DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage entry of PCT/IL2022/050341 filed on 03/30/2022, which claims priority to U.S. Provisional Application No. 63/279,486 filed on 11/15/2021 and U.S. Provisional Application No. 63/167,721 filed on 03/30/2021.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 13-23) drawn to a method for preventing or treating a QR2-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by or comprising Formula 1 in the reply filed on March 24, 2026 is acknowledged. Applicant’s election without traverse of traumatic brain injury (TBI) as a species of a QR2-related disease or disorder and YB-537 as a species of a compound represented by Formula 1 in the reply filed on March 24, 2026 is also acknowledged.
Claims 15 and 24-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group or species, there being no allowable generic or linking claim.
Applicant’s elected species of a compound of formula 1 YB-537:
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was not found in the prior art. Thus, the search has been expanded to include additional species of a compound of formula 1 wherein formula 1 has the following structure:
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and R’ is
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or
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wherein both Xs are N.
Claims 13, 14 and 16-23 are being examined as they read on traumatic brain injury (TBI) as a species of a QR2-related disease or disorder.
Drawings Objection
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 13 is objected to because of the following informalities: claim 13 recites “
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represents a single or a double bond.” However,
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is not included anywhere in the structure of Formula 1. Appropriate correction is required.
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 13, 14 and 16-23 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 Alzheimer’s disease comprising the administration of YB-537 and compositions thereof, does not reasonably provide enablement for a method for preventing or treating any QR2-related disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the YB-537 compound or any other compound represented by Formula 1. 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 specification does not provide sufficient information to support the claimed invention of treating any QR2-related disease or disorder in a subject in need thereof comprising administering a composition comprising YB-537 or any other compound represented by Formula 1.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity 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 for preventing or treating a QR2-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by or comprising Formula 1 having the following structure:
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such as YB-537 having the following structure:
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Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that any compound of formula 1, which includes an infinite number of compounds can be used to treat any QR2-related disease or disorder which includes an infinite number of disorders including traumatic brain injury (TBI), any neurodegenerative disease or disorder, any cell-proliferative disease or disorder, malaria, drug direct or indirect toxicity, NAD-related metabolic toxicity, epilepsy, ischemia, depression and/or anxiety, restenosis, glaucoma, any immune-response related disease, and any combination thereof. Thus the cited claims are deemed very broad since these claims read on treating any QR2-related disease or disorder which includes numerous diseases comprising the administration of any compound of formula 1 which includes thousands or more compounds.
State of the Prior Art: A thorough search of the prior art did not find any well-known QR2 inhibitors being administered to a patient for the treatment of traumatic brain injury or any other QR2-related disease or disorder as claimed. While quinone reductase 2 (QR2) is implicated in the etiology of neurodegenerative disorders, and other disorders, prior to the effective filing date of the claimed invention, its role in these disorders were highly speculative and underdeveloped. Cassagnes et al. (Free Radical Biology and Medicine, Volume 120, 20 May 2018, Pages 56-61) teaches that overproduction of reactive oxygen species (ROS) and oxidative stress is involved in the pathogenesis and etiology of neurodegenerative disorders (abstract). Cassagnes et al. teaches that the overproduction of QR2 increases production of ROS (abstract). Cassagnes et al. teaches that it thus seems likely that QR2 is an important indirect source of ROS generation in neurodegeneration, an idea that was supported by the results of experiments that used several types of cells (page 60). Thus Cassagnes et al. provides evidence that the role of QR2 in certain diseases and disorders are likely but not absolute. Singleton et al. (Journal of Neurotrauma, Volume 27, Issue 6, June 2010, Pages 1091-1099) teaches that resveratrol which is a known QR2 inhibitor has been shown to be neuroprotective and useful in neurodegenerative disorders and traumatic brain injury (page 1091). Singleton et al. teaches that although binding characteristics are not known for many of the targets of resveratrol, it is known that the highest-affinity binding partner is QR2, which is thought to mediate some of the indirect antioxidant/ free-radical scavenging activities of the drug (page 1097). However, although Singleton et al. teaches that resveratrol may have beneficial effects for traumatic brain injury treatment, the mechanisms by which resveratrol mediates its neuroprotection is unclear (abstract and page 1097). Thus, prior to the effective filing date of the claimed invention, it was uncertain whether QR2 modulation would be effective in treating traumatic brain injury and other neurodegenerative disorders. Thus the state of the art prior to the effective filing date of the claimed invention does not support the broad use of any compound of formula I for the treatment of any QR2-related disease or disorder as claimed in the instant application.
