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 .
Election/Restrictions
Applicant’s response to the restriction/ election requirement from 2/27/2026 is acknowledged. Applicant has made the following election without traverse.
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On further search, the elected species was found to be free of art, and the search was expanded across the breadth of claims. Claims 1-7, 12, 18-21 and 28-31 are pending, and have been examined herewith across their breadth.
Claim Objections
Claim 2 is objected to because of the following informalities. The claim contains abbreviations- COPD and CKD, of which the Examiner has not heard at all the latter as a common abbreviation. Appropriate correction is requested by fully spelling out the claimed disorders- chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD).
Claim 2 is further objected to because it recites a disorder to be “high cholesterol”. This is a marker, not a disease per se. The disease is hypercholesterolemia, or hyperlipidemia, or atherosclerosis, etc.
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 1-7, 12, 18-21 and 28-31 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding the description "disorders associated with oxidative stress" appearing Claim 1, it is not clear what disease is encompassed by the "disorders," even considering the disclosures in [0002]-[0004] and [0029] of the present application.
Per Applicant’s specification: “Oxidative stress occurs when there is an imbalance between formation and regulation of reactive oxygen (ROS) and nitrogen species (RNS) in cells and tissues, causing ROS and RNS to accumulate. This imbalance leads to damage of important biomolecules and cells, with potential impact on the whole organism. Oxidative stress influences many physiological processes including the immune system and cellular communication, and has been linked to intense exercise, inadequate diet, ageing and several age-related disorders, as well as many chronic diseases. Some of the chronic diseases shown to be associated with increased levels of oxidative stress include; cardiovascular diseases, including vascular diseases like atherosclerosis, high cholesterol, stroke, heart failure, and hypertension; cancer; Parkinson's disease; Alzheimer's disease; diabetes; pain disorders; multiple sclerosis; kidney disease; rheumatoid arthritis; sepsis; respiratory distress syndrome, and metabolic disorders such as mitochondrial diseases, lipid metabolism disorders, and DNA repair-deficiency disorders. Other conditions may include chronic obstructive pulmonary disease (COPD) which includes conditions emphysema, chronic bronchitis & chronic asthma and chronic kidney disease (CKD).
[…]
[0029] In disorders associated with oxidative stress, the present investors have recognized that peroxide oxidants such as HP and PN are elevated in certain cells, tissues and biological compartments, as such circulating compounds of formula (I) will release MMF stoichiometrically in line with the amount of oxidant and therefore activate the NRF2 pathway at the site best suited to effect amelioration of the disorder by restoring redox balance in regions specifically under oxidative stress. This tissue targeting concept has for the first time been evidenced by the inventors in efficacy models of neuropathic pain. Furthermore, systemic delivery of MMF has been recognized to cause certain problems, one of them is reduced lymphocyte count. The present inventors have obtained data showing that the compounds disclosed herein do not lead to reduced lymphocyte count.”
([0004], [0029]).
As can be seen from this disclosure, the list of diseases, potentially encompassed by this claim term, is of a very vast array of disease of highly disparate pathology and etiology, and no known common cure to particularly include not a common restoration of redox balance cure. Moreover, redox imbalance is at its core a pathological phenomenon that is linked with everyday exposure to various stressors, such as uv light, consumption of iron from food, the effect of various free radicals, etc. Moreover, it is not even in reference to specific disorders in which there is oxidative stress, but can be interpreted, under the broadest reasonable interpretation, to encompass any disorders, even not ones associated with oxidative stress/ redox imbalance per se, but rather just ones “associated with” them. The term “disorders associated with oxidative stress” is thus vast and indefinite. The limitation of claim 3 “wherein treatment of the disorder associated with oxidative stress is through site directed target engagement of the NRF2 pathway is further vague and ambiguous, because it is unclear which of a potentially vast number of diseases undergo a redox imbalance through target engagement of the NRF2 pathway.
The invention of Claim 1 encompasses an "isomer" of a compound represented by Formula (I). The specification does not define the claim term. The only guidance from the Specification is not a definition per se, but only specifies that the compounds may have a chiral center and include stereoisomers too. “[0102] It will be appreciated that the compounds of the invention may have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form. The invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers may be separated conventionally by chromatographic methods or using a resolving agent. Alternatively, the individual isomers may be prepared by asymmetric synthesis using chiral intermediates.” However, the term "isomer" can be regarded to include a structural isomer, and given the broadest reasonable interpretation, these structural isomers too are included within the scope of the claim. Structural isomers (or constitutional isomers) are molecules that share the exact same molecular formula—meaning they have the same number and types of atoms—but differ in the way their atoms are connected (structural arrangement). This variation in connectivity leads to distinct chemical and physical properties. Therefore, the scope of structure of the compound set forth in the claim is unclear.
To exemplify, this an example of structural isomers.
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Turning to Applicant’s claims, they recite, for instance, alkyl chains of any length, that are further optionally substituted. In fact, all substituents below are noted to be optionally substituted with undefined groups.
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Thus, this creates a virtually limitless list of substituents, to include various structural isomers thereof, with a vague and indefinite scope of structure of the compound.
Claim Rejections - 35 USC § 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.
