Case 1:15-cv-01078—GMS Document 4 Filed 11/23/15 Page 1 of 1 PagelD #: 222
`A0 120 Rev 08/10
`
`TRADEMARK
`
`TO‘
`
`Mail Stop 8
`Director of the US. Patent and Trademark Office
`PO. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § 1116 you are hereby advised that a court action has been
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`filed in the U.S. District Court
`for the District Of Delaware
`on the following
`
`[1 Trademarks or
`
`MPatents.
`
`( [I the patent action involves 35 U.S.C. § 292.):
`
`11/23/2015
`
`PLAINTIFF
`
`DEFENDANT
`
`
`
`for the District of Delaware
`
`
`
`INVAGEN PHARMACEUTiCALS INC.
`FOREST LABORATORIES, LLC, et al.
`
`
`
`%€E&$‘Lflf§£§
`
`
`
`
`
`
`
`
`
`
`—
`
`
`
`
`
`
`DATE INCLUDED
`
`In the aboveventitled case, the following patent(s)/ trademark(s) have been included:
`INCLUDED BY
`
`[:1 Answer
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`[:1 Cross Bill
`
`D Other Pleading
`
`[:1 Amendment
`PATENT OR
`DATE OF PATENT
`TRADEMARK NO.
`OR TRADEMARK
`HOLDER OF PATENT OR TRADEMARK
`___
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`___
`__—
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`In the above—entitled case, the following decision has been rendered or judgement issued:
`DECISION/JUDGEMENT
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`CLERK
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`(BY) DEPUTY CLERK
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`DATE
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`Copy 1—-Upon initiation of action, mail this copy to Director Copy 3—Upon termination of action, mail this copy to Director
`Copy 2—Upon filing document adding patent(s), mail this copy to Director Copy 4—Case file copy
`Argentum EX1021
`Argentum EX1021
`Page 1
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`Page 1
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`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`APPLICATION NO.
`
`: 8,673,921 B2
`: 14/032183
`
`DATED
`
`: March 18, 2014
`
`INVENTOR(S)
`
`: Andreas Bathe et a1.
`
`Page 1 of 1
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:
`
`Title Page, under “Foreign Application Priority Data,” item (30), left column, replace
`
`“Jun. 19, 2001
`
`(EP) ...................... 01113674” with
`
`--Jun. 19, 2001
`
`(EP) ...................... 01113647--
`
`Signed and Sealed this
`
`First Day of March, 2016
`
`WMKKZQL.
`
`Michelle K. Lee
`
`Director ofthe United States Patent and Trademark Oflice
`
`Page 2
`
`Page 2
`
`

`

`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.:
`
`8673921
`
`Page 1 of
`
`1
`
`DATED:
`
`March 18, 2014
`
`|NVENTOR(S):
`
`Andreas Bathe et al.
`
`It is certified that error appears in the above-identified patent and that said
`Letters Patent is hereby corrected as shown below:
`
`On page 1, under "Foreign Application Priority Data," item (30), left column, replace
`
`"Jun. 19, 2001 (EP) ............ 01113674" with
`-- Jun. 19,2001
`(EP) .............. O1113647--
`
`
`
`
`
`
`
`US Patent and Trademark Office
`PTO-1050
`
`Page 3
`
`/Joseph K. McKane/
`Supervisory Patent Examiner, Art Unit 1626
`
`Page 3
`
`

`

`I hereby certify that this paper (along with any paper referred to as being
`attached or enclosed) is being transmitted via the Office electronic filing system
`in accordance with § 1.6( )(4).
`
`Dated: November 24, 2015
`Electronic Signature for Jin Wang, Esq., J.D.: /Jin Wang/
`
`(PATENT)
`
`DOCkCt No.: 120140-00110
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`In re Application of:
`Andreas Bathe et al.
`
`US. Patent No.:
`
`8,673,921
`
`Issued:
`
`March 18, 2014
`
`Confirmation No.:
`
`2870
`
`Art Unit:
`
`1626
`
`Application No.:
`
`14/032,183
`
`Examiner: Samantha L. Shterengarts
`
`Filing Date:
`
`September 19, 2013
`
`For: POLYMORPHIC FORMS OF 1—[4—(5—
`
`CYANOINDOL—3—YL)BUTYL]—4—(2—
`
`CARBAMOYLBENZOFURAN—S—YL)
`PIPERAZINE HYDROCHLORIDE
`
`Attention: Certificate of Correction Branch
`
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313—1450
`
`REQUEST FOR CERTIFICATE OF CORRECTION
`PURSUANT TO 37 C.F.R.
`1.323
`
`Dear Sir:
`
`Upon reviewing the above—identified patent, Patentee noted a typographical error on the
`
`patent which should be corrected.
`
`On the cover page of the patent, in the left—hand column under item (30) “Foreign
`
`Application Priority Data,” the foreign priority is incorrectly shown as “Jun. 19, 2001
`
`(EP) 01113674.”
`
`The foreign priority should be corrected to show:
`
`—— Jun. 19, 2001
`
`(EP) 01113647 --
`
`MEI 18810129V.1
`
`Page 4
`
`Page 4
`
`

