`Jensen
`
`( 10 ) Patent No . : US 10 , 335 , 462 B2
`( 45 ) Date of Patent :
`* Jul . 2 , 2019
`
`US010335462B2
`
`( 54 ) USE OF LONG - ACTING GLP - 1 PEPTIDES
`( 71 ) Applicant : Novo Nordisk A / S , Bagsvaerd ( DK )
`Inventor : Christine Bjoern Jensen ,
`( 72 )
`Charlottenlund ( DK )
`( 73 ) Assignee : Novo Nordisk A / S , Bagsvaerd ( DK )
`( * ) Notice :
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U . S . C . 154 ( b ) by 0 days .
`This patent is subject to a terminal dis
`claimer .
`( 21 ) Appl . No . : 15 / 656 , 042
`( 22 ) Filed :
`Jul . 21 , 2017
`( 65 )
`Prior Publication Data
`US 2018 / 0085435 A1 Mar . 29 , 2018
`Related U . S . Application Data
`( 63 ) Continuation of application No . 14 / 409 , 493 , filed as
`application No . PCT / EP2013 / 063004 on Jun . 21 ,
`2013 , now Pat . No . 9 , 764 , 003 .
`( 60 ) Provisional application No . 61 / 708 , 162 , filed on Oct .
`1 , 2012 , provisional application No . 61 / 694 , 837 , filed
`on Aug . 30 , 2012 .
`Foreign Application Priority Data
`( 30 )
`Jul . 1 , 2012
`( EP ) . .
`. . . . . . . . . 12174535
`. . . 12186781
`Oct . 1 , 2012
`( EP ) . . . .
`. . . . . . .
`( 51 ) Int . Cl .
`A61K 38 / 26
`( 2006 . 01 )
`( 2006 . 01 )
`A61P 5 / 50
`( 2006 . 01 )
`A61P 3 / 04
`A61P 3 / 10
`( 2006 . 01 )
`U . S . CI .
`A61K 38 / 26 ( 2013 . 01 )
`CPC
`Field of Classification Search
`None
`See application file for complete search history .
`References Cited
`U . S . PATENT DOCUMENTS
`8 , 129 , 343 B2
`3 / 2012 Lau et al .
`8 , 536 , 122 B2
`9 / 2013 Lau et al .
`2010 / 0047762 A1
`2 / 2010 Button et al .
`11 / 2010 Spetzler et al .
`2010 / 0292133 AL
`2011 / 0301080 Al
`12 / 2011 Bush et al .
`FOREIGN PATENT DOCUMENTS
`11 / 2011
`102229668 A
`2409349 C2
`1 / 2011
`
`( 52 )
`
`( 58 )
`
`( 56 )
`
`CN
`RU
`
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`2413530 C2
`2006 / 097537 A2
`2010 / 092163 A2
`2011 / 080103 A1
`2011138421 A1
`12016419 Al
`2012080471 A1
`2012107476 AL
`12130136 A
`12136790 Al
`2012177929 A2
`
`3 / 2011
`9 / 2006
`8 / 2010
`7 / 2011
`11 / 2011
`2 / 2012
`6 / 2012
`8 / 2012
`10 / 2012
`10 / 2012
`12 / 2012
`
`OTHER PUBLICATIONS
`Madsbad S et al . An Overview of once - weekly glucagon - like
`peptide - 1 receptor agonists available efficacy and safety data and
`perspectives for the future , Diabetes , Obesity and Metabolism Year
`2011 , vol . 13 , No . 5 , pp . 394 - 407 .
`Buse B . J . et al . , Exenatide once weekly versus liraglutide once
`daily in patients with type 2 diabetes ( DURATION - 6 ) : a randomised ,
`open - label study , Lancet , 2013 , vol . 381 , pp . 117 - 124 .
`Kim et al . “ Effects of Once - Weekly Dosing of a Long - Acting
`Release Formulation of Exentide on Glucose Control and Body
`Weight in Subjects with Type 2 Diabetes . ” Diabetes care ( 2007 ) vol .
`30 pp . 1487 - 1493 .
`Bydureon NDA 022200 / S - 008 Package Information pp . 1 - 179 ( Feb .
`2014 ) .
`Clinical Trial NCT00696657 entitled “ A Randomized Controlled
`Clinical Trial in Type 2 Diabetes Comparing Semaglutide to Pla
`cebo and Liraglutide . ” pp . 1 - 5 Mar . 2015 . Accessed Sep . 24 , 2015
`at clinicaltrials . gov / archive / NCT00696657 / 2011 _ 03 _ 25 .
`Lau et al . “ Discovery of the Once - WEekly Glucagon - Like Peptide - 1
`( GLP - 1 ) Analogue Semaglutide . " J . Med . Chem . ( 2015 ) vol . 58 pp .
