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 .
This is the first action on the merits.
Claims 1-27 are pending and under consideration.
Claim Objections
Claim 1 is objected to because of the following informalities: the term “straightchain” should be replaced with “straight chain” in the definitions of Z, R1, R3b, R4 and R5. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: the phrase “an effective amount of” should be after the term “administering” in line 2. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 21 and 23 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 pre-AIA the applicant regards as the invention.
In claims 10 and 21, the terms “oxadiazolone, oxathiadiazolone, and thioxo- oxadiazole” are not heteroaryl rings, and thus, are vague.
Regarding claim 23, the phrase “disease, condition, or disorder associated with IP6K” is indefinite because it is not clear what Applicant is claiming. The diseases disclosed in the specification are defined as “In some aspects” or “In some embodiments” on pages 2 and 11, respectfully, of the specification, which is open- ended language. Is this the entire scope of the therapeutic claims or are there other diseases? Note that the claim also covers diseases, which themselves trigger changes in IP6K levels, e.g. IP6K change as effect rather than cause. There is no standard list for a “disease, condition, or disorder associated with IP6K.”
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The term “phenyl” does not further limit claim 6, which depends from claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 21 is rejected under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The terms “cyclobutyl” and “phenyl” in subsection c) does not further limit claim 11, which depends from claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 23-27 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 a method of inhibiting IP6K and/or the treatment of chronic kidney disease, does not reasonably provide enablement for the prevention or treatment of Alzheimer’s Disease, diabetes or psychiatric disordes,r generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification on page 16 defines treatment as prevention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(A) Breadth of claims.
(a) Scope of the compounds. The compounds of structure I thousands of [1,2,4]triazolo[1,5-a]pyrazine bicycle with 3 variables.
(b) Scope of the diseases covered. Psychiatric disorders are extremely diverse, and fall into an assortment of categories. The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the American Psychiatric Association's standard reference for psychiatry which includes over 450 different definitions of mental disorders. The International Statistical Classification of Diseases and Related Health Problems (ICD) is published by the World Health Organization, and it contains a section on psychological and behavioral disorders. The diagnostic criteria and information in the DSM and ICD are revised and updated with each new version. This list contains conditions currently recognized descriptions of mental disorders as defined by these two documents.
There is disagreement in various fields of mental health care, including the field of psychiatry, over the definitions and criteria used to delineate various disorders. Of particular concern to some professionals is whether some of these conditions should be classified as 'mental illnesses' at all, or whether they would be better described as neurological disorders, or in other ways.
A
Absence epilepsy
Acute stress disorder
Adjustment disorder
Adolescent antisocial behavior
Adult antisocial behavior
Agoraphobia
Alcohol abuse
Alcohol dependence
Alcohol withdrawal
Alcoholic hallucinosis
Avoidant/restrictive food intake disorder
Alzheimer's disease
Amnestic disorder
Amphetamine dependence
Anorexia nervosa
Anterograde amnesia
Antisocial personality disorder
Anxiety disorder
Attention deficit disorder
Attention deficit hyperactivity disorder
Autism
Autophagia
Avoidant personality disorder
Atelophobia
Asperger syndrome
B
Barbiturate dependence
Benzodiazepine dependence
Benzodiazepine misuse
Benzodiazepine withdrawal
Bereavement
Bibliomania
Binge eating disorder
Bipolar disorder
Bipolar I disorder
Bipolar II disorder
Body dysmorphic disorder
Borderline intellectual functioning
Borderline personality disorder
Brief psychotic disorder
Bulimia nervosa
C
Caffeine-induced sleep disorder
Cannabis dependence
Claustrophobia
Catatonic disorder
Catatonic schizophrenia
Circadian rhythm sleep disorder
Cocaine dependence
Cocaine intoxication
Cognitive disorder
Communication disorder
Conduct disorder
Cotard delusion
Cyclothymia
D
Dauren Shukirbay disorder
Delirium tremens
Depersonalization disorder
Depressive disorder
Derealization disorder
Dermatillomania
Desynchronosis
Developmental coordination disorder
Diogenes Syndrome
Dispareunia
Dissociative identity disorder
Dyspraxia
Dyslexia
E
EDNOS
Ekbom's Syndrome (Delusional Parasitosis)
Encopresis
Epilepsy
Enuresis (not due to a general medical condition)
Erotomania
Exhibitionism
Euphoria
F
Factitious disorder
Fregoli delusion
Fugue State
G
Ganser syndrome
Gender dysphoria
Generalized anxiety disorder
General adaptation syndrome
Grandiose delusions
H
Hallucinogen-related disorder
Hallucinogen persisting perception disorder
Histrionic personality disorder
Huntington's disease
Hypomanic episode
Hypochondriasis
I
Insomnia
K
Kleptomania
Korsakoff's syndrome
L
Lacunar amnesia
M
Major depressive disorder
Major depressive episode
Maladaptive Daydreaming
Male erectile disorder
Malingering
Manic episode
Mathematics disorder
Melancholia
Minor depressive disorder
Misophonia
Mixed episode
Mood disorder
Morbid jealousy
Munchausen's syndrome
N
Narcolepsy
Narcissistic personality disorder
Neurocysticercosis
Nicotine withdrawal
Night eating syndrome
Nightmare disorder
O
Obsessive-compulsive disorder (OCD)
Obsessive-compulsive personality disorder (OCPD)
Oneirophrenia
Opioid dependence
Opioid-related disorder
Oppositional defiant disorder (ODD)
Orthorexia (ON)
Ondine's curse
P
Pain disorder
Panic disorder
Paranoid personality disorder
Parasomnia
Parkinson's Disease
Pathological gambling
Perfectionism
Persecutory delusion
Personality disorder
Phencyclidine (or phencyclidine-like)-related disorder
Phobic disorder
Pica (disorder)
Psychosis
Phonological disorder
Physical abuse
Polysubstance-related disorder
Post-traumatic embitterment disorder (PTED)
Posttraumatic stress disorder (PTSD)
Premature ejaculation
Primary hypersomnia
Primary insomnia
Psychogenic amnesia
Psychotic disorder
Pyromania
R
Reactive attachment disorder of infancy or early childhood
Recurrent brief depression
Relational disorder
Residual schizophrenia
Retrograde amnesia
Rumination syndrome
S
Schizoaffective disorder
Schizoid personality disorder
Schizophrenia
Schizophreniform disorder
Schizotypal personality disorder
Seasonal affective disorder
Sedative-, hypnotic-, or anxiolytic-related disorder
Selective mutism
Separation anxiety disorder
Severe mental retardation
Shared psychotic disorder
Sleep disorder
Seasonal Affective Disorder
Sleep terror disorder
Sleepwalking disorder
Social anxiety disorder
Social phobia
Somatization disorder
Somatoform disorder
Specific phobia
Stendhal syndrome
Stereotypic movement disorder
Stuttering
Substance-related disorder
T
Tardive Dyskinesia
Tourette Syndrome
Transient Tic Disorder
Transient Global Amnesia
Trichotillomania
The term "psychiatric disorders" covers an immense array of largely unrelated disorders that have different modes of action and different origins. The term covers such diverse disorders as Alzheimer's Disease; Parkinson's Disease; ALS and variants such as forms of ALS-PDC; dementia of the frontal lobe type (DFT) and DFT with motor neuron disease (DFT-MND); Diffuse Lewy Body Disease; Cortical Lewy body disease; Hallervordon-Spatz disease; Senile dementia of the neurofibrillary tangle type (“tangle-only dementia”); progressive familiar myoclonic epilepsy; Corticodentatonigral degeneration; more than a dozen dementias collectively called "frontotemporal dementia” (FTD); Tourette's syndrome; multiple systems atrophy (MSA; once called Shy-Drager syndrome), which exists in two forms: MSA-P type or MSA-C type; Neurological syphilis; Neurosarcoidosis; Pure autonomic failure (Bradbury-Eggleston syndrome); Friedreich ataxia and other spinocerebellar degenerations; Olivopontocerebellar atrophy (OPCA); spasmotic torticollis; Striatonigral degeneration; various types of torsion dystonia; certain spinal muscular atrophies, such as Werdnig-Hoffmann and Wohlfart-Kugelberg-Welander; Hereditary spastic paraplegia, Primary lateral sclerosis; peroneal muscular atrophy (Charcot-Marie-Tooth); Hypertrophic interstitial polyneuropathy (Dejerine-Sottas); ophthalmic disorders such as primary open-angle glaucoma (POAG) and retinitis pigmentosa; Leber's Disease; Wallerian degeneration, and Hypertrophic interstitial polyneuropathy.
