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 .
DETAILED ACTION
Claim 1, 6-10 and 35-43 are pending and are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/27/2025, 02/29/2024, 05/19/2025 and 02/02/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a U.S. National phase application under 35 U.S.C 371 of PCT application PCT/JP2022/026755, filed 07/05/2022, which claims benefit under Title 35 U.S.C 119 to Japanese patent application no. JP2021-113378 filed on 07/08/2021. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Claim Rejections - 35 USC § 112 1st Paragraph
The following is a quotation of the first paragraph of 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 12-31 are rejected under 35 U.S.C. 112, first paragraph, because the specification , while being enabling for suppression of Dopamine oxidation accelerated in presence of Iron Ions by addition of glutathione trisulfide, pantethine trisulfide, N,N'-diacetyl-L-cysteine trisulfide does not reasonably provide enablement for preventing or treating Parkinson’s disease, the method comprising administering a trisulfide compound, and a drug utilized in dopamine replacement therapy or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, a compound represented by Formula (1):. wherein X represents -OR1 or -NR2R3, R1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R(2 and R(3 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, the alkyl group optionally having one or more substituents selected from the group consisting of an amino group and a carboxy group, a pharmaceutically acceptable salt thereof or a cyclodextrin clathrate thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine trisulfide or a pharmaceutically acceptable salt thereof. The claims 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.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and the nature of the invention
The nature of the invention is a method for preventing or treating Parkinson's disease, the method comprising administering a trisulfide compound, and a drug utilized in dopamine replacement therapy or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, a compound represented by Formula (1):
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174
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wherein X represents -OR1 or -NR2R3, R1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R(2 and R(3 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, the alkyl group optionally having one or more substituents selected from the group consisting of an amino group and a carboxy group, a pharmaceutically acceptable salt thereof or a cyclodextrin clathrate thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine trisulfide or a pharmaceutically acceptable salt thereof.
The breadth of the claims is extensive
Scope of the diseases covered
The applicants claim Prevention and treatment of Parkinson’s disease with the combination of the trisulfide compounds with drug utilized in dopamine replacement therapy.
The term "prevention' can be construed broadly as either prevention of the increase in clinically evident symptoms of the Parkinson’s disease altogether or preventing the onset of a preclinically evident stage of the Parkinson’s disease in individuals at risk. In other words, the instant claims are drawn to a composition and method of preventing all preclinical stages of any and all stages of Parkinson;s disease, which includes any undetectable stages of the disease.
Scope of the compounds covered
This is extensive considering the variables which can be used for X in the compound of formula I as defined in the claims
The state of the prior art and the predictability or lack thereof in the art
The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific disease). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic or preventive regimen on its face.
The instant claimed invention is highly unpredictable as discussed below:
Parkinson’s Disease(PD) is a neurodegenerative disorder which, like most neurodegenerative disorders, has been highly resistant to pharmaceutical treatment. The disease is characterized primarily by the degeneration and death of dopamine-producing cells in the substantia nigra, located in the midbrain, along with the presence of cytoplasmic protein inclusions called Lewy bodies. However, PD is recognized as a very extensive pathology that covers many neurotransmitter systems as well as the autonomic nervous system. Non-dopamine symptoms include bowel and bladder problems, attacks of low blood pressure, falling, “freezing,” sleep disorders, pain, depression, speech difficulties, and dementia. PD is widely considered to be a cluster of related disorders. The majority of cases of PD are deemed sporadic, but there are also familial forms of PD. This death in the substantia nigra is of unknown origin (idiopathic), and cannot itself be stopped. Current drug regimens for Parkinson’s disease are aimed instead at symptomatic relief, primarily through a dopaminergic effect. This includes dopamine replacement therapy (L-dopa), COMT inhibitors (which facilitate the conversion of L-Dopa to dopamine itself), Amantadine (which appears to increase dopamine synthesis in the remaining cells), dopamine agonists (which mimic dopamine) or MAO B inhibitors (e.g. Selegeline which reduces or delays the breakdown of dopamine). These do not actually treat the disease itself, but instead seek to boost the amount of dopamine available by various mechanisms. With regards to utilizing antioxidants in the therapy for Parkinson’s disease, Martinez-Banaclocha (Antioxidants, 2023, 12, 1373 pages 1-31) teaches that the central role of oxidative stress in PD was shown a long time ago, including its harmful effects on specific proteins implicated in the pathophysiology of the disease. Likewise, aging impairs oxidative phosphorylation, decreases GSH levels, and increases oxidative species in the mitochondrial dopaminergic system Indeed, low levels of GSH seem to be the first biochemical event identified in the substantia nigra of early PD patients, which may contribute to the damage of susceptible proteins via oxidative modifications. Also, a decreased reduced/oxidized glutathione ratio correlates with the severity of PD, and it is the earliest indicator of dopaminergic neurodegeneration associated with mitochondrial complex I deficiency. The accumulation of oxidative damage decreases the antioxidant ability impairing the mitochondrial energetic power in the brain via mechanisms that include protein oxidation and the deregulation of the cysteine proteome, which are the basis for supplying GSH precursors in PD. Any therapy contributing to the redox proteome rejuvenation can potentially modulate highly regulated biological processes but can also have harmful secondary effects (page 19, under conclusions and future perspectives).
