`
`UNITED STATES PATENT AND TRADEMARK OFFICE
` UNTTED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
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`
`
`
`
`
`APPLICATION
`NUMBER
`
`61/383,156
`
`
`
`FILING or
`371(c) DATE
`
`09/15/2010
`
`
`
`GRP ART
`UNIT
`
`
`
`30623
`MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C
`ONE FINANCIAL CENTER
`BOSTON, MA 02111
`
`
`
`FIL FEE REC'D
`
`220
`
`
`
`ATTY.DOCKET.NO
`
`40737-509P01US
`
`
`
`
`TOT CLAIMSQIND CLAIMS
`
`
`
`CONFIRMATION NO. 3664
`FILING RECEIPT
`LLL
`
`000000043 75256
`
`Date Mailed: 10/04/2010
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
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`
`Applicant(s)
`
`Kunwar Shailubhai, Audubon, PA;
`
`Power of Attorney:
`Cynthia Kozakiewicz--42764
`
`If Required, Foreign Filing License Granted: 09/28/2010
`
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/383,156
`
`Projected Publication Date: None, application is not eligible for pre-grant publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`Title
`
`Formulations Of Guanylate Cyclase C Agonists And Methods Of Use Thereof
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in
`a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`page 1 of 3
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`
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`0001
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`MYLAN - EXHIBIT 1025
`
`

`

`patent” and does not eliminate the need of applicants to file additional documents and fees in countries where patent
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`
`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
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`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`
`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof unless
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`0002
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`

`

`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
`Treasury (31 CFR Parts 500+) and the Department of Energy.
`
`NOT GRANTED
`
`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
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`
`page 3 of 3
`
`0003
`
`

`

`Application Data Sheet
`
`
`
`Application Information:
`
`Application Type::
`
`Provisional
`
`Subject Matter::
`
`Suggested Group Art Unit:
`
`CD-ROM or CD-R?::
`
`Sequence submission?::
`
`Utility
`
`N/A
`
`None
`
`None
`
`Computer Readable Form (CRF)?::
`
`No
`
`Title::
`
`Formulations Of Guanylate Cyclase C Agonists
`
`And Methods Of Use Thereof
`
`Attorney Docket Number:
`
`40737-509P01US
`
`Request for Early Publication?::
`
`Request for Non-Publication?::
`
`Small Entity?::
`
`Petition included?::
`
`Secrecy Order in Parent Appl.?::
`
`No
`
`No
`
`No
`
`No
`
`No
`
`Applicant Information:
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country:
`
`us
`
`Status:
`
`Given Name:
`
`Family Name::
`
`Full Capacity
`
`Kunwar
`
`Shailubhai
`
`Page # 1
`
`Initial 09/15/10
`
`0004
`
`

`

`City of Residence:
`
`Audubon
`
`State or Province of Residence:
`
`Country of Residence:
`
`PA
`
`us
`
`Street of mailing address:
`
`2707 Bald Eagle Circle
`
`City of mailing address::
`
`Audubon
`
`State or Province of mailing address:
`
`PA
`
`Postal or Zip Code of mailing address:
`
`19403
`
`Correspondence Information:
`
`Correspondence Customer Number:
`
`30623
`
`Representative Information:
`
`Representative Customer Number:
`
`30623
`
`Domestic Priority Information:
`
`Foreign Priority Information:
`
`Page # 2
`
`Initial 09/15/10
`
`0005
`
`

`

`Assignee Information:
`
`Synergy Pharmaceuticals, Inc.
`420 Lexington Avenue, Suite 609
`New York, NY 10170
`
`Signature:
`
`/Cynthia Kozakiewicz/
`
`Date: September 15, 2010
`
`First: Cynthia
`
`Last: Kozakiewicz
`
`Reg. No.: 42,764
`
`5024977v.1
`
`Page # 3
`
`Initial 09/15/10
`
`0006
`
`

`

`
` Kunwer Shailub
`
`Chief Scientifi 0 :
`
`
`
`0007
`
`

`

`Background
`
`La]
`
`
`& ical development
`
`Pr
`
`ell veal ele A \
`
`NE DI)
`
`Preclinical development of SP-333
`
`
`
`ad
`
`NJ
`
`J J
`
`
`
`
`
`
`
`0008
`
`

