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 without traverse of Group II (Claims 10-15) in the reply filed on 1 December 2025 is acknowledged. Claims 1-9 and 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1 December 2025.
Claims 10-15, submitted on 1 December 2025, represent all claims currently under consideration.
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.
Priority
This application claims priority to provisional US 63/316,685, filed 4 March 2022. The effective filing date is 4 March 2022.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 2 October 2023 and 30 December 2025, are acknowledged and have been considered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of neurovascular inflammation and damage in a subject, does not reasonably provide enablement for the prevention of neurovascular inflammation and damage in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating or preventing neurovascular inflammation and damage in a subject comprising administering a pharmaceutically effective amount of a composition comprising a pharmaceutically acceptable amount of eriodictyol. The claims further specify that this method prevents neurovascular inflammation and damage in patients which suffer from conditions such as ALS, Alzheimer’s disease, and traumatic brain injury.
The state of the prior art and the predictability or unpredictability of the art:
Ferreira (See IDS, 2 October 2023) performed a study to determine if eriodictyol has neuroprotective effects against the neuronal damage, motor and memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) in mice. Animals were orally treated with eriodictyol (1, 2, and 4 mg/kg) or vehicle (saline) 30 minutes before pMCAO, 2h after, and then once daily for the following five days. Treatment with eriodictyol prevented neuronal death, reduced infarct area, and improved neurological and memory deficits induced by brain ischemia. The increase of MPO activity, and TNFα, iNOS, and GFAP expression were also reduced by eriodictyol treatment. The findings demonstrate that eriodictyol exhibits promising neuroprotection effects against permanent focal ischemia cerebral injury in a mouse model and the underlying mechanisms might be mediated through inhibition of neuroinflammation (Abstract). He (See IDS, 2 October 2023) investigated the neuroprotective effects of eriodictyol on LPS-induced neuroinflammation, oxidative stress, synaptic dysfunctions, and the potential mechanisms involved. Eriodictyol explicitly restored LPS-triggered decrease of cell viability, mitochondrial potential, as well as inflammation responses via MAPK and NF-kB pathways regulated by reactive oxygen species. Eriodictyol alleviated LPS-induced oxidative stress via NF-E2-Related factor2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway in vivo and in vitro. Eriodictyol reduced LPS-elicited synaptic dysfunctions via increasing the expression of silent information regulator 1 (Sirt1). Overall, eriodictyol protects against LPS-triggered oxidative stress, neuroinflammation, and synaptic dysfunctions partially through MAPKs, NF-kB mediated by ROS, Sirt1, and Nrf2/Keap1 signal pathways, which further supports that eriodictyol is a potentially nutritional preventive strategy for oxidative stress related neurodegenerative diseases (Abstract). There is no consensus as to eriodictyol being capable of preventing this neurovascular inflammation in the art, and this has not been demonstrated through the cited references. Kip (Frontiers in Neuroscience, 2023 Feb 15) provides an overview of the current state of the prevention of neuroinflammation. Prioritizing a healthy lifestyle to maintain wellbeing may slow the onset or reduce the severity of pathologies. A balanced lifestyle is increasingly being adopted globaly, with many doctors encouraging meditation and prescribing non-pharmaceutical interventions to treat depression. In psychiatric and neurodegenerative disorders, the inflammatory response of the brain is activated. Many risk factors are known to be linked to this inflammation, such as stress, pollution, and a high saturated and trans fat diet. On the other hand, many studies have linked healthy habits with lower levels of neuroinflammation and a reduced risk of neurodegenerative and psychiatric disorders. Most strategies to manage these diseases are palliative because neurodegeneration has been progressing silently for decades before symptoms appear (Abstract). The authors describe several risk and protective factors for neuroinflammation (Section 4. Risk and protective factors for neuroinflammation in neurodegenerative and psychiatric diseases). These protective factors include physical activity, eating a healthy diet which to foster a healthy gut microbiome, reduced alcohol consumption or complete abstinence from alcohol, reductions in chronic stressors in everyday life, spending time outside in natural environments and breathing air which does not have pollutants, quality sleep, not smoking tobacco, and use of cannabinoid therapeutics. Risks for elevated neuroinflammation include exposure to pesticides and heavy metals. The authors conclude by stating that lifestyle factors can be harnessed to reduce the population risk of neurodegenerative and psychiatric disorders by modulating neuroinflammation (5. Conclusion). Thus, the current state of the art does not provide evidentiary support for the use of eriodictyol for the prevention of neurovascular inflammation, with the current art supporting lifestyle modifications resulting in a healthy lifestyle to promote reduced neurovascular inflammation.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various neurological and vascular diseases; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to eriodictyol can be used to prevent neurovascular
