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 371 National Stage Entry of PCT/CN2023/089682 filed on April 21, 2023. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in a People’s Republic of China Application No. CN202210805342.5, filed on July 08, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 29, 2024 is acknowledged and has been considered.
Status of the Claims
Acknowledgement is made of claims in the filed Application 18/861,307; Claims 1-4 (amended); claims 5-6 (new). No new matter was introduced. Thus, claims 1-6 are currently under consideration.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, and 4-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zheng et al. 2012, (Zheng et al., CN102816151A; Published, 12 December, 2012; cited in the IDS), hereon after ‘151. ‘151 teaches a genus compound of formula (I) (shown below), or a pharmaceutically acceptable salt (abstract & claim 1), The disclosed ‘151 genus compound and its defined variables of m, R1 and R2 overlap with the instant claimed compound of Formula I (instant claim 1).
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‘151 also discloses compounds that read on the instant claimed invention as follows,
‘151 exemplified embodiments (‘151; Claim 6, pages 54-69 and Table 2 – Machine Translate copy);
6-[(S)-3-ethyl-3-(3′-hydroxyphenyl)-azacycloheptane-1-yl]-N-[2-(1H-indol-3-yl)ethyl]-hexamamide – where R1 is H, R2 is H and m is 1 (‘151, Ex. 8);
8-[(S)-3-ethyl-3-(3′-hydroxyphenyl)- azepan-1-yl]-N-[2-(1H-indol-3-yl)ethyl]-octanamide – where R1 is H, R2 is H and m is 3, (‘151, Ex. 9);
7-[(S)-3-ethyl-3-(3'-hydroxy phenyl)-azepan-1-yl]-N-[2-(1H-indol-3-yl) ethyl]-heptamide - where R1 is H, R2 is H and m is 2 (‘151. Ex. 11);
8-[(S)-3-ethyl-3-(3′-hydroxyphenyl)-azacycloheptane-1-yl]-N-[2-(1H-5-methoxyindol-3-yl)ethyl]-octylamide – where R1 is C1alkoxy, R2 is H and m is 3 (‘151, Ex. 12);
8-[(S)-3-ethyl-3-(3′-hydroxyphenyl)-azacycloheptane-1-yl]-N-[2-(1H--5-chloroindol-3-yl)ethyl]-octylamide – where R1 is halogen, R2 is H and m is 3 (‘151, Ex. 13);
8-[(S)-3-ethyl-3-(3′-hydroxyphenyl)-azacycloheptane-1-yl]-N-[2-(1H-5-hydroxyindol-3-yl)ethyl]-octylamide – where R1 is hydroxy, R2 is H and m is 3 (‘151, Ex. 14);
8-[(S)-3-ethyl-3-(3′-hydroxyphenyl)-azacycloheptane-1-yl]-N-[2-(1H-5,6-dimethoxyindol-3-yl)ethyl]-octylamide – where R1 is C1alkoxy, R2 is C1alkoxy and m is 3 (‘151, Ex. 15).
Thus, regarding instant claims 1 and 4; ‘151 discloses a compound of formula (I) as shown above, wherein the compound and defined variables of m, R1 and R2 are identical with the claimed invention (instant claims 1 and 4). Furthermore, ‘151 teaches examples of embodiments, (Ex. 9, 11-15, as listed above), that map onto the claimed invention.
Regarding instant claims 2 and 5; ‘151 teaches the use of the disclosed compound(s), or a pharmaceutically acceptable salt in the preparation of medicament for treating and/ or prevention of neurodegenerative diseases preferably selected from dementia, Parkinson’s disease and Huntington’s disease (‘151 – claim 10). The instant application claims an Nrf2 activator being a compound of Formula I or a pharmaceutically acceptable salt and wherein the Nrf2 activator is used for preparing medicament for treatment and/ or prevention of diseases mediated by Keap1-Nrf2/ARE signaling pathway or mediated by oxidative stress (instant claim 2); and a method as recited in instant claim 5. The compound(s) in the instant application correspond to compound(s) disclosed in ‘151. In addition, ‘151 teaches the compound(s) are used in preparation of medicament for treatment and/or prevention of neurodegenerative diseases preferably selected from dementia, Parkinson’s disease and Huntington’s disease.
Per MPEP § 2112.01, products of identical chemical composition cannot have mutually exclusive properties. "In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). 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.
Accordingly, ‘151 teaches the disclosed compound(s), or pharmaceutically acceptable salt for preparation of medicament for treatment and /or prevention of neurodegenerative diseases. Instant application claims identical compound (s) for preparation of medicament for treatment and/ or prevention of diseases mediated by Keap1-Nrf2/ARE signaling pathway or mediated by oxidative stress. As stated above, a chemical composition and its properties are inseparable, one would expect the compound(s) disclosed in ‘151 to have same properties of, Nrf2 activator, as claimed in the instant application.
