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 .
Claim Rejections - 35 USC § 112
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.
Claims 1-15 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for some disease states of GLP1 associated diseases, does not reasonably provide enablement for the method for treating any and all GLP-1 associated disease, disorder, or condition. Enablement can be acknowledged
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. Thus being an appetite suppressant, GLP1 signaling also helps to lose body weight, especially if in combination with metformin.” [ see below, Paternoster page 6 column 2].The specification is also not enabling for making solvates of the pictured compounds/active ingredient in the method claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the relevant factual considerations.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art.
All of the factors have been considered with regard to the claims, with the most relevant factors discussed below:
Solvates:
The specification does not reasonably provide enablement for making hydrates (solvates) of the claimed compounds. The specification does not enable any person skilled in the art of synthetic organic chemistry to make the invention commensurate in scope with these claims. The factors to be considered in making an enablement rejection have been summarized above. In the present case the important factors leading to a conclusion of undue experimentation are the absence of any working example of a formed hydrate, the lack of predictability in the art, and the broad scope of the claims. There is no working example of any solvate or hydrate formed. None of the compounds made (based on data provided) form hydrates. These cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 "The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However ... there is no evidence that such compounds exist.., the examples of the '881 patent do not produce the postulated compounds.., there is ... no evidence that such compounds even exist." The same circumstance appears to be true here. There is no evidence that hydrates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that hydrates can be made, or limit the claims accordingly. g) The state of the art is that is not predictable whether hydrates will form or what their composition will be. In the language of the physical chemist, a hydrate of organic molecule is an interstitial solid solution. This phrase is defined in the second paragraph on page 358 of West (West, Solid State Chemistry and Its Applications, john Wiley & Sons, 1984). The solvent molecule is a species introduced into the crystal and no part of the organic host molecule is left out or replaced. Note in this case solvent is water (H2O). In the first paragraph on page 365, West (Solid-State Chemistry) says, "it is not usually possible to predict whether solid solutions will form, or if they do form what is their compositional extent".. Excipients can interact with the active pharmaceutical ingredient, and thus have an influence on its stability. The picture becomes even more complex when the hydrate can exist as two or more different polymorphic forms. Therefore, the predictable formation and use of hydrates of the claimed compounds finds no support in the specification.
Thus, in the absence of experimentation one cannot predict if a particular solvent will hydrate any particular crystal. One cannot predict the stoichiometry of the formed hydrate, i.e. if one, two, or a half a molecule of solvent added per molecule of host. In the same paragraph on page 365 West (Solid State Chemistry) explains that it impossible to make meta-stable non-equilibrium hydrates, further clouding what Applicants mean by the word hydrate. Compared with polymorphs, there is an additional degree of freedom to hydrates, which means a different solvent or even the moisture of the air that might change the stabile region of the hydrate. h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula (I) as well as the presently unknown list of solvents embraced by the term "hydrate". Thus, the scope is broad. In addition,
The pictured compounds do contain different cyclic groups joined together corresponding to different Markush structures. Biological properties are unpredictable and are ultimately tide to the chemical structure. See “Role of the Development Scientist in Compound Lead Selection and Optimization” by Venkatesh, J. Pharm. Sci. 89, 145-154 (2000) (p. 146, left column). Likewise, J. G. Cannon, Chapter Nineteen in Burger's Medicinal Chemistry and Drug Discovery, Fifth Edition, Volume I: Principles and Practice, Wiley-Interscience 1995, pp. 783-802, teaches many caveats in analog design such as the following at page 799 column B:
Alteration of distances between portions of the pharmacophore of a molecule (or even' between other portions). may produce profound qualitative and/or quantitative changes in pharmacological actions.
Consistent with the above noted unpredictability is the data disclosed at page 153: Of the tested compounds show a range of activities (+ to +++). That productive small-molecule-protein interaction requires specific structural including stereochemical and geometrical, features is well taught and art acknowledged, see for example, Sundaresan, Protein Science (2002), 11:1330–1339. There is no structural guidance such as pharmacophore definition disclosed in the specification to guide one of skill in the art to choose from the possibilities pictured in the claims. For example, while the compounds share similarities with respect to Danuglipron (discussed below), it is unclear whether
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all provide equally for predictable results given that there these moieties form only part of the overall structures.