The amount of direction or guidance presented and the presence or absence of working examples:
The specification does not provide any data or representative examples demonstrating that eriodictyol is capable of preventing neurovascular inflammation or damage in patients with or without the claimed brain disorders.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of evidence in the current state of the art that neurovascular inflammation and damage can be prevented using eriodictyol, in particular, in patients which suffer from the claimed brain disorders, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
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 10-15 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. Regarding Claim 10, the phrase "including" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 11-15 are rejected as dependent upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claims 10-15 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. Claim 10 claims both an analog or physically modified form of eriodictyol in the pharmaceutical composition. The specification does not define what comprises an analog or physically modified form of eriodictyol, causing the metes and bounds of Claim 10 to be undefined, and therefore, indefinite. Claims 11-15 are rejected as dependent upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claims 10-15 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. Claim 10 claims the use of a composition comprising a pharmaceutically effective amount of eriodictyol and/or any pharmaceutically acceptable form. It is unclear how the and/or modifies the composition. Can the composition contain both eriodictyol and a pharmaceutically acceptable salt, or does the composition contain one or the other? The Examiner suggests changing the and/or to “or” to overcome this rejection.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 15 claims that the subject is administered a composition which contains about 0.0125 mg to about 62.5 mg of eriodictyol per kg bodyweight. The specification does not define “about”, causing the metes and bounds of this dosage to be undefined and therefore indefinite.
Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 14 claims the method of Claim 10 wherein the subject has been diagnosed with a disorder of the brain selected from several conditions. It is unclear if that is a specific patient population, i.e., treatment of neurovascular inflammation and damage in a subject that also has these conditions, or if the neurovascular inflammation and damage in these subjects is caused by the claimed conditions, and the claimed method reduces the neurovascular inflammation and damage which is caused by the claimed conditions.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 10, 11, 13, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ferreira (Behavioral Brain Research, Volume 312, 1 October 2016, Pages 321-332).
Ferreira (See IDS, 2 October 2023) performed a study to determine if eriodictyol has neuroprotective effects against the neuronal damage, motor and memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) in mice. Animals were orally treated with eriodictyol (1, 2, and 4 mg/kg) or vehicle (saline) 30 minutes before pMCAO, 2h after, and then once daily for the following five days. Treatment with eriodictyol prevented neuronal death, reduced infarct area, and improved neurological and memory deficits induced by brain ischemia. The increase of MPO activity, and TNFα, iNOS, and GFAP expression were also reduced by eriodictyol treatment. The findings demonstrate that eriodictyol exhibits promising neuroprotection effects against permanent focal ischemia cerebral injury in a mouse model and the underlying mechanisms might be mediated through inhibition of neuroinflammation (Abstract). The eriodictyol was administered to the animals in a pharmaceutical composition (eriodictyol and saline by mouth, orally p.o.) (2.4, Experimental protocols).
Claims 10, 11, 13, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by He (Journal of Cellular Biochemistry, 2019; 120: 14756-14770).
He (See IDS, 2 October 2023) investigated the neuroprotective effects of eriodictyol on LPS-induced neuroinflammation, oxidative stress, synaptic dysfunctions, and the potential mechanisms involved. Eriodictyol explicitly restored LPS-triggered decrease of cell viability, mitochondrial potential, as well as inflammation responses via MAPK and NF-kB pathways regulated by reactive oxygen species. Eriodictyol alleviated LPS-induced oxidative stress via NF-E2-Related factor2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway in vivo and in vitro. Eriodictyol reduced LPS-elicited synaptic dysfunctions via increasing the expression of silent information regulator 1 (Sirt1). Overall, eriodictyol protects against LPS-triggered oxidative stress, neuroinflammation, and synaptic dysfunctions partially through MAPKs, NF-kB mediated by ROS, Sirt1, and Nrf2/Keap1 signal pathways, which further supports that eriodictyol is a potentially nutritional preventive strategy for oxidative stress related neurodegenerative diseases (Abstract). Mice were treated with eriodictyol at a dosage of 25, 50, and 100 mg/kg/day intragastrically (2.2 Animals and Treatment).
