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
1. This application is a CON of PCT/KR2018/013159 11/01/2018 and claims priority to KOREA, REPUBLIC OF 10-2017-0160506 11/28/2017.
Claims 1 and 25 are pending.
Response to Amendments/Arguments
2. The rejection of claim 1 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn based upon the amendments. A new ground of rejection under the same statute is set forth below based upon the amendments.
The rejection of claim 1 under 35 U.S.C. 103 as being unpatentable over Barr and Lee is maintained. Applicants’ representative’s arguments submitted on December 11, 2025 have been fully considered but are not persuasive The declaration under 37 C.F.R. 132 of inventor Kim of December 11, 2025 has been fully considered but is also unpersuasive. The declaration is an opinion declaration. According to the arguments in the declaration which are reiterated by the attorney argument, Barr does not use volinanserin for treating dystonia but is drawn to treating another movement disorder. However the deficiency is cured by Lee. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
According to the arguments, Lee is drawn to treating dyskinesia while the instant claims are drawn to treating dystonia. According to Lee “Alterations of dopaminergic function in striatum play an important role in primary dystonias.” Lee states that Paroxysmal nonkinesigenic dyskinesia (PNKD) have “attacks consisting of dystonia” occurring “frequently when patients are stressed.” Lee explicitly describes PNKD as a dystonia, which is directly quoted in the rejection and also reproduced here: “PNKD is a highly penetrant autosomal dominant disorder in which individuals have 1- to 4-hour attacks consisting of dystonia and choreoathetosis (3). These attacks can be induced reliably by administration of caffeine or alcohol and frequently when patients are stressed.” Applicant points to a different animal model in the specification as compared to Lee and a different motivation for using this model, however a different reason for following the suggestion of the prior art cannot be the basis for patentability.
According to the arguments “stress-induced dystonia addressed by the present invention is not a dopaminergic excess state.” [Declaration page 4 at ¶ 13.] Dystonia is a heterogenous disorder, and while the statements regarding dopamine deficiency may be true for some dystonic Parkinson’s patients, this is not the case for the claimed condition of “stress-induced dystonia”. Hamann “Striatal increase of extracellular dopamine levels during dystonic episodes in a genetic model of paroxysmal dyskinesia” Neurobiology of Disease 16 (2004) 78 – 84 explains that stress induced dystonia is hallmarked by overactivity of the dopaminergic system:
In line with the present finding of an increase of extracellular dopamine levels in the striatum of mutant hamsters during dystonic attacks, several observations suggest that dopaminergic dysfunctions are important also in human dystonia and paroxysmal dyskinesia with dystonia. It has to be considered that the pathogenesis is obviously different in various types of human dystonia or dyskinesia. Hereditary dopa-responsive dystonia seems to be related to reduced endogenous striatal dopamine content (Leenders et al., 1995), while measurements of dopamine and metabolites in tissue homogenates of postmortem DYT1 dystonia brains pointed to an increased activity of dopamine (Augood et al., 2002). In accordance with the present finding, several lines of evidence suggest that an overactivity of the dopaminergic system is critically involved in paroxysmal dystonia in humans. Thus, triggers of dystonic episodes in paroxysmal nonkinesigenic dyskinesia are stress, caffeine, and alcohol (Demirkiran and Jankovic, 1995; Matsuo et al., 1999), that is, compounds which can elevate dopamine concentrations within the striatum (Abercrombie et al., 1989; Bradberry, 2002; Okada et al., 1997). Neuroleptics have been reported to exert beneficial effects in patients with this type of paroxysmal dystonia (Przuntek and Monninger, 1983). Furthermore, case reports pointed to enhanced levels of HVA and of 5- HIAA in the cerebrospinal fluid of patients during a paroxysmal exercise-induced dystonia (Barnett et al., 2002; Jarmann et al., 2000). Apart from this finding of increased concentrations of 5-HIAA in the cerebrospinal fluid, pharmacologic observations in dystonic patients and in dtsz hamsters suggested that an altered serotonergic activity may be involved in dystonia (Gerber and Lynd, 1998; Richter and Loscher, 1995).
