throbber
(19) United States
`c12) Reissued Patent
`Larsen et al.
`
`I IIIII
`
`11111111
`
`1111111111111111111111111111111111111111111111
`USOORE45313E
`
`US RE45,313 E
`(10) Patent Number:
`(45) Date of Reissued Patent:
`Dec. 30, 2014
`
`(54) EXENDIN VARIANT PEPTIDES
`
`(71) Applicant: Zealand PharmaA/S, Glostrup (DK)
`
`(72)
`
`Inventors: Bjarne Due Larsen, Roskilde (DK);
`Jens Damsgaard Mikkelsen, Kgs.
`Lyngby (DK); Soren Neve, Kgs. Lyngby
`(DK)
`
`(73) Assignee: Zealand PharmaA/S, Glostrup (DK)
`
`(21) Appl. No.: 13/944,735
`
`(22) Filed:
`
`Jul. 17, 2013
`
`Related U.S. Patent Documents
`
`Reissue of:
`(64) Patent No.:
`Issued:
`Appl. No.:
`Filed:
`U.S. Applications:
`(60) Provisional application No. 60/143,591, filed on Jul.
`12, 1999.
`
`6,528,486
`Mar. 4, 2003
`09/614,847
`Jul. 12, 2000
`
`7,223,725 Bl
`7,226,990 B2
`7,235,627 B2
`7,297,761 B2
`7,348,404 B2
`7,399,489 B2
`7,407,932 B2
`7,414,107 B2
`7,419,952 B2
`7,442,680 B2
`7,452,858 B2
`7,521,423 B2
`7,544,657 B2
`7,601,691 B2
`7,608,692 B2
`7,623,530 B2
`7,683,030 B2
`7,691,963 B2
`7,696,161 B2
`7,700,549 B2
`7,741,269 B2
`7,858,740 B2
`7,928,065 B2
`7,935,786 B2
`8,026,210 B2
`8,057,822 B2
`8,097,698 B2
`8,263,550 B2
`
`5/2007 Beeley eta!.
`6/2007 Knudsen et a!.
`6/2007 Knudson et al.
`1112007 Beeley eta!.
`3/2008 Holm eta!.
`7/2008 Kolterman et al.
`8/2008 Young eta!.
`8/2008 Larsen
`9/2008 Beeley eta!.
`10/2008 Young eta!.
`1112008 Hiles eta!.
`4/2009 Young eta!.
`6/2009 Ebbehoj et a!.
`10/2009 Bridon eta!.
`10/2009 Prickett et a!.
`1112009 Hurtta
`3/2010 Prickett et a!.
`4/2010 Prickett et a!.
`4/2010 Beeley eta!.
`4/2010 Beeley eta!.
`6/2010 Young eta!.
`12/2010 Beeley eta!.
`4/2011 Young eta!.
`5/2011 Larsen
`9/2011 Young eta!.
`1112011 Prickett et a!.
`112012 Knudsen et a!.
`9/2012 Beeley eta!.
`(Continued)
`
`(51)
`
`Int. Cl.
`A61K 38100
`(52) U.S. Cl.
`USPC ............ 514/7.2; 514/1.1; 514/11.7; 530/300;
`530/303
`
`(2006.01)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,424,286 A
`5,545,618 A
`5,795,861 A
`5,846,937 A
`6,114,304 A
`6,136,784 A
`6,191,102 Bl
`6,268,343 Bl
`6,344,180 Bl
`6,358,924 Bl
`6,384,016 Bl
`6,410,511 B2
`6,451,974 Bl
`6,458,924 B2
`6,506,724 Bl
`6,528,486 Bl
`6,703,359 Bl
`6,767,887 Bl
`6,858,576 Bl
`6,872,700 Bl
`6,902,744 Bl
`6,924,264 Bl
`6,956,026 B2
`6,989,366 B2
`7,056,734 Bl
`7,115,569 B2
`7,138,375 B2
`7,153,825 B2
`7,157,555 Bl
`7,176,282 Bl
`7,220,721 Bl
`
`6/1995 Eng ................................... 514/2
`8/1996 Buckley eta!. ................. 514/12
`8/1998 Kolterman eta!.
`12/1998 Drucker
`9/2000 Kolterman eta!.
`10/2000 L'Italien eta!.
`2/2001 DiMarchi et a!.
`7/2001 Knudsen et a!.
`212002 Holst eta!.
`3/2002 Hoffmann
`5/2002 Kaarsholm
`6/2002 L'Italien eta!.
`9/2002 Hansen
`10/2002 Knudsen et a!.
`112003 Hiles eta!.
`3/2003 Larsen eta!.
`3/2004 Young et al.
`7/2004 Hoffmann eta!.
`2/2005 Young et al.
`3/2005 Young et al.
`6/2005 Kolterman eta!.
`8/2005 Prickett et a!.
`10/2005 Beeley et al.
`112006 Beeley et al.
`6/2006 Egan eta!.
`10/2006 Beeley et al.
`1112006 Beeley et al.
`12/2006 Young et al.
`112007 Beeley et al.
`2/2007 Holmet al.