There is the neuroacanthocytosis family, a difficult to define group of genetic disorders which includes Bassen-Kornsweig disease (abetalipoproteinemia), Familial hypobetalipoproteinemia, Chorea-acanthocytosis (ChAc), McLeod syndrome (MLS) , Huntington disease–like2 (HDL2) and Pantothenate kinase–associated neurodegeneration (PKAN), FHBL1, FHBL2, Familial acanthocytosis with paroxysmal exertion-induced dyskinesias and epilepsy (FAPED), and Anderson disease.
There is a group of Prion diseases, notably Creutzfeldt-Jakob Disease (CJD), which occurs in both sporadic and familial forms; Gerstmann-Straussler-Scheinker Disease (GSS); and fatal familial insomnia.
There is another group called the Taupathy diseases, which includes Pick's disease; cortical-basal ganglionic degeneration (CBGD or CBD); progressive supranuclear palsy (PSP); Parkinsonism-dementia complex (PDC), and the amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS-PDC).
Another group is the Polyglutamine diseases: Huntington's disease; spinal-bulbar muscular atrophy (Kennedy's disease or SBMA), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Machado-Joseph disease (MJD, also called spinocerebellar ataxia type 3), and the other SCA diseases, viz SCA-1, SCA-2, SCA-6, and SCA-7.
The leukodystrophies are a group of over 30 assorted genetic disorders that affect the central nervous system by disrupting the growth or maintenance of the myelin sheath. This category includes 18q-Syndrome, Acute disseminated encephalomyeolitis (ADEM), Acute Disseminated Leukoencephalitis, Acute Hemorrhagic Leukoencephalopathy, Adrenoleukodystrophy, Adrenomyeloneuropathy (AMN), Aicardi-Goutieres Syndrome, Alexander Disease, Adult-onset Autosomal Dominant Leukodystrophy (ADLD), Autosomal Dominant Diffure Leukoencephalopathy with neuroaxonal spheroids, Autosomal Dominant late-onset leukoencephalopathy, Childhood Ataxia with diffuse CNS Hypomyelination (CACH or Vanishing White Matter Disease), Canavan Disease, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts (CADASIL) and Leukoencephalopathy, Cerebrtendinous Xanthomatosis (CTX), Craniometaphysical dysplasia with leukoencephalopathy, Extensive Cerebral White Matter abnormality without clinical symptoms, Familial adult-onset leukodystrophy manifesting as cerebellar ataxia and dementia, Familial leukodystrophy with adult onset dementia and abnormal glycolipid storage, Globoid Cell Leukodystrophy (Krabbe Disease), Hereditary adult onset leukodystrophy simulating chronic progressive multiple sclerosis, Lipomembranous osteodysplasia with leukodystrophy (Nasu Disease), Metachromatic Leukodystrophy, Megalencephalic leukodystrophy with subcortical cysts (MLC), Neuroaxonal leukoencephalopathy with axonal spheroids,Oculodetatoldigital Dysplasia with cerebral white matter abnormalities, Orthochromatic leukodystrophy with pigmented glia, Ovarioleukodystrophy Syndrome, Pelizaeus-Merzbacher Disease, Refsum Disease, Sjogren-Larsson Syndrome, Sudanophilic Leukodystrophy, Van der Knapp Syndrome, Vanishing White Matter Disease, X-linked Adrenoleukodystrophy (X-ALD), and the Zellweger Spectrum: Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease.
The neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative disorders of childhood. These are generally characterized by loss of vision, seizures, motor dysfunction leading to spastic quadriplegia, cognitive loss, and early death. Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease is the most common of these. Different forms arise from different genes: CLN1 most commonly causes infantile onset, but also late Infantile- and Juvenile-Onset, as well as adult-onset. There is also late infantile (CLN2), juvenile-onset disease (CLN3), and late-infantile forms (CLN5). CLN8 underlies a form of progressive myoclonic epilepsy. The adult Kufs disease appears to be associated with CLN4. There are forms of late infantile NCL that are associated with CLN7 and CLN8, and another forms associate with NCL6. Of the 9 identified so far (CLN1-9), only 6 have their gene even identified.
Neurodegeneration can arise from the attack of known or unknown viruses on the brain. For example, HIV-associated dementia (HAD) arises from HIV-1; some strains of influenza A can cause apoptotic neurodegeneration; West Nile virus can cause neurodegeneration, possibly as a result of cytotoxic lymphocytes.
Neurodegeneration can also arise from stroke, and from certain types of spinal cord injuries.
