigating the likelihood of developing neurodegenerative disorders. Therefore, it would have been obvious to apply the method taught by U.S. Patent No. 12467932 B2 in view of Hsu to Huntington’s Disease and help these patients. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12467932 B2 in view of Hsu and Burgess teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain for mitigating a likelihood of developing a neurodegenerative disorder.
Claims 1-2 and 4-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12366583 B2 in view of Hsu.
Regarding claims 1-2 and 4-5, U.S. Patent No. 12366583 B2 recites a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder ("[a] method of improving a neurodegenerative disorder in a human patient suffering therefrom" claim 1) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the human patient's brain ("comprising:...applying a focused ultrasound (FUS) sonication via an ultrasound delivery device to the target site" claim 1); detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter, wherein the biomarker of the neurodegenerative disorder is a beta-amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder; determining the likelihood of the human patient of developing a neurodegenerative disorder based on the detection; delivering a therapeutic agent to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder, and mitigating the likelihood of the human patient of developing the neurodegenerative disorder (based on at least one feedback parameter comprising an optical parameter; and introducing a therapeutic agent to the target site before, during, or after application of the FUS sonication" claim 1, "wherein the least one feedback parameter comprises at least one or more of a physiological, a cognitive, a psychosocial, or a behavior parameter" claim 9, claim 10). U.S. Patent No. 12366583 B2 further recites applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the therapeutic agent and/or applying the LiFUS sonication (“adjusting the dose of the LiFUS sonication” claim 6).
U.S. Patent No. 12366583 B2 fails to recite viral vector and wherein the neurodegenerative disorder is Alzheimer's Disease.
Hsu is relied upon as cited above (see citations of Hsu above).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12366583 B2 to rely on the viral vector for mitigating the likelihood of developing Alzheimer’s Disease taught by Hsu because Hsu suggests this enables safe and effective treatment of neurodegenerative diseases and U.S. Patent No. 12366583 B2 is interested in mitigating a likelihood of developing a neurodegenerative disorder. Therefore, it would have been obvious to apply the technique of Hsu to the base method of mitigating a likelihood of developing neurodegenerative disorders taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12366583 B2 and Hsu teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain.
Claim 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12366583 B2 in view of Hsu as applied to claim 1 above, and further in view of Reddi.
Regarding claim 3, U.S. Patent No. 12366583 B2 in view of Hsu address the method of claim 1 as discussed above.
U.S. Patent No. 12366583 B2 in view of Hsu fails to recite determining the likelihood of the human patient developing chronic traumatic encephalopathy (CTE)
Reddi is relied upon as cited above (see citations above).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12366583 B2 in view of Hsu to include CTE in the determining step taught by Reddi because Reddi suggests that there is a need for methods to determine the likelihood of retired NFL players of developing CTE and U.S. Patent No. 12366583 B2 is interested in developing methods of mitigating a likelihood of a human patient of developing a neurodegenerative disorder. Therefore it would have been obvious to include CTE in order to address the current need. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12366583 B2 in view of Hsu and Reddi teach methods comprising determining the likelihood of developing a neurodegenerative disorder.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12366583 B2 in view of Hsu as applied to claim 1 above, and further in view of Burgess.
Regarding claim 6, U.S. Patent No. 12366583 B2 in view of Hsu address the method of claim 1 as discussed above.
U.S. Patent No. 12366583 B2 in view of Hsu fail to recite wherein the neurodegenerative disorder is Hungtington’s Disease.
Burgess is relied upon as cited above (see citations above).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12366583 B2 in view of Hsu to rely on the neurodegenerative disorder being Huntington’s Disease taught by Burgess because Burgess teaches that there is a need for methods to mitigate the likelihood of developing Hungtington’s Disease and U.S. Patent No. 12366583 B2 in view of Hsu are interested in methods of mitigating the likelihood of developing neurodegenerative disorders. Therefore, it would have been obvious to apply the method taught by U.S. Patent No. 12366583 B2 in view of Hsu to Huntington’s Disease and help these patients. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12366583 B2 in view of Hsu and Burgess teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain for mitigating a likelihood of developing a neurodegenerative disorder.
Claims 1-2 and 4-5 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/383386 in view of Hsu.
