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`1111111111111111111111111111111111111111111111111111111111111
`US008057822B2
`
`c12) United States Patent
`Prickett et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,057,822 B2
`*Nov. 15, 2011
`
`(54) MODIFIED EXENDINS AND EXENDIN
`AGONISTS
`
`(75)
`
`Inventors: Kathryn S. Prickett, San Diego, CA
`(US); Andrew A. Young, San Diego, CA
`(US)
`
`(73) Assignee: Amylin Pharmaceuticals, Inc., San
`Diego, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 860 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 11/174,089
`
`(22) Filed:
`
`Jun.30,2005
`
`(65)
`
`Prior Publication Data
`
`US 2005/0267034 AI
`
`Dec. 1, 2005
`
`Related U.S. Application Data
`
`(63) 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 9114
`(2006.01)
`(2006.01)
`A61K 38/00
`(52) U.S. Cl. .................. 424/489; 514/2; 514/3; 514/12;
`424/278.1; 530/300
`(58) Field of Classification Search . ... ... ... ... .. ... 530/308,
`530/322,303,402, 421; 514/2
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`514/2
`530/302
`
`530/399
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`EP
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`wo
`wo
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`wo
`wo
`wo
`wo
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`
`(Continued)
`Primary Examiner- Anand Desai
`Assistant Examiner- Samuel Liu
`(74) Attorney, Agent, or Firm- Connolly Bove Lodge &
`Hutz LLP
`
`ABSTRACT
`(57)
`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.
`25 Claims, 20 Drawing Sheets
`
`SANOFI-AVENTIS Exhibit 1008 - Page 1
`
`IPR for Patent No. 8,951,962
`
`

`
`US 8,057,822 B2
`Page 2
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`
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`
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`Nucci eta!., The Therapeutic Value ofPoly(Ethylene glycol)-Modi(cid:173)
`fiedProteins,Adv. Drug Delivery Rev. 6:133-151 (1991).
`Parkes et a!., Pharmacokinetic Actions of Exendin-4 in the Rat:
`Comparison with Glucagon-Like Peptide-], Drug Develop. Res.
`5:3260-267 (200 1 ).
`Praz eta!., Regulation of Immunoreactive-Insulin Release from a Rat
`Cell Line (RINm5F), Biochem. J. 210:345-352 (1983).
`Qiagen, Q-proteome Plasma Membrane Protein Handbook
`(QIAGEN Apr. 2006).
`
`SANOFI-AVENTIS Exhibit 1008 - Page 3
`
`IPR for Patent No. 8,951,962
`
`

`
`US 8,057,822 B2
`Page 4
`
`Simonsen et a!., Exendin-4, but Not Glucagon-like Peptide-], is
`Cleared Exclusively by Glomerular Filtration in Anaesthetised Pigs,
`Diehetologia 49(4):706-12 (2006).
`Zaidi eta!., Effects of Copper Chloride Toxicity on Copus Striatum of
`Rat Brain-A Histological Study, JAnat.Soc. India 51(1):55-56
`(2002).
`
`Canadian Patent Application No. 2,372,214: Protest Udner Section
`34.1 filed in Canadian Patent Application No. 2,372,214 (Jun. 26,
`2009).
`
`* cited by examiner
`
`SANOFI-AVENTIS Exhibit 1008 - Page 4
`
`IPR for Patent No. 8,951,962
`
`

`
`N = N
`00 = u.
`
`N
`Oo
`-....l
`
`rJl
`d
`
`0
`N
`0 .....
`....
`.....
`rFJ =- ('D
`
`('D
`
`~ ....
`z
`
`0
`
`N
`~Ul
`
`....
`0 ....
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`lie Glu Trp Leu Lys Asn Gly Gly Pro Ser
`
`30
`
`15
`
`25
`
`10
`
`lie 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 1008 - Page 5
`
`IPR for Patent No. 8,951,962
`
`