These exhibit a very broad range of effects and origins. For example, some give no dementia and affect only vision, such as POAG. Many give distinctive and different patterns of effect. For example, FTDs, which have bilateral atrophy of the frontal and anterior temporal lobes, produce progressive nonfluent aphasia and semantic dementia, but, in contrast to e.g. Alzheimer's Disease, visuospatial skills and day-to-day memorizing is largely unaffected. Some give muscular wasting without sensory changes, e.g. ALS, and some do have the sensory changes such as Werdnig-Hoffmann. Some affect only vision such as retinitis pigmentosa, while others affect both vision and cognitive functions, such as Posterior cortical atrophy (PCA). Some produce abnormalities of posture, movement or speech, such as Striatonigral degeneration, and others produce progressive ataxias, such as OPCA. Some give an extremely broad range of effects. For example, CBD can give apraxia, alien limb phenomenon, cortical sensory loss, aphasia, myoclonus, bradykinesia, rigidity, dystonia, tremor, memory impairment and/or personality/behavioral changes.
The toxic protein, for those diseases that involve one, also varies. In some cases it is tau, i.e. in Alzheimer's Disease and other taupathies, and some are so linked to tau only sometimes (FTD). Alzheimer's Disease also involves β-amyloid. For Parkinson's disease it is α-synuclein. Prion disease involves PrPSc as its toxic protein, which involves missense. The polyglutamine diseases involve polyglutamine containing proteins. For Huntington's disease, it is huntingtin, for SBMA it is an androgen receptor, for DRPLA it is atrophin, for SCA-1 it is Ataxin-1, for SCA-2 it is Ataxin-2, for SCA-3 it is Ataxin-3, for SCA-6 it is a calcium channel protein, and for SCA-7 it is Ataxin-7.
In other cases, it is a matter of deficiency or absence of a protein. In Friedreich ataxia, the problem is frataxin deficiency, which affects sensory neurons in the dorsal root ganglion responsible for position sense.
The nature of the protein deposits, when these occur, varies as well. In Alzheimer's Disease, there are extracellular plaques from β-amyloid and neurofibrillary tangles (from tau). In Parkinson’s disease it is Lewy bodies and in ALS it is Bunina bodies. Taupathy produces cytoplasmic tangles, and Polyglutamine disease produce neuropil aggregates, intranuclear inclusions and cytoplasmic tangles. Prion disease produces prion plaque. And note that the disease form is not necessarily related to the protein deposits. For example, Alzheimer's Disease and Pick's disease both give progressive dementia without other prominent neurological signs. But the characteristic Alzheimer's neurofibrillary tangles are not seen in Pick's Disease, which has straight fibrils, as opposed to the paired helical filaments of Alzheimer's Disease. Pick's Disease gives lobal atrophy, not seen in Alzheimer's Disease.
The disease genes vary considerably as well. In Alzheimer's Disease, there is toxic gain of function with APP and loss of function of Presenilin 1 and presenilin 2. With Parkinson’s disease, there is toxic gain of function with α-synuclein, and loss of function of Parkin and UCHL1. In the Polyglutamine diseases, there is toxic gain of function with 9 different genes with CAG repeat expansion. In Prion disease, there is toxic gain of function with PRNP. In ALS there is toxic gain of function with SOD1. FTDP-17 arises from mutations at chromosome 17, Huntington's Disease from chromosome 4, and the neurodegenerative disorder that people with Down's syndrome develop later in life is presumably connected in some way to chromosome 21. Certain forms of Retinitis pigmentosa have been linked to deficiency in production of the kinase CERKL. Friedreich ataxia results from a mutation at the centromeric region of chromosome 9; it is the only disease known to be the result of a GAA trinucleotide repeat.
Finally, it must be noted that there are disorders that may or may not be neurodegenerative. Multiple sclerosis is perhaps the best known example; it is regarded by some as an autoimmune disease but by others as a metabolically dependent neurodegeneration.
As can be seen from the above, unlike in some areas of medicine, there is no representative, or “typical” psychiatric disorder. Some affect the mind, some affect movement, some affect both, and some effect neither. Alzheimer's Disease is the most common neurodegenerative disorder. However, its etiology involves both tau protein and β-amyloid. Such a statement is not true for any other important neurodegenerative disorder, and indeed the vast majority of neurodegenerative disorders involve neither one of those.
This covers any dysfunction of memory. Memory is the capacity to retain and retrieve an impression of past experiences. Memory is thus inseparable from learning, as learning cannot take place without memory and memory is the expression of learning.
Memory can be classified in two ways. One is, approximately, by duration. The sensory memory (milliseconds to seconds) corresponds to the initial moment that an item is perceived by the sense. Some of this information in the sensory area is transferred to short-term memory (retention for seconds to minutes). The capacity of these memories is quite limited. Some of this information is consolidated into long-term memory (retention for days up to a lifetime). The capacity of long term memory is immense. There is also something called working memory, which refers to a short-term storage needed for certain mental tasks but is not specifically defined in terms of duration, but rather in terms of purpose. It appears to be a form of short-term memory combined with some attentional control.
In addition, long term memory (the most important type) can be classified according to the information type. The two main categories are declarative (explicit) and non-declarative (implicit) memories. Declarative memory requires conscious recall, in that some conscious process must explicitly call back the information. This includes semantic memory, which concerns facts taken independent of context (mostly, general knowledge about the world); and episodic memory, which concerns information specific to a particular context, such as a time and place (mostly, personal memories and personal associations of a particular place or time, sometimes called autobiographical memory). The other main category’s most important type is called procedural memory and is not based on the deliberate recall of information, but on an implicit learning of certain patterns about the world. This form of learning is responsible for improvements in performance due purely to repetition. Examples of this include Classical conditioning and motor learning (e.g. “muscle memory”), and many types of skills. The other type of non-declarative memory is perceptual-representational, a kind of “priming”, so that the experience of an object on one occasion facilitates the perception of the same (or a similar) object on a later occasion.
Memory involves many different parts of the CNS, including basal ganglia, amygdala, the neostriatum, the cerebellum, the mammillary bodies and hippocampus.
The formation of memory requires three steps or stages: 1) Encoding (sensory registration, the processing of received information, including combination if the information comes from e.g. more than one sense organ), 2) Storage (creation of a permanent record of this encoded information), and 3) Retrieval (calling back this stored information in response to some cue for its use). As all of these are essential; a dysfunction of any stage will result in memory impairment. Thus, if the initial encoding does not take place, or if this information is not transferred to short term memory, such as occurs in the various agnosias, then memory impairment will occur. If information cannot be moved from short term to long term memory (a disorder called anterograde amnesia), then memory impairment occurs. If retrieval from long term memory is delayed, if it cannot be performed (memories lost), or if it is defective (false memories), then there is memory impairment.
As a result of the wide range of different types of memories which the brain forms, and the great complexity of the processes for memory, this covers a very wide range of disorders.
These include language memory disorders, such as aphasias (e.g. conduction aphasia), apraxia, dysarthria, alexia, receptive dysphasia, and agraphia.