`5/2007 Beeley et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`
`212001
`1076066 Al
`6/2003
`1196444 Bl
`(Continued)
`
`OTHER PUBLICATIONS
`
`Bedford et a!., "Amino acid structure and "difficult sequences" in
`solid phase peptide synthesis," Int J Pept Protein Res. 40:300-307
`(1992).
`Behme et al., "Glucagon-likepeptide 1 improved glycemic control in
`Type 1 diabetes," BMC Endocr Disord. 3:1-9 (2003) .
`Burcelin et a!., "Long-lasting antidiabetic effect of a dipeptidyl
`peptidase IV-resistant analog of glucagon-like Peptide-!," Metabo(cid:173)
`lism 48(2):252-258 (1999).
`Buse, "Progressive use of medical therapies in Type 2 diabetes,"
`Diabetes Spectrum. 13(4):211-220 (2000).
`Carpenter et a!., "Rational design of stable lyophilized protein for(cid:173)
`mulations: Some practical advice," Pharm Res. 14(8):969-975
`(1997).
`Ed veil eta!., "Initiation of increased pancreatic islet growth in young
`normoglycemic mice (Umea+/7)," Endocrinology 140(2):778-783
`(1999).
`Euorpean Medicines Agency, European Public Assessment Report
`(EPAR): Humalog Information (2006) (11 pages).
`
`(Continued)
`
`Primary Examiner- Dong Jiang
`(74) Attorney, Agent, or Firm- Kristina Bieker-Brady;
`Clark & Elbing LLP
`
`(57)
`
`ABSTRACT
`
`The present invention relates to novel peptide conjugates
`which have increased stability and are useful in the treatment
`of excess levels of blood glucose.
`
`2 Claims, 8 Drawing Sheets
`
`SANOFI-AVENTIS Exhibit 1012 - Page 1
`
`IPR for Patent No. 8,951,962
`
`

`
`US RE45,313 E
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`8,288,338 B2
`8,445,647 B2
`2002/0137666 Al
`2004/0106547 AI
`2006/0057137 Al
`2006/0194719 Al
`2007/0111940 AI
`2009/0088369 Al
`201110312878 Al
`2014/00807 57 AI
`2014/0187483 AI
`
`10/2012 Young et al.
`5/2013 Prickett et a!.
`9/2002 Beeley et al.
`6/2004 Larsen eta!.
`3/2006 Steiness
`8/2006 Ebbehoj et al.
`5/2007 Larsen eta!.
`4/2009 Steiness
`12/2011 Larsen
`3/2014 Tolborg et al.
`7/2014 Steiness
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`1329458 A2
`2028192 Al
`1525219 Bl
`2112161 A2
`W0-95/05848 Al
`W0-97/46584 Al
`wo 98/05351
`W0-98/05351 Al
`wo 98/08871
`W0-98/08871 Al
`W098/11125
`W098/11126
`W098/11126 A
`W0-98/11126 Al
`W0-98/19698 Al
`WO 98/22577 A
`W0-98/22577 Al
`WO 98/30231 A
`W0-98/30231 Al
`W0-98/35033 Al
`W0-98/39022 Al
`W0-98/50351 Al
`wo 99/07404
`W0-99/07404 Al
`wo 99/25727
`W0-99/25727 A2
`wo 99/25728
`W0-99/25728 Al
`W0-99/40788 Al
`wo 99/43707
`W0-99/43707 Al
`wo 99/43708
`W0-99/43708 Al
`wo 99/46283
`W0-99/46283 Al
`W0-99/64060 Al
`W0-00/09666 A2
`W0-00/41546 A2
`W0-00/41548 A2
`W0-00/66629 Al
`W0-00/73331 A2
`W0-01104156 Al
`W0-01132158 A2
`W0-2004/005342 Al
`
`7/2003
`212009
`5/2009
`10/2009
`3/1995
`12/1997
`2/1998
`2/1998
`3/1998
`3/1998
`3/1998
`* 3/1998
`3/1998
`3/1998
`5/1998
`5/1998
`5/1998
`7/1998
`7/1998
`8/1998
`9/1998
`1111998
`2/1999
`2/1999
`5/1999
`5/1999
`5/1999
`5/1999
`8/1999
`9/1999
`9/1999
`9/1999
`9/1999
`9/1999
`9/1999
`12/1999
`212000
`7/2000
`7/2000
`1112000
`12/2000
`1/2001
`5/2001
`112004
`
`C07K 11107
`
`OTHER PUBLICATIONS
`Fineman eta!., Abstract 343-0R: "AC2993 (Synthetic Exendin-4)
`added to existing metformin (Met) and/or Sulfonylurea (SFU) treat(cid:173)
`ment improved glycemic control in patients with type 2 diabetes
`(DM2) during 28 days of treatment," Diabetes 5l(Supplement
`2):A85, Abstract Book, 62nd Scientific Sessions (2002).
`Holst, "Glucagon-like peptide-!, a gastrointestinal hormone with a
`pharmaceutical potential," Curr Med Chern. 6:1005-1017 (1999).
`Hui eta!, "The short half-life of glucagon-like-peptide-1 in plasma
`does not reflect its long-lasting beneficial effects," Eur J Endocrinol.
`146:863-869 (2002).
