Attorney Docket No.: SYPA-009/X01US 321994-2142
`Application No.: 13/421,769
`Page 2
`
`C]
`
`C]
`
`C]
`
`C]
`
`C]
`
`. Pursuant to
`Enclosed is a copy of a non-English publication(s)
`§609 of the M.P.E.P., Applicant submits the attached foreign search or
`examination report, which cites such non-English language publication(s).
`Enclosed is a copy of a non-English publication(s)
`English
`language publication
`(copy enclosed) claims priority from this non-
`English publication.
`Enclosed is an explanation of non-English publication(s)
`an English translation is not available.
`Enclosed is an English translation of non-English publication(s)
`cited in the attached Form PTO/SB/08.
`Enclosed is a copy of pending patent Application Serial No.
`
`for which
`
`This Information Disclosure Statement is filed after the period specified in 37
`C.F.R. § 1.97(b), but before the mailing of any of the following:
`
`Xx
`Xx
`Xx
`
`a final action under 37 C.F.R. §1.113;
`a notice of allowance under 37 C.F.R. §1.311; or
`an action that otherwise closes prosecution in this application.
`
`In accordance with 37 C.F.R. §1.97(c) also enclosedis:
`C]
`Fee under 37 C.F.R. §1.17(p) in the amount of $180.00;
`Xx
`Fee under 37 C.F.R. §1.17(p) in the amount of $90.00;
`C]
`Fee under 37 C.F.R. §1.17(p) in the amountof $45.00; or
`[|
`Statement as specified in 37 C.F.R. §1.97(e):
`[|
`Each item of information contained in the Information
`Disclosure Statement cited herein was first cited in a
`communication from a
`foreign patent office
`in
`a
`counterpart foreign application not more than three months
`prior to the filing date of the Information Disclosure
`Statement; or
`
`[|
`
`No item of information contained in the Information
`Disclosure Statement submitted herewith was cited in a
`communication from a
`foreign patent office
`in
`a
`counterpart foreign application, and, to the knowledge of
`the undersigned, having made a reasonable inquiry, no item
`of information contained in the Information Disclosure
`Statement was known to any individual designated in
`37 C.F.R. §1.56(c) more than three months prior to the
`filing date of the Information Disclosure Statement.
`
`134704012 v1
`
`MYLAN - EXHIBIT 1022 Part 15 of 16
`4805
`
`4805
`
`MYLAN - EXHIBIT 1022 Part 15 of 16
`
`

`

`Attorney Docket No.: SYPA-009/X01US 321994-2142
`Application No.: 13/421,769
`Page 3
`
`The Director is hereby authorized to charge any deficiency or credit any
`
`overpayment in the fees filed, asserted to be filed or which should have been filed
`
`herewith to our Deposit Account No. 50-1283 which the undersigned is authorized to
`
`draw.
`
`It
`
`is
`
`respectfully requested that
`
`the Examiner consider
`
`the above-noted
`
`information and return an initialed copy of the attached Form PTO/SB/08 to the
`
`undersigned.
`
`Dated: July 27, 2016
`
`COOLEY LLP
`ATTN: IP Docketing Department
`1299 Pennsylvania Avenue NW,Suite 700
`Washington, DC 20004
`
`By:
`
`(202) 728-7030
`Tel:
`Fax: (202) 842-7899
`
`Respectfully submitted,
`COOLEY LLP
`
`;
`/Anne E. Fleckenstein/
`AnneE.Fleckenstein
`Reg. No. 62951
`
`134704012 v1
`
`4806
`
`4806
`
`

`

`Electronic Patent Application Fee Transmittal
`
`Title of Invention:
`
`Formulations of Guanylate Cyclase C Agonists and Methods of Use
`
`ee
`
`Extension-of-Time:
`
`Filing Fees for Utility under 35 USC 111(a)
`
`Description
`
`Fee Code
`
`Quantity
`
`Sub-Total in
`
`USD(S)
`
`Basic Filing:
`
`Miscellaneous-Filing:
`
`Patent-Appeals-and-Interference:
`
`Post-Allowance-and-Post-Issuance:
`
`4807
`
`4807
`
`

`

`Total in USD ($)
`
`2806 Prfgfm
`
`Miscellaneous:
`
`Submission- Information Disclosure Stmt
`
`4808
`
`4808
`
`

`

`Electronic AcknowledgementReceipt
`
`Application Number:
`
`13421769
`
`International Application Number:
`
`Confirmation Number:
`
`3135
`
`
`
`ee
`
`Title of Invention:
`
`Formulations of Guanylate Cyclase C Agonists and Methods of Use
`
`Paymentinformation:
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpaymentas follows:
`
`Deposit Account
`
`501283
`
`4809
`
`4809
`
`

`

`File Listing:
`
`Multi
`File Size(Bytes)/
`DocumentDescription
`Document
`Pages
`
`
`Number Message Digest|Part/.zip|P (if appl.)
