throbber
Mylan Pharmaceuticals Inc.,
`Wockhardt Bio AG, Teva Pharmaceuticals USA, Inc.,
`Aurobindo Pharma U.S.A. Inc., and Sun Pharmaceutical
`Industries, Ltd., Sun Pharma Global FZE and
`Amneal Pharmaceuticals LLC,
`Petitioners
`v.
`AstraZeneca AB,
`Patent Owner
`
`IPR2015-01340
`US RE44,186 E
`
`January 25, 2017
`
`

`

`Otsuka v. Sandoz, 678 F.3d 1280, 1292 (Fed. Cir. 2012)
`
`“In determining whether a chemist would
`have selected a prior art compound as a
`lead, the analysis is guided by evidence of
`the compound’s pertinent properties.”
`
`Source: Institution Dec. at 9.
`
`2
`
`

`

`Daiichi Sankyo v. Matrix Labs., 616 F.3d 1346, 1354 (Fed. Cir. 2010)
`
`in
`“[T]he lead compound analysis must,
`keeping with KSR, not rigidly focus on the
`selection of a single, best lead compound . . .”
`
`Source: Institution Dec. at 10.
`
`3
`
`

`

`Ashworth 25 is a Pertinent Lead Compound
`
`P2 
`Substituent
`
`P1 
`Substituent
`
`Ashworth 25
`
` Potency:
`Ki < 2 nM
` Solution Stability: t1/2 > 48 hours
`
`Source: EX1007 (Ashworth I) at 1166.
`
`4
`
`

`

`Ashworth 25 Has Good Potency and Stability
`
`Source: EX1007 (Ashworth I) at 1165‐66.
`
`5
`
`

`

`Measuring Potency by Ki and IC50 Values
`
`Smaller Ki and IC50 values 
`represent greater potency
`
`the “concentration of
`is
`IC50
`inhibitor producing 50 per cent
`inhibition[.]”
`
`Ki is the “dissociation constant of the enzyme‐
`inhibitor complex, or the reciprocal of the
`binding affinity of
`the inhibitor
`to the
`enzyme[.]”
`
`Source: EX1025 (Cheng) at 3099; EX1003 (Rotella Decl.), ¶64.
`
`6
`
`

`

`Ashworth I Table II Compounds
`
`Source: EX1007 (Ashworth I) at 1166.
`
`7
`
`

`

`Cyanopyrrolidines Were of Interest
`
`NVP‐DPP728, containing a 
`cyanopyrrolidine, entered clinical 
`trials in humans.
`
`NVP‐DPP728
`“By the time of the invention,
`Novartis had selected NVP‐DPP728
`as a clinical candidate, and it was
`reported to be safe and effective
`in initial studies in humans.”
`Source: PO Resp. at 12, 14; EX2012 (Rothenberg) at A39; EX1074 (Second Rotella Decl.), ¶15.
`
`8
`
`

`

`Ashworth 25 More Potent than Other Clinical Candidates
`
`NVP‐DPP728
`
`Ki = 11 nM 
`
`P32/98
`
`IC50 = 2800 nM 
`
`Ashworth 25
`
`Ki = 1.4 nM 
`
`Dr. Weber concedes that “compound 25 of Ashworth‐I 
`[is] more potent than the clinical candidates NVP‐
`DPP728 and P32/98[.]”
`
`Source: EX1074 (Second Rotella Decl.), ¶11; EX2016 (Hughes) at 11600; 
`EX1007 (Ashworth I) at Table 2, 1166; EX2078 (Schon) at 308; EX2056 (Weber Decl.), ¶172 .
`
`9
`
`

`

`Superior Stability of Ashworth 25
`
`Ashworth II compound 3
`
`Ashworth I compound 25
`
`t1/2 = 27 h 
`
`t1/2 = >48 h 
`
`Ashworth 25 has greater in vitro stability (longer half‐
`life, t1/2) than compound  3 from Ashworth II.
`
`Source: EX1074 (Second Rotella Decl.), ¶14; EX2001 (Ashworth II) at 2748.
`
`10
`
`