`Juntti-Berggren eta!., "The anti diabetogenic effect ofGLP-1 is main(cid:173)
`tained during a 7 -day treatment period and improves diabetic
`dyslipoproteinemia m NIDDM patients," Diabetes Care
`19(11):1200-1206 (1996).
`
`Krchnak et a!., "Aggregation of resin-bound peptides during solid(cid:173)
`phase peptide synthesis. Prediction of difficult sequences," Int J Pept
`Protein Res. 42:450-454 (1993).
`Larsen et a!., "Sequence-assisted peptide synthesis (SAPS)," J
`Peptide Res. 52:470-476 (1998).
`Owens et a!., "Insulins today and beyond," Lancet. 358:739-746
`(200 1).
`Parkes et al., "Insulinotropic actions of exendin-4 and glucagon-like
`peptide-! in vivo and in vitro," Metabolism. 50(5):583-589 (2001).
`Petersen eta!., "ZP 10-A new GLP-1 agonist that prevents diabetes
`progression and increases insulin mRNA expression in db/db mice,"
`38th Annual Meeting of the European Association for the Study of
`Diabetes (EASD). Budapest, Hungary, Sep. 1-5,2002, Diabetologia
`45 (Suppl. l):Al47, Abstract No. 447, 2002.
`Pohl et a!, "Molecular cloning of the helodermin and exendin-4
`cDNAs
`in
`the
`lizard. Relationship
`to vasoactive
`intestinal
`polypeptide/pituitary adenylate cyclase activating polypeptide and
`glucagon-like peptide 1 and evidence against the existence of mam(cid:173)
`malian homologues," J Bioi Chern. 273(16):9778-9784, 1998.
`Roach eta!., "Improved postprandial glycemic control during treat(cid:173)
`ment with humalog Mix25, a novel protamine-based insulin lispro
`formulation," Diabetes Care. 22(8): 1258-1261 (1999).
`Stoffers et a!., "Insulinotropic glucagon-like peptide 1 agonists
`stimulate expression ofhomeodomain protein IDX-1 and increases
`islet size in mouse pancreas," Diabetes 49:741-748 (2000).
`Thorkildsen et a!., "ZPlO-A New GLP-1 agonist that increases
`insulin mRNA expression," Nedergaard Symposium, Odense, Den(cid:173)
`mark, Jan. 24, 2002 (Poster presentation).
`Thorkildsen et a!., "ZPlO-A New GLP-1 agonist that increases
`insulin mRNA expression," Nedergaard Symposium, Odense, Den(cid:173)
`mark, Jan. 24, 2002 (abstract only).
`Thorkildsen eta!., "ZPlO-A new GLP-1 agonist that prevents dia(cid:173)
`betes progression and increases insulin mRNA expression in db/db
`mice," 38th Annual Meeting of the European Associate for the Study
`of Diabetes (EASD), Budapest, Hungary, Sep. 1-5, 2002, Poster
`presentation.
`Tourrel et a!., "Persistent improvement of type 2 diabetes in the
`Goto-Kakizaki Rat model by expansion of the b-ee!! mass during the
`prediabetic period with glucagon-like peptide-! or exendin-4," Dia(cid:173)
`betes. 51:1443-1452 (2002).
`Wang eta!., "Glucagon-like peptide-! treatment delays the onset of
`diabetes in 8 week-old db/db mice," Diabetologia. 45:1263-1273
`(2002).
`Xu et a!., "Exendin-4 stimulates both 13-cell replication and
`neogenesis, resulting in increased 13-cell mass and improved glucose
`tolerance in diabetic rats," Diabetes. 48:2270-2276 (1999).
`Young et a!., "Glucose-lowering and insulin-sensitizing actions of
`exendin-4: Studies in obese diabetic (ob/ob, db/db) mice, diabetic
`fatty zucker rats, and diabetic rhesus mondays (macaca mulatta),"
`Diabetes. 48:1026-1034 (1999).
`Zander eta!., "Additive glucose-lowering effects of glucagon-like
`peptide-! and metformin in type 2 diabetes," Diabetes Care.
`24(4):720-725 (2001).
`European Search Opinion and Extended European Search Report for
`European Patent Application No. 08016668.9, dated Jan. 27,2009 (5
`pages).
`Notice of Opposition for European Patent No. 1525219, dated Feb.
`26, 2010 (24 pages).
`International Search Report for International Application No. PCT/
`DK00/00393, dated Nov. 11, 2000 (3 pages).
`International Search Report for International Application No. PCT/
`DK03/00463, dated Oct. 22, 2003 (7 pages).
`International Preliminary Examination Report for International
`Application No. PCT/DK03/00463, dated Sep. 20, 2004 (5 pages).
`European Search Report for European Patent Application No.
`99610043, dated Jan. 18, 2000 (2 pages).
`Partial European Search Report for European Patent Application No.
`99610043, dated Jan. 18, 2000 (4 pages).
`Partial European Search Report for European Patent Application No.
`03005786, dated Oct. 23, 2003 (6 pages).
`European Search Report for European Patent Application No.
`09002937, dated Mar. 15, 2010 (5 pages).