`7370 - 7380 .
`Eperzan Assessment Report . Euro . Med . Agency . pp . 1 - 124 ( 2014 )
`accessed Sep . 24 , 2015 at URL ema . europa . ed / docs / en _ GB / document _
`library / EPAR _ - _ Public _ assessment _ report / human / 002735 /
`WC500165119 . pdf .
`Trulicity Assessment Report . Euro . Med . Agency . pp . 1 - 172 ( 2014 )
`accessed Sep . 24 , 2015 at URL ema . europa . ed / docs / en _ GB / document _
`library / EPAR _ - _ Public _ assessment _ report / human / 002825 /
`WC500179473 . pdf .
`Mizuta et al . “ The Role for GLP - 1 in Regulation of Body Weight . ”
`Progress in Medicine 2008 vol . 28 No . 8 pp . 1909 - 1912 .
`CDC , “ National Health and Nutrition Examination Survey : Healthy
`Weight , Overweight and Obesity among U . S . adults ” 03 - 0260 pp .
`1 - 2 ( Jul . 2003 ) , accessed May 10 , 2016 at URL cdc . gov / nchs / data /
`nhanes / databriefs / adultweight . pdf .
`
`Primary Examiner — Julie Ha
`Assistant Examiner — Kristina M Hellman
`( 74 ) Attorney , Agent , or Firm — Leon Y . Lum
`
`ABSTRACT
`( 57 )
`The invention relates to use of long - acting GLP - 1 peptides
`in certain dosage regimes for the treatment of type 2
`diabetes , obesity , etc .
`
`10 Claims , 6 Drawing Sheets
`Specification includes a Sequence Listing .
`
`MPI EXHIBIT 1001 PAGE 1
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`MPI EXHIBIT 1001 PAGE 1
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`atent
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`Jul . 2 , 2019
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`Sheet 1 of 6
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`US 10 , 335 , 462 B2
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`Semaglutide
`Liraglutide
`8 . 0
`8 . 1
`8 . 1
`8 . 1
`8 . 1
`8 . 2
`8 . 2
`8 . 2
`Baseline 8 . 1
`Placebo 0 . 1 mg 0 . 2 mg 0 . 4 mg 0 . 8 mg 0 . 8 mg 1 . 6 mg 1 . 2 mg 1 . 8 mg
`
`*
`
`- 0 . 25
`- 0 . 50 - 0 . 5
`HbAc ( % ) - 0 . 75
`
`0 . 58
`
`LLIR LEITERIILE
`
`XXXXXXXXXXX
`WXXXXXXXXX
`WWWXXXXXXXX
`XXXXXXXXXXXXXXXXXX WOWWWWWW
`
`XX
`XX
`XX
`
`XX VYYYYYYYYYYYYYYYYYYYYYYYY
`xxxxxxxxxxxxxxxxxxxx XX
`XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
`
`XX
`XX
`XX
`XX
`XX
`XX
`XX
`XX
`XX
`XX
`XX
`
`* *
`
`XXXXXXXXXXXXXXXXXXX
`XXXXXXXXXXXXXXXXXXXXXXXX
`
`- 2 . 00
`
`* p < 0 . 05 vs . placebo
`* * p < 0 . 001 vs , placebo
`* Semaglutide 1 . 6 mg T superior to liraglutide 1 . 2 mg and 1 . 8 mg
`Data are LS means .
`
`Fig . 1
`
`.
`
`MPI EXHIBIT 1001 PAGE 2
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`MPI EXHIBIT 1001 PAGE 2
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`atent
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`Jul . 2 , 2019
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`Sheet 2 of 6
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`US 10 , 335 , 462 B2
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`12
`
`11
`
`10
`
`9
`
`8
`
`*
`
`* *
`
`2022
`
`wwwwwwwwwwww
`
`semaglutide 0 . 2 mg
`
`7
`
`Time 5 6
`
`Fig . 2
`
`0 semaglutide 0 . 1 mg
`
`wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwand
`
`4
`
`3
`
`2
`
`1
`
`www
`
`0
`
`
`
`Bankinamakanan dan
`
`
`
`in HbA1c
`
`Change
`
`MPI EXHIBIT 1001 PAGE 3
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`MPI EXHIBIT 1001 PAGE 3
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`atent
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`Jul . 2 , 2019
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`Sheet 3 of 6
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`US 10 , 335 , 462 B2
`
`MBALE $ 6 . 5 % ( AACE )
`
`Fig . 3A
`
`MPI EXHIBIT 1001 PAGE 4
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`MPI EXHIBIT 1001 PAGE 4
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`atent
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`Sheet 4 of 6
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`US 10 , 335 , 462 B2
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`87
`
`XXXXXXXXXXXX
`
`HbA1 < 7 % ( ADA )
`
`.
