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( 12 ) United States Patent US010292977B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 292 , 977 B2 Azhir (45 ) Date of Patent: *May 21, 2019 ( 54 ) COMPOSITIONS AND METHODS FOR 7 ,718 ,677 B2 5 /2010 Quik et al . TREATMENT RELATED TO FALL AND 8 , 192 ,756 B2 6 / 2012 Berner et al. FALL FREQUENCY IN 2005 /0021092 A1 1 / 2005 Yun et al . 2006 / 0053046 A1 3 / 2006 Bonnstetter et al. NEURODEGENERATIVE DISEASES 2008 /0260825 A1 10 / 2008 Quik et al . 2011/ 0268809 AL 11/ 2011 Brinkley et al . (71 ) Applicant: Neurocea, LLC , Los Altos, CA (US ) 2013/ 0017259 A1* 1 / 2013 Azhir .. .. A61K 31 /465 424 /461 (72 ) Inventor : Arasteh Ari Azhir , Los Altos , CA (US ) 2016 /0220553 AL 8 /2016 Azhir ( 73 ) Assignee : NEUROCEA , LLC , Los Altos , CA 2016 /0235732 AL 8 /2016 Quik (US ) 2018 /0125837 AL 5 /2018 Azhir FOREIGN PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this patent is extended or adjusted under 35 WO WO -9712605 A1 4 /1997 U . S . C . 154 ( b ) by 0 days . WO WO - 9855107 Al 12 / 1998 WO WO - 03039518 A15 / 2003 This patent is subject to a terminal dis WO WO -03061656 A1 7 / 2003 claimer . WO W O - 2009003147 Al 12 / 2008 (21 ) Appl. No. : 15 / 853 , 151 OTHER PUBLICATIONS ( 22 ) Filed : Dec . 22, 2017 Wikipedia page for Parkinsonian gait; retrieved Aug. 23, 2018 ( Year: 2018 ) . * (65 ) Prior Publication Data Abood , et al. Structure -activity studies of carbamate and other esters : agonists and antagonists to nicotine . Pharmacol Biochem US 2018 /0177775 A1 Jun . 28, 2018 Behav . Jun . 1988 ;30 ( 2 ) :403 - 8 . Meshul, Charles K . et al . Nicotine Affects Striatal Glutamatergic Related U . S . Application Data Function in 6 -OHDA Lesioned Rats . Advances in Behavioral Biol (63 ) Continuation - in -part of application No . 15 /484 , 960 , ogy , 54 (Basal Ganglia VI) , 589 -598 , 2003 . filed on Apr. 11 , 2017 , now Pat. No . 10 , 143 ,687 . Chung , K . A . et al. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease . Neurology . Oct . 5 , (60 ) Provisional application No . 62/ 320 , 871, filed on Apr. 2010 ;75 ( 14 ) : 1263 - 9 . Epub Sep . 1 , 2010 . 11 , 2016 . Damaj, et al. Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in (51 ) Int. Ci. mice . J Pharmacol Exp Ther. Mar . 1998 ; 284 ( 3 ) : 1058 -65 . A61K 31465 ( 2006 . 01 ) International Application No. PCT/ US17 /68271 International Search A61P 25 / 26 ( 2006 . 01 ) Report and Written Opinion dated May 1 , 2018 . A61K 45 /06 ( 2006 .01 ) ( 52 ) U . S . CI. (Continued ) CPC .. .. .. .. A61K 31/ 465 ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61P 25 / 26 ( 2018 .01 ) Primary Examiner — Sarah Pihonak (58 ) Field of Classification Search CPC . .. .. .. .. .. .. .. .. .. .. A61K 31/ 465 ; A61P 25 / 26 Assistant Examiner — Jason Deck See application file for complete search history . (74 ) Attorney , Agent, or Firm — Wilson Sonsini Goodrich & Rosati ( 56 ) References Cited U . S . PATENT DOCUMENTS (57 ) ABSTRACT 4 , 321 , 387 A 3 / 1982 Chavdarian et al . The present disclosure provides methods and compositions 4 , 327, 725 A 5 / 1982 Cortese et al . 