PCT
`
`go» INTELLECTUALPROPERTY|
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`Intemational Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 7 :
`A6GIK 31/00
`
`(11) International Publication Number:
`
`WO 00/66099
`
`(43) International Publication Date:
`
`9 November 2000 (09.11.00)
`
`for the treatment of sexual dysfunction.
`
`(22) International Filing Date:
`
`26 April 2000 (26.04.00)
`
`(30) Priority Data:
`60/132,036
`
`30 April 1999 (30.04.99)
`
`US
`
`(21) International Application Number:
`PCT/US00/11129}(81) Designated States: AE, AG, AL, AM, AT, AU, AZ, BA, BB,
`BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM,
`DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU,ID, IL,
`IN,IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
`LY, MA, MD, MG, MK, MN, MW,MX,NO, NZ, PL, PT,
`RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ,
`UA, UG, US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH,
`GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (for ail designated States except US): LILLY ICOS
`LLC [US/US]; 1209 Orange Street, Wilmington, DE 19801
`(US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): PULLMAN, William,
`Emest [US/US] 3004 Towne Drive, Carmel, IN 46032
`(US). WHITAKER,John, Steven [US/US]; 19340 162nd
`Avenue, Weodinville, WA 98072 (US).
`(74) Agent: NAPOLI, James,
`J.; Marshall, O’Toole, Gerstein,
`Murray & Borun, 6300 Sears Tower, 233 South Wacker
`Drive, Chicago, IL 60606 (US).
`
`Published
`Without international search report and to be republished
`upon receipt of that report.
`
`(54) Title: UNIT DOSAGE FORM
`
`The present invention relates to highly selective phosphodiesterase (PDE) enzymeinhibitors and to their use in pharmaceutical
`Jes of manufacture. In particular, the present invention relates to potent inhibitors of cyclic guanosine 3’,5°-monophosphate specific
`sphodiesterase type 5 (PDES) that when incorporated into a pharmaceutical product at about 1 to about 20 mg unit dosage are useful
`
`ATI 1009-0001
`
`ATI v. ICOS
`
`IPR2018-01183
`
`ATI 1009-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`Return receipt postcard
`
`An assignment documentfor recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`A FIRSTpreliminary amendment.
`A SECOND or SUBSEQUENTpreliminary amendment.
`A substitute specification.
`A change of powerof attorney and/or addressletter.
`A computer-readable form ofthe sequence listing in accordance with PCT Rule 13ter.2 and 35 U.S.C. 1.821 - 1.825.
`A second copy of the published international application under 35 U.S.C. 154(d)(4).
`A second copy of the English languagetranslation of the international application under 35 U.S.C. 154(d)(4).
`Certificate of Mailing by Express Mail
`Other items or information:
`
`
`
`
`
`
`
`.
`
`
`
`11-2000)
`AREY1PTO-1. (Modified) U.S. DEPARTMENT OF COMMERCE PATENTAND TRADEMARK OFFICE
`
`TRANSMITTAL LETTER TO THE UNITED STATES
`29342/36206A
`
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A FILING UNDER35 U.S.C. 371
`
`US.“T0/0NO. L55¢ SEE37 CFR
`/0 5 5 5 6
`
`INTERNATIONAL APPLICATION NO.
`PCT/US00/11129
`TITLE OF INVENTION
`
`INTERNATIONAL FILING DATE
`26 April 2000
`
`PRIORITY DATE CLAIMED
`30 April 1999
`
`APPLICANT(S) FOR DO/EO/US
`PULLMAN,William Ernest and WHITAKER, John Steven
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US)the following items and other information:
`
`& This isa FIRST submission of items concerninga filing under 35 U.S.C.371.
`This is a SECOND or SUBSEQUENTsubmission of items concerning a filing under 35 U.S.C. 371.
`This is an express request to begin national examination procedures (35 U.S.C. 371(f)). The submission mustincludeitens (5), (6),
`(9) and (24)indicated below.
`
`
`
`
`
`
`The UShas been elected by the expiration of 19 months from the priority date (Article 31).
`& A copy ofthe International Application as filed (35 U.S.C. 371 (c) (2))
`a. 0 is attached hereto (required only if not communicated by the International Bureau).
`-b.
`has been communicated by the International Bureau.
`c. KI
`is not required, as the application was filed in the United States Receiving Office (RO/US).
`An English tanguage translation of the International Application as filed (35 U.S.C. 371(c)(2)).
`Li
`is attached hereto.
`
` [1
`
`has been previously submitted under 35 U.S.C. 154(d)(4).
`[1
`endments to the claims of the International Application under PCT Article 19 (35 U.S.C. 371 (c)(3))
`[1
`are attached hereto (required only if not communicated by the International Bureau).
`[1
`have been communicated by the International Bureau.
`have not been made; however,the time limit for making such amendments has NOT expired.
`d. & have not been made and will not be made.
`
`
`
`An English language translation of the amendmentsto the claims under PCT Article 19 (35 ULS.C. 371(c)(3)).
`An oath or declaration of the inventor(s) (35 U.S.C. 371 (c)(4)).
`An English language translation of the annexesto the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371 (c)(5)).
`
`A copy ofthe International Preliminary Examination Report (PCT/ATPEA/409).
`A copy of the International Search Report (PCT/ISA/210).
`
`Iteras 13 to 20 below concern document(s) or information included:
`An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
` ROOOOOOBOOA
`
`is
`
`Page 1 of 2
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`PCTUS1/REVO3
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`ATI 1009-0002
`
`ATI 1009-0002
`
`

