(12) United States Patent
`Prickett et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006924264 B 1
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,924,264 Bl
`Aug. 2, 2005
`
`(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 0 days.
`
`(21) Appl. No.: 09/561,226
`
`(22) Filed:
`
`Apr. 28, 2000
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/132,018, filed on Apr. 30,
`1999.
`
`Int. Cl? ................................................ A61K 38/22
`(51)
`(52) U.S. Cl. ........................... 514/2; 530/308; 530/322;
`530/402; 530/412
`(58) Field of Search ................................. 530/308, 322,
`530/303, 402, 421, 333; 514/2
`
`(56)
`
`References Cited
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`Bobo
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`Larsen eta!. ................. 514/12
`
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`EP
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`wo 99/43708
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`Raufman, J.-P. et al. (1991) Exendin-3, a novel peptide
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`Eissele et al. "Rat Gastric somatostatin and Gastrin Release:
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`creting -Cells", J. Bioi. Chern., 268:19650--55 (1993).
`
`(Continued)
`
`Primary Examiner-Karen Cochrane Carlson
`Assistant Examiner-Samuel Wei Liu
`(74) Attorney, Agent, or Firm-Arnold & Porter, LLP
`
`(57)
`
`ABSTRACT
`
`Novel modified exendins and exendin agonist analogs hav(cid:173)
`ing an exendin or exendin agonist analog linked to one or
`more polyethylene glycol polymers, for example, and
`related formulations and dosages and methods of adminis(cid:173)
`tration thereof are provided. These modified exendins and
`exendin agonist analogs, compositions and methods are
`useful in treating diabetes and conditions that would be
`benefited by lowering plasma glucose or delaying and/or
`slowing gastric emptying or inhibiting food intake.
`
`23 Claims, 20 Drawing Sheets
`
`SANOFI-AVENTIS Exhibit 1031 - Page 1
`
`IPR for Patent No. 8,951,962
`
`

`
`US 6,924,264 Bl
`Page 2
`
`01HER PUBLICATIONS
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`Protein Encoded by the obese Gene," Science 269:543-546
`(1995).
`Hudecz, F., et al, "Synthesis, Conformation, Biodistribution,
`and
`in Vitro Cytotoxicity of Daunomycin-Branched
`Polypeptide Conjugates," Bioconjugate Chemistry 3:49-57
`(1992).
`Malhotra et al. "Exendin-4, a new peptide from Heloderma
`suspectum venom, potentiates cholecystokinin-induced
`amylase release from rat pancreatic acini", Regulatory Pep(cid:173)
`tides, 41:149-56 (1992).
`Meurer, J.A., et al, "Properties of native and in vitro gly(cid:173)
`cosylated forms of the glucagon-like peptide-1 receptor
`antagonist exendin (9-39)," Metabolism Clinical and
`Experimental 48(6):716-724 (1999).
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`physiological inhibitor of gastric acid secretion in man," J
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`Glucagonlike Peptide-1 7-36 Amide and glucagonlike Pep(cid:173)
`tide-1 7-37 in Healthy Subjects Are Indistinguishable",
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`Product on Body Weight Regulation in ob/ob Mice," Science
`269:540-543 (1995).
`Pratesi, G., et al, "Poly-L-aspartic acid as a carrier for
`doxorubicin: a comparative in vivo study of free and poly(cid:173)
`mer-bound drug," British Journal of Cancer 52:841-848
`(1985).
`Raufman et al. "Truncated Glucagon-like Peptide-1 Inter(cid:173)
`acts with Exendin Receptors in Dispersed Acini from
`Guinea Pig Pancreas",J. Bioi. Chern. 267:21432-37 (1992).
`Schepp et al. "Exendin-4 and exendin-(9-39)NH2 : agonist
`and antagonist, respectively, at the rat parietal cell receptor
`for glucagon-like peptide-1-(7-36)NH2 ,'' Eur. J. Pharm.
`269:183-91 (1994).
`
`Schjoldager et al. "GLP-1 (Glucagon-like Peptide 1) and
`Truncated GLP-1, Fragments of Human Proglucagon,
`Inhibit Gastric Acid Secretion in Humans," Dig Dis Sci 34
`(5): 703-8 (1989).
`
`Singh et al. "Use of 125I-{Y39
`] exendin-4 to characterize
`exendin receptors on dispersed pancreatic acini and gastric
`chief cells from guinea pig," Regul. Pept. 53:47-59 (1994).
`
`Thorens, "Expression cloning of the pancreatic cell receptor
`for the gluco-incretin hormone glucagon-like peptide 1,"
`Proc. Natl. Acad. Sci. USA 89:8641-45 (1992).
`
`"An Anti---a-Fetoprotein
`al,
`et
`Tsukada,
`Y.,
`Antibody-Daunorubicin Conjugate With
`a Novel
`Poly-L-fiutamic Acid Derivative as Intermediate Drug Car(cid:173)
`rier," JNCI 73:721-729 (1984).
`
`Turton, M.D., et al, "A role for glucagon-like peptide-1 in
`the central regulation of feeding," Nature 379 ( 6560): 69-72
`(1996).
`
`Veale, P.R., et al, "The presence of islet amyloid polypep(cid:173)
`tide/calcitonin gen-related peptide/salmon calcitonin bind(cid:173)
`ing sites in the rat nucleus accumbens," European Journal of
`Pharmacology 262:133-141 (1994).
`
`(Proglucagon
`"Truncated GLP-1
`Wettergren et al.
`78-107-Amide) Inhibits Gastric and Pancreatic Functions
`in Man," Dig Dis Sci 38 (4): 665-73 (1993).