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 encompasses the treatment of any disorder/disease related to QR2, which include a great number of diseases with different etiologies such as Alzheimer’s disease, cancer, depression, etc. Thus, the skilled artisan would view that the treatment of all disorders/diseases encompassed by the claims, by administering all compounds as claimed is highly unpredictable.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering any compound as claimed for treating all disorders/diseases encompassed by the claims.
Guidance of the Specification/Working Examples: In the instant specification, it is stated that the QR2-related disease or disorder is selected from the group consisting of: a neurodegenerative disease or disorder, a cell-proliferative disease or disorder, malaria, drug direct or indirect toxicity, NAD-related metabolic toxicity, epilepsy, ischemia, depression and/or anxiety, restenosis, glaucoma, immune-response related disease, and any combination thereof [023]. In some embodiments, the neurodegenerative disease or disorder is selected from the group comprising: Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), prion disease, and any combination thereof [024]. Applicant provides data demonstrating that certain compounds of formula I inhibit QR2 and/or QR1 (Table 3 pages 63-73). Furthermore, out of all of the compounds, Applicant identifies 3 leading compounds YB-800, YB-540, and YB-537 which have low toxicity and are able to reduce reactive oxygen species (ROS) (pages 74-75). Applicant further states that their data demonstrates that compound YB-537 improves learning in animals (page 76-78). Finally, Applicant further states that their data demonstrates in a mouse model of Alzheimer’s disease that YB-537 improves cognitive function and reduces brain pathologies in female mice (pages 81-83). No other data demonstrating the effective treatment for any other disease with the administration of any compound other than YB-537 is found in the instant specification. Thus, the data provided for in the instant specification pertains to the treatment of Alzheimer’s disease with the administration of YB-537 and therefore the specification fails to provide sufficient evidence to support of the broad treatment of any disorder/disease related to QR2 comprising the administration of any compound of formula 1 as recited in the instant claims.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to determine if one of the thousands of compounds as claimed can be used to treat one of the many claimed diseases or disorders. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, 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”. A method for preventing or treating any QR2-related disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the YB-537 compound or any other compound represented by Formula 1 is not enabled by the instant specification.
Claims 13, 14 and 16-23 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 Alzheimer’s disease comprising the administration of YB-537 and compositions thereof, does not reasonably provide enablement for a method for preventing or treating Alzheimer’s disease or any QR2-related disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the any compound represented by Formula 1. 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 specification does not provide sufficient information to show that all compounds represented by Formula 1 can be used to treat all diseases or disorders as claimed.
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 for preventing or treating a QR2-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by or comprising Formula 1 having the following structure:
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such as YB-537 having the following structure:
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Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that any compound of formula 1, which includes an infinite number of compounds can be used to treat any QR2-related disease or disorder which includes an infinite number of disorders including traumatic brain injury (TBI), any neurodegenerative disease or disorder, any cell-proliferative disease or disorder, malaria, drug direct or indirect toxicity, NAD-related metabolic toxicity, epilepsy, ischemia, depression and/or anxiety, restenosis, glaucoma, any immune-response related disease, and any combination thereof. Thus the cited claims are deemed very broad since these claims read on treating any QR2-related disease or disorder which includes numerous diseases comprising the administration of any compound of formula 1 which includes thousands or more compounds.
