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.
Election/Restrictions
Applicant's election without traverse of the following species:
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in the reply filed on June 16, 2026 is acknowledged. Applicant indicated claims 1-13 read on said species.
Based on the search, the species election is withdrawn.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The rejection of claims 10-11 under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131,149 USPQ 475 (D.D.C. 1966). Said claims are non-statutory “use” claims.
The MPEP section 2173.05(q) states “It is appropriate to reject a claim that recites a use but fails to recite steps under 35 U.S.C. 101 and 35 U.S.C. 112(b) if the facts support both rejections.”
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 and 11 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.
Specifically, since the claimed invention is not supported by either an asserted utility or a well-established utility for the reasons set forth above, one skilled in the art clearly would not know how to use the claimed invention.
Claims 10-11 provide a use of the compound or salt thereof of claim 1, but, since the claims do not set forth any steps involved in the methods/processes, it is unclear what methods/processes applicants are intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
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 12 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. Said claim is drawn to a compound and therefore, the intended use does not further limit the claim. 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.
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 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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.
Moreover, the claims embrace prevention by stating “preventing” and the phrase “limiting development,” see page 18, which states “in a subject at risk of developing” a disease.
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: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) 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 scope of the compounds embraces millions of compounds of formula (I), with ten variables.
(b) Scope of the diseases covered. The scope is drawn to a method of treatment or prevention of a neuromuscular disease, generally.
A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junction, or skeletal muscle, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and weakness. Issues with sensation can also occur.
Those affecting the muscle include Muscular dystrophies, such as Dystrophinopathies (e.g. Duchenne muscular dystrophy, Becker muscular dystrophy and DMD-associated dilated cardiomyopathy); and Limb girdle muscular dystrophies (e.g. LGMD D1 DNAJB6-related, LGMD D2 TNP03-related, LGMD D3 HNRNPDL-related, LGMD D4 calpain3-related, LGMD D5 collagen 6-related, LGMD R1 calpain3-related (Calpainopathy), LGMD R2 dysferlin-related, LGMD R3 α-sarcoglycan-related, LGMD R4 β-sarcoglycan-related, LGMD R5 γ-sarcoglycan-related, LGMD R6 δ-sarcoglycan-related, LGMD R7 telethonin-related, LGMD R8 TRIM 32-related, LGMD R9 FKRP-related, LGMD R10 titin-related, LGMD R11 POMT1-related, LGMD R12 anoctamin5-related, LGMD R13 Fukutin-related, LGMD R14 POMT2-related, LGMD R15 POMGnT1-related, LGMD R16 α-dystroglycan-related, LGMD R17 plectin-related, LGMD R18 TRAPPC11-related, LGMD R19 GMPPB-related, LGMD R20 ISPD-related, LGMD R21 POGLUT1-related, LGMD R22 collagen 6-related, LGMD R23 laminin α2-related, and LGMD R24 POMGNT2-related), and Congenital muscular dystrophies (e.g. LAMA2-related (merosin deficient) congenital muscular dystrophy (Emery–Dreifuss muscular dystrophy), Collagen VI-related muscular dystrophy (Bethlem myopathy, Ullrich congenital muscular dystrophy), α-Dystroglycanopathies (Walker–Warburg syndrome, muscle-eye-brain disease) and Laminopathies), Distal muscular dystrophy).
Distal muscular dystrophy, also called distal myopathy, is essentially any muscle disease that preferentially affects the hands and/or feet, a much less common pattern than proximal muscle weakness. Examples include Late adult-onset type 1, Late adult-onset type 2a, Late adult-onset type 2b, Early adult-onset type 1, Early adult-onset type 2, and Early adult-onset type 3.
Myofibrillar myopathies are diseases that cause similar findings of affected muscle when viewed under a microscope and include Desminopathy, Myotilinopathy, Zaspopathy, Filaminopathy and Bag3opathy.
Other muscular dystrophies include Myotonic dystrophy, Facioscapulohumeral muscular dystrophy, Emery–Dreifuss muscular dystrophy (EDMD) and Congenital myopathies (e.g. Nemaline myopathy, Central core myopathy, Centronuclear myopathy, Congenital fiber type disproportion, Multi/minicore myopathy and Cylindrical spirals myopathy).