`
`Willms, B., et al, "Gastric Emptying, Glucose Responses,
`and Insulin Secretion after a Liquid Test Meal: Effects of
`Exogenous Glucagon-Like Peptide-1
`(GLP-1)-(7-36)
`Amide in Type 2 (Noninsulin-Dependent) Diabetic Patients,
`"Journal of Clinical Endocrinology and Metabolism
`81(1):327-332 (1996).
`
`Zalipsky, S., "Functionalized Poly (ethylene glycol) for
`Preparation of Biologically Relevant Conjugates," Biocon(cid:173)
`jugate Chern 6:150-165 (1995).
`
`* cited by examiner
`
`SANOFI-AVENTIS Exhibit 1031 - Page 2
`
`IPR for Patent No. 8,951,962
`
`

`
`U.S. Patent
`
`Aug. 2, 2005
`
`Sheet 1 of 20
`
`US 6,924,264 Bl
`
`Figure 1
`
`His Se:;:- Asp Gly Thr Phe Thr Ser Asp Leu Ser I.ys Gln Met Glu Glu
`1
`10
`5
`15
`Glu Ala va: Arg Leu Phe Ile Glu Trp Leu Lys .ll.sn Gly G:y Pro Ser
`25
`20
`30
`Ser Gly Ala Pro ?ro Pro Ser-NH 2
`[SEQ. ID. NC. 1]
`35
`
`Figure 2
`
`His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
`10
`5
`1
`15
`Glu Ala Val Arg Leu Phe Ile G2.u Trp Leu Lys Asn Gly Gly P::o Ser
`20
`25
`30
`Se:: Gly Ala Pro Pro Pro Ser-NH 2
`[SEQ.
`35
`
`ID. NO. 2]
`
`SANOFI-AVENTIS Exhibit 1031 - Page 3
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`\Jl
`e
`
`'N a-..
`
`1--"
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`'JJ. =(cid:173)~
`
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`
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`
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`
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`
`~ = ......
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`~
`•
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`d •
`
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`Glu
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`Glu
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`Glu
`Glu
`Xaa12
`
`---
`
`lie
`Ile
`lle
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`tBuG
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`
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`naph
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`
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`Met
`Met
`Leu
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`Met
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`Met
`Met
`Leu
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`Met
`Leu
`Met
`Met
`pGly
`Xaa9
`
`Leu
`Leu
`Leu
`Leu
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`Leu
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`Leu
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`Leu
`Leu
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`Leu
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`Xaas
`
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`ASQ
`Asp
`Asp
`Asp
`Asp
`Asp
`Asp
`ASQ
`Asp
`Asp
`Xaa7
`
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Scr
`Ser
`Ser
`Ser
`Ser
`Xa<l{;
`
`Thr
`Thr
`Thr
`Thr
`Thr
`Thr
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`Thr
`Thr
`Thr
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`
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`Phe
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`Phc
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`Phe
`Phe
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`Phe
`Phc
`Phe
`Phe
`Phe
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`
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`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 m. NO.
`
`FIGURE3A1
`
`SANOFI-AVENTIS Exhibit 1031 - Page 4
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`rJ'l
`e
`
`'N a-..
`
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`
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`
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`
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`
`N c c
`
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`
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`
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`
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`
`:
`
`,
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`
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`
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`
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`
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`
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`
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`NH2
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`NHz
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`NH2
`NHz
`NHz
`NHz
`NHz
`NHz
`NHz
`NHz
`NHz
`z
`
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Ser
`Scr
`Ser
`Ser
`Xaa1~
`
`MeAl a
`MeAl a
`MeAl a
`hPro
`tPro
`hPro
`hPro
`tPro
`tPro
`Pro
`Pro
`Pro
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`Pro
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`
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`hPro
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`tPro
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`Pro
`Pro