`
`* * *
`
`Fig . 3 B
`
`MPI EXHIBIT 1001 PAGE 5
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`MPI EXHIBIT 1001 PAGE 5
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`atent
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`Jul . 2 , 2019
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`Sheet 5 of 6
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`US 10 , 335 , 462 B2
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`Time ( weeks )
`
`wwwwwwwwwwwww
`
`* * * * * * * * * * * *
`
`*
`
`* *
`
`MYXX
`
`
`
`w semaglutide 0 . 8 mg * semaglutide 0 . 8 mg T iraglutide 1 . 2 mg weten liraglutide 1 . 8 mg
`
`
`semaglutide 0 . 4 mg motne semaglutide 16 mg T
`www
`
`Fig . 4
`
`Change
`
`EN
`
`
`
`) ( kg weight in body
`
`
`
`
`
`
`
`MPI EXHIBIT 1001 PAGE 6
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`MPI EXHIBIT 1001 PAGE 6
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`
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`U . S . Patent
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`atent
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`Jul . 2 , 2019
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`Sheet 6 of 6
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`US 10 , 335 , 462 B2
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`* * * * *
`* * * * * * * * * *
`*
`* * * * * * * * *
`* * *
`* * * * * * * * *
` titttttttitate * * * * * * * *
`* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
`*
`* * * * * * * * * * * * * * * * * WANA
`
`
`281121111111712TITTTTTTTT * * * * * * * * * * * * * * * 1 : 21 des 12 : 18 :
` 37311315 * 12 * * * * * *
`
`PR * * * * * *
`* * * * * * * * * * *
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`Fig . 5
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`Borooroondocomo
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`
`
`) Weight ( kg
`
`
`
`MPI EXHIBIT 1001 PAGE 7
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`MPI EXHIBIT 1001 PAGE 7
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`
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`US 10 , 335 , 462 B2
`
`USE OF LONG - ACTING GLP - 1 PEPTIDES
`
`less often , and wherein said GLP - 1 agonist and / or admin
`istration optionally is as defined herein .
`CROSS - REFERENCE TO RELATED
`BRIEF DESCRIPTION OF DRAWINGS
`APPLICATIONS
`FIG . 1 shows change in HbAlc following subcutaneous
`This application is a continuation of U . S . application Ser .
`administration of placebo , semaglutide , or liraglutide to
`No . 14 / 409 , 493 , filed Dec . 19 , 2014 , which is a 35 U . S . C . §
`human subjects . * p < 0 . 05 vs . placebo ; * * p < 0 . 001 vs . placebo
`371 National Stage application of International Application
`( based on adjusted means ) . Baseline values are for infor
`PCT / EP2013 / 063004 ( WO 2014 / 005858 ) , filed Jun . 21 ,
`ica 10 mation only : data are model - adjusted for baseline HbAlc .
`2013 , which claimed priority of European Patent Applica
`Data are model - adjusted LS means , FAS LOCF . The esti
`tion 12174535 . 0 , filed Jul . 1 , 2012 and European Patent
`mates are from an ANOVA model with treatment , country
`Application 12186781 . 6 , filed Oct . 1 , 2012 ; this application
`and previous treatment as fixed effects and baseline HbAlc
`claims priority under 35 U . S . C . $ 119 of U . S . Provisional
`as covariate .
`Application 61 / 694 , 837 ; filed Aug . 30 , 2012 and U . S . Pro 15
`FIG . 2 shows mean change in HbAlc from baseline
`visional Application 61 / 708 , 162 , filed Oct . 1 , 2012 .
`versus time ; data are mean ( 1 . 96SE ) , FAS LOCF . The
`The present invention relates to improved uses of GLP - 1
`treatments are placebo ( A ) ; semaglutide 0 . 1 mg ( B , dashed
`peptides in therapy .
`line ) , 0 . 2 mg ( C ) , 0 . 4 mg ( D ) , 0 . 8 mg ( E ) , 0 . 8 mg T ( F ,
`dashed line ) , 1 . 6 mg T ( G ) ; liraglutide 1 . 2 mg ( H ) , 1 . 8 mg
`SEQUENCE LISTING
`20 ( I ) .
`FIG . 3A and FIG . 3B show subjects reaching the AACE
`The instant application contains a Sequence Listing which
`( FIG . 3A ) or ADA ( FIG . 3B ) criteria for glycaemic control .