The claims are drawn to stress induced dystonia. The mice in Lee are clearly dystonic as highlighted in the rejection and have elevated dopamine upon response to stress. According to Lee “Alterations of dopaminergic function in striatum play an important role in primary dystonias.” Lee states that Paroxysmal nonkinesigenic dyskinesia (PNKD) have “attacks consisting of dystonia” occurring “frequently when patients are stressed.” According to Lee, “Thus, dysfunction of dopamine signaling is associated with PNKD pathophysiology.”
According to the arguments “Lee does not teach that dystonia is a stress-induced condition that is mediated through the 5HT-2A receptors” however Barr explains that “these data indicate that selective 5-HT2A receptor antagonists, such as M100907 (volinanserin), may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.” Lee explains that dystonia caused by stress is such a disorder, “Thus, dysfunction of dopamine signaling is associated with PNKD pathophysiology.” “Alterations of dopaminergic function in striatum play an important role in primary dystonias….Interestingly, unlike dtsz hamsters, Pnkd mice have reduced extracellular dopamine in striatum in vivo, but, when challenged by stress, caffeine, or alcohol, there is a relative increase in dopamine compared with controls.” The use of 5HT2a antagonists for the treatment of dystonias is well-established, as discussed in the non-final rejection of January 27, 2023 pages 5-8. Oulis used low-dose aripiprazole, an antagonist at the 5-HT2A receptors, in the treatment of selective serotonin reuptake inhibitors-induced orofacial and buccal dystonia. Van Harten described the treatment of a number of dystonia patients with severe painful forms including “a very disabling dystonia containing a severe backward bending, severe retrocollis”, “dystonia of both arms and mouth”, blepharospasm, torticollis, trunk dystonia a “dystonia of both arms, and frequent eye-blinking” “myoclonus of the upper palatum” “dyskinesia of facial muscles, jaw and arms”. All the patients were given clozapine, a 5HT2A receptor antagonist. Poyurovsky successfully treated fluoxetine-Induced dystonia with low-dose mianserin, a 5HT2A antagonist. The dystonia was caused by “myotonic condition….caused by an abnormal increase of serotonin following administration of a selective serotonin reuptake inhibitor” (the SSRI was fluoxetine) with a 5HT2A antagonist, mianserin. Hughes teaches the treatment of Huntington’s disease with a number of 5HT2A antagonists. Part of the Huntington’s disease symptomology includes various dystonias. Applicant argues that “The literature [Oulis, Van Harten, Poyurovsky] cited by the Office for alleged 5-HT₂A "benefit" in movement disorders involves non-selective agents (e.g., clozapine, aripiprazole, mianserin) with complex receptor profiles, and even the evidence is mixed or limited”. However the original claims themselves classify these agents as in the same class and as useful for treating dystonia, based upon the single example of volinanserin. The original claims 1, 4 and 6 are reproduced below [Underlining added]:
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According to the arguments “there is no motivation to combine Barr and Lee to arrive at the claimed invention” However Barr makes the link between the specific drug claimed, volinanserin AKA M100907, and treatments of conditions with an aberration in dopaminergic neurophysiology. Barr also discusses work of others, “Additional support for a role for the 5-HT2A receptor in modulation of dopamine-induced hyperactivity in DAT KO mice is indicated by the capacity of the 5-HT2A receptor antagonist ketanserin to reduce significant locomotion at doses of 0.4 and 2.0 mg/kg (Gainetdinov et al, unpublished results).” Barr’s mice had reduced PPI, which is observed in various dystonias, including blepharospasm.
According to the arguments, volinanserin exhibits “an unexpectedly superior therapeutic effect in tottering mice” as compared to other serotonin receptor antagonists. It was known that “dysfunction of dopamine signaling is associated with PNKD pathophysiology”, “when challenged by stress, caffeine, or alcohol, there is a relative increase in dopamine compared with controls.” When the Pnkd mice “are stressed, striatal dopamine release is increased in Pnkd mice and receptor sensitivity is increased due to low basal extracellular dopamine levels. Excessive dopaminergic signaling under these conditions may lead to abnormal neuronal activity in Pnkd basal ganglia accompanied by significantly increased dopamine turnover.” Using the known compound, volinanserin, to modulate of dopamine-induced hyperactivity is expected to treat the subject. This is an expected result. Assuming the results were unexpected, the claims are not limited to tottering mice and are drawn to additional subjects including the mice of Lee and all the other subjects known to exhibit dystonia.