`
`1426883
`
`Foreign Reference
`
`WO2013138352A1.pdf
`
`25eaf030b8f7e29be932ach02b64e4c743dq
`
`Non Patent Literature
`
`EP11825961_EESR.pdf
`
`188619
`
`ed3ab66f6ddf022270f6b0b95da239f97369
`2cea
`
`Information:
`
`Information:
`
`150638
`
`SB08.pdf
`
`c40234f367627feb1317d16555 10c9a0a45 oy
`926e
`
`1877395
`
`Information Disclosure Statement (IDS)
`Form (SB08)
`
`Information:
`
`This is not an USPTO supplied IDSfillable form
`
`Transmittal Letter
`
`b8340fd5336603ef73c777bdc9Sece219ae4
`4abf
`
`Information:
`
`Information:
`
`Fee Worksheet (SB06)
`
`fee-info.pdf
`
`e19f5e56e6ccc2566ba0abdf9728cd090c74]
`#504
`
`Total Files Size (in bytes)
`
`4810
`
`4810
`
`

`

`New Applications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary componentsfora filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shownonthis
`AcknowledgementReceiptwill establish the filing date of the application.
`
`National Stage of an International Application under 35 U.S.C. 371
`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903indicating acceptanceof the application as a
`national stage submission under35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`This AcknowledgementReceipt evidences receipt on the noted date by the USPTO ofthe indicated documents,
`characterized by the applicant, and including page counts, where applicable.It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`the application.
`
`New International Application Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/RO/105)will be issued in due course, subject to prescriptions concerning
`national security, and the date shownon this AcknowledgementReceiptwill establish the international filing date of
`
`4811
`
`4811
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`19 September 2013 (19.09.2013)
`
`WIPO!) PCT
`
`\a
`
`(10) International Publication Number
`WO 2013/138352 Al
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL
`NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU,
`RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ,
`TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`GD)
`
`International Patent Classification:
`A61K 38/10 (2006.01)
`AGIP 1/10 (2006.01)
`A61P 1/00 (2006.01)
`
`(81)
`
`QD
`
`International Application Number:
`
`PCT/US2013/030551
`
`(22)
`
`International Filing Date:
`
`12 March 2013 (12.03.2013)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(7)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`13/421,769
`
`15 March 2012 (15.03.2012)
`
`US
`
`Applicant: SYNERGY PHARMACEUTICALS INC.
`[US/US]; 420 Lexington Avenue, Suite 1609, New York,
`NY 10170 (US).
`
`Inventors; and
`Applicants
`(or US only): COMISKEY, Stephen
`[US/US]; 105 Steeplechase Drive, Doylestown, PA 18902
`(US). FENG, Rong [CA/US]; 74 Pine Glen Road, Lang-
`horne, PA 19047 (US). FOSS, John [US/US]; 525 Linden
`Avenue,
`Doylestown,
`PA
`18901-4435
`(US).
`SHATLUBHAT, Kunwar
`[US/US]; 2707 Bald Fagle
`Cirelc, Audubon, PA 19403 (US).