It includes many types of disorders called amnesias. There is anterograde amnesia (new events are not transferred to long-term memory) and retrograde amnesia (inability to recall events that occurred before the onset of amnesia). There is lacunar amnesia (loss of memory about one specific event), Fugue amnesia (Psychogenic amnesia or hysterical amnesia, including “repressed memories”), Childhood amnesia (inability to remember events from early childhood), Transient epileptic amnesia (TEA), Autobiographical Amnesia, Transient Global Amnesia (total memory loss), Source amnesia (in which someone can recall certain information, but not where or how it was obtained) and amnesias arising from complex partial seizures, and alcoholic blackouts.
It also includes various agnosias, such as Prosopagnosia, Integrative agnosias, asogmatoagnosia, Associative agnosias, Autotopagnosia , Time Agnosia, Apperceptive agnosia, object agnosia, finger agnosia, phonagnosia, central achromatopsia, topographical agnosia, dyslexia, dyscalculia, right-left disorientation, Optic ataxia and Ocular apraxia, Color Agnosia, Simultanagnosia, Anosognosia, Auditory Agnosia (including amusia and word meaning deafness), and Somatosensory Agnosia (including Microsomatagnosia, Macrosomatagnosia, tactile agnosias and astereoagnosia), and constructional dyspraxia.
There is also Korsakoff's syndrome (Memory loss caused by alcoholism) and Post-traumatic stress disorder (spontaneous, vivid retrieval of unwanted traumatic memories), selective memory loss from head trauma, Accelerated Forgetting (excessively rapid decay of memories that appear to have been acquired successfully), and various types of false memory syndromes. There is the very common AAMI (age-associated memory impairment). Certain forms of Confusional States (e.g. those arising from Iatrogenic toxicity from some sedatives) will present acute memory disorders. There is also hyperthymesic syndrome, although there is dispute as to whether this qualifies as a disorder. There is also seizure-induced memory loss, which can erase access, temporarily or permanently, to declarative memory. There is also memory distrust syndrome, sometimes considered a type of delusional disorder.
There is a spectrum of Vascular dementia, which includes (1) mild vascular cognitive impairment, (2) multi-infarct dementia (MID), (3) vascular dementia due to a strategic single infarct, (4) vascular dementia due to lacunar lesions, (5) vascular dementia due to hemorrhagic lesions, (6) Binswanger disease (subcortical leukoencephalopathy), (7) subcortical vascular dementia, and (8) mixed dementia (combination of AD and vascular dementia).
Neurological disorders covers forms of cognitive impairment aside from the above. Anxiety disorders include specific phobia, generalized anxiety disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, Obsessive-Compulsive Disorder, Post-traumatic stress disorder.
Mood disorders include Clinical depression (or Major depression), and in milder form, depression can be diagnosed as dysthymia. Bipolar disorder involves abnormally "high" or pressured mood states, known as mania or hypomania, alternating with normal or depressed mood.
The principle forms are Schizophrenia (including Paraphrenias and paranoias), and Schizoaffective disorder, with schizotypy as a less severe form. These disorders arise when patterns of belief, language use and perception have become disordered.
There are an assortment of delusional disorders. These are generally classified into six types: Erotomanic Type (erotomania); Grandiose Type; Jealous Type; Persecutory Type; Somatic Type (e.g. delusional parasitosis) and Mixed Type (delusions with characteristics of more than one of the above types but with no one theme predominating).
There are an assortment of different personality disorders which arise when a person’s cognition, motivation, and behavior becomes abnormally rigid maladaptive or distorted. These include paranoid personality disorder, schizoid personality disorder, antisocial personality disorder, Borderline personality disorder, Histrionic personality disorder, Narcissistic personality disorder, avoidant personality disorder, obsessive-compulsive personality disorder and others.
Related to these are behavioral disorders, such as the eating disorders which include Anorexia nervosa, Bulimia nervosa, Exercise Bulimia or Binge eating disorder. Urge disorders include kleptomania and Pyromania.
There are also identity disorders, such as Dissociative identity disorder and the somatoform disorders, including Somatization disorder. There are also disorders of the perception of the body, including Body dysmorphic disorder and neurasthenia.
It covers social cognitive disorders and development disorders including autism, Social Learning Disability, Asperger’s Syndrome, Rett syndrome, childhood disintegrative disorder and pervasive developmental disorders (PDD). It includes assorted Hypochondriasis, and Expressive Language Disorder. Other behavioral disorders include Reactive attachment disorder; Separation Anxiety Disorder; Oppositional Defiant Disorder; and Attention Deficit Hyperactivity Disorder.
It covers Delirium, a disturbance of consciousness, which includes a clouded sensorium (lack of clear awareness of surroundings), problems with attention and memory, incoherent speech, inability to think clearly, and perceptual disturbances (usually, auditory or visual hallucinations). Often included under delirium are the Delusional disorders. These can be of quite varied type: Jealous type (including Othello syndrome), Grandiose type, Erotomanic type (including Clerambault syndrome), Persecutory type, and the Somatic type. Included also are Delusional misidentification syndromes (including Capgras syndrome, syndrome of subjective doubles, Fregoli syndrome, and the syndrome of intermetamorphosis), as well as Cotard syndrome.
Somewhat related is Todd's syndrome (Alice in Wonderland syndrome) which affects perception by causing micropsia, macropsia, or other types of size distortion. There may also be marked distortions in the perception of the flow of time, in hearing and in touch.
It includes an assortment of sensory integration disorders (such as Irlen syndrome), including both hyposensitivities and hypersensitivities, Central Auditory Processing Disorder and gravitational insecurity.
It includes a wide array of special syndromes such as Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Clérambault's syndrome, Kandinsky-Clérambault syndrome, Postconcussional disorder, and Body dysmorphic disorder, and many more.
There are a wide assortment of Demyelinating Diseases, in two broad categories. Primary demyelination is a loss of myelin sheaths with relative preservation of the demyelinated axons, arising either from damage to the oligodendroglia from a direct attack on the myelin itself. Secondary demyelination, occurs following axonal degeneration. For example, Leukodystrophies are diseases of the white matter resulting from an error in the myelin metabolism, giving impaired myelin formation. Each involves the deficiency of a different enzyme. Examples include Krabbe's disease, Adrenoleukodystrophy (which exists in 4 forms), adrenomyeloneuropathy, Alexander Disease, Canavan Disease, Metachromatic Leukodystrophy (which exists in three forms), Pelizaeus-Merzbacher Disease, Refsum Disease, and Zellweger Syndrome. Other examples include Multiple Sclerosis (MS), progressive multifocal leukoencephalopathy, and Acute Disseminated Encephalomyelitis. Some are inherited diseases, such as peroneal muscular atrophy, hypertrophic polyneuropathy and Refsum's diseases.