The rejection of claim(s) 1 under 35 U.S.C. 103 as being unpatentable over Ansah “The 5-HT2A receptor antagonist M100907 produces antiparkinsonian effects and decreases striatal glutamate” Frontiers in Systems Neuroscience June 2011 | Volume 5 | Article 48 | 1 AND Djamshidian A, Lees AJ (2014) “Can stress trigger Parkinson’s disease?” J Neurol Neurosurg Psychiatry 85, 879–882 is withdrawn based upon the amendments.
The rejection of claim(s) 1 and new claim 25 under 35 U.S.C. 103 as being unpatentable over Hanagasi, Raoofi AND Ansah is maintained. Applicants’ representative’s arguments submitted on December 11, 2025 have been fully considered but are not persuasive. According to the arguments, clozapine is not a selective 5-HT2A antagonist and Hanagasi does not attribute the effects to 5-HT2A. Clozapine has a number of effects and can be classified a number of ways. The original claims classify these agents as in the same class. The original claims 1, 4 and 6 were reproduced above and claim 6 includes clozapine. Clozapine was well known as a 5-HT2A antagonist at the time of filing used to treat OMD, and Ansah shows that the claimed compound treated dystonia. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim Interpretation
3. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The claims use the term “subject who has a dystonic attack under stress condition”. The specification page 7 defines dystonia:
The term "dystonia" as used in this document is an involuntary abnormal movement that leads to persistent postural or twisting muscle movements irrespective of one's will. As a neurological disease characterized by symptoms, familial or stress-related dystonia is known to exist. In particular, the stress-related dystonia may be caused by extreme stress ahead of a performance or presentation, even if there is no other genetic predisposition.
Page 17 line 10ff. explains what the stress includes:
The term "stress" as used in this document refers to the psychological and physical tension that a subject feels when exposed to an environment that is difficult to adapt. Accordingly, the "stress condition" refers to a state in which the subject is exposed to an unfamiliar and unfamiliar environment. These stressful conditions are when a person encounters a new environment, such as contacting new people, presenting in a new place, taking on new tasks, moving to a new area, or going to a higher school. If one develops dystonia under stress conditions, he/she will have a major obstacle in his/her social life.
Page 21 further describes the stressed dystonic patients:
As can be seen through the above-described experimental results, the pharmaceutical composition comprising a selective 5-HT2A antagonist according to an embodiment of the present invention can be used effectively for the patients suffering from dystonia, especially for dystonia patients caused by stress conditions. In addition, an effective option with respect to the prevention of outbreaks of dystonia is to prescribe patients the pharmaceutical composition of the present invention before stressful situations. It can prevent symptoms of dystonia and improve patients' quality of life. In addition, it is possible to suppress mistakes caused by abnormal muscle tension by lowering the effect of muscle tension in presenters preparing to present, players preparing to perform and athletes ahead of the game in front of many people as well as dystonia patients. Normally, in a tense situation, a slight muscle tension is transferred to a mental burden, which in turn develops into a large muscle tension, which is thought to be effectively treated or preventable by the pharmaceutical composition of the present invention. It is usually thought to be useful for voice tremors or muscle tension when one performs a presentation. Also, it is thought that it is possible to prevent and treat muscle dysfunction caused by excessive muscle tension by ingesting the pharmaceutical composition of the present invention before and after muscle tension, not only in dystonia patients but also in normal people at an appropriate concentration. In addition, it is believed that the discovery of therapeutic drugs will be effective not only for dystonia, but also for exercise disorders such as Parkinson's disease and tick disorders exacerbated by stress.
The stress that is “psychological and physical tension that a subject feels when exposed to an environment that is difficult to adapt” is any stressor. Dystonic features described as “players preparing to perform and athletes ahead of the game in front of many people” and “the stress-related dystonia may be caused by extreme stress ahead of a performance or presentation” are classic descriptions of focal dystonia. Focal dystonia, also called focal task-specific dystonia, is a neurological condition that affects a muscle or group of muscles in a specific part of the body during specific activities, causing involuntary muscular contractions (spasms) and abnormal postures. There are many different types of focal dystonia, each affecting a different region of the body. For example, in focal hand dystonia, or writer's cramp, the fingers either curl into the palm or extend outward without control. In musicians, the condition is called musician's focal dystonia, or simply, musician's dystonia. In sports, it may be involved in what is commonly referred to as the yips. This also includes Oromandibular Dystonia (OMD), a focal neurological disorder that affects mouth, face, and jaws and also includes large number of other dystonias.
