111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US00844564 7B2
`
`c12) United States Patent
`Prickett et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,445,647 B2
`*May 21, 2013
`
`(54) MODIFIED EXENDINS AND EXENDIN
`AGONISTS
`
`(75)
`
`Inventors: Kathryn S. Prickett, San Diego, CA
`(US); Andrew A. Young, San Diego, CA
`(US)
`
`(73) Assignees: Amylin Pharmaceuticals, LLC, San
`Diego, CA (US); AstraZeneca
`Pharmaceuticals LP, Wilmington, DE
`(US)
`
`( *) 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(cid:173)
`claimer.
`
`(21) Appl. No.: 13/296,120
`
`(22) Filed:
`
`Nov. 14, 2011
`
`(65)
`
`Prior Publication Data
`
`US 2012/0135922 Al
`
`May 31,2012
`
`Related U.S. Application Data
`
`(63)
`
`Continuation of application No. 11/174,089, filed on
`Jun. 30, 2005, now Pat. No. 8,057,822, which is a
`continuation of application No. 09/561,226, filed on
`Apr. 28, 2000, now Pat. No. 6,924,264.
`
`(60) Provisional application No. 60/132,018, filed on Apr.
`30, 1999.
`
`(51)
`
`Int. Cl.
`A61K 38138
`A61K 38/00
`(52) U.S. Cl.
`USPC ..................... 530/387.3; 530/387.9; 530/350;
`514/3; 514/776
`
`(2006.01)
`(2006.01)
`
`312003 Larsen eta!.
`6,528,486 B1
`6,723,530 B1 * 412004 Drucker ....................... 435169.1
`6,753,165 B1
`612004 Cox eta!.
`6,767,887 B1
`712004 Hoffmann et al.
`6,872,700 B1
`312005 Young eta!.
`6,924,264 B1
`812005 Prickett et a!.
`6,924,624 B2
`812005 Baur eta!.
`6,956,026 B2
`1012005 Beeley eta!.
`6,982,248 B2
`112006 Coolidge et al.
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`1212006 Young eta!.
`7,189,690 B2
`312007 Rosen eta!.
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`312010 Prickett et a!.
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`412010 Prickett et a!.
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`1112011 Prickett et a!.
`200110047084 A1
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`200510026834 A1
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`2007100377 50 A1
`212007 Young eta!.
`
`EP
`wo
`wo
`wo
`wo
`wo
`wo
`
`FOREIGN PATENT DOCUMENTS
`0619322 A2
`1011994
`W0-9507098 A1
`311995
`W0-9746584 A1
`1211997
`W0-9805351 A1
`211998
`W0-9808871 A1
`311998
`W0-9830231 A1
`711998
`W0-9907404 A1
`211999
`
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`
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`
`(Continued)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`Primary Examiner- Manjunath Rao
`Assistant Examiner- Samuel Liu
`(74) Attorney, Agent, or Firm- Womble Carlyle Sandridge
`&RiceLLP
`
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`
`ABSTRACT
`
`Novel modified exendins and exendin agonists having an
`exendin or exendin agonist linked to one or more polyethyl(cid:173)
`ene glycol polymers, for example, and related formulations
`and dosages and methods of administration thereof are pro(cid:173)
`vided. These modified exendins and exendin agonists, com(cid:173)
`positions and methods are useful in treating diabetes and
`conditions that would be benefited by lowering plasma glu(cid:173)
`cose or delaying and/or slowing gastric emptying or inhibit(cid:173)
`ing food intake.
`
`6 Claims, 20 Drawing Sheets
`
`SANOFI-AVENTIS Exhibit 1017 - Page 1
`
`IPR for Patent No. 8,951,962
`
`

`

`US 8,445,647 B2
`Page 2
`
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`Like Peptide-! (GLP-1 )-(7 -36) Amide on Type 2 (noninsulin-Depen(cid:173)
`dent) Diabetidc Patients," J. Clin. Endocrinol. and Metabolism
`81( 1 ):327 -332 ( 1996).
`
`Yeh et al., Proc. Nat!. Acad. Sci. USA, 89:1904-1908 (1992).
`Zaidi eta!., Effects of Copper Chloride Toxicity on Corpus Striatum
`of Rat Brain-A Histological Study, J. Anat. Soc. India 51(1):55-56
`(2002).
`Zalipsky, "Funztionalized Poly (ethylene glycol) for Preparation of
`Biologically Relevant Conjugates," Bioconjugate Chern. 6:150-165
`(1995).
`Zimmerman eta!.; "Schedule Dependency of the Antitumor Activity
`and Toxicity ofPolythylene Glycol-modified Interleukin 2 in Murine
`Tumor Models"; Cancer Res., 49:6521-6528 (Dec. 1989).
`* cited by examiner
`
`SANOFI-AVENTIS Exhibit 1017 - Page 4
`
`IPR for Patent No. 8,951,962
`
`