`
`(74)
`
`Agents: ELRIFI, Ivor, R. et al.; Mintz Levin Cohn Ferris
`Glovsky and Popeo, P.C., One Financial Center, Boston,
`MA 02111 (US).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR,NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`with sequencelisting part ofdescription (Rule 5.2(a))
`
`(54) Title: FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND METHODS OF USE
`
`(57) Abstract: The invention provides low-dose formulations of guanylate cyclase-C ("GCC") agonist peptides and methods for
`their use. The formulations of the invention can be administered either alone or in combination with one or more additional thera -
`peutic agents, preferably an inhibitor of cGMP-dependent phosphodiesterase or a laxative.
`
`4812
`
`
`
`
`
`WO2013/138352A1|IMTIINMNMIIMTANNUITYTANTATAA
`
`4812
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND
`
`METHODSOF USE
`
`RELATED APPLICATIONS
`
`[01]
`
`This application claims priority to U.S. Patent Application No. 13/421,769 filed on
`
`March 15, 2012, the content of which is incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`[02]
`
`The present invention relates to low-dose formulations of guanylate cyclase C peptide
`
`agonists uscful for the treatment and prevention of various discascs and disordcrs.
`
`BACKGROUNDOF THE INVENTION
`
`10
`
`[03]
`
`Guanylate cyclase C is a transmembrane form of guanylate cyclase that is expressed
`
`on variouscells, including gastrointestinal epithelial cells (reviewed in Vaandrager 2002 Mol.
`
`Cell. Biochem, 230:73-83). It was originally discovered as the intestinal receptor for the heat-
`
`stable toxin (ST) peptides secreted by enteric bacteria and which cause diarrhea. The ST
`
`peptides share a similar primary amino acid structure with two peptides isolated from
`
`15
`
`intestinal mucosa and urine, guanylin and uroguanylin (Currie, et al., Proc. Nat’l Acad. Sci.
`
`USA 89:947-951 (1992); Hamra, et al., Proc. Nat’l Acad. Sci. USA 90:10464-10468 (1993);
`
`Forte, L., Reg. Pept. 87:25-39 (1999); Schulz, et al., Cell 63:941-948 (1990); Guba, et al.,
`
`Gastroenterology 111:1558-1568 (1996); Joo, et al., Am. J. Physiol. 274:G633-G644 (1998)).
`
`[04]
`
`Inthe intestines, guanylin and uroguanylin act as regulators of fluid and electrolyte
`
`20
`
`balance. In response to high oral salt intake, these peptides are released into the intestinal
`
`lumen where they bind to guanylate cyclase C localized on the luminal membrane of
`
`enterocytes (simple columnarepithelial cells of the small intestines and colon). The binding
`
`of the guanylin peptides to guanylate cyclase C induces electrolyte and water excretion into
`
`the intestinal lumen via a complex intracellular signaling cascade thatis initiated by an
`
`25
`
`increase in cyclic guanosine monophosphate (cGMP).
`
`4813
`
`4813
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`[05]
`
`The cGMP-mcdiated signaling that is initiated by the guanylin peptidesis critical for
`
`the normal functioning of the gut. Any abnormality in this process could lead to
`
`gastrointestinal disorders such asirritable bowel syndrome (IBS) and inflammatory bowel
`
`diseases. Inflammatory bowel disease is a general name given to a group of disorders that
`
`cause the intestines to become inflamed, characterized by red and swollen tissue. Examples
`
`include ulcerative colitis and Crohn’s disease. Crohn's disease is a serious inflammatory
`
`disease that predominantly affects the ileum and colon, but can also occurin other sections of
`
`the gastrointestinal tract. Ulcerative colitis is exclusively an inflammatory disease of the
`
`colon, the large intestine. Unlike Crohn's disease, in which all layers of the intestine are
`
`10
`
`involved, and in which there can be normal healthy bowel in between patches ofdiseased
`
`bowel, ulcerative colitis affects only the innermost lining (mucosa) of the colon in a
`
`continuous manner. Depending on whichportion of the gastrointestinal tract is involved,
`
`Crohn's disease may bereferred to asileitis, regional enteritis, colitis, etc. Crohn's disease
`
`and ulcerative colitis differ from spastic colonorirritable bowel syndrome, which are
`
`15
`
`motility disorders of the gastrointestinal tract. Gastrointestinal inflammation can be a chronic
`
`condition. It is estimated that as many as 1,000,000 Americansareafflicted with
`
`inflammatory bowel disease, with male and female patients appearing to be equally affected.