With that being said, there is no clearly defined set of “subject who has a dystonic attack under stress condition”1 in the specification and the patient population is not limited to those with diagnosed medical conditions, “but also in normal people at an appropriate concentration.” The specification suggests that they “will be effective not only for dystonia, but also for exercise disorders [movement disorders?] such as Parkinson's disease and tick [sic] disorders exacerbated by stress.” Parkinson forms involve stress induced dystonia, “These two neurological disorders can occur together. For example, rapid-onset dystonia with parkinsonism (RDP) or DYT12 dystonia is a rare form of generalized, primary dystonia with Parkinson’s disease features. DYT12 dystonia patients do not present with any symptoms until triggered by a physiological stressor (e.g. fever), typically in late adolescence or early adulthood [7,8].” [ DeAnrade “Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism.” Behavioural Brain Research 216 (2011) 659–665; page 659] This suggests that the “subject who has a dystonic attack under stress condition” embrace Parkinson's disease dystonias, which is specifically disclaimed, and tic disorders like Tourrette’s with potential application to “normal people”.
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.
4. Claim 1, 25 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a rejection for new matter. The claims are now drawn to treating dystonia “in a subject who has a dystonic attack under stress condition” “thereby suppressing increased concentration of calcium ion in cerebellum and reducing dystonia severity or attack frequency”. According to the arguments at page 1 paragraph 2) of the response of December 11, 2025, all of the new language is supported by the animal model in Examples 1 to 5 which is to be supported by a publication to Wilson & Hess (2013, attached as reference 8). The claim language does not appear in the specification. Wilson & Hess (2013) is not incorporated by reference the specification, and it is not clear that it has been cited in the specification at all. As per 37 C.F.R. 1.57 (c):
(c) Except as provided in paragraph (a) or (b) of this section, an incorporation by reference must be set forth in the specification and must: (1) Express a clear intent to incorporate by reference by using the root words "incorporat(e)" and "reference" (e.g., "incorporate by reference"); and (2) Clearly identify the referenced patent, application, or publication.
Moreover essential material must be a U. S. patent or US PGPub not a journal article as per 37 C.F.R. 1.57 (c):
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to:
(1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a);
(2) Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by 35 U.S.C. 112(b); or
(3) Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by 35 U.S.C. 112(f).
Assuming such a reliance on the Wilson & Hess paper were proper, which it is not, this paper is limited to mice, while the claim is drawn to “subjects”. According to the arguments on page 4 “In addition, the present specification describes that ‘the present inventors measured the concentration of calcium ions in the cerebellum of stress-induced dystonia model animals using the GCaMP6 method. As a result, the calcium ion concentration in the cerebellum was significantly increased in animals directly displaying dystonia symptoms, but it was confirmed that the increase in calcium ion concentration in the cerebellum was suppressed in the group administered with the 5-HT2A selective antagonist (see FIGS. 4A to 4F).’” This is limited to mice, while the claim is drawn to “subjects”.
Claim 25 is drawn to a subject which “has reduced striatal extracellular dopamine during the dystonic attack”, there is no description of such subjects in the specification. This is new matter.