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`Pro
`Pro
`Pro
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`Xaa16
`
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`MeAl a
`MeAl a
`hPro
`tPro
`hPro
`hPro
`tPro
`tPro
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
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`Pro
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`
`-
`
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`
`------------
`
`Pro
`
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`tPro
`Pro
`hPro
`Pro
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`Pro
`Pro
`Pro
`Pro
`Pro
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`
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`Trp
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`Phe
`Trp
`TII'
`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 1031 - Page 5
`
`IPR for Patent No. 8,951,962
`
`

`
`1--"
`~
`~
`
`~ 'N a-,
`
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`lie Glu
`lie Glu
`lie
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`lie Glu
`lie
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`lie
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`lie Glu
`lie Glu
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`llc Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
`lie Glu
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`lie Glc
`lie Glu
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`lie
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`23
`24
`
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`22
`
`V"l
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`_ G,u L_~J~ /\~3
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`Leu
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`Ala
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`Ala
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`Val
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`Met Glu Glu
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`Val
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`Arg
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`Arg
`Leu Glu Glu
`Leu
`Ala Val
`Leu
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`Arg
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`Ala
`Ulu
`Val
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`Glu Glu
`Ala Val
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`Glu Glu
`Glu Ala Val
`Ala
`l£11
`Leu
`Ala
`Leu
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`Ala Val
`Glu
`Glu Ala
`Leu
`Glu
`Glu
`Ala
`l.cu
`Arr,
`Glu Glc Ala
`Leu
`Leu
`Arg
`Ulu
`Val
`Arg
`Ala
`Leu
`Glu Glu
`Leu
`Val
`Arll
`Leu
`Ala Glu Glu Ala Val
`Leu
`Leu
`Glu Ala Val
`Ala
`Glu Glu
`Arg
`Glu Ala Val
`Leu
`Glu Glu
`Arg
`Leu
`Leu
`Arg
`Glu
`Ala
`Val
`Leu
`Glu Glu
`Leu
`Leu
`Arg
`Glu Ala
`Glu
`Val
`G;u
`LcJ
`Arg
`Glu Ala Val
`Leu
`Glu Glu
`Arg
`Ala
`Leu Glu Glu
`Ulu
`l..c.u
`Val
`Leu
`Ala Val
`Cilu
`Le~ Glu Glu
`Arg
`Leu
`Ala
`Arg
`Val
`Leu
`Glu Gtu
`(Jlu
`Glu Ala
`Leu
`Leu
`Val
`Glu Glu
`Arg
`Leu
`Arg
`Ala
`Val
`Glu
`Leu
`Glu
`Glu
`Met
`Leu
`Arg
`Ala
`Glu
`Glu
`Glu
`Val
`ArJL
`Leu
`Ala Val
`Glu
`Met Glu
`(llu
`21
`16
`I K
`20
`17
`15
`14
`19
`
`Glu
`Glu
`
`Ala
`
`Glu Glu Giu
`G\u
`G'.u
`Ulu
`
`Scr
`(.i'n
`Ser LE Gin
`Cln
`Se1
`Gin
`Scr
`Ser
`(Jln
`1 Lys Gin
`Scr
`Lys Gin
`Scr
`Ser
`Lvs
`CJin
`Lys
`Gln
`Scr
`Ser
`Ciln
`Lvs
`Lvs Gin
`Ser
`Gin
`Scr
`LV>
`Lys Gin
`Ser
`Lys Gin
`Ser
`Lys Gin
`Ser
`L_2'0
`Ser
`Gin
`Ser
`Lvs Gin
`Lys Gb
`Ser
`LL_S
`Gin
`Scr
`Lys Gin
`SLT
`Lys Gin
`Scr
`Ser
`Lys Gin
`Lys Gin
`Ser
`Ser
`Lys Gin
`Lys Gin
`Sec
`l_j'S
`Scr
`Gin
`Ser
`Lys Gin
`Gin
`Scr
`Lys
`Lys Gin
`Ser
`Ser
`Lys Gln
`Lvs
`Ala
`Ser
`Ala Glr.
`Ser
`Lvs Gin
`Al2
`Lys Gin
`Ser
`Lys Gin
`Scr
`Lys Gin
`Ser
`Lys Gin
`Scr
`Lvs Gh
`Ser
`Ser
`Lys Gin
`Lys
`Ser
`(Jln
`L_XS
`Scr
`(!In
`IJ
`12
`II
`
`Lys
`Lys
`ic1S
`
`L"
`
`A'P
`Ser
`Leu
`Thr
`Asp
`"lhr
`Scr
`1-CL,
`Thr
`Leu
`Ser
`Asp
`Asp
`Leu
`Scr
`"lhr
`Ser
`Asp
`Leu
`"!llr
`Leu
`1r.r
`Asp
`Scr
`Ser
`Asp
`Leu
`llrr
`As_p_
`Leu
`Scr
`Thr
`Ser Asr
`Leu
`l"hr
`Thr
`Scr Asp
`Lc.J
`Leu
`Scr
`Asp
`l1lf
`Thr
`Scr
`Asp
`Leu
`Asp_
`Leu
`Ser
`Thr
`lhr
`Ser Asp
`J.cu
`Scr Asp
`lnr
`Leu
`lhr
`As:J
`Scr
`l.eu
`Thr
`Asp
`Leu
`Ser
`Leu
`Asp
`Thr
`Ser
`Thr
`Ser
`Leu
`Asp
`Ser Asp
`Thr
`Leu
`Ser Asp
`Leu
`TI1r
`Asp
`Ser
`Leu
`Thr
`Ser
`Leu
`Asp
`"lhr
`Thr
`Leu
`Ser Asp
`Scr Asp
`Leu
`"lhr
`Thr
`Ser Asp
`Leu
`Ser
`Asp
`Leu
`Thr
`ASJl. Leu
`Thr
`Ser
`ASJl. Leu
`Thr
`Ser
`Leu
`Scr Asp
`lnr
`Ser Asp
`Leu
`Thr
`Asp
`Thr
`Ser
`Leu
`Ser
`Thr
`Asp
`Leu
`Scr Asp
`Ala
`Thr
`lh Ala Asp
`Leu
`As"
`Leu
`Thr
`Asp
`Thr
`[..£LJ
`Thr
`A~p Leu
`lhr
`Leu
`Leu
`lhr
`Leu
`Thr
`7
`10
`
`Ser
`Ser
`Ser
`Scr Asp
`Ser A;p
`Ser Asp __
`~
`
`'l
`
`Phc
`Phc
`Phe
`Phc
`Phe
`Phe
`Phe
`Phc
`Phe
`Phe
`Phe
`Phc
`I' he
`Phe
`Phe
`Phc
`Phe
`Phc
`Phe
`Phc
`Phe
`Phc
`Phe
`Phc
`Phe
`Phe
`Phc
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`I' he
`Phe
`Phc
`Phe
`Pr.e
`Phe
`Phe
`Phc
`6
`
`FIGURE 4Al
`
`r-·-
`
`His
`(j]y Glu
`lhr
`(jly
`Gl)'
`His
`Cllv
`Glu
`Th:
`His
`(j]y Glu
`Gly
`Thr
`His Gly Glu
`Gly
`"Ill!"