Guidance of the Specification/Working Examples: In the instant specification, it is stated that the QR2-related disease or disorder is selected from the group consisting of: a neurodegenerative disease or disorder, a cell-proliferative disease or disorder, malaria, drug direct or indirect toxicity, NAD-related metabolic toxicity, epilepsy, ischemia, depression and/or anxiety, restenosis, glaucoma, immune-response related disease, and any combination thereof [023]. In some embodiments, the neurodegenerative disease or disorder is selected from the group comprising: Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), prion disease, and any combination thereof [024]. Applicant provides data demonstrating that certain compounds of formula I inhibit QR2 and/or QR1 (Table 3 pages 63-73). Furthermore, out of all of the compounds, Applicant identifies 3 leading compounds YB-800, YB-540, and YB-537 which have low toxicity and are able to reduce reactive oxygen species (ROS) (pages 74-75). Applicant further states that their data demonstrates that compound YB-537 improves learning in animals (page 76-78). Finally, Applicant further states that their data demonstrates in a mouse model of Alzheimer’s disease that YB-537 improves cognitive function and reduces brain pathologies in female mice (pages 81-83). No other data demonstrating the effective treatment for any other disease with the administration of any compound other than YB-537 is found in the instant specification. Thus, the data provided for in the instant specification pertains to the treatment of Alzheimer’s disease with the administration of YB-537 and therefore the specification fails to provide sufficient evidence to support of the broad treatment of any disorder/disease related to QR2 comprising the administration of any compound of formula 1 as recited in the instant claims.
State of the Art: Prior to the effective filing date of the claimed invention, certain compounds of formula 1 were known in the art. For example, Almario-Garcia et al. (U.S. Publication No. 20090253735 A1) renders obvious a compound of formula 1 as claimed wherein R of R’ is substituted aryl, since Almario-Garcia et al. teaches a compound of formula (I) wherein R1 is phenyl, substituted with SO2NRaRb wherein RaRb together with the nitrogen atom form piperazine
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(see claim 1). Almario-Garcia et al. teaches that the compounds disclosed therein are useful for the treatment of certain neurodegenerative diseases such as Alzheimer’s disease however, it is not disclosed therein that these compounds inhibit QR2 (see claim 17). Goldfarb (U.S. Publication No. 20090163545) discloses
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which is a compound of formula I as claimed when both R1s are methyl and R is halogen. However, it is not disclosed therein that this compound inhibits QR2 and can be used to treat any QR2 related diseases. Zoller et al. (U.S. Publication No. 2010/0113412 A1) teaches the following compounds
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which are compounds of formula 1 as claimed wherein R on R’ is CO2R” and R” is methyl, both R1s are H, and the other R on the phenyl ring is halogen (see examples 21 and 22 on pages 20-21). These compounds are taught in Zoller et al. to increase nitric oxide (abstract). However, it is not disclosed therein that these compound inhibit QR2 and can be used to treat all QR2 related diseases. A thorough review of the prior art did not discover any of the claimed compounds having the activity of inhibition of QR2. While the compounds disclosed in the prior art are taught to be useful for the treatment of certain neurodegenerative diseases such as Alzheimer’s disease, this activity is not known to be due to QR2 inhibition. Thus the state of the art prior to the effective filing date of the claimed invention does not support the use of all compounds as claimed for the treatment of all QR2-related diseases or disorders as claimed.
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 encompasses the treatment of any disorder/disease related to QR2, which include a great number of diseases with different etiologies such as Alzheimer’s disease, cancer, depression, etc. Thus, the skilled artisan would view that the treatment of all disorders/diseases encompassed by the claims, by administering all compounds as claimed is highly unpredictable.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering any compound as claimed for treating all disorders/diseases encompassed by the claims.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to determine if one of the thousands of compounds as claimed can be used to treat one of the many claimed diseases or disorders. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, 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”. A method for preventing or treating Alzheimer’s disease or any QR2-related disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the any compound represented by Formula 1 is not enabled by the instant specification.
Claims 13, 14 and 16-23 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 Alzheimer’s disease comprising the administration of YB-537, does not reasonably provide enablement for a method for preventing Alzheimer’s disease or any other QR2-related disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the YB-537 or any other compound represented by Formula 1. 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 specification does not provide sufficient information to show that the compounds represented by Formula 1 can be used to prevent any diseases or disorders as claimed.
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 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 for preventing or treating a QR2-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by or comprising Formula 1 having the following structure:
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such as YB-537 having the following structure:
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Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that any compound of formula 1, which includes an infinite number of compounds can be used to not only treat but also prevent any QR2-related disease or disorder which includes an infinite number of disorders including traumatic brain injury (TBI), any neurodegenerative disease or disorder, any cell-proliferative disease or disorder, malaria, drug direct or indirect toxicity, NAD-related metabolic toxicity, epilepsy, ischemia, depression and/or anxiety, restenosis, glaucoma, any immune-response related disease, and any combination thereof. Thus the cited claims are deemed very broad since these claims read on treating as well as preventing any QR2-related disease or disorder which includes numerous diseases comprising the administration of any compound of formula 1 which includes thousands or more compounds.