5. Claim 25 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Claim 25 is drawn to a subset of “subject who has a dystonic attach under stress condition” “wherein the subject has reduced striatal extracellular dopamine”. They therefore seek to limit the scope of the “subject who has a dystonic attach under stress condition” that meet the functional requirements of “reduced striatal extracellular dopamine”. The specification, however, does not provide any specific correlation between stress-induced dystonia patients and the reduced striatal extracellular dopamine. There is no mention of dopamine in the specification. The working examples on page 25 show a transgenic tottering mouse model, however exactly how this applies to the multitude of dystonias is unclear. In addition to generalized dystonia, often starting in legs and frequently initially misdiagnosed as cerebral palsy, the clinical spectrum of the DRD phenotype includes focal oromandibular or cervical dystonia, spasmodic dysphonia, parkinsonism, postural instability, levodopa-induced dyskinesia, spastic paraplegia, scoliosis, and myoclonus. Morgante “Dystonia” Continuum (Minneap Minn) 2013;19(5):1225- 1241 describes the complex classification of dystonia with a “phenotypic heterogeneity” and “[P]aroxysmal dystonias and dyskinesias show characteristic temporal patterns and are elucidated by different triggers. Dystonia can be associated not only with other movement disorders, such as parkinsonism or myodonus (previously referred to as the dystonia-plus category), but also with a wide variety of other neurologic and non-neurologic features.” [ibid page 1226]. Albanese, cited above, on page 864 describes the difficulty in classifying dystonia,
The classification of dystonia has evolved over time. Fahn and Eldridge first distinguished primary dystonia (with or without a hereditary pattern) from secondary dystonia (with other hereditary neurological conditions or due to known environmental cause), and psychological forms of dystonia. Subsequently, Fahn, Marsden, and Calne proposed a classification of dystonia based on three axes: age at onset, distribution, and etiology. Later, the etiological classification was expanded to include four subgroups of dystonia syndromes: primary, dystonia-plus, secondary, and heredodegenerative. Bressman further refined the etiological classification and proposed a dichotomous distinction between primary (autosomal dominant or other genetic causes), and secondary dystonia syndromes (including dystonia-plus and degenerative, complex/ unknown, and acquired forms). The European Federation of Neurological Societies guidelines distinguished the etiology of dystonia syndromes as primary, heredodegenerative and secondary (or symptomatic). The changing system of classifications for dystonia reflects, in part, an increased understanding of the various clinical manifestations and etiologies, but also varied opinion on the merits and criteria used for grouping certain disorders together. [citations omitted]
Evidence of record, Lee, shows that in paroxysmal nonkinesigenic dyskinesia (PNKD) “individuals have 1- to 4-hour attacks consisting of dystonia and choreoathetosis (3). These attacks can be induced reliably by administration of caffeine or alcohol and frequently when patients are stressed. The causative gene was mapped to chromosome 2q33–q35 (4, 5), and mutations in the PNKD gene (formerly called MR-1) were subsequently identified in PNKD families (6–10).” According to Lee “Pnkd mice have reduced extracellular dopamine in striatum in vivo, but, when challenged by stress, caffeine, or alcohol, there is a relative increase in dopamine compared with controls”. This is the opposite dopamine level claimed. Hamman also explains that:
In accordance with the present finding, several lines of evidence suggest that an overactivity of the dopaminergic system is critically involved in paroxysmal dystonia in humans. Thus, triggers of dystonic episodes in paroxysmal nonkinesigenic dyskinesia are stress, caffeine, and alcohol (Demirkiran and Jankovic, 1995; Matsuo et al., 1999), that is, compounds which can elevate dopamine concentrations within the striatum (Abercrombie et al., 1989; Bradberry, 2002; Okada et al., 1997).
Applicants identifies no subject in the specification “who has a dystonic attack under stress condition” “wherein the subject has reduced striatal extracellular dopamine”. According to the applicants’ arguments of December 27, 2023 on page 4 ¶ 3 “It is widely known that dyskinesia's dopamine involvement would not logically link to a serotonin receptor antagonist such as volinanserin for treating dystonia.”
For these reasons, the rejection due to lack of written description is proper.
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.
