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 .
Notice of Priority
This applications claims priority for U.S. Provisional Application 63/300,715 filed 19 January 2022.
DETAILED ACTION
Information Disclosure Statement
No Information Disclosure Statement (IDS) has filed, and therefore has not been considered by the Examiner.
Claim Status
Claim(s) 1-6, 8, 10-13, 18, and 20-28 are examined on the merits herein.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 8, 10-13, 18, and 20-27 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for certain species such as those listed in Table 4 [Specification; pgs. 2693-308], is not considered enabled for the other compound species encompassed by formula (I). 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 standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (16936) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below:
Nature of the Invention and Breadh of the claims: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claims are drawn to compounds of formula (I) shown below, all of which are claimed to be useful in the method of a neurological and/or psychiatric disorder in a mammal.
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The formula contains R groups which include heteroaryl, heterocyclyl, alkyl, aryl or carbocycle. In addition these variables include substituted and unsubstituted functional groups where in the claims does not define what and where the substitutions are in the recited groups.
As such the compounds of the claim encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the millions given the number of possible rings, ring systems and substitutions covered by the claims' scope along with varying choices for remaining variables.
As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation”. Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 19693), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry our the invention commensurate with the scope of his claims". Amgen, In.c, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 19693). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to compounds of formula (I), which are alleged by the Specification to act as positive allosteric modulators (i.e. potentiators) of the muscarinic acetylcholine receptor M4 (mAChR M4) [Specification; pg. 7; [0016]]. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
Just taking into example the heterocyclic substitutions of the variables in the compounds, although the field of synthetic heterocyclic chemistry has several named reactions applicable to C, H, O, N, X, and S functional groups. Further, the term heterocyclyl in the instant application can encompass mono or fused systems with 3-8 ring members and one or more N, O, or S heteroatoms which may be substitutes. Lack of definition of the substituents in the claim indicates that this substituent can be any group of any size. This definition as such includes a wide range of complex heterocycles which are difficult to synthesize.
However the state of the art of formula (I) as instantly claimed with several substituted or unsubstituted moieties is very poor.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan' s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound's ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound' s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
The invention is pharmaceutical in nature as it involves allosteric activation of the mAChR M4. The skilled artisan would view that the synthesis of all possible variations of the compounds of formula (I) would require much experimentation. The level of predictability in the synthetic chemistry art is low given that a change of substituent, reagent, catalyst in a reaction can lead to very different reaction products and/or different regioselectivity of the reaction. This being the case, one of ordinary skill in the art would not have reasonable assurance that each possible compound claimed in the instant application would be feasible to make and use. 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 unpredictable. The pharmaceutical art is unpredictable and target compounds need to be individually assessed for viability.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification [Table 4] discloses 623 structurally related compound species encompassed by formula (I) all of which have the following substituents in common.
R1 = hydrogen;
R3 = hydrogen;
R4 = hydrogen;
R6 = hydrogen or methyl;
R7 = methyl;
R8 = hydrogen;
Further R1 and R3-8 are claimed to be at least one of hydrogen, halogen, cyano, C1-4 alkyl, C1-4 fluoroalkyl, -OC1-4 alkyl, or -OC1-4 fluoroalkyl [Claim 1]. The application however support to only a limited numbers of such compounds.
Applicants further provide synthetic procedures for roughly 37 compounds [Specification; pgs. 164-288; [0470]-[0508]].
As such it is noted that there is no enablement in the specification wherein the groups for R1 an R3-8 of formula (I) comprises moieties other than, at least, hydrogen or C1-C4 alkyl. Further the substitutions at R2 as claimed can be highly varied and different and the specification does not provide any enablement for that.
Amount of Experimentation Necessary and conclusion: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of formula (I), which are alleged by the Specification to act as allosteric activators of the mAChR M4 for use in methods of treating a neurological and/or psychiatric disorder in a mammal. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of formula (I) with respect to the disclosure since formula (I) encompasses thousands or millions of compound species, whereas the instant Specification discloses only 693 such compound species all of which have a similar core. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of compounds encompassed by formula (I) would exert the alleged activity based on the limited disclosure of 693 compounds. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound' s ability to modulate the activity of a specific receptor or enzyme. Thus, in order to identify usable compounds of formula (I), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 693 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within formula (I) for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays and “hit rates are on the order of one in ten”, It is highly unpredictable whether any compound within the subgenus of compounds of formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of formula (I) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of claimed compounds encompassed by formula (I) are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Claim(s) 28 are also rejected under 35 U.S.C. 112, first paragraph as failing to comply with the scope of enablement requirement for the method of treating a neurological and/or psychiatric disorder in a mammal. The claim 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. In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). These factors include, but are not limited to:
(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.