`

`f
`
`
`
`
`B97 DaAprre”
`INTERNATIONAL APPLICATION NO.
`PCT/US00/11129
`
`7uy
`19 OCT
`ATTORNEY'S DOCKET NUMBER
`29342/36206A
`
`
`
`
`
`
`
`
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`
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`$1040.00
`
`$890.00
`
`$740.00
`
`$710.00
`
`Li 30
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`on
`v«
`+
`, SEES 7,
`U.S. APPLICATIOMING:
`TOPOS E356
`CALCULATIONS_PTO USE ONLY
`24,
`The following fees are submitted:.
`
`
`BASIC NATIONALFEE(37 CFR 1.492 (a) (1) - (5)):
`
`Neither international preliminary examination fee (37 CFR 1.482) nor
`international search fee (37 CFR 1.445(a)(2)) paid to USPTO
`and International Search Report not prepared by the EPO or JPO........-.--
`
`Internationalpreliminary examination fee (37 CFR 1.482) not paid to
`USPTObut International Search Report prepared by the EPO or JPO ........
`International preliminary examination fee (37 CFR 1.482) not paid to USPTO
`but international search fee (37 CFR 1.445(a)(2)) paid to USPTO............
`
`International preliminary examination fee (37 CFR 1.482) paid to USPTO
`but all claims did not satisfy provisions of PCT Article 33(1)-(4)............
`International preliminary examination fee (37 CFR 1.482) paid to USPTO
`$100.00
`andall claims satisfied provisions of PCT Article 33(1)-(4)..........
`
`ENTER APPROPRIATEBASIC FEE AMOUNT =
`
`
`Surcharge of $130.00 for furnishing the oath or declaration later than
`O 20
`months from the earliest claimed priority date (37 CFR 1.492 (e)).
`NUMBER EXTRA
`outcins|__17205|0~~i800 S00
`
`
`Independentesins|___2_-3=|0—~+Yx$84.00 50.0
`
`
`
`
`MuliipleDependentClaims(@heckiappliabigy| 50.0
`
`5390.0
`t
`G. Apphzant claims small entity status. See 37 CFR 1.27). The fees indicated above are
`
`
`= reduced by 1/2.
`$890.0
`
`
`
`
`
`
`P£Abessing fee of $130.00 for furnishing the English translation later than
`months from the earliest claimedpriority date (37 CFR 1.492 (f)).
`
`
`fo
`
`
`‘or recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be
`TOTAL FEES ENCLOSED
`jaecompanied by an appropriate cover sheet (37 CFR 3.28, 3.31) (check if applicable).
`
`
`
`
`
`
`
`NOTE: “Wherean appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR
`1.137(a) or (b)) must be filed and granted to restore the application to pending status.
`——
`
`
`SEND ALL CORRESPONDENCETO:
`
`
`<P. SIGNATURE
`
`NAPOLI, James J.
`Customer No. 04743
`
`Marshall, Gerstein & Borun
`
`
`James J. Napoli
`6300 Sears Tower
`
`NAME
`233 South Wacker Drive
`
`
`
`Chicago, Illinois 60606
`
`32,361
`United States of America
`REGISTRATION NUMBER
`
`
`19 October 2001
`DATE
`
`
`
`The Commissioneris hereby authorized to charge any additional fees which may be required, or credit any overpayment
`to Deposit Account No.
`13-2855
`A duplicate copy ofthis sheet is enclosed.
`Feesare to be charged to accredit card. WARNING:Information on this form may become public. Credit card
`information should not be included on this form. Provide credit card information and authorization on PTO-2038.
`
`
`
`X]
`
`
`
`
`
`[1
`
`OO
`
`
`
`foe‘eoa
`
`=o
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`oAeS Soo
`°
`
`$0.00
`
`$0.00
`$890.0
`
`SSSSl[s{jsjs
`
`$0.00
`
`$890.0
`>3SeS => s a®
`refunded
`charged
`
`
`
`to cover the abovefees.
`
`A check in the amount of
`
`$890.00
`
`to cover the above fees is enclosed.
`
`Please charge my Deposit Account No.
`A duplicate copy of this sheet is enclosed.
`
`in the amount of
`
`(1
`
`X]
`
`°C)
`
`
`
`c
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`d.
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`Page 2 of 2
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`ATI 1009-0003
`
`ATI 1009-0003
`
`