The extremely diverse range of sleep disorders covers Dyssomnias, Parasomnias, Medical/Psychiatric Sleep Disorders and others. First there are the Intrinsic Sleep Disorders, including Psychophysiological Insomnia, Sleep State Misperception, Idiopathic Insomnia, Narcolepsy, Recurrent Hypersomnia, Idiopathic Hypersomnia, Posttraumatic Hypersomnia, Obstructive Sleep Apnea Syndrome, Central Sleep Apnea Syndrome, Central Alveolar Hypoventilation Syndrome, Periodic Limb Movement Disorder, Restless Legs Syndrome, and Intrinsic Sleep Disorder NOS. Second there are the Extrinsic Sleep Disorders, including Inadequate Sleep Hygiene, Environmental Sleep Disorder, Altitude Insomnia, Adjustment Sleep Disorder, Insufficient Sleep Syndrome, Limit-Setting Sleep Disorder, Sleep-Onset Association Disorder, Food Allergy Insomnia, Nocturnal Eating (Drinking) Syndrome, Hypnotic-Dependent Sleep Disorder, Stimulant-Dependent Sleep Disorder, Alcohol-Dependent Sleep Disorder, Toxin-Induced Sleep Disorder, and Extrinsic Sleep Disorder NOS. Third, there are Circadian Rhythm Sleep Disorders, including Time Zone Change (Jet Lag) Syndrome, Shift Work Sleep Disorder, Irregular Sleep-Wake Pattern, Delayed Sleep Phase Syndrome, Advanced Sleep Phase Syndrome, Non-24-Hour Sleep-Wake Disorder, and Circadian Rhythm Sleep Disorder NOS. Fourth, there are Arousal Disorders, including Confusional Arousals, Sleepwalking, and Sleep Terrors. Fifth, there are Sleep-Wake Transition Disorders, including Rhythmic Movement Disorder, Sleep Starts, Sleep Talking, and Nocturnal Leg Cramps. Sixth, there are Parasomnias Usually Associated with REM Sleep, including, Nightmares, Sleep Paralysis, Impaired Sleep-Related Penile Erections, Sleep-Related Painful Erections, REM Sleep Related Sinus Arrest, and REM Sleep Behavior Disorder. Seventh, there are Other Parasomnias, including Sleep Bruxism, Sleep Enuresis, Sleep-Related Abnormal Swallowing Syndrome, Nocturnal Paroxysmal Dystonia, Sudden Unexplained Nocturnal Death Syndrome, Primary Snoring, Infant Sleep Apnea, Congenital Central Hypoventilation Syndrome, Sudden Infant Death Syndrome, Benign Neonatal Sleep Myoclonus, and Other Parasomnia NOS. Eighth, there are Sleep Disorders Associated with Mental Disorders, including Psychoses, Mood Disorders, Anxiety Disorders, Panic Disorder and Alcoholism. Ninth, there are Sleep Disorders Associated with Neurological Disorders, including, Cerebral Degenerative Disorders, Dementia, Parkinsonism, Fatal Familial Insomnia, Sleep-Related Epilepsy, Electrical Status Epilepticus of Sleep, and Sleep-Related Headaches. Tenth, there are Sleep Disorders Associated with Other Medical Disorders, including, Sleeping Sickness, Nocturnal Cardiac Ischemia, Chronic Obstructive Pulmonary Disease, Sleep-Related Asthma, Sleep-Related Gastroesophageal Reflux, Peptic Ulcer Disease and Fibrositis Syndrome. In addition, there are an assortment of poorly defined disorders and syndromes, including Short Sleeper, Long Sleeper, Subwakefulness Syndrome, Fragmentary Myoclonus, Sleep Hyperhidrosis, Menstrual-Associated Sleep Disorder, Pregnancy-Associated Sleep Disorder, Terrifying Hypnagogic Hallucinations, Sleep-Related Neurogenic Tachypnea, Sleep-Related Laryngospasm, and Sleep Choking Syndrome.
Central nervous system cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation. These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma, and pleomorphic xanthoastrocytoma. GBM exists in two forms, primary and secondary, which have very different clinical histories and different genetics, but GBM is considered to be one clinical entity. Second, there are the oligodendroglial tumors (oligodendrogliomas): low grade oligodendroglioma and anaplastic oligodendroglioma. Third, there is oligoastrocytomas (“mixed glioma”), a type of tumor with both astrocytoma & oligodendroglioma features. The fourth type is the ependymomas, which are intracranial gliomas, including papillary ependymoma, myxopapillary ependymoma, tanycytic ependymoma, anaplastic ependymoma and subependymal giant-cell astrocytomas. A fifth type is the gangliogliomas (glioneuronal tumors or glioneurocytic tumors), which have both glial and neuronal components, and are extremely varied, based in part on what types of glial and what types of neuronal components are present. These include Papillary Glioneuronal Tumor (PGNT), a range of supratentorial gangliogliomas, assorted intramedullary spinal cord gangliogliomas, pineal ganglioglioma, hypothalamic ganglioglioma, cerebellar ganglioglioma, ganglioglioma of the right optic tract, rosetted glioneuronal tumor (“glioneurocytic tumor with neuropil rosettes”), composite pleomorphic xanthoastrocytoma (PXA)-ganglioglioma, desmoplastic ganglioglioma (both infantile (DIG) and non- infantile), angioganglioglioma, and others. There are also some glial tumors which do not comfortably fit into these five categories, notably astroblastoma, gliomatosis cerebri, and chordoid glioma, which is found solely in the hypothalamus and anterior third ventricle. Other neuroepithelial tumors include astrocytic tumors (e.g. astrocytomas) oligodendroglial tumors, ependymal cell tumors (e.g. myxopapillary ependymoma), mixed gliomas (e.g. mixed oligoastrocytoma and ependymo-astrocytomas) tumors of the choroid plexus(choroid plexus papilloma, choroid plexus carcinoma), assorted neuronal and neuroblastic tumors (e.g. gangliocytoma, central neurocytoma, dysembryoplastic neuroepithelial tumor, esthesioneuroblastoma, olfactory neuroblastoma, olfactory neuroepithelioma, and neuroblastomas of the adrenal gland), pineal parenchyma tumors (e.g. pineocytoma, pineoblastoma, and pineal parenchymal tumor of intermediate differentiation), embryonal tumors (e.g. medulloepithelioma, neuroblastoma, ependymoblastoma, atypical teratoid/rhabdoid tumor, desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma) and others such as polar spongioblastoma and gliomatosis cerebri. A second Division is tumors of the meninges. this includes tumors of the meningothelial cells, including meningiomas (meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, metaplastic, clear cell, chordoid, atypical, papillary, rhabdoid, anaplastic meningioma) and the non- meningioma tumors of the meningothelial cells (malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid haemangioendothelioma, haemangiopericytoma, angiosarcoma, kaposi sarcoma). There are also mesenchymal, non-meningothelial tumors (liposarcoma, (intracranial) solitary fibrous tumor, and fibrosarcoma) as well as primary melanocytic lesions (diffuse melanocytosis, melanocytoma, malignant melanoma, and meningeal melanomatosis). A third division are the tumors of cranial and spinal nerves. This includes cellular schwannomas, plexiform schwannomas and the melanotic schwannomas (e.g. psammomatous melanotic schwannoma, neuro-axial melanotic schwannoma, dorsal dumb-bell melanotic schwannoma). There is also Perineurioma (Intraneural and Soft tissue) and malignant peripheral nerve sheath tumor (MPNST), including Epithelioid, MPNST with divergent mesenchymal differentiation, and MPNST with epithelial differentiation. A fourth division are germ cell tumors, including germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma (mature teratoma, immature teratoma, and teratoma with malignant transformation). A fifth division are the tumors of the sellar Region, viz. pituitary adenoma, pituitary carcinoma, granular cell myoblastoma and craniopharyngiomas (adamantinomatous and papillary). Yet another division are local extensions from regional tumors, including paraganglioma, chodroma, chordoma, and chondrosarcoma. There are also Primitive Neuroectodermal Tumors (PNETs) including medulloblastomas, medulloepitheliomas, ependymoblastomas and polar spongioblastomas. There are Vascular brain Tumors e.g. the hemangioblastomas, there is CNS Lymphoma (which can be primary or secondary) and Meningeal Carcinomatosis. There are lymphoma and haemopoietic neoplasms including malignant lymphomas (which can be primary or secondary), plasmacytoma, and granulocytic sarcoma. And there are many, many others.