`G_lt
`His
`Gly
`"lhr
`Clu
`Gl~ Glu
`HlS
`Gly
`lhr
`Ills Gly Glu
`Gly
`"lk
`------Hts Gly Glu
`Gly_
`Thr
`H~> Gly Glu
`Gly
`11n
`'------
`Hrs
`Uly Glu
`Gly
`Thr
`Gly_ Glu
`IIi>
`lh
`Gly
`Thr
`Gly Glu G!y
`Hrs
`His Gly Glu
`Gly_
`lnr
`Glv nu
`llis Glv Glu
`His Glv Glu
`Thr
`Gly
`His Gly Glu
`Thr
`Gly
`His Gly
`Thr
`Glu Gly
`His
`lhr
`Uly_
`Thr
`llis Gly Glu Gly
`Thr
`His Gly Glu Gly
`His Gly Glu
`Thr
`Gly
`45
`Gly_ Ulu
`His
`Gly_
`Thr
`His
`Gly_ Glu
`44
`Thr
`Gly
`43
`His Gly Glu Gly
`Thr
`42
`His Gly Glu Gly
`Tiu
`Thr
`Hrs Gly Glu
`Gl_y_
`41
`His Gly Glu Gly
`40
`Thr
`39
`Thr
`1-l:s
`Gly
`38
`His Gly Glu Gly
`Thr
`Gly
`37
`Thr
`His Giy Glu
`Hrs Gly Glu
`36
`Gly
`Thr
`35
`Gly_ Glu
`Gly_
`Thr
`His
`34
`Thr
`vly Glu
`Hrs
`Gly
`33
`His G\v Glu Gly
`Thr
`32
`Thr
`Gly
`His
`Glv Glu
`31
`Gly
`His
`Gly Glu
`rhr
`30
`Ala
`Glv
`His Gly Glu
`-------c-::-----
`G_ly_
`H~; Ala Glu
`Thr
`29 ---
`28 ~ Glv Glu Gly
`Thr
`II,; Gly Glu Gly
`27
`"lhr
`26 ---
`Gly_
`His
`lnr
`4
`5
`SEQ llJ NO
`I
`
`-------
`
`66
`65
`64
`td
`62
`h]
`(,0
`59
`
`Gly Glu
`
`Gly Glu
`
`Gly_ Glu
`2
`3
`
`---
`
`---
`
`-
`
`--
`
`5R
`57
`56
`
`54
`SJ
`52
`51
`50
`49
`4~
`47
`
`-----ss
`
`--46
`
`SANOFI-AVENTIS Exhibit 1031 - Page 6
`
`IPR for Patent No. 8,951,962
`
`

`
`""' ~
`'N a-..
`""'
`
`1--"
`
`N
`\0
`-..a-..
`rJ'l
`e
`
`N c
`0 .....,
`Ul
`~ .....
`'Jl =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`NH2
`NH2
`
`l\H2
`Nll2
`Pro
`l'ro
`
`NH2
`NH2
`Pro
`l'ro
`Pro
`Pro
`
`--
`
`I
`
`NH2
`'4H2
`Pro
`Pro
`Pro
`Pro
`Pro
`Pro
`
`Nll2
`1:\112
`(il) -~ -
`Glv
`Cilv
`Gly
`Glv
`G\y
`(.ly
`Gil'_
`(ily
`G\y
`
`NH2
`Ala
`Ala
`Ala
`Ala
`Ala
`Ala
`Ala
`Ala
`
`NH2
`NH2
`Scr Nll2
`Ser
`NH2
`Ser
`Scr
`Ser
`Sci
`Sn
`Scr
`Ser
`Scr
`Scr
`Scr
`Ser
`Scr
`Ser
`SIT
`Ser
`Ser
`Scr
`Scr
`Ser
`Scr
`Scr
`Ser
`Scr
`Ser
`
`NH2
`Prn
`Pr0
`reo
`Prn
`Pn1
`Pro
`l'ro
`Pro
`Pro
`Pro
`Pro
`Pro
`l'ro
`Pro
`Pro
`Pro
`
`NH2 I
`Giv
`Gly
`Gly
`Gly
`Glv
`<_;ii_
`G\y
`Ciiv
`Glv
`Glv
`Gly
`Glv
`Glv
`Glv
`Gly
`Gly
`Gly
`
`3~
`
`38
`
`37
`
`36
`
`35
`
`34
`
`33
`
`32
`
`NH2
`31
`
`(ily
`30
`
`!
`
`FIGURE4A2
`
`I Leu
`I y<
`As'1
`(]',y
`Leu
`Asr1
`Glv
`Lvs
`l,r_s Asn
`Leu
`Cilv
`Leu
`Glv
`Lvs
`Asn
`Leu
`Lys Asn
`Glv
`Leu
`Gly
`Lys Asn
`Leu
`Cly
`Lys
`A.sn
`l . .cu ~ Asn
`Gly
`Lvs Asn
`Leu
`Gly
`Leu
`Lys Asn
`Glv
`Leu
`Lys Asn
`Gly
`Leu
`Lys Asn
`Gly
`Leu
`Lys Asn
`Gly
`Leu
`Lys Asn
`Gly
`Leu
`Lys Asn
`Gly
`Gly
`Lys Asn
`Leu
`Leu
`Lys
`Gly
`Asn
`Leu
`Lys Asn
`Gly
`Lys Ala NH2
`Leu
`L<:u Ala Asn NH2
`Lvs Asn Nll2
`Ala
`Lvs Asn
`Nll2
`!..t:u
`Lys Asn NH2
`I.£U
`Leu
`Asn Nll2
`Lys
`Lvs Asn
`Leu
`~H2
`Leu
`Lys A<n
`~H2
`Lvs
`Leu
`As~ Nll2
`Lys Asn NH2
`Leu
`!,ys A<n Nll2
`Leu
`Lvs Asn NH2
`Leu
`Lys A<n NH2
`Leu
`Lys Asn NH2
`Leu
`Lys Asn NH2
`Leu
`Lrs_ Asn Nll2
`Leu
`Lys Asn NH2
`Leu
`Lys Asn NH2
`Leu
`Lys
`Leu
`A_r.;,n NH2
`1_15 Asn NH2
`(£11
`L~s Am NH2
`Leu
`Lys Asn
`Leu
`N112
`Gl:i_
`Lys Asn
`Leu
`26
`2R
`27
`29
`
`6(1
`65
`64
`63
`62
`(,(
`60
`59
`58
`57
`56
`55
`54
`53
`52
`)I
`50
`4'1
`48
`47
`46
`45
`44
`43
`42
`41
`40
`39
`38
`37
`36
`35
`34
`33
`32
`r---31
`30
`29
`28
`27
`26
`
`SEQ ID. NO
`
`r-·
`
`SANOFI-AVENTIS Exhibit 1031 - Page 7
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`\Jl
`e
`
`'N a-..