`

`Patent No.: 8,673,921
`
`Docket No.: 120140—001 10
`
`Transmitted herewith is a proposed Certificate of Correction effecting such amendment.
`
`Patentees respectfully solicit the granting of the requested Certificate of Correction.
`
`Please charge the fee of $100.00 as required under 37 CPR § 1.20(a) from our Deposit
`
`Account No. 50-4876, under Order No. 120140-00110 from which the undersigned is authorized
`
`to draw.
`
`Dated: November 24, 2015
`
`Respectfully submitted,
`
`Electronic signature: / Jin Wang /
`Jin Wang, Esq.
`Registration No.: 66,467
`McCARTER & ENGLISH, LLP
`265 Franklin Street
`
`Boston, Massachusetts 02110
`
`(617) 449—6580
`
`(617) 607-9200 (Fax)
`
`Attorney for Patentee
`
`MEI 18810129V.1
`
`Page 5
`
`Page 5
`
`

`

`I hereby certify that this paper (along with any paper referred to as being
`attached or enclosed) is being transmitted via the Office electronic filing system
`in accordance with § 1.6( )(4).
`
`Dated: November 24, 2015
`Electronic Signature for Jin Wang, Esq., J.D.: /Jin Wang/
`
`(PATENT)
`
`DOCkCt No.: 120140-00110
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`In re Application of:
`Andreas Bathe et al.
`
`US. Patent No.:
`
`8,673,921
`
`Issued:
`
`March 18, 2014
`
`Confirmation No.:
`
`2870
`
`Art Unit:
`
`1626
`
`Application No.:
`
`14/032,183
`
`Examiner: Samantha L. Shterengarts
`
`Filing Date:
`
`September 19, 2013
`
`For: POLYMORPHIC FORMS OF 1—[4—(5—
`
`CYANOINDOL—3—YL)BUTYL]—4—(2—
`
`CARBAMOYLBENZOFURAN—S—YL)
`PIPERAZINE HYDROCHLORIDE
`
`MS Petition
`
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313—1450
`
`PETITION TO ACCEPT UNINTENTIONALLY DELAYED CLAIM FOR
`
`FOREIGN PRIORITY PURSUANT TO 37 C.F.R. § 1.551e!
`
`Dear Sir:
`
`Patentee requests correction of the foreign priority, as stated on the above—identified
`
`patent. The foreign priority, as shown on the cover page of the patent, in the left—hand column
`
`under item (30) “Foreign Application Priority Data,” is incorrectly shown as “Jun. 19, 2001
`
`(EP) 01113674.”
`
`The foreign priority should be corrected to show:
`
`—— Jun. 19, 2001
`
`(EP) 01113647 --
`
`Patentee submits that the entire delay between the date the priority claim was due under
`
`37 C.F.R. § 1.55(d) and the date the priority claim was filed was unintentional. Specifically,
`
`the Applicant Data Sheet filed in this patent contains an inadvertent typographical error of the
`
`ME120117231V.1
`
`Page 6
`
`Page 6
`
`