`

`
`
`000
`
`
`
`0009
`
`

`

`
`
`A
`
`|
`
`
`
`k. Coli 5ST
`
`Guanylin
`
`
`
`
`
`
`
`
`NS WU UN
`I
`Sed AQONISS
`Ho
`3
`§
`
`i}
`
`Extraceliular
`Soman
`
`Juslamembrane
`Domain
`
`
`Kinase
`
`
`
`Domain
`
`Guanylate
`Cyclase
`
`SHTC B1CAFAACAGC
`|
`
`
`
`
`
`Uroguanylin
`
`NDDCELCYNVACTGCOL
`
`
`
`
`
`
`
`Lymphoguarylin
`
`~~ Q EEC E LC INMACTGY
`)
`|
`
`
`
`E. coli enterotoxin ST peptide exploits the same GC-C signaling
`
`ee a gf
`ier
`\
`NSSNY CCE » CNPA CTGLY
`\
`
`\
`
`
`to cause traveler's diarrhea
`
`
`
`
`0010
`
`

`

`
`
`
`=
`=
`Fo
`£58
`poses
`Law
`E
`Frooo
`a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`r=
`pr
`a
`£52
`so
`22
`Boon
`£33
`
`pa
`13
`
`siti
`
`hd
`
`=
`=
`i
`£52
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`£3
`3
`foes
`£52
`ting)
`£3
`—
`ri
`
`=
`
`ial functions of UG are in tons and fluid
`
`o UG regulates the normal renewal process via
`
`proliferation of epithelial cells in GI mucosa
`
`
`
`
`
`
`
`Ra
`i
`
`;
`]
`ROWTH ARE FHARYNX
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CY
`
`GALELADDEH
`
`
`
` BALL INTESTINE
`
`0011
`
`

`

`
`
`
`
`rHewting
`iy
`
`0012
`
`
`
` asling
`
`
`
`0012
`
`
`

`

` p—
`
`o
`
`Produced by goblet and
`enterochromatfin cells
`
`a, oN
`
`*
`
`to stimulate
`UG binds to GC-C
`cGMP production, which activates
`CFTR, the chloride channel
`
`® CFTR activation leads fo ion and
`fluid secretion in the GI tract
`
`o
`
`UG also regulat tes
`homeostasis in cells
`Mucosa
`
`lining the GI
`
`
`
`Is UG suitable for drug development ?
`
`)
`
`Shaitubhai 2002
`
`
`
`
`
`
`
` _
`
`0013
`
`

`

`
`
`
`
`0014
`
`

`

`
`
`Aqueous
`|
`solution
`
`Active
`
`
`
`0015
`
`

`

`we
`SN
`&s
`‘‘
`x
`oveaoaea
`
`
`
`x LsAlAccLAcLAsLsLLsTLLTLLLLLLLLELTLTILTTTIILLLILTTTLTILIILTIDIDTILSIDIIAIIDIIDIIDILDILTILIITLITDILLILILTELTILAILTILTTTILTILTTLTILLITLETTESTISLLILLTLLTASLISILSILIILTILTASIISELSELSTsSIsSASLISSISIODADADITITTTIITIDTllllllDslDsillldllslldlliiliIblibtiblEb
`gZ=2ZEg"2ggZg2g2ZZZzZgzgzZZzzZ2Zg~,Zg5s2Zz=ag2g=gzggzgzgzZ2Z.ZgzgzZZgzg2ZZZzZgzgzZZgzg2ZZZzZgzgzZZzzgzZZae
`eo5g2ggzggzgZZZgzg2ZZZzZgzgzZZgzg2ZZZZg32gSega2g<.S.2gaNL,ZzgOeZgZZgzg2ZZg=Zg:zgzZzzggi2g2+Z2z=gheeZzyereesgiat2gms2Z2gzZZ&a2z=
`AooAAAAAWARROADAAOAAAOROAAAWAAWAAWAAA
`3333333%3xx3xx3x33333333%3xx3xx3x33333333%3xx3xx3x33333333%3xx3xx3x33333333%3xx3xx3x33333333%3xx3xx3x33333333%3xx3xx3x33333333%3xx3
`
`SpeoooeneernSTEET
`
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`
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`
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`
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`
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`
`:xi‘‘%t%:xi‘‘%t%:xi‘‘%t%:xi‘‘%t%:xi‘‘%t%:xi‘‘%‘:%%\
`
`0016
`
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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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`
`
`
`
`
`
`
`Log Peptide IW
`
`
`
`
`ETE Wi Ran EF Ta QC 7.7 Cl
`
`on)
`
`0016
`
`
`
`
`
`
`