`

`Summary of Structural Differences
`
`Ashworth 25
`
`Cyclopropanation of the 
`pyrrolidine ring
`o EX1007: Ashworth I
`o EX1010: Hanessian
`
`c
`Replace cyclohexyl ring with 
`hydroxyadamantyl
`o EX1007: Ashworth I
`o EX1008: Villhauer WO 98
`o EX1009: Raag
`
`Saxagliptin
`
`11
`
`

`

`Petitioner’s Motivation to Modify P1
`
`Cyclopropanation
`o flattens and rigidifies 
`pyrrolidine ring
`o modulates cyano position
`Optimizes interaction with 
`DPP‐4 enzyme to improve 
`activity and stability
`
`P1 
`Substituent
`
`Source: Pet. at 29; EX1003 (First Rotella Decl.), ¶134; EX1010 (Hanessian).
`
`12
`
`

`

`Cyclopropanation Modulates Proline Conformation
`
`“The structures and conformations of 6 and 8 in the
`solid state were unambiguously confirmed by single‐
`crystal X‐ray analysis. Table 1 lists selected torsion
`angles for compounds 6 and 8, where considerable
`‘flattening’ of the pyrrolidine ring is observed relative
`to N‐Boc‐L‐proline[.]”
`
`CO2H
`
`N
`Boc
`N-Boc-
`L-proline
`
`CO2H
`
`N
`Boc
`6
`
`CO2H
`
`N
`Boc
`8
`
`Source: EX1010 (Hanessian ‘97) at 1882; EX1003 (Rotella Decl.), ¶135.
`
`13
`
`

`

`Cyclopropanation Confers Conformational Rigidity
`
`Source: EX2174 (Rotella Depo. Trans.), 119:10‐21.
`
`14
`
`

`

`Increase in Cyanopyrrolidine Stability Was Predictable
`
`Source: EX2174 (Rotella Depo. Trans.), 139:22‐140:3; EX2002 (Magnin) at 2591.
`
`15
`
`

`

`Patent Owner Cites Augustyns 1997
`
`“[T]he inhibitory capacity increases from
`azetidine 8b (270 μM) and pyrroline 9b (100
`μM) to the optimal five‐rings pyrrolidine 3
`(21 μM) and thiazolidine 4 (18 μM), and
`decreases
`when
`larger
`rings
`like
`tetrahydropyridine 10b (310 μM), piperidine
`6b (510 μM) or hexamethyleneimine 7b
`(2700 μM) are at the P1 position.”
`
`Patent Owner: “Increasing the 
`pyrrolidine ring size to a 6‐ or 
`7‐membered ring . . . was not 
`well tolerated.”
`
`Source: Patent Owner Resp. at 10; EX2151 (Augustyns 1997) at 303.
`
`16
`
`

`

`Small Changes to P1 Ring Size Were Tolerated
`
`Ashworth II compound 5 
`
`Ashworth II compound 3 
`
`Ki = 2.2 nM
`
`Ki = 0.41 nM
`
`Source: EX2001 (Ashworth II) at 2747; EX1074 (Second Rotella Decl.), ¶40.
`
`17
`
`

`

`Cyclopropanation Has Minimal Effect on Ring Size
`
`“[T]hese compounds have a cyclopropane ring in place
`of the choline moiety and are considered to be the
`smallest chemical structure among Ach derivatives
`capable of conferring conformational rigidity.”
`
`Source: EX1021 (Chiou) at 243; EX1003 (Rotella Decl.), ¶135; Pet. at 22.
`
`18
`
`

`

`Cyclopropanation Fits with 5‐Membered Ring Preference
`
`A POSA “would understand that cyclopropanation 
`preserves the saturated five‐membered ring, while also 
`providing controlled modifications to the pyrrolidine 
`conformation, as taught by Hanessian.”
`
`“Therefore, we believe that the S‐1
`subsite of DPP IV ideally fits a five‐
`membered saturated ring.”
`
`Source: EX2151 (Augustyns) at 303; EX1074 (Second Rotella Decl.), ¶40.
`
`19
`
`

