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 .
Priority
The instant application is a 35 US 371 National Stage filing of international application PCT/CN2023/073216, filed January 19, 2023, which claims priority under 35 USC 119(a)-(d) from Chinese Application CN202210112894.8, filed January 29, 2022.
Information Disclosure Statements
The information disclosure statements (IDS) dated October 14, 2024 and February 2, 2026 were in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS documents were considered and signed copies of the 1449 forms are attached.
Status of Claims
Currently, claims 1-19 are pending and under consideration herein.
Claim Objections
Claim 10 is objected to for containing several typographical errors. Each instance of “P is 0” should be replaced with “p is 0” since no uppercase “P” exists in the claimed formula.
Claim 11 is objected to because each listed compound should be separated by a comma with the word “or” between the last two compounds.
Claims 5-7, 12 and 15-19 are objected to for depending on a rejected base claim but appear allowable if rewritten in independent form.
Claim Rejections – 35 U.S.C. § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 14 is rejected under 35 U.S.C. 112(a), as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Such a utility cannot be deemed enabled.
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:
1) Breadth of claims. The claimed category of “mental disease” and “neurodegenerative disease” is extremely diverse, and fall into an assortment of categories.
The term "mental disease" 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.
The term also includes neurodegeneration which can 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.
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 “brain diseases.” 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” mental disease. 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.
II. 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.
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.
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).
Psychotic disorders arise when patterns of belief, language use and perception have become disordered. The principle forms are Schizophrenia (including Paraphrenias and paranoias), and Schizoaffective disorder, with schizotypy as a less severe form.
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.
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
This list is by no means complete, and there are different ways of ordering the wide variety of seizures. The categories are broad and include different disorders which are sometimes difficult to slot into specific areas, and sometimes very poorly understood.
Brain diseases cover all drug addictions. Drug addiction is not a single disease or cluster of related disorders, but in fact, a collection with relatively little in common. Addiction to barbiturates, alcohol, cocaine, opiates, amphetamines, benzodiazepines, nicotine, etc. all involve different parts of the CNS system; different receptors in the body. For example, cocaine binds at the dopamine reuptake transmitter. Heroin addiction arises from binding at the opiate receptors, cigarette addiction arises from some interaction at the nicotinic acid receptors, many tranquilizers involve the benzodiazepine receptor, alcohol involves yet another system, etc.
2) 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).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
(3) Direction or Guidance: That provided is very limited. Thus, there is no specific direction or guidance regarding a regimen or dosage effective specifically for treating a mental or neurodegenerative disease.
(4) State of the Prior Art: The compound recited in the instant claims is a tricyclic compound. So far as the examiner is aware, no compounds of this type have been used for the treatment of the full scope of mental or neurodegenerative diseases.
(5) Working Examples: Applicant has provided no working examples that correlate to the entire breadth of “mental disease” or “neurodegenerative disease.”
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
(6) Skill of those in the art: The skill level is quite low in the art of brain disease, including neurodegenerative 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 arise 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. 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 "brain disease" category means that it is contrary to medical understanding that any agent 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 agonists), 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.
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 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 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.
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 brain tumors, mental retardation and autism and ALS and dyslexia have no pharmaceutical treatments at all.
(7) The quantity of experimentation needed: Especially in view of points 1, 4 and 6, 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.
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.
It is noted that with respect to the rejection below, for the purposes of determining if a reference is a “printed publication” for the purposes of 102(a)(1), MPEP 2128 states the following:
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Specifically regarding electronic publications, such as online databases, as prior art the following is noted:
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where “prior art disclosures…on an on-line database are considered to be publicly available as of the date the item was publicly posted.” Since the database entries below list the dates that the compounds were entered into the on-line database, the compounds were made publicly available as of those dates in the citation, and the claims are anticipated.
Claim(s) 1-4, 8-9 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the STN Registry database entry for CAS RN 2411784-84-2, which has an entry date of 12 March 2020.
Since the entry date represents the date that the compound entered a publicly available database on STN, this represents the date that the compound was made accessible to the public.
The STN Registry database entry listed above discloses the compound
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which reads on the formula (I) where R1 is methyl; R2 is Cl where p is 1; Y is C; X is NRa where Ra is H; L is –(CRcRd)m- where Rc and Rd are each H and m is 1; M is NH-C(O)- where the NH is attached to Q; Q is phenyl; R3 is Cl where q is 1 and r is 0. Note that the claim is interpreted as including any direction of connectivity for the “M” group, which is supported by the claims and disclosure. For example, dependent claim 2 further limits the scope of claim 1 and specifies the direction of connectivity of the M group – an indication that either direction is encompassed by claim 1. Since the compound disclosed in the prior art has the same structure as the instantly claimed compound, each and every required element of the claim is taught and the claim is anticipated. With respect to the instantly claimed pharmaceutical composition, it is noted that the prior art discloses molar solubility data which describes the anticipatory compound in unbuffered water, which is a pharmaceutically acceptable carrier. Accordingly, the claims are anticipated.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699
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