`

`is approximately
`inity of plecanatide towards 6C-C
`-fold higher than that of uroguanylin
`
`oe
`
`
`
`
`
`Table 1, Calculated and observed (M+H)* values and ICs values (+
`SD} for characierized pepides.
`
`L
`
`
`
`
`
`
`Peptide
`
`(MeH)* Cae.
`
`(M4H)? Obs.
`
`
`
`1Cq (aM) |
`
`Hy
`
`| wg oan
`
`=
`=
`
`=
`
`=
`
`“ a DOTA Te—
`
`-- Uroguanyle
`
`\
`
`FS
`
`= Radiozoctivity boisred
`
`
`
`Liv ef al, 2008
`
`wh hy
`:
`y ~g DOTA ail “i,
`
`
`
`| Brogan
`86
`16816
`50403
`
`
`
`
`
`
`
`
`
`96:19
`
`CDOTA-E woguamylin ~~ 20676
`20679
`Wis Sa wig sn a IS ni bio?
`
`
`
`
`[peptide] {1
`
`
`
`
`
`Figure 2. IC yy analyses of uroguanlin anclog displacement of B91 FY.
`NTH 1-19) from 184 han colorecial ooncet cells,
`
`
`
`E3-uroguanylin Plecanatide
`
`
`
`
`
`0017
`
`

`

`nig
`
`Z
`pre
`
`\
`RY
`
`Wd
`
`W
`
`RY
`3
`
`NDDCELCYNVACTGCL
`|
`
`N N
` — 3
`
`rad
`
`\ | \
`
`Hl ——
`Z
`
`Plecanatide
`
`Uroguanylin Analog
`
`hn NERA TRIN
`NE
`N
`3
`Yaad
`AN
`NOR
`NENA
`WY
`Jedd I
`Je TEEN Nw
`
`SN
`RR
`Ta
`
`NDECELCYNVACTGCL
`\
`\
`
`HY
`
`St—
`
`
`
`
`CEYCCNPACTGCY
`
`N
`N
`
`0018
`
`

`

` > _
`___________________________________________________~_~_________________________________—__________________
`
`
`
`_
`
`Lisa] bog i)
`
`[Uraguansin], [og (Bh
`
`{Guanylin],
`
`log (i
`
`-
`
`Majority of water secretion occurs in the duodenum where pH is 5.5,
`
`-
`
`At pH 5.5, UG exhibits binding affinity comparable to ST peptide
`
`Fretren 2000
`
`
`
`
`
`
`
`
`
`
`_—
`
`
`
`
`
`
`
`Ee SE C= RN R=" of Po
`
`|
`
`pa] 125
`
`
`
`fo]
`
` -
`
`ou
`
`hil
`
`
`
`
`0019
`
`

`

`
`
`
`UG
`
`NDDCELCVNVACTGCL
`
`NDECELCVNVACTGCL
`
`{UiraguanyfinSsomy, Log (4)
`
`ST (5-17)
`
`CCELCCNPACAGC
`
`[roquenylin®-1%, Log [1
`
`NDD af the N-terminus of uroguanylin (UG) - and
`NDE of plecanatide - are crucial for the
`
`ay
`
`
`
`
`[Unagadaylipddu He Logs (M§
`
`
`
`
`=
`
`=
`
`=
`
`=
`
`am
`
`niles CBP per wel]
`
`
`
`
`OzzzzZ2-22»z;
`
`z?z2#>>2z27z#»oz2b zz?2»r
`
`0020
`
`

`

`« Physiological activity of uroguanylin is
`regulated by mucosal acidity
`
`)
`
`NDD
`of
`
`Engg”
`
`are critical for pH-mediated binding
`uroguanylin fo GC-C
`
`
`
`
`0021
`
`