`
`N = N
`00 = u.
`
`N
`Oo
`-....l
`
`rJl
`d
`
`0
`N
`0 .....
`N
`.....
`rFJ =(cid:173)
`
`('D
`('D
`
`~ ....
`z 0
`
`N
`~Ul
`
`....
`0 ....
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`I
`
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Asp
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Xaa12
`
`Ile
`Ile
`Ile
`Ile
`lie
`lie
`lie
`lie
`lie
`lie
`lie
`
`tBuG
`tBuG
`Val
`Val
`lie
`lie
`Xaan
`
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`naph
`Phe
`Xaaw
`
`--
`Leu
`Met
`Met
`Leu
`Leu
`Met
`Met
`Met
`Met
`Leu
`Met
`Leu
`Met
`Leu
`Met
`Met
`pGly
`Xaa9
`
`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
`Xaa1
`
`~----
`
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Xacl(;
`
`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
`Xae14
`
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Glu
`Xaa3
`
`Gly
`Gly
`G!Y
`Gly
`Gly
`Gly
`Gly
`Gly
`Gly
`Ala
`Gly
`Gly
`G!Y
`Gly
`Gly
`Gly
`Gly
`Xaaz
`
`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 1008 - Page 6
`
`IPR for Patent No. 8,951,962
`
`

`
`N = N
`00 = u.
`
`N
`Oo
`-....l
`
`rJl
`d
`
`0
`N
`0 .....
`
`(.H
`
`.....
`rFJ =(cid:173)
`
`("D
`("D
`
`~ ....
`z 0
`
`N
`~Ul
`
`....
`0 ....
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`1
`
`1
`
`i
`
`i
`
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`NH2
`z
`
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Xaa1s
`
`MeAla MeAl a
`MeAl a MeAl a
`Me Ala MeAl a
`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
`Xaa17
`
`MeAl a MeAla
`Me Ala
`MeAl a Me Ala
`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
`Xaa1s
`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.
`
`FIGURE3A2
`
`SANOFI-AVENTIS Exhibit 1008 - Page 7
`
`IPR for Patent No. 8,951,962
`
`