Thus, Zheng et al. 2012, CN102816151A anticipates the instant claims 1-2 and 4-5.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al., 2012, (Zheng et al., CN102816151A; Published, 12 December 2012; cited in the IDS), hereon after ‘151, in view of Brandes and Gray, 2020, (Brandes M.S. and Gray N.E., “NRF2 as a Therapeutic Target in Neurodegenerative Diseases”, Review Article, American Society for Neurochemistry, Vol. 12. Pages 1-23; Published December 3, 2019), hereon after, Brandes and Dinkova-Kostava et al., 2018, (Dinkova-Kostava et al. “The role of Nrf2 signaling in counteracting neurodegenerative diseases”, Review Article, The FEBS Journal, 285, page 3576-3590; Published 8 January, 2018), hereon after, Dinkova-Kostava.
Regarding instant claim 1-2 and 4-5; The teachings of Zheng, ‘151, as set forth in the above 35 U.S.C. 102 Rejection are incorporated herein.
‘151 teaches a genus compound of formula (I), or a pharmaceutically acceptable salt and further discloses examples 9,11-15 as discussed above. ‘151 teaches the use of the compound(s), or a pharmaceutically acceptable salt in the preparation of medicament for treatment and/or prevention of neurodegenerative diseases preferably selected from dementia, Parkinson’s disease and Huntington’s disease (‘151 – claim 10). ‘151 cites reactive oxygen species (ROS) as an occurrence in the early stages of neurodegenerative diseases (page 14 - ‘151 - Machine Translate copy).
How prior art differs from instant claim: ‘151 does not distinctly teach compound(s) as Nrf2 activator (instant claims 1-4); or a method of treating and/or preventing diseases mediated by a Keap1-Nrf2/ARE signaling pathway or diseases mediated by oxidative stress (instant claim 5); wherein the disease is amyotrophic lateral sclerosis, Friedrich’s ataxia, multiple sclerosis, apoplexia, follicular abnormal development, premature ovarian failure or infertility (instant claim 6).
Brandes teachings on Nrf2 as a therapeutic target in neurodegenerative diseases reveal that increased reactive oxygen species (ROS) production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions and in aging. Neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Friedrich’s ataxia, multiple sclerosis, and stroke, among others. (Abstract) .
Brandes explains the endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes and is regulated by transcription factor, nuclear factor erythroid 2-related factor (Nrf2). Thus, Nrf2 regulates the expression of antioxidant genes, exerts anti-inflammation effects and modulates both mitochondrial function and biogenesis. Brandes states that because mitochondrial dysfunction and neuroinflammation are features in many neurodegenerative diseases, Nrf2 is a promising therapeutic target (Abstract).
Regarding instant claims 1-6 and Nrf2 activation; Brandes teaches that while Nrf2 activation occurs endogenously in response to increased oxidative stress, it can also be induced by exogenous agents i.e., compounds, that activate the Nrf2 pathway (pg. 8). Furthermore, Nrf2 regulates the endogenous antioxidant response pathway by binding to antioxidant response elements (AREs) in the promoters of oxidant genes (Introduction, pg. 1). Nrf2 is normally bound in cytosol to Kelch-Like ECH-Associated Protein 1 (KEAP1) which causes its proteasomal degradation. Brandes explains that in the presence of electrophiles or oxidative stress, cysteine residues in Keap1 are modified, diminish the Keap1-dependent degradation of Nrf2 and allow the transcription factor to accumulate in the nucleus – which is the classical mode of Nrf2 activation (page 2). The activated Nrf2 in the nucleus binds to antioxidant response element (ARE). Brandes further discusses how examples of Nrf2 activators, activate the Nrf2 via signaling pathways either via cysteine modification on KEAP1, or via disrupting the KEAP1/Nrf2 complex and regulating oxidative stress, or in some cases through induction of AMPK which then phosphorylates Nrf2 (page 10).
Regarding diseases mediated by Keap1-Nrf2/ARE signaling pathway and oxidative stress mediated diseases; Brandes teaches Nrf2 activation as a therapeutic target, that is well established in multiple sclerosis (MS), a chronic inflammatory neurodegenerative disorder. Oxidative stress and mitochondrial dysfunction are prominent features of the MS. Brandes teaches that multiple reports suggest a role for Nrf2 in MS pathogenesis and loss of Nrf2 has been shown to result in more rapid onset of the disease. In addition, Nrf2 activation is a clinical target for treating MS patients. The reference discusses several Nrf2-activating compounds that have demonstrated beneficial results in MS patients (page 3).
