IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`1 of 26
`
`CEO and President, Syrrx, Inc.
`
`Steve Kaldor, PhD
`
`DP4 Inhibitor-Syrrx
`
`
`CFAD V. UPENN
`PENN EX. 2046
`
`1 of 26
`
`CEO and President, Syrrx, Inc.
`
`Steve Kaldor, PhD
`
`DP4 Inhibitor-Syrrx
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`2 of 26
`
`Clinical Candidate
`< 2 years
`
`Gene
`
` Clinical trials initiated on first Syrrx compounds (4Q2004)
`
` Additional validating R&D alliances
`
`2004
`
`2003
`
`First three clinical candidates delivered
`World class staff of >70 certified drug hunters
`Structural biology alliances (Celera, Roche, Pharmacia, Sankyo)
`Best-in-Class HTP structural biology engine
`
` DP4 development alliance with PPD
`
`2002
`Syrrx Progression
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`3 of 26
`
`therapeutic areas
`Internal discovery expertise in these
`
`•
`
`•Large unmet medical needs
`
`Internal expertise in kinases & proteases
`expertise
`
`•Most effective way to build knowledge &
`
`•
`
`•Distinctive structural biology capabilities
`•Barrier to entry high for others
`
`at Syrrx
`
`Diabetes, Inflammation
`Therapeutic Areas – Cancer,
`
`kinases & proteases
`Gene Superfamilies –
`
`no structures exist
`Targets for which
`
`•Higher return on R&D investment
`•Lower risk
`Rationale
`
`Clinically Validated Targets
`
`Selection Criteria
`
`Syrrx Portfolio Strategy
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`Jan. 2004
`
` <20 nM
`Syrrx cpds
`Numerous
`
`PD / efficacy
`Best-in-Class
`SYR106584
`
`development
`in preclinical
`Three cpds
`
`4 of 26
`
`Jan. 2003
`
`Mar. 2002
`
`(e.g. c-KIT, AIK,
`Additional Targets
`
`11b-HSD-1)
`
`Multiple
`
`SYR105732
`
`8 nM
`
`START
`HDAC
`
`START
`DP4
`by Structure
`High Speed Drug Discovery Enabled
`
`Efficacious
`6 nM; 100% F
`SYR110085
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`5 of 26
`
` all with above average odds of launch
`Sustainable Pipeline of Candidates,
`
`Kinase #1 CC IND FHD
`HDAC #2 CC
`HDAC #1 CC IND FHD
`
`Cancer
`11b-HSD-1 #2 CC
`11b-HSD-1 #1 CC IND
`DP4 #3 CC (explore clinically for other indications)
`DP4 #2 CC IND FHD TBA
`DP4 #1 CC IND FHD TBA
`
`2005
`
`2004
`
`2003
`
`Diabetes
`
`Pipeline Projections
`Syrrx Near-Term Development
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`6 of 26
`
`•Other DP4 Family Members of Interest: Yes
`
`•Structure Known: First disclosed by Syrrx
`
`•Target Validation: Efficacy Demonstrated in Clinic
`
`•Gene Superfamily: Protease
`
`•Therapeutic Area: Diabetes
`
`A High Priority Syrrx Diabetes Target
`Dipeptidyl Peptidase 4 (DP4):
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`7 of 26
`
`in the clinic by non-oral routes with promising efficacy results
`A number of companies are studying stable GLP-1 analogs
`
`GLP-1:
`GLP-1 is a peptide released from the gut following meals
`Metabolism
`The Role of GLP-1 in Glucose
`
`• Delays gastric emptying
`• Reduces free fatty acids
`• Inhibits glucagon secretion
`• Stimulates insulin biosynthesis
`• Stimulates beta cell growth
`• Beta cells in the pancreas