`

`
`
`0022
`
`
`
`0022
`
`

`

`
`
`0023
`
`
`
`
`
`
`
`
`
`
`
`0023
`
`

`

`
`
`
`
`
`
`
`
`01
`
`03
`
`09
`
`271
`
`54
`
`81
`
`162
`
`243
`
`486
`
`Placebo 2
`
`SE SSS SN
`
`PR ISS RUSS SUP
`
`~d
`
`© » EY « >]
`
`—
`
`* I
`
`Eee" J
`
`oS
`
`Bristol Score of first Baa
`
`
`
`
`Shalt | bhai 2006
`
`* Wilcoxon Two-sample test treatment vs placebo one-sided
`
`0024
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`6.0
`
`5
`
`3.0
`
`20
`
`
`
`
`Bristol Score
`
`haifubhai 2006
`
`Dose (mg)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0025
`
`

`

`
`
`
`
`n=16
`
`Placebo
`
`0.1
`
`03
`
`09
`
`27
`
`54
`
`81
`
`162
`
`243
`
`486
`
`60
`
`40
`
`20
`
`1
`
`Humber of Subliects
`
`24
`
`
`
`0026
`
`

`

`¢ Plecanatide was well-tolerated
`
`¢ Did not reach an MTD
`
`® No serious adverse events reported
`
`
`
`® Minimal AES reported
`
`0027
`
`

`

`
`
`0028
`
`
`
`
`
`
`
`
`
`0028
`
`

`

`
`
`- Oral piecanatide, once-day dosing for 14 days
`
`v
`
`&
`eR Y
`%
`ss
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`ST A FE GF :
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`GC-C receptors are expressed throughout the GI tract
`- Proximal intestine (CC and IBS-C)
`- Colon (IBD)
`
`Orally administered plecanatide may primarily act in
`proximal intestine to stimulate water secretion
`
`»
`
`7
`
`h- 7
`
`» CMC and cGMP-scale manufacturing accomplished
`
`Plecanatide is a safe oral drug
`=
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`(CNS, CV, Respiratory and Repro)
`No toxicity in human
`=
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`=
`Acts in GI lumen to produce PD activity
`=
`- Anti-inflammatory (IBS-C and IBD)
`
`7 7
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`plecanatide
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`ND i E LEVATA CT bet
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`
`

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`
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`33 digestion with simulated
`intestinal fluid
`
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`SIF 2 hy
`
`
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`SP333 SIF
`
`
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`
`
`
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`
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`
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`250
`
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`
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`
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`
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`
`
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`
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`Peptide Concentration (mM)
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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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`
`

`

`
`
` »
`
`»
`
`Oral dose of $P-333 is expected to reach colon to activate GC-C
`receptor to ameliorate inflammation in different segments of colon
`
`»
`
`SP-333 developmental plan
`
`- Non-clinical t toxicology studies (mice and monkeys)
`- Efficacy studies in DSS and TNBS induced colitis models
`
`- Preclinical and IND-enabling studies are ongoing
`- Formulation strategies are being developed
`- IND is anticipated to be filed in 10 2010
`
`A more potent and a highly stable analog of Uroguanylin
`
`» 8P-333 is completely resistant to SGF
`
`P-333 1s stable against digestion with SIF
`
`7
`
`%/
`
`uy
`
`0041
`
`

`

`
`
`
`
`
`GC-C agonists are emerging as a new class of drugs to
`treat Gl disorders, inflammatory diseases and for
`prevention of colon cancer
`
`CC, 1B5-C and IBD are major medical needs that would
`greatly benefit from a safe and effective oral drug
`
`SP-304 and SP-333 act locally in the gut lumen to
`activate GC-C and stimulate cGMP production at the
`target site
`
`Enhancement in cyclic GMP production leads to
`activation of chloride channels to increase water
`secretion in the gut and to ameliorate inflammation in
`distal intestine
`
`SP-304, an analog of the natural hormone uroguanylin,
`has the potential to be ‘best-in-class’ for Gl treatment
`
`§P-333 as a safe and oral drug candidate for treatment
`
`and maintenance of UC in human
`
`0042
`
`

`

`PTO/SB/16 (12-08)
`Approved for use through 09/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`Given Name (first and middle [if any] }
`Family Name or Surname
`Residence
`(City and either State or Foreign Country)
`
`Kunwar
`Shailubhai
`Audubon, Pennsylvania
`
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`Formulations Of Guanylate Cyclase C Agonists And Methods Of Use Thereof
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`Date
`September 15, 2010
`
`
`TYPED or PRINTED NAME
`
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`REGISTRATION NO.
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`Kunwar Shailubhai
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`
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`30623
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