There is a family of the Polymicrogyrias, a malformation of cortical development characterized by excessive cortical folding and by shallow sulci. Children with polymicrogyria commonly have some degree of global developmental disabilities or delays, seizures, feeding difficulties, respiratory problems, motor dysfunction and mental retardation, often severe. This includes Bilateral Perisylvian polymicrogyria (also known as Congenital Bilateral Perisylvian Syndrome (CBPS) and Worster-Drought Syndrome) which often causes problems using the muscles of the face, throat, jaws and tongue (leading to severe dysarthria or even anarthria; Bilateral Frontoparietal polymicrogyria which can cause dysconjugate gaze, and bilateral pyramidal and cerebellar signs; Bilateral Posterior Parietal polymicrogyria; Bilateral mesial occipital polymicrogyria; Bilateral diffuse polymicrogyria; Bilateral parieto-occipital polymicrogyria; Bilateral parasagittal parietooccipital polymicrogyria; Bilateral frontal polymicrogyria; and Unilateral perisylvian polymicrogyria (also known as multilobar polymicrogyria). Causes include a genetic disorder, viral (CMV) infections of the baby during the 2nd trimester; insufficient blood supply to the baby's brain during the 2nd trimester.
Lyme disease (Lyme borreliosis), which is caused by spirochetal bacteria from the genus Borrelia, triggers neurological disorders, called neuroborreliosis, including neuropsychiatric problems and cognitive impairment. It is believed that the Borrelia burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction. The spirochetes may also induce host cells to secrete products toxic to nerve cells, including quinolinic acid and the cytokines IL-6 and TNF-alpha, and this cytokine response may contribute to cognitive impairment. There is also the distinct possibility that the chronic secretion of stress hormones as a result of Borrelia infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated proinflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically glucocorticoids and catecholamines. It also can cause cerebral arteritis.
These are just some the diseases and disorders embraced by psychiatric disorder. Moreover, as noted above, prevention is also embraced.
Diabetes mellitus is a disease in which the body does not produce or properly use insulin. Insulin is a hormone that is needed to convert sugar, starches and other food into energy needed for daily life. The cause of diabetes continues to be a mystery, although both genetics and environmental factors such as obesity and lack of exercise appear to play roles.
There are many types of diabetes. For example:
Type 1 diabetes: An autoimmune disorder, which results from the body's failure to produce insulin.
Type 2 diabetes: A metabolic disorder, which results from insulin resistance (a condition in which the body fails to properly use insulin), combined with relative insulin deficiency.
Gestational diabetes: Results from being pregnant. There is no known specific cause but it is believed the hormones of pregnancy reduce a woman's receptivity to insulin resulting in high blood sugar.
Diabetes insipidus: Results from increased urine production caused by inadequate secretion of vasopressin by the pituitary gland.
Also, autoimmune diabetes, insulinopathies, idiopathic type I diabetes (Type Ib), latent autoimmumne diabetes in adults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), type A insulin resistance syndrome, type B insulin resistance syndrome, tipaU'ophic diabetes, diabetes induced by beta-cell toxins, diabetes induced by drug therapy (such as diabetes induced by antipsychotic agents).
This list is not exhaustive.
(B) The nature of the invention and predictability in the art: The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
(C) Direction or Guidance: That provided is very limited. The dosage range information is found on page 24, about 0.05 to about 10 mg/kg body weight per day. Moreover, this is generic, the same for the many disorders covered by the specification. Thus, there is no specific direction or guidance regarding a regimen or dosage effective specifically for the treatment and prevention of pyschiatric disorders generally.
(D) State of the Prior Art: These compounds are substituted spiro-2-oxo-2,3-dihydro-1 H-benzo[d]imidazole compounds. So far as the examiner is aware, no substituted spiro-2-oxo-2,3-dihydro-1 H-benzo[d]imidazole compounds of any kind have been used for the treatment of pyschiatric disorders generally.
(E) Working Examples: There is a pharmacological assays disclosed on pages 108-124 of the specification, drawn to the inhibition of IP6K.
(F) Skill of those in the art: The skill level is quite low in the art of psychiatric disorders. There are huge differences in origins of these disorders, even with what little is known. Chronic wasting disease (CWD), Creutzfeldt-Jakob Disease (CJD), Bovine spongiform encephalopathy (BSE) and other transmissible spongiform encephalopathies are caused by an infectious agent (a prion, a type of misfolded protein). Some other disorders arises from viruses, known and unknown. So far as can be determined, this is not so for Huntington's disease. Even among the hereditary disorders, the origins are clearly different, since different genes are involved. For example, in Batten’s disease, a genetic loss of CLN3P enzymatic activity leads to intracellular proteolipid accumulation and thence to neuronal loss. Many, e.g. neurosarcoidosis, are of unknown origin.