Regarding claims 1-2 and 4-5, copending Application No. 18/383386 recites a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder (“A method of improving a neurodegenerative disorder in a human patient suffering therefrom” claim 1) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the human patient's brain (“comprising…applying a focused ultrasound (FUS) sonication via an ultrasound delivery device to the target site” claim 1); detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter, wherein the biomarker of the neurodegenerative disorder is a beta-amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder; determining the likelihood of the human patient of developing a neurodegenerative disorder based on the detection; delivering a therapeutic agent to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder, and mitigating the likelihood of the human patient of developing the neurodegenerative disorder (“based on at least one feedback parameter comprising an optical parameter; and introducing a therapeutic agent to the target site before, during, or after application of the FUS sonication” claim 1, “wherein the least one feedback parameter comprises at least one or more of a physiological, a cognitive, a psychosocial, or a behavior parameter” claim 9). Copending Application No. 18/383386 further recites applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the therapeutic agent and/or applying the LiFUS sonication (“adjusting the dose of the LiFUS sonication” claim 6).
Copending Application No. 18/383386 fails to recite viral vector and wherein the neurodegenerative disorder is Alzheimer’s Disease.
Hsu is relied upon as cited above (see citations above).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of copending Application No. 18/383386 to rely on the viral vector for mitigating the likelihood of developing Alzheimer’s Disease taught by Hsu because Hsu suggests this enables safe and effective treatment of Alzheimer’s and copending Application No. 18/383386 is interested in mitigating a likelihood of developing a neurodegenerative disorder. Therefore, it would have been obvious to apply the technique of Hsu to the base method of mitigating a likelihood of developing neurodegenerative disorders taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18/383386 and Hsu teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain.
Claim 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/383386 in view of HSU as applied to claim 1 above, and further in view of Reddi.
Regarding claim 3, copending Application No. 18/383386 in view of Hsu address the method of claim 1 as discussed above.
Copending Application No. 18/383386 in view of Hsu fail to recite determining the likelihood of the human patient developing chronic traumatic encephalopathy (CTE)
Reddi is relied upon as cited above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of copending Application No. 18/383386 in view of Hsu to include CTE in the determining step taught by Reddi because Reddi suggests that there is a need for methods to determine the likelihood of retired NFL players of developing CTE and copending Application No. 18/383386 in view of Hsu is interested in developing methods of mitigating a likelihood of a human patient of developing a neurodegenerative disorder. Therefore it would have been obvious to include CTE in order to address the current need. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18/383386 in view of Hsu and Reddi teach methods comprising determining the likelihood of developing a neurodegenerative disorder.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/383386 in view of Hsu as applied to claim 1 above, and further in view of Burgess.
Regarding claim 6, copending Application No. 18/383386 in view of Hsu address the method of claim 1 as discussed above.
Copending Application No. 18/383386 in view of Hsu fail to recite wherein the neurodegenerative disorder is Hungtington’s Disease.
Burgess is relied upon as cited above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of copending Application No. 18/383386 in view of Hsu to rely on the neurodegenerative disorder being Huntington’s Disease taught by Burgess because Burgess teaches that there is a need for methods to mitigate the likelihood of developing Hungtington’s Disease and copending Application No. 18/383386 in view of Hsu are interested in methods of mitigating the likelihood of developing neurodegenerative disorders. Therefore, it would have been obvious to apply the method taught by copending Application No. 18/383386 in view of Hsu to Huntington’s Disease and help these patients. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18/383386 in view of Hsu and Burgess teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain for mitigating a likelihood of developing a neurodegenerative disorder.
Claims 1-2 and 4-5 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18383367 in view of Hsu.
Regarding claims 1-2 and 4-5, copending Application No. 18383367 recites a method of mitigating a likelihood of a human patient of developing a neurodegenerative disorder (“A method of improving a neurodegenerative disorder in a human patient suffering therefrom” claim 1) comprising: applying a low intensity focused ultrasound (LiFUS) sonication via an ultrasound delivery device to a target site of the human patient's brain (“comprising…applying a focused ultrasound (FUS) sonication via an ultrasound delivery device to the target site” claim 1); detecting the presence of a biomarker of the neurodegenerative disorder based on at least one or more of an imaging parameter, an optical parameter, or a bodily fluid parameter, wherein the biomarker of the neurodegenerative disorder is a beta-amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder; determining the likelihood of the human patient of developing a neurodegenerative disorder based on the detection; delivering a therapeutic agent to the target site of the human patient's brain upon a determination that the human patient has a likelihood of developing the neurodegenerative disorder, and mitigating the likelihood of the human patient of developing the neurodegenerative disorder (“based on at least one feedback parameter comprising at least one or more of an imaging parameter; an acoustic microbubble vibration analysis; an optical parameter; a bodily fluid parameter; or a physiological or anatomical parameter; and introducing a therapeutic agent to the target site before, during, or after application of the FUS sonication” claim 1, “wherein the determining step comprises determining one or more regions of the human patient's brain having a beta amyloid protein, a tau protein, Alpha synuclein, lysosomal enzymes, markers of amyloid and tau pathology, neurofilament light chain and other biomarkers detected in blood, CSF, brain, and other tissues and body fluids, and/or another biomarker of the neurodegenerative disorder” claim 2). Copending Application No. 18383367 further recites applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the therapeutic agent and/or applying the LiFUS sonication (“adjusting the dose of the LiFUS sonication” claim 5).