`
`SANOFI-AVENTIS Exhibit 1012 - Page 2
`
`IPR for Patent No. 8,951,962
`
`

`
`US RE45,313 E
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Byrne et a!., "Inhibitory effects of hyperglycaemia on fed jejunal
`motility: potential role ofhyperinsulinaemia," Eur. J. of Clin. Invest.
`28( 1 ):72-8 ( 1998).
`Chen et a!., "Tissue-specific expression of unique mRNAs that
`encode proglucagon-derived peptides or exendin 4 in the lizard," J
`Bioi Chern. 272(7):4108-15 (1997).
`Cleland et al., "The development of stable protein formulations: a
`close look at protein aggregation, deamidation, and oxidation," Crit
`Rev Ther Drug Carrier Syst. 10(4):307-77 (1993).
`Deacon et a!., "Dipeptidyl peptidase IV resistant analogues of
`glucagon -like peptide-! which have extended metabolic stability and
`improved biological activity," Diabetologia 41(3):271-8 ( 1998).
`Deacon et al., "Dipeptidyl peptidase IV inhibition potentiates the
`insulinotropic effect of glucagon-like peptide 1 in the anesthetized
`pig," Diabetes 47(5):764-9 (1998).
`Action Closing Prosecution in Inter Partes Reexam 95/000,276,
`mailed Mar. 17, 2011 (25 pages).
`Decision in Inter Partes Reexam 95/000,276, mailed Nov. 25, 2013
`(29 pages).
`D' Alessio et a!., "Glucagon-like peptide 1 enhances glucose toler(cid:173)
`ance both by stimulation of insulin release and by increasing insulin(cid:173)
`independent glucose disposal," J Clin Invest. 93(5):22636 (1994).
`Giike eta!., "Distribution of GLP-1 binding sites in the rat brain:
`evidence that exendin-4 is a ligand of brain GLP-1 binding sites," Eur
`J Neurosci. 7(11):2294-300 (1995).
`Giike et a!., "Exendin-4 is a high potency agonist and truncated
`exendin-(9-39)-amide an antagonist at the glucagon-like peptide
`1-(7-36)-amide receptor of insulin-secreting beta-cells," J Bioi
`Chern. 268(26): 19650-5 (1993).
`Gombotz et a!., "Biodegradable Polymers for Protein and Peptide
`Drug Deliver," Bioconjugate Chemistry 6:332-351 (1995).
`Greig et al., "Once daily injection of exendin-4 to diabetic mice
`achieves long-term beneficial effects on blood glucose concentra(cid:173)
`tions," Diabetologia 42(1):45-50 (1999).
`Gunn eta!., "Central glucagon-like peptide-! in the control of feed(cid:173)
`ing," Biochem. Soc. Trans. 24:581-584 (1996).
`Hoist, "Enteroglucagon," Annu Rev Physiol. 59:257-71 (1997).
`Manning et al., "Stability of protein pharmaceuticals," Pharm Res.
`6(11):903-18 (1989).
`Meyer eta!., Chapter 4: Effects of conformation on the Chemical
`Stability of Pharmaceutically Relevant Polypeptides. Rational
`design of stable protein formulations. Ed. Carpenter et a!, 85-6
`(2002).
`Meurer eta!., "Properties of native and in vitro glycosylated forms of
`the glucagon-like peptide-! receptor antagonist exendin(9-39),"
`Metabolism. 48(6):716-24 (1999).
`Nauck eta!., "Glucagon-like peptide 1 and its potential in the treat(cid:173)
`ment of non-insulin-dependent diabetes mellitus," Horm Metab Res.
`29(9):411-6 (1997).
`Navarro eta!., "Colocalization of glucagon-like peptide-! (GLP-1)
`receptors, glucose transporter GLUT-2, and glucokinase mRNAs in
`
`rat hypothalamic cells: evidence for a role ofGLP-1 receptor agonists
`as an inhibitory signal for food and water intake," J Neurochem
`67(5):1982-91 (1996).
`Orskov, "Glucagon-like peptide-!, a new hormone of the entero(cid:173)
`insular axis," Diabetologia. 35(8):701-11 (1992).
`Pederson et al., "Improved glucose tolerance in Zucker fatty rats by
`oral administration of the dipeptidyl peptidase IV inhibitor isoleucine
`thiazolidide," Diabetes 47(8): 1253-8 (1998).
`Pohl et a!., "Molecular cloning of the helodermin and exendin-4
`cDNAs
`in
`the
`lizard. Relationship
`to vasoactive
`intestinal
`polypeptide/pituitary adenylate cyclase activating polypeptide and
`glucagon-like peptide 1 and evidence against the existence of mam(cid:173)
`malian homologues," J Bioi Chern. 273(16):9778-84 (1998).
`Poon eta!., "Exenatide improves glycemic control and reduces body
`weight in subjects with type 2 diabetes: a dose-ranging study," Dia(cid:173)
`betes Techno! Ther. 7(3):467-77 (2005).
`Pride! et a!., "Absorption of glucagon-like peptide-! can be pro(cid:173)
`tracted by zinc or protamine," Int. J. Pharmaceutics 136:53-59
`(1996).
`Raufman et a!, "Truncated glucagon-like peptide-! interacts with
`exendin receptors on dispersed acini from guinea pig pancreas. Iden(cid:173)
`tification of a mammalian analogue of the reptilian peptide exendin-
`4," J Bioi Chern. 267(30):21432-7 (1992).