`The number of patients reaching the criteria per treatment is
`has been submitted in ASCII format via EFS - Web and is
`hereby incorporated by reference in its entirety . Said ASCII
`indicated in each bar . The treatments are placebo ( A ) ;
`copy , created on Jun . 17 , 2013 and amended on Jul . 12 , 25 semaglutide 0 . 1 mg ( B ) , 0 . 2 mg ( C ) , 0 . 4 mg ( D ) , 0 . 8 mg ( E ) ,
`2017 , is named 8545US02 _ SeqList . txt and is 7 , 975 bytes in
`0 . 8 mg T ( F ) , 1 . 6 mg T ( G ) ; liraglutide 1 . 2 mg ( H ) , 1 . 8 mg
`( I ) .
`* p < 0 . 05 vs . placebo ;
`* * p < 0 . 001 vs . placebo ;
`size .
`* * * p < 0 . 0001 vs . placebo ( based on adjusted means ) . Data
`are FAS LOCF . The estimates are from a logistic regression
`SUMMARY
`30 model treatment , country and previous treatment as fixed
`effects and baseline HbAlc as covariate . ADA , American
`In one embodiment the invention relates to a method for
`Diabetes Association ; AACE , American Association of
`a ) reduction of HbAlc ; b ) prevention or treatment of type 2
`Clinical Endocrinologists .
`diabetes , hyperglycemia , impaired glucose tolerance , or
`FIG . 4 shows mean body weight change versus time ; data
`non - insulin dependent diabetes ; or c ) prevention or treat
`ment of obesity , reducing body weight and / or food intake , or 35 are mean ( 1 . 96SE ) , FAS LOCF . The treatments are placebo
`( A ) ; semaglutide 0 . 1 mg ( B , dashed line ) , 0 . 2 mg ( C ) , 0 . 4 mg
`inducing satiety ; wherein said method comprises adminis
`( D ) , 0 . 8 mg ( E ) , 0 . 8 mg T ( F , dashed line ) , 1 . 6 mg T ( G ) ;
`tration of a GLP - 1 agonist to a subject in need thereof ,
`wherein said GLP - 1 agonist i ) has a half - life of at least 72 ?
`â ? timâ??§Â?Ò?§ \ §Â?Ò?§â????8?? – ? ? §â§?§
`FIG . 5 shows body weight change from baseline at week
`hours , wherein said half - life optionally is determined by 40 12 . * * p < 0 . 001 vs . placebo ; * * * p < 0 . 0001 vs . placebo ( based
`Assay ( II ) ; ii ) is administered in an amount of at least 0 . 7 mg on adjusted means . † : Baseline values for information only :
`per week , such an amount equivalent to at least 0 . 7 mg data are model - adjusted for baseline weight . Data are model
`semaglutide per week ; and iii ) is administered once weekly
`adjusted LS means , FAS LOCF . The estimates are from an
`or less often .
`ANOVA model with treatment , country and previous treat
`In one embodiment the invention relates to a GLP - 1 45 ment as fixed effects and baseline weight as covariate .
`SE : Standard error . FAS : Full analysis set . LOCF : Last
`agonist for use in a ) the reduction of HbAlc ; b ) the preven -
`tion or treatment of type 2 diabetes , hyperglycemia ,
`observation carried forward .
`impaired glucose tolerance , or non - insulin dependent dia
`DESCRIPTION
`betes ; or c ) the prevention or treatment of obesity , for
`reducing body weight and / or food intake , or for inducing 50
`The present invention relates to an improved use of
`satiety ; wherein said use comprises administration of said
`GLP - 1 agonist in an amount of at least 0 . 7 mg per week ,
`GLP - 1 agonists in therapy . In one embodiment the invention
`such an amount equivalent to at least 0 . 7 mg semaglutide per
`relates to certain dosage regimes of GLP - 1 agonists which
`week , and wherein said GLP - 1 agonist and / or administration
`provide improved effect in diseases or conditions , such as
`optionally is as defined herein .
`55 prevention and / or treatment of type 2 diabetes and obesity .
`In one embodiment the invention relates to a composition
`In one embodiment the methods of the present invention
`comprising a GLP - 1 agonist for use in a ) the reduction of
`provides surprisingly showed improved reduction of HbAlc
`HbAlc ; b ) the prevention or treatment of type 2 diabetes ,
`and reduction of body weight . In one embodiment the
`hyperglycemia , impaired glucose tolerance , or non - insulin
`GLP - 1 agonist is administered in an amount which provides
`dependent diabetes ; or c ) the prevention or treatment of 60 an improved a ) reduction in HbAlc or b ) reduction in body
`obesity , for reducing body weight and / or food intake , or for
`weight compared to administration of 1 . 8 mg liraglutide or
`inducing satiety ; wherein said GLP - 1 agonist i ) has a
`less , such as 0 . 8 mg liraglutide or less , per day .