`

`Methods For Cyclopropanating Pyrrolidine were Known
`
`Hanessian teaches 
`synthesis of cis‐4,5 and 
`trans‐4,5 cyclopropyl 
`cyanopyrrolidine.
`Source: EX1010 (Hanessian ‘97) at 1882; EX1074 (Second Rotella Decl.), ¶38.
`
`4
`
`5
`
`20
`
`

`

`Limited Number of Positions to Cyclopropanate Pyrrolidine
`
`Only 5 possible ways to 
`cyclopropanate pyrrolidine ring 
`(including cis and trans isomers).
`
`Source: EX1010 (Hanessian ‘97) at 1882; EX1003 (Rotella Decl.), ¶¶139‐40.
`
`21
`
`

`

`Magnin Confirms Ease of Evaluating Each Option
`
`Magnin confirms the straightforward task of screening 
`cyclopropanation derivatives at each of the available 
`cyanopyrrolidine positions.
`Source: EX2002 (Magnin) at 2588; EX1074 (Second Rotella Decl.), ¶50.
`
`22
`
`

`

`Motivation to Modify P2
`
`Sterically bulky P2 substituents
`o improve stability
`o improve potency
`o favor trans confirmation 
`and reduce cyclization
`
`P2 
`Substituent
`
`Cyclization
`
`Source: Pet. at 7, 24; EX1003 (Rotella Decl.), ¶¶ 114‐15; EX1007 at 1165‐66.
`
`23
`
`

`

`Intramolecular Cyclization Favored in Cis‐Conformation
`
`Intramolecular cyclization is minimized by favoring trans‐
`conformation, instead of cis‐conformation.
`
`Source: EX1003 (Rotella Decl.), ¶¶46‐47; EX1015 (Lin) at 14022; Pet. at 7.
`
`24
`
`

`

`Bulky P2 Groups Improve Stability
`
`Source: EX1007 (Ashworth I) at 1165‐66; EX1074 (Second Rotella Decl.), ¶19.
`
`25
`
`

`

`Steric Bulk Localized at the Beta Position
`
`Beta 
`position
`
`Beta 
`position
`
`Ashworth I Compound 25
`t1/2= >48 h
`Ki = 1.4  ± 0.5 nm
`
`Ashworth I Compound 27
`t1/2= >48 h
`Ki = 3.8  ± 0.8 nm
`
`Source: EX1007 (Ashworth I) at Table 2; EX1074 (Second Rotella Decl.), ¶24.
`
`26
`
`

`

`Steric Bulk Localized at the Beta Position
`
`Beta 
`position
`
`Beta 
`position
`
`Ashworth I Compound 25
`t1/2= >48 h
`Ki = 1.4  ± 0.5 nm
`
`Ashworth I Compound 24
`t1/2= 48 h
`Ki = 1.1  ± 0.2 nm
`
`Source: EX1007 (Ashworth I) at Table 2; EX1074 (Second Rotella Decl.), ¶24.
`
`27
`
`

`

`More Atoms Alone ≠ Steric Bulk
`
`Lys(Z) group is longer with 
`more atoms.
`
`Lys(Z) is less sterically bulky 
`compared to a cyclohexyl 
`group, with a smaller 
`footprint at the β‐position.
`
`Lys(Z) has decreased 
`stability compared to a 
`cyclohexyl substituent.
`
`Lys(Z)/
`Lys(Cbz)
`
`Beta 
`position
`
`Ashworth I Compound 28
`t1/2= 24 h
`
`Source: EX1007 (Ashworth I) at Table 2; EX1074 (Second Rotella Decl.), ¶24; EX2261 (PO Demonstrative).
`
`28
`
`

`

`Use of Adamantyl at P2 was Known in DPP‐4 Inhibitors
`
`Source: EX1008 (Villhauer WO ’98) at 13; EX1074 (Second Rotella Decl.), ¶20.
`
`29
`
`

`

`Hydroxyadamantyl Was Known From Villhauer 2000
`
`Source: EX1073 (Weber Depo. Trans.), 63:2‐8; EX1074 (Second 
`Rotella Decl.), ¶33; EX2013 (Villhauer 2000), 7:15‐27 .
`
`30
`
`

`

`Hydroxyadamantyl at P2 was Known in DPP‐4 Inhibitors
`
`Vildagliptin
`
`Source: EX2013 (Villhauer 2000), 7:15‐27; Pet. Reply at 14.
`
`31
`
`