`
`N = N
`00 = u.
`
`N
`Oo
`-....l
`
`rJl
`d
`
`0
`N
`0 .....
`
`.....
`rFJ =(cid:173)
`
`('D
`('D
`
`.j;o.
`
`~ ....
`z 0
`
`N
`~Ul
`
`....
`0 ....
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`Trp
`Phe
`Phe
`Trp_
`Phe
`Trp
`Phe
`Trp_
`Phe
`Trp
`Phe
`Tro
`Phe
`Trp
`Phe
`Trp
`Phe
`Trp_
`Phe
`Phe
`Phe
`Ala
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Trp
`Trp
`25
`
`lie Glu
`lle Glu
`lie Glu
`lie Glu
`lle Glu
`lie Glu
`lle Glu
`lie Glu
`lle Gtu
`lie Glu
`lie Glu
`lle Glu
`lle Glu
`Tie Glu
`lie Glu
`Tie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`Tie Glu
`lie Ala
`lie Glu
`Tie Glu
`Tie Glu
`lie Glu
`Tie Glu
`Tie Glu
`Tie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`Tie Glu
`Tie Glu
`Tie Glu
`Tie Glu
`Tie Glu
`Tie Glu
`Tie Glu
`23
`24
`
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`22
`
`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
`21
`
`Met Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Met Glu Glu Glu Ala Vat Arg
`Leu Glu Glu Gtu Ala Val _t.rg
`Met Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Met Glu Glu Gtu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Met Glu Glu Glu Ala Val Arg
`Leu Glu Gtu Glu Ala Val Arg
`Met Glu Glu Glu Ala Val Arg
`Leu Glu Gtu Glu Ala Val
`Ar_g_
`Met Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val
`Arg
`Met Glu Glu Glu Ala Val
`Ar_g
`Leu Glu Glu Glu Ala Val Arg
`Met Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Ala
`Leu Glu Glu Glu Ala Ala Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Ala Ala Val Arg
`Leu Ala Glu Glu Ala Val Arg
`Ala Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`ArJ!;
`Leu Glu Glu Glu Ala Val
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val Arg
`Leu Glu Glu Glu Ala Val
`Arg
`Met Glu Glu Glu Ala Val Arg
`Met Glu Glu Glu Ala Val Arg
`20
`14
`
`17
`
`16
`
`15
`
`19
`
`18
`
`Lys Gin
`Ser
`Ser
`Lys Gin
`Lys Gin
`Ser
`Lvs Gin
`Ser
`Lvs Gin
`Ser
`Lvs Gin
`Ser
`Ser
`Lys Gin
`Lvs Gin
`Ser
`Lys Gin
`Ser
`Lys Gin
`Ser
`Ser
`Lys Gin
`Lvs Gin
`Ser
`Lvs Gin
`Ser
`Lvs Gin
`Ser
`Ser
`Lys Gin
`Lvs Gin
`Ser
`Lys Gin
`Ser
`Ser
`Lys Gin
`Ser
`Lys Gin
`Lys Gin
`Ser
`Ser
`Lys Gin
`Ser
`Lys Gln
`Lvs Gin
`Ser
`Lys Gin
`Ser
`Lvs Gin
`Ser
`Ser
`Lys Gin
`Lvs Gin
`Ser
`Ser
`Lys Gin
`Ser
`Lys Gin
`Ser
`Lys Gin
`Ser
`Lys Ala
`Ser Ala Gin
`Lys Gin
`Lys Gin
`Lvs Gin
`Lvs Gin
`Lys Gin
`Lys Gin
`Lys Gin
`Lys Gin
`Lys Gin
`13
`12
`
`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
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu Ala
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`II
`
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser
`Asp
`Ser Asp
`Ser
`Asp
`Ser Asp
`Ser
`Asp
`Ser _l.sp
`Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser
`Asp
`Ser
`Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp
`Ser Asp Ala
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`Leu
`10
`
`Thr _ _ Phe _Thr
`His Gly Glu Gly
`Thr
`Phe
`Thr
`His Gly Glu Gly
`Phe
`His Gtv Glu
`Gly_ Thr
`Thr
`Thr
`Phe
`·Giu Gly
`Thr
`His Gly
`Thr
`Phe
`Thr
`His Gly Glu Gly
`Phe
`Thr
`Thr
`His Gly
`·otu Gly
`Thr
`Phe
`Thr
`His Gly Glu Gly
`His Gly Gtu Gly
`Phe
`Thr
`Thr
`Phe
`Thr
`Thr
`His Glv Glu Glv
`Phe Thr
`His Gly Gtu Gly Thr
`Phe
`Thr
`Thr
`His Gty Glu Gly
`Thr
`Phe
`Thr
`His Gly Glu Gly
`Phe Thr
`His Gly Glu Gly Thr
`Thr
`Phe
`His Gly Glu Gly
`Thr
`Phe Thr
`Thr
`His Gly Glu Gly
`Phe Thr. Ser
`His Gly Glu Glv Thr
`Phe Thr
`His Glv Glu Glv
`Thr
`Phe
`Gly__ Thr
`Thr
`His Gly Glu
`Thr
`Phe
`His Gly Glu Gtv
`Thr
`Thr
`Phe
`Thr
`His Gly Glu Gly
`Thr
`Thr
`Phe
`Gly_ Glu Gly
`His
`Phe
`Thr
`Thr
`His Gly Glu Gly
`Thr
`Thr
`Phe
`His Gly Glu Gly
`Phe
`Thr
`Thr
`His Gly Glu Gly
`Thr
`Thr
`Phe
`His Gly Glu Gly
`Phe
`Thr
`Thr
`His Gly Glu Gly
`His Gly Glu Gly
`Phe
`Thr
`Thr
`Phe
`His Glv Glu Glv
`Thr
`Thr
`Gly_ Glu Gly Thr
`Phe
`Thr
`His
`Gly_ Thr
`Thr
`Phe
`His Glv Glu
`Phe
`Thr
`Thr
`His Gly Glu Gly
`Phe Thr
`His Glv Glu
`GJy_ Thr
`Phe
`Thr
`Thr
`His Gly Glu Gly
`Thr
`His Gly Glu Gly
`Phe
`Thr
`Thr Ala Asp
`Thr
`Phe
`His Gly Glu Gly
`Ser Asp
`Phe
`His Gly Glu Gly Thr
`Thr
`Ser Asp
`Phe
`Thr
`His Gly Glu
`Gly_ Ala
`Ser Asp
`Phe
`Thr
`Thr
`His Ala Glu Gly
`Ser Asp
`Phe
`Thr
`Thr
`His Gly Glu Gly
`Ser Asp
`Thr
`Phe
`Thr
`His Gly Glu Gly
`Ser Asp
`Phe
`Thr
`Thr
`His Gly Glu Gly
`5
`9
`8
`7
`6
`4
`I
`
`3
`
`2
`
`66
`65
`64
`63
`62
`61
`60
`59
`58
`57
`56
`55
`54
`53
`52
`51
`50
`49
`48
`47
`46
`45
`44
`43
`42
`41
`40
`39
`38
`37
`36
`35
`34
`33
`32
`31
`30
`29
`28
`27
`26
`
`SEQ. ID. NO.
`
`FIGURE4Al
`
`SANOFI-AVENTIS Exhibit 1008 - Page 8
`
`IPR for Patent No. 8,951,962
`
`