`Raufman et a!. "Exendin-3, a novel peptide from Heloderma hor(cid:173)
`ridum venom, interacts with vasoactive intestinal peptide receptors
`and a newly described receptor on dispersed acini from guinea pig
`pancreas," J Bioi Chern. 266(5):2897-902 (1991).
`Raufman, "Bioactive peptides from lizard venoms," Regul Pept.
`61( 1 ): 1-18 ( 1996).
`Ritzel et a!., "A synthetic glucagon-like peptide-! analog with
`improved plasma stability," J Endocrinol. 159( 1 ):93-1 02 ( 1998).
`Tang-Christensen et a!., "Central administration of GLP-1-(7-36)
`amide inhibits food and water intake in rats," Am J. Physiol. 271( 4 Pt
`2):R848-56 ( 1996).
`Turton eta!., "A role for glucagon-like peptide-! in the central regu(cid:173)
`lation of feeding," Nature 379(6560):69-72 (1996).
`Underwood et al., "Crystal structure of glucagon-like peptide-! in
`complex with the extracellular domain of the glucagon-like peptide-!
`receptor," J Bioi Chern. 285(1):723-30 (2010).
`Wettergren et al., "Truncated GLP-1 (proglucagon 78-107-amide)
`inhibits gastric and pancreatic functions in man," Dig Dis Sci.
`38(4):665-73 (1993).
`U.S. Appl. No. 60/132,018, filed Apr. 30, 1999 (99 pages).
`U.S. Appl. No. 14/095,667, filed Dec. 3, 2013 (99 pages).
`U.S. Appl. No. 14/116,268, filed Nov. 7, 2013 (164 pages).
`J. Eng et a!. Isolation and characterization of Exendin-4, an
`Exendin-3 analogue, from Heloderma suspectum venom. 1992. J.
`Bioi. Chern., 267(11): 7402-05.*
`
`* cited by examiner
`
`SANOFI-AVENTIS Exhibit 1012 - Page 3
`
`IPR for Patent No. 8,951,962
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 1 of8
`
`Us RE45,313 E
`
`mz_._<m-—DZDOn=>_O0Iol
`
`89.8v-—OZDOn:>_OOIII o2
`
`om.
`
`99,gags...I
`
`onasto-.oz:oa_>_ooIII‘8
`..uII..u....|..|..I.t1a.Al’.889.q.FDZDOn=>_OO|Iu
`
`8
`
`om
`
`9.
`
`'13/\3’| 9flElG'38d :lO %
`
`
`
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 2 of 8
`
`US RE45,3l3 E
`
`
`
`mz_._<m-Noz:on_s_oo.|O|
`
`_._._A3_|
`
`%O4..dH9OHn9.|
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 3 of8
`
`Us RE45,313 E
`
`8ms82-moz:oas_ooIII
`
`
`
`882:-mozaoazoo|_1|
`
`88.-mDZDOn_S_OOll:
`
`88S-mDZDOn:>_OOIII8
`
`982:-moz:oas_ooIol8
`
`mz_._<m-moz3on__>_oo.+03
`
`om.
`
`om.
`
`OZ,
`
`o9
`
`om
`
`E
`
`on
`
`ow
`
`"I3/\3"| 9fiHC|'3Hd :10 %
`
`SANOFI-AVENTIS Exhibit 1012 - Page 6
`IPR for Patent No. 8,951,962
`
`
`
`
`
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 4 of8
`
`Us RE45,313 E
`
`ICOMPOUNDGM OCOMPOUND4
`
`100120140160180
`204060
`
`80
`
`0
`
`(wu) '0No:>
`
`0.1
`
`SANOFI-AVENTIS Exhibit 1012 - Page 7
`IPR for Patent No. 8,951,962
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 5 of8
`
`Us RE45,313 E
`
`-0- COMPOUND 2
`
`-0- COMPOUND 14
`+ COMPOUND15
`
`—v— COMPOUND 16
`
`0 —I— COMPOUND 18
`-0- COMPOUND 19
`
`+ COMPOUND (i)
`
`100
`
`O1O
`
`AUC0_240mm(%OFRESPONSETOVEHICLE)
`
`VEHICLE 0.001
`
`0.01
`
`0.1
`
`1
`
`10
`
`100
`
`DOSE (nmol/kg i.p.)