`
`1--"
`~
`~
`
`N c
`0 ......,
`0'1
`~ .....
`'JJ. =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`Phe
`Phc
`Phe
`Phe
`Phe
`n<~E_h
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phc
`Phe
`Phe
`Phe
`22
`
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Ar_g_ Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`Val Ar_g_ Leu
`Val Arg Leu
`Val Arg Leu
`Val Arg Leu
`21
`19
`
`20
`
`--.----
`
`J,.ys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`(Jln Leu Glu Glu Glu Ala
`Lys
`Lys Gln Leu Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Leu Glu Glu Glu Ala
`Lvs Gin Leu Glu Giu Glu Ala
`Lvs Gin Met Ala Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Leu Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`L_ys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`Lys Gin Met Glu Glu Glu Ala
`()[u Glu Ala
`Lys Gin Leu Glu
`18
`16
`15
`12
`
`17
`
`14
`
`13
`
`-
`
`FIGCRE 481
`
`Thr Scr Asp Ala
`Phe
`Ser
`Phe Thr Scr Asp Ala
`Scr
`Phe Thr Ser AS!'_ Ala
`Ser
`Phc Thr Ser Asp Leu
`Ser
`Phe Thr Scr Asp Leu
`Ser
`Phe Thr Ser Asp Leu
`Scr
`Phe Thr Ser Asp pGly Ser
`Phe Tlu Scr Glu
`Ser
`Ser
`Phe
`Phe
`Ser
`Ser
`Ser
`Ser
`Ser
`Scr
`Ser
`Scr
`Ser
`Scr
`Ser
`11
`
`g
`
`7
`
`9
`
`His Gly Glu Gly Thr
`His Gly_ Glu Gly Thr
`His Gly_ Glu Gly Thr
`His Gly Glu Gly Thr
`His Gly Glu Gly Thr
`His Gly Glu Gly Tlu
`His Gly Glu Gly Thr
`Glu Gly Thr
`His
`Leu
`His Gly Glu Gly Thr
`Ser Thr Asp Leu
`His Gly Glu Gly Thr
`Ser Ser Asp Leu
`His Gly Glu Gly Tlu naph Thr Ser Asp Leu
`His Gly Asp Gly Thr
`Phe Thr Ser Asp Leu
`Arg Gly Glu Gly Thr
`Phc Thr Scr Asp
`Leu
`His Gly Glu Gly Thr
`Phe Thr Ser Asp
`Leu
`His Gly Glu Gly Thr
`Phe Thr
`S~:r Asp Leu
`Phe Thr Ser As.2_ Leu
`His Gly Glu Gly Thr
`Phe Thr Ser Asp Leu
`His Gly Glu Gly Thr
`Phe Thr Ser Asp Leu
`His Gly Glu Gly Tlu
`His Gly Glu Gly Thr
`Phe 1br Ser Asp Leu
`Phe Thr Ser Asp
`His Gly Glu Gly Thr
`Leu
`6
`5
`10
`
`Gly
`
`4
`
`3
`
`2
`
`I
`
`·-·
`
`86
`85
`84
`83
`82
`81
`80
`79
`78
`77
`76
`75
`74
`73
`72
`71
`70
`69
`68
`67
`
`f--·
`
`1-·
`
`f----
`1--
`
`-
`
`1-----
`r----
`
`r----···-
`
`SEQ. 10. NO.
`
`-----·-···-··
`
`SANOFI-AVENTIS Exhibit 1031 - Page 8
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`\Jl
`e
`
`'N a-..
`
`1--"
`~
`~
`
`hPro NII2
`
`hPro
`
`hPro Ser Se1 Gly Ala
`
`Ser Ser Nll2
`
`Pro
`
`N c
`0 ......,
`-..J
`~ .....