.Borah et al. (Medical Hypotheses 79 (2012) 271-273) discloses that till date the cause and the progressive nature of the PD is not yet known. Earlier studies have established that endogenous molecule (such as 6-OHDA) can be produced in parkinsonian brain after L-DOPA therapy and the level of which can be attenuated by scavengers of anti-oxidants (conclusion ) and Hypothesizes that that L-DOPA induced increase in endogenous 6-OHDA levels will have the ability to cause oxidative stress and mitochondrial dysfunctions that eventually leads to Lewy body formation in dopaminergic neurons resulting in its degeneration. Concomitant use of potent anti-oxidants along with L-DOPA would help in attenuating the neurodegeneration caused by endogenous 6-OHDA and would ultimately delay the progression of PD (Abstract), but they do not show any experimental data to confirm their hypothesis.
At the time of filing, and indeed at present, no drug has been scientifically demonstrated to treat Parkinson’s disease let alone prevent it itself, rather than provide relief for this or that symptom, such as bradykinesia, tremors, and other motor symptoms, constipation, poor balance, etc.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. Drugs that are used to treat the central nervous system (CNS) face several hurdles. First of all, the drug needs to be able to reach the site of action. There are several natural barriers to drug penetration into the CNS including physical impediments, such as the blood-brain barrier and blood-cerebral spinal fluid barrier, in addition to the presence of drug specific transporters in the cells comprising these barriers. A drug intended for the CNS must cross the blood-brain barrier either via passive diffusion or receptor-mediated transport. Typically the more lipid-soluble a drug, the easier it is for it to successfully penetrate the physical barriers present in the CNS. . Nature has put in place a formidable set of barriers to prevent drug penetration into the CNS. Agents targeting neurodegenerative diseases must overcome them in order to be effective. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to therapeutic and preventive effects of Parkinson’s disease , whether or not the disease is effected by the instantly claimed compounds and more importantly, if all the compounds encompassed by the claims can even penetrate the blood-brain barrier, would make a difference.
The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific disease). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic or preventive regimen on its face.
Parkinson’s disease is an inherited disease conditioned by abnormal movements, dementia and psychiatric problems. Accordingly for prevention of this disease first requires a genetic screening to identify if indeed the person has a potential for developing this disease. Further , prevention of occurrence of Parkinson’s disease in a person prone to that disease is not possible as such subject suffering from this disease is treated with medications aimed at easing different symptoms associated with this disease as detailed above, Accordingly, prevention of the occurrence of Parkinson’s disease in subjects who have not inherited the faulty gene from their parents is not needed since they will not get the disease and the prevention of the occurrence of Parkinson’s disease in subjects who have inherited the faulty gene from their parents is impossible.
Skill of those in the art:
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine the combination of each of the claimed trisulfide compounds with each of the dopamine rescue drugs known in the art, exhibit the ability to cure and prevent Parkinson’s disease
The amount of direction or guidance present and the presence or absence of working examples
The only direction or guidance present in the instant specification is in Example 1, Suppression test of dopamine oxidation accelerated in presence of Iron ions: Here applicants have tested just four trisulfide agents, glutathione trisulfide, Lipoic acid trisulfde, Pantethine trisulfide and N,N’-diacetyl-L-Cysteine trisulfide at three specific concentrations. , the results showed that these agents suppressed the dopamine oxidation in the presence of Iron and they make a prediction that this administration would enhance the therapeutic effect of the dopamine replacement therapy.
Applicants do not present any working examples invitro or in vivo showing the actual ability of these agents to enhance the effect of the dopamine replacement therapy. There is no examples showing them used together. Additionally, the disclosure is bereft of any information as to how the in vitro data presented correlates to the improvement of any specific condition or symptom associated with the myriad symptoms of Parkinson’s disease. It is also noted that applicants have not provided any working examples for the instantly claimed kit and pharmaceutical composition comprising the trisulfide compounds and the dopamine replacement therapy.
Furthermore, Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the clinical use of the instantly claimed compounds in terms of dosage, administration methods and specific conditions or symptoms of Parkinson;s which are improved. Pharmacological activity in general is a very unpredictable area, especially in dealing with the CNS.
The quantity of experimentation needed
The quantity of experimentation needed is undue. First of all, one of skill in the art would need to determine whether or not these compounds have any physiological effect in vivo on the CNS. One of skill in the art would first need to know the compatibility of the claimed trisulfide compounds with the dopamine replacement therapy and also need to determine if these combination is effective to treat each and every one of the myriad symptoms of Parkinson’s. Secondly, in terms of prevention, these agents needs to be studied in subjects who do not show any symptoms of any of the Parkinson’s disease and evaluating prevention of this diseases would requires an enormous amount of experimentation.
6.Conclusion
Thus, the specification fails to provide sufficient support of the broad use of the instantly claimed compounds in combination with dopamine replacement therapy for the prevention and treatment of Parkinson’s disease, in order to practice the claimed invention.
Thus, factors such as “sufficient working examples”, “the level of skill in the art”, and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instant claimed methods. In view of the breadth of the claims, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compound or combination of compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate with the scope of the claims.
Genetech Inc. V. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, 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”.
Therefore, in view of the Wands factors discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompasses in the instant claims, with no assurance of success. Thus, rejection of claims 12-31 under 35 U.S.C. §112, first paragraph, is deemed proper.
Conclusion
Claims 12-31 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/Primary Examiner, Art Unit 1691