The majority of these have no treatment at all, and of those that do, none or virtually none have been treated with agents such as are disclosed in this application. As an important example, ALS is a virtually untreatable disease. Riluzole, approved in 1996, is as of 2008 the sole FDA approved drug for the disease. Even as of 2007, the toxin that kills motor neurons --- assuming that this is what is occurring --- has not even been identified. Spinal Muscular Atrophy (SMA), which apparently kills more infants than any other genetic disease, arises when the SMN gene is deleted or mutationally inactivated, is untreatable. CWD and other transmissible spongiform encephalopathies are untreatable. The NCLs are all untreatable. Pretty much none of the leukodystrophies are considered to have a well established pharmaceutical treatment; some are amenable to bone marrow transplantation, gene therapy or hormone replacement. The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are untreatable. Retinitis pigmentosa (RP), the most common hereditary cause of adult blindness, has no form of pharmacological treatment which has been established as effective, although for some people, vitamin A may slightly retard the progression of the disease. The great diversity of diseases falling within the "neurodegenerative disorder" category means that it is contrary to medical understanding that any agent (let alone a genus of so many compounds) could be generally effective against such diseases. The intractability of these disorders is clear evidence that the skill level in this art is low relative to the difficulty of the task. Further, what little success there has been does not point in the direction of the mode of action in this application.
Alzheimer's Disease is an extraordinarily difficult disease to treat, and has been the subject of a vast amount of research, exceeded in recent years only by research into AIDS and cancer. The channel hypothesis of Alzheimer's disease proposes that the beta-amyloid peptides which accumulate in plaques in the brain actually damage and/or kill neurons by forming ion channels. An abnormal phosphorylation of tau proteins is being investigated as one of the important events in the process leading to their aggregation. There appears to be a specific alteration of a p53-mediated intracellular pathway involved in sensing and repairing DNA damage in peripheral cells, and the role of neuronal apoptosis is under investigation. But even as of 2007, there are great unknowns relating to the links between amyloid-ß and tau, to the mechanisms that determine the selective vulnerability of defined neuronal and glial populations, and to the molecular species that cause nerve cell degeneration. Many kinds of therapies have been investigated in the past, including Hydergine-LC (actually approved by the FDA for Alzheimer's Disease, but later determined to make the disease worse), Cu/Zn chelators (or Cu and Zn homeostasis regulators), endothelin B receptor agonists, [Symbol font/0x61]-TNF inhibitors, angiotensin II receptor antagonists, ACE inhibitors, EAA agonists (including partial agoinists), estrogens, metabotropic receptor agonists, muscarinic M2 receptor antagonists, free-radical scavengers, butyrylcholinesterase inhibitors, cholinergic agonists, potassium-channel blockers, P38 kinase inhibitors, sigma-1 Receptor Agonists, 5-HT1A receptor antagonists, [Symbol font/0x61] secretase stimulants, and others. From this immense body of work, only two kinds of drugs ever emerged. Four Acetylcholinesterase inhibitors were found to have some limited value: tacrine (Cognex®, no longer clinically used); donepezil (Aricept®); galantamine (Razadyne®/Reminyl®/Nivalin®) and rivastigmine (Exelon®). In addition, one voltage-dependent NMDA-antagonist, Memantine (Axura®/Akatinol®/Namenda®/Ebixa®) was also found effective. Categories of agents and techniques under investigation as of 2007 include Aß aggregation inhibitors, assorted antioxidants, [Symbol font/0x67]-Secretase modulators, [Symbol font/0x67]-Secretase inhibitors, NGF mimics, PPAR agonists, HMG-CoA reductase inhibitors (statins), Ampakines, Calcium channel blockers, GABA receptor antagonists, Glycogen synthase kinase inhibitors, Intravenous immunoglobulin, Muscarinic receptor agonists, cholinesterase inhibitors, Nicotinic receptor modulators, Passive Aß immunization, Phosphodiesterase inhibitors, Serotonin receptor antagonists, Active Aß immunization, NGF gene therapy, H3-receptor antagonists, NSAIDs (including NO-NSAIDs and COX-2 Inhibitors), and CB1 and CB2 cannabinoid receptor agonists. It is or course entirely possible that one or more of these will eventually be made to work. However, as can be seen by the many, many categories of drugs which never panned out, so simply being the subject of active investigation is no indication that enablement is present at that time. The skill level in this art is so low that only Acetylcholinesterase inhibitors and NMDA-antagonists have been made to work.
POAG is treated with beta-blockers and other IOP lowering drugs. Such drugs are not used for any other form of neurodegenerative disorder.
Parkinson’s Disease is a neurodegenerative disorder which, like most neurodegenerative disorders, has been highly resistant to pharmaceutical treatment. The disease is characterized primarily by the degeneration and death of dopamine-producing cells in the substantia nigra, located in the midbrain, along with the presence of cytoplasmic protein inclusions called Lewy bodies. However, PD is recognized as a very extensive pathology that covers many neurotransmitter systems as well as the autonomic nervous system. Non-dopamine symptoms include bowel and bladder problems, attacks of low blood pressure, falling, “freezing,” sleep disorders, pain, depression, speech difficulties, and dementia. PD is widely considered to be a cluster of related disorders. The majority of cases of PD are deemed sporadic, but there are also familial forms of PD. This death in the substantia nigra is of unknown origin (idiopathic), and cannot itself be stopped. Current drug regimens for Parkinson’s disease are aimed instead at symptomatic relief, primarily through a dopaminergic effect. This includes dopamine replacement therapy (L-dopa), COMT inhibitors (which facilitate the conversion of L-Dopa to dopamine itself), Amantadine (which appears to increase dopamine synthesis in the remaining cells), dopamine agonists (which mimic dopamine) or MAO B inhibitors (e.g. Selegeline which reduces or delays the breakdown of dopamine). These do not actually treat the disease itself, but instead seek to boost the amount of dopamine available by various mechanisms. At the time of filing, and indeed at present, no drug has been scientifically demonstrated to treat the disease itself, rather than provide relief for this or that symptom, such as bradykinesia, tremors, and other motor symptoms, constipation, poor balance, etc.
The skill level for pharmaceutically treating memory impairment in general is very low. The art knows that memory impairment can arise from a huge number of extremely diverse sources. There is a cluster of memory disorders which arise from the subcortical dementias, specifically the dementia associated with Huntington's disease, Parkinson's disease, progressive supranuclear palsy, and Multiple System Atrophy (MSA). Memory impairment arises from other dementias, such as Alzheimer's disease, Lewy body Dementia, multi-infarct dementia (MID), strategic infarct dementia, LID, ThD, and Binswanger's disease, and Pick's Disease. It can arise from many types of brain tumors. A number of mental disorders, including schizophrenia, bipolar disorder and obsessive-compulsive disorder can cause memory impairment. It can arise from Fibromyalgia, Vitamin B1 deficiency, psychological trauma, and complex partial seizures. Any number of syndromes, such as Down’s syndrome, XXX syndrome, Hurler’s syndrome, Kleine-Levin syndrome, Landau-Kleffner syndrome, and Klüver-Bucy Syndrome give rise to memory impairment. Memory impairment can arise from the ingestion of psychotropic drugs, such as alcohol (e.g. alcoholic blackouts), marihuana and glue sniffing. It can arise from toxic neuropathies, radiation injury to the brain, electroshock treatment, metabolic disorders (e.g. Mucopolysaccharidosis I) and from some Demyelinating Diseases (notably Multiple Sclerosis). Other common causes include epilepsy, mental retardation, head injury, Meningitis, and atherosclerosis. Because the formation and retrieval of memories is such a complex process, there cannot be a treatment of it in general because so many entirely different things can go wrong. For example, a method which prevents degeneration of long term memory will have no effect on a e.g. anterograde amnesia, since that is a problem which occurs prior to the production of the long-term memory. Note that categories of memory disorders do not necessarily have related causes. For example, Agnosias can result from strokes, dementia, or other neurological disorders, head trauma, brain infection or genetic defects.