`half - life of at least 72 hours , wherein said half - life optionally
`In one embodiment the invention relates to a method for
`is determined by Assay ( II ) ; and ii ) is administered in an
`reduction of HbAlc or for prevention or treatment of type 2
`amount of at least 0 . 7 mg per week , such an amount 65 diabetes , hyperglycemia , impaired glucose tolerance , or
`equivalent to at least 0 . 7 mg semaglutide per week ; and
`non - insulin dependent diabetes , said method comprising
`wherein said composition is administered once weekly or
`administration of a GLP - 1 agonist to a subject in need
`
`MPI EXHIBIT 1001 PAGE 8
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`MPI EXHIBIT 1001 PAGE 8
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`US 10 , 335 , 462 B2
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`thereof in an amount of at least 0 . 7 mg per week , such an
`In one embodiment the GLP - 1 peptide is a DPPIV pro
`amount equivalent to at least 0 . 7 mg semaglutide per week .
`tected GLP - 1 peptide . In one embodiment the GLP - 1 pep
`In one embodiment the method is for reduction of HbAlc .
`tide is DPPIV stabilised .
`In one embodiment the method is for prevention or treat -
`In one embodiment the GLP - 1 agonist has an EC50 at or
`ment of type 2 diabetes . In one embodiment the method is
`5 below 3000 PM , such as at or below 500 PM or at or below
`for prevention or treatment of hyperglycemia . In one
`or treatment of hyperglycemia . In one
`100 PM , optionally determined by Assay ( I ) .
`embodiment the method is for prevention or treatment of
`a GLP - 1
`In one embodiment the invention relates to
`impaired glucose tolerance . In one embodiment the method
`agonist for use in the reduction of HbAlc or for use in the
`is for prevention or treatment of non - insulin dependent
`prevention or treatment of type 2 diabetes , hyperglycemia ,
`diabetes . In one embodiment the method of the invention 10 impaired glucose tolerance , or non - insulin dependent dia
`comprises delaying or preventing diabetic disease progres
`betes comprising administering a GLP - 1 agonist in an
`sion . In one embodiment a HbAlc level below 7 %
`is
`amount of at least 0 . 7 mg per week , such an amount
`achieved . In one embodiment the level of HbAlc is deter
`equivalent to at least 0 . 7 mg semaglutide per week . In one
`mined according to the method defined by the Diabetes
`Control and Complications Trial ( CCT ) . In one embodi - 15 embodiment the GLP - 1 agonist and / or administration is as
`defined herein .
`ment the level of HbAlc is determined according to the
`method defined by the International Federation of Clinical
`In one embodiment the invention relates to a GLP - 1
`agonist for use in the prevention or treatment of obesity , in
`Chemistry ( IFCC ) .
`In one embodiment the invention relates to a method for
`the reduction of body weight and / or food intake , or in the
`treating or preventing obesity , for reducing body weight 20 induction satiety comprising administering a GLP - 1 agonist
`and / or food intake , or for inducing satiety , said method
`in an amount of at least 0 . 7 mg per week , such an amount
`comprising administration of a GLP - 1 agonist to a subject in
`equivalent to at least 0 . 7 mg semaglutide per week . In one
`need thereof in an amount of at least 0 . 7 mg per week , such
`embodiment the GLP - 1 agonist and / or administration is as
`an amount equivalent to at least 0 . 7 mg semaglutide per
`defined herein .
`week . In one embodiment the method is for prevention or 25
`In one embodiment the invention relates to a composition
`treatment of obesity . In one embodiment the method is for
`comprising a GLP - 1 agonist and one or more pharmaceuti
`reducing body weight and / or food intake . In one embodi -
`cally acceptable excipients for use in reduction of HbAlc or
`for prevention or treatment of type 2 diabetes , hyperglyce
`ment the method is for inducing satiety .
`In one embodiment the GLP - 1 agonist has a half - life of at
`mia , impaired glucose tolerance , or non - insulin dependent
`least 24 hours , such as at least 48 hours , at least 60 hours , 30 diabetes , wherein said GLP - 1 agonist is administered in an
`or at least 72 hours , or such as at least 84 hours , at least 96
`amount of at least 0 . 7 mg per week , such an amount
`hours , or at least 108 hours , or optionally at least 120 hours ,
`equivalent to at least 0 . 7 mg semaglutide per week . In one
`at least 132 hours , or at least 144 hours , wherein said
`embodiment the GLP - 1 agonist and / or administration is as
`half - life optionally is determined by Assay ( II ) .
`defined herein .
