DETAILED ACTION
This office action is in response to applicant’s filing dated January 11, 2024.
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 .
Status of claims
Claims 1 - 29 are pending in the instant application.
Priority
The present application was filed on January 11, 2024 and claims the benefits of priority to U.S. Provisional application No. 63/479,781 filed January 13, 2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 11, 2024 and April 26, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on January 11, 2024. These drawings are accepted.
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.
Claim 7 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The term “greater than 100% to about 120% or less” in claim 7 is a relative term which renders the claim indefinite. The term “greater than 100% to about 120% or less” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what standard for measuring the degree of relativity claimed under the term “about 120% or less”. Appropriate amendments, clarifying claim’s limitations is needed.
Claims 8 and 14 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 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 8 recites the broad recitation: “2 mg to about 100 mg per day”, and the claim also recites: “5 mg to about 50 mg per day, or about 20 mg to about 40 mg per day”, which is the narrower statement of the range/limitation. Similarly claim 14 recites the broad recitation: “piromelatine is administered about 10 minutes to about 60 minutes prior to sleep time”, and the claim also recites: “or about 30 minutes prior to sleep time”, 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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 4, 8 – 10 and 12 – 26 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Laudon et al (WO 2007/093880 A2, hereinafter Laudon) in view of Videnovic et al (J Neurol Neurosurg Psychiatry 2020;91:740–749 (2020)).
Regarding claims 1 – 4, 8 – 10 and 12 – 15, drawn to a method for treating a subject having parasomnias related to Rapid Eye Movement (REM) sleep, such as REM sleep without atonia (RSWA) or the subject has Rapid Eye Movement (REM) sleep behavior disorder (RBD). The method comprises administering a formulation comprising an effective amount of piromelatine to the subject, wherein the effective amount of piromelatine is about 2 mg to about 100 mg per day, such as about 50 mg per day, and wherein the effective amount of piromelatine is the amount that attenuates disease progression into synucleinopathies or Parkinson’s disease. Instant claims are further drawn to a method where the formulation, comprising an effective amount of piromelatine, is administered orally, such as in a unit dosage form, once daily about 10 minutes to about 60 minutes prior to sleep time.
Laudon teaches compounds of formula (I), such as compound of formula:
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(page 32, ex. 6), which corresponds to the structure of piromelatine, and a method of treating various sleep disorders, e.g. insomnia, REM sleep interruptions, night terror, sleep disorders accompany aging, conditions associated with circadian rhythmicity, mental and physical disorders etc., comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as well as any stereoisomer covered by formula (I) (page 16, [0039]), wherein the therapeutically effective amount is an amount effective for treating or preventing of sleep disorders or sleep disturbance or for improving sleep quality or for altering a circadian rhythm, as well as treating or preventing a neurodegenerative disease such as Parkinson's disease (page 13, [0032], claims 21, 25 and 27). Compounds taught by Laudon are related to melatonin or serotonin and act as MT-1 and MT-2 or serotonin receptor agonists/antagonists. Laudon teaches formulations, adapted for oral administration such as formulated in the unit dosage form, wherein the daily oral dosage of compound of formula (I), such as compound of ex. 6, is within the range of about 0.5 to about 50 mg and is administered once a day to night-time (page 23, [0060] and [0062]). In the experiment 1 Laudon teaches that CD1 mice were given piromelatine 15 minutes before sleep time (page 39, experiment 1). The amount ranges of piromelatine in the formulations taught by Laudon correspond to the amount ranges of instant claims. MPEP 2144.05 states: In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Laudon teaches formulations comprising piromelatine are useful for treating multiple sleep disorders without explicitly teaching the treatment of REM sleep behavior disorder.
However, Videnovic teaches exogenous melatonin and melatonin agonists as recommended therapy for RBD, where in doses (6 to 18 mg at bedtime) melatonin improved frequency and severity of RBD symptoms in up to 70% of patients. Relative melatonin receptor agonists have established their place in the management of RBD as well, where RBD (Rapid Eye Movement (REM) Sleep Behavior Disorder) is a sleep disorder, characterized by the loss of the inherent muscle atonia observed during normal REM sleep. This phenomenon is often referred to as REM Sleep without Atonia (RSWA), Videnovic further teaches that RBD patients have a high risk of developing one of the neurodegenerative synucleinopathy diseases: over 70% will develop parkinsonism or dementia within 20 years of their diagnosis (page 740, “introduction”).