Copending Application No. 18383367 fails to recite viral vector and wherein the neurodegenerative disorder is Alzheimer’s Disease.
Hsu is relied upon as cited above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of copending Application No. 18383367 to rely on the viral vector for mitigating the likelihood of developing Alzheimer’s Disease taught by Hsu because Hsu suggests this enables safe and effective treatment of Alzheimer’s and copending Application No. 18383367 is interested in mitigating a likelihood of developing a neurodegenerative disorder. Therefore, it would have been obvious to apply the technique of Hsu to the base method of mitigating a likelihood of developing neurodegenerative disorders taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18383367 and Hsu teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain.
Claim 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18383367 in view of Hsu as applied to claim 1 above, and further in view of Reddi.
Regarding claim 3, copending Application No. 18383367 in view of Hsu address the method of claim 1 as discussed above.
Copending Application No. 18383367 in view of Hsu fail to recite determining the likelihood of the human patient developing chronic traumatic encephalopathy (CTE)
Reddi is relied upon as cited above.
It would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of copending Application No. 18383367 in view of Hsu to include CTE in the determining step taught by Reddi because Reddi suggests that there is a need for methods to determine the likelihood of retired NFL players of developing CTE and copending Application No. 18383367 in view of Hsu is interested in developing methods of mitigating a likelihood of a human patient of developing a neurodegenerative disorder. Therefore it would have been obvious to include CTE in order to address the current need. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18383367 in view of Hsu and Reddi teach methods comprising determining the likelihood of developing a neurodegenerative disorder.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18383367 in view of Hsu as applied to claim 1 above, and further in view of Burgess.
Regarding claim 6, copending Application No. 18383367 in view of Hsu address the method of claim 1 as discussed above.
Copending Application No. 18383367 in view of Hsu fail to recite wherein the neurodegenerative disorder is Hungtington’s Disease.
Burgess is relied upon as cited above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of copending Application No. 18383367 in view of Hsu to rely on the neurodegenerative disorder being Huntington’s Disease taught by Burgess because Burgess teaches that there is a need for methods to mitigate the likelihood of developing Hungtington’s Disease and copending Application No. 18383367 in view of Hsu are interested in methods of mitigating the likelihood of developing neurodegenerative disorders. Therefore, it would have been obvious to apply the method taught by copending Application No. 18383367 in view of Hsu to Huntington’s Disease and help these patients. A person having ordinary skill in the art would have had a reasonable expectation of success because both copending Application No. 18383367 in view of Hsu and Burgess teach the use of low-intensity focused ultrasound and microbubbles to deliver agents to the brain for mitigating a likelihood of developing a neurodegenerative disorder.
Claims 1-6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/383398 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because copending Application No. 18/383398 recites “A method of improving a neurodegenerative disorder in a human patient suffering therefrom comprising…providing a therapy to the human patient comprising: applying a LiFUS sonication via an ultrasound delivery device to the target site; and introducing a therapeutic agent to the target site before, after, or during application of the LiFUS sonication” (claim 1). Copending Application No. 18/383398 further recites “wherein the target site is a region of the human patient's brain comprising a beta amyloid protein, a tau protein and/or another biomarker of the neurodegenerative disorder” (claim 2). Copending Application No. 18/383398 further recites “wherein the neurodegenerative disorder is… Alzheimer's disease…(CTE); Huntington's disease” (claim 6). Copending Application No. 18/383398 further recites “wherein the therapeutic agent is a…viral vector” (claim 8). Copending Application No. 18/383398 further recites “further comprising: applying a neuromodulation signal to a brain region during or after introducing the therapeutic agent and/or applying a LiFUS sonication” (claim 20). Therefore, copending Application No. 18/383398 recites claims 1-6.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 7/27/2026 have been fully considered but they are not persuasive.