Claims 10, 11, and 13-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by He (Journal of Agricultural and Food Chemistry, 2018, 66, 10205-10214).
He (See IDS, 2 October 2023) performed a study to determine the protective effects of eriodictyol on LPS-induced neuroinflammation, amyloidogenesis, cognitive impairment, and the potential mechanisms involved. Behavioral tests and histological examinations showed that eriodictyol significantly prevented memory and neuronal damage triggered by LPS. Eriodictyol reduced the formation of Aβ compared to LPS control group. Eriodictyol suppressed LPS-induced glial overactivation and regulated inflammatory mediators and cytokines by inhibiting the NF-kB and MAPK pathways. These results indicated that eriodictyol alleviated amyloidogenesis and memory impairment triggered by LPS via inhibition of TLR4, MAPKs, and PI3K/Akt, and activating Sirt1 pathways and thus blocking downstream translocation of NF-kB, which offers a potential nutritional preventative strategy for neuroinflammation diseases such as Alzheimer’s disease (Abstract). Mice were treated with eriodictyol at a dosage of 25, 50, and 100 mg/kg/day intragastrically (Animals and Treatments). The LPS model used in this paper is a well-recognized animal model of Alzheimer’s disease, and thus, reads on the treatment of a patient with Alzheimer’s disease as claimed in Claim 14.
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 10-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Ferreira (Behavioral Brain Research, Volume 312, 1 October 2016, Pages 321-332).
The teachings of Ferreira are described previously and are fully incorporated into this rejection.
Ferreira fails to teach a method wherein the neurovascular inflammation and damage results in multiorgan failure. However, in view of the teachings of Ferreira, it would be obvious to one of ordinary skill in the art to apply pharmaceutical compositions of eriodyctiol to treat or prevent neurovascular inflammation and damage in a subject wherein the damage results in multiorgan failure as Ferreira demonstrates that administration of eriodyctiol decreased expression and activity of inflammatory markers, and the authors state that this treatment likely inhibits neuroinflammation. Thus, the artisan would be motivated, and have a reasonable success in, applying this treatment in a patient which has multiorgan failure as Ferreira shows that eriodyctiol inhibits the expression and activity of inflammatory mediators implicated in the pathogenesis of neurovascular inflammation and damage, predictably resulting in a method which treats or prevents neurovascular inflammation or damage in a subject which has multiorgan failure.
Claims 10-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over He (Journal of Cellular Biochemistry, 2019; 120: 14756-14770).
The teachings of He are described previously and are fully incorporated into this rejection.
He fails to teach a method wherein the neurovascular inflammation and damage results in multiorgan failure. However, in view of the teachings of He, it would be obvious to one of ordinary skill in the art to apply pharmaceutical compositions of eriodyctiol to treat or prevent neurovascular inflammation and damage in a subject wherein the damage results in multiorgan failure as He demonstrates that administration of eriodyctiol decreased expression and activity of inflammatory markers and oxidative stress both in vitro and in vivo, and the authors state that this treatment represents a strategy for the prevention of oxidative stress related to neurodegenerative diseases. Thus, the artisan would be motivated, and have a reasonable success in, applying this treatment in a patient which has multiorgan failure as He shows that eriodyctiol inhibits the expression and activity of inflammatory mediators and markers of oxidative stress implicated in the pathogenesis of neurovascular inflammation and damage, predictably resulting in a method which treats or prevents neurovascular inflammation or damage in a subject which has multiorgan failure.
Claims 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over He (Journal of Agricultural and Food Chemistry, 2018, 66, 10205-10214).
The teachings of He are described previously and are fully incorporated into this rejection.