`
`Mostcases are diagnosed before age 30, but the disease can occur in the sixth, seventh, and
`
`later decadesof life.
`
`20
`
`[06]
`
`IBS and chronic idiopathic constipation are pathological conditions that can cause a
`
`great deal of intestinal discomfort and distress but unlike the inflammatory bowel diseases,
`
`IBS doesnot cause the serious inflammation or changes in boweltissue andit is not thought
`
`to increase the risk of colorectal cancer. In the past, inflammatory bowel disease, celiac
`
`disease and IBS were regarded as completely separate disorders. Now, with the description
`
`25
`
`of inflammation, albeit low-grade, in IBS, and of symptom overlap between IBS and celiac
`
`disease, this contention has come under question. Acute bacterial gastroenteritis is the
`
`strongest risk factor identified to date for the subsequent development of postinfective
`
`uritable bowel syndrome. Clinical risk factors include prolonged acute illness and the
`
`absence of vomiting. A genetically determined susceptibility to inflammatory stimuli may
`
`30
`
`also be a risk factor for irritable bowel syndrome. The underlying pathophysiology indicates
`
`increased intestinal permeability and low-grade inflammation, as well as altered motility and
`
`visceral sensitivity. Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut
`
`2
`
`4814
`
`4814
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`function and is known to play a major rolc in pathophysiology of IBS. The activity of 5-HT is
`
`regulated by cGMP.
`
`[07] While the precise causes of IBS and inflammatory bowel diseases (IBD) are not
`
`known,a disruption in the process of continual renewal of the gastrointestinal mucosa may
`
`contribute to discasc pathology in IBD and aggravate IBS. The renewalprocess of the
`
`gastrointestinal lining is an efficient and dynamic process involving the continual
`
`proliferation and replenishment of unwanted damagedcells. Proliferation rates of cells lining
`
`the gastrointestinal mucosa are very high, second only to the hematopoietic system.
`
`Gastrointestinal homeostasis depends on both the proliferation and programmedcellular
`
`10
`
`death (apoptosis) of epithelial cells lining the gut mucosa. Cells are continually lost from the
`
`villus into the lumen of the gut and are replenished at a substantially equal rate by the
`
`proliferation of cells in the crypts, followed by their upward movementto the villus. The
`
`rates of cell proliferation and apoptosis in the gut epithelium can be increased or decreased in
`
`a varicty of circumstanccs, e.g., in responsc to physiological stimuli such as aging,
`
`15
`
`inflammatory signals, hormones, peptides, growth factors, chemicals and dietary habits. In
`
`addition, an enhancedproliferation rate is frequently associated with a reduction in turnover
`
`time and an expansion of the proliferative zone. The proliferation index is much higher in
`
`pathological states such as ulcerative colitis and other gastrointestinal disorders. Intestinal
`
`hyperplasia is a major promoter of gastrointcstinal inflammation. Apoptosis and ccll
`
`20
`
`proliferation together regulate cell number and determinethe proliferation index. Reduced
`
`rates of apoptosis are often associated with abnormal growth, inflammation, and neoplastic
`
`transformation. Thus, both increased proliferation and/or reduced cell death may increase the
`
`proliferation index of intestinal tissue, which may in turn lead to gastrointestinal
`
`inflammatory diseases.
`
`25
`
`[08]
`
`In addition to a role for uroguanylin and guanylin as modulators of intestinal fluid and
`
`ion secretion, these peptides may also be involved in the continual renewal of gastrointestinal
`
`mucosa by maintaining the balance between proliferation and apoptosis. For example,
`
`uroguanylin and guanylin peptides appear to promote apoptosis by controlling cellular ion
`
`flux. Given the prevalence of inflammatory conditions in Western societies a need exists to
`
`30
`
`improve the treatment options for inflammatory conditions, particularly of the gastrointestinal
`
`tract.
`
`4815
`
`4815
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`[09]
`
`Peptide agonists of guanylate cyclase C agonists (‘GCC agonists”) are described in
`
`U.S. Patent Nos. 7,041,786, 7,799,897, and U.S. Patent Application Publication Nos.