`'JJ. =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`'
`
`'
`
`tPro NH2
`tPro NH2
`
`NH2
`hPro
`hPro NH2
`Nme NH2
`Pro NH2
`tPro
`tPro
`
`NH2
`tPro Ser Scr Gly Ala NH2
`Ser Ser Gly Ala
`tPro
`hPro
`tPro
`Ser Ser Gly Ala
`hPro
`tPro
`Ser Scr Gly Ala Nme
`LPro
`Ser Ser Gly Ala
`Pro
`tPro Ser Ser Gly Ala
`tPro
`tPro
`Scr Scr Gly Ala
`tPro
`
`39
`
`38
`
`37
`
`36
`
`35
`
`34
`
`33
`
`32
`
`31
`
`FIGURE 482
`
`T_!P Leu Lys Asn Gly
`
`29
`
`28
`
`27
`
`26
`
`25
`
`.___
`
`--------f--
`
`·-
`
`86
`85
`84
`83
`82
`81
`80
`79
`78
`77
`76
`75
`74
`73
`2
`71
`70
`69
`68
`67
`
`llc
`Glu
`Gly
`Glu Trp Leu Lys Asn Gly NH2
`lle
`Glu Phc Leu Lys Asn Gly
`Ile
`(ily
`Ile
`Asp Phe Leu Lys Asn 1\!U
`tBug Glu Trp Leu Lys Asn NH2
`Ilc
`Glu Phc Leu Lys Asn NH2
`Glu Phe Leu Lys Asn NH2
`lie
`Glu T~ Leu Lys Asn NH2
`Tlc
`Glu Trp Leu Lys Asn NH2
`Ile
`Glu Trp Leu Lys Asn NH2
`Ile
`Glu Phe Leu Lys Asn NH2
`llc
`Glu Trp Leu Lys Asn Gly
`Ile
`Gly
`Glu TI£ Leu L_ys Asn G!J' Gl)'
`Tie
`Glu Trp Leu Lys Asn Gly Gly
`Ilc
`Glu Trp Leu Lys Asn Gly Gly
`lie
`Glu Trp Leu Lys Asn Gl}' Gl}'
`Ile
`Glu Trp Leu Lys Asn Gly Gly
`Ile
`Glu Trp Leu Lys Asn Gly Gly
`Ile
`Glu Trp Leu Lys Asn Gly Gly
`Ile
`Glu Phc Leu Lys Asn Gly NH2
`lie
`23
`24
`30
`
`____ ._ ______ r--
`------
`------------f--
`
`f------r-
`--
`
`--
`
`--
`----------
`
`SEQ. ID. NO.
`
`,..---.-----------,-------
`
`SANOFI-AVENTIS Exhibit 1031 - Page 9
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`rJ'l
`e
`
`'N a-..
`
`1-"
`~
`~
`
`Figure 4C
`
`N c
`0 ......,
`00
`~ .....
`'JJ. =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`4 -lmidazolylpropionyl-Gly Glu Gly Thr Phc Thr Scr Asp Leu Ser ~ya Oln Met Glu Cllu Olu Ala Val Jlt·g I.eu
`
`66
`
`(SF0. ID No. Q])
`
`Phc Ilc Glu Trp Leu llsn Lys-NH"octanoyl Gly Gly-mT,
`
`4-Imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lyo Gln Leu Glu Glu Glu Ala Val Arg Leu
`
`67
`
`(SEO_:__l_D No. 02)
`
`Phe Ilc Glu Phe Leu Asn Lys-tnfoctanoyl-Ml,
`
`4-Im.i.dazolylpropionyl-Gly Glu Oly Thr Phe Thr Ser Asp Leu Ser Lya Gln Met Olu Glu Glu Ala Val Ju:g Leu
`
`66
`
`(SEf1. ID No. q l)
`
`Phc Ile Glu Trp Leu Asn Lys-mroctanoyl-M~
`
`(SEO. ID No. 90)
`
`Arg Leu Phe I le Glu Phe Leu ~ya -Nll'octanoyl Aon Gly Gly-NH1
`
`4-Imid~zolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Aap Leu Ser Lyo Gln Leu Glu Glu Glu Ala Val
`
`65
`
`4-Imidazolylpropionyl-Gly Glu Gly Thr Phc Thr Ser Asp Leu Ser Lya Gln Met Glu Glu Glu Ala Val Arg Leu
`
`64
`
`(SECl. ID~-~
`
`Phe Ile Glu Trp Leu Lys-NH'octanoyl Asn Gly Gly·NH1
`
`4-lmidazolylpropionyl-Gly Glu Gly Thr Phe Thr Scr Asp Leu Ser Lyo Gln Leu Glu Glu Glu Ala Val Arg Leu
`
`GJ
`
`(SEO. 1D No. _ _§Pl._
`
`Phe Ile Glu Phe Leu Lyc-NH'octanoyl Aon-mT,
`
`4-lmidazolylpropionyl-Gly Glu Gly Thr Phe Thr Scr Acp ~cu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu
`
`62
`
`(SEQ. ID No. -~
`
`Phe Ile Glu Trp ~eu Lys-NH'octanoyl Aan -NH,
`
`_tl._Q_,_
`Compound
`
`SANOFI-AVENTIS Exhibit 1031 - Page 10
`
`IPR for Patent No. 8,951,962
`
`

`
`~ 'N a-..
`
`1--"
`~
`~
`
`N
`\0
`-..a-..
`rJ'l
`e
`
`Figure 4D
`
`N c
`0 ......,
`'0
`~ .....
`'JJ. =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`4-Imidazolylpropionyl-Gly Glu Gly Thr Phc Thr Scr 1\sp Leu Scr Lyo Gln Leu Glu Glu Glu 1\la Val Arg I,t"u
`
`G9
`
`(SEn. ID No. 911)
`
`Phe Ile Glu Phe Leu Aon Lys-NH'oc:t.anoyl Gly Gly-Nff.
`
`_N.Q_,_
`Compound
`
`SANOFI-AVENTIS Exhibit 1031 - Page 11
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`\Jl
`e
`
`'N a-..
`
`J-oo"
`~
`~
`
`N c
`0 ......,
`'"""' c
`~ .....
`'JJ. =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`Arg Leu
`Phc
`Arg Leu
`Phe
`Ar)! Leu
`Phc
`Arf!