He fails to teach a method wherein the neurovascular inflammation and damage results in multiorgan failure. However, in view of the teachings of He, it would be obvious to one of ordinary skill in the art to apply pharmaceutical compositions of eriodyctiol to treat or prevent neurovascular inflammation and damage in a subject wherein the damage results in multiorgan failure as He demonstrates that administration of eriodyctiol decreased expression and activity of inflammatory markers and translocation of NF-kB , and the authors state that this treatment represents a strategy for the prevention of oxidative stress related to neurodegenerative diseases. Thus, the artisan would be motivated, and have a reasonable success in, applying this treatment in a patient which has multiorgan failure as He shows that eriodyctiol inhibits the expression and activity of inflammatory mediators and markers of oxidative stress implicated in the pathogenesis of neurovascular inflammation and damage, predictably resulting in a method which treats or prevents neurovascular inflammation or damage in a subject which has multiorgan failure.
Claims 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Ferreira (Behavioral Brain Research, Volume 312, 1 October 2016, Pages 321-332) in view of Mun (Stroke, 2022, 53:427-436), Kursun (Journal of Headache Pain, 2021, 22:55), Naveed (Neurochemistry International, 126, 2019, 165-177), MacKay (International Journal of Immunopathology and Pharmacology, 2018 Dec 6; 32), Abdul-Muneer (Molecular Neurobiology, Volume 51, Pages 966-979, 2015), Siniscalco (Pharmaceuticals (Basel), 2018 June 4; 11(2):56), and Muttal (Frontiers in Cellular Neuroscience, 2019 March 20; 13: 110).
The teachings of Ferreira are previously described and are fully incorporated into this rejection.
Ferreira fails to teach the treatment or prevention of neurovascular inflammation or damage in a subject which has been diagnosed by the claimed conditions.
Mun provides a review of inflammation and vascular brain health. The role of cerebrovascular infections, such as the SARS-CoV-2 virus, and its association with increased risk of stroke is reviewed. Inflammation acts as a trigger for vascular brain injury by steadily increasing the risk of chronic cerebrovascular disease. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke (Abstract). The COVID-19 pandemic has highlighted the emerging role of inflammatory cascades as both cause and consequence of vascular brain injury. The relationship of COVID-19 and various phenotypes of stroke has sharpened the focus on the role of inflammation in cerebrovascular disease. Numerous previous studies have implicated chronic sterile inflammation as a significant cardiovascular and cerebrovascular risk factor. The pandemic highlights a new and novel role for accelerated acute viral inflammation in the pathogenesis of stroke, and accumulating evidence indicates that brain-specific inflammatory mechanisms underlie the entire spectrum of cerebrovascular disease (Introduction). Chronic injury to the brain’s microcirculation is increasingly valued as a primary driver of cognitive impairment and dementia as well as increasing the risk of clinical stroke. Various studies have demonstrated that chronic inflammatory signals associate with cerebral small vessel disease injury, and demonstrate that sustained increases in inflammation lead to progressive cerebrovascular disease (Inflammatory Pathways Driving Chronic Cerebrovascular Disease). The COVID-19 pandemic triggered by SARS-Cov-2 is associated with a 1.8% risk of stroke with the unusual feature of causing stroke events in younger patients. The risk of stroke is comparatively higher in COVID-19 infection compared with nonpandemic seasonal influenza infection. Without any preexisting immunity to SARS-CoV-2, infection with this novel pathogen appears to active both direct and indirect pathways that drive up the thrombotic potential and risk of stroke, even in the absence of any preexisting chronic vascular risk factors (Infections Associated with Stroke that Target Brain Vasculature). By understanding the specific roles of various inflammatory signaling mechanisms in the diverse range of vascular brain insults, distinct molecular cascades provide new insights into disease phenotypes. The development of anti-inflammatory treatments as a means to improve vascular brain health and reduce cerebrovascular risk is just beginning (Conclusions).
Kursun provides an overview of neuroinflammation in migraine headaches. Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The review article highlights the findings of cortical spread depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. The activation of inflammasomes causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The review discusses cortical spreading depolarization induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke. Neuroinflammatory pathways, specifically those involving inflammasome proteins, are promising candidates as treatment targets and biomarkers for migraine (Abstract).