`
`US2009/0048175, US 2010/0069306, US 2010/0120694, US 2010/0093635, and US
`
`2010/0221329. However, the formulation of peptides for pharmaceutical delivery presents a
`
`numberof special problems. For example, peptides are subject to structural modifications by
`
`a variety of degradation mechanismsresulting in problems of chemical and physical
`
`instability of the formulation.
`
`SUMMARYOF THE INVENTION
`
`[10]
`
`The present invention provides low-dose formulations of peptide agonists of
`
`10
`
`guanylate cyclase C (“GCC”) and methodsfor their use in the treatment and prevention of
`
`humandiseases and disorders, such as a gastrointestinal motility disorder, irritable bowel
`
`syndrome, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional
`
`heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic
`
`intestinal pseudo-obstruction, colonic pseudo-obstruction; Crohn's disease, ulcerative colitis,
`
`15
`
`inflammatory bowel disease, colonic pseudo-obstruction, obesity, congestive heart failure,
`
`and benign prostatic hyperplasia.
`
`In certain embodiments, the formulations are stabilized
`
`against chemical degradation of the peptide. The low-dose formulations of the invention
`
`have unexpected efficacy in humans in a dosage range that was not predicted based on
`
`studies in primates. The formulations of the invention are particularly useful for the
`
`20
`
`treatment or prevention of chronic idiopathic constipation. In certain embodiments, the GCC
`
`agonists are analogs of uroguanylin and bacterial ST peptides. In preferred embodiments, the
`
`analogs have superior properties comparedto the naturally occurring or “wild-type” peptides.
`
`Examples of such superior properties include a high resistance to degradation at the N-
`
`terminus and C-terminus from carboxypeptidases, aminopeptidases, and/or by other
`
`25
`
`proteolytic enzymes present in the stimulated human intestinal juices and human gastric
`
`juices. Examples of GCC agonists that can be used in the formulations and methods of the
`
`invention are described in more detail below and in U.S. Patent Nos. 7,041,786, 7,799,897,
`
`and U.S. Patent Application Publication Nos. US2009/0048175, US 2010/0069306, US
`
`2010/0120694, US 2010/0093635, and US 2010/022 1329, each of which is incorporated
`
`30
`
`herein by reference inits entirety.
`
`4816
`
`4816
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`[11]
`
`The invention provides an oral dosage formulation comprising one or more
`
`pharmaceutically acceptable excipients and at least one GCC agonist peptide, wherein the
`
`amount of GCC agonist peptide per unit dose is from 0.01 mg to 10 mg, and wherein the
`
`GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1-54 and 56-249.
`
`Tn one embodiment, the GCC agonist peptide has a chromatographic purity of no less than
`
`90%, no less than 90.5%, no less than 91%, no less than 92%, no less than 93%, no less than
`
`94%, no less than 95%, no less than 96%, no less than 97%, no less than 98%, or no less than
`
`99%. The chromatographic purity of the GCC agonist peptide is determined as area percent
`
`by HPLC. In one embodiment, the GCC agonist peptide is selected from the group
`
`10
`
`consisting of SEQ ID NOs: 1, 8, 9, or 56. In one embodiment, the GCC agonist peptide is
`
`selected from the group consisting of SEQ ID NOs: | and 9. In one embodiment, the GCC
`
`agonist peptide is selected from the group consisting of SEQ ID NOs: 8 and 9.
`
`In one
`
`embodiment, the amount of GCC agonist peptide per unit dose is 0.1 mg, 0.3 mg, 0.6 mg, 1.0
`
`meg, 3.0 mg, 6.0 mg, 9.0 mg or 9.5 mg.
`
`15
`
`[12]
`
`In one embodiment, the GCC agonist peptide has a total impurity content of no
`
`greater than 10%, no greater than 9.5%, no greater than 9%, no greater than 8%, no greater
`
`than 7%, no greater than 6%, no greater than 5%, no greater than 4%, no greater than 3%, no
`
`greater than 2%, or no greater than 1%. The total impurity content is determinedastotal area
`
`percentages of impuritics by HPLC. The impuritics do not include any pharmaccutically
`
`20
`
`acceptable excipient used for the formulation. In one embodiment, the formulation is
`
`substantially free of inorganic acids and carboxylic acids, e.g., HCI, phosphoric acid, or
`
`acetic acid. In this context, carboxylic acids do not include aminoacids or peptides. In this
`
`context “substantially” free of acids means that the acid content of the formulation at the time
`
`of packaging is preferably less than 0.2%, less than 0.1%, less than 0.05%, less than 0.01%,
`
`25
`
`less than 0.005%,or less than 0.001% of the total weight of the formulation.
