PCT
`
`ORLD INTELLECTUAL PROPERTY ORGANIZ
`International Bureau
`
`\
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 7 :
`A61K 31/00
`
`(43) International Publication Date:
`
`9 November 2000 (09.11.00)
`
`(11) International Publication Number:
`
`WO 00/66099
`
`(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, IP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
`LV, MA, MD, MG, MK, MN, MW, MX, NO, N PL, PT,
`RO, RU, SD, SE, 86, SI, SK, SL, TI, TM, TR, TI‘, TZ,
`UA, UG, US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH,
`GM, ICE, LS, MW, SD, SL, 82, 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).
`
`Published
`Without international search report and to be republished
`upon receipt of that report.
`
`(21) International Application Number:
`
`PCP/USOO/l 1 129
`
`(22) International Filing Date:
`
`26 April 2000 (26.04.00)
`
`(30) Priority Data:
`60/132,036
`
`30 April 1999 (3004.99)
`
`US
`
`(71) Applimnt (for all 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,
`Ernest [US/US]; 3004 Towne Dn‘ve, Carmel, IN 46032
`(US). WHITAKER, John, Steven [US/US]; 19340 162nd
`Avenue, Woodinville, WA 98072 (US).
`
`J.; Marshall, O’Toole, Gel-stein,
`(’74) Agent: NAPOLI, James,
`Murray & Borun, 6300 Sears Tower, 233 South Wacker
`Drive, Chicago, IL 60606 (US).
`
`(54) Title: UNIT DOSAGE FORM
`
`tor the treatment of sexual dysfunction.
`
`The present invention relates to highly selective phosphodiesterase (PDE) enzyme inhibitors and to their use in pharmaceutical
`les 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
`
`

`

`11-2000
`U.S. DEPARTMENT OF COMJWERCE PATENT AND TRADEMARK OFFICE
`(185W Pro-1390 (Modified)
`TRAN SMITTAL LETTER TO THE UNITED STATES
`
`2934256206“
`
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A FILING UNDER 35 U.S.C. 371
`INTERNATIONAL APPLICATION NO.
`INTERNATIONAL FILING DATE
`PCT/U500“ I 129
`26 A t ril 2000
`
`U-S- ATL5A7ONNO- fiFKNOWN’ SEE 37 CFR
`U 3 5 5 6
`PRIORITY DATE CLAIMED
`30 A I Ti] 1999
`
`. PLICANT(S) FOR DO/EO/US
`' ULLMAN, William Ernest and WHITAKER, John Steven
`
`‘ pplicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`
`1. Z This is a FIRST submission of items concerning a filing under 35 U.S.C. 371.
`
`
`2.
`This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`
`
`3.
`This is an express request to begin national examination procedures (35 U.S.C. 371(0). The submission must include itens (5), (6),
`(9) and (24) indicated below.
`
`‘
`
`The US has been elected by the expiration of 19 months from the priority date (Article 31).
`
`4.
`
`5.
`
`I. A copy of the International Application as filed (35 U.S.C. 371 (c) (2))
`a. Cl
`is attached hereto (required only if not communicated by the International Bureau).
`' b.
`has been communicated by the International Bureau.
`c. E is not required, as the application was filed in the United States Receiving Office (RO/U S).
`An English language translation of the International Application as filed (35 U.S.C. 371 (c)(2)).
`:I
`is attached hereto.
`
`
`
`
`
`Return receipt postcard
`
`
` EDUDUUUEAJU
`
`
`
`
`
`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))
`:I
`are attached hereto (required only if not communicated by the International Bureau).
`:1
`have been communicated by the International Bureau.
`:l
`have not been made; however, the time limit for making such amendments has NOT expired.
`have not been made and will not be made.
`
`.
`(1.
`
`An English language translation of the amendments to the claims under PCT Article 19 (35 U.SIC. 371(c)(3)).
`An oath or declaration of the inventor(s) (35 U.S.C. 371 (c)(4)).
`An English language translation of the annexes to the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371 (c)(5)).
`
`A copy of the International Preliminary Examination Report (PCT/IPEA/409).
`A copy of the International Search Report (PCT/lSA/ZIO).
`
`Items 13 to 20 below concern document(s) or information included:
`An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`A FIRST preliminary amendment.
`A SECOND or SUBSEQUENT preliminary amendment.
`A substitute specification.
`A change of power of attorney and/or address letter.
`A computer-readable form of the 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 language translation of the international application under 35 U.S.C. 154(d)(4).
`Certificate of Mailing by Express Mail
`Other items or information:
`
`[2
`
`Page 1 of 2
`
`Pcrusunevoa
`
`ATI 1009-0002
`
`ATI 1009-0002
`
`

`

`Indeendent claims
`
`17
`
`2
`
`~20—
`
`- 3= “ x
`
`$84.00
`
`
`
`m
`
`x
`
`$18-00
`
`
`
`
`
`
`
`D5 V, Applicant claims small entity status. See 37 CFR 1.27). The fees indicated above are
`5" reduced by 1/2.
`
`
`
`
`
`
`
`
`
`Pistessing fee of $130.00 for furnishing the English translation later than
`ngeaths from the earliest claimed priority date (37 CFR 1.492 (0).
`
`
`
`
`
`
`
`
`$890_00-
`$0.00
`
`$0.0
`
`$0.0
`$0-0
`$890-0
`
`66ea99s:P9CGgGCODGO
`
`$890.00
`
`$890.00
`
`$890.00
`Amount to be:
`refunded
`charged
`
`
`
`24.
`
`$1040.00
`
`$890.00
`
`
`
`
`
`$740.00
`
`$710.00
`
`
`
`
`
`
`.
`
`v
`2
`, u
`I:
`:.‘
`ATTORNEY'S DOCKET NUMBER
`29342/36206A
`CALCULATIONS PTO USE ONLY
`
`
`
`
`
`
`
`
`
`J
`
`._
`’
`,.
`.
`.
`g:
`,05E 7 7”—
`U.S. APPLICATIO
`I
`.
`INTERNATIONAL APPLICATION NO.
`TWIKE‘E .1. ‘5} 5%
`PCT/USOO/11129
`
`The following fees are submitted:.
`
`BASIC NATIONAL FEE ( 37 CFR 1.492 (a) (1) - (5)) :
`
`
`El Neither international preliminary examination fee (37 CFR 1.482) nor
`international search fee (37 CFR l.445(a)(2)) paid to USPTO
`and International Search Report not prepared by the EPO or PO ............
`
`E International preliminary examination fee (37 CFR 1.482) not paid to
`
`USPTO but 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 .
`.
`.
`. ........
`:1 International preliminary examination fee (37 CFR 1.482) paid to USPTO
`but all claims did not satisfy provisions of PCT Article 33(1)-(4) ............
`Z International preliminary examination fee (37 CFR 1.482) paid to USPTO
`and all claims satisfied provisions of PCT Article 33(1)—(4) ..........
`$100.00
`ENTER APPROPRIATE BASIC FEE AMOUNT =
`
`
`i: 20
`Surcharge of $130.00 for furnishing the oath or declaration later than
`:1 30
`
`months fiom the earliest claimed priority date (37 CFR 1.492 (e)).
`NUMBERHLED
`
`or recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be
`accompanied by an appropriate cover sheet (37 CFR 3.28, 3.31) (check if applicable).
`
`
`
`$890.00
`
`to cover the above fees is enclosed.
`
`
`
`A check in the amount of
`
`to cover the above fees.
`
`
`
`c.
`
`M
`
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment
`to Deposit Account No.
`13-2855
`A duplicate copy of this sheet is enclosed.
`
`d.
`
`' El
`
`Fees are to be charged to a credit 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.
`
`Please charge my Deposit Account No.
`in the amount of
`
`A duplicate copy of this sheet is enclosed.
`
`
`
`
`NOTE: ‘Where an 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 CORRESPONDENCE TO:
`
`
`
`
`@
`NAPOLI, James J.
` SIGNATURE
`
`Customer No. 04743
`Marshall, Gerstein & Borun
`
`
`
`James J. Napoli
`6300 Sears Tower
`
`NAME
`233 South Wacker Drive
`
`
`Chicago, Illinois 60606
`
`32,361
`
`United States 01' America
`REGISTRATION NUMBER
`
`19 October 2001
`
`DATE
`
`
`Page 2 of 2
`
`ATI 1009-0003
`
`ATI 1009-0003
`
`

`

`10/031556
`1% OCT 23m
`
`PATENT
`
`IN THE UNITED STATES PATENT
`AND TRADEMARK OFFICE
`
`Applicants:
`
`WILLIAM E. PULLMAN ET AL.
`
`U.S. National Phase of
`PCT/USOO/11129 filed April 26,
`2000
`
`Filed: Herewith
`
`For: UNIT DOSAGE FORM
`
`Group Art Unit: Unassigned
`
`Examiner: Unassigned
`
`Attorney Docket No. 29342/36206A
`
`
`
`"EXPRESS MAIL" mailing label
`No. EK657817671US
`
`Date of Deposit:
`October 19, 2001
`
`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 §l.10 on
`the date indicated above and is
`addressed to:
`Assistant Commissioner for
`Patents, Washington, D.C.
`20231.
`
` VVVVVVVVVVVVVVVVVVVVVV
`
`immermann
`
`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—REFEQENCE TO RELATED APPLICATION in its entirety
`and insert therefor:
`
`
`
`ATI 1009-0004
`
`ATI 1009-0004
`
`

`

`19/Q3155fi
`53"? gm??? ”#5“ "‘
`19 OCT 2001
`
`-—CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This is the U.S. national phase application of
`
`International Application No. PCT/USOO/lll29, 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 PDES is desirable.
`
`[YT11009-0005
`
`ATI 1009-0005
`
`

`

`i3.@2l§§@
`5‘3"? R962? FEW 1% GCT 20m
`
`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. §l.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
`
`
`
`(iEEQLGZ?
`
`James J. Napoli
`(Registration No. 32,361)
`Attorneys for Applicants
`6300 Sears Tower
`233 South Wacker Drive
`
`Chicago, Illinois
`(312) 474—6300
`
`60606
`
`Chicago, Illinois
`October 19, 2001
`
`
`
`ATI 1009-0007
`
`ATI 1009-0007
`
`

`

`“3% imam;
`
`L; w
`
`Version With Markings to Show Changes Made
`(U.S. National Stage of PCT/USOO/lll29
`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/USOO/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:
`
`
`
`
`
`The dosage form of
`(Amended)
`
`through 6] claim 1, 2, 3, 4, 5, or 6 wherein the unit
`
`[claims 1
`
`7.
`
`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,
`
`3E 4, 5, or 6 wherein the unit
`
`dose is in the form of a tablet.
`
`ATI 1009-0008
`
`ATI 1009-0008
`
`

`

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

`

` WO 00166099
`
`_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
`
`5
`
`10
`
`
`
`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
`
`15
`
`potent inhibitor of cyclic guanosine 3',5'—mono—
`
`phosphate specific phosphodiesterase type 5
`
`(PDES)
`
`that when incorporated into a pharmaceutical product
`
`is useful for the treatment of sexual dysfunction.
`
`The unit dosage form described herein is character—
`
`20
`
`ized by selective PDES inhibition, and accordingly,
`
`provides a benefit in therapeutic areas where
`
`inhibition of PDES is desired, with minimization or
`
`elimination of adverse side effects resulting from
`
`inhibition of other ph0sphodiesterase enzymes.
`
`25
`
`BACKGROUND OF THE INVENTION
`
`The biochemical, physiological, and
`
`clinical effects of cyclic guanosine 3',5'—mono—
`
`30
`
`phosphate specific phosphodiesterase (cGMP—specific
`
`inhibitors suggest their utility in a variety
`PDE)
`of disease states in which modulation of smooth
`
`muscle, renal, hemostatic,
`
`inflammatory, and/or
`
`ATI 1009-0010
`
`ATI 1009-0010
`
`

`

`WO 00/66099
`
`PCT/U800/1 1 129
`
`_2_
`
`endocrine function is desired.
`
`Type 5 cGMP-specific
`
`phosphodiesterase (PDE5)
`
`is the major cGMP hydro-
`
`lyzing enzyme in vascular smooth muscle, and its
`
`expression in penile corpus cavernosum has been
`
`5
`
`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
`
`10
`
`is currently available and marketed
`PDES inhibitor,
`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
`
`15
`
`package insert provides that sildenafil is a more
`
`potent inhibitor of PDE5 than other known phospho-
`
`diesterases (greater than 80 fold for PDEl inhibi-
`
`tion, greater than 1,000 fold for PDEZ, PDE3, and
`
`PDE4 inhibition).
`
`The ICso for sildenafil against
`
`20
`
`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
`
`25
`
`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
`
`30
`
`significant adverse side effects,
`
`including facial
`
`flushing (10% incidence rate). Adverse side effects
`
`limit the use of sildenafil in patients suffering
`
`from vison abnormalities, hypertension, and, most
`
`
`
`ATI 1009-0011
`
`ATI 1009-0011
`
`

`

`WO 00166099
`
`PCT/US00/l 1129
`
`-3-
`
`significantly, by individuals who use organic
`
`nitrates (Welds et al., Amer. J. of Cardiology,
`
`83(5A), pp. 21(C)—28(C)
`
`(1999)).
`
`5
`
`organic nitrates causes a clinically significant
`
`The use of sildenafil in patients taking
`
`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.,
`
`10
`
`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
`
`15
`
`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.
`
`20
`
`Daugan U;S. Patent 5,859,006 discloses
`
`certain tetracyclic derivatives that are potent
`
`The IC50
`inhibitors of cGMP—specific PDE, or PDES.
`of the compounds disclosed in U.S. Patent No.
`
`5,859,006 is reported in the range of 1 nM to 10 uM.
`
`25
`
`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
`
`30
`
`disclosed in U.S. Patent No. 5,859,006 are not
`disclosed.
`
`Applicants have discovered that one such
`
`tetracyclic derivative,
`
`(6R,12aR)—2,3,6,7,12,12a—
`
`
`
`ATI 1009-0012
`
`ATI 1009-0012
`
`

`

`W0 (JO/66099
`
`PCT/USOO/l 1 129
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`>
`
`V
`
`
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`_ 4 _
`
`hexahydro—Z—methyl-G—(3,4—methylenedioxyphenyl)—
`
`pyrazino[2',l':6,l]pyrid0[3,4—b]indole—l,4—dione,
`
`alternatively named (GR-trans)—6-(1,3—benzodioxol—S—
`
`yl)—2,3,6,7,12,lZa—hexahydro—Z—methylpyrazino-
`
`5
`
`[l',2':l,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 PDES inhibitor, sildenafil.
`
`10
`
`Prior to the present invention such side effects
`
`were considered inherent to the inhibition of PDES.
`
`Significantly, applicants' Clinical
`
`studies also reveal that an effective product having
`
`a reduced tendency to cause flushing in susceptible
`
`15
`
`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 PDES inhibitor and an organic
`nitrate.
`Thus,
`the contraindication once believed
`
`2O
`
`necessary for a product containing a PDES 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—
`
`25
`
`viduals who previously were untreatable or suffered
`
`from unacceptable side effects,
`
`including individ-
`
`uals having cardiovascular disease, such as in
`
`individuals requiring nitrate therapy, having
`
`suffered a myocardial infarction more than three
`
`30
`
`months before the onset of sexual dysfunction
`
`therapy, and suffering from class 1 congestive heart
`
`failure, or individuals suffering from vision ab—
`normalities.
`
`ATI 1009-0013
`
`ATI 1009-0013
`
`

`

`W0 (JO/66099
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`PCT/USOO/11129
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`-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
`
`5
`
`to about 20 mg Compound (I).
`
`fiflMMAEX.QE_IHE_lEEEHIlQH
`
`
`
`lO
`
`ceutical dosage form for human pharmaceutical use,
`
`The present invention provides a pharma—
`
`comprising about 1 to about 20 mg of
`
`(6R,12aR)-
`
`2,3,6,7,12,lZa-hexahydro—Z—methyl—6-(3,4-methylene—
`
`dioxyphenyl)pyrazino[2',l':6,l]pyrido[3,4~b]indole—
`
`15
`
`l,4-dione in a unit dosage form suitable for oral
`administration.
`
`The present
`
`invention further provides a
`
`method of treating conditions where inhibition of
`
`PDES is desired, which comprises administering to a
`
`patient in need thereof an oral dosage form con—
`
`20
`
`taining about 1 to about 20 mg of a selective PDES
`
`inhibitor, as needed, up to a total dose of 20 mg
`
`per day.
`
`The invention further provides the use of
`
`an oral dosage form comprising a selective PDES
`
`inhibitor at a dosage of about
`
`1 to about 20 mg for
`
`25
`
`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,
`
`30
`
`also known as female sexual arousal disorder.
`
`In particular,
`
`the present
`
`invention is
`
`directed to a pharmaceutical unit dosage composition
`
`ATI 1009-0014
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`ATI 1009-0014
`
`

`

`WO 00166099
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`PCT/USODII l 129
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`_ 6 _
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`comprising about 1 to about 20 mg of a compound
`
`having the structural formula:
`
`10
`
`N
`
`N
`
`_
`N
`H H :
`‘
`
`O
`
`0
`04
`
`
`
`
`15
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`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.
`
`25
`
`and closure therefor suitable for storing, shipping,
`
`The term "container" means any receptacle
`
`dispensing, and/or handling a pharmaceutical prod—
`uct.
`
`The term ”ICE" is the measure of potency
`
`of a compound to inhibit a particular PDE enzyme
`
`30
`
`(e.g., PDElc, PDE5, or PDEG).
`
`The IC5° is the con—
`
`centration of a compound that results in 50% enzyme
`
`inhibition in a single dose—response experiment.
`
`Determining the IC50 value for a compound is readily
`
`ATI 1009-0015
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`ATI 1009-0015
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`

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`WO 00/66099
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`PCT[USOO/l 1129
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`-7-
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`carried out by a known in Vitro methodology
`
`generally described in Y. Cheng et al., Biochem.
`
`Pharmacol., 22, pp. 3099—3108 (1973).
`
`The term "package insert" means informa-
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`5
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`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
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`10
`
`package insert generally is regarded as the "label"
`
`for a pharmaceutical product.
`
`The term "oral dosage form" is used in a
`
`general sense to reference pharmaceutical products
`
`administered orally. Oral dosage forms are recog—
`
`15
`
`nized by those skilled in the art to include such
`
`forms as liquid formulations,
`
`tablets, capsules, and
`
`gelcaps.
`
`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.
`
`The presently claimed dosage form
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`30
`
`preferably is packaged as an article of manufacture
`
`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
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`ATI 1009-0016
`
`

`

`WO 00/66099
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`PCT/USOO/11129
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`_
`
`8
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`_
`
`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
`
`S
`
`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
`
`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,
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`15
`
`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
`
`20
`
`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.
`
`25
`
`Significantly,
`
`the package insert supports
`
`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
`
`30
`
`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
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`ATI 1009-0017
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`

`

`WO 00/66099
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`PCI‘IU800/11129
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`-9-
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`preferably,
`
`the package insert also is free of any
`
`cautions or warnings both associated with retinal
`
`diseases, particularly retinitis pigmentosa, and
`
`associated with individuals prone to vision ab-
`
`5
`
`normalities. Preferably,
`
`the package insert also
`
`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—
`
`10
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`ment over prior pharmaceutical products containing a
`PDES inhibitor.
`
`The container used in the article of
`
`manufacture is conventional
`
`in the pharmaceutical
`
`arts. Generally,
`
`the container is a blister pack,
`
`15
`
`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
`
`20
`
`forms, and most preferably,
`forms.
`
`5 to 30 solid dosage
`
`
`
`Oral dosage forms are recognized by those
`
`skilled in the art to include,
`
`for example, such
`
`forms as liquid formulations,
`
`tablets, capsules, and
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`25
`
`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
`
`3O
`
`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
`
`ATI 1009-0018
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`ATI 1009-0018
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`

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`W0 [JO/66099
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`PCT/USDDII l 129
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`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 withou2 film coating; dry
`
`blending followed by compre sion 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-
`
`ally,
`
`the solid dosage forms have identifying marks
`
`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 PDES 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
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`ATI 1009-0019
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`

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`WO 00/66099
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`PCT/USOO/l 1 129
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`_11_
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`ously believed unavoidable. These side effects
`
`include facial flushing, vision abnormalities, and a
`
`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 PDES inhibitor to patients
`
`suffering from a retinal disease,
`
`like diabetic
`
`10
`
`retinopathy or retinitis pigmentosa.
`
`Compound (I) has the following structural
`
`formula:
`
`15
`
`20
`
`H
`III,.
`
`/CH3
`
`N
`
`:t: m
`
`Ill!
`
`‘10
`
`(I)
`
`The compound of structural formula (I) was demon—
`
`25
`
`strated in human clinical studies to exert a minimal
`
`impact on systolic blood pressure when administered
`
`in conjunction with organic nitrates.
`
`By contrast,
`
`sildenafil demonstrates a four—fold greater decrease
`
`30
`
`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 PDES and
`
`PDE6 IC50 values for the compound of structural
`
`ATI 1009-0020
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`ATI 1009-0020
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`

`

`W0 (IO/66099
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`PCT/USOG/l 1129
`
`_12_
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`formula (I) determined by the procedures described
`herein.
`
`
`
`
`
`
`PDES Ic5°
`
`(nM)
`
`
`
`PDES :ccsu
`
`(nM)
`
`PDEG/PDES
`
`
`
`
`
`
`The compound of structural formula (I) additionally
`
`10
`
`demonstrates an IC'50 against PDElc of 10,000, and a
`
`ratio of PDElc/PDES of 4,000.
`
`PREPARATIONS
`
`Human PDES Preparation
`
`15
`
`Recombinant production of human PDES was
`
`carried out essentially as described in'Example 7 of
`
`U.S. Patent No. 5,702,936,
`
`incorporated herein by
`
`reference, except that the yeast transformation
`
`20
`
`vector employed, which is derived from the basic
`
`ADH2 plasmid described in V. Price et al., Methods
`
`in Enzymologyy 1985, pages 308—318 (1990),
`
`incorpor—
`
`ated yeast ADH2 promoter and terminator sequences
`
`rather than ADHl promoter and terminator sequences
`
`25
`
`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 cells 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.
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`ATI 1009-0021
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`ATI 1009-0021
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`

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`WO 00166099
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`PCT/U800/1 1 129
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`_ 13 _
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`Cell pellets (29 g) were thawed on ice
`
`with an equal volume of lysis buffer (25 mM Tris—Cl,
`
`pH 8,
`
`5 mM MgClZ, 0.25 mM dithiothreitol,
`
`1 mM
`
`benzamidine, and 10 uM ZnSO4). Cells were lysed in
`
`5
`
`a microfluidizer with N2 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
`
`10
`
`mM Bis~Tris Propane, pH 6.8,
`
`1 mM MgClz, 0.25 mM
`
`dithiothreitol, 10 uM ZnSO4) 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
`
`15
`
`were applied to a 180 mL ceramic hydroxyapatite
`
`column in Buffer B (20 mM Bis—Tris Propane (pH 6.8),
`
`1 mM MgC12, 0.25 mM dithiothreitol, 10 uM ZnSO4, and
`
`250 mM KCl). After loading,
`
`the column was washed
`
`with 2 volumes of Buffer B and eluted with a linear
`
`20
`
`gradient of 0—125 mM potassium phosphate in Buffer
`
`B. A