`

`10/031556
`
`
`IN THE UNITED STATES PATENT
`AND TRADEMARK OFFICE
`
`"EXPRESS MAIL" mailing label
`No. EK6578176710S
`
`Date of Deposit:
`October 19, 2001
`
` eeeeeeeeeeeeeeeeSe
`
`I hereby certify that this
`paper
`(or fee)
`is being
`deposited with the United
`States Postal Service "EXPRESS
`MAIL POST OFFICE TO ADDRESSEE"
`service under 37 CFR §1.10 on
`the date indicated above and is
`addressed to:
`Assistant Commissioner for
`Patents, Washington, D.C.
`20231.
`
`immermann
`
`Applicants:
`
`WILLIAM E. PULLMAN ET AL.
`
`U.S. National Phase of
`PCT/US00/11129 filed April 26,
`2000
`
`Filed: Herewith
`
`For: UNIT DOSAGE FORM
`
`Group Art Unit: Unassigned
`
`Examiner: Unassigned
`
`Attorney Docket No. 29342/36206A
`
`
`
`PRELIMINARY AMENDMENT
`ACCOMPANYING APPLICATION TRANSMITTAL
`
`Commissioner of Patents
`Washington, D.C.
`20231
`
`Sir:
`
`Please amend the above-identified application
`as follows:
`
`IN THE SPECIFICATION:
`
`Page 1, after the title, please delete the
`
`CROSS-REFERENCE TO RELATED APPLICATION in its entirety
`and insert therefor:
`
`
`
`ATI 1009-0004
`
`ATI 1009-0004
`
`

`

`16, 031556
`237 Rec'd Bo”
`19 OCT 2061
`
`--~CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This is the U.S. national phase application of
`
`International Application No. PCT/US00/11129, filed on
`
`April 26, 2000, which claims the benefit of provisional
`
`patent application Serial No. 60/132,036, filed April 30,
`1999.--
`
`IN THE CLAIMS:
`
`Cancel claims 18 and 19 without prejudice.
`Amend claims 7-9 as follows:
`
`7.
`
`(Amended)
`
`The dosage form of claim 1, 2,
`
`3, 4, 5, or 6 wherein the unit dose is in a form selected
`
`from the group consisting of a liquid, a tablet, a cap-
`
`sule, and a gelcap.
`
`8.
`
`(Amended)
`
`The dosage form of claim 1, 2,
`
`3, 4, 5, or 6 wherein the unit dose is in the form of a
`
`tablet.
`
`9.
`
`(Amended)
`
`(Amended)
`
`The dosage form of
`
`claim 1, 2, 3, 4, 5, or 6 for use in treating a condition
`
`wherein inhibition of PDE5 is desirable.
`
`
`
`ATI 1009-0005
`
`ATI 1009-0005
`
`

`

`7
`4 woot
`we I eHtk
`
`537 Ree’d PGtir.
`
`Fi
`
`ey5
`§
`OCT 2003
`co
`
`REMARKS
`
`Claims 1-19 are pending in the application.
`
`Claims 18 and 19 have been cancelled. Therefore, claims
`
`1-17 are at issue in this application.
`
`The amendments are described in more detail
`
`below.
`
`Pursuant to 37 C.F.R. §1.121, a marked-up version
`
`of the changes made to the claims by the present amend-
`
`ment is attached hereto following the signature page of
`
`this amendment.
`
`The first page of the marked-up version
`
`of the changes is captioned "Version With Markings to
`
`Show Changes Made."
`
`This preliminary amendment adds no new matter.
`
`The specification has been amended to insert a cross-
`
`reference to a related application. Claims 7-9 have been
`
`amended to improve the form of the claims.
`
`It is submitted that the amendment should be
`
`entered, and that the claims are of a proper form and
`
`scope for allowance. An early and favorable action on
`
`‘the merits is respectfully requested.
`
`Should the examiner wish to discuss the fore-
`
`going, or any matter of form in an effort to advance this
`
`application toward allowance,
`
`the examiner is urged to
`
`telephone the undersigned at the indicated number.
`
`
`
`ATI 1009-0006
`
`ATI 1009-0006
`
`