`
`In one
`
`embodiment, the formulation is free of HCI.
`
`[13]
`
`In one embodiment, the formulation is a solid formulation.
`
`In one embodiment, the
`
`formulation is in the form of a powder, granule, sachet, troche, tablet, or capsule. In another
`
`embodiment, the formulation is a liquid formulation and the GCC agonist peptide is in
`
`30
`
`solution or suspension in a lipophilic liquid. In one embodiment, the liquid is a refined
`
`specialty oil or a medium chain triglyceride or related ester. In one embodiment, the refined
`
`specialty oil is selected from Arachis oil, Castor oil, cottonseed oil, maize (corn) oil, olive oil,
`5
`
`4817
`
`4817
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`sesame oil, soybean oil, and sunflower oil. In one embodiment, the medium chain
`
`triglyceride or related ester is AKOMED E, AKOMEDR, CAPTEX 355, LABRAFAC CC,
`
`LABRAFAC PG, LAUROGLYCOL FCC, MIGLYOL 810, MIGLYOL 812, MIGLYOL
`
`829, MIGLYOL 840, and SOFTISAN 645. In one embodiment, the liquid is selected from
`
`the group consisting of medium chaintriglycerides, propylene glycol dicaprylocaprate,
`
`vitamin E, soybean oil, Cremaphor, PG, and PG 400.
`
`In one embodiment, the unit dose is a
`
`powder, tablet, or capsule. In one embodiment, the unit dose is a liquid-filled capsule. In one
`
`embodiment, the capsule or tablet is in a blister pack or strip. Preferably, the blister pack or
`
`strip is made of a material that is impermeable to water vapor and oxygen. In one
`
`10
`
`embodimentthe blister pack is comprised of a metal foil. In one embodiment the blister pack
`
`is a FOIL/FOIL blister pack. In one embodiment, the container of the blister pack is flushed
`
`with an inert gas such as nitrogen or argon. In one embodiment, the container further
`
`includes a desiccant. In a preferred embodiment the desiccant is a molecular sieve. In one
`
`embodiment, the unit dose is in a high density polyethylene bottle having a seal.
`
`In one
`
`15
`
`embodiment, the bottle further comprises a desiccant. In one embodiment, the bottle further
`
`comprises an oxygen scavenger or molecular sieve. In one embodiment, the bottle is nearly
`
`impermeable to oxygen and water vapor(e.g., much more impermeable than a HDPEbottle),
`
`such as an OxyGuardbottle.
`
`[14]
`
`In one embodiment, the one or more pharmaccutically acceptable cxcipicnts include
`
`20
`
`an inert carrier. In one embodiment, the inert carrier is a selected from mannitol, lactose, a
`
`microcrystalline cellulose, or starch. In one embodiment, the inert carrier has a particle size
`
`of from 50 to 900 microns, from 50 to 800 microns, from 50 to 300 microns, from 50 to 200
`
`microns, from 75 to 150 microns, from 75 to 200 microns, or from 75 to 300 microns.
`
`[15]
`
`In one embodiment, the GCC agonist peptide is stabilized against chemical or
`
`25
`
`physical degradation for a period of at least 18 months at 30 °C and 65% relative humidity, or
`
`at least 18 monthsat 25 °C and 60% relative humidity, or at least 18 months at 2-8 °C.
`
`[16]
`
`In one embodiment, the one or more pharmaceutically acceptable excipients include a
`
`divalent cation salt such as calcium chloride. In one embodiment, the one or more
`
`pharmaceutically acceptable excipients comprise an amino acid, such as leucine, histidine, or
`
`30
`
`arginine, or an amine such TRIS or TRIS/HC1.