Regarding the 101 rejections,
Applicant argues that “Claim recites a practical implementation of any allegedly recited abstract idea as it is 1) tied to a specific machine (an ultrasound device) and 2) delivering a viral vector is a specific prophylactic treatment” (page 4 para. 3).
However, reciting “an ultrasound device” and “viral vector” is not considered sufficient to integrate the judicial exception(s) into a practical application given that these limitations fail to use, rely on or apply the judicial exception(s) such to amount to a practical application thereof. Furthermore, contrary to Applicant’s argument, “an ultrasound device” is not a specific machine, it merely describes a generic device. Similarly, a “vial vector” is not a specific treatment, it is just a vector, a means for transporting a compound via a virus. Also, these limitations are considered well-understood, routine and conventional in the art, and therefore also fail to amount to significantly more than the judicial exception(s). See the rejection above for a complete analysis.
Regarding the 103 rejections,
Applicant argues that “The Examiner cites to the statement in Rezai:…to studies in mice and not humans (to which the current claims are directed), which are an entirely different species. Results in mice studies are not necessarily translatable to humans as indicated by Rezai itself: "[F]US-mediated BBB opening in preclinical models has been found to promote amyloid-beta clearance, delivery of endogenous antibodies, activation of microglia (8, 12), and potential modulation of the glymphatic system (13). The significance with respect to human translation of amyloid reduction observed in animal models with FUS-mediated BBB disruption is unknown." (See Rezai pg. 9181, first col.)” (page 4-5 bridge paragraph).
However, although Rezai shows results of mitigating a likelihood of developing a neurodegenerative disorder in mice and not humans, Rezai contemplates the human translation of this method because Rezai shows data proving that using LiFUS and microbubbles enables selective blood-brain barrier disruption in humans. Regarding Applicant’s citation of Rezai: “significance with respect to human translation of amyloid reduction observed in animal models with FUS-mediated BBB disruption is unknown”, this passage is not considered to be suggesting that a clinical translation is not possible or to be teaching away from human translation. Rezai is merely disclosing that the overall outcomes of this method in the clinic are not known. Nevertheless, a person having ordinary skill in the art would be motivated to try this method in humans in order to help Alzheimer’s disease patients. There would be a reasonable expectation of success because Rezai shows data proving that using LiFUS and microbubbles enables selective blood-brain barrier disruption in humans. See the rejection above for the complete analysis.
Applicant further argues that “such mice already have a neurodegenerative disorder (i.e. Alzheimer's Disease). The patients involved in the study reported by Rezai also involved humans that were already diagnosed with Alzheimer's Disease and as such the method of such studies are not relevant to mitigating the likelihood that a human patient develop a neurodegenerative disorder” (page 5 para. 2).
However, although Rezai relies on mice and patients that already have Alzheimer’s Disease, the claims are not limited to mitigating a likelihood of developing a new neurodegenerative disease or wherein the patient does not currently have a neurodegenerative disease. Note that neurodegenerative diseases are progressive, meaning they continue developing (see for example Burgess et al. Journal of Controlled Release 163 (2012) 125–129 http://dx.doi.org/10.1016/j.jconrel.2012.08 “a progressive neurodegenerative disease... resulting in neuronal dysfunction and cell death” page 125 col. 1 para. 1). Therefore, although the patient may already have the neurodegenerative disorder, the development of said neurodegenerative disorder would still be capable of being mitigated.
Applicant further argues that “Rezai does not describe or suggest administering a viral vector to a patient as recited in claim 1” (page 5 para. 3).
However, new grounds of rejection are set forth above in view of Hsu (see rejection above). Hsu teaches administering a viral vector.
Applicant further argues that “Regarding claim 4, this claim recites applying an additional focused ultrasound neuromodulation signal via an ultrasound device to a brain region during or after introducing the viral vector and/or applying the LiFUS sonication. Rezai does not describe or suggest this step” (page 5 para. 5).
However, Rezai does teach this step (see rejection above for the complete analysis). Briefly, given that the LiFUS sonication involves applying a focused ultrasound signal that neuromodulates the target brain region (see specification para. 47), the LiFUS sonication inherently provides the claimed neuromodulation signal of claim 4.
Applicant further argues that “Reddi does not make up for these deficiencies” (page 5 para. 6).
However, there are no deficiencies in the rejections set forth above.
Applicant further “requests that the double patenting rejections be held in abeyance until an indication of allowable subject matter has been made” (page 6 para. 1).
However, no claim is allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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