`

`Patent No.: 8,673,921
`
`Docket No.: 120140—001 10
`
`foreign priority application number, i. e. (EP) 011136fl, which should be (EP) 01113647.
`
`However, Patentee notes that the correct priority information is shown on page 2 of the
`
`Preliminary Amendment under “Related Applications” submitted on September 19, 2013 during
`
`prosecution of this patent. In addition, it is indicated on the Notice of Allowability mailed on
`
`December 13, 2013 that “[a]ckn0wledgement is made ofa claim for foreign priority under 35
`
`U.S.C. §119(a)—(d) or (f)” and that “[a]ll certified copies of the priority documents have been
`
`received [by the Patent Office].” Furthermore, Patentee submits that all parent patents, US
`
`8,318,744 issued on November 27, 2012 , US 7,981,894 issued on July 19, 2011, US 7,834,020
`
`issued on November 16, 2010, and US 7,381,726 issued on June 3, 2008, which are relied upon
`
`in this patent for an earlier filing date under 35 U.S.C. 120, 121, 365(c), or 386(c), have all
`
`claimed the correct foreign priority application number European Patent Office (EPO)
`
`01113647.0. Therefore, the priority claim was unintentionally delayed.
`
`A certified copy of the foreign application EP 01113647.0 was filed in the prior—filed
`
`nonprovisional application 10/481,270, now US. Patent No. 7,381,726, which the instant patent
`
`claims a benefit under 35 U.S.C. 120, 121, 365(c), or 386(c). However, for the convenience of
`
`the Office, Patentee enclose herewith a certified copy of the foreign priority application
`
`EP 01113647.0
`
`Applicant additionally requests that all pertinent US. Patent and Trademark Office
`
`records relating to the subject application be changed to reflect this correction.
`
`Please charge the fee of $1,700.00 as required under 37 CPR § 1.17(m) from our
`
`Deposit Account No. 50-4876, under Order No. 120140-00110 from which the undersigned is
`
`authorized to draw.
`
`Dated: November 24, 2015
`
`Respectfully submitted,
`
`Electronic signature: / Jin Wang /
`Jin Wang, Esq.
`Registration No.: 66,467
`McCARTER & ENGLISH, LLP
`265 Franklin Street
`
`Boston, Massachusetts 02110
`
`(617) 449—6580
`
`(617) 607-9200 (Fax)
`Attorney for Patentee
`
`ME120117231v.1
`
`Page 7
`
`Page 7
`
`

`

`It is certified that an error appears or errors appear in the above-identified patent and that said
`Letters Patent is hereby corrected as shown below:
`
`On page 1, under “Foreign Application Priority Data,” item (30), left column, replace
`
`“Jun. 19, 2001
`
`(EP) ..................... 01113674” with
`
`-- Jun. 19,2001
`
`PTO/SB/44 (09-07)
`Approved for use through 08/31/2013. OMB 0651-0033
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`(Also Form PTO-1050)
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`
`APPLICATION NO.
`
`ISSUE DATE
`
`|NVENTOR(S)
`
`:
`
`:
`
`:
`
`:
`
`8,673,921
`
`14/032,183
`
`March 18, 2014
`
`Andreas Bathe et al.
`
`(EP) ..................... 01113647--
`
`MAILING ADDRESS OF SENDER (Please do not use customer number below):
`Jin Wang
`MCCARTER & ENGLISH, LLP
`265 Franklin Street
`
`1
`
`Boston, Massachusetts 021 10
`
`ME1 18809901v.1
`
`Page 8
`
`Page 8
`
`

`

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`Page 9
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`

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`PCT/EPOZ/OSiBE
`.
`.
`.
`1__________.__— _.__.__——________._—
`
`‘
`
`Europfilsches
`
`J
`
`Patentamt
`
`EurOpean
`
`Patent Office
`
`Office européen
`
`des brevetsREC'D 08 AUG 2002
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Les documents fixés a
`The attached documents
`Die angehefteten Unterla-
`cette attestation sont
`are exact copies of the
`gen stimmen mit der
`urspranglich eingereichten European patent application conformes a la version
`Fassung der auf dem nach- described on the following
`initialement déposée de
`sten Blatt bezelchneten
`page, as originally filed.
`la demande de brevet
`europaischen Patentanmel-
`européen spécifiée a la
`dung fiberein.
`page suivante.
`
`_—___-_________—__———————-————————_—'
`
`Patentanmeldung Nr.
`
`Patent application No. Demande de brevet n°
`
`01113647. 0
`
`Der Président des Europaischen Patentamts;
`lm Auftrag
`
`For the President of the European Patent Office
`
`Le President de l'Office européen des brevets
`p.o.
`
`R c van Dijk
`
`DEN HAAG,DEN
`THE HAGUE,
`LA HAYE,LE
`
`25/01/02
`
`EPA/EPOIOEB Form 1014
`
`4231
`
`PRIORITY DOCUNIENT !
`SUBMITTED ORTRANSMITI‘EDIN
`COMPLIANCEWITH
`RULE 17.1(a) OR (b)
`
`Page1
`
`.
`.
`.
`‘
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`Page 10
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`