`• Enhances glucose stimulated insulin release from
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`8 of 26
`
`Modulates the Activity of GLP-1
`DP4: A Serine Protease which
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`9 of 26
`
`GLP-1 levels, reduce glucagon release and maintain normal
`Orally dosed inhibitors of DP4 have been shown to increase
`
` glucose levels following a meal in type II diabetics
`
`Probiodrug/Merck (P32/98)
`
`Novartis (NVP-DPP728)
`
`S
`
`N
`
`e
`OM
`
`H2N
`
`Me
`
`CN
`
`N
`
`O
`
`NH
`
`NC
`
`HN
`
`N
`
`Drug Discovery Target
`Clinical Validation of DP4 as a
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`10 of 26
`
`•Good safety and tolerability profile
`•Slowed gastric emptying; decreased appetite
`
`•Excellent additive response in combination with
`
`Metformin
`
`100mg/day)
`
`•Linear dose response in HbA1c (25 mg/day to
`
`•“LAF-237 monotherapy as effective as Extenatide plus
`•Expected increases in GLP-1 levels
`from Novartis on LAF-237 (Novartis R&D day)
`Phase II Clinical Data Just Released
`
`Metformin”
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`11 of 26
`
`Total elapsed time from gene to structure: 5 months
`
`•2.1A structure determined R = 22%
`
`•154 crystals screened for diffraction
`
`•750 crystals grown
`
`images collected & annotated
`conducted 307,008 crystallization
`•59,328 crystallization experiments
`
`•28 protein samples made for
`Access to Structure
`DP4 Drug Discovery Through Early
`Enabling a Competitive Advantage in
`
`crystallization
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`12 of 26
`
`10/6/03
`
`8/17/03
`
`6/28/03
`
`5/9/03
`
`3/20/03
`
`1/29/03
`
`12/10/02
`
`10/21/02
`
`9/1/02
`
`7/13/02
`
`• Total number of chemotypes: 14 (10 novel; 4 known)
`• Total number of complexes refined and deposited: >70
`
`pharmacophore
`DP4 Composite
`
`10 nM inhibitor
`Proprietary
`First Syrrx
`
`chosen on 10-19-03
`3 clinical candidates
`
`Oral bioavailability
`With 80-100%
`Syrrx inhibitors
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`# of complexes
`
`DP4 Drug Discovery
`High Speed, Structure-enabled
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`nt
`
`Syrrx superior (rat)
`
`stable in HLM
`
`stable in HLM
`
`(t ½ > 1 hr)
`stable in HLM
`(t ½ > 3 hr)
`stable in HLM
`F = 100% (dog)
`stable in HLM;
`F > 60% (rat)
`stable in HLM;
`F=85% (rat)
`stable in HLM;
`
`DMPK
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`superior
`Syrrx
`superior
`Syrrx
`
`200 nM
`
`158 nM
`
`16 nM
`
`25 nM
`
`6 nM
`
`16 nM
`
`10 nM
`
`13 of 26
`
`No
`
`Yes
`
`Yes
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`CoXtal?
`Series
`
`DPP4 IC50
`
`Covalent
`
`?
`
`ClogP: 1.6
`MW < 300
`
`ClogP: -
`MW < 350
`ClogP: 0.6
`MW = 335
`ClogP: 1.8
`MW = 392
`ClogP: 0.8
`MW = 412
`ClogP: 1.6
`MW = 395
`ClogP: 1.7
`MW = 388
`ClogP: 2.5
`MW = 460
`ClogP: 2.6
`MW = 377
`likeness
`Drug-
`
`0.1
`
`SYR105559A
`
`SYR103628A
`
`SYR105913B
`
`SYR105869B
`
`SYR110129A
`
`SYR110011T
`
`SYR110085B
`
`SYR110052B
`
`SYR10612B
`
`Representative
`
`Compound
`
`Competitor
`
`#2
`
`Competitor
`
