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
The instant application is a 35 USC 371 National Stage filing of international application PCT/KR2022/018008, filed November 15, 2022, which claims priority under 35 USC 119(a)-(d) from Korean application KR10-2021-0157942, filed November 16, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) dated May 14, 2024 was in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS was considered and a signed copy of the 1449 form is attached.
Status of the Claims
Currently, claims 1-10 are pending in the instant application all of which are under consideration herein.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 5-7 and 9 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 the intended use of treating particular diseases in a subject already having the condition is not enabling for the full scope of the claims which also include improving all types of cognitive function, which includes preventing or treating degenerative brain disease (claim 6), which may be Alzheimer’s disease, ALS, brain tumor, MS, Huntington’s disease, and many others. 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
The above factors, regarding the present invention, are summarized as follows:
The Nature of the Invention
The nature of the invention therefore, is the treatment of a very broad class of diseases and disorders, many of which would not be reasonably expected to have the same pathologies or be affected by the same receptors and drugs.
The State of the Prior Art and the Predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific diseases by what mechanism). 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 preventative regimen on its face.
The instantly claimed invention is highly unpredictable as discussed below. 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 instantly claimed invention is highly unpredictable since one skilled in the art would not readily recognize, in regards to their preventative effects on depression, whether or not the instantly claimed agents would have any effect.
For example, the claimed “degenerative brain disease” encompasses any and all degenerative diseases affecting the brain, spinal cord, nerves or myelin, including but not limited to: Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and many others. These diseases/disorders are of a wide range of origins, including infection (for example, by prions), tumors, autoimmune and genetic defect. Among these diseases, which serve merely as some examples of the extraordinary breadth of claimed diseases, are any type of cancer affecting the brain, which would not be expected to be treatable by the same method as autoimmune diseases which are notoriously difficult to treat and recognized in the art as being impossible to prevent (see MedLine Plus article). It is known in the art that the treatment and development of new treatments for autoimmune diseases such as multiple sclerosis is notoriously difficult. This is a result of the fact that the “underlying mechanisms associated with the pathology of these autoimmune diseases remain unknown” (Wang et al., J. Immunol. 2007, 179, pp.5958-65, See Introduction). For diseases, such as MS, with pathologies that have yet to be discovered there can be no nexus between in vitro tests and in vivo results. That is, although there are suspicions and speculations as to the pathways that may be involved in disease development and progression, because there is no definitive pathology known in the art at this time, it is not possible to say with any confidence that a compound with any particular in vitro assay results will be able to successfully treat a disease which has alluded researches for many years.
With regard to the cognitive dysfunction, for which there is currently no treatment, patients with schizophrenia show significant deficits in specific cognitive domains, especially executive function, working memory, and episodic memory. Cognitive domains which are dysfunctioning in these two disorders are complex functions involving many neurotransmitters and brain regions; however, dopamine signaling in the dorsolateral prefrontal cortex (DLPFC) has been shown to play a critical role in these processes (Goldman-Rakic, Castner et al. 2004). One approach to rectifying cortical dopamine neurotransmission is to take advantage of the differential modes of clearance of dopamine from the different brain regions. In the midbrain, there is extensive expression of the dopamine transporter (DAT), which is thought to be primarily responsible for dopamine clearance from the synapse (Ciliax, Heilman et al. 1995). In contrast, cortical regions exhibit only low levels of DAT expression, and dopamine is cleared primarily by enzymatic catabolism of dopamine, with a contribution from the norepinephrine transporter (NET) (Yavich, Forsberg et al. 2007; Kaenmaki, Tammimaki et al. 2010). The primary enzymes responsible for dopamine catabolism in the prefrontal cortex ("PFC") are monoamine oxidase (MAO) and catechol-O-methyltransferase ("COMT").
Neurological disorders are diseases of the central and peripheral nervous system. In other words, the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscles. There are more than 600 diseases of the nervous system. These disorders include epilepsy, Alzheimer disease and other dementias, cerebrovascular diseases including stroke, migraine and other headache disorders, multiple sclerosis, Parkinson's disease, neuroinfections, brain tumours, traumatic disorders of the nervous system due to head trauma, and neurological disorders as a result of malnutrition.
Moreover, cognitive disorders are disorders in a brain that prevents someone from thinking well, from solving problems, or from storing information. Three main types of cognitive disorders are: Delirium, Dementia, and Amnesia.