`

`Respectfully submitted,
`
`MARSHALL, GERSTEIN & BORUN
`
`—_—_———
`
`By Neues
`
`
`
`James J. Napoli
`{Registration No. 32,361)
`Attorneys for Applicants
`6300 Sears Tower
`233 South Wacker Drive
`Chicago, Illinois
`60606
`(312) 474-6300
`
`Chicago, Illinois
`October 19, 2001
`
`
`
`ATI 1009-0007
`
`ATI 1009-0007
`
`

`

`foe
`fs
`sginevdhti. Low
`BRE Breet Sly
`rere
`
`4
`fi
`
`Version With Markings to Show Changes Made
`(U.S. National Stage of PCT/US00/11129
`filed October 19, 2001)
`
`IN THE SPECIFICATION:
`
`The following cross-reference to related
`
`application has been inserted into the specification:
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This is the U.S. national phase application
`
`of International Application No. PCT/US00/11129, filed
`
`on April 26, 2000, which claims the benefit of
`
`provisional patent application Serial No. 60/132,036,
`
`filed April 30, 1999.
`
`IN THE CLAIMS:
`
`Claims 18 and 19 have been cancelled without
`
`prejudice.
`
`Claims 7-9 have been amended as follows:
`
`7.
`
`(Amended)
`
`The dosage form of
`
`[claims 1
`
`through 6] claim 1, 2, 3, 4, 5, or 6 wherein the unit
`
`dose is in a form selected from the group consisting of
`a liquid, a tablet, a capsule, and a gelcap.
`
`8.
`
`(Amended)
`
`The dosage form of
`
`[claims 1
`
`through 6] claim 1, 2, 3, 4, 5, or 6 wherein the unit
`
`dose is in the form of a tablet.
`
`
`
`
`
`ATI 1009-0008
`
`ATI 1009-0008
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`

`

`9.
`
`(Amended)
`
`The dosage form of
`
`[claims i
`
`through 6] claim 1, 2, 3, 4, 5, or 6 for use in treat-
`
`ing a condition wherein inhibition of PDES5 is desir-
`
`able.
`
`
`
`ATI 1009-0009
`
`ATI 1009-0009
`
`

`

`WO 00/66099
`
`
`
`-~1-
`
`UNIT DOSAGE FORM
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application claims the benefit of
`
`provisional patent application Serial No.
`
`60/132,036, filed April 30, 1999,
`
`FIELD OF THE INVENTION
`
`The present invention relates to a highly
`selective phosphodiesterase (PDE) enzyme inhibitor
`
`and to its use in a pharmaceutical unit dosage form.
`
`In particular,
`
`the present invention relates to a
`
`potent inhibitor of cyclic guanosine 3',5'-mono-
`
`phosphate specific phosphodiesterase type 5
`
`(PDES5)
`
`that when incorporated into a pharmaceutical product
`is useful for the treatment of sexual dysfunction.
`
`The unit dosage form described herein is character-
`
`ized by selective PDES inhibition, and accordingly,
`provides a benefit in therapeutic areas where
`
`inhibition of PDE5 is desired, with minimization or
`
`elimination of adverse side effects resulting from
`
`inhibition of other phosphodiesterase enzymes.
`
`BACKGROUND OF THE INVENTION
`
`The biochemical, physiological, and
`
`clinical effects of cyclic guanosine 3',5'-mono-
`
`phosphate specific phosphodiesterase (cGMP-specific
`PDE)
`inhibitors suggest their utility in a variety
`of disease states in which modulation of smooth
`
`muscle, renal, hemostatic,
`
`inflammatory, and/or
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ATI 1009-0010
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`ATI 1009-0010
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`