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`____—___._
`
`
`
` ' . .
`
`
`
`—_—______—_ _—___.____
`
`.
`
`a)
`
`Europfilsches
`
`Patentamt
`
`European
`
`Patent Office
`
`Office européen
`
`des brevets
`
`Blatt 2 der Bescheinigung
`Sheet 2 of the certificate
`
`Page 2 de l’attestation
`
`
`
`Anmeldetag:
`Date offiling:
`Date de depot:
`
`.
`19/06/01
`
`01113647 . 0
`
`Anmeldung Nr.:
`Application no.:
`Demande n':
`Anmelder:
`Applicant(s):
`Demandeur(s):
`Merck Patent GmbH
`64293 Damstadt
`GERMANY
`
`Bezeichnung der Erflndung:
`Title of the Invention:
`Tltre de i'invention:
`
`Polymer-phi c forms of 1-( 4-( S-cyanot ndo‘i -3-y‘l)buty1)—4—-(2—carbamoy1benzofuran-S-y‘l )pi perazt ne
`fwdrochl ortde
`
`in Anspruch genommene Prioriéiuen) I Priority(les) claimed I PI10rlté(s) revandiquée(s)
`Staat:
`Tag:
`Aktenzeichen:
`State:
`Date:
`File no.
`Pays:
`Date:
`Nurnéro de dépét:
`
`Internationale Patentklasslflkatlon:
`international Patent classification:
`Classification Internationale des brevets:
`
`/
`
`Am Anmeldetag benennte Vertragstaaten:
`Contracting states designated at date of filing: AT/BE/CH/CY/DE/DK/ES/Fl/FR/GBIGRIIE/lT/LI/LU/MC/NL/PT/SE/TR
`Etats contractants désignés lors du depét:
`Bemerkungen:
`Remarks:
`Remarques:
`
`EPA/EPO/OEE Form
`
`1012
`
`- 11.00
`
`Pa e 11
`g
`
`Page 11
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`

`

` - “WW:? 21':
`
`=
`E
`fg‘fiifigifléu
`2001
`EM01662.doc 1/47
`.
`
`
`
`.
`
`EPO - Munich
`
`.
`
`
`
`Merck Patent Gesellschafl
`
`mit beschrfinkter Haftung
`
`64271 Darmstadt
`
`Polymorphic forms of 1 -[4-(5-cyanoindol-3-
`yl)butyl]44-(2-carbamoylbenzofuran-5-
`yl)piperazine hydrochloride
`
`Druckdatum: 18.06.2001
`Speicherdatum: 13.06.2001
`
`Page 12
`
`

`

`
`
`
`
`.
`
`. 11 Juni 2001
`
`67
`
`
`
`Polymorphic forms of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoylbenzoiuran-5-yl)piperazine hydrochloride
`
`FIELD OF THE lNVENTlON
`t invention relates to novel compounds. to processes for
`sorders.
`preparing them and to their use in treating medical di
`
`The presen
`
`BACKGROUND OF THE INVENTION
`1—[4-(5-Cyanoindol-3~yl)butyl1-4-(2—carbamoyl-benzofuran-5-yl)-piperazine,
`its physiologically acceptable salts thereof (US 5,532,241. column 7, lines
`30 to 58), a process (US 5,532,241, Example 4) by which itlthey can be
`prepared and their use in treating certain medical disorders are known from
`US. Patent US 5,532,241 and WO 00/72832.
`Example 4 of US 5,532,241 describes the preparation of 1-[4-(5—
`-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)—piperazine
`cyanoindoI-3
`hydrochloride by reacting 1-[4-(5-cyanoindol—3-yl)butyl1—4—(2—
`1-methylpyridinium
`carboxybenzofuran-5-yl)piperazine at first with 2-chloro-
`methanesulfonate in N-methylpyrrolidine and then with dried NH3.
`Customary working up gives the free base 1-[4-(5-cyanoindol-3-yl)butyl]-4-
`(2-carboxybenzofuran-S—yl)piperazine. 700 mg of the base are dissolved in
`30 ml 2—propanol under heating and then treated with 0.1n 2-propanolic
`k-Art. No. 1.00326) until precipitation of hydrochloride is
`HCL—solution (Merc
`lether and
`precipitate was filtered off and washed with diethy
`complete. The
`~[4-(5-cyanoindol—3—yl)butyl]-4-(2—
`dried at room temperature to yield 1
`ydrochloride having a melting point
`carbamoyI-benzofuran-5-yl)-piperazine h
`the document of any
`of 269-272°C. There is no clear teaching elsewhere in
`modification to the process which would generate new
`altemative route or
`—cyanoindol-3-yl)butyl]-4-(2-carbamoyl—
`crystal modifications of 1-[4-(5
`ew solvates or hydrates of 1-
`-piperazine hydrochloride or n
`benzofuran—S—yl)
`(2-carbamoyl-benzofuran-5-yl)-piperazine
`[4-(5—cyanoindol-3-yl)butyl]-4-
`hydrochloride in different crystal modifications.
`
`5
`
`10
`
`1 5
`
`20
`
`25
`
`30
`
`
`
`
`
`Page 13
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`

`

`
`
`
`
`
`
`Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-S-yl)-
`
`piperazine hydrochloride having a melting point of 269-272°C was a mixture
`of amorphous 1-[4-(5-cyanoindoI-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, crystallized 1-[4—(5-cyanoindol-3-yl)buty|]-4-(2-
`carbamoyl—benzofuran-5-yl)-piperazine hydrochloride and the free base 1-
`
`[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yI)—piperazine.
`
`Methods for preparing pure crystals of 1~[4-(5-cyanoindoI-3-yl)butyl]—4-(2-
`carbamoyl—benzofuran—5-yl)-piperazine hydrochloride has now been found.
`Furthermore, surprinsingly, 1-[4—(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`benzofuran—5-y|)-piperazine dihydrochloride, five (four + dihyd rochloride
`
`Xlll) new forms of 1—[4—(5-Cyanoindol—3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl):piperazine hydrochloride, three new forms of 1-[4-(5-
`cyanoindol—3-y|)butyl]-4-(2-carbamoyl-benzofuran—5-yI)—piperazine
`hydrochloride hydrate, six new forms of solvates of 1-[4—(5-cyanoindol—3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5—yl)-piperazine hydrochloride and
`pure amorphous 1~[4-(5-cyanoindol-3-yl)butyl]-4-(2—carbamoyl-benzofuran-
`5-yl)-piperazine hydrochloride have been found as have processes for their
`preparation. These forms are hereinafter referred to as I, ll, III. IV, V, VI, VII,
`VIII, IX, X, Xl, Xlll, XlV, XV and XVI respectively.
`
`.-
`
`SUMMARY OF THE INVENTION
`
`Accordingly, the present invention provides soivates of 1-[4-(5-cyanoindol-
`3-yl)butyl]-4-(2-oarbamoyl-benzofuran—5~y|)-piperazine hydrochloride in
`crystalline modifications and their use for the treatment and prevention of
`depressive disorders, anxiety disorders, bipolar disorders, mania, dementia,
`substance~re|ated disorders, sexual dysfunctions, eating disorders, obesity,
`fibromyalgia, sleeping disorders, psypsychiatric disorders, cerebral infarct,
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`
`amenorrhea, premenstrual syndrome and undesired puerperal lactation.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 14
`
`

`

`
`
`
`
`The present invention furthermore provides 1-[4-(5—cyanoindol-3-yl)butyl1-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrates in
`modifications and their use for the treatment and prevention of
`crystalline
`bipolar disorders, mania, dementia,
`depressive disorders, anxiety disorders,
`sexual dysfunctions, eating disorders. obesity,
`substance-related disorders,
`hiatric disorders, cerebral infarct,
`fibromyalgia, sleeping disorders, psypsyc
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal lactation.
`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The present invention also provides 1- 4-(5-cyanoindol-3-yl)butyI]-4-(2-
`carbamoyl—benzofuran-5-yl)—piperazine hydrochloride anhydrates in
`crystalline modifications and their use for the treatment and prevention of
`depressive disorders. anxiety disorders, bipolar disorders, mania, dementia,
`nee-related disorders, sexual dysfunctions, eating disorders, obesity,
`substa
`orders, cerebral infarct,
`fibromyaigia, sleeping disorders, psypsychiatric dis
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal lactation.
`
`The present invention. relates additionally to 1-[4-(5-cyanoindol—3-yl)butyl]—4-
`-5—yl)—piperazine dihydrochloride in its crystalline
`(2-carbamoyl—benzofuran
`nt and prevention of depressive
`modification and its use'for the treatme
`disorders, anxiety disorders, bipolar disorders, mania, dementia,
`d disorders, sexual dysfunctions, eating disorders, obesity,
`substance—relate
`orders, cerebral infarct,
`fibromyalgia, sleeping disorders, psypsychiatric dis
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders. chronic pain, acromegaly, hypogonadism, secondary
`and undesired puerperal lactation.
`amenorrhea, premenstrual syndrome
`
`
`
`
`
`Page 15
`
`