6. Claim(s) 1 is/are rejected under 35 U.S.C. 103 as being unpatentable over Barr “The Selective Serotonin-2A Receptor Antagonist M100907 Reverses Behavioral Deficits in Dopamine Transporter Knockout Mice” Neuropsychopharmacology (2004) 29, 221–228 and Lee “Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia” J Clin Invest. 2012;122(2):507–518. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Barr teaches the use of the elected species, volinanserin AKA M100907, a 5HT2a inverse agonist for the treatment of mice with behavioral disorders. “Prior to drug treatment, DAT KO mice exhibited increased levels of locomotor activity and highly linearized movement in a novel environment, as well as reduced prepulse inhibition (PPI) of acoustic startle, compared to wild-type littermates. Treatment with M100907 (0.3–1.0 mg/ kg, but not 0.1 mg/kg) reversed locomotor deficits in DAT KO mice. Similarly, treatment with 1.0 mg/kg M100907 reversed the PPI deficits in DAT KO mice. These data indicate that selective 5-HT2A receptor antagonists, such as M100907, may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.” (abstract) “The finding that M100907 can reverse hyperactivity selectively in DAT KO mice, which have elevated synaptic levels of dopamine (Gainetdinov et al, 1999), complements earlier reports that M100907 reverses the behavioral hyperactivity induced by indirect dopamine agonists, such as cocaine, d-amphetamine and GBR 12909, in both rats and mice (Sorensen et al, 1993; Carlsson, 1995; Kehne et al, 1996; O’Neill et al, 1999; McMahon and Cunningham, 2001).” [Barr page 225 column 1-2]. “Additional support for a role for the 5-HT2A receptor in modulation of dopamine-induced hyperactivity in DAT KO mice is indicated by the capacity of the 5-HT2A receptor antagonist ketanserin to reduce significant locomotion at doses of 0.4 and 2.0 mg/kg (Gainetdinov et al, unpublished results).” [ibid].
“These data indicate that selective 5-HT2A receptor antagonists, such as M100907, may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.” [Barr] “The results of the present study indicate that 5-HT2A receptor antagonists such as M100907 may have therapeutic potential for the treatment of human disorders in which hyperactivity and deficits in sensorimotor gating occur, especially when such indications reflect an underlying aberration in dopaminergic neurophysiology….” “The behavioral deficits and hyperdopaminergia exhibited by DAT KO mice are also of relevance to other human disorders.” [ibid. page 226 column 2]
Lee describes the biochemistry and physiology of stress induced dystonia. According to Lee “Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress.” [Lee, abstract, emphasis added]
“The paroxysmal dyskinesias consist of clinically and genetically distinct phenotypes, including paroxysmal kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and paroxysmal nonkinesigenic dyskinesia (PNKD) (1, 2). PNKD is a highly penetrant autosomal dominant disorder in which individuals have 1- to 4-hour attacks consisting of dystonia and choreoathetosis (3). These attacks can be induced reliably by administration of caffeine or alcohol and frequently when patients are stressed. The causative gene was mapped to chromosome 2q33–q35 (4, 5), and mutations in the PNKD gene (formerly called MR-1) were subsequently identified in PNKD families (6–10).” [Lee page 507 column 1, emphasis added].
“Dopamine plays an important role in modulation of cortical and thalamic glutamatergic signal processing in the striatum, thus regulating movement (13–15). Therefore, we measured dopamine and its metabolites in the striatum by HPLC both before and after stimulating attacks. Pnkd and control mice had similar dopamine levels in striatum at rest (Figure 3D). After i.p. injection of caffeine (25 mg/kg), Pnkd mice had significantly higher levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and higher DOPAC/dopamine ratios than untreated animals.” [Lee Page 508, column 2 last paragraph] “Thus, dysfunction of dopamine signaling is associated with PNKD pathophysiology.” “Alterations of dopaminergic function in striatum play an important role in primary dystonias….Interestingly, unlike dtsz hamsters, Pnkd mice have reduced extracellular dopamine in striatum in vivo, but, when challenged by stress, caffeine, or alcohol, there is a relative increase in dopamine compared with controls. Pnkd mice have normal dopamine content in striatal dopaminergic terminals and apparently normal dopamine production. But dopamine receptors are upregulated, and when animals are stressed, striatal dopamine release is increased in Pnkd mice and receptor sensitivity is increased due to low basal extracellular dopamine levels. Excessive dopaminergic signaling under these conditions may lead to abnormal neuronal activity in Pnkd basal ganglia accompanied by significantly increased dopamine turnover.” [Lee page 815 col. 1]. “These findings imply that dysfunction of the striatal dopamine signaling system plays a pivotal role in PNKD pathophysiology.”