Brandes teaches Nrf2 activation is targeted in treatment of Friedrich’s Ataxia, an inherited degenerative neuromuscular disorder. The reference cites increased oxidation stress is thought to be one of the causes leading to chronic depletion of antioxidants and causing neurodegeneration associated with the condition; Brandes further teaches that Nrf2 signaling dysfunction has been widely reported in animals models of Friedrich’s ataxia; a decreased Nrf2 expressed and increased Keap1 expression was observed in a conditional frataxin knockout mice and in contrast Nrf2 activating compounds in neural stem cells isolated from a Friedrich’s ataxia mouse model have been shown to reestablish proper differentiation which was previously impaired in those cells (page 7).
Additionally, Dinkova-Kostova teaches on the role of Nrf2 signaling in counteracting neurodegenerative diseases. Dinkova-Kostova explains although clinical manifestation and genetic causes of neurodegenerative diseases are distinct, several of these disorders share strikingly similar pathological mechanism including mitochondrial impairment, excessive levels of reactive oxygen species (ROS), neuroinflammation and disturbances in protein homeostasis (proteostasis) (3577).
Dinkova-Kostova further explains the function of Nrf2 is altered in many neurogenerative disorders such as amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington disease and Alzheimer’s disease, among others. In addition, Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function and maintenance of protein homeostasis (abstract). Notably, the reference states that, oxidative stress mediated by Nrf2 signaling and neuroinflammation have been implicated as the key therapeutic targets for amyotrophic lateral sclerosis (page 3581).
Dinkova-Kostava illustrates a Fig. 4 (page 3585), on the multiple neuroprotective effects of Nrf2 and human pathologies, showing that Nrf2 activation (i) decreases oxidative stress and neuroinflammation (via down regulation of pro-inflammatory cytokines in astroglia); and (ii) increases antioxidant capacity, mitochondrial biogenesis, removal and clearance of misfolded/mutant proteins (by autophagy and proteasomal degradation). The resulting neuroprotective effects from the two points above lead to amelioration of neuropathology in the various neurodegenerative diseases associated with Nrf2.
Therefore, it would have been obvious to one of ordinary skill in the art either before the effective filling date of the claimed invention or otherwise at the time the claimed invention was to made to arrive at the claimed invention in view of prior art with reasonable expectation of success.
Per MPEP § 2144.07, a prima facie case of obviousness exists for the selection of known material based on its suitability for its intended use. In addition, per MPEP § 2144.05(I), a prima facie case of obviousness exists when the claimed invention overlaps with, or is close to prior art.
Prior art ‘151 teaches a genus compound along with exemplified embodiments that read on the claimed structure in the instant invention but treating different conditions namely, neurodegenerative diseases, preferably selected from dementia, Parkinson’s disease and Huntington’s disease. ‘151 teaches reactive oxygen species are known as markers of early stages of neurodegeneration.
Brandes and Dinkova-Kostova teach Nrf2 activation mitigates multiple pathogenic processes involved in neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, Friedrich’s ataxia, multiple sclerosis, and stroke, among others. Dinkova-Kostova teaches the neurological disorders share strikingly similar pathological mechanism including mitochondrial impairment and excessive levels of reactive oxygen species (ROS), among others and they are targeted for treatment via Nrf2 signaling-pathway. Brandes teaches the relationship between Nrf2 and Keap1 – that Nrf2 is bound by Keap1, but electrophilic or oxidative stress result in Nrf2 activation and that the activated Nrf2 bind to ARE. Brandes also teaches Nrf2 activation can be induced using exogenous Nrf2 activating agents.
Thus it would have been obvious to claim an Nrf2 activator, a compound represented by Formula I or pharmaceutically acceptable salt (instant claim 1), wherein the Nrf2 activator is used for preparing a medicament for treatment and/or prevention of a disease mediated by a Keap1-Nrf2/ARE signaling pathway and /or a disease mediated by oxidative stress (instant claim 2); wherein the Nrf2 activator used for treatment and /or prevention of diseases as recited in instant claim 3; a compound with further limitations of variables as recited in instant claim 4; a method of treatment and /or preventing diseases mediated by a Keap1-Nrf2/ARE as recited in instant claim 5; a method wherein the disease is further limited as recited in instant claim 6.
One of ordinary skill in the art would have been motivated to arrive at the claimed invention because (i) The claimed compound(s) were known from previous disclosure (ii) The prior art was drawn to neurodegenerative disorders Alzheimer’s, Parkinson’s and Huntington’s diseases (iii) all the neurological diseases in ‘151 and those claimed in the instant application are known to share similar pathological mechanism and (iv) the diseases are mediated by oxidative stress and targeted for treatment via a Keap1-Nrf2/ARE signaling pathway.