Thus, since Laudon teaches formulations comprising a therapeutically effective amount of piromelatine, which amounts are corresponding to instantly claimed amounts, which formulations are effective in the method of treating multiple sleep disorders and preventing neurodegenerative disease such as Parkinson's disease, where piromelatine acts as MT-1 and MT-2 or serotonin receptor agonist, and since Videnovic teaches exogenous melatonin or relative melatonin receptor agonists are effective in the method of treatment of RBD, where developing of parkinsonism is possible worsening of RBD conditions, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to apply known agent (piromelatine) of the same mechanism of action (MT-1 and MT-2 or serotonin receptor agonist) and useful in treating sleep disorders, to the method of treating RBD to arrive at claimed method. The one of ordinary skills would be motivated to do so in search for a new drug to effectively treat RBD conditions with the reasonable expectation of success, especially since prior art teaches that melatonin receptor agonists are effective in the method of treatment of RBD.
Regarding claims 16 – 22 and 29, drawn to a method wherein the formulation comprising an effective amount of piromelatine is administered as a combination therapy with a second therapeutic agent concomitantly or separately, wherein the combination therapy comprises an anti-inflammatory, anxiolytic, a hypnotic, a benzodiazepine etc., such as adinazolam or flurazepam, wherein the formulation comprising an effective amount of piromelatine is administered in combination with a physical treatment method, such as light therapy. Said formulation further comprises one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients and/or carriers.
Laudon teaches formulations comprising a therapeutically effective amount of piromelatine where piromelatine is administered alone or in combination with other agents, such as sedatives, hypnotics, anxiolytics, benzodiazepines etc., such as adinazolam or flurazepam. The term “in combination" means that the compound of formula (I) and the other agent can be co-administered, either in concomitant therapy or in a fixed physical combination, or they may be administered at separate times but so as to complement one another (page 18 – 19, [0047] and [0049]). The formulations taught by Laudon further comprise one or more pharmaceutically acceptable diluents, preservatives, excipients and carriers (page 16, [0039]). Laudon further teaches that said formulations can be administered in combination with physical treatment methods, such as light therapy (page 19, [0051]).
Thus, Laudon teaches the same or similar formulations and combination therapies as instantly claimed.
Regarding claims 23 - 26, drawn to the method where the subject is diagnosed with RBD by video polysomnography (vPSG), wherein the vPSG measurement is quantified using a RBD Severity Scale (RBDSS), wherein the subject is diagnosed using a Clinical Global Impression-Improvement (CGI-I) scale or wherein the subject is assessed using a dopamine transporter imaging- DaTscan, a blood testing, or a combination thereof.
Videnovic teaches RBD diagnosis, where the diagnostics is an overnight video polysomnography (v-PSG) study, the RBD Severity Scale (RBDSS) is a validated method to assess both frequency and severity of motor and vocalization events during REM sleep. Videnovic also teaches the clinical global impression of change (CGI) as recommended primary outcome measure, for a clinician to estimate a trend of RBD symptom improvement after treatment (page 745, right column, “outcome measures”). Videnovic further teaches dopamine transporter imaging (DaTSCANs), as a way to visualize presynaptic dopamine transporter density, which is a reliable biomarker in the prediction of risk of developing PD (Parkinson’s disease) in RBD patients (page 743 “Outcome measures”).
Thus, since Videnovic teaches the same methods of diagnostics and evaluation of RBD conditions as instantly claimed, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to apply known methods of diagnosis and evaluation of RBD severity conditions or improvement after treatment, to the method of treating RBD conditions with known agent piromelatine, to arrive at claimed method with the reasonable expectation of success.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Laudon et al (WO 2007/093880 A2) in view of Weber et al (Neuropsychobiology 2022;81:85–97, hereinafter Weber).
Instant claim is drawn to a method of attenuating disease progression of parasomnias related to Rapid Eye Movement (REM) sleep into chronic post-traumatic stress disorder (PTSD) in a subject comprising administering a formulation comprising an effective amount of piromelatine to the subject.
Laudon teaches compound of formula:
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(page 32, ex. 6), which corresponds to the structure of piromelatine, and a method of treating various sleep disorders, e.g. insomnia, REM sleep interruptions, night terror, mental and physical disorders, as well as treating or preventing psychiatric disorders, comprising administering a therapeutically effective amount of piromelatine (page 16, [0039]) wherein the therapeutically effective amount is an amount effective for treating or preventing sleep disorders or sleep disturbance or for improving sleep quality or for altering a circadian rhythm, as well as treating or preventing psychiatric disorders or a neurodegenerative diseases (page 13, [0032], claims 21, 25 and 27).