Method of treating:
The specification discloses that the claimed compounds are agonists at the GLP-1 receptor. Table 3on page 153 shows EC50 values for the claimed compounds. There are no working examples present showing efficacy of instant compounds in animal models of any disease condition. In absence of such teachings, guidance, prior art and working examples, it would require undue experimentation to demonstrate efficacy of instant compounds in animal models of any and all diseases recited. However, the indicated acknowledgement of enablement is based on state of the art teachings in Choe, Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists. Endocrinol Metab. 2021;36(1):22-29 and Griffith J. Med. Chem. 2022, 65, 12, 8208-8226 with regards to danuglipron which has structural arrangements similar to that of the instant claims. According to Griffith “Danuglipron demonstrated an in vitro signaling profile similar to that of GLP-1, potentiated glucose-stimulated insulin release, de creased the rate of food intake in monkeys, and was orally available in healthy human participants. Furthermore, danuglipron demonstrated beneficial changes during a recently reported multiple-dose study in volunteers with T2DM. See above for more on the instantly claimed compounds”.
The description on page 1 of the specification discusses the use of GLP-1 agonists for treating patients with type 2 diabetes mellitus (T2DM). Page 4 has a laundry list of diseases said to be a “GLP-1 mediated disease” which are:
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A fundamental problem with the claims is that they are drawn to any “GLP-1 associated disease, disorder, or condition” however only a specific type of agonism at GLP-1 Receptor has been shown for the compounds in the specification. GLP-1 has activity at the GLP-1 receptor but also exerts its activity in different ways including through a number of metabolites. Paternoster “Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1” Frontiers in Endocrinology October 2018 | Volume 9 | Article 584 1-26 discusses these metabolites:
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According to Tomas “GLP-1(28-36)amide, the Glucagon-like peptide-1 metabolite: friend, foe, or pharmacological folly?” Drug Design, Development and Therapy 2014, 8, 677-688, regarding the GLP-1 metabolites, “Accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor.” (abstract). “Emerging evidence indicates that GLP-1 nonapeptide is biologically active and has pharmacological effects in vitro and in vivo…..[T]hese effects appear to be largely independent of the GLP-1R….” [Conclusions].
In view of the foregoing discussion the only biochemical basis of therapeutic action for the claimed compounds is through the GLP-1R receptor not through the claimed GLP-1 association. Moreover, the compounds in question only create a certain type of signaling bias, agonism at the receptor, which is not equivalent to the natural ligand GLP-1. The GLP-1R receptor is capable of signaling through multiple pathways as discussed in MONTROSE-RAFIZADEH “Pancreatic Glucagon-Like Peptide-1 Receptor Couples to Multiple G Proteins and Activates Mitogen-Activated Protein Kinase Pathways in Chinese Hamster Ovary Cells” Endocrinology 1999, 40(3), 1132-1140.
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Taing discuses “the ability of ligands for the same GPCR to trigger distinct patterns of intracellular signaling by preferentially stabilizing specific active conformations of the receptor [7].” “In the case of the GLP-1R, two distinct domains have been identified to control peptide-mediated biased agonism [8]. Changes in the spatial orientation of transmembrane helices (TMs) 5 and 6 and restructuring of the extracellular loop (ECL) 2 are critical for the propagation of signals related to cAMP generation and elevation of intracellular Ca2+, while re-ordering of TMs 1 and 7 is required for extracellular signal-regulated kinase (ERK) 1/2 activity. In this context, backbone modifications of the natural GLP-1R agonist (GLP-1RA), GLP-1, via the replacement of selected amino acid residues, have been used to generate GLP-1 analogs with distinct preferences for promoting G protein activation versus β-arrestin recruitment [9].” [Taing “New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling Journal of Molecular Biology (2020) 432, 1347–1366.] Since the instantly claimed compounds are not structurally similar to the natural peptide ligand, GLP-1, or the other known synthetic peptide agonists and are not similar to known synthetic ligands there is no reason to believe the signaling bias would be the same. [See also Bavec “Different role of intracellular loops of glucagon-like peptide-1 receptor in G-protein coupling.” Regul Pept 2003, 111:137–144; Hallbrink “Different domains in the third intracellular loop of the GLP-1 receptor are responsible for Galpha(s) and Galpha(i)/ Galpha(o) activation.” Biochim Biophys Acta 2001, 1546:79–86].
The claims are drawn to a number of conditions that on the face would be exacerbated by the use of a GLP-1R agonists, i.e. cases in which abnormal GLP-1R activation is associated with a disease. Hypoglycemia as a result of excessive insulin secretion from the pancreatic β-cell (hyperinsulinemic hypoglycemia, HI) which untreated can result in cognitive impairment, loss of consciousness, seizures and in infants the risk of permanent brain damage. HI is the hallmark of a number of disorders including congenital hyperinsulinism (CHI) and post-bariatric hypoglycemia (PBSH). Postbariatric hypoglycemia is a complication of bariatric surgery, with significant associated morbidity, and many patients often require multimodal treatment. These conditions are claimed diseases associated with GLP-1 but would clearly not benefit from GLP-1 receptor agonism.