Guidance of the Specification/Working Examples: In the instant specification, it is stated that the QR2-related disease or disorder is selected from the group consisting of: a neurodegenerative disease or disorder, a cell-proliferative disease or disorder, malaria, drug direct or indirect toxicity, NAD-related metabolic toxicity, epilepsy, ischemia, depression and/or anxiety, restenosis, glaucoma, immune-response related disease, and any combination thereof [023]. In some embodiments, the neurodegenerative disease or disorder is selected from the group comprising: Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, Down syndrome, amyotrophic lateral sclerosis (ALS), prion disease, and any combination thereof [024]. Applicant provides data demonstrating that certain compounds of formula I inhibit QR2 and/or QR1 (Table 3 pages 63-73). Furthermore, out of all of the compounds, Applicant identifies 3 leading compounds YB-800, YB-540, and YB-537 which have low toxicity and are able to reduce reactive oxygen species (ROS) (pages 74-75). Applicant further states that their data demonstrates that compound YB-537 improves learning in animals (page 76-78). Finally, Applicant further states that their data demonstrates in a mouse model of Alzheimer’s disease that YB-537 improves cognitive function and reduces brain pathologies in female mice (pages 81-83). No other data demonstrating the effective treatment for any other disease with the administration of any compound other than YB-537 is found in the instant specification. Thus, the data provided for in the instant specification pertains to the treatment of Alzheimer’s disease with the administration of YB-537.
Applicant has provided no guidance showing the actual “prevention” of any disease or disorder comprising the administration of any compound of formula 1 as claimed. All the guidance is directed to the treatment of Alzheimer’s disease rather than the prevention. Therefore the specification fails to provide sufficient evidence to support the prevention of any disorder/disease related to QR2 comprising the administration of any compound of formula 1 as recited in the instant claims.
State of the Art: While the state of the art is relatively high with regard to the treatment of the symptoms of certain QR2-related diseases or disorders such as Alzheimer’s disease and other neurodegenerative diseases, the state of the art with regard to prevention of such disorders is underdeveloped. The state of the art, (Tobinick, U.S. Patent 6,379,666) teaches that Alzheimer's disease is a common form of progressive dementia, of unknown cause and without an effective cure; Huntington's disease (Huntington's chorea) is a rare, progressive, fatal neurological disorder for which there is currently no effective treatment; Parkinson's disease is a common neurologic disorder characterized by tremor, gait disorder, and dementia, for which there is no known cure; and amyotrophic lateral sclerosis (ALS) is a progressive fatal, neurological disease and has no known cure (column 8 line 58-column 9 line 59). Thus the state of the art teaches that there is no known cure or effective treatments for neurodegenerative diseases and moreover, some have no known cause, and therefore it is highly speculative and highly unlikely that a neurodegenerative disease is preventable as claimed. Thus the state of the are fails to support the prevention of any QR2-related disease or disorders claimed comprising the administration of any compound as claimed.
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 encompasses the prevention of any disorder/disease related to QR2, which include a great number of diseases with different etiologies such as Alzheimer’s disease, cancer, depression, etc. which the state of the art does not recognize as preventable. Thus, the skilled artisan would view that the prevention of all disorders/diseases encompassed by the claims, by administering all compounds as claimed is highly unpredictable.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to determine if a compound as claimed can prevent any disease or disorder as claimed. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
Accordingly, a method for preventing Alzheimer’s disease or any other QR2-related disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising YB-537 or any other compound represented by Formula 1 is not enabled by the instant specification.
Claim Rejections - 35 USC § 112(b)
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 13, 14, and 16-23 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.