`#1
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Series
`
`DP4 Inhibitors
`Multiple Series of World Class Syrrx
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`14 of 26
`
`Probable once-a-day oral therapy in humans
`
`CL = 3.7 mL/kg/min; Vdss = 1699
`AUCpo = 14.7 ug*h/mL (3 mpk)
`
`F = 100%
`mL/kg
`
`percent DPP4 inhbition
`
`0%
`10%
`20%
`30%
`40%
`50%
`60%
`70%
`80%
`90%
`100%
`
`24
`
`22
`
`20
`
`18
`
`16
`
`time (hours)
`10
`14
`
`12
`
`IV t 1/2 = 5.3 h
`
`8
`
`6
`
`4
`
`2
`
`0
`
`1
`
`IC90 (dog plasma)
`
`Y
`
` [110085B] (3 mg/kg)
`
` % Inhibition (3 mg/kg)
`
`10
`
`100
`
`1000
`
`10000
`
`(ng/ml)
`log plasma concentration
`
`Inhibition in Beagles for SYR110085A (3 mpk po)
`Plasma Concentrations and DP4
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`15 of 26
`
`on C-peptide)
`(Similar effects
`
`10 mpk
`2 mpk
`vehicle
`
` SYR106124B (10 mpk po)
` SYR106124B (2 mpk po)
` Vehicle
`
`90
`
`60
`
`Minutes
`30
`20
`
`10
`
`0
`
`4.5
`
`4
`
`3.5
`
`LN t
`
`3
`
`2.5
`
`2
`
`0
`
`0.5
`
`1
`
`1.5
`
`2
`
`2.5
`
`3
`
`3.5
`
`150
`
`200
`
`250
`
`300
`
`350
`
`400
`
`450
`
`mg/dl
`BG
`
`Insulin
`
`Efficacy in ZDF Rats Following OGT
`Syrrx Inhibitors Demonstrate Oral
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`16 of 26
`
` - SYR110612
` - SYR110322
` - SYR110085
`•3 Syrrx inhibitors in preclinical development
`
`multiple key parameters (e.g. oral bioavailability)
`
`•Superior to competitor compounds on
`
`•7 Series of potent Syrrx DP4 Inhibitors
`Start of PPD Alliance
`Syrrx DP4 Program: Assets at
`
` - Clean in rodent toxicology; Herg; Ames
` - Orally efficacious in animal models
` - Amenable to once-a-day oral dosing
` - >10,000-fold selective for DP4
` - Proprietary (>8 IP filings)
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`17 of 26
`
`•50/50 profit sharing
`•50/50 cost sharing in Phase III (Syrrx loan for its 50%)
`•Development milestones
` Phase II completion
`•PPD covers majority of development costs through
`•$25M upfront (equity)
`
`•Deal covers entire Syrrx DP4 program for multiple
` Announced Nov. 19, 2003
`PPD – Syrrx DP4 Deal
`
`indications (e.g. diabetes, obesity)
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`18 of 26
`
`Aim is to match Syrrx’s research efficiency (gene to multiple pre-
`
`clinical candidates in <20 months) with a similarly efficient
`
`development timeline
`
`DP4 #3 CC (explore clinically for other indications)
`DP4 #2 CC IND FHD TBA
`DP4 #1 CC IND FHD TBA
`
`2005
`
`2004
`
`2003
`
`•Also examining other indications (e.g. obesity)
`•Multiple “shots on goal” to enhance probability of success
`•Primary short term focus is on Type II diabetes
`Development Program Scope
`PPD – Syrrx DP4 Inhibitor
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`19 of 26
`
`- IMS Therapy Forecast 2002
`
`Market: Rapid Growth for Oral Antidiabetic Drugs
`Sales Forecasts for Global Diabetes
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`20 of 26
`
`-- Datamonitor, Drugs of Tomorrow 2001: Diabetes, p. 269
`
`and also to potentially reverse the progression of type I diabetes.”