`
`4818
`
`4818
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`[17]
`
`In one embodiment, the oral dosage formulation consists of the GCC agonist peptide
`
`described herein, an inert carrier (e.g., Celphere SCP-100, Avicel PH 102, or Avicel PH 112),
`
`and a lubricant (e.g., magnesium stearate). In one embodiment, the formulation consists of
`
`the GCC agonist peptide, an inert carrier (e.g., Avicel PH 200), a divalent cation salt (e.g.,
`
`calcium chloride or calcium ascorbate), an aminoacid (e.g., leucine, histidine, or arginine) or
`
`a protective amine (e.g., TRIS), a coating agent (e.g., Methocel ES Premium LV) and
`
`optionally a lubricant (e.g., magnesium stearate) or another additive (e.g., trehalose). In one
`
`embodiment, the formulation consists of the GCC agonist peptide, a binder(e.g., Provsolv
`
`SMCC 90 LM), and a disintegrant (e.g., Explotab). In one embodiment, the formulation
`
`10
`
`consists of the GCC agonist peptide, a diluent (e.g., Mannogem EZ), a binder(e.g., Provsolv
`
`SMCC 90 LM), a disintegrant (e.g., Explotab), a lubricant (e.g., Pruv).
`
`[18]
`
`The invention also provides a process for making the oral dosage formulations
`
`described herein, wherein the process comprises a step of dry granulation, wet granulation, or
`
`spray coating followed by drying. In another cmbodiment, the proccss compriscs a step of
`
`15
`
`dry mixing. In a preferred embodiment the step of dry mixing includes geometric blending.
`
`In one embodiment, the process comprises a step of direct compression. In one embodiment,
`
`the process for making the oral dosage formulations described herein is a spray coating-
`
`drying process which includes (a) providing an aqueous solution comprising: a GCC agonist
`
`peptide selected from the group consisting of SEQ ID NOs: 1-54 and 56-249, and one or
`
`20
`
`more pharmaceutically acceptable excipients, wherein the concentration of the GCC agonist
`
`peptide ranges from 10 to 60 mg/mL;and (b) applying the aqueoussolution to a
`
`pharmaceutically acceptable carrier to generate a GCC agonist peptide-coated carrier.
`
`[19]
`
`In one embodimentof the spray coating-drying process above, the one or more
`
`pharmaceutically acceptable excipients comprise a divalent cation salt wherein the divalent
`cation is selected from Ca”’, Mg”, Zn’*, and Mn**.
`In one embodiment, the one or more
`
`25
`
`pharmaceutically acceptable excipients comprise an amino acid selected from leucine,
`
`isoleucine, and valine. In one embodiment, the one or more pharmaccutically acceptable
`
`excipients comprise a coating agent (such as hypromellose Methocel ES PremLV). In one
`
`embodiment, the aqueous solution has a pH greater than 4 (e.g., 4.5-5.5, 5-6, about 5, or
`
`30
`
`greater than 5) or even greater than 7. In one embodiment, the aqueous solution is
`
`substantially free of inorganic acids and carboxylic acids. In one embodiment, the GCC
`
`4819
`
`4819
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`agonist peptide is sclected from the group consisting of SEQ ID NOs: 1, 8, 9, and 56. In one
`
`embodiment, the process further includes drying the GCC agonist peptide-coated carrier.
`
`[20]
`
`The invention further provides an oral dosage formulation made by the process
`
`described herein. Preferably, the GCC agonist peptide as madeis stabilized against chemical
`
`or physical degradation for a period of at least 18 months at 30 °C and 65% relative humidity,
`
`or at least 18 months at 25 °C and 60% relative humidity, or at least 18 months at 2-8 °C.
`
`[21]
`
`The invention also provides a method for treating or preventing a disease or disorder
`
`in a subject in need thereof, comprising administering to the subject an oral dosage
`
`formulation comprising at least one GCC agonist peptide, wherein the amount of GCC
`
`agonist peptide per unit dose is from 0.01 mg to 10 mg, and wherein the GCC agonist peptide
`
`is selected from the group consisting of SEQ ID NOs: 1-54 and 56-249. Preferably, the
`
`subject is a human subject. In one embodiment, the GCC agonist peptide is selected from the
`
`group consisting of SEQ ID NOs: 1, 8, 9, or 56. In one embodiment, the GCC agonist
`
`peptide is selected from the group consisting of SEQ ID NOs: | and 9. In one embodiment,
`
`the amount of GCC agonist peptide per unit dose is 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg, 3.0 mg,
`
`6.0 mg, 9.0 mg, 9.5 mg, or 10 mg.