`

`Patent Owner Cites Mentlein 1993
`
`“Preferential amino acids for the
`P’1 position are not known.”
`
`Source: EX2056 (Weber Decl.), ¶91; EX2096 (Mentlein) at 833.
`
`32
`
`

`

`Mentlein: Bulky Groups are Preferred at P2
`
`“In the P2 position bulky amino acids with
`an obligate free amino group are preferred.”
`
`Source: EX2096 (Mentlein) at 833; EX1074 (Second Rotella Decl.), ¶19.
`
`33
`
`

`

`Hydroxyadamantyl is a Bulky Group
`
`Source: Pet. Reply at 13; EX1073 (Weber Depo. Trans.), 60:11‐19.
`
`34
`
`

`

`Metabolites Guide Modification of Drug Candidates
`
`“Metabolite identification in drug discovery provides
`early information that can lead to structural changes
`in the current
`lead compound,
`improving such
`pharmacokinetic parameters as oral bioavailability,
`half‐life (t1/2), or Cmax.”
`
`Source: EX1020 (Korfmacher) at 534; EX1003 (Rotella Decl.), ¶53.
`
`35
`
`

`

`Metabolites Guide Modification of Drug Candidates
`
`provide
`can
`identification
`“Early metabolite
`information on how to improve the metabolic stability
`of
`the lead structure.
`In this way,
`future lead
`compounds might be a metabolite identified from the
`previous lead drug or an analogue of the previous
`drug designed to block
`the major
`route of
`metabolism.”
`
`Source: EX1020 (Korfmacher) at 534; EX1003 (Rotella Decl.), ¶53.
`
`36
`
`

`

`Adamantane is Metabolized at Tertiary Carbons
`
`substrate we have
`the only
`“Adamantane is
`investigated, in this study, that is metabolized to a
`single product despite having a relatively high active
`site mobility. The single product can be attributed to
`the existence of only two types of unique carbon
`atoms in adamantane, together with the greater
`reactivity of tertiary versus secondary carbons.”
`
`Source: EX1009 (Raag) at 2678; EX1003 (Rotella Decl.), ¶¶ 80, 126.
`
`37
`
`

`

`Hydroxylated  Adamantane Can Impede Metabolism
`
`“Blocking metabolism at the 3‐position would result in greater 
`metabolic stability.”
`
`Source: EX1003 (Rotella Decl.), ¶¶ 53, 127; EX1020 (Korfmacher) at 534.
`
`38
`
`

`

`Hydroxyadamantyl at P2 was Known in DPP‐4 Inhibitors
`
`Tertiary
`carbon
`
`Vildagliptin
`
`Source: EX2013 (Villhauer 2000), 7:15‐27; Pet. Reply at 14.
`
`39
`
`

`

`Saxagliptin is also Metabolized at a 3˚ Carbon
`
`3˚
`
`3˚
`
`3˚
`
`Saxagliptin 
`
`Saxagliptin Metabolite M2
`
`M2 metabolite predictably results from a second oxidation at one 
`of only two remaining tertiary adamantyl carbons.
`
`Source: EX2045 (Su) at 1346; EX1074 (Second Rotella Decl.), ¶32.
`
`40
`
`

`

`Summary of Structural Modifications
`
`Cyclopropanate the pyrrolidine 
`ring
`o Smallest possible fusion confers 
`conformational rigidity and modulate 
`position of cyano group
`Source: EX1007 (Ashworth I) at 1163
`EX1010 (Hanessian) at 1882 
`Replace cyclohexyl ring with 
`hydroxyadamantyl
`c
`o Sterically bulky substituent favors trans
`conformation to maintain or improve 
`stability and prevent intramolecular 
`cyclization; potential to improve potency
`Source: EX1007 (Ashworth I) at 1163
`EX1008 (Villhauer) at 13
`o Routine evaluation of metabolites
`Source: EX1009 (Raag)
`
`Ashworth 25
`
`Saxagliptin
`
`41
`
`