4 , 332 ,945 A 6 / 1982 Edwards, III for treating fall - related symptoms in patients with neurode 4 , 442 , 292 A 4 / 1984 Edwards, III generative diseases such as Parkinson ' s disease or Parkin 4 ,452 ,984 A 6 / 1984 Edwards , III son -related diseases. In some embodiments , the disclosure 4 ,590 ,278 A 5 / 1986 Edwards, III 5 , 232 , 704 A 8 / 1993 Franz et al. utilizes nicotine or a salt thereof in combination of dop 5 , 965 , 571 A 10 / 1999 Hutchinson aminergic agent treatments for reducing fall - related symp 5 ,972 , 389 A 10 / 1999 Shell et al . toms such as reducing frequency of fall, reducing injuries 6 ,024 , 981 A 2 / 2000 Khankari et al. related to fall , reducing severity of injuries related to fall , 6 , 120 , 803 A 9 /2000 Wong et al. 6 , 221, 392 B1 4 / 2001 Khankari et al. freezing of gait, improving posture stability , improving 6 , 238 ,689 B1 5 / 2001 Rhodes et al. locomotion ability , improving balance and gait. In some 6 , 365, 182 B1 4 / 2002 Khankari et al . embodiments , the methods predict fall frequency and ten 6 , 368 ,625 B1 4 / 2002 Siebert et al . dency of recurrent falls in patients with Parkinson ' s disease , 6 ,723 , 340 B2 4 / 2004 Gusler et al. 6 , 911 , 475 B16 / 2005 Cesaro et al. in particular, patients with typical Parkinson ' s disease . 7 , 229 ,641 B2 6 / 2007 Cherukuri 7 , 282 ,217 B1 10 / 2007 Grimshaw et al . 7 , 384 ,653 B2 6 / 2008 Wright et al . 18 Claims, 12 Drawing Sheets US 10 , 292 , 977 B2 Page 2 ( 56 ) References Cited Lieberman , A . et al. Comparison of Parkinson Disease Patients Who Fell with Patients Who Fell More than Once (Recurrent Fallers ) . Journal of Alzheimer ' s Disease & Parkinsonism 4 ( 2 ) : 1 - 4 (Mar . 15 , OTHER PUBLICATIONS 2014 ) . Ishikawa, A . et al. Effects of smoking in patients with early - onset U . S . Appl. No. 15 /484 , 960 Non - Final Office Action dated Jul. 11 , Parkinson 's disease . Journal of Neurological Sciences , 117 ( 1 - 2 ) : 2018 . 28 -32 ( Jul. 1 , 1993 ) . Co -pending U . S . Appl . No . 16 / 109 ,458 , filed Aug . 22 , 2018 . Lieberman . Pharmaceutical Dosage Forms. vol . 1 , 2nd ed .. New Co -pending U . S . Appl. No . 16 / 109 , 463 , filed Aug. 22 , 2018 . York Marcel Dekker, Inc . 1989 ; 195 - 246 . Co -pending U . S . Appl . No . 16 / 151, 203 , filed Oct . 3 , 2018 . Lieberman . Pharmaceutical Dosage Forms. vol. 1 , 2nd ed .. New Fasano , Alfonso et al . Falls in Parkinson ' s Disease : A Complex and York Marcel Dekker, Inc . 1989 ; 266 - 271 . Quik , et al . Nicotine and Parkinson ' s disease : implications for Evolving Picture , Movement Disorders , vol. 32 , No . 11 , ( 2017 ) . therapy . Mov Disord . 2008 ; 23 ( 12 ) : 1641 - 52 . U . S . Appl . No. 15 / 484 , 960 Notice of Allowance dated Sep . 25 , Quik et al. Nicotine and Nicotinic Receptor . Neuro Toxicology 23 ; 2018 . 581 - 594 ( 2002 ) . U . S . Appl . No . 16 / 109 ,458 Non - Final Office Action dated Nov. 23 , Quik , Maryka Smoking , nicotine and Parkinson ' s disease , Trends in 2018 . Neurosciences 27 ( 9 ) ; 561 -568 (Sep . 2004 ) . U . S . Appl. No. 16 / 109 ,463 Non - Final Office Action dated Nov . 