Ascertainment of the difference between the prior art and the claims
Barr only treated mice with increased levels of locomotor activity and reduced prepulse inhibition (PPI) of acoustic startle with volinanserin, while the instant claims are drawn to treating dystonia caused by stress with volinanserin.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to treat dystonia caused by stress as discussed in Lee, which is suggested by Barr. Since the PKND subject described by Lee has upregulated dopamine when challenged by stress, and this dysfunction of the dopamine signaling system plays a pivotal role in the dysktonia pathophysiology, using the known compound, volinanserin, to modulate of dopamine-induced hyperactivity is expected to treat the subject. Barr explains that “The behavioral deficits and hyperdopaminergia exhibited by DAT KO mice are also of relevance to other human disorders.” [ibid. page 226 column 2] and explains that volinanserin could “treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior”.
With regard to the claim limitation, “thereby suppressing increased concentration of calcium ion in the cerebellum” is only a result that is desired to be achieved and reflects no change in the actual steps recited.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
7. Claim(s) 1 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hanagasi “Clozapine Treatment in Oromandibular Dystonia” Clin Neuropharmacol • Volume 27, Number 2, March - April 2004, 84-86; Saeed Raoofi “Etiology, Diagnosis and Management of Oromandibular Dystonia: an Update for Stomatologists” J Dent Shiraz Univ Med Sci., 2017 June; 18(2): 73-81 AND Ansah “The 5-HT2A receptor antagonist M100907 produces antiparkinsonian effects and decreases striatal glutamate” Frontiers in Systems Neuroscience June 2011 | Volume 5 | Article 48 | 1. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Hanagasi shows that clozapine can treat the stress-induced dystonia, OMD. “Oromandibular dystonia (OMD) is a form of focal dystonias, which can be associated with substantial disability and is frequently refractory to all antidystonic therapies. Clozapine is a dibenzodiazepine derivative atypical neuroleptic that has been reported to be effective in the treatment of primary or symptomatic dystonia….We report here two patients with severe OMD refractory to other antidystonic therapies, who had substantial improvement with clozapine. We suggest that clozapine should be considered in patients with OMD who fail to response to other treatments.” [abstract]
“Our patients had been refractory to all other previous pharmacological interventions. They both had substantial improvement under treatment with clozapine. An important aspect of the cases presented here was the significant improvement in quality of life. On the basis of these two cases we suggest that clozapine can be effective in the treatment of OMD, which is otherwise notoriously resistant to pharmacological treatment. In case other treatment modalities fail a trial with clozapine should be considered in patients with OMD.” [page 85] Clozapine is a 5HT-2A antagonist.
Raoofi explains that OMD is a stress-induced dystonia:
“The onset of symptoms is usually between the ages of 40 to 70 years and is more common in women. The symptoms only occur during activities such as speaking or mastication. Patients usually report triggers like stress, talking, chewing something and praying. [9]”
Ansah teaches that the 5-HT2A receptor antagonist M100907, volinanserin, can be used to treat Parkinsonism, one of the hallmarks of which is dystonia. Ansah abstract teaches the use of 5-HT2A receptor antagonist M100907, Volinanserin, for the treatment of Parkinson’s Disease. According to the abstract:
5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson’s disease (PD). Clinical studies have suggested that 5-HT2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of PD.
“In conclusion we have shown that the antiparkinsonian effects of 5-HT2A receptor antagonists may be mediated by regulation of striatal glutamate and that antagonism of striatal 5-HT2A receptors may offer non-dopaminergic therapeutic target for the motor symptoms of PD.” Dystonia is a motor symptom of PD.
Ascertainment of the difference between the prior art and the claims
Hanagasi used 5-HT2A receptor antagonist, clozapine, to treat OMD, while the instant claims use another 5-HT2A antagonist, volinanserin.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to treat OMD caused by stress with volinanserin. Since Hanagasi had already shown that a 5-HT2A receptor antagonist, clozapine, was effective a simple substitution to use another known 5-HT2A receptor antagonist, volinanserin, to treat this subset of stress induced patients is prima facie obvious. With regard to the claim limitation, “thereby suppressing increased concentration of calcium ion in the cerebellum” is only a result that is desired to be achieved and reflects no change in the actual steps recited.
Conclusion
8. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 For the classification of dystonias see: Albanese “Phenomenology and Classification of Dystonia: A Consensus Update” Movement Disorders, Vol. 28, No. 7, 2013 863-873. Jinnah “The New Classification System for the Dystonias: Why Was It Needed and How Was It Developed?” 2014 MOVEMENT DISORDERS CLINICAL PRACTICE 280-284.