`

`
`
`
`
`The present invention relates additionally to amorphous 1-[4-(5-cyanoindol-
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yI)-piperazine hydrochloride and its
`use for the treatment and prevention of depressive disorders, anxiety
`
`disorders, bipolar disorders, mania, dementia, substance-related disorders,
`
`sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping
`
`disorders, psypsychiatric disorders, cerebral infarct, tension, for the therapy
`of side-effects in the treatment of hypertension, cerebral disorders. chronic
`pain, aoromegaly, hypogonadism, secondary amenorrhea, premenstrual
`
`syndrome and undesired puerperal lactation.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`1 is a IR absorption spectra of Form I
`
`2 is a IR absorption spectra of Form II
`
`3 is a IR absorption spectra of Form XV
`
`4 is a IR absorption spectra of Form XI
`
`5 is a IR absorption spectra of Form XIV
`
`6 is a IR absorption spectra of Form V
`
`7 is a IR absorption spectra of Form VI
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`8 is a IR absorption spectra of Form VIII
`
`9 is a IR absorption spectra of Form IV
`
`10 is a IR absorption spectra of Form In
`
`1 1 is a IR absorption spectra of Form VII
`
`12 is an x-ray diffractogram for Form l
`
`13 is an x-ray diffractogram for Form II
`
`14 is an x-ray diffractogram for Form XV
`
`15 is an x—ray diffractogram for Form X
`
`16 is an x-ray diffractogram for Form XI
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`
`Fig.
`Fig.
`
`Fig.
`
`Fig.
`
`17 is an x-ray diffractogram for Form XIV
`
`18 is an x-ray diffractogram for Form V
`
`19 is an x—ray diffractogram for Form VI
`
`20 is an x-ray diffractogram for Form Vlll
`
`21 is an x-ray diffractogram for Form IV
`
`
`
`xii. -nfianm
`
`10
`
`15
`
`20
`
`‘25
`
`30
`
`Page 16
`
`

`

`
`
`
`
`Fig. 22 is an x-ray diffractogram for Form III
`Fig. 23 is an x—ray diffractogram for Form VII
`Fig. 24 is an x-ray diffractogram for Form IX
`Fig. 25 is an x-ray diffractogram for Form XIII
`Fig. 26 is an x-ray diffractogram for amorphous hydrochloride (Form XVI)
`Fig. 27 is an energy/temperature diagram
`Fig. 28 is a diagram of thermal analysis from Form I
`Fig. 29 is a diagram of thermal analysis from Form II
`Fig. 30 is a diagram of thermal analysis from Form III
`Fig. 31 is a diagram of thermal analysis from Form IV
`Fig. 32 is a diagram of thermal analysis from Form V
`Fig. 33 is a diagram of thermal analysis from Form VI
`Fig. 34 is a diagram of thermal analysis from Form VII
`35 is a diagram of thermal analysis from Form VIII
`Fig.
`Fig. 36 is a diagram of thermal analysis from Form IX
`Fig. 37 is a diagram of thermal analysis from Form XI
`Fig. 38 is a diagram of thermal analysis from Form XIV
`Fig. 39 is a diagram of thermaI analysis from Form XV
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`It has been found that 1-[4-(5-cyanoindoI—3-yl)butyI]-4-(2-carbamoyl—
`benzofuran-5-yI)-piper'azine hydrochloride is able to form solvates in
`ifications'. Examples of such solvates include solvates from
`crystalline mod
`-oI or propan-Z-ol; solvates
`alcohols such as methanol, ethanol, propan-1
`from organic esters such as ethyl acetate; solvates 1‘
`stone and butanone; solvates
`acetonitrile; solvates from ketones such as ac
`from ethers such as tetrahydrofuran and solvates from chlorinated
`hydrocarbons such as chloroform and solvates of hydrocarbons such as n-
`heptane or toluene.
`
`rom nitriIes such as
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`
`
`Page 17
`
`

`

`
`
`
`
`Preferably, 1-[4-(5-cyanoindol-3-yl)butyl]-4—(2-carbamoyl—benzofuran-S-yl)-
`
`piperazine hydrochloride forms solvates with acetone, tetrahydrofuran,
`
`methanol, ethyl acetate or n-heptane in crystalline modifications that means
`
`the bound solvent together with 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2—
`
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride build the crystal
`
`structure. The ratio of the solvent to 1-[4-(5-cyanoindol-3-yl)butyl1-4-(2-
`
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride could vary as known
`
`for skilled persons in the art. Preferably, the ratio is between 0,25z1 to 25:1
`
`more preferably between 0.5:1 to 1:1, most preferably 1:1. (n-heptan
`
`10
`
`solvate 1/15 : 1)
`
`15
`
`20
`
`It should be understood that the present solvates of the invention may’
`
`contain unbound water that is to say water which is other than water of
`
`crystallization.
`
`Preferred forms of solvates of 1--[-4(5-cyanoindol~3—yl)buty|]—4--(2-carbamoyl-
`benzofuran-5-yl)--piperazine hydrochloride include:
`.
`a) 1-[4-(5-cyanoindol-3-yl)butyl]—4-(2—carbamoyl-benzofuran-5—yl)-piperazine
`hydrochloride solvate with acetone in Form l; (as hereinafter defined)
`:
`
`b) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5—yl)-piperazine
`
`hydrochloride solvate with tetrahydrofuran in Form II; (as hereinafter
`
`defined)
`
`c) 1—[4-(5-cyanoindol-3-yl)butyl]—4-(2-carbamoyI-benzofuran-5-yI)-piperazine
`hydrochloride solvate with tetrahydrofuran in Form XV; (as hereinafter
`
`25
`
`defined)
`
`d) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl—benzofuran-S-yl)-piperazine
`
`hydrochloride selvate with tetrahydrofuran in Form X; (as hereinafter
`
`defined)
`
`e) 1-[4-(5-cyanoindol-3-yl)butyl]—4-(2—carbamoyl-benzofuran-5-yl)—piperazine
`
`30'
`
`hydrochloride solvate with methanol in Form Xi; (as hereinafter defined)
`
`f) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran—5-yl)-piperazine
`
`hydrochloride solvate with n—heptane in Form XIV; (as hereinafter defined).
`
`P
`
`8...._.,._.,. .
`egg—06.9001,i
`
`Page 18
`
`

`

`
`
`ording to the invention has the characteristic lR absorption
`Form l acc
`X-ray diffraction pattern as
`spectra as shown in Fig. 1 and the charasteristic
`shown in Fig. 12. XRD pattern were recorded usin
`ransmission mode (Cu K alpha 1,
`diffractometer (Bruker AXS 05000) in t
`
`g a x-ray powder
`
`5
`
`PSD).
`
`IR absorption spectra were measured in the spectral range 4000 - 400 cm‘1
`on a Bruker lFS48. Spectral resolution was 2 cm". The spectra as shown in
`ple preparation was
`the figures were converted to transmission. Sam
`performed generally as KBr disk. The spectra co
`specific acetone absoption band at 1709cm“.
`
`ntains additionally a
`
`r characterized with the aid of thermal analysis
`Form I can be furthe
`°C. Fig. 28 shows the DSC (TA
`measured in the range of 30° to 350
`instruments DSC 2920) and TGA (TA instruments TGA 2950)
`measurements. Form l shows a desolvation process between 50°C and
`180°C. Analysis by thermogravimetry showed the presence of 10 % to 11
`% of acetone (theory of 1 : 1 solvate 10.82 %). The DSC measurement
`gives a phase transition to form Vll between 200°C and 260°C. The
`thermoanalytically resulting form Vll melts between 280°C and 290°C.
`The ratio of acetone to 1-[4—(5-cyanoindol—3-yl)butyl]-4—(2—carbamoyl-
`benzofuran-5-yl)—piperazine hydrochloride in said crystal modification is 1:1,
`that means the compound of the invention in crystal modification of Form 1
`is 1-[4—(5-cyanoindol-3-y|)butyl]-4-(2—carbamoyl-benzofuran—5-yl)-piperazine
`hydrochloride monoacetonate.
`
`The invention also provides a process for preparing the above Form l
`according to the invention. which comprises:
`(1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2—carbamoyl-benzofuran-5—
`yI)-piperazine in acetone
`9 the 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl—
`(2) convertin
`1N hydrochloric acid
`benzofuran-5-yl)-piperazine base, by addition of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`
`
`Page 19
`
`

`

`
`
`
`
`
`
`into the hydrochloride salt at temperatures between 30°C and the
`
`boiling point of acetone, preferably between 40° C and 50°C
`
`(3) precipitation of Form l at room temperature
`
`(4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`carbamoyl-benzofuran~5-yl)-piperazine hydrochloride acetonate by
`
`filtration, and drying in vacuo at room temperature.
`
`Alternatively, Form I can be prepared according to a process which -
`
`comprises:
`
`1O
`
`(1) suspending Form ill of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`benzofuran-5-yl)-piperazine hydrochloride, which will be described later
`
`in detail, in acetone
`
`(2) stirring at room temperature between a few hours or days, preferably
`
`10 to 20 days.
`
`15
`
`(3) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`carbamoyl-benzofuran-S-yl)-piperazine hydrochloride solvate with
`
`tetrahydrofuran by filtration, and drying in vacuo at room temperature.
`
`Form ll according to the invention has the charasteristic IR absorption
`
`spectra as shown in Fig. 2 and the charasteristic X—ray diffraction pattern as
`shown in Fig. 13. XRD pattern were recorded using a x-ray powder
`diffractometer (Bruker AXS D5000) in transmission mode (Cu K alpha 1,
`
`'
`PSD).
`IR absorption spectra were measured in the spectral range 4000 - 400 cm'1
`on a Bruker IFS48. Spectral resolution was 2 cm“. The spectra as shown in
`
`20
`
`25
`
`the figures were converted to transmission.
`
`Form II can be further characterized with the aid of thermal analysis
`
`measured in the range of 30° to 350°C. Fig. 29 shows the DSC (TA
`Instruments DSC 2920) and TGA (TA Instruments TGA 2950)
`
`30
`
`measurements. Form II shows a desolvation process between 120°C and
`
`180°C. Analysis by thermogravimetry showed the presence of 13 % to 14
`% of ‘l’HF (theory of 1 : 1 solvate 13.11 %). The DSC measurement gives a
`
`
`
`Page 20
`
`

`

`
`
`
`
`phase transition to form VII between 200°C and 260°C. The
`thermoanalytically resulting form V“ melts between 280°C and 292°C.
`The ratio of tetrahydrofuran to 1-[4-(5-cyanoindol-3-yl)butyl]—4-(2-
`carbamoyl—benzofuran-5-yI)-piperazine hydrochloride in said crystal
`modification is 1:1, that means the compound of the invention in crystal
`
`(2-carbamoyl-benzofuran—5-yl)-piperazine hydrochloride with
`
`tetrahydrofuran.
`
`modification of Form II is a monosolvate of 1-[4-(5-cyanoindol-3-yl)butyl]—4w
`
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`The invention also provides a process for preparing the above Form ll
`
`according to the invention, which comprises:
`(1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl—benzofuran-5-
`yI)-piperazine in tetrahydrofuran
`(2) converting the 1-[4-(5-cyanoindol-3-y|)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine base. by addition of 1N hydrochloric acid
`into the hydrochloride salt at temperatures between 10°C and 60°C,
`preferably between 20° C and 30°C
`(3) precipitation of Form ll between -10°C and 10°C
`(4) recovering the precipitated 1-[4-(5~cyanoindol—3—yl)butyl]-4—(2-
`carbamoyl-benzofuran—5—yl)—piperazine hydrochloride solvate with
`tetrahydrofuran by filtration, and drying in vacuo at room temperatUre.
`
`Alternatively, Form II can be prepared according to a process which
`comprises:
`'
`(1) suspending Form III of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yI)-piperazine hydrochloride, which will be described later
`
`in detail, in tetrahydrofuran
`(2) stirring at room temperature between a few hours or days, preferably
`1 5 to 30 days,
`(3) recovering the precipitated 1-[4-(5-cyanoindoI—3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride acetonate by
`filtration, and drying in vacuo at room temperature.
`
`
`
`
`
`Page 21
`
`

`

`
`
`
`
`
`
`Form XV according to the invention has the charasteristic IR absorption
`
`spectra as shown in Fig. 3 and the charasteristic X-ray diffraction pattern as
`shown in Fig. 14. XRD pattern were recorded using a x-ray powder
`
`diffractometer (Bruker AXS D5000) in transmission mode (Cu K alpha 1,
`
`PSD).
`IR absorption spectra were measured in the spectral range 4000 - 400 cm'1
`on a Bruker IFS48. Spectral resolution was 2 cm“. The spectra as shown in
`the figures were converted to transmission.
`'
`Form XV can be further characterized with the aid of thermal analysis
`
`measured in the range of 30° to 350 °C. Fig. 39 shows the DSC (TA
`
`Instruments DSC 2920) and TGA (TA Instruments TGA 2950)
`
`measurements. Form XV shows a desolvation process between 75°C and
`
`180°C. Analysis by thermogravimetry showed the presence of 13 % to 14
`% of THF (theory of 1 : 1 solvate 13.11 %). The DSC measurement gives a
`
`phase transition to form VII between 200°C and 260°C. The
`thermoanalytically resulting form Vll melts between 280°C and 290°C. The
`ratio of tetrahydrofuran to 1-[4—(5-cyanoindoI-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride in said crystal modification is 1:1,
`that means the compound of the invention in crystal modification of Form
`XV is a monosolvate of 1~[4-(5—‘cyanoindol-3—yl)butyl]—4—(2-carbamoyl—
`
`benzofuran-5-yl)-piperazine hydrochloride with tetrahydrofuran.
`
`10
`
`15
`
`20
`
`The invention also provides a process for preparing the above Form XV
`
`25
`
`according to the invention, which comprises:
`(1) dispersing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`
`yl)-piperazine in tetrahydrofuran
`(2) converting the 1-[4-(5-cyanoindoI-3-yl)butyl]-4-(2—carbamoyl-
`benzofuran-5-yl)-piperazine base, by addition of 1 N hydrochloric acid