Also “eating disorders” are of three main types, “Anorexia nervosa and bulimia nervosa are characterized by severe disturbances of eating behavior. The salient feature of anorexia nervosa ( AN) is a refusal to maintain a minimally normal body weight. Bulimia nervosa (BN) is characterized by recurrent episodes of binge eating abnormal compensatory behaviors, such as self-induced vomiting.... Binge eating disorder (BED) is a more recently described syndrome characterized by repeated episodes of binge eating, similar to those of BN, in the absence of inappropriate compensatory behavior.” [Timothy Walsh “Eating Disorders" in Harrison's Principles of Internal Medicine (McGraw-Hill Book Company, New York, 2005 Kasper, Dennis L., Harrison, Tinsley Randolph. Eds. pp. 430-433] Treatment is largely supportive with cognitive behavioral therapy and sometimes antidepressants. It makes no sense to give patients suffering from what is ostensibly a psychiatric illness whose main symptom is a failure to eat an appetite suppressant.
Diabetes is not a single disease. Diabetes insipidus for example is caused by the inability of the kidneys to conserve water, which is caused by a lack of ADH (central diabetes insipidus) or by failure of the kidneys to respond to ADH (nephrogenic diabetes insipidus). Type 1 and Type 2 diabetes mellitus are the two most important forms. There is maturity-onset diabetes of the young (MODY, which comes in 6 completely different forms arising from different genetic defects), gestational diabetes mellitus and neonatal diabetes, which also arises from a specific genetic defect. There are forms of diabetes that arise from endocrinopathies, such as acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma and aldosteronoma. There are, aside from Type 1, two forms arising from immune-mediated diabetes: from "Stiff-man" syndrome and from anti-insulin receptor antibodies. Other forms arise from Diseases of the exocrine pancreas, including pancreatitis, trauma/pancreatectomy, hemochromatosis and fibrocalculous pancreatopathy. Still other arise from genetic defects in insulin action, notably lipoatrophic diabetes, type A insulin resistance, leprechaunism and Rabson-Mendenhall syndrome. There is a form of diabetes arising from congenital rubella or Cytomegalovirus infections. There are forms of diabetes that can arise from drugs or chemicals, especially glucocorticoids, thyroid hormone, Diazoxide, adrenergic agonists, thiazides, Dilantin and interferon.
Type 2 diabetes mellitus is a heterogeneous syndrome, with a complex interaction of genetic and environmental factors, which affect multiple phenotypic manifestations in the body, such as insulin secretion and action, pancreatic b-cell mass, distribution of body fat and development of obesity. Type 2 DM is generally characterized by two main pathophysiologic entities: i) resistance to the action of insulin; and ii) insufficient secretion of insulin from the -cells of the pancreas. Both of these pathophysiologic disturbances (insufficient secretion and peripheral insulin resistance) are thought to be necessary for the development of the disease….It is deemed certain today that these two pathophysiologic defects are subject to both genetic (mainly) and environmental (obesity - intracellular lipid accumulation) influences, which sometimes renders the exact determination of the aetiology of diabetes in a certain person extremely difficult." The use of GLP 1 receptor agonists is an established therapy for the treatment of type 2 diabetes and there is at least some evidence that other types of diabetes might be treatable with GLP1R agonists. They have been used adjunctively with insulin in type 1 diabetes. [See Nauck “GLP-1 receptor agonists in type 1 diabetes: a MAG1C bullet?” Volume 8, Issue 4, April 2020, Page 262.]
The claims are drawn to treatment of all addiction including various specific embodiments alcohol use disorder, smoking cessation, cocaine dependence. The causes of addiction are diverse and include various chemical substances and can include foods, drugs, gambling, shopping and other behaviors. Substance abuse disorders are caused by a number of different drugs and cause a variety of psychological symptoms including substance-induced delirium, substance-induced persisting dementia, substance-induced persisting amnestic disorder, substance-induced psychotic disorder, substance-induced mood disorder, substance-induced anxiety disorder, hallucinogen persisting perceptual disorder, substance-induced sexual dysfunction, substance-induced sleep disorder. Abstinence from the drug and psychotherapy is often recommended. Care is often palliative with management of withdrawal symptoms. Some drugs like benzodiazepines are used to calm anxiety. Certain drugs may be used to treat opioid addition by mimicking the effect of the drug without perpetuating drug seeking. Some drugs like disulfiram may make taking the drug less pleasant. These treatments rely on certain drug actions. There is no evidence that the compounds have any activity at receptors involved in addictive drugs (dopamine, serotonin, opioid, cannabinoid, GABA, etc.) or behaviors, or otherwise impact reward circuits in the brain or provide any palliative relief.