Delirium - is a severe disturbance in consciousness and thought that is not better accounted for by dementia. Delirium is likely to have a sudden onset, be variable, and have a better chance of remission than dementia. Delirium involves disorientation and memory loss, along with distorted consciousness and cognitive deficits. The victim may not know what time it is, or where she or he is, or be able to speak coherently. Short-term memory loss is almost always noted. The patient is usually agitated, with the agitation worse at night; if in the hospital, the patient may fight, break things or tear out intravenous tubes, and have to be restrained. The onset of delirium is typically fairly sudden, taking a few hours to a few days, and delirium rarely lasts for more than a month; unfortunately, one reason for this is that the patient may die. Especially for this reason, the occurrence of delirium is a clear medical emergency calling for prompt treatment. One cause of delirium is substance intoxication via overdoses of drugs or exposure to toxins, or withdrawal from drugs. Another is various medical conditions, brain trauma caused by an accident or stroke, for example. The type of delirium is determined by what caused it; for example, two types are substance intoxication delirium and delirium caused by a medical condition.
If intoxication or treatable medical problems are detected and treated, the delirium is probably reversible. If treatment is not possible, permanent brain damage is either present or likely to develop, and the delirium may progress to dementia.
Delirium can be subcategorized into one of the following depending on the causes:
From substance intoxication From withdrawal From multiple causes
Dementia, like delirium, involves cognitive deficits, but the deficits are different. One universal characteristic of dementia is short-term memory loss. It may be accompanied by inability to find words (aphasia), to recognize objects (agnosia), or to carry out a sequence of motor activities (apraxia), despite the ability to make the individual movements. The onset of dementia tends to be more gradual than the onset of delirium, and may go unnoticed for long periods. The person with dementia may behave quite inappropriately, for example by telling dirty jokes to strangers or exposing genitalia. Violent behavior, although less common than in cases of delirium, sometimes occurs. In early cases of dementia, when the individual is aware of his or her deteriorating condition but still able to execute plans, suicide is a possibility.
Despite the fact that many causes of dementia are age-related, one should not assume that dementia is a normal consequence of aging. Although little can be done to prevent or ameliorate dementia in many cases, a medical examination is necessary in order to evaluate causes and possible treatments. One study of cases of dementia at three centers showed that 26% of the cases were treatable. The most common treatable cases are those with chronic drug toxicity, major depression, normal pressure hydrocephalus, or operable brain masses.
Amnesia - is loss of memory; it is retrograde if memories before a fixed event are lost, and anterograde if memories after a fixed event are lost. An individual may have both kinds of amnesia.
Amnesias, as the name indicates, are characterized by memory losses without sufficient cognitive deficits to indicate a diagnosis of delirium or dementia, and can be subcategorized into those: caused by medical conditions, caused by substance abuse, etc. As shown above, the disorders of central nervous system (CNS) are very broad and the disorders also vary one from the other. It is also shown that cognitive and motor disorders are also broad in nature and the disorders vary one from the other. The burden is on applicants, to show that the claimed compound can treat the disorders that are listed above.
A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant or cancerous tumors and benign tumors. Cancerous tumors can be divided into primary tumors that start within the brain, and secondary tumors that have spread from somewhere else, known as brain metastasis tumors
Epidemiological studies are required to determine risk factors. Aside from exposure to vinyl chloride or ionizing radiation, there are no known environmental factors associated with brain tumors. Mutations and deletions of so-called tumor suppressor genes, such as P53, are thought to be the cause of some forms of brain tumor. Inherited conditions, such as Von Hippel–Lindau disease, multiple endocrine neoplasia, and neurofibromatosis type 2 carry a high risk for the development of brain tumors. People with celiac disease have a slightly increased risk of developing brain tumors.
When a brain tumor is diagnosed, a medical team will be formed to assess the treatment options presented by the leading surgeon to the patient and his/her family. Given the location of primary solid neoplasms of the brain in most cases a "do-nothing" option is usually not presented. Neurosurgeons take the time to observe the evolution of the neoplasm before proposing a management plan to the patient and his/her relatives. These various types of treatment are available depending on neoplasm type and location and may be combined to give the best chances of survival:
Surgery: complete or partial resection of the tumor with the objective of removing as many tumor cells as possible.
Radiotherapy: the most commonly used treatment for brain tumors; the tumor is irradiated with beta, x rays or gamma rays.
Chemotherapy: is a treatment option for cancer, however, it is not always used to treat brain tumors as the blood-brain barrier can prevent some drugs from reaching the cancerous cells.
A variety of experimental therapies are available through clinical trials.
Concerning anxiety, the exact cause of GAD is not fully known, but a number of factors -- including genetics, brain chemistry and environmental stresses –appear to contribute to its development.