Naveed provides a review of cerebrovascular inflammation and its role in disease. The cerebrovascular system is not only inert by standard that support the metabolic demands of the brain but also elicit the barrier functions against risk factors mediated neurovascular injury. The onsets of cerebrovascular inflammation are considered as stimuli that can provoke the host defense system and trigger the development of neurological disorders. Homeostasis of the brain function is regulated by the movement of endothelial, glial, and neuronal cells within the neurovascular unit (NVU), which acts as a “platform” for the coordinated action of antiand pro-inflammatory mechanisms. The cerebrovascular system plays an integral role in the inflammatory response by either producing or expressing a variety of cytokines, adhesion molecules, metalloproteinases, and serine proteases. Excessive inflammatory cytokine production can further be affecting the blood-brain barrier (BBB) integrity and lead to brain tissue damage (Abstract). Table 1 (Page 172) provides an overview of different inflammatory factors implicated in cerebrovascular injury and neurological disorders, with different targets and pathways being implicated in conditions such as stroke, encephalopathy, multiple sclerosis, Alzheimer’s disease, ALS, vascular dementia, disruption of the blood brain barrier, and general neurodegeneration. Attenuation of neurovascular injury is a promising approach to control neuroinflammation. The development of innovative research designs with anti-inflammatory and other antioxidant agents would provide a better therapeutic strategy to treat the pathophysiology of neurological disorders. The therapeutic aspects by reducing neuroinflammation and attenuating neurological disorders are other scopes of future studies (Conclusions).
MacKay presents a neuroinflammatory paradigm to help explain the pathophysiology of ME/CFS. The hypothalamic paraventricular nucleus (PVN) is responsible for absorbing and processing multiple stress signals, and if this cluster of neurons is affected by neuroinflammation, the hypersensitivity of ME/CFS patients to different stressors can be explained. Neuroinflammation that was chronic and fluctuating, as ‘inflammatory-marker’ studies support, could reflect a dynamic change in the hypothalamic PVN’s threshold for managing incoming ‘stress’ signals. This may not only be a mechanism underpinning the characteristic feature of ME/CFS, post-exertional malaise, and its associated debilitating relapses, but could also be responsible for mediating the long-term perpetuation of the disease. Triggers (sustained physiological ‘stressors’) of ME/CFS, such as a particular viral infection, toxin exposure, or a traumatic event, could also target the hypothalamic PVN, a potentially vulnerable site in the brains of ME/CFS susceptible people, and disruption of its complex neural circuitry could account for the onset of ME/CFS. In common with the different ‘endogenous factors’ identified in the early ‘neuroinflammatory’ stages of the ‘neurodegenerative’ diseases, an as yet, unidentified factor within the brains and central nervous system (CNS) of ME/CFS patients might induce both an initial and then sustained ‘neuroinflammatory’ response by its ‘innate immune system’. Positron emission tomography/magnetic resonance imaging has reinforced evidence of glial cell activation centered on the brain’s limbic system of ME/CFS patients. Neuroinflammation causing dysfunction of the limbic system and its hypothalamus together with a consequently disrupted autonomic nervous system could account for the diverse range of symptoms in ME/CFS relating, in particular to fatigue, mood, cognitive function, sleep, thermostatic control, gastrointestinal disturbance, and hypotension (Abstract).
Abdul-Muneer provides a review which addresses the role of oxidative stress in TBI-mediated secondary damages by affecting the function of the vascular unit, changes in blood-brain barrier (BBB) permeability, posttraumatic edema formation, and modulation of various pathophysiological factors such as inflammatory factors and enzymes associated with trauma. Oxidative stress plays a major role in many pathophysiologic changes that occur after TBI. In fact, oxidative stress occurs when there is an impairment or inability to balance antioxidant production with reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels. ROS directly downregulate proteins of tight junctions and indirectly activate matrix metalloproteinases (MMPs) that contribute to open the BBB. Loosening of the vasculature and perivascular unit by oxidative stress-induced activation of MMPs and fluid channel aquaporins promotes vascular or cellular fluid edema, enhances leakiness of the BBB, and leads to progression of neuroinflammation. Likewise, oxidative stress activates directly the inflammatory cytokines and growth factors such as IL-1β, tumor necrosis factor-α (TNF-α), and transforming growth factor-beta (TGF-β) or indirectly by activating MMPs. In another pathway, oxidative stress-induced degradation of endothelial vascular endothelial growth factor receptor-2 (VEGFR-2) by MMPs leads to a subsequent elevation of cellular/serum VEGF level. The decrease in VEGFR-2 with a subsequent increase in VEGF-A level leads to apoptosis and neuroinflammation via the activation of caspase-1/3 and IL-1β release (Abstract). The development of innovative research designs with antioxidants and other anti-inflammatory agents would provide a better therapeutic strategy to treat the pathophysiology of TBI (Conclusions).