`

`WO 00/66099
`
`PCT/US00/11129
`
`
`
`- 2-
`
`Type 5 cGMP-specific
`endocrine function is desired.
`phosphodiesterase (PDE5)
`is the major cGMP hydro-
`lyzing enzyme in vascular smooth muscle, and its
`
`expression in penile corpus cavernosum has been
`
`reported (Taher et al., J. Urol., 149, p. 285A
`(1993)). Thus, PDE5 is an attractive target in the
`
`treatment of sexual dysfunction (Murray, DN&P 6(3),
`
`Pp- 150-56 (1993)).
`
`A pharmaceutical product, which provides a
`
`PDES inhibitor,
`is currently available and marketed
`under the trademark VIAGRA. The active ingredient
`in VIAGRA. is sildenafil.
`The product is sold as an
`article of manufacture including 25, 50, and 100 mg
`tablets of sildenafil and a package insert.
`The
`
`5
`
`10
`
`15
`
`package insert provides that sildenafil is a more
`
`potent inhibitor of PDE5 than other known phospho-
`diesterases (greater than 80 fold for PDE1 inhibi-
`
`tion, greater than 1,000 fold for PDE2, PDE3, and
`
`The Ic,, for sildenafil against
`PDE4 inhibition).
`PDE5 has been reported as 3 nM (Drugs of the Future,
`
`22(2), pp. 138-143 (1997)) and as 3.9 nM (Boolel et
`
`al., Int. J. of Impotence, 8, pp. 47-52 (1996)).
`
`Sildenafil is described as having a 4,000-fold
`
`selectivity for PDE5 versus PDE3, and only a 10-fold
`selectivity for PDE5 versus PDE6.
`Its relative lack
`
`of selectivity for PDE6 is theorized to be the basis
`
`for abnormalities related to color vision.
`
`While sildenafil has obtained significant
`
`commercial success, it has fallen short due to its
`
`including facial
`significant adverse side effects,
`flushing (10% incidence rate). Adverse side effects
`
`limit the use of sildenafil in patients suffering
`from vison abnormalities, hypertension, and, most
`
`20
`
`25
`
`30
`
`ATI 1009-0011
`
`ATI 1009-0011
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`~ 3 +
`
`significantly, by individuals who use organic
`nitrates (Welds et al., Amer. J. of Cardiology,
`83(5A), pp. 21(C)-28(C)
`(1999)).
`
`The use of sildenafil in patients taking
`organic nitrates causes a clinically significant
`drop in blood pressure which could place the patient
`in danger. Accordingly,
`the package label for
`sildenafil provides strict contraindications against
`its use in combination with organic nitrates (e.g.,
`nitroglycerin,
`isosorbide mononitrate,
`isosorbide
`
`nitrate, erythrityl tetranitrate) and other nitric
`
`oxide donors in any form, either regularly or
`intermittently, because sildenafil potentiates the
`hypotensive effects of nitrates.
`See C.R. Conti et
`
`al., Amer. J. of Cardiology, 83(5A), pp. 29C-34C
`(1999). Thus, even with the availability of
`Sildenafil,
`there remains a need to identify
`improved pharmaceutical products that are useful in
`
`treating sexual dysfunction.
`
`Daugan U.S. Patent 5,859,006 discloses
`
`certain tetracyclic derivatives that are potent
`inhibitors of cGMP-specific PDE, or PDES5.
`The IC,,
`ef the compounds disclosed in U.S. Patent No.
`
`5,853,006 is reported in the range of 1 mM to 10 UM.
`The oral dosage for such compounds is 0.58 mg daily
`for an average adult patient
`(70 kg).
`Thus, unit
`dosage forms (tablets or capsules) are reported as
`0.2 to 400 mg of active compound. Significant
`adverse side effects attributed to compounds
`
`disclosed in U.S. Patent No. 5,859,006 are not
`disclosed.
`
`Applicants have discovered that one such
`
`tetracyclic derivative,
`
`(6R,12aR)-2,3,6,7,12,l12a-
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ATI 1009-0012
`
`ATI 1009-0012
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`- 4 -
`
`hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl1) -
`pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione,
`alternatively named (6R-trans) -6-(1,3-benzodioxol -5-
`
`yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-
`[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, and re-
`ferred to herein as Compound (I), can be admin-
`istered in a unit dose that provides an effective
`
`treatment without the side effects associated with
`
`the presently marketed PDE5 inhibitor, sildenafil.
`
`Prior to the present invention such side effects
`
`were considered inherent to the inhibition of PDES5.
`
`Significantly, applicants! clinical
`studies also reveal that an effective product having
`a reduced tendency to cause flushing in susceptible
`individuals can be provided. Most unexpectedly,
`the
`product also can be administered with clinically
`insignificant side effects associated with the com-
`
`bined effects of a PDE5 inhibitor and an organic
`nitrate.
`Thus,
`the contraindication once believed
`
`necessary for a product containing a PDE5 inhibitor
`is unnecessary when Compound (I)
`is administered as
`a unit dose of about 1 to about 20 mg, as disclosed
`herein.
`Thus,
`the present
`invention provides an
`effective therapy for sexual dysfunction in indi-
`viduals who previously were untreatable or suffered
`
`including individ-
`from unacceptable side effects,
`uals having cardiovascular disease, such as in
`
`individuals requiring nitrate therapy, having
`suffered a myocardial infarction more than three
`
`months before the onset of sexual dysfunction
`therapy, and suffering from class 1 congestive heart
`failure, or individuals suffering from vision ab-
`normalities.
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ATI 1009-0013
`
`ATI 1009-0013
`
`