Mutations causing defects in metabolism can cause muscle damage due to inadequate energy for muscles or accumulation of waste products. Mitochondrial myopathies are diseases caused by mutations related to mitochondria, and thus are generally inherited from the mother with variable expressivity due to heteroplasmy, which include Kearns–Sayre syndrome, Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Myoclonic epilepsy with ragged red fibers (MERRF), Cytochrome c oxidase (COX) deficiency, Mitochondrial complex I deficiency, Mitochondrial complex II deficiency, Mitochondrial complex III deficiency (cytochrome b deficiency) and mtDNA deletion.
Glycogen storage diseases (GSD) are a group of diseases caused by mutations related to glycogen metabolism and include GSD type II (Pompe disease), GSD type V (McArdle disease), GSD type VII (Tarui disease), GSD type XI (Lactate dehydrogenase deficiency), GSD type X (Phosphoglycerate mutase deficiency) and Phosphoglycerate kinase deficiency.
Fat oxidation defect disorders are Carnitine palmitoyltransferase I deficiency, Carnitine palmitoyltransferase II deficiency, Medium-chain acyl-coenzyme A dehydrogenase deficiency, Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and Very long-chain acyl-coenzyme A dehydrogenase deficiency.
Other metabolic myopathies include Myoadenylate deaminase (MADA) deficiency, Inflammatory myopathies, Inclusion body myositis, Dermatomyositi, Polymyositis and Statin-associated autoimmune myopathy.
Other diseases of muscle include Rippling muscle disease and Drug-induced myopathy.
Those diseases or disorders affecting the nerve include Troyer syndrome, Cramp fasciculation syndrome, Hereditary spastic paraplegia, Spinocerebellar ataxia, and Spinal and bulbar muscular atrophy.
A neuronopathy affects the cell body of a nerve cell in the peripheral nervous system and include Amyotrophic lateral sclerosis, Spinal muscular atrophy, Spinal muscular atrophy with respiratory distress type 1, Atypical motor neuron diseases and Dorsal root ganglion disorders.
A neuropathy condition that affects the peripheral nerves include Guillain–Barré syndrome, Charcot–Marie–Tooth disease and Chemotherapy-induced peripheral neuropathy.
There are many other neuropathies which have not been included.
Conditions affecting neuromuscular junction include Myasthenia gravis, Congenital myasthenic syndrome, Lambert–Eaton myasthenic syndrome and Isaac's syndrome.
Other conditions include multiple sclerosis and Stiff-person syndrome.
This list is by no means complete. The categories are broad and include different disorders which are sometimes difficult to slot into specific areas, and sometimes very poorly understood.
(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 33, about 0.1 to about 10 mg/kg body weight. 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 plethora of the diseases or disorders embraced by the scope.
(D) State of the Prior Art: So far as the examiner is aware, no compounds similar to compounds of formula (I) have been used for the treatment or prevention of embraced by the scope.
(E) Working Examples: There is an in vivo assay drawn to the suppression of grip strength in a myasthenia gravis mice model, see pages 30-32 and the drawings for results. The drawings show results for compounds 2, 18 and 19 at various concentrations but is less than the normal control. The specification states a suppression action on decrease in grip strength by administration of the test compound indicates that the test compound has a therapeutic effect. However, the bar chart on the y-axis does not show a suppression action on decrease in grip strength, which would be an increase in grip strength.
(F) Skill of those in the art: The skill level is quite low in the art of neuromuscular 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 with very few drugs approved by the FDA for the 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. The great diversity of diseases falling within the "neuromuscular degenerative 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.
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.
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.
Treatment of the toxic neuropathies begins with removal of the toxin, but whether the damage which has already occurred can be ameliorated depends greatly on the circumstances, and in some cases, very little can be offered.
The metabolic neuropathies so commonly arise from genetic disorders which cannot be reversed, although in some cases, partial relief of symptoms is available.
In the majority of cases, there are currently no pharmaceutical treatments for peripheral nerve disorders themselves, only supportive treatments directed at the symptoms.
In summary, vast numbers of neuromuscular 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. Moreover, there is nothing in the art that supports the present mode of action as a treatment for neuromuscular disease generally. Some of the most devastating neurological diseases, such as ALS 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.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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