`

`Secondary Considerations Don’t Overcome Prima Facie Case
`
`Did not meet a long‐felt need
`
`No commercial success
`
`No evidence of failure of others
`
`No unexpected results
`
`42
`
`

`

`Metformin is Still the Most Preferred Anti‐Diabetic Drug
`
`“Metformin has the strongest
`evidence base and demon‐
`strated long‐term safety as
`pharmacological
`therapy for
`diabetes prevention.”
`
`“In my opinion, there is no drug 
`(including saxagliptin) that stands 
`out above the others as the 
`c
`second best choice alternative to 
`metformin.”
`
`Source: EX2065 (American Diabetes) at 44; EX1041 (Tanenberg Decl.), ¶¶20‐21; Pet. Reply at 4.
`
`43
`
`

`

`Metformin is Essential Medicine for Type 2 Diabetes
`
`The World Health Organization DOES NOT 
`list saxagliptin as an essential medicine in 
`the treatment of Type 2 Diabetes.
`
`Source: EX1043 (WHO) at 34; EX1041 (Tanenberg Decl.), ¶¶19, 21.
`
`44
`
`

`

`Metformin is Still the Most Preferred Anti‐Diabetic Drug
`
`“What we were expecting
`was
`that
`by
`the
`time
`omarigliptin was ready to be
`approved
`that
`DPP‐4
`inhibitors would be used as
`first class therapy in the U.S.
`That,
`however,
`has
`not
`happened and Metformin
`continues to be used as first
`line therapy in the U.S.”
`
`Source: EX1073 (Weber Depo. Trans.), 105:15‐20; 
`EX1041 (Tanenberg Decl.), ¶¶20‐21; Pet. Reply at 23.
`
`45
`
`

`

`Vildagliptin was Invented Before Saxagliptin
`
`Vildagliptin
`
`Source: EX2013 (Villhauer 2000), 7:15‐27; Pet. Reply at 14.
`
`46
`
`

`

`Vildagliptin Received Regulatory Approval Before Saxagliptin
`
`“Galvus (vildagliptin) , an oral
`DPP‐4 inhibitor, and Eucreas, a
`single‐pill
`combination
`of
`vildagliptin and metformin, are
`indicated for the treatment of
`type 2 diabetes. The products
`were first approved in 2008.
`Galvus is currently approved in
`more than 100 countries[.]”
`
`Source: EX1048 (2012 Novartis Annual Report) at 0039; Pet. Reply at 23.
`
`47
`
`

`

`Sitagliptin was FDA‐Approved Before Saxagliptin
`
`Source: EX1073 (Weber Depo. Trans.), 25:15‐22; EX1028 (Lenhard Depo. Trans.), 397:23‐25.
`
`48
`
`

`

`Sitagliptin is the Highest Selling Gliptin
`
`Source: EX1073 (Weber Depo. Trans.), 27:3‐10.
`
`49
`
`

`

`Saxagliptin Under‐Performs Sitagliptin (Januvia®)
`
`Kombiglyze® XR
`Onglyza®
`
`Saxagliptin products failed to capture a substantial 
`share of the U.S. DPP‐4 inhibitor market.
`
`Source: EX1060B (McDuff Decl.), ¶20; EX1062B (McDuff Attachments) at B‐3; EX1035, 
`¶36; EX2117 (IMS Health Audit); EX1029 (Meyer Depo. Trans.), 422:4‐13.
`
`50
`
`

`

`Large and Increasing Rebates for Saxagliptin
`
`Onglyza® 
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`Net Sales Adjustments 
`as a % of Gross Sales
`
`11%
`
`32%
`
`33%
`
`37%
`
`35%
`
`54%
`
`66%
`
`Kombiglyze® XR
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`Net Sales Adjustments as 
`a % of Gross Sales
`
`26%
`
`33%
`
`37%
`
`38%
`
`53%
`
`57%
`
`Net sales adjustments are a large percentage of gross 
`sales and have increased continuously and significantly 
`from launch through 2015.
`
`Source: EX1060B (McDuff Decl.), ¶41; EX1062B (McDuff Attachments) at B‐8a; EX1035, ¶63.
`
`51
`
`