`
`N = N
`00 = U'l
`
`N
`Oo
`-....l
`
`rJl
`d
`
`0
`N
`0 .....
`Ul
`.....
`rFJ =(cid:173)
`
`('D
`('D
`
`NH2
`NH2
`
`Pro NH2
`NH2
`Pro
`Pro
`Pro
`Pro
`Pro
`
`Pro NH2
`Pro NH2
`Pro
`Pro
`Pro
`Pro
`
`NH2
`NH2
`NH2
`Ala
`Ala NH2
`Ala
`Ala
`Ala
`Ala
`Ala
`Ala
`
`Ser NH2
`Ser NH2
`Ser
`Glv
`Ser
`Gly
`Ser
`Gly
`Ser
`Glv
`Ser
`Gly
`Ser
`Gly
`Ser
`Gly
`Ser
`Gly
`Ser
`Gly
`Ser
`Glv
`
`NH2
`NH2
`Ser NH2
`Ser NH2
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`
`~ ....
`z 0
`
`N
`~Ul
`
`....
`0 ....
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`39
`
`38
`
`37
`
`36
`
`35
`
`34
`
`33
`
`32
`
`FIGURE4A2
`
`Gly NH2
`Pro
`Gly
`Pro
`Glv
`Gly
`Pro
`Gly
`Pro
`Gly
`Pro
`Pro
`Gly
`Pro
`Glv
`Gly
`Pro
`Pro
`Gly
`Glv
`Pro
`Pro
`Gly_
`Gly
`Pro
`Pro
`Gly
`Pro
`Gly
`Pro
`Gly_
`Glv
`Pro
`
`Gly_ NH2
`30
`31
`
`Leu Lys Asn Gly NH2
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Leu Lys Asn Glv
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Lys Asn Gly
`Leu
`Leu Lys Asn
`· Gly
`Leu Lvs Asn
`· Glv
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Leu Lvs Asn Gly
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Leu Lys Asn Gly
`Leu Lys Asn Glv
`Leu Lys Ala NH2
`Leu Ala Asn NH2
`Ala Lys Asn NH2
`I..ys Asn NH2
`Leu
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`[.ys Asn NH2
`Leu
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu
`Lys Asn NH2
`Leu Lvs Asn NH2
`Leu Lys Asn NH2
`Lys Asn NH2
`Leu
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu Lys Asn NH2
`Leu
`[.ys Asn NH2
`Leu Lys Asn Gly
`26
`29
`
`28
`
`27
`
`-· 66 -·
`65
`64
`63
`62
`61
`60
`59
`58
`57
`56
`55
`54
`53
`52
`51
`50
`49
`48
`47
`46
`45
`44
`43
`42
`41
`40
`39
`38
`37
`36
`35
`34
`33
`32
`31
`30
`29
`28
`27
`26
`
`SEQ. !D. NO.
`
`SANOFI-AVENTIS Exhibit 1008 - Page 9
`
`IPR for Patent No. 8,951,962
`
`

`
`N = N
`00 = u.
`
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`
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`
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`
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`
`~ = ~
`
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`22
`
`Val Arg Leu
`Val Ar~ Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Ar~ Leu
`Val Arg Leu
`Val Arg Leu
`Val Ar~ Leu
`Val Ar~ Leu
`Val Arg Leu
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`21
`19
`
`20
`
`Gin Met Glu Glu Glu Ala
`Gin 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
`Gin Met Ala Glu Glu Ala
`Gin Met Glu Glu Glu