The claims are drawn to a diverse array of psychiatric conditions including bipolar disorder/major depressive disorder and schizophrenia. Mood Disorders are disorders that have a disturbance in mood as the predominant feature and include depression. Depression is not a single disorder and consists of many types including: Major Depressive Disorders (MDD), unipolar depression, single or recurrent major depressive episodes, recurrent brief depression, catatonic features, melancholic features including feeding disorders, such as anorexia, weight loss, atypical features, anxious depression, or postpartum onset, neurotic depression, vascular dementia with depressed mood, child abuse induced depression, schizoaffective disorder of the depressed type, and adjustment disorder with depressed mood, depression, psychotic major depression (PMD), Catatonic depression, Seasonal affective disorder (SAD), Dysthymia, Depressive Disorder Not Otherwise Specified (DD-NOS), Depressive personality disorder (DPD), Recurrent brief depression (RBD), Minor depressive disorder, the Bipolar Disorders (Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, and Bipolar Disorder not Otherwise Specified), Mood Disorder Due to a General Medical Condition and Substance-induced Mood Disorder (alcoholic hallucinosis, alcohol-induced mood disorders, amphetamine-induced mood disorder, cannabis related disorders, cocaine-related mood disorders, hallucinogen-induced mood disorder, opioid-Induced mood disorder, phencyclidine-induced mood disorder, sedative- hypnotic- or anxiolytic-induced mood disorder, polysubstance-related disorder and premenstrual dysphoric disorder, and other (or unknown). The forced swimming test is an art recognized test that reasonably correlates with depression treatment [See: Petit-Demouliere et. al. "Forced swimming test in mice: a review of antidepressant activity." Psychopharmacology 2005, 177, 245-255]. However the specification lacks any tests for treating depression or other mood disorders.
Schizophrenia is a poorly understood disease which affects approximately 1% of the population and is thought to be caused by a large number of genetic and environmental factors. Various theories have been put for the disease including hypothesized abnormality in dopaminergic neurotransmission and various theories regarding glutamatergic neurotransmission. Miyamoto “Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents” Molecular Psychiatry (2012) 17, 1206 – 1227 discusses known therapies. Major modalities of therapy include modification of dopamine receptors, serotonin receptors, drugs that target NMDA receptors and others. Table 1 and Table 2 summarize the various effects of these drug classes. Potential drug targets involving glutamatergic synaptic transmission are shown in figure 1, no discussion of GLP1 R agonists is given. Typically a pre-clinical study would involve establishing a clear link between some pharmacological activity and disease treatment followed by some animal studies. Unfortunately, there are no effective animal models, see Eric R. Marcotte J “Animal models of schizophrenia: a critical review” Psychiatry Neurosci 2001;26(5):395-410 “despite the advent of sophisticated analysis and imaging tools, or perhaps even because of them, our ability to synthesize a coherent model of schizophrenia remains as elusive as ever.” The instant specification does not have any tests for the treatment of schizophrenia.
The claims are drawn to treating Parkinson's with no evidence. There is a basic lack of understanding of Parkinson's disease and its proximal cause. The protein -synuclein is involved, but the relationship between -synuclein and Parkinson’s is not clear. DeWeerdt “Parkinson's disease 4 Big Questions” Volume 538, October 2016, S17, answers Question 2, “What is the role of the α-synuclein protein?”
The brains of people with Parkinson’s contain characteristic clumps of α-synuclein. But whether these clumps are the cause or merely a marker of the disease is not yet certain.
The claims are also drawn to treating Alzheimer's disease and impaired cognition with no evidence. Kidney disease is a poorly understood disease caused by a number of factors including diabetes, toxins (As, pesticides, excessive Na, etc.), viral infections (Hepatitis C), and others. Therapy is largely supportive and new approaches have been reviewed, see Ramos "Designing drugs that combat kidney damage" Expert Opinion on Drug Discovery (2015), 10(5), 541-556. "Table 1. Pipeline for promising drug/drug targets for kidney damage." lists various new approaches. Use of GLP1-R agonists has not been recommended. The specification has no data regarding treating kidney disorders. There is no explanation of how the compounds could treat kidney disease. According to Ramos, "several barriers should be overcome for the correct design of drugs that combat kidney damage and may successfully reach the clinic. Thus, there is a growing disconnect between basic research advances on the pathophysiology of kidney injury at the experimental animal level and translational nephrology. Part of the issue lies on the low representativeness of certain experimental animal models of kidney injury of events or pathophysiological pathways relevant to human kidney disease [10]. In this regard, most experimental 'therapeutic' approaches are in fact preventive rather than therapeutic, while kidney disease patients are diagnosed after the disease has developed."
The claims are drawn to treating all skin and connective tissue disorders including foot ulcerations, psoriasis, arthritis, as well as diseases of the gut including ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome various forms of cardiovascular disease with no evidence.
Based upon the data show above it is reasonable to believe that the compounds could treat various types of diabetes and conditions involving weight gain.
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