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 .
Non-Final Rejection
The Status of Claims:
Claims 1, 7,9,18, 22-23, 27-28, 35,42,49,56,62-63,134,151, 153,161,174-175 are pending.
Claims 1, 7,9,18, 22-23,151,153,161,174 are rejected.
Claims 1, 9, 23 and 161 are objected.
Claims 27-28, 35, 42, 49, 56, 62-63, 175 are withdrawn from consideration.
DETAILED ACTION
1. Claims 1, 7,9,18, 22-23,151,153,161,174 are under consideration in this
Office Action.
Priority
2. It is noted that this application is a 371 of PCT/US21/65049 12/23/2021 , which has a priority of 63130011 12/23/2020.
Drawings
3. The drawings filed on 6/22/23 are accepted by the examiner.
IDS
4. The IDS filed on 7/6/23, 2/2/24,2/06/25,12/03/25 were reviewed by the
examiner.
Claim Objections
Claims 1, 9, 23, and 161 are objected to because of the following informalities:
In claims 1, 9, 23, and 161, the parentheses in the limitations “(i.e., to form a carbamate)”, “ (e.g., methyl, …,or cyclohexyl)”, “(e.g., phenyl)” , “(e.g., thiophenyl)”, ” (e.g., L-malate)”, “(e.g., L-aspartate)”, (e.g., L-glutamate)”, or “(e.g., L-tartrate)”, “(including, e.g., Creutzfeldt-Jakob Disease, variant Creutzfeldt-Jakob Disease, Bovine Spongiform Encephalopathy (BSE),Kuru, Gerstmann-Straussler-Scheinker disease, fatal familial insomnia (FFI), scrapie, andother animal TSEs)” and “ (MND: including, e.g., Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Progressive Bulbar Palsy (PBP),Pseudobulbar Palsy, Progressive Muscular Atrophy, Spinal Muscular Atrophy (Type 1, Type 2, Type 3, Type 4)” are recited. These can be confusing . the examiner recommends to remove the parentheses from the claims.
Appropriate correction is required.
Election/Restriction
Applicant’s election with traverse of Group I (claims 1, 7,9,18, 22-23,151,153,161,174) on 12/03/2025 is acknowledged.
Claims 27-28, 35, 42, 49, 56, 62-63, 175 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to the nonelected groups II-V there being no allowable generic or linking claim.
The elected species:
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is found to be allowable.
Applicants Argue in the followings:
The Examiner contends that the claims lack special technical features because "the structura element shared by all the inventions is,. "·
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, without Rl, R3, substituents .. .is well-known in the art." Applicants respectfully disagree, at least because the structures recited in the pending claims require a substituent at the R 1 position. Even if the Examiner considers that the aminonorbornane core is disclosed in the art, this does not negate the unity of invention for compounds having the specific substitution pattern as recited in the claims. Although the Restriction Requirement cites generally to the corresponding PCT Search Report, the Examiner has provided no explanation as to how any of the references listed therein relate to the pending claims.1
Accordingly, Applicants submit that the Examiner has not established that the alleged special technical feature is disclosed in the cited art, and respectfully request reconsideration of the Restriction Requirement.
Regarding applicant’s arguments, the examiner has considered them. However,
there is still a lack of the unity among the claimed i inventions in the followings:
for example, the invention of Group I is drawn to compounds of formula (I):
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, whereas the invention of Group III is the first process of making compounds of formula VI:
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.
However, according to Dvela-Levitt et al (Cell 178, July 25,2019, 521–535),
it does disclose the following compound:
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, which can be used for the treatment of MKD and other toxic proteinopathies.
From this, they lack a special technical feature between them since Dvela-Levitt et al does disclose BRD4780, which is the same as the invention of Group I. Thus, formula (I) can not serve as a “specifical technical feature” to confer the unity of the invention. Therefore, there is no special technical feature between them and no single general inventive concept and no unity of invention for the method or the process as defined in 37 CFR 1.475.
For another example , the invention of Group I is drawn to compounds of formula (I):
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, whereas the invention of Group IV is the second process of making compounds of formula VI:
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However, according to Dvela-Levitt et al (Cell 178, July 25,2019, 521–535),
it does disclose the following compound:
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, which can be used for the treatment of MKD and other toxic proteinopathies.