Siniscalco provides an overview of autism spectrum disorder and neuroinflammation. Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interaction and restricted-repetitive patterns of behavior, interests, or activities. Strong inflammation states are associated with ASD. This inflammatory condition is often linked to immune system dysfunction. Several cell types are enrolled to trigger and sustain these processes. Neuro-inflammation and neuro-immune abnormalities have now been established in ASD as key factors in its development and maintenance (Abstract).
Muttal provides a review of mast cells and their involvement in neural inflammation. Mast cells (MCs) are located in the periphery as well as the central nervous system (CNS). Known for sterile inflammation, MCs play a critical role in neuroinflammation, which is facilitated by their close proximity to nerve fibers in the periphery and meninges of the spinal cord and the brain. Multifaceted activation of MCs releasing neuropeptides, cytokines and other mediators has direct effects on the neural system as well as neurovascular interactions. Emerging studies have identified the release of extracellular traps, a phenomenon traditionally meant to ensnare invading pathogens, as a cause of MC-induced neural injury. In this review article, we will discuss mechanisms of MC interaction with the nervous system through degranulation, de novo synthesis, extracellular vesicles (EVs), tunneling nanotubes, and extracellular traps with implications across a variety of pathological conditions (Abstract). It is well document that mast cell mediators contribute to endothelial dysfunction in the vasculature, and activation of mast cells locally increases blood brain barrier permeability. Inflammation caused by mast cells can further activate mast cells in an autocrine manner. Increase in BBB permeability is associated with higher levels of neuroinflammation and brain dysfunction. Additionally, BBB disruption may further changes by systemic inflammation. Activation of meningeal MCs has been shown to worsen stroke pathology in mice. Therefore, activation of MCs in the periphery, as well as CNS, has implications in altering the neural activity and function directly and/or via neurovascular interactions (Neurovascular Interactions and Pathological Outcomes). MCs contribute to neural and vascular injury directly as well as induce neurovascular interactions (Conclusions).
Ferreira and the cited references are considered analogous to the claimed invention as all are involved in the treatment and study of conditions which involve cerebrovascular, neurovascular, and neuroinflammation. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to apply pharmaceutical compositions of eriodictyol to treat or prevent neurovascular inflammation and damage in subjects which suffer from the claimed conditions as Ferreira demonstrates that eriodyctiol mitigates neurovascular inflammation in vivo, and each of the cited conditions are known in the art to be associated with neurovascular inflammation. Thus, there would be a reasonable expectation of success in applying compositions of eriodyctiol for the treatment or prevention of neurovascular inflammation and damage in these subjects as these conditions are known to have a neurovascular inflammation component, which, as Ferreira has shown, will predictably be treated by eriodictyol. The application of these compositions for the treatment of these claimed conditions is prima facie obvious use of a known technique to improve similar methods in the same way (See MPEP § 2143 I (C)); eriodictyol is known in the art to have potent anti-inflammatory activity in models of neurovascular inflammation, and each of these conditions are known to have a neurovascular inflammation component.
Regarding the treatment of angiitis and encephalitis, these conditions are inflammation of blood vessels and the brain, respectively. It would be prima facie obvious to one of ordinary skill in the art to apply eriodictyol to treat neurovascular inflammation or damage in a patient which suffers from these conditions as Ferreira demonstrates that eriodictyol mitigates activity and expression of markers of neuroinflammation. It flows from the art of Ferreira that eriodictyol would be useful for treating or preventing neurovascular inflammation or damage in a patient which suffers from angiitis or encephalitis as these are inflammatory conditions of the blood vessels and brain, respectively.
Conclusion
Claims 10-15 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625