Claims 3 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al., 2012, (Zheng et al., CN102816151A; Published, 12 December 2012; cited in the IDS), hereon after ‘151, in view of Brandes and Gray, 2020, (Brandes M.S. and Gray N.E., “NRF2 as a Therapeutic Target in Neurodegenerative Diseases”, Review Article, American Society for Neurochemistry, Vol. 12. Pages 1-23; Published December 3, 2019), hereon after, Brandes and Dinkova-Kostava et al., 2018, (Dinkova-Kostava et al. “The role of Nrf2 signaling in counteracting neurodegenerative diseases”, Review Article, The FEBS Journal, 285, page 3576-3590; Published 8 January, 2018), hereon after, Dinkova-Kostava, and further in view of Englehardt E. 2017, (Englehardt E., “Apoplexy, cerebrovascular disease and stroke history; Dement Neuropsychol, Vol. 11, Issue 4, page 449-453; Published October 16, 2017), hereon after Englehart, and Akino et al., 2019 (Akino et al. “Activation of Nrf2/Keap1 pathway by oral dimethyl fumarate administration alleviates oxidative stress and age associated infertility might be delayed in the mouse ovary” Reproductive Biology and Endocrinology. Vol. 17, (23) page 1-10; Published February 13, 2019 – Cited in the IDS) hereon, Akino.
All the teachings of Zheng - ‘151, Brandes and Dinkova-Kostava as set forth in the above 35 U.S.C. 103 Rejection are incorporated herein.
Prior art does not distinctly teach on the limitation apoplexia, follicular abnormal development, premature ovarian failure or infertility as recited in instant claims 3 and 6.
Regarding apoplexia, Englehardt teaches the term apoplexy (or apoplexia) is an older term for a cerebrovascular condition that is now covered under the term stroke (page 450).
Brandes teaches concerning Nrf2 and stroke; that a cascade of biochemical events occur following ischemic stroke that promote tissue damage including inflammatory activation and mitochondrial dysfunction leading to an overproduction of ROS. Animal studies have shown that mice in which Nrf2 has been deleted have enhanced infarct size, inflammatory response and neurobehavioral deficits when compared with Nrf2 expressing mice. Conversely, Nrf2 activation has been shown to be beneficial in protecting the brain from injury (page 7).
Regarding follicular abnormal development, premature ovarian failure or infertility; Akino teaches age-associated infertility is a problem that is associated with oxidative stress. Notably, Akino reveals that Nrf2/Keap1-antioxidant response element (ARE) signaling pathway works as the essential defense mechanism against oxidative stress (abstract).
Akino teaches oxidative stress (OS) as state characterized by an imbalance between reactive oxygen species and antioxidant scavenger enzymes; Akino explains that although an adequate amount of reactive oxygen species (ROS) is known to be necessary for normal ovulation, exposure of excess ROS is unfavorable for oocytes resulting in infertility (page 2).
Akino further discusses results from a mice study, comparing mice oocytes between a control group and a group treated with an Nrf2 activator, dimethyl fumarate (DMF). Following controlled ovarian stimulation, significantly more oocytes were collected from the DMF treated mice oocytes compared to the control, approx. 5.1 vs 0.8 oocytes per mouse respectively – indicating a positive effect of an Nrf2 activator on ovarian reserve; additionally DMF decreased oxidative stress in ovarian tissue, and more primordial follicles survived – a hall mark of mammalian female reproductive competence (pg. 5-7). Akino states Nrf2/Keap1 pathway is one of the most important mechanisms against oxidative stress (page 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the instant claimed invention with reasonable expectation of success.
Brandes teaches overproduction of reactive oxygen species in stroke also referred to as apoplexia based on Englehardt teachings. Akino teaches oxidative stress is associated with infertility, follicle abnormal development and premature ovarian failure. Akino also teaches the importance of Nrf2/ Kea1p pathway against oxidative stress.
Accordingly, it would have been obvious to claim an Nrf2 activator, wherein the Nrf2 activator is used to prepare a medicament for treatment and /or prevention of apoplexia, follicular abnormal development, premature ovarian failure or infertility (instant claim 3) and a method according to the claimed compound wherein the disease is apoplexia follicular abnormal development, premature ovarian failure or infertility (instant claim 6).
One would have been motivated to do so because it is known from prior art that (i) Nrf2/Keap1 pathway is one of the most important mechanisms against oxidative stress (ii) oxidative stress plays a big role in both apoplexia and the conditions associated with infertility; (iii) the claimed compounds are known and previously used to treat other neurodegenerative diseases mediated by oxidative stress.
Conclusion
Claims 1-6 are rejected. No claim is allowed.
Communication
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/P.O./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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