From this, they lack a special technical feature between them since Dvela-Levitt et al does disclose BRD4780, which is the same as the invention of Group I. Thus, formula (I) can not serve as a “specifical technical feature” to confer the unity of the invention. Therefore, there is no special technical feature between them and no single general inventive concept and no unity of invention for the method or the process as defined in 37 CFR 1.475.
For third example , the invention of Group I is drawn to compounds of formula (I):
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, whereas the invention of Group V is the a process of making compounds of formula VII.:
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However, according to Dvela-Levitt et al (Cell 178, July 25,2019, 521–535),
it does disclose the following compound:
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, which can be used for the treatment of MKD and other toxic proteinopathies.
From this, they lack a special technical feature between them since Dvela-Levitt et al does disclose BRD4780, which is the same as the invention of Group I. Thus, formula (I) can not serve as a “specifical technical feature” to confer the unity of the invention. Therefore, there is no special technical feature between them and no single general inventive concept and no unity of invention for the method or the process as defined in 37 CFR 1.475.
Similarly, the similar/same reasoning can be applied between the invention of Group I and that of Group II.
Thus, the requirement is still deemed proper and is therefore made FINAL.
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, 7,9,18, 23, 151,153,161,174 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
In claim 1 , a limitation “(i.e., to form a carbamate)” is recited. The expression of “i.e.” can be indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In claim 9 , the limitations “ alkyl (e.g., methyl, …,or cyclohexyl)”, and “aryl (e.g., phenyl)” and “ heteroaryl (e.g., thiophenyl)” are recited. The phrase "for example" or the expression “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In claim 23 , the limitations” malate (e.g., L-malate)”, “aspartate (e.g., L-aspartate)”, “glutamate (e.g., L-glutamate)”, or “tartrate (e.g., L-tartrate)”are recited. The phrase "for example" or the expression “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In claim 161 the phrases “ prion disease (including, e.g., Creutzfeldt-Jakob Disease, variant Creutzfeldt-Jakob Disease, Bovine Spongiform Encephalopathy (BSE),Kuru, Gerstmann-Straussler-Scheinker disease, fatal familial insomnia (FFI), scrapie, andother animal TSEs)” and “ motor neuron diseases (MND: including, e.g., Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Progressive Bulbar Palsy (PBP),Pseudobulbar Palsy, Progressive Muscular Atrophy, Spinal Muscular Atrophy (Type 1, Type 2, Type 3, Type 4)” are recited. The phrase "for example" or the expression “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, the term ”including” can be vague because the claim does not explain or limit what is excluded from the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 161 recites the broad recitation “ a proteinopathy”, and the claim also recites “ the proteinopathy is preferably selected from” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 151,153,161,174 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating specific diseases, does not reasonably provide enablement for preventing a toxic proteinopathy or a proteinopathy or preventing MUC1-associated kidney disease (MKD) in a subject or at risk of developing a proteinopathy. 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. Applicants are not enabled for preventing any of the diseases. The only established prophylactics are vaccines not the claimed drug such as present here. In addition, it is presumed that “prevention” of the claimed diseases would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted.
“The factors to be considered [in making an enablement rejection] have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art, and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. 1) As discussed above, preventing diseases requires identifying those patients who will acquire the disease before a toxic proteinopathy or a proteinopathy or MUC1-associated kidney disease (MKD) occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 3) The claims rejected are drawn to clinical preventative medicine and are therefore physiological in nature. 4) The state of the art is that no general procedure is art-recognized for determining which patients generally will become the patients with preventing a toxic proteinopathy or a proteinopathy or preventing MUC1-associated kidney disease (MKD) in a subject a before the fact. 6) The artisan using Applicants invention would be a Board Certified physician in a toxic proteinopathy or a proteinopathy or MUC1-associated kidney disease (MKD) in a subject with an MD degree and several years of experience. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of a toxic proteinopathy or a proteinopathy or MUC1-associated kidney disease (MKD) in a subject ibrosis in the subject generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent psoriasis generally. That is, the skill is so low that no compound effective generally against the fibrosis has ever been found let alone one that can prevent such conditions. 7) It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases.
The Examiner suggests deletion of the word “preventing” or “ prevention” or “at risk of “ from the claims.
Claims 151, 153, 161 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding Claim 153, it is directed to a method of treating the toxic proteinopathy selected from a neurodegenerative disease; furthermore, Claim 161 is directed to a method for treating or preventing a proteinopathy resulting from mutant protein accumulation in the early secretory pathway in a subject, wjerein the proteinopathy is selected from neurodegenerative disease , Alzheimer's disease (AD) and other dementias: Parkinson's disease (PD).
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.[4] Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies (like proteinopathy) and induced cell death.
Parkinson's disease is a progressive neurodegenerative disorder (synucleopathy) diagnosed on the basis of characteristic motor disturbances, asymmetry of symptoms onset and response to levodopa (Litvan et al., 2003). Lewy bodies, neurofibrillary tangles and plaques are observed in nigral, limbic and neocortical regions. These degenerations are supposed to affect catecholaminergic (dopamine and norepinephrine) and cholinergic neurotransmission. In particular, an important part of cognitive deficits (executive function and working memory) have been related to a decreased prefrontal dopaminergic signaling in non demented patients (Nandakumar et al., 2013).
Regarding Alzheimer’s Disease (AD), many scientists and medical doctors are in search for finding the main causative factors in order to treat the Alzheimer’s Disease. For example, according to Meda et al (Nature 374,647 (1995) and Larner (Neurosci. Res. Commun. 20 , 147 (1997), [Arial font/0x62]-amyloid peptide was shown to exert direct toxic effects on neutrons and to inhibit neurite growth in vitro. Thus, therapeutic approaches that can modulate [Arial font/0x62]A peptide toxicity have been hypothesized to represent important methods for controlling the onset of AD. It is postulated that if neuronal cells can be protected from A peptide/senile plaque-induced toxicity, the onset of AD may be delayed; furthermore, St. George-Hyslop et al (Nature 400, 116 (1999) indicates that an anti-[Arial font/0x62]A protein antiboby was shown to clear senile plaques and protect mutant PDAPP mice from the onset of AD. From this, the generation of reactive oxygen intermediates through oxidative stress caused by A peptide has been suggested to be the major pathway of A peptide-induced cytotoxicity. Thus, there is no positive correlation between the peptide-induced toxicity against certain cells and the treatment as claimed.
Regarding the working examples for treating neurodegenerative diseases such as Parkinson's disease and Alzheimer’s Disease and others, there is no actual working example for those diseases-treatment by using the claimed compounds in the patient with the compounds except for the examples of biological properties of compounds regarding the level of levels of MUC1-fs and MUC1-wt. Also, the compounds which are disclosed in the specification have no pharmacological data regarding the treatment of those diseases with neurological components using the claimed compounds. Moreover, the specification fails to provide sufficient working examples as to how those diseases can be treated by the compounds using the MPO activity in the patient with, i.e. again, there is no direct correlation between the listed diseases and the claimed compounds.
The specification falls short because data essential for treating any neurodegenerative diseases such as Parkinson's disease and Alzheimer’s Disease is not described in the specification.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 7, 9 , 18 are rejected under 35 U.S.C. 102(a)(1) as being
anticipated clearly by Alder et al(Berichte der Deutschen Chemischen
Gesellschaft Abteiluna B: Abhandlunaen 71.12 (1938): 2451-2461).
Alder et al discloses the following compounds:
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(see page 2452, compounds#XIII &XIV)
These are identical with the claims.
Claim(s) 1, 7, 9 , 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated clearly by Manetti et al ( J. Med. Chem. 2019, 62, p. 1887-1901)..
Manetti et al discloses the following compound and its pharmaceutical composition :
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(see page 1890, Scheme 1)
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(see page 1889, Table 1) These are identical with the claims.
Claim(s) 1, 7, 9 , 18, 22-23, 151,153,161,174 are rejected under 35 U.S.C. 102(a)(1) as being anticipated clearly by Dvela-Levitt et al (Cell 178, July 25,2019, 521–535).
Dvela-Levitt et al discloses that BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathie clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. (see page 521, a section of summary)
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(see page 526, Figure 3 , A).
These are inherently identical with the claims
Conclusion
Claims 1, 7,9,18, 22-23,151,153,161,174 are rejected.
Claims 1, 9, 23 and 161 are objected.
Claims 27-28, 35, 42, 49, 56, 62-63, 175 are withdrawn from consideration.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAYLOR V OH whose telephone number is (571)272-0689. The examiner can normally be reached 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached on 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TAYLOR V OH/Primary Examiner, Art Unit 1625 1/09/2023