`
`FIG. 5
`
`SANOFI-AVENTIS Exhibit 1012 - Page 8
`IPR for Patent No. 8,951,962
`
`

`
`U.S. Patent
`
`4102093oneD
`
`Sheet 6 of 8
`
`US RE45,3l3 E
`
`ll
`
`Z_._.__0_n:2<
`
`eam
`
`_meow
`
`Coo5<oC<oE9.Eooto5oo<oo<oo<ooF<<<oo<<B.6bE<oB»<o<oE<o<5om<o5.o»<ow»<_m
`
`..m<<._.O<<0<<O<<O<<O<<O<<.rU._.<0U<U0.rOO._.O0._.0._.._.O._.<O0._.0O._.O0._.<<0<<0
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 7 of8
`
`Us RE45,313 E
`
`N.O_n_
`
`
`
`2:9:025mmoo
`
`2:9_to
`
`5.om:o__..m>
`
`om-
`
`IIIIIIIIIIIIIIII OU
`
`’)
`
`.3omooam;n_z30n_s_OoJr!uuuuuuuuuuIddmmoosm.3oz:on_s_oono:
`
`IIIIIIIIIIIIIIII'
`
`(3'IoIH3/\ OJ. 3SNOdS32:I :10 %) ”'“’ °"3'°onv
`
`SANOFI-AVENTIS Exhibit 1012 - Page 10
`IPR for Patent No. 8,951,962
`
`
`
`
`
`.3.$0834ozaomzooIon
`
`

`
`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 8 of8
`
`US RE45,313 E
`
`'El1lIIK% I¢$T‘ZIIfiIIa&II%IIfl
`
`\\\u\\\~\-\\\\\\\\\\\---_.\\\\~..\\\\\\~-
`
`AO)OO
`
`M0
`
`\m......m.~....\.....~.m...........‘.\..
`
`Ins\\~ms~\\\~\vn\\\\x\\uI\vc\&\\s\v\\\A\\\\VA\\\\v\\\v>\vwnn\\\\\x\\u-an-a\\\\\\x\\A~\
`
`Lu
`to
`
`zOo
`
`.
`<0
`LU
`tr
`LL]
`_I
`QI
`
`m> $EEOV
`
`!‘
`
`Nd03<
`
`O
`
`120
`
`240
`
`360
`
`480
`
`600
`
`720
`
`840
`
`960
`
`1080
`
`1200 13201440
`
`TIME OF DRUG ADMINISTRATION (min BEFORE OGTT)
`
`*1 p<0.05 VERSUS VEHICLE
`
`SANOFI-AVENTIS Exhibit 1012 - Page 11
`IPR for Patent No. 8,951,962
`
`

`
`US RE45,313 E
`
`1
`EXENDINVARIANT PEPTIDES
`
`Matter enclosed in heavy brackets [ ] appears in the
`original patent but forms no part of this reissue specifica-
`tion; matter printed in italics indicates the additions
`made by reissue.
`
`5
`
`2
`era! strategies circumventing this problem have been pro(cid:173)
`posed, some using inhibitors of DPP-IV and other DPP-IV
`resistant analogues of GLP-1 (7-36)amide (Deacon, 1998,
`Diabetologia 41:271-287; Deacon et a!., 1998, Diabetes
`47:764-769; Ritzel, 1998, J. Endocrinol. 159:93-102; U.S.
`Pat. No. 5,545,618; Pederson, 1998, Diabetes 47:1253-
`1258).
`Exendins, another group of peptides that lower blood glu(cid:173)
`cose levels have some sequence similarity (53%) to GLP-1
`[7-36]NH2 (Goke eta!., 1993, J. Bioi. Chern. 268: 19650-55).
`The exendins are found in the venom of Helodermatidae or
`beaded lizards (Raufman, 1996, Reg. Peptides 61:1-18).
`Exendin-3 is present in the venom of Heloderma horridum,
`the Mexican beaded lizard and exendin-4 is present in the
`15 venom of Heloderma suspectum, the Gila monster. Exen(cid:173)
`din-4 differs from exendin-3 at just positions two and three.
`The eDNA encoding the exendin-4 precursor protein, a 47
`amino acid peptide fused to the amino terminus of exendin-4
`has been cloned and sequenced (Pohl et a!., 1998, J. Bioi.
`20 Chern. 273:9778-9784 and W098/35033). Both exendin-3
`and exendin-4 stimulate an increase in cellular cAMP pro(cid:173)
`duction in guinea pig pancreatic acinar cells by interacting
`with exendin receptors (Raufman, 1996, Reg. Peptides 61:1-
`18). Exendin-3 causes a biphasic increase in cellular cAMP
`25 production, but a monophasic increase in amylase release in
`pancreatic acinar cells. In contrast, exendin-4 causes a
`monophasic increase in cAMP production and does not alter
`amylase release.
`Exendin-4 is a strong GLP-1 receptor agonist on isolated
`30 rat insulinoma cells (Goke eta!., 1993, J. Bioi. Chern. 268:
`19650-55). This is expected as the (His Ala) domainofGLP-1
`recognised by DPP-IV is not present in exendin-4 (Goke et
`a!., 1993, J. Bioi Chern. 268:19650-55). Binding of [125I]
`GLP-1 to the nucleus of the solitary tract was inhibited con-
`35 centration-dependently by unlabelled GLP-1 and [Tyr39]ex(cid:173)
`endin-4 with Ki values of 3.5 and 9.4 nM respectively, and
`similar values are found in cell lines (Goke eta!., 1995, Eur.
`J. Neurosci. 7:2294-2300 and Goke et a!., 1993, J. Bioi.
`Chern. 268: 19650-55). Further, exendin-4 given systemically
`40 lowers blood glucose levels by 40% in diabetic db/db mice
`(W0/99/07404). Recently, Grieg et a!. (1999, Diabetologia
`42:45-50) has shown a long lasting blood glucose lowering
`effect of once daily intraperitoneal injection of exendin-4 to
`diabetic ob/ob mice). U.S. Pat. No. 5,424,286 discloses that a
`45 considerable portion of theN-terminal sequence is essential
`in order to preserve insulinotropic activity ( exendin-4(1-31)
`andY31 -exendin-4 (1-31 )) whereas anN-terminallytruncated
`exendin ( exendin-4(9-39) has inhibitory properties.