`

`Large Marketing Expenditure on Saxagliptin
`
`$571 million in promotional expenditures on Onglyza and 
`Kombiglyze XR in the U.S. from 2009 to 2015, which is 
`23.0% of total U.S. sales over the same time period.
`
`Source: EX1060B (McDuff Decl.), ¶25; EX1062B (McDuff Attachments) at B‐4.
`
`52
`
`

`

`Saxagliptin Also Underperforms Vildagliptin (Galvus)
`
`Sitagliptin
`
`Vildagliptin
`
`Saxagliptin
`
`Worldwide sales of vildagliptin beat 
`worldwide sales of saxagliptin.
`
`Source: EX1060B (McDuff Decl.), ¶18; EX1062B (McDuff Attachments) at B‐1b.
`
`53
`
`

`

`Saxagliptin Also Underperforms Vildagliptin (Galvus)
`
`Vildagliptin (non-US)
`
`Saxagliptin (total sales)
`
`Saxagliptin (non-US)
`
`Even without U.S. sales, worldwide sales of 
`vildagliptin beat worldwide sales of saxagliptin.
`
`Source: EX1060B (McDuff Decl.), ¶18; EX1062B (McDuff Attachments) at B‐1c.
`
`54
`
`

`

`They Call Vildagliptin a “Failure”
`
`Source: EX1073 (Weber Depo. Trans.), 23:8‐16, 28:7‐10; EX2057 (Lenhard Decl.), ¶76.
`
`55
`
`

`

`Best‐in‐class Glyptin “a Failure”
`
`Dr. Weber’s own “best in class of the 
`gliptins” omarigliptin qualifies as
`an FDA‐approval  “failure.”
`
`Source: EX1073 (Weber Depo. Trans.), 99:9‐100:20.
`
`56
`
`

`

`FDA‐Approved DPP‐4 Inhibitors are Interchangeable
`
`Source: EX1028 (Lenhard Depo. Trans.), 402:2‐14; EX1041 (Tanenberg Decl.), ¶¶24‐25; Pet. Reply at 21. 57
`
`

`

`FDA‐Approved DPP‐4 Inhibitors are Interchangeable
`
`Source: EX1028 (Lenhard Depo. Trans.), 398:12‐19, 399:4‐7; EX1041 (Tanenberg Decl.) , ¶¶ 25‐29.
`
`58
`
`

`

`FDA Requires Safety Warning on Saxagliptin Product Label
`
`“Saxagliptin and alogliptin may increase the
`risk of heart failure, particularly in patients
`who already have heart or kidney disease. . . .
`As a result, we are adding new warnings to
`the drug labels about this safety issue.”
`
`Sitagliptin does not have 
`a heart failure warning.
`
`Source: EX1032 (FDA Drug Safety Communication); 
`EX1041 (Tanenberg Decl.), ¶26; EX1060 (McDuff Decl.), ¶35.
`
`59
`
`

`

`Vildagliptin Also Has a Once‐Daily Combination Form
`
`“When used in dual 
`combination with a 
`sulphonylurea, the 
`recommended dose of 
`vildagliptin is 50 mg once 
`daily administered in the 
`morning.”
`
`Source: EX2080 (Galvus Summary of Product Characteristics) at 3; Pet. Reply at 22.
`
`60
`
`

`

`Additional Slides
`
`Additional Slides
`
`61
`
`

`

`Patent Owner’s Cyanopyrrolidine Arguments
`
`“But there were additional reasons to dismiss 
`Compound 25 as a lead. For instance, the cyano group 
`introduced the concern of toxic cyanide release in vivo 
`(Ex. 2056, ¶162), leading Merck to dismiss 
`cyanopyrrolidine compounds[.]”
`
`Source: Patent Owner Resp. at 15, 23‐25.
`
`62
`
`

`

`Cyanopyrrolidines Do Not Release HCN
`
`Source: EX1073 (Weber Cross‐Examination), 52:1‐8.
`
`63
`
`

`

`Cyanopyrrolidines Do Not Release HCN
`
`Source: EX1073 (Weber Depo. Trans.), 52:9‐15.
`
`64
`
`