In fact, memory problems are generally approached by treating the underlying cause, in cases where such treatment actually exists. Thus, the memory impairment in Alzheimer's Disease can be treated by treating the Alzheimer's Disease itself. Those arising from schizophrenia, meningitis and atherosclerosis can be approached by medicines for those disorders. Direct therapy for memory deficits associated with epilepsy is rarely attempted. Instead, one tries to suppress the seizures themselves. Of course, there is no one drug that can treat these generally, since these have different modes of action. However, many, many of these disorders have no pharmaceutical treatment. Mental retardation and Down’s syndrome for example are common causes of memory impairment, but there is no treatment for either. Most brain tumors cannot be treated with pharmaceuticals. Many dementias, such as MSA, Binswanger's disease, or Pick's Disease, simply do not respond to drugs. And in many cases, e.g. AAMI the true causes are unknown. As a result, large numbers of memory impairments have no pharmaceutical treatments which are accepted as effective. For example, the aphasias cannot be treated per se. There is no drug for AAMI, one of the most common memory problems, or for Korsakoff's syndrome or multi-infarct dementia. Anterograde amnesia, a devastating condition in which the person can no longer form durable new memories, has no pharmaceutical treatment. Retrograde amnesia likewise has no treatment. So far as the examiner is aware, there is not one of the entire broad array of agnosias, which has a pharmacological treatment.
Delusional disorders sometimes arise from substance abuse, particularly stimulants, antihistamines, sympathomimetics, steroids, dopamine agonists, hallucinogens, and alcohol. These can arise from specific diseases such as or many forms of brain cancers. They can arise from assorted toxic neuropathies, such as from Lead and other heavy metal poisoning. Others arise from metabolic neuropathies, such as the Mitochondrial Encephalomyopathies. Some dementias arise from neurodegenerative disorders, such as Huntington disease, Alzheimer's Disease, and others arise from structural causes, e.g. Chronic communicating hydrocephalus (also called normal pressure hydrocephalus). Still others can arise from infectious agents, e.g. AIDS dementia from the HIV virus. Metabolic, nutritional and endocrine disorders such as Wilson's disease, hepatic cirrhosis, cyanocobalamine (vitamin B12) deficiency, thyroid, parathyroid and adrenal endocrinopathies all have been associated with dementia syndromes. Some cognitive disorders arise from trauma to the brain, such as concussion, electroshock treatment and surgery. Stroke, severe psychological trauma, genetic disorders, and alcoholism, is responsible for many kinds of cognitive impairments. Thus, treatment if it exists at all, tends to go to the underlying disorder. For many of these, however, the original is completely unknown. Mental retardation arises from genetic conditions such as Down syndrome, Klinefelter syndrome, Fragile X syndrome, Neurofibromatosis, Hypothyroidism congenital, Williams syndrome, Phenylketonuria, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, and and phenylketonuria (PKU). Other causes include problems during pregnancy (including fetal alcohol syndrome and rubella), problems at birth (e.g. not getting enough oxygen), diseases like whooping cough, measles, or meningitis, exposure to heavy metals, especially lead or mercury, Iodine deficiency, and malnutrition.
Elsewhere, the skill level varies. Mood disorders for example respond well to pharmaceuticals. However, mental retardation, autism, etc. do not respond at all to pharmaceuticals. A bewildering variety of problems can cause cognitive disorders, such as the somewhat mysterious tuberous sclerosis complex (TSC), which can cause severe mental retardation and autism, and Phelan McDermid Syndrome, a genetic disorder which can cause autistic-like behaviors. It isn’t even clear whether the cognitive problems arising from TSC come from just the tubers themselves, or whether disruptions in the mTOR pathway have a significant or even dominant role. D. Demyelinating Diseases are especially difficult to treat. No pharmaceutical treatment is available to any of the leukodystrophies. Acute Necrotizing Hemorrhagic Leukoencephalitis is believed to be mediated by autoimmune attack on CNS myelin, triggered by a viral infection. It is usually fatal, generally just within days on onset.
In the majority of cases, there are currently no pharmaceutical treatments for peripheral nerve disorders themselves, only supportive treatments directed at the symptoms.
No treatment is available for the Polymicrogyrias; medicines are given only for relief of symptoms, e.g. anti-seizure medicine.
All attempts to find a pharmaceutical to treat chemical addictions generally have thus far failed, and are not expected to succeed because different drugs act at different receptors in the brain, and activate different reward systems.
In summary, vast numbers of CNS disorders have no pharmacological treatment at all, and of those that do, none or virtually none have been treated with such inhibitors as are disclosed here. Some of the most devastating neurological diseases, such as many mental retardation and autism and ALS and dyslexia have no pharmaceutical treatments at all.
(G) The quantity of experimentation needed: Especially in view of points A, D and F, this is expected to be great.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 8, 9, 11-15, 17-24, 26 and 27 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Terao et al. (US 20200377458).
The reference teaches the following species:
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, see the Examples spanning pages 21-28 that teach the hydrolysis of the methyl ester to the carboxylic acids, which are also embraced by the present claims. The references teaches the same methods of treatment, see pages 15-19 (bridged). The method in claim 27 is a property of the compound, and therefore, inherent.
Thus, said claims are anticipated.
Claim(s) 1, 4 and 5 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Aurora Fine Chemicals (Registry number 2180787-78-2, February 27, 2018).
The reference teaches the following species:
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,
see the above STN printout. Thus, said claims are anticipated.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claim(s) 1, 8, 9, 11-15 and 17-27 is/are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Terao et al. (US 20200377458).
The 102 rejection above is incorporated here.
The present application claims a method of treating bipolar disorder.
The reference teaches emotional disorders, see page 16, left hand column, first paragraph.
Bipolar disorder is a mood or emotional disorder.
Thus, it would be obvious to treat bipolar disorder with the compounds in the Tereo reference since said reference teaches the treatment of emotional disorders.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 8, 9, 11-15 and 18-27 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-23 of copending Application No. 18256092. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims in the ‘092 application are a subgenus of the present claimed formula (I), wherein X is C(O)OR5.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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