`The use of exendin-3, exendin-4 and exendin agonists has
`50 been proposed for the treatment of diabetes mellitus, reducing
`gastric motility and delaying gastric emptying and the pre(cid:173)
`vention of hyperglycemia (U.S. Pat. No. 5,424,286, W098/
`0535) as well as for the reduction of food intake (W098/
`30231). There has been proposed ways of obtaining novel
`55 compounds by modifYing the native exendin sequences. One
`way is to attach lipophilic substituents to the molecule, e.g. as
`described in WO 99/43708 which discloses derivatives of
`exendin with just one lipophilic substituent attached to the
`C-terminal amino acid residue.
`A major approach has been to devise exendin analogues
`characterised by amino acid substitutions and/or C-terminal
`truncation of the native exendin-4 sequence. This approach is
`represented by the compounds of W099/07404, WO
`99/25727 and WO 99/22728. W099/07404 discloses exendin
`65 agonists having a general formula I that defines a peptide
`sequence of39 amino acid residues with Gly Thr in positions
`4-5, Ser Lys GLn in positions 11-13, Glu Glu GluA!a Val Arg
`
`This application is a reissue of U.S. Pat. No. 6,528,486, 10
`which claims benefit ofU.S. Provisional application Ser. No.
`60/143,591, filed on Jul. 12, 1999.
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel peptide agonists of
`GLP-1 activity. More specifically the invention relates to
`novel peptides that lower blood glucose levels comprising
`variants of the exendin-4 polypeptide sequence and peptide
`conjugates comprising variants of the GLP-1 or the exendin-4
`polypeptide sequences which are pharmacologically active
`and stable, and as agonists of GLP-1 activity are useful in the
`treatment of diseases that benefit from regulation or excess
`levels ofblood glucose and/or regulation of gastric emptying,
`such as diabetes and eating disorders. The present invention
`also relates to methods of preparing said novel peptides, a
`composition, e.g., a pharmaceutical composition, comprising
`a peptide of the invention and a physiologically acceptable
`carrier, to said peptide for use in therapy, a method of treating
`a disorder and to the use of said peptide for the manufacture
`of a pharmaceutical composition for use in therapy.
`
`BACKGROUND OF THE INVENTION
`
`A number of hormones that lower blood glucose levels are
`released from the gastrointestinal mucosa in response to the
`presence and absorption of nutrients in the gut. These include
`gastrin, secretin, glucose-dependent insulinotropic polypep(cid:173)
`tide (GIP) and glucagon-like peptide-! (GLP-1). The most
`potent substance known is GLP-1 (0orskov, 1992, Diabeto(cid:173)
`logia 35:701-711). Glucagon-like peptide 1 (GLP-1) is a
`product of pro glucagon, a 180 amino acid peptide (Drucker,
`1998 Diabetes 47: 159-169). The overall sequence of pro glu(cid:173)
`cagon contains the 29-amino acid sequences of glucagon, the
`36 or 37 amino acid sequence ofGLP-1 and the 34 amino acid
`sequence of glucagon-like peptide-2 (GLP-2), an intesti(cid:173)
`notrophic peptide. GLP-1 has a number of functions. It is a
`physiological hormone that enhances the effect on insulin
`secretion in normal humans and is therefore an incretin hor(cid:173)
`mone. In addition, GLP-1 also lowers glucagon concentra(cid:173)
`tions, slows gastric emptying, stimulates (pro) insulin biosyn(cid:173)
`thesis, and enhances insulin sensitivity (Nauck, 1997, Harm.
`Metab. Res. 47:1253-1258). The peptide also enhances the
`ability for the ~-cells to sense and respond to glucose in
`subjects with imparted glucose tolerance (Byrne, 1998, Eur.
`J. Clin. Invest. 28:72-78). The insulinotropic effect of the
`GLP-1 in humans increases the rate of glucose disappearance
`partly because of increased insulin levels and partly because
`of enhanced insulin sensitivity (D' Alessio, 1994, Eur. J. Clin.
`Invest. 28:72-78). This has placed GLP-1 as a promising 60
`agent for treatment of type II diabetes. Active fragments of
`GLP-1 have been found to be GLP-1(7-36) andGLP-1(7-37).