Laudon does not teach where administering formulations comprising piromelatine attenuates disease progression of parasomnias related to Rapid Eye Movement (REM) sleep specifically into chronic post-traumatic stress disorder (PTSD).
However, Weber teaches that sleep disorders such as or parasomnia (e.g., a behavioral disorder in REM sleep) have been classified among the core symptoms of post-traumatic stress disorder (PTSD). Pretraumatically disturbed sleep may be a risk factor for later developing PTSD. Pronounced sleep disturbances in PTSD also represent an important prognostic factor for the outcome, as they may increase the severity of the condition. Conversely, effective treatment of sleep disorders and nightmares may lead to a clinically significant decrease in PTSD symptoms (page 86, “bidirectional relationship” and page 88, Fig. 1).
Thus, since Laudon teaches formulations comprising a therapeutically effective amount of piromelatine, which formulations are effective in the method of treating multiple sleep disorders and treating or preventing psychiatric disorders or a neurodegenerative diseases and Weber teaches direct relationship between sleep disorders such as parasomnia related to RBD, where sleep disorders identified as core symptoms of developing (PTSD), and where treatment of sleep disorders may lead to a clinically significant decrease in PTSD symptoms, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to apply known agent piromelatine, useful for treating sleep disorders and treating or preventing psychiatric disorders, to the method of treating RBD to arrive at claimed method. The one of ordinary skills would be motivated to do so in search for a new method to effectively treat RBD conditions and prevent worsening of conditions, such as developing chronic PTSD symptoms with the reasonable expectation of success, especially since prior art teaches that effective treatment of sleep disorders can significantly decrease PTSD symptoms.
Claims 6, 7 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Laudon et al (WO 2007/093880 A2, hereinafter Laudon) in view of Videnovic et al (J Neurol Neurosurg Psychiatry 2020;91:740–749 (2020)), as applied to claims 1 – 4, 8 – 10, 12 – 23, 25, 26 and 29 above, and further in view of PRNewswire (Neurim Pharmaceuticals Announces Positive Phase 2 Clinical Trial Results of Piromelatine for the Treatment of Insomnia, (2013), hereinafter PRNewswire) and Valomon et al (Sci Rep 11, 4758 (2021, hereinafter Valomon).
Laudon and Videnovic teach all the limitations of claims 6, 7 and 28 as discussed supra and are applied here in the same manner, except where a non-REM sleep (NREM) low frequency band between 0.5 to 1.5 Hz is increased compared to baseline after administering piromelatine to the subject for about 4 weeks and wherein a percentage ratio of an NREM low frequency band between 0.5 to 1.5 Hz is greater than 100% to about 120% compared to baseline after administering piromelatine to the subject for about 4 weeks, or where the subject is assessed using a Pittsburgh Sleep Quality Index (PSQI).
However, PRNewswire teaches clinical trials of efficacy of piromelatine in treatment of primary insomnia, where piromelatine at 20 or 50 mg/d was given to the patients over 4 weeks and resulted in significantly improved sleep architecture. Piromelatine enhanced sleep EEG delta power (low frequency band) and significantly reduced beta power (p<0.05). The decrease in EEG beta activity, a marker of cortical arousal, is a physiological surrogate marker of the efficacy of Piromelatine in sleep maintenance. Improvements in quality of sleep and total sleep time was measured by the Pittsburg Sleep Quality NREM Questionnaire (PSQI) (page 1).
Furthermore, Valomon, in the study review, discusses abnormalities in sleep EEG of RBD patients, where Valomon defines RBD as Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by REM sleep abnormalities including failure to maintain muscle atonia resulting in nocturnal enactments of motor behaviors. The EEG analysis reveals that RBD patients to two different control groups show consistent abnormalities in both REM sleep and NREM sleep. While both control groups displayed a global reduction in beta power in phasic compared to tonic REM sleep, this decrease was limited to midline parietal regions in RBD patients. During NREM sleep RBD patients displayed a blunted overnight decrease in delta (low frequency waves 0.5-4Hz) and theta power (4-8Hz), including a blunted decrease in slow-wave amplitude compared to both control groups. Valomon concludes that, the decreased attenuation of beta frequency EEG activity during phasic compared to tonic REM sleep in RBD patients may reflect higher cortical arousal during phasic REM sleep, which may favor motor enactments. In addition, the reduced overnight decline in slow-wave activity (SWA) observed in RBD patients during NREM sleep suggests a reduced capacity for neural plasticity in RBD patients, which may account for cognitive deficits and their predisposition to progress towards neurodegenerative diseases (page 8, “discussion”).