The term “QR-2-related disease or disorder” in claim 13 is a relative term which renders the claim indefinite. The term “QR-2-related disease or disorder” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus an ordinary skilled artisan would not understand how to determine if a particular disease or disorder is QR-2 related. In the instant specification Applicant provides a broad definition: “As used herein, the term "QR2-related disease or disorder" refers to any disease, disorder, or condition involving QR2 function and/or activity in the pathogenesis and/or pathophysiology of the disease, disorder, or condition [0129]. As used herein, the term "QR2 function or activity" refers to quinone reduction. In some embodiments, QR2 function or activity is co-factor dependent. In some embodiments, the co-factor comprises or is dihydronicotinamide riboside (NRH) or other nicotinamide molecules [0130].” However, this definition does not provide adequate guidance such as what kind of change and how much of a change is necessary to be considered QR2-related. Thus without such guidance, an ordinary skilled artisan cannot ascertain the metes and bounds of the claim. Thus claim 13 and all claims dependent upon claim 13 (claims 14 and 16-23) are rejected.
Claim 13 is further indefinite because it recites “wherein the compound is represented by or comprising Formula 1.” It is unclear how the compound can comprise Formula 1 since either the compound is represented by Formula 1 or it is not. The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“like the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended.”). Invitrogen Corp. v. Biocrest Manufacturing, L.P., 327 F.3d 1364, 1368, 66 USPQ2d 1631, 1634 (Fed. Cir. 2003) (“The transition ‘comprising’ in a method claim indicates that the claim is open-ended and allows for additional steps.”); Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997) (“Comprising” is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986); In re Baxter, 656 F.2d 679, 686, 210 USPQ 795, 803 (CCPA 1981); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) ("comprising” leaves “the claim open for the inclusion of unspecified ingredients even in major amounts”).
Thus it is unclear if the compound is a compound represented by Formula 1 or if the compound is a part of or combined with some other unrecited compound or component. Thus claim 13 and all claims dependent upon claim 13 (claims 14 and 16-23) are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 13, 14, 16-20 and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Zoller et al. U.S. Publication No. 2010/0113412 A1 in view of Terpolilli et al. (Journal of Cerebral Blood Flow & Metabolism (2013) 33, 311–318).
Claims 13, 14 and 16-23 of the instant application claim a method for preventing or treating a QR2-related disease or disorder in a subject in need thereof, such as traumatic brain injury comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by or comprising Formula 1 having the following structure:
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wherein R’ is
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R on R’ is H and CO2R” and R” is methyl; R on the phenyl ring is halogen; and both R1s are hydrogen.
Zoller et al. teaches compounds of formula I which modulate the transcription of endothelial nitric oxide (NO) synthase and are valuable pharmacologically active compounds (abstract). Specifically, the compounds of formula I upregulate the expression of the enzyme endothelial NO synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired (abstract). Zoller et al. further teaches pharmaceutical compositions comprising compounds of Formula I, and the use of compounds of formula I for the stimulation of the expression of endothelial NO synthase or for the treatment of various diseases including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency (abstract).
Zoller et al. teaches that the compounds of the formula I are useful pharmacologically active, or pharmaceutically active compounds which modulate the expression of endothelial NO synthase, and more specifically upregulate, or stimulate, the expression, or transcription, of endothelial NO synthase, and which can be employed as pharmaceuticals, or active ingredients of medicaments, for the treatment of various diseases [0265]. Diseases which can be treated with the compounds of the formula I include, for example, cardiovascular diseases like stable and unstable angina pectoris, coronary heart disease, coronary artery disease, Prinzmetal angina (spasm), acute coronary syndrome, cardiac insufficiency, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease (PAOD), endothelial dysfunction, atherosclerosis, restenosis, endothelial damage after PTCA (percutaneous transluminal coronary angioplasty), hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), erectile dysfunction, and ventricular arrhythmia [0265].
Zoller et al. teaches that the compounds of the formula I can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another, or in the form of pharmaceutical compositions [0267]. The pharmaceuticals according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories [0268]. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously, for example in the form of solutions for injection or infusion [0268]. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods [0268].
Zoller et al. specifically teaches the following compounds useful in the disclosed methods:
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which are compounds of formula 1 as claimed wherein R on R’ is hydrogen and CO2R” and R” is methyl, both R1s are H, and the other R on the phenyl ring is halogen (see examples 21 and 22 on pages 20-21).
Zoller et al. does not specifically teach the treatment of traumatic brain injury as claimed in claim 14. However, Zoller et al. specifically teaches other indications as claimed in claim 14 such as restenosis and conditions involving ischemia such as coronary heart disease, coronary artery disease, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease (PAOD), and atherosclerosis (see claim 2).