`However, a major pharmacological problem with native
`GLP-1 is its short half-life. In humans and rats, GLP-1 is
`rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) into
`GLP-1 (9-36)amide, acting as an endogenous GLP-1 receptor
`antagonist (Deacon, 1998, Diabetologia 41:271-278). Sev-
`
`SANOFI-AVENTIS Exhibit 1012 - Page 12
`
`IPR for Patent No. 8,951,962
`
`

`
`US RE45,313 E
`
`3
`Leu in positions 15-21, Leu Lys Asn Gly Gly in positions
`26-30, Ser Ser Gly Ala in positions 32-35, and wherein the
`remaining positions may be occupied by wild-type exendin
`amino acid residues or may be occupied by specified amino
`acid substitutions. The formula I does not cover any exendin 5
`agonists or analogues having specific amino acid deletions
`and/or being conjugates as described herein, such as the novel
`compounds desPro36-exendin-4 (1-39), exendin-4(1-39)-K6
`or desPro36 -exendin-4(1-39)-K6. WO 99/25727 discloses
`exendin agonists having a general formula I that defines a 10
`peptide sequence of from 28 to 38 amino acid residues with
`Gly in position 4 and Ala in position 18, and wherein the
`remaining positions may be occupied by wild-type exendin
`amino acid residues or may be occupied by specified amino
`acid substitutions. Formula I does not comprise a peptide 15
`sequence having Ser as the C-terminal amino acid and exen(cid:173)
`din agonists or analogues having specific amino acid dele(cid:173)
`tions and/or being conjugates as described herein, such as the
`novel compounds desPro36-exendin-4(1-39), exendin-4(1-
`39)-K6 or desPro36-exendin-4)1-39)-K6. Further, formula II 20
`of WO 99/25727 defines a peptide sequence similar to for(cid:173)
`mula I, but including exendin derivatives having a C(l-10)
`alkanoyl or cycloalkylalkanoyl substituent on lysine in posi(cid:173)
`tion 27 or 28. When treating inappropriate post-prandial
`blood glucose levels the compounds are administered fre- 25
`quently, for example one, two or three times a day. WO
`99/25728 discloses exendin agonists having a general for(cid:173)
`mula I that defines a peptide sequence offrom 28 to 39 amino
`acid residues with fixed Ala in position 18, and wherein the
`remaining positions may be occupied by wild-type exendin 30
`amino acid residues or may be occupied by specified amino
`acid substitutions. Said exendin agonists all correspond to a
`truncated exendin analogues having a varying degree of
`amino acid substitutions. Peptide sequences of from 34 to 38
`amino acid residues do not have Ser C-terminally. A peptide 35
`sequence of39 amino acid residues may have either Ser orTyr
`C-terminally, but no further residues. Exendin agonist or ana(cid:173)
`logues having specific amino acid deletions and/or being
`conjugates according to the invention described herein are not
`comprised by formula I. Further, formula II defines a peptide 40
`sequence similar to formula I, but including exendin deriva(cid:173)
`tives having a C(1-10)alkanoyl or cycloalkylalkanoyl sub(cid:173)
`stituent on lysine in position 27 or 28.
`WO 99/46283 (published 16.09.99) discloses peptide con(cid:173)
`jugates comprising a pharmacologically active peptide X and 45
`a stabilising peptide sequence Z of 4-20 amino acid residues
`covalently bound to X, where said conjugates are character(cid:173)
`ised in having an increased half-life compared to the half-life
`of X. X may be exendin-4 or exendin-3.
`
`4
`(a) an exendin having at least 90% homology to exendin -4;
`(b) a variant of said exendin wherein said variant comprises
`a modification selected from the group consisting of
`between one and five deletions at positions 34-39 and
`contains a Lys at position 40 having a lipophilic substitu(cid:173)
`ent; or
`(c) GLP-1 (7-36) or GLP-1 (7-37) having at least one
`modification selected from the group consisting of:
`(i) substitution of D-alanine, glycine or alpha-amino
`isobutyric acid for alanine at position 8 and
`(ii) a lipophilic substituent;
`and Z, a peptide sequence of 4-20 amino acid units covalently
`bound to said variant, wherein each amino acid unit in said
`peptide sequence, Z is selected from the group consisting of
`Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His,
`Met, Om, and amino acid units of the general formula I
`
`(I)
`wherein R 1 and R 2 are selected from the group consisting of
`hydrogen, cl-6-alkyl, phenyl, and phenyl-methyl, wherein
`C 1 - 6-alkyl is optionally substituted with from one to three
`substituents selected from halogen, hydroxy, amino, cyano,
`nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is
`optionally substituted with from one to three substituents
`selected from cl-6-alkyl, c2-6-alkenyl, halogen, hydroxy,
`amino, cyano, nitro, sulfono, and carboxy, or R 1 and R2
`together with the carbon atom to which they are bound form
`a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g., 2,4-di(cid:173)
`aminobutanoic acid and 2,3-diaminopropanoic acid, with the
`proviso that X is not exendin-4 or exendin-3.
`The peptide X is further characterised in being effective in
`improving glucose tolerance in a diabetic mammal.
`Furthermore, the invention is directed to a novel variant of
`a parent exendin, wherein said parent exendin has an amino
`acid sequence having at least an 90% homology to exendin-4
`and wherein said variant lowers the blood glucose level in a
`mammal, binds to a GLP-1 receptor and has at least one
`modification selected from the group consisting of (a)
`between one and five deletions at positions 34-38, and (b)
`contains a Lys at position 40 having a lipophilic substituent
`attached to the epsilon amino group of said lysine.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`OBJECTIVE OF THE INVENTION
`
`There is a need for compounds that lower blood glucose
`levels in mammals, and are stable and effective. Therefore, it
`is an objective of the invention to provide novel compounds
`that lower blood glucose levels in mmals. Ideally, the

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket