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
Claims 1-9 and 16-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.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 and 15 have undergone amendments. Claims 10-15 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.
Response to Arguments
The 35 U.S.C. § 112(a) rejection of Claims 10-15 is withdrawn. Applicant has amended Claim 10 to remove “or preventing”.
The 35 U.S.C. § 112(b) rejection of Claims 10-15 is withdrawn. Applicant has amended the claim to remove the phrase “including salt, cocrystal, analog, or physically modified form thereof”. Applicant has also replaced “and/or” with “or”.
The 35 U.S.C. § 112(b) rejection of Claim 15 is withdrawn. Applicant has removed “about”.
The 35 U.S.C. § 112(b) rejection of Claim 14 is withdrawn. Applicant argues that the claim is not indefinite because the claim is stating that the method is for the treatment of neuroinflammation in a patient diagnosed with these conditions. The Examiner finds this argument to be persuasive.
The 35 U.S.C. § 102 (a)(1) rejection of Claims 10, 11, 13, and 15 and 35 U.S.C. § 103 rejection of Claims 10-13 and 15 over Ferreira is maintained. Applicant argues that Ferreira fails to teach or suggest a method of treating neurovascular inflammation and damage in a subject as recited in Claim 10 as the teachings of Ferreira are limited to a study of permanent focal ischemia cerebral injury and only speculates as to the role of eriodictyol in neurovascular inflammation. The Examiner does not find these arguments to be persuasive. Focal ischemia cerebral injury is a form of neurovascular inflammation and/or damage. Ferreira demonstrates that application of eriodicytol results in a reduction in the expression and activity of inflammatory markers within the neurovascular system in a model of neurovascular inflammation and damage. Thus, Ferreira teaches the use of eriodictyol in the treatment of neurovascular inflammation.
The 35 U.S.C. § 102 (a)(1) rejection of Claims 10, 11, 13, and 15 and 35 U.S.C. § 103 rejection of Claims 10-13 over He is withdrawn. Applicant argues that the teachings of He are limited to IP injection of LPS, inducing systemic acute inflammation and models conditions such as bacterial sepsis and systemic inflammatory response syndrome. However, He does not teach or suggest a method of treating neurovascular inflammation and damage in a subject. The Examiner finds these arguments to be persuasive.
The 35 U.S.C. § 102 (a)(1) rejection of Claims 10, 11, 13, and 15 and 35 U.S.C. § 103 rejection of Claims 10-15 over He is withdrawn. As stated above, the teachings of He are limited to IP injection of LPS and does not teach, suggest, or provide motivation for the treatment of neurovascular inflammation or damage.
The 35 U.S.C. § 103 rejection of Claims 10-15 over Ferreira in view of Mun, Kursun, Naveed, MacKay, Abdul-Muneer, Siniscalco, and Muttal is maintained. Applicant argues that there is no reasonable basis or motivation provided by which one of ordinary skill in the art would look to combine Ferreira with the proposed secondary references. The Examiner respectfully disagrees. As described previously, Ferreira teaches the treatment of neurovascular inflammation and damage, and each of the cited references teaches that the claimed conditions are associated with neurovascular inflammation and damage. Thus, there would be a motivation to apply the eriodictyol for the treatment of neurovascular inflammation and damage, as Ferrieria demonstrates its utility in reducing markers of inflammation and damage in a model of neurovascular inflammation and damage, and there would be a reasonable expectation of success as each of these references teaches individually that the claimed conditions are associated with neurovascular inflammation and damage.
Claim Rejections - 35 USC § 102- REJECTION MAINTAINED
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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).
Claim Rejections - 35 USC § 103- REJECTION MAINTAINED
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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).
Determining the Scope and Contents of the Prior Art:
The teachings of Ferreira are previously described and are fully incorporated into this rejection.
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).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Ferreira discloses the use of eriodicytol for the treatment of neurovascular inflammation and damage but does not disclose the treatment of a patient diagnosed with one of the cited conditions. The remaining references teach that the claimed conditions are associated with neurovascular inflammation and damage.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would likely be a medical practitioner with further training in the diagnosis and treatment of conditions mediated which exhibit neurovascular inflammation and damage, and further training in the use of pharmaceuticals for the treatment and management of these conditions.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
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.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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