Claims 1-7, 12, 18-21 and 28-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating pain comprising administering to a subject in need thereof 1,5-dimethyl (2E)-4-oxopent-2-enedioate or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, does not reasonably provide enablement for a method of treating a disorder associated with oxidative stress comprising administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or isomer thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention without undue experimentation. Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: 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, the relative skill of those in the art, and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant invention pertains to a method of treating a disorder associated with oxidative stress, comprising administering to a subject in need thereof a compound of formula (I):
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Breadth of the claims: The instant claims are deemed very broad since these claims read on treating a very broad array of disorders, which encompass, but are not limited to, such diverse diseases of different pathology and etiology as cardiovascular diseases, including vascular diseases like atherosclerosis, high cholesterol, stroke, heart failure, and hypertension; cancer; Parkinson's disease; Alzheimer's disease; diabetes; pain disorders; multiple sclerosis; kidney disease; rheumatoid arthritis; sepsis; respiratory distress syndrome, and metabolic disorders such as mitochondrial diseases, lipid metabolism disorders, and DNA repair-deficiency disorders; chronic obstructive pulmonary disease (COPD) which includes conditions emphysema, chronic bronchitis & chronic asthma and chronic kidney disease (CKD). The claims are also directed to a very broad class of compounds of formula (I), with a very broad array of optional substituents of unclear nature, to include structural isomers thereof.
Guidance of the Specification/Working Examples: Applicant shows in the specification testing with a single compound according to Applicant’s claims- 1,5-dimethyl (2E)-4-oxopent-2-enedioate- and in a single animal model of pain.
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Applicant’s specification states: “[0029] In disorders associated with oxidative stress, the present investors have recognized that peroxide oxidants such as HP and PN are elevated in certain cells, tissues and biological compartments, as such circulating compounds of formula (I) will release MMF stoichiometrically in line with the amount of oxidant and therefore activate the NRF2 pathway at the site best suited to effect amelioration of the disorder by restoring redox balance in regions specifically under oxidative stress. This tissue targeting concept has for the first time been evidenced by the inventors in efficacy models of neuropathic pain.” However, besides as to 1,5-dimethyl (2E)-4-oxopent-2-enedioate, there is no evidence provided that other compounds of the class will also release DMF (structure provided hereto).
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Nor is there an explanation of why such an assumption is even being made. It is noted that with the various substituents claimed, to include complex ones as various aryl and heteroaryl groups, and even amino acids and peptides, there is nothing in the specification to provide evidence underlying this mechanism of release of DMF. Nor is there any evidence whatsoever, that even if this DMF was released, it will result in the treating of the vast number of disorders claimed.
The state of the prior art: Carlström et al., Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes, Nature Communications volume 10, Article number: 3081, 12 July 2019 (“Carlström”) is used in this rejection vis-à-vis its effect in relapsing-remitting multiple sclerosis, a disorder associated with oxidative stress. The following is relevant disclosure from Carlström. “Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive.” “An increasing body of evidence suggests that redox reactions are important for the regulation of immune responses during infection, malignancies and autoimmunity1. Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune disease associated with dysregulation of adaptive immunity, leading to the periodic entry of immune cells into the central nervous system (CNS) and subsequent tissue damage with symptoms of neurological dysfunction. Among a number of different pathological disease mechanisms, an imbalance in the oxidative environment has also been described2,3. Dimethyl fumarate (DMF; Tecfidera®) is a oral disease modulating treatment (DMT) and the most prescribed drug for RRMS in the U.S. It’s suggested to act by activating the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2)4,5, which is a transcript of the NFE2L2 gene.” “The net activity of DMF has been described to be mainly anti-oxidative5,7,8.” “So far targeting of redox regulation has not been a generally accepted therapeutic strategy in autoimmune diseases.” “DMF has been ascribed cyto-protective effects of potential relevance for CNS cells during inflammation, but conclusive data on degree of CNS penetration in humans is still lacking12,13 and modulation of disease relevant T cell subsets14,15,16,17,18,19, therefore remains the most likely mechanism for reducing clinical and neuroradiological disease activity in RRMS5,20,21.” “Experimental evidence establish ROS as potent immune regulators, suggesting that dampening of oxidative reactions paradoxically may increase susceptibility to autoimmune diseases22,23,24. Thus, a naturally occurring genetic variant in the rat Ncf1 gene, encoding a ROS-generating NADPH oxidase subunit, leading to lowered ROS generation is associated with increased susceptibility to both experimental autoimmune arthritis25 and encephalomyelitis (EAE)22,26, the animal model for MS. Experiments in genetically modified mice have pin-pointed this effect to incapacity of myeloid cells to limit T cell proliferation and to induce regulatory T cell (Treg) activation via superoxide generation27,28,29.” “Herein, we identify DMF to increase monocyte ROS generation and that epigenetic methylation changes in monocytes precede those occurring in CD4+ T cells. Furthermore, a reduced capacity to generate ROS and lower monocyte counts is associated with reduced clinical efficacy of DMF.”
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation of treating the vast array of disorders associated with oxidative stress with the significantly broad genus of compounds with unclear mechanism of action is highly unpredictable.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to conduct an exhaustive amount of experiments. Applicant would need to provide reasonable data showing that multiple disorders encompassed by Applicant’s claims can be treated by the claimed method and mechanism, and that the various compounds claimed share both a common structure and a common function. In order to do so, Applicant would need to perform pharmacokinetic and pharmacological experiments to determine efficacy, potency, etc. for each of the broad genus of compounds in multiple animal models of various diseases of different pathology. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
Genentech states that "patent 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." Genentech v. Novo Nordisk, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627