`In one embodiment the GLP - 1 agonist is administered 35
`In one embodiment the invention relates to a composition
`twice weekly or less often , once weekly or less often , or
`comprising a GLP - 1 agonist and one or more pharmaceuti
`once weekly or less often . In one embodiment the GLP - 1
`cally acceptable excipients for use in the prevention or
`agonist is administered once every secondly week or less
`treatment of obesity , in the reduction of body weight and / or
`often , once every third week or less often , or once a month
`food intake , or in the induction satiety , wherein said GLP - 1
`40 agonist is administered in an amount of at least 0 . 7 mg per
`or less often .
`In one embodiment the GLP - 1 agonist is administered in
`week , such an amount equivalent to at least 0 . 7 mg sema
`an amount per week of at least 0 . 8 mg , at least 0 . 9 mg , or at
`glutide per week . In one embodiment the GLP - 1 agonist
`least 1 . 0 mg . In one embodiment the GLP - 1 agonist is
`and / or administration is as defined herein .
`administered in an amount per week of at least 1 . 1 mg , at
`In one embodiment the GLP - 1 agonist is administered
`least 1 . 2 mg , or at least 1 . 3 mg . In one embodiment the 45 with another therapeutic agent . Administration with another
`GLP - 1 agonist is administered in an amount per week of at
`therapeutic agent may be carried out as administration of the
`GLP - 1 agonist and the other therapeutic agent within the
`least 1 . 4 mg , at least 1 . 5 mg , or at least 1 . 6 mg .
`In one embodiment the GLP - 1 agonist is administered in
`same therapeutic window ( e . g . within a period of two weeks ,
`a period of one week , or in a 96 , 72 , or 48 hour period , etc . ) .
`an amount per week equivalent to at least 0 . 8 mg , at least 0 . 9
`mg , or at least 1 . 0 mg semaglutide . In one embodiment the 50 The treatment with a GLP - 1 agonist according to the present
`GLP - 1 agonist is administered in an amount per week
`invention may be combined with one or more additional
`equivalent to at least 1 . 1 mg , at least 1 . 2 mg , or at least 1 . 3
`therapeutic agents , e . g . selected from antidiabetic agents ,
`mg semaglutide . In one embodiment the GLP - 1 agonist is
`antiobesity agents , appetite regulating agents , antihyperten
`administered in an amount per week equivalent to at least
`sive agents , agents for the treatment and / or prevention of
`1 . 4 mg , at least 1 . 5 mg , or at least 1 . 6 mg semaglutide .
`55 complications resulting from or associated with diabetes and
`In one embodiment the GLP - 1 agonist is selected from the
`agents for the treatment and / or prevention of complications
`group consisting of semaglutide , exenatide , albiglutide , and
`and disorders resulting from or associated with obesity ;
`dulaglutide .
`examples of these therapeutic agents are : sulphonylureas ,
`In one embodiment the GLP - 1 agonist is administered by
`thiazolidinediones , biguanides , meglitinides , glucosidase
`parenteral administration , such as subcutaneous injection .
`60 inhibitors , glucagon antagonists , and DPP - IV ( dipeptidyl
`In one embodiment the GLP - 1 agonist is a GLP - 1 peptide .
`peptidase - IV ) inhibitors .
`In one embodiment the GLP - 1 peptide comprises no more
`In one embodiment , as used herein , an " amount equiva
`than 5 , such as no more than 4 or no more than 3 , amino acid
`lent to ” when used in relation to GLP - 1 agonists refers to
`residues which have been substituted , inserted or deleted as
`amounts of a first GLP - 1 agonist and a second GLP - 1
`compared to GLP - 1 ( 7 - 37 ) . In one embodiment the GLP - 1 65 agonist having GLP - 1 receptor potency ( i . e . EC50 ) within
`peptide comprises no more than 4 amino acid residues which
`+ 30 % , such as within + 20 % or within + 10 % , of each other
`optionally determined by Assay ( I ) described herein and
`are not encoded by the genetic code .
`
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`US 10 , 335 , 462 B2
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`5
`
`The present invention also relates to a GLP - 1 agonist of
`having a half - life within + 30 % , such as within + 20 % or
`the invention , for use as a medicament . In particular embodi
`within + 10 % , of each other optionally determined by Assay
`( II ) described herein .
`ments , the GLP - 1 agonist of the invention may be used for
`the following medical treatments :
`In one embodiment an “ effective amount of a GLP - 1
`( i ) prevention and / or treatment of all forms of diabetes ,
`agonist as used herein means an amount sufficient to cure ,
`alleviate , or partially arrest the clinical manifestations of a
`such as hyperglycemia , type 2 diabetes , impaired glucose
`given disease or state and its complications . An amount
`tolerance , type 1 diabetes , non - insulin dependent diabetes ,
`adequate to accomplish this is defined as “ effective amount ” .