15 , Villafame, Gabriel et al. Long - Term Nicotine Administration Can 2018 . Improve Parkinson ' s Disease Report on a Case After Three Years of Treatment. Revista Neurologica Argentina , 27 ( 2 ) ; 95 -97 (2002 ) . * cited by examiner U . S . Patent May 21, 2019 Sheet 1 of 12 US 10 ,292 , 977 B2 FIG.1 U . S . Patent May 21 , 2019 Sheet 2 of 12 US 10 ,292 , 977 B2 **** FIG.2 WY WWW atent May 21 , 2019 Sheet 3 of 12 US 10 ,292 , 977 B2 1111111111111111111111111111111111111111111111111111111111111111111111111111111111111 3mg te 4 mg PlasmaNicotine(ngmi) . wwwwwwww wwwwwwwwww 200 300 400 FIG . 3 Dyskinesiaratings/timepoint FIG . 4 U . S . Patent May 21 , 2019 Sheet 4 of 12 US 10 ,292 , 977 B2 ATA * V . t FIG . 5 1932 . MM Fakty Screening v? Dose Escalation and Treatment ( 10 wie1 FIG . 6A U . S . Patent May 21 , 2019 Sheet 5 of 12 US 10 ,292 , 977 B2 SafetyAntyos 2wks NicotineWithdrawal Dose jade 12 HYY Visit3,6mg 491383 DoseEscalationand Treatment(10wks) FIG.6B Visit2,4 buu ygitana SAMZK Visit1,2 every6h 2 SYMZkona? ALATAN 49Alasa SXML Screening U . S . Patent May 21, 2019 Sheet 6 of 12 US 10 ,292 , 977 B2 FIG . 7 PercentDissolved(%) pomimmediate Release so thingsMultiparticulate Release at 6 hours tempo 2 Pulse Combination 8 10 12 14 16 Time (hours ) FIG . 8 atent May 21 , 2019 Sheet 7 of 12 US 10, 29 , 977 B2 3 % % % % % % %% %% ?? ?? ???? ?* FIG . 9 , " : )Dissolved(%Percent ? * ? se immediate Release men in Delayed Release $ 246 3333 34 36 - -- -- - - -- - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - -- - - - Time (hours ) FG. 1 U . S . Patent May 21, 2019 Sheet 8 of 12 US 10, 292 , 977 B2 PlasmaNicotino(ng/ml) DO FIG . 11A * wwinguin FIG . 11B U . S . Patent May 21 , 2019 Sheet 9 of 12 US 10 ,292 , 977 B2 . *. FIG . 12 * * * * * * * 1111 111111111 ???????? ???????????? ??????? ?????????????? ???????????? ??? ? WY FIG . 13 U . S . Patent May 21, 2019 Sheet 10 of 12 US 10 ,292 , 977 B2 * * * *** FIG . 14 + FIG . 15 Very Vigorous METS . Moderate Wed Thurs Fri Sat Sun Mos 10 Jan 11 Jan 12 Jan 13 Jan 19 180 15 last 16 jan 17 lans FIG . 16 atent May 21 , 2019 Sheet 11 of 12 US 10 ,292 , 977 B2 FIG . 17 rrrrrrr ONPOO2 Placebo Week 10 FIG . 18 U . S . Patent May 21, 2019 Sheet 12 of 12 US 10 ,292 , 977 B2 Decrease in FOG Assessed by Hart ll of the UPDRS , ' , , , V , V , V , V , V , V , V , V , V , . ONP002 Placebo Week 10 FIG . 19 NP002 kogenuriBuowaroxis Placebo Week 10 FIG . 20 US 10 , 292 , 977 B2 COMPOSITIONS AND METHODS FOR form . The administration of the nicotine or salt thereof may TREATMENT RELATED TO FALL AND result in a peak plasma nicotine levels above 7 . 5 ng/ mL FALL FREQUENCY IN about 25 minutes to about 50 minutes followed by a plasma NEURODEGENERATIVE DISEASES nicotine level of below about 5 ng /mL about 180 minutes after administration of the dosage form . The administration CROSS -REFERENCE of the nicotine or salt thereof may result in a peak plasma nicotine level above 5 ng /mL about 25 minutes to about 50 This application is a continuation -in -part of U . S . patent minutes after administration of the dosage form . The admin application Ser. No . 15 /484 , 960 , filed Apr. 11, 2017 , which istration of the nicotine or salt thereof may result in a peak claims the benefit of U .
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