In addition, Terpolilli et al. teaches that ischemia is one of the leading causes of secondary brain damage after traumatic brain injury (TBI), wherein typically, cerebral blood flow (CBF) is markedly reduced immediately after and during the first few hours after trauma, especially in the pericontusional region (page 311 and abstract). The primary lesion evolving at the time of injury increases in size when CBF in the critically perfused tissue around the contusion (‘traumatic penumbra’) gradually decreases below the ischemic threshold giving rise to secondary injury (page 311). Terpolilli et al. teaches that the development of a vasodilator with a specific action on vessels in hypoxic/ischemic tissue would certainly be a viable strategy for the treatment of pericontusional ischemia (page 311). Terpolilli et al. teaches that inhaled nitric oxide (NO), the most potent known endogenous vasodilator, has the properties of an ideal vasodilator for ischemic tissue and when NO, a gas, is given by inhalation after cerebral ischemia, it dilates cerebral resistance vessels selectively in the ischemic penumbra without any effect on systemic blood pressure, thereby increasing CBF and preventing ischemic cell death (page 311). Terpolilli et al. teaches that their data demonstrates that NO inhalation effectively reduces brain damage and improves neurological function after TBI as a result of a selective dilation of resistance vessels with a concomitant increase of CBF in the traumatic penumbra (page 317).
Thus Terpolilli et al. teaches that traumatic brain injury is a condition in which an increased expression of the enzyme endothelial NO synthase or an increased NO level or the normalization of a decreased NO level is desired.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Zoller et al. which teaches compounds of the formula I which modulate the expression of endothelial NO synthase, and more specifically upregulate, or stimulate, the expression, or transcription, of endothelial NO synthase, and which can be employed as pharmaceuticals, or active ingredients of medicaments, for the treatment of various diseases in which an increased expression of the enzyme endothelial NO synthase or an increased NO level or the normalization of a decreased NO level is desired, with the teachings of Terpolilli et al. which teaches that traumatic brain injury is a condition in which an increased NO level or the normalization of a decreased NO level is desired. Thus, an ordinary skilled artisan would have been motivated to administer the compounds of Zoller et al. which can be administered intranasally to increase NO levels in the brain and thus treat traumatic brain injury with a reasonable expectation of success. Thus treating traumatic brain injury according to the methods of Zoller et al. to arrive at the instant invention is rendered obvious.
Although the cited references do not teach inhibiting QR2 function or activity in a cell of the subject, as claimed in claims 16 and 17, since Zoller et al. teaches the administration of a compound of formula 1 as claimed, said compound will necessarily have the same property of inhibiting QR2 function or activity as claimed since a compound and its properties are inseparable. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963). "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Claim 19 of the instant application is rendered obvious since diagnosing a patient before treatment is the standard of care and necessarily taught in the prior art. Claim 20 is rendered obvious since the prior art renders obvious treating the same QR2-related disease as claimed and thus said subject necessarily has an increase in QR2 function or activity as compared to a control subject as claimed.
Claims 22 and 23 are rendered obvious since the method of claim 13 is rendered obvious and thus the same effects as claimed in claims 22 and 23 are also rendered obvious since administration of the same compound as claimed for the treatment of the same disorder as claimed will necessarily result in the same effects as claimed. Thus administering a compound of formula 1 as claimed will necessarily reduce reactive oxygen species and modulate autophagy as claimed. It is not necessary that the prior art suggests the same advantage or result discovered by applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991). The mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Prindle, 297 F.2d 251, 254 (CCPA 1962). Here, the latent properties identified by Applicant are reducing the amount or level of reactive oxygen species (ROS), modulating autophagy including increasing autophagy or reducing autophagy, and reducing or inhibiting inflammation which will necessarily occur by following the teachings and suggestion of the prior art cited and administering a compound of formula 1 for the treatment of traumatic brain injury.
Thus the cited claims of the instant application are rejected in view of the cited prior art teachings.
Conclusion
Claims 1-12 are canceled. Claim 13 is objected to. Claims 13, 14, and 16-23 are rejected. Claims 15 and 24-26 are withdrawn. No claims are allowed.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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