`have been shown to treat the underlying cause of type II diabetes
`could make a major impact on the market as a whole since they
`the dipeptidyl peptidase inhibitor which Datamonitor believes
`manner once launched. However, there is one new class of drugs,
`not impact the diabetes market in a particularly impressive
`formulations. For these reasons, many drugs in development will
`needs in the diabetes market, including side effects and delivery
`“Many of the drugs in R&D do not address the current unmet
`
`impact on the diabetes market as a whole
`treatments in their potential to have a major
`DP4 inhibitors are unique among emerging
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`21 of 26
`
`-- Datamonitor, Treatment Algorithms 2001: Diabetes, p. 40
`
`first-line therapies for mild to moderate diabetes
`conjunction with, and to compete with, existing
`DP4 inhibitors are expected to be used in
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`22 of 26
`
`2023
`
`2022
`
`2021
`
`2020
`
`2019
`
`2018
`
`2017
`
`2016
`
`2015
`
`2014
`
`2013
`
`2012
`
`2011
`
`2010
`
`2009
`
`2008
`
`2007
`
`2006
`
`2005
`
`2004
`
`Sulphonylurea
`Biguanide
`Glit, PGR, …
`DPP4 Other
`DPP4 Syrrx
`Other 2nd & 3rd Line
`
`competitors.
`based on average performance vs. 4 non-Syrrx
`treatments after 2015. Syrrx compound’s share
`line treatments, 10% share of 2nd/3rd line
`
`•Illustration shows DPP4’s as 33% share of 1st
`
`US Treatments for Type II Diabetes
`
`2003
`0.0
`
`5.0
`
`10.0
`
`15.0
`
`20.0
`
`25.0
`
`Prescriptions (mm)
`
`share in Type II diabetes treatments by mid next decade
`DP4 inhibitors promise to gain significant
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`23 of 26
`
`PPD and Syrrx are pursuing a “fast follower” approach
`
`and have factored this into our market projections
`
`•>10 companies working on the target
`
`•Several other companies in Ph I / Ph II
`
`>e.g. GSK, BMS
`
`>Targeting Ph III start in mid-2004
`
`•Close second: Merck
`
`>Targeting submission in 2006
`>Ph III start in 1Q2004
`
`•Leader in the field: Novartis
`
`DP4 Competitive Landscape
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`24 of 26
`
`compound sales based on average performance vs. 4 non-Syrrx competitors.
`average price, 75% compliance, and rest-of-world sales at 75% of U.S. sales (compared to 100% today). Syrrx
`•Illustrated DP4 sales are based on 33% share of 1st line treatments, 10% share of 2nd/3rd line treatments, $5/day
`
`200320042005200620072008200920102011201220132014201520162017201820192020202120222023
`
`0
`
`2000
`
`4000
`
`6000
`
`8000
`
`10000
`
`12000
`
`14000
`
`$ millions
`
`Worldwide Sales (DPP4s and Syrrx)
`
` worldwide by the latter part of the next decade*
`The DP4 market may exceed $10 billion
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`25 of 26
`
`•~$890 mm EV (probability-weighted NPV of product value) – accounting for
`•~20% probability of $1 - $7 billion in peak sales ($3.6 billion EV)
`
`full range success and failure uncertainties
`
`•PPD-Syrrx DP4 inhibitors have enormous potential/significant risk
`
`•Translates to 10-90 range of 1-7 non-Syrrx DP4 inhibitors reaching market
`•Clinical candidates being pursued by many different companies
`
`by 2018
`
`•Competition is intense
`
`•Translates to worldwide sales of $10 billion by late next decade
`•33% of 1st line and 10% of 2nd/3rd line treatments treatments by 2018
`•DP4 inhibitors are expected to impact this market significantly
`
`•Combination treatments expected to increase from 16% today to 30%-60%
`•High unmet medical need
`•Prevalence increasing at 1.2%-2.9% annually
`
`over the next two decades
`
`•The therapy market for Type II diabetes is growing rapidly
`DP4 Market Analysis Summary
`
`
`
`IPR2015-01836
`CFAD V. UPENN
`PENN EX. 2046
`
`26 of 26
`
` value of our DP4 inhibitors in non-diabetes indications
`•Our market estimates do not account for the potential
`
`>Door open for collaborations on additional targets
`>Opportunity to enjoy unique R&D efficiencies
`
` PPD’s proven Development engine is intriguing
`•The coupling of Syrrx’s efficient Research engine with
`
` to manage risk and maximize market opportunities
` alliance and are developing multiple Syrrx DP4 inhibitors
`•Syrrx and PPD have entered into a broad strategic DP4
`
`Concluding Thoughts
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