`Leu
`Phe
`Arg Leu
`Phe
`Arg Leu Phe
`Arg Leu Phc
`Arg Leu Phc
`Arg Leu Phe
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu Phc
`Arg Leu Phc
`Arg Leu Phe
`Arg Leu
`p
`Arg Leu Phc
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu Phe
`Arg Leu Phe
`Arg Leu
`Phc
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu Phe
`Arg Leu Phe
`Arg Leu Phe
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu Phc
`Phe
`Arg Leu
`Phe
`Arg Leu
`Arg Leu
`Phc
`Arg Leu
`Phe
`20 I 21
`22
`
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Vul
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`Glu Ala Val
`19
`17
`
`18
`
`f---
`
`Leu
`Ser Lys Ala
`Leu Glu Gh1
`Leu
`Scr Lys Ala Met Glu Glu
`Leu
`Ser Ala Gin Leu Glu Glu
`Ser Ala Gin Met Glu Glu
`Leu
`Leu Ala Lvs Gin
`I .Cll Glu Glu
`Leu Ala Lys Gin Met Glu Glu
`P~lv Ser Lys Gin Leu Glu Glu
`Pgly Scr Lys Gin Met Glu Glu
`Ala
`Ser Lys Gin Leu Glu Glu
`Ser
`Ala
`Lys Gin Met Glu Glu
`Ser Lvs Gin Leu Glu Glu
`Leu
`Ser Lys Gin Met Glu Glu
`l.cu
`Scr Lys Gin Leu Glu Glu
`Leu
`Scr Lvs Gin Met Glu Glu
`Leu
`Leu
`Ser Lvs Gin Leu Glu Glu
`Ser Lys Gin Met Glu Glu
`Leu
`Ser Lys Gin Leu Glu Glu
`Leu
`Ser Lys Gin Met Glu Glu
`Leu
`Ser Lys Gin Leu Glu Glu
`Leu
`Leu
`Ser Lys Gin Met Glu Glu
`Scr Lys Gin Leu Glu Glu
`Leu
`Ser Lys Gin Met Glu Glu
`Leu
`Leu
`Ser Lys Gin Leu Glu Glu
`Ser Lys Gin Met Glu Glu
`Leu
`Scr Lys Gin Leu Glu Glu
`Leu
`Leu
`Scr Lys Gin Met Glu Glu
`Ser Lys Gin Met Glu Glu
`Ala
`Scr Lys Gin Met Glu Glu
`Leu
`Ser Lys Gin Met Glu Glu
`Leu
`Ser Lys Gin Met Glu Glu
`Leu
`Ser Lys Gin Met Glu Glu
`Leu
`Scr Lys Gin Met Glu Glu
`Leu
`Ser Lvs Gin Leu Glu Glu
`Leu
`Ser Lvs Gin Leu Glu Glu
`Leu
`Leu
`Ser Lvs Gin Leu Glu Glu
`10
`II
`16
`
`15
`
`14
`
`13
`
`12
`
`--
`
`FIGURE 4El
`
`A~_
`
`8
`
`I
`
`Phe
`Phc
`Phc
`Phe
`Phe
`Phc
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phe
`Phc
`Phe
`6
`
`Ala Gly Asp Gly Tlu
`Thr
`Ser Asp
`Phe
`Scr A~
`Ala G!y
`As_[)_ Gly Thr
`Thr
`Phc
`Ala Glv Asp Glv Thr
`Phe
`/\sp
`Thr
`Scr
`Ala Gly Asp Gly Thr
`Scr Asp
`Phe
`Thr
`Ala Gly Asp Glv Thr
`Phe
`Thr
`Ser Asp
`Ala Glv Asp Glv Thr
`Thr Sn Asp
`Phc
`Ala Gly Asp Glv Thr
`Scr Asp
`Phc
`Thr
`Ala Gly Asp Glv Thr
`Thr
`Sc1 Asp
`Phe
`Ala Gly Asp Glv Thr
`Ser Asp
`Phc
`Thr
`Ala Gly Asp Gly Thr
`Phc
`Thr
`Scr Asp
`Ala Gly Asp Gly Thr
`Phe
`Thr
`Scr Glu
`Ala Gly Asp Gly Thr
`Phe
`Thr
`Ser Glu
`Ala Gly Asp Gly_ Thr
`Phe
`Thr
`Scr Ala
`Ala Gly Asp Gl)' Thr
`Phe
`Ser Ala
`"lbr
`Ala Gly Asp Gly Thr
`Phe
`Thr Ala Asp
`Ala Gly Asp Gly Thr
`Phe Thr Ala Asp
`Ala Gly Asp Gly Thr
`Scr
`Ser Asp
`Phc
`Ala Gly Asp Gly Thr
`Ser
`Scr Asp
`Phe
`Gly As_!J_ Gly Thr Nala Thr
`Ala
`Ser Asp
`Ala Gly Asp Gly Thr Nala Thr
`Ser Asp
`Ala Gly Asp Gly Ala
`Thr
`Ser Asp
`Ser Asp
`Ala Gly Asp Gly Ala
`Thr
`Ala Gly Asp Gly Thr
`Thr Ser Asp
`Ala Gly Asp Gly Thr
`Thr Scr Asp
`Ala Ala Glu Gly Thr
`Thr Ser Asp
`Ala Ala Glu Gly Thr
`Thr Scr Asp
`Ser Asp
`Thr
`His Gly Glu Gly Thr
`Scr Ala
`Thr
`His Gly Glu Glv Tlu
`His Gly Glu Ala Thr
`Scr Asp
`Thr
`HIS Gly Ala Gly Thr
`Scr Asp
`Thr
`H1s Gly Glu Glv Thr
`Scr Asp
`Thr
`His Gly Glu Glv
`Ser Ala
`Thr
`'Thr
`His Gly Glu Ala Thr
`Ser Asp
`Thr
`IllS Gly Ala Gly Thr
`Ser
`Thr
`Thr Sn Asp
`Ala Gly Glu Glv Thr
`9
`7
`I
`5
`
`4
`
`3
`
`2
`
`129
`128
`127
`126
`125
`124
`123
`122
`-· 121
`120
`119
`118
`f----_117
`116
`115
`114
`__ !J]__
`-----
`112
`Ill
`110
`109
`108
`f-------
`r----107
`r--------1 06
`105
`104
`103
`102
`--
`101
`------·--·
`100
`--------·-
`')')
`98
`97
`96
`')5
`
`--
`
`_? _E __g:_ 10. N 0
`
`-------
`
`·------·~---·--~---
`
`SANOFI-AVENTIS Exhibit 1031 - Page 12
`
`IPR for Patent No. 8,951,962
`
`

`
`~
`N
`\0
`-..a-..