Genetics: Some research suggests that family history plays a part in increasing the likelihood that a person will develop GAD. This means that the tendency to develop GAD may be passed on in families.
Brain chemistry: GAD has been associated with abnormal levels of certain neurotransmitters in the brain. Neurotransmitters are special chemical messengers that help move information from nerve cell to nerve cell. If the neurotransmitters are out of balance, messages cannot get through the brain properly. This can alter the way the brain reacts in certain situations, leading to anxiety.
Environmental factors: Trauma and stressful events, such as abuse, the death of a loved one, divorce, changing jobs or schools, may lead to GAD. GAD also may become worse during periods of stress. The use of and withdrawal from addictive substances, including alcohol, caffeine, and nicotine, can also worsen anxiety.
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), -amyloid peptide was shown to exert direct toxic effects on neutrons and to inhibit neurite growth in vitro. Thus, therapeutic approaches that can modulate 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-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.
In addition, there is a clear cause for epilepsy in only a minority of the cases. Typically, the known causes of seizure involve some injury to the brain. Some of the main causes of epilepsy include: low oxygen during birth
head injuries that occur during birth or from accidents during youth or adulthood
brain tumors
genetic conditions that result in brain injury, such as tuberous sclerosis
infections such as meningitis or encephalitis
stroke or any other type of damage to the brain
abnormal levels of substances such as sodium or blood sugar
From these findings, there is no single common cause for all these disorders; therefore, there is no clear assurance that only the interaction of the claimed compound with the recited enzymes would be resulted in the treatment of the above diseases.
Although the state of the prior art with regards to each and every disease encompassed by the claims cannot be discussed due to the breadth of the claimed conditions, the previous paragraphs are meant to serve as examples.
The amount of direction or guidance present and the presence or absence of working examples
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the compounds which fall within the scope of a claim will possess the alleged activity. The only direction or guidance present in the specification is the listing of diseases Applicant considers treatable as well as various statements throughout the specification regarding the expectation that the compounds are able to treat the claimed diseases. The data provided is limited to in vitro assays for dopamine receptor activity of the limited compounds exemplified in the specification. Receptor activity is generally unpredictable and a highly structure specific area, and the data provided is insufficient for one of ordinary skill in the art to extrapolate.
The disclosure does not provide how this in vitro data correlates to the treatment of the assorted diseases claimed. See MPEP 2164.02 (“The issue of “correlation” is related to the issue of the presence or absence of working examples. “Correlation” as used herein refers to the relationship between in vitro … assays and a disclosed or a claimed method of use. An in vitro … example, in the specification, in effect, constitutes a “working example” if that example “correlates with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” … For a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art … would expect the claimed genus could be used in the manner without undue experimentation”). While Applicants do indeed make various statements in the specification that their claimed compounds will effectively treat or prevent the genus of claimed diseases, such is not supported by conclusive examples.
The breadth of the claims
The claims are extremely broad in that they encompass both the treatment of any neurological disorders, cognitive dysfunction, several types of cancer, and many others, with any compound of the claimed formula, which could reasonably encompass at least millions of compounds or more when the breadth of each variable is considered.
The level of the skill in the art
The level of skill in the art is high, with the skilled artisan typically possessing an advanced degree such as a Ph.D. or MD. However, due to the unpredictability in the pharmaceutical art, as discussed above, 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 which compound exhibits the desired pharmacological activity.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of the instant claims for the treatment and prevention of these conditions, as a result necessitating one of skill to perform an exhaustive search for which compounds of the instant claims will be useful in order to practice the claimed invention.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine what compounds, out of all compounds, would be effective in treating the entire scope of claimed diseases. As determined in the “Amount of direction or guidance” section above, this would entail the task of determining which individuals would develop any and all diseases associated estrogen receptor activity in order to prevent its onset, a task that is not possible with what is currently known in the medical field regarding the claimed diseases and would thus require undue experimentation.
Since this assertion that such a broad group of compounds would be effective to treat the entirety of claimed diseases is contrary to what is known in medicine, proof must be provided that this assertion has merits. The existence of such a compound is contrary to our present understanding of modern medicine.
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 instantly 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 compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims.
Genentech 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 and In re Fisher (CCPA 1970) 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 agents of the claimed compounds, if any, would prevent multiple sclerosis with no assurance or reasonable expectation of success.
It is suggested that in response to this rejection, Applicants amend the claims to limit the generic classes of diseases recited to specific diseases which would be reasonably expected to be treatable by the claimed agents based on the evidence provided in the instant application.
Conclusion
Claims 1-4, 8 and 10 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on M-Th 8:00 a.m. -6:00 p.m..
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699
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