`

`Ashworth I Table I Explores Optimal N‐Terminal Residues
`
`“To establish an optimal N‐terminal
`residue, we prepared a series of
`amino acid pyrrolidides[.]”
`
`Source: EX1007 (Ashworth I) at 1165.
`
`65
`
`

`

`Bulky Cylcohexyl at P2 Was Most Potent
`
`“In particular, β‐branched α‐amino
`acid derivatives were the most potent
`compounds
`with
`the
`non‐
`proteinogenic
`amino
`acid,
`(S)‐
`cyclohexylglycine providing the most
`active
`pyrrolidide
`(compound
`5
`possessing a Ki value of 64 nM). We
`then applied these findings to a series
`of 2‐cyanopyrrolidides.”
`
`Source: EX1007 (Ashworth I) at 1165.
`
`66
`
`

`

`Ashworth I Table I SAR Applied to Table II
`
`“The series of dipeptide nitriles
`described in Table ll were prepared
`….We were gratified to find that these
`compounds were potent inhibitors of
`DP‐IV. The S.A.R. for the N‐terminal
`residue developed in the pyrrolidide
`series
`correlated well
`for
`the
`dipeptide nitrile series and the most
`potent compounds 24, 25, 26 and 27
`possessed activity comparable to the
`boroprolines, 1 and 2.”
`
`Source: EX1007 (Ashworth I) at 1165.
`
`67
`
`

`

`Ashworth I Finds Excellent Stability Greater Than 48 Hours
`
`“Stability studies revealed excellent
`half‐lives (t1/2)
`in aqueous solution
`(pH 7.4) at room temperature (Table
`II) with several examples having (t1/2)
`greater than 48h.”
`
`Source: EX1007 (Ashworth I) at 1165.
`
`68
`
`

`

`Ashworth Promises Further Investigation at P1
`
`“Further work on optimization of the
`pyrrolidine ring will be reported shortly.”
`
`Source: EX1007 (Ashworth I) at 1165.
`
`69
`
`

`

`Ashworth II Supports Selection of Compound 25
`
`“We recently reported a series of
`aminoacyl‐2‐cyanopyrrolidides6'7
`which possess Ki values of less than 5
`nM versus human DP‐IV and half‐lives
`(t1/2) of greater than 48h in aqueous
`solution (pH 7.4).”
`
`Source: EX2001 (Ashworth II) at 2745.
`
`70
`
`

`

`Ashworth II Seeks Even Greater Potency
`
`“In a quest to improve the potency 
`of this class of inhibitors, we 
`investigated replacing the 
`pyrrolidide ring with other nitrogen 
`heterocycles.” 
`
`Source: EX2001 (Ashworth II) at 2746.
`
`71
`
`

`

`Ashworth II Supports Selection of Compound 25
`
`“From a range of compounds with
`various heteroatoms
`in 5‐ or 6‐
`membered rings, we were pleased to
`find that
`the 4‐cyanothiazolidide
`analogue 3 was approximately 5‐fold
`more
`active
`than
`the
`2‐
`cyanopyrrolidide inhibitor 57 (Table
`I). However, this increase in activity
`was accompanied by a slight decrease
`in stability.”
`
`Source: EX2001 (Ashworth II) at 2746.
`
`72
`
`

`

`Many Structures Successfully Inhibit DPP‐4
`
`Source: EX2246 (AstraZeneca Demonstrative Exhibit).
`
`73
`
`

`

`In Vivo Toxicity Testing Not Required
`
`Source: EX2174 (Rotella Depo. Trans.), 56:3‐9; Institution Dec. at 11.
`
`74
`
`

`

`Double Bonds Affect Pyrrolidine Conformation Differently
`
`Source: EX2174 (Rotella Depo. Trans.), 124:23‐125:10.
`
`75
`
`

`

`Dr. Rotella’s Prior Art Search
`
`“Q. What I'm trying to get at is how
`you came to know of the existence of
`the materials that you principally rely
`upon in your report.”
`
`“THE WITNESS: I was asked by 
`counsel to provide…opinions on 
`obviousness related to the 
`discovery[,] synthesis[,]  
`identification[,] and discovery of 
`saxagliptin. And I carried out a 
`literature search for documents that 
`might be rel[evant]…. In some cases, I 
`could ‐‐ I could get those references 
`easily; in other cases, I could not.”
`
`Source: EX2174 (Rotella Depo.), 22:15‐26:4.
`
`76
`
`