`

`WO 00/66099
`
`PCT/US60/11129
`
`-5-
`
`The present invention provides Compound
`(I} in a unit dosage form. That is,
`the present
`invention provides a pharmaceutical unit dosage form
`Suitable for oral administration comprising about 1
`to about 20 mg Compound (I).
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a pharma-
`ceutical dosage form for human pharmaceutical use,
`comprising about 1 to about 20 mg of
`(6R,12aR)-
`2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylene-
`dioxyphenyl) pyrazino[2',1':6,1]pyrido[3,4-b]indole-
`1,4-dione in a unit dosage form suitable for oral
`administration.
`
`invention further provides a
`The present
`method of treating conditions where inhibition of
`PDE5 is desired, which comprises administering to a
`patient in need thereof an oral dosage form con-
`taining about 1 to about 20 mg of a selective PDES
`inhibitor, as needed, up to a total dose of 20 mq
`per day.
`The invention further provides the use of
`
`an oral dosage form comprising a selective PDES5
`inhibitor at a dosage of about
`1 to about 20 mg for
`the treatment of sexual dysfunction.
`Specific conditions that can be treated by
`the present invention,
`include, but are not limited
`
`to, male erectile dysfunction and female sexual
`dysfunction, particularly female arousal disorder,
`also known as female sexual arousal disorder.
`
`In particular,
`the present
`invention is
`directed to a pharmaceutical unit dosage composition
`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ATI 1009-0014
`
`ATI 1009-0014
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`-6-
`
`comprising about 1 to about 20 mg of a compound
`
`having the structural formula:
`
`°
`
`10
`
`H Oo
`whces
`
`=
`N
`H H =
`~
`
`N
`
`oO
`
`oO
`o—/
`
`15
`
`said unit dosage form suitable for oral administra-
`
`tion, and method of treating sexual dysfunction
`
`using the pharmaceutical unit dose composition.
`
`20
`
`DETAILED DESCRIPTION
`
`For purposes of the present invention as
`
`the following terms
`disclosed and described herein,
`and abbreviations are defined as follows.
`
`The term "container" means any receptacle
`
`25
`
`and closure therefor suitable for storing, shipping,
`
`dispensing, and/or handling a pharmaceutical prod-
`uct.
`
`The term "Ic.," is the measure of potency
`
`of a compound to inhibit a particular PDE enzyme
`
`30
`
`(e.g., PDElc, PDE5, or PDE6).
`
`The IC,, is the con-
`
`centration of a compound that results in 50% enzyme
`
`inhibition in a single dose-response experiment.
`
`Determining the IC;, value for a compound is readily
`
`
`
`
`ATI 1009-0015
`
`ATI 1009-0015
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`
`
`- 7 -
`
`carried out by a known in vitro methodology
`generally described in ¥. Cheng et al., Biochem.
`
`Pharmacol., 22, pp. 3099-3108 (1973).
`
`The term "package insert" means informa-
`
`5
`
`tion accompanying the product that provides a de-
`scription of how to administer the product, along
`with the safety and efficacy data required to allow
`
`the physician, pharmacist, and patient to make an
`
`informed decision regarding use of the product.
`
`The
`
`10
`
`package insert generally is regarded as the "label"
`
`for a pharmaceutical product.
`
`The term "oral dosage form" is used ina
`general sense to reference pharmaceutical products
`administered orally. Oral dosage forms are recog-
`nized by those skilled in the art to include such
`
`15
`
`forms as liquid formulations,
`gelcaps.
`
`tablets, capsules, and
`
`The term "vision abnormalities" means ab-
`
`normal vision characterized by blue-green vision
`
`20
`
`believed to be caused by PDE6 inhibition.
`
`The term "flushing" means an episodic
`
`redness of the face and neck attributed to vaso-
`
`dilation caused by ingestion of a drug, usually
`accompanied by a feeling of warmth over the face and
`
`25
`
`neck and sometimes accompanied by perspiration.
`
`The term "free drug" means solid particles
`of drug not intimately embedded in a polymeric
`
`coprecipitate.
`
`30
`
`preferably is packaged as an article of manufacture
`
`The presently claimed dosage form
`
`for human pharmaceutical use, comprising a package
`insert, a container, and a dosage form comprising
`about
`1 to about 20 mg of Compound (I)
`
`ATI 1009-0016
`
`ATI 1009-0016
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`-
`
`8
`
`-
`
`5
`
`The package insert provides a description
`of how to administer a pharmaceutical product, along
`with the safety and efficacy data required to allow
`
`the physician, pharmacist, and patient to make an
`
`informed decision regarding the use of the product.
`The package insert generally is regarded as the
`label of the pharmaceutical product.
`The package
`insert incorporated into the article of manufacture
`
`indicates that Compound (I)
`
`is useful in the
`
`10
`
`treatment of conditions wherein inhibition of PDES
`
`
`
`i5
`
`20
`
`25
`
`30
`
`is desired.
`
`The package insert also provides
`
`instructions to administer one or more about 1 to
`
`about 20 mg unit dosage forms as needed, up to a
`maximum total dose of 20 mg per day. Preferably,
`the dose administered is about 5 to about 20 mg/day,
`more preferably about 5 to about 15 mg/day. Most
`
`preferably, a 10 mg dosage form is administered once
`
`per day.
`
`Preferred conditions to be treated include
`
`sexual dysfunction (including male erectile dysfunc-
`tion; and female sexual dysfunction, and more
`
`preferably female arousal disorder (FAD)).
`
`The
`
`preferred condition to be treated is male erectile
`
`dysfunction.
`
`the package insert supports
`Significantly,
`the use of the product to treat sexual dysfunction
`in patients suffering from a retinal disease, for
`
`example, diabetic retinopathy or retinitis pig-
`
`mentosa, or in patients who are using organic
`nitrates.
`Thus,
`the package insert preferably is
`free of contraindications associated with these
`
`conditions, and particularly the administration of
`
`the dosage form with an organic nitrate. More
`
`ATI 1009-0017
`
`ATI 1009-0017
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`-9-
`
`the package insert also is free of any
`preferably,
`cautions or warnings both associated with retinal
`diseases, particularly retinitis pigmentosa, and
`associated with individuals prone to vision ab-
`
`the package insert also
`normalities. Preferably,
`reports incidences of flushing below 2%, preferably
`below 1%, and most preferably below 0.5%, of the
`
`patients administered the dosage form.
`
`The inci-
`
`dence rate of flushing demonstrates marked improve-
`
`ment over prior pharmaceutical products containing a
`PDE5 inhibitor.
`
`The container used in the article of
`
`manufacture is conventional
`
`in the pharmaceutical
`
`the container is a blister pack,
`arts. Generally,
`foil packet, glass or plastic bottle and accompany-
`ing cap or closure, or other such article suitable
`
`for use by the patient or pharmacist. Preferably,
`the container is sized to accommodate 1-1000 solid
`
`dosage forms, preferably 1 to 500 solid dosage
`forms, and most preferably,
`5 to 30 solid dosage
`forms.
`
`Oral dosage forms are recognized by those
`skilled in the art to include,
`for example, such
`forms as liquid formulations,
`tablets, capsules, and
`gelcaps.
`Preferably the dosage forms are solid
`dosage forms, particularly,
`tablets comprising about
`1 to about 20 mg of Compound (I). Any pharmaceut-
`ically acceptable excipients for oral use are suit-
`
`able for preparation of such dosage forms. Suitable
`pharmaceutical dosage forms include coprecipitate
`forms described, for example,
`in Butler U.S. Patent
`
`No. 5,985,326,
`
`incorporated herein by reference.
`
`In
`
`preferred embodiments,
`
`the unit dosage form of the
`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ATI 1009-0018
`
`ATI 1009-0018
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`-~ 10 -
`
`present invention is a solid free of a coprecipitate
`
`form of Compound (I), but rather contains solid
`
`Compound (I) as a free drug.
`
`Preferably,
`
`the tablets comprise pharma-
`
`ceutical excipients generally recognized as safe
`
`such as lactose, microcrystalline cellulose, starch,
`
`calcium carbonate, magnesium stearate, stearic acid,
`
`talc, and colloidal silicon dioxide, and are pre-
`
`pared by standard pharmaceutical manufacturing tech-
`
`niques as described in Remington's Pharmaceutical
`
`Sciences, 18th Ed., Mack Publishing Co., Easton, PA
`
`(1990).
`
`Such techniques include, for example, wet
`
`granulation followed by drying, milling, and com-
`
`pression into tablets with or without film coating;
`dry granulation followed by milling, compression
`
`into tablets with or withouy film coating; dry
`
`blending followed by compreSsion into tablets, with
`
`or without film coating; molded tablets; wet gran-
`ulation, dried and filled into gelatin capsules; dry
`
`blend filled into gelatin capsules; or suspension
`
`and solution filled into gelatin capsules. Gener-
`
`the solid dosage forms have identifying marks
`ally,
`which are debossed or imprinted on the surface.
`
`The present invention is based on detailed
`
`experiments and clinical trials, and the unexpected
`
`observations that side effects previously believed
`
`to be indicative of PDE5 inhibition can be reduced
`
`to clinically insignificant levels by the selection
`
`of a compound and unit dose. This unexpected obser-
`
`vation enabled the development of a unit dosage form
`that incorporates Compound (I)
`in about 1 to about
`
`20 mg per unit dosage forms that, when orally admin-
`istered, minimizes undesirable side effects previ-
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ATI 1009-0019
`
`ATI 1009-0019
`
`

`

`WO 60/66699
`
`PCT/US00/11129
`
`-~ 1t
`
`-
`
`ously believed unavoidable. These side effects
`
`include facial flushing, vision abnormalities, anda
`significant decrease in blood pressure, when Com-
`pound (I)
`is administered alone or in combination
`
`5
`
`with an organic nitrate.
`The minimal effect of
`Compound (I), administered in about 1 to about 20 mg
`unit dosage forms, on PDE6 also allows the adminis-
`
`tration of a selective PDE5 inhibitor to patients
`suffering from a retinal disease,
`like diabetic
`
`10
`
`retinopathy or retinitis pigmentosa.
`
`15
`
`20
`
`Compound (I) has the following structural
`
`formula:
`
`Ho
`we NTCH;
`
`iar
`
`He
`
`vt
`
`is
`
`(I)
`
`The compound of structural formula (I} was demon-
`
`25
`
`strated in human clinical studies to exert a minimal
`
`30
`
`impact on systolic blood pressure when administered
`in conjunction with organic nitrates.
`By contrast,
`Sildenafil demonstrates a four-fold greater decrease
`in systolic blood pressure over a placebo, which
`leads to the contraindications in the VIAGRA» in-
`sert, and in warnings to certain patients.
`
`The following illustrates the PDE5 and
`
`PDE6 IC,, values for the compound of structural
`
`ATI 1009-0020
`
`ATI 1009-0020
`
`

`

`WO 00/66099
`
`PCT/US00/11129
`
`- 12 -
`
`formula (I) determined by the procedures described
`herein.
`
`
`
`PDE5 IC,, (mM)|PDE6 IC,, (nM) PDE6 /PDE5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The compound of structural formula (I) additionally
`demonstrates an IC.,, against PDElc of 10,000, and a
`
`ratio of PDE1c/PDES5 of 4,000.
`
`PREPARATIONS
`
`Human PDE5 Preparation
`
`10
`
`15
`
`Recombinant production of human PDE5 was
`
`carried out essentially as described in‘Example 7 of
`
`incorporated herein by
`U.S. Patent No. 5,702,936,
`reference, except that the yeast transformation
`
`20
`
`vector employed, which is derived from the basic
`
`25
`
`ADH2 plasmid described in V. Price et al., Methods
`
`incorpor-
`in Enzymology, 1985, pages 308-318 (1990),
`ated yeast ADH2 promoter and terminator sequences
`rather than ADH1 promoter and terminator sequences
`and the Saccharomyces cerevisiase host was the
`
`protease-deficient strain BJ2-54 deposited on August
`31, 1998 with the American Type Culture Collection,
`
`Manassas, Virginia, under accession number ATCC
`
`74465. Transformed host celis were grown in 2X SC-
`
`30
`
`leu medium, pH 6.2, with trace metals, and vitamins.
`
`After 24 hours, YEP medium containing glycerol was
`added to a final concentration of 2X YEP/3% glycer-
`ol. Approximately 24 hours later, cells were
`
`harvested, washed, and stored at -70°C.
`
`ATI 1009-0021
`
`ATI 1009-0021
`
`

`

`WO 06/66099
`
`PCT/US00/11129
`
`- 13 -
`
`Cell pellets (29 g) were thawed on ice
`with an equal volume of lysis buffer (25 mM Tris-Cl,
`PH 8,
`5 mM MgCl,, 0.25 mM dithiothreitol,
`1 mM
`benzamidine, and 10 pM ZnSO,). Cells were lysed in
`a microfluidizer with N, at 20,000 psi.
`The lysate
`was centrifuged and filtered through 0.45 pm dis-
`posable filters.
`The filtrate was applied to a 150
`mL column of Q Sepharose Fast Flow (Pharmacia).
`The
`column was washed with 1.5 volumes of Buffer A (20
`mM Bis-Tris Propane, pH 6.8,
`1 mM MgCl,, 0.25 m™
`dithiothreitol, 10 pM ZnSO,) and eluted with a step
`gradient of 125 mM NaCl in Buffer A followed by a
`linear gradient of 125-1000 mM NaCl in Buffer A.
`
`Active fractions from the linear gradient
`were applied to a 180 mL ceramic hydroxyapatite
`column in Buffer B (20 mM Bis-Tris Propane (pH 6.8),
`1 mM MgCl,, 0.25 mM dithiothreitol, 10 BM ZnSO,, and
`250 mM KCl). After loading,
`the column was washed
`with 2 volumes of Buffer B and eluted with a linear
`gradient of 0-125 mM potassium phosphate in Buffer
`B. Active fractions were pooled, precipitated with
`60% ammonium sulfate, and resuspended in Buffer Cc
`(20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM
`dithiothreitol, and 1