`rJ'l
`e
`
`'N a-..
`
`1-"
`~
`~
`
`N c
`'"""' 0 ......,
`'"""'
`~ .....
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`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
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`~
`•
`\Jl
`d •
`
`I
`
`39
`
`38
`
`37
`
`36
`
`35
`
`34
`
`33
`
`32
`
`31
`
`30
`
`FIGURE 4E2
`
`~~~ ~H2 j
`Asn NH2'
`Asn NII2
`Asn NH2
`Asn NH2 I
`Asn NH2
`Asn NH2
`!'\H2
`Asn
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn
`~112
`Asn NH2
`Asn NH2
`Asn NH2
`Asn Nll2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn NH2
`Asn N112
`Asn NH2
`Asn Nl!2
`28
`29
`
`lie GltJ_ ___l'_llc Leu
`Lys
`lie Giu Trp Leu
`Lys
`Phe Leu Lys
`lie Giu
`lie Glu Trp
`Lys
`Lys
`lie Glu
`Lys
`llc Glu Trp
`llr Glu
`Lys
`Leu Lys
`lie Giu Trp
`lie Giu
`Phc Leu Lys
`lle Giu Trp Leu
`Lys
`lie Glu
`Phe Leu Lys
`Leu Lys
`lie Glu Trp
`Phe Leu Lys
`lle Glu
`lie Glu Trp Leu Lys
`Phe Leu Lys
`lie Glu
`lie Glu Trp
`Leu Lys
`lie Glu
`l.ys
`lie Glu Trp
`l.ys
`lie Glu
`Phe Leu Lys
`lie Giu Trp Leu Lys
`lie Glu Phe Leu Lvs
`lie Glu Trp Leu Lys
`Phe Leu Lys
`lie Giu
`lie Giu Trp Leu Lys
`lie Giu
`Phe Leu
`Lys
`lie Giu Trp Leu
`Lys
`lie Glu Trp Leu Lys
`lie Glu Trp
`Lys
`lie Glu Trp
`Lys
`lie Glu Trp Leu Lys
`l'rp Leu
`lie Glu
`Lys
`Phe Leu Lys
`lie Glu
`Phe Leu Lys
`lie Glu
`Phe Leu
`lie Glu
`Lys
`Ik Glu
`Leu
`Phc
`Lys
`26
`27
`25
`24
`
`129
`I 28
`127
`12fi
`125
`124
`123
`122
`121
`120
`119
`118
`117
`116
`115
`114
`liJ
`112
`Ill
`110
`109
`108
`107
`i06
`105
`104
`~-:~~
`lUI
`100
`99
`Y8
`97
`96
`95
`
`r-·
`
`------
`
`SEQ.JD. NO. 23
`
`~------------
`
`Leu
`Phe Leu
`Leu
`Phe Leu
`
`Phe Leu
`Leu
`
`Leu
`Leu
`
`SANOFI-AVENTIS Exhibit 1031 - Page 13
`
`IPR for Patent No. 8,951,962
`
`

`
`1--"
`~
`~
`
`~
`N
`\0
`... a-..
`\Jl
`e
`
`'N a-,
`
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`0 ......,
`'"""' N
`~ .....
`'JJ. =(cid:173)~
`
`Ul
`
`N c c
`
`~N
`
`~ ({Q
`
`~ = ......
`~ ......
`~
`•
`\Jl
`d •
`
`Arg
`Phc
`l.c11
`Arg Leu
`I' he
`ArQ Leu
`Phc
`!'he
`ArQ Leu
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu
`Phc
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu
`Phe
`Arg Leu
`Phe
`Arg Leu Nala
`Arg Leu Nata
`Phc
`Arg Ala
`Arg Ala
`Phc
`Phc
`Ala Leu
`Ala Leu
`Phe
`Phe
`Arg Leu
`Phe
`Arg Leu
`Phc
`Arg Leu
`Phe
`Arg Leu
`Arg Leu
`Phe
`Phc
`Arg Leu
`Arg Leu
`Phe
`Arg Leu
`Phc
`Phc
`Arg Leu
`Phe
`Ar_g Leu
`Ar_g_ Leu
`Phc
`20
`21
`22
`
`--
`
`Met Glu Glu Glu Ala Val
`Met Glu Ulu Ulu Ala Val
`Leu Glu Glu Glu Ala Val
`Met Glu Glu Glu Ala Val
`Glu Glu Glu Ala Val
`Leu
`Met Glu Glu Glu Ala Val
`c;;u Glu Ala Val
`Leu Glu
`Met Glu Glu Glu Ala Val
`Leu Glu Glu Glu Ala Val
`Met Glu Glu Glu Ala Val
`Leu Glu Glu Glu Ala Val
`Met