`MODY ( maturity onset diabetes of the young ) , gestational
`Effective amounts for each purpose will depend on the
`diabetes , and / or for reduction of HbAlc ;
`severity of the disease or injury as well as the weight and 10
`( ii ) delaying or preventing diabetic disease progression ,
`general state of the subject . It will be understood that
`such as progression in type 2 diabetes , delaying the pro
`determining an appropriate dosage may be achieved using
`gression of impaired glucose tolerance ( IGT ) to insulin
`routine experimentation , by constructing a matrix of values
`requiring type 2 diabetes , and / or delaying the progression of
`and testing different points in the matrix , which is all within
`15 non - insulin requiring type 2 diabetes to insulin requiring
`the ordinary skills of a trained physician or veterinary
`type 2 diabetes ;
`In one embodiment the term “ treatment ” or “ treating ” as
`( iii ) prevention and / or treatment of eating disorders , such
`used herein means the management and care of a patient for
`as obesity , e . g . by decreasing food intake , reducing body
`the purpose of combating a condition , such as a disease or
`weight , suppressing appetite , inducing satiety ; treating or
`a disorder . In one embodiment the term “ treatment ” or
`“ treating " is intended to include the full spectrum of treat - 20 preventing binge eating disorder , bulimia nervosa , and / or
`ments for a given condition from which the patient is
`obesity induced by administration of an antipsychotic or a
`suffering , such as administration of the active compound to
`steroid ; reduction of gastric motility ; and / or delaying gastric
`alleviate the symptoms or complications ; to delay the pro -
`emptying .
`gression of the disease , disorder , or condition ; to alleviate or
`In another particular embodiment , the indication is ( i ) . In
`relieve the symptoms and complications , and / or , to cure or 25 a further particular embodiment the indication is ( ii ) . In a
`eliminate the disease , disorder , or condition as well as to
`still further particular embodiment the indication is ( iii ) . In
`prevent the condition . In one embodiment prevention is to be
`one embodiment the indication is type 2 diabetes and / or
`understood as the management and care of a patient for the
`obesity .
`purpose of combating the disease , condition , or disorder and
`In one embodiment the method comprises prevention ,
`includes the administration of the active compounds to 30 treatment , reduction and / or induction in one or more dis
`prevent the onset of the symptoms or complications .
`eases or conditions defined herein . In one embodiment the
`In one embodiment the term “ hydrophilic spacer " as used
`indication is ( i ) and ( iii ) . In one embodiment the indication
`herein means a spacer that separates a peptide and an
`is ( ii ) and ( iii ) . In one embodiment the method comprises
`albumin binding residue with a chemical moiety which
`prevention , treatment , reduction and / or induction in one or
`comprises at least 5 non - hydrogen atoms where 30 - 50 % of 35 more diseases or conditions selected from a ) and b ) , a ) and
`these are either N or O .
`c ) , b ) and c ) , or a ) , b ) and c ) as defined in claim
`1 .
`In one embodiment the term " analogue ” as used herein
`In one embodiment the invention relates to administration
`referring to a polypeptide means a modified peptide wherein
`of an effective amount of a GLP - 1 agonist .
`one or more amino acid residues of the peptide have been
`In one embodiment as used herein , specific values given
`substituted by other amino acid residues and / or wherein one 40 in relation to numbers or intervals may be understood as the
`or more amino acid residues have been deleted from the
`specific value or as about the specific value .
`peptide and or wherein one or more amino acid residues
`Functional Properties
`have been added to the peptide . Such addition or deletion of
`In a first functional aspect , the GLP - 1 agonists of the
`amino acid residues can take place at the N - terminal of the
`invention have a good potency . Also , or alternatively , in a
`peptide and / or at the C - terminal of the peptide . A simple 45 second functional aspect , the GLP - 1 agonists of the inven
`system
`is used to
`describe analogues : For example
`t ion have a protracted pharmacokinetic profile . Also , or
`Arg34GLP - 1
`( 7 - 37 ) Lys designates a GLP - 1 analogue
`alternatively , in a third functional aspect , the GLP - 1 agonists
`wherein the naturally occurring lysine at position 34 has
`of the invention are stable against degradation by gastro
`been substituted with arginine and a lysine residue has been
`intestinal enzymes .
`50 Biological Activity ( Potency )
`added to the C - terminal ( position 38 ) .
`In one embodiment the term “ GLP - 1 peptide ” as used
`According to the first functional aspect , the GLP - 1 ago
`nists of the invention are biologically active , or potent . In a
`herein means GLP - 1 ( 7 - 37 ) , a GLP - 1 analogue , a GLP - 1
`particular embodiment , " potency ” and / or “ activity ” refers to
`derivative or a derivative of a GLP - 1 analogue .
`In one embodiment the term “ exendin - 4 peptide ” as used
`in vitro potency , i . e . performance in a functional GLP - 1
`herein means exendin - 4 ( 1 - 39 ) , an exendin - 4 analogue , an 55 receptor assay , more in particular to the capability of stimu
`exendin - 4 derivative or a derivative of an exendin - 4 ana -
`lating CAMP formation in a cell line expressing the cloned
`human GLP - 1 receptor .
`logue .
`In one embodiment the term “ DPP - IV protected as used
`The stimulation of the formation of CAMP in a medium
`containing the human GLP - 1 receptor may preferably be
`herein referring to a polypeptide means a polypeptide which
`has been chemically modified in order to render said com - 60 determined using a stable transfected cell - line such as
`pound resistant to the plasma peptidase dipeptidyl amino -
`BHK467 - 12A ( tk - ts 13 ) , and / or using for the determination
`peptidase - 4 ( DPP - IV ) . The DPP - IV enzyme in plasma is
`of cAMP a functional receptor assay , e . g . based on compe
`known to be involved in the degradation of several peptide
`tition between endogenously formed cAMP and exog
`hormones , e . g . GLP - 1 , Exendin - 4 etc . Thus a considerable
`enously added biotin - labelled CAMP , in which assay CAMP
`effort is being made to develop GLP - 1 agonists less suscep - 65 is more preferably captured using a specific antibody , and / or
`tible to DPP - IV mediated hydrolysis in order to reduce the
`wherein an even more preferred assay is the AlphaScreen
`CAMP Assay , such as the one described in Assay ( I ) .
`rate of degradation by DPP - IV .
`
`MPI EXHIBIT 1001 PAGE 10
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`MPI EXHIBIT 1001 PAGE 10
`
`
`
`US 10 , 335 , 462 B2
`
`15
`
`In one embodiment the amino acid residue in position 7
`In one embodiment the term half maximal effective
`of said GLP - 1 peptide is selected from the group consisting
`concentration ( EC50 ) generally refers to the concentration
`of D - histidine , desamino - histidine , 2 - amino - histidine , B - hy
`which induces a response halfway between the baseline and
`droxy - histidine , homohistidine , N
`- acetyl - histidine , a - fluo
`maximum , by reference to the dose response curve . EC , is
`used as a measure of the potency of a compound and 5 romethyl - histidine ,
`d - methyl - histidine ,
`3 - pyridylalanine ,
`represents the concentration where 50 % of its maximal
`2 - pyridylalanine and 4 - pyridylalanine .
`In one embodiment the GLP - 1 peptide is attached to a
`effect is observed .
`hydrophilic spacer via the amino acid residue in position 23 ,
`The in vitro potency of the GLP - 1 agonists of the inven
`26 , 34 , 36 or 38 relative to the amino acid sequence of
`tion may be determined as described above , and the EC 50 of
`the GLP - 1 agonist in question determined . The lower the 10 GLP - 1 ( 7 - 37 ) .
`In one embodiment the GLP - 1 peptide is exendin - 4 , an
`EC50 , the better the potency .
`exendin - 4 - analogue , or a derivative of exendin - 4 .
`In a particular embodiment , the medium has the following
`In one embodiment the GLP - 1 agonist peptide comprises
`composition ( final in - assay concentrations ) : 50 mM TRIS
`the amino acid sequence of the following formula :
`HCl ; 5 mM HEPES ; 10 mM MgCl2 , 6H2O ; 150 mM NaCl ; 15
`0 . 01 % Tween ; 0 . 1 % BSA ; 0 . 5 mM IBMX ; 1 mM ATP ; 1 UM
`H - His - Gly - Glu - Gly - Thr - Phe - Thr - Ser - Asp - Leu - Ser
`Lys - Gln - Met - Glu - Glu - Glu - Ala - Val - Arg - Leu
`GTP ; pH 7 . 4 .
`Phe - Ile - Glu - Trp - Leu - Lys - Asn - Gly - Gly - Pro - Ser
`In a further particular embodiment , the GLP - 1 agonist of
`Ser - Gly - Ala - Pro - Pro - Pro - Ser - NH2
`( SEQ ID NO : 2 ) .
`the invention has an in vitro potency corresponding to an
`In one embodiment the GLP - 1 agonist comprises an
`EC50 at or below 3000 PM , such as below 2000 PM , below 20 albumin binding residue attached via a hydrophilic spacer to
`1000 PM , or below 500 PM , or such as below 200 PM or
`the C - terminal amino acid residue of said GLP - 1 peptide .
`below 100 pM .
`In one embodiment the GLP - 1 agonist comprises a second
`In another particular embodiment the GLP - 1 agonist of
`albumin binding residue is attached to an amino acid residue
`the invention are potent in vivo , which may be determined
`which is not the C - terminal amino acid residue .
`as is known in the art in any suitable animal model