`
`[22]
`
`In one embodiment, the disease or disorderis a gastrointestinal disease or disorder
`
`selected from the group consisting ofirritable bowel syndrome, non-ulcer dyspepsia, chronic
`
`intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction,
`
`20
`
`duodenogastric reflux, gastro esophageal reflux disease, constipation, gastroparesis,
`
`heartburn, gastric cancer, and H. pylori infection. In a preferred embodiment, the
`
`gastrointestinal disease or disorder is chronic idiopathic constipation.
`
`[23]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amount of an inhibitor of a cGMP-specific phosphodiesterase. In one embodiment,
`
`25
`
`the cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of
`
`suldinac sulfone, zaprinast, and motapizone, vardenifil, and suldenifil.
`
`[24]
`
`In one cmbodiment, the method further compriscs administering to the subjcct an
`
`effective amount of at least one laxative. In one embodiment, the at least one laxativeis
`
`selected from the group consisting of SENNA, MIRALAX, PEG,or calcium polycarbophil.
`
`4820
`
`4820
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`[25]
`
`In onc cmbodiment, the method further compriscs administering to the subjcct an
`
`effective amountof at least one anti-inflammatory agent.
`
`[26]
`
`The invention also provides pharmaceutical compositions comprising the
`
`formulations described herein.
`
`[27]
`
`Other features and advantages of the invention will be apparent from and are
`
`encompassed by the following detailed description and claims.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[28]
`
`Figure 1: Plecanatide (SP-304) treatment reduced timeto first BM following daily
`
`dose.
`
`10
`
`[29]
`
`Figure 2: Effect of daily treatment with plecanatide on spontaneous bowel
`
`movements (SBM)in chronic constipation patients.
`
`[30]
`
`Figure 3: Effect of daily treatment with plecanatide on complete spontaneous bowel
`
`movements (CSBM) in chronic constipation patients.
`
`[31]
`
`Figure 4: Effect of daily treatment with plecanatide on Bristol Stool Form Scores
`
`15
`
`(BSFS) in chronic constipation patients.
`
`[32]
`
`Figure 5: Effect of daily treatment with plecanatide on straining scores in chronic
`
`constipation patients
`
`[33]
`
`Figure 6: Percentage of subjects reporting improvements in abdominal discomfort
`
`scores after 14-days of daily treatment with plecanatide.
`
`20
`
`DETAILED DESCRIPTION
`
`[34]
`
`The invention provides pharmaccutical formulations of peptide GCC agonists. It is
`
`intended that the formulations of the invention are “pharmaceutical” formulations, meaning
`
`that they are suitable for pharmaceutical use. Accordingly, the term “formulations” as used
`
`herein is meant to encompass pharmaceutical formulations even if “pharmaceutical”is not
`
`25
`
`expressly stated. Pharmaceutical compositions comprising the formulations described herein
`
`9
`
`4821
`
`4821
`
`

`

`WO 2013/138352
`
`PCT/US2013/030531
`
`are also provided by the invention. The formulations of the invention prefcrably provide
`
`stability against chemical and physical degradation of the peptide, e.g., plecanatide (i.e., SEQ
`
`ID #1).
`
`[35]
`
`The invention is based in part upon the discovery that mannitol mixes very effectively
`
`with the GCC agonist peptides described hercin and provides stability against degradation,
`
`allowing the peptides to be formulated at very low doses. The invention is also based in part
`
`on the discovery that very low doses of the GCC agonist peptides described herein are
`
`effective for the treatment of diseases and disorders in humans. The dosage range found to
`
`be effective was not predicted based on animal studies. The invention is also based in part
`upon the discovery that a divalent cation (e.g., Ca**) and/or an aminoacid (e.g., leucine or
`
`10