`

`Dr. Rotella’s Prior Art Search
`
`“[C]an you identify the publications of which
`you had preexisting knowledge prior to the
`commencement of the formulation of your
`opinions?
`A. Ashworth[I]…, Cheng,… Chiou,… Hanessian,
`Korfmacher,… the Villhauer patent….”
`
`“Q. Were there other materials you were
`provided when you began working on this
`program at BMS beyond those two, if you
`recall?
`A. Well, I'm reasonably certain that all of the
`ones I identified were part of the literature
`that we were provided with as a part of
`working on that program…. I apologize. The
`Chiou paper and the Cheng and Prusoff
`paper,
`I was aware of
`from my days in
`graduate school.”
`
`Source: EX2174 (Rotella Depo.), 23:25‐24:22, 25:20‐26:6 .
`
`77
`
`

`

`Dr. Rotella’s Prior Art Search
`
`“Q. No, no, no. At the time that was the subject
`of your report, before the invention of saxagliptin
`was made.
`A. Okay. So to be clear, you're talking about the
`late 1990s? Because my report was written in
`2016, and so I want to make certain that we have
`our date references because ‐‐ the reason I say
`that is because drug discovery has evolved in the
`period of time.
`Q. Well, which period of
`referencing in your report?
`A. I was using the priority dates as provided to me
`by counsel.”
`
`time were you
`
`Source: EX2174 (Rotella Depo.), 58:2‐22.
`
`78
`
`

`

`Dr. Rotella
`
`“Q. And over under the heading
`Conclusion, in the second sentence
`you stated that,
`‘this
`template
`confers substantial
`improvement in
`PDE
`selectivity
`and
`potency
`compared to sildenafil.’ Those were
`your words there, right?
`
`A. Those are – those are my words.
`The substantial
`improvement refers
`primarily, of course, to selectivity.”
`
`Source: EX2221 (Rotella Depo. Transcript), 37:6‐13.
`
`79
`
`

`

`CERTIFICATE OF SERVICE
`
`On 23 January 2017, Mylan served a copy of its demonstrative exhibits on
`
`counsel for Patent Owner AstraZeneca AB at the following electronic service
`
`addresses:
`
`Charles E. Lipsey
`
`charles.lipsey@finnegan.com
`
`Eric E. Grondahl
`
`egrondahl@mccarter.com
`
`John D. Livingstone
`
`john.livingstone@finnegan.com
`
`Anthony A. Hartmann
`
`anthony.hartmann@finnegan.com
`
`M. David Weingarten
`
`david.weingarten@finnegan.com
`
`Nicole A. Conlon
`
`nicole.conlon@finnegan.com
`
`Daniel M. Silver
`
`dsilver@mccarter.com
`
`Kassandra M. Officer
`
`kassandra.officer@finnegan.com
`
`on Wockhardt at the following service electronic addresses:
`
`Frederick R. Ball
`
`FRBall@duanemorris.com
`
`Patrick C. Gallagher
`
`PCGallagher@duanemorris.com
`
`on Teva at the following service electronic addresses:
`
`Iain A. McIntyre
`
`IMcIntyre@carlsoncaspers.com
`
`Gary J. Speier
`
`GSpeier@carlsoncaspers.com
`
`
`
`-1-
`
`

`

`on Aurobindo at the following service electronic addresses:
`
`Sailesh K. Patel
`
`SPatel@schiffhardin.com
`
`Joel Wallace
`
`George Yu
`
`JWallace@schiffhardin.com
`
`GYu@schiffhardin.com
`
`
`and on Sun/Amneal at the following service electronic addresses:
`
`Samuel S. Park
`
`spark@winston.com
`
`Andrew R. Sommer
`
`asommer@winston.com
`
`Respectfully submitted,
`
`
`
`
`By: /Richard Torczon /
`
`Richard Torczon, Backup Counsel
`
`Reg. No. 34,448
`
`
`
`
`
`
`
`Dated: 23 January 2017
`
`
`
`
`
`-2-
`
`

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