`

`-....l = N
`
`~
`0..,
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`~
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`rJl
`d
`
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`
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`Ile Glu Trp Leu Lys Asn Gty Gly Pro Ser
`
`30
`
`15
`
`25
`
`10
`
`Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
`
`30
`
`15
`
`Fig. 2
`
`25
`
`10
`
`Ser Gly Ala Pro Pro Pro Ser-NH2
`
`35
`
`20
`
`Glu Ala Val Arg Leu Phe
`
`5
`
`His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu
`
`Fig. 1
`
`Ser Gly Ala Pro Pro Pro Ser-NH2
`
`35
`
`Glu Ala Val Arg Leu Phe
`1
`His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu
`
`20
`
`5
`
`SANOFI-AVENTIS Exhibit 1017 - Page 5
`
`IPR for Patent No. 8,951,962
`
`

`

`-....l = N
`
`~
`0..,
`~ u.
`~
`00
`rJl
`d
`
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`Glu
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`Glu
`Glu
`Glu
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`
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`lie
`Ile
`Ile
`He
`Ile
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`tBuG
`Val
`Val
`Ile
`Ile
`Xaau
`
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`naph
`Phe
`Xaa10
`
`Leu
`Met
`Met
`Leu
`Leu
`Met
`Met
`Met
`Met
`Leu
`Met
`Leu
`Met
`Leu
`Met
`Met
`pGly
`X329
`
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Xaas
`
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Xaa7
`
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`XM6
`
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
`Xaas
`
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`X3a4
`
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Xaa3
`
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Ala
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Xaa2
`
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`His
`Xaa1
`
`25
`24
`23
`22
`21
`20
`19
`18
`17
`16
`15
`14
`13
`12
`11
`10
`9
`
`SEQ ID NO.
`
`FIGURE3Al
`
`SANOFI-AVENTIS Exhibit 1017 - Page 6
`
`IPR for Patent No. 8,951,962
`
`

`

`-....l = N
`
`~
`0..,
`~ u.
`~
`00
`rJl
`d
`
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`~
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`~
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`i
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`NH:z
`NH2
`NH:z
`NH:z
`NH:z
`NH:z
`NH:z
`NH:z
`NH:z
`NH:z
`NH2
`NH:z
`NH:z
`NH:z
`NH:z
`NH:z
`NH:z
`z
`
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Xaa1s
`
`MeAla Me Ala
`MeAla MeAl a
`MeAla MeA Ia
`hPro
`hPro
`tPro
`tPro
`hPro
`hPro
`hPro
`hPro
`tPro
`tPro
`tPro
`tPro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Xaa16
`Xaa11
`
`MeAla MeAl a
`MeAla
`MeAl a MeAla
`hPro
`hPro
`tPro
`tPro
`hPro
`Pro
`hPro
`hPro
`tPro
`Pro
`tPro
`tPro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`Xaats
`Xaa14
`
`Pro
`
`Phe
`Trp
`Trp
`Phe
`Phe
`Trp
`Trp
`Trp
`Trp
`Phe
`Trp
`Phe
`Trp
`Phe
`Trp
`Trp
`Phe
`Xaa13
`
`25
`24
`23
`22
`21
`20
`19
`18
`17
`16
`15
`14
`13
`12
`11
`10
`9
`
`SEQ ID NO.
`
`FIGURE 3A2
`
`SANOFI-AVENTIS Exhibit 1017 - Page 7
`
`IPR for Patent No. 8,951,962
`
`

`

`-....l = N
`
`~
`0..,
`~ u.
`~
`00
`rJl
`d
`
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`
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`Tro .
`Glu
`Phe
`Olu
`Glu
`Phe
`Tm
`Glu
`Phe
`Glu
`TI"Jl
`Olu
`Phe
`Glu
`TI"Jl
`Glu
`Phe
`Olu
`Tm
`Glu
`Phe
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`Olu
`Trn
`Olu
`Phc
`Tro
`Glu
`Glu
`Phe
`Tro
`Glu
`Phe
`Glu
`Tro
`Glu
`Phc
`Olu
`Phe
`Olu
`Phe
`Glu
`Glu Ala
`Phe
`Ala
`Phe
`Glu
`Phe
`Glu
`Phe
`Olu
`Phe
`Olu
`Phe
`Olu
`Phe
`Olu
`Phe
`Glu
`Phe
`Glu
`Phe
`Glu
`Phe
`Glu
`Phe
`Olu
`Phe
`Glu
`Phe
`Glu
`Phe
`Glu
`Olu
`Phe
`Phe
`Olu
`Tro
`Glu
`Glu
`Trn
`2S
`24
`
`lie
`Phe
`lie
`Phe
`lie
`Phe
`Phe
`lie
`Phe
`lie
`Phe
`n..,
`ne
`Phe
`lie
`Pile
`De
`Phe
`Jle
`Phe
`Jle
`Phe
`lie
`Phe
`lie
`Phc
`lie
`Phe
`lie
`Phe
`Phe
`lie
`Phe
`1\c
`Phc
`lie
`Phe
`lie
`lie
`Ph~
`Phe
`lie
`lie
`Phe
`lie
`Phe
`lie
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`lle
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`lie
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`lle
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`lie
`lie
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`lie
`Phe
`Phe He
`Phe He
`ile
`Phe
`Phe
`lie
`Phe He
`Phe He
`22
`23
`
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`leu
`Ala
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`:n
`
`Met Olu Glu Olu Ala , Val
`Arg
`Leu Glu Glu Glu Ala Val Ar2
`ArR
`Leu Glu G\u Glu Ala Val
`Met Olu Glu Olu Ala Val
`Arll.
`Leu Glu Glu Glu Ala Val
`Ar2
`Met Glu Glu Glu Ala Val Ar2
`Leu Glu Glu Glu Ala Val
`Arll:
`Met Glu Glu Glu Ala Val
`Ar~~:
`Leu Glu Glu Glu Ala Val Mfl
`Met Olu Glu Glu Ala Val 7\ii.
`r...u Olu Glu Glu Ala Val Ar2
`Met Glu Glu Glu Ala Val 7\ii.
`Val At£
`Leu Glu Glu Olu Ala
`Met Glu Glu Glu Ala Val ArR
`Leu Glu Olu Glu Ala Val ArR
`ArR
`Mel Glu Glu Glu Ala Val
`Leu Glu Glu Glu Ala Val A Til
`Met Glu Glu Glu Ala Val
`ArR
`Leu Glu Glu Giu Ala Val
`ANI.
`Leu Glu Glu
`Olu Ala Val
`Arll
`Leu Glu Glu G\u Ala Val
`AT;
`A!"2
`Leu Glu Glu Glu Ala Val
`ArK
`Leu Glu Glu Glu Ala Val
`Arll:
`Leu Glu Glu Glu Ala Val
`Leu Olu Glu
`0\u Ala Val Ala
`Leu Olu Olu Glu Ala Ala Am
`Leu Olu Glu Glu Ala Val
`. Ant
`Leu Glu Glu Ala Ala Val Art.
`Leu Ala Glu Glu Ala Val
`.AnE
`Ala Olu Glu Glu Ala Val
`Arll.
`Leu Glu Glu Glu Ala Val
`Airz-
`Leu Glu Glu Glu Ala Val An
`Leu Oiu Glu Glu Ala Val Arrl
`Arll:
`Leu Olu Glu Olu Ala Val
`Leu Glu Glu Glu Ala Val An:
`Leu Glu Glu Olu Ala Val
`Ale.
`Leu Glu Glu Olu Ala Val Ala
`Leu Olu Olu Glu Ala Val
`AIR
`Leu Giu Glu Glu Ala Val Ar2
`Mel Glu Glu Olu Ala Val An
`Mel Oiu Giu Oiu Ala Val
`Anl
`20
`19
`14
`
`17
`
`16
`
`15
`
`18
`
`Ser
`Lvs Gin
`Lys Gin
`Ser
`Lys Gin
`Ser
`Lys Gin
`Ser
`Ser
`Lys Gin
`Ser
`Lys Gin
`Lvs Gln
`Sa-
`Lys Gln
`Ser
`Lys Gin
`Ser
`Ser
`Ly& Gin
`Ser
`Lys Gin
`Ser
`Lys Gin
`Ser
`Lys Gln
`Ser
`Lys Gln
`Lys Gin
`Ser
`Lys Gin
`Ser
`Ser Ln Gin
`Ser
`Lys Gin
`Lys Gin
`Ser
`Lys Gin
`Ser
`Lvs Gin
`Ser
`Lvs Gin
`Ser
`Lvs Gin
`Ser
`Lys Gin
`Ser
`Ser
`Lys Gin
`Ser
`Lys Oln
`Ser Ln Gin
`Lys Gin
`Ser
`Ser Ln Gin
`Ser
`l..ys Gin
`LYS Ala
`Ser
`Ser Ala Gin
`LYS Oln
`Lys Oln
`Lys Gin
`Lys Gin
`Lys Gin
`Lys Gin
`Lys Gin
`Lys Gin
`Lys Gin
`13
`12
`
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`L.cu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu Ala
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`II
`
`FIGURE4Al
`
`Asp Ala
`Leu
`Leu
`Leu
`leu
`Leu
`Leu
`uu
`10
`
`Thr
`His Glv Glu GIV ~ Phe
`Thr
`His Glv Glu Glv
`Phe
`Thr
`Thr
`Phc
`His Olv Olu Giv
`Thr
`His Glv Glu Glv
`Thr
`Thr
`Phc
`Thr
`His G\y Glu Gly Thr
`Phe
`Thr
`Phe
`His Gly Glu Giy
`Thr
`Thr
`Phe
`Hi• Olv Glu Olv
`Thr
`Phe Thr
`His Olv Glu Olv Thr
`Phe Thr
`His Glv Olu Olv Thr
`Phe Thr
`His Olv Glu Glv
`Thr
`Thr
`Phe
`Thr
`His Olv Glu Glv
`Phe Thr
`Thr
`His Glv Glu Glv
`Phc
`Hi$ Glv Glu Glv
`Thr
`Thr
`Phe Thr
`Hi a Glv Glu Olv
`Thr
`Phe Thr
`His Olv Olu Glv
`Thr
`Phe Thr
`His Glv Glu Gly
`Thr
`Phe Thr
`His Glv G\u Gty
`Thr
`Phe Thr
`Thr
`His Glv G\u G\v
`Phe Thr
`His Glv Glu Gly
`Thr
`His Oly Olu Olv Thr
`Thr
`Phe
`Phe Thr
`His Glv Glu
`01v Thr
`Phe Thr
`Thr
`His Glv Glu Glv
`Thr
`Phe
`His Glv G\u Gly
`Thr
`His Glv Olu Oly Thr
`Phe Thr
`Thr
`Phe
`His Glv Glu Gly
`Thr
`Thr
`Phc
`Thr
`His Glv Glu Glv
`Phe Thr
`Hi!; Olv Olu Olv Thr
`Thr
`Phe
`His Gly Glu Gly
`Thr
`Thr
`Phe
`0\u Glv Thr
`His Gly
`Ph~ Thr
`Thr
`His Gly Glu Glv
`Phe Thr
`His Gly Glu Glv Thr
`Phe Thr
`His Gly Olu Glv
`Thr
`Thr
`Phe
`His Glv Glu Glv
`Thr
`Thr
`His Glv Glu Glv Thr
`Phe
`Phe Thr Ala Asp
`His Gly Olu Gly Thr
`Ser Asp
`Phe Thr
`His Gly Glu Gly Thr
`Ser Asp
`His Gly Glu Gly Ala
`Phe
`Thr
`Pile Thr
`Ser Asp
`His Ala Glu Gly
`Thr
`Thr
`His Gly Glu Glv Thr
`Phe
`Ser Asp
`ASD
`His Gly Glu Glv Thr
`Ser
`Phe Thr
`Thr
`ASD
`Ser
`Pile
`His Gly Glu Glv
`Tbr
`s
`9
`4
`7
`8
`6
`I
`
`3
`
`2
`
`66
`65
`64
`63
`62
`61
`60
`59
`58
`57
`~6
`55
`S4
`$3
`52
`.51
`j{)
`49
`48
`47
`46
`4S
`44
`43
`42
`41
`40
`39
`38
`37
`36
`35
`34
`3~
`32
`31
`3D
`29
`28
`27
`26
`
`SEQ 10 NO.
`
`Ser Asn
`Ser Asp
`Ser Asp
`Scr Asp
`Ser Asp
`Ser Asp
`Ser
`rup
`Ser A so
`Ser A so
`Ser Asp
`Ser Asp
`Ser Asp
`ruP
`Ser
`Ser
`rup
`Ser Asp
`Ser Asp
`Ser A so
`Ser Asp
`Ser Asp
`Ser Asp
`Ser A so
`Scr A so
`Ser A so
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser A aD
`Ser A so
`A so
`Se.-
`ASD
`Ser
`Ser
`ASD
`Ser A so
`Se.-
`
`SANOFI-AVENTIS Exhibit 1017 - Page 8
`
`IPR for Patent No. 8,951,962
`
`

`

`-....l = N
`
`~
`0..,
`U"l
`~
`~
`00
`rJl
`d
`
`0
`N
`0 .....
`Ul
`.....
`rFJ =(cid:173)
`
`('D
`('D
`
`NH2
`NH2
`
`Pro NH2
`Pro
`NH2
`Pro NH2
`Pro
`Pro NH2
`Pro
`Pro
`Pro
`Pro
`I'm
`Pro
`Pro
`
`NH2
`NH2
`NH:Z
`Ala
`Ala NH2
`Ala
`Ala
`Ala
`Ala
`Ala
`Ala
`
`NH2
`NH2
`Ser NH2
`Scr NH2
`Ser
`Ser
`NH2
`Ser NH2
`Ser
`Ser
`Scr
`Glv
`Gb'
`Ser
`Ser
`Ser
`Ser
`Gly
`Ser
`Scr
`Oly
`Scr
`S;r-
`Oly
`Ser
`Ser
`Gly_
`Ser
`Ser
`Oly
`Ser
`Ser
`Gly
`Ser
`Ser
`Gly
`Ser
`Ser
`Oly
`
`0 ....
`N .... ~
`~
`~
`
`N
`
`(.H
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`39
`
`38
`
`37
`
`36
`
`35
`
`34
`
`33
`
`32
`
`FIGURE4A2
`
`NH2
`31
`
`Glv
`30
`
`Leu
`Leu Lys Asn Gly
`Gly NH2
`Leu
`Pro
`Lys Asn Gly
`Gly
`Leu Lys Asn Oly
`Pro
`Gly
`Leu Lys Asn Gly
`Pro
`Gly
`Leu
`Lys Asn Gly
`I'm
`Gly
`Lys Asn
`G.!Y_ Gly
`Leu
`Pro
`Leu
`lys Asn Gly
`Pro
`Gly
`Pro
`Leu
`Ly~ Asn
`Gly Gly
`Lys Asn Gb'
`Leu
`Pro
`Gly
`LY5 Asn Gly
`Pro
`Leu
`Gly
`Lc:u
`Lys Asn Gly
`Pro
`Qly
`I'm
`Leu
`Lvs Asn Qly
`Qly
`Leu
`lys Asn QJy_ GJy
`Pro
`Leu
`Lys Asn GJy
`Pro
`Gly
`LY5 Asn Qly
`Leu
`Pro
`Gly
`Leu
`lys Asn Q)y
`Pro
`Gly
`Leu
`lys Asn Oly Gly
`Pro
`Leu
`lys Ala NH2
`Leu Ala Asn NH2
`Ala Lys Asn Nll2
`Leu
`lys Asn NH2
`Leu
`lys Asn Nll2
`Leu Lys Asn NH2
`Lys Asn NH2
`Leu
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu
`Lys Asn NlU
`Leu Lys Asn NH2
`~ Lvs Asn NH2
`~ Lys Asn NH2
`Leu Lys Asn NH2
`Leu
`Lys Asn NH2
`Leu Lys Asn NH2
`Leu
`Lys Asn NH2
`Leu
`Lys Asn NH2
`Lys Asn NH2
`Leu
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Lys Asn Glv
`Leu
`29
`26
`27
`
`Lys Asn_ L_(jly NH2
`
`28
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`49
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`31
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`26
`
`SEQ ID NO.
`
`SANOFI-AVENTIS Exhibit 1017 - Page 9
`
`IPR for Patent No. 8,951,962
`
`

`

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`
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`22
`
`-
`
`Val Ar~ Leu
`Val Arg Leu
`Val Arg Leu
`Val Ar~ Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
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`19
`21
`
`20
`
`Gin Met Glu Glu Glu Ala
`Gln Met Glu Glu Glu Ala
`Gin Leu Glu Glu Glu Ala
`Gin Leu Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Leu Glu Glu Glu Ala
`Gin Leu Glu Glu Glu Ala
`Gln Met Ala Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Leu Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gln Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Met Glu Glu Glu Ala
`Gin Leu Glu Glu Glu Ala
`13