Thus, since PRNewswire teaches that piromelatine administered to insomnia patients enhanced sleep EEG delta power and significantly reduced beta power, and Valomon teaches that RBD patients have alterations in sleep EEG compared to healthy control, specifically alterations were detected in delta and beta power, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to apply known agent piromelatine, useful for treating sleep disorders, and affecting sleep EEG as desired, to the method of treating RBD to arrive at claimed method. The one of ordinary skills would be motivated to do so in search for a new drug to effectively treat RBD conditions and improve sleep quality with the reasonable expectation of success, especially since prior art teaches that effective amount of piromelatine administered for over 4 weeks improves sleep quality as demonstrated by measurements of sleep EEG.
Regarding claim 7 limitations, which limitation is “a percentage ratio of an NREM low frequency band between 0.5 to 1.5 Hz is greater than 100% to about 120% compared to baseline”, the prior art discusses sleep quality improvements after administering piromelatine during 4 weeks without explicitly pointing out percentages. However, treatment with piromelatine during the same period of time would inherently result in the same level of improvement of sleep EEG, because: the same agent (piromelatine) is being administered to the patient with the same alterations in sleep EEG (e.g. alterations in delta and beta power), in the same amounts and during the same period of time. In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances (see MPEP 2112.01).
Claim 11 is rejected is rejected under 35 U.S.C. 103 as being unpatentable over Laudon et al (WO 2007/093880 A2, hereinafter Laudon) in view of Videnovic et al (J Neurol Neurosurg Psychiatry 2020;91:740–749 (2020)), as applied to claims 1 – 4, 8 – 10, 12 – 23, 25, 26 and 29 above, and further in view of Sharma et al (Ars Pharm. 2016; 57(3): 97-109, hereinafter Sharma).
Laudon and Videnovic teach all the limitations of claim 11 as discussed supra and are applied here in the same manner, except where the formulation comprising an effective amount of piromelatine is administered in a self-microemulsifying drug delivery system (SMEDDS).
However, Sharma teaches lipid based formulations, commonly referred to as self-micro emulsifying drug delivery systems (SMEDDS), which improve oral bioavailability of drugs especially those with poor aqueous solubility. SMEDDS substantially improve solubility/dissolution, absorption and bioavailability of poorly water-soluble drugs (page 100, “Selection of suitable drug candidate” and 107, “conclusions”). Based on the chemical structure of molecule piromelatine:
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, this compound should have low water solubility and thus would be a good candidate for the formulations in unit dosage forms, such as SMEDDS.
Thus, since Sharma teaches SMEDDS as formulations suitable for better bioavailability of drugs with poor aqueous solubility, and chemical structure of piromelatine predicts its poor aqueous solubility, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to formulate known lipophilic drug piromelatine into known self-micro emulsifying drug delivery systems (SMEDDS), to arrive at claimed method The one of ordinary skills would be motivated to do so in search of an effective formulation to enhance bioavailability of lipophilic active moieties with the reasonable expectation of success.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Laudon et al (WO 2007/093880 A2, hereinafter Laudon) in view of Videnovic et al (J Neurol Neurosurg Psychiatry 2020;91:740–749 (2020)), as applied to claims 1 – 4, 8 – 10, 12 – 23, 25, 26 and 29 above, and further in view of Kim et al (Parkinsonism and Related Disorders 81 (2020) 1–7).
Laudon and Videnovic teach all the limitations of claim 27 as discussed supra and are applied here in the same manner, except where the blood testing comprises measuring tumor necrosis factor-α (TNF-α) and/or C-reactive protein (CRP) levels in a serum sample of the subject.
However, Kim teaches association of peripheral cytokine markers with the disease conversion to neurodegenerative disorders in iRBD patients. The baseline data analyses revealed increased TNF-α levels in the iRBD patients at a high risk of neurodegeneration (page 4, “discussion”). Thus, the measurements of serum cytokines, specifically TNF-α, may provide evidence that cytokine levels are a reliable biomarker for predicting the risk of phenoconversion in iRBD (page 6, left column, 4th paragraph).
Thus, since Kim teaches elevated levels of TNF-α in RBD patients, where elevated level of TNF-α is a biomarker, predicting the risk of developing PD, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to apply known methods of testing of TNF-α level in RBD patients, to the method of treating RBD conditions with known agent piromelatine to arrive at claimed method with the reasonable expectation of success, especially since prior art teaches elevated levels of TNF-α indicate a risk of phenoconversion in iRBD patients.
Therefore, taking all together, taught by prior art, the invention as a whole is 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.
Conclusion
Claims 1 – 29 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
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/E.V.V./Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691
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