The breadth of the claims: The nature of the invention is a method for treating a a neurological and/or psychiatric disorder in a mammal, said method comprising administering to the mammal a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. The breadth of the claims is extensive. The term "neurological 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); Friedrich's 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. Some give progressive dementia without other prominent neurological signs, such as Alzheimer's Disease, whereas other dementias do have such signs, such as Diffuse Lewy Body Disease. 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 are abnormalities of posture, movement or speech, such as Striatonigral degeneration, and other are 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.
As can be seen from the above, unlike in some areas of medicine, there is no representative, or “typical” neurological 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 neurological disorder, and indeed the vast majority of neurological disorders involve neither one of those.
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).
The state of the prior art: The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific disease). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic or preventive regimen on its face.
The instant claimed invention is highly unpredictable as discussed below:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. Drugs that are used to treat the central nervous system (CNS) face several hurdles. First of all, the drug needs to be able to reach the site of action. There are several natural barriers to drug penetration into the CNS including physical impediments, such as the blood-brain barrier and blood-cerebral spinal fluid barrier, in addition to the presence of drug specific transporters in the cells comprising these barriers. A drug intended for the CNS must cross the blood-brain barrier either via passive diffusion or receptor-mediated transport. Typically the more lipid-soluble a drug, the easier it is for it to successfully penetrate the physical barriers present in the CNS. However, many drug efflux transporters can effectively prevent the accumulation of the substance within the CNS (Löscher and Potschka, Drug Resistance in Brain Diseases and the Role of Drug Efflux Transporters, Nature Reviews. Neuroscience, vol. 6, Aug. 2005, 591-602, see specifically the section on Drug efflux transporters in the brain on pages 592 and 593). Nature has put in place a formidable set of barriers to prevent drug penetration into the CNS. Agents targeting NDDs must overcome them in order to be effective. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to therapeutic and preventive effects of the above listed diseases, whether or not the disease is effected by obovatol and more importantly, if obovatol can even penetrate the blood-brain barrier, would make a difference.
There is no common mechanism by which all, or even most, NDDs arise. Accordingly, treatments for NDDs are normally tailored to the particular type of NDD, as there is no, and there can be no “magic bullet” against NDDs in general. The pathogenesis of all NDDs is complex. The varied anatomic specificities of each of the NDDs need to be considered.
Take for instance the NDD Alzheimer' s disease which is associated with aging, as just one example. It is the state of the art that there is no known cure or prevention for Alzheimer' s disease. In fact, the cause of the disease is still not clear. It is well known that the major pathological observations in Alzheimer' s disease are b-amyloid deposits and neurofibrillary tangles in the patient' s brain. However, it has not been well established what the molecular mechanisms of the etiology of Alzheimer's disease. Since the prior art has not well deciphered the cause of Alzheimer's disease, it is very difficult to treat the disease without knowing its full scope of etiology and molecular mechanisms.
The amount of direction or guidance present and the presence or absence of working examples: Applicants have demonstrated only in vitro binding of several exemplary compounds to the mAChR M4 receptor [Specification; Table 4]. However there are no examples or guidance present in the disclosure with regards to the use of this specific agent in the treatment of neurological/psychiatric conditions or disorders. The dosage range information is not provided and thus, there is no specific direction or guidance regarding a regimen or dosage effective specifically for the diseases encompassed by the broad term neurological disorders.
Skill of those in the art: The skill level is quite low in this art. 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). Others 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 an untreatable 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. Thus, what very few treatments that the massive research effort on Alzheimer's Disease has produced are means of providing Acetylcholinesterase inhibition, (Aricept®, Cognex®, Exelon®, and Reminyl®), or voltage-dependent NMDA-antagonists (Memantine), properties that the claimed compounds are not disclosed to have. POAG is treated with beta-blockers and other IOP lowering drugs. Such drugs are not used for any other form of neurodegenerative disorder.
The quantity of experimentation needed: The quantity of experimentation needed is undue especially in view of the unpredictability, breadth covered by the terms and the skill of those in the art. It is exceedingly difficult to treat the disease without knowing its full scope of etiology and molecular mechanisms, which indicates that undue experiments are required.
Thus, factors such as “sufficient working examples”, breadth of the claims, “the level of skill in the art”, and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instant claimed methods. In view of the breadth of the claims, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compound, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate with the scope of the claims.
Genetech Inc. V. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompasses in the instant claims, with no assurance of success. Thus, rejection of Claim 28 under 35 U.S.C. §112, first paragraph, is deemed proper.
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.
Therefore, Claim(s) 1-6, 8, 10-13, 18, and 20-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Conclusion
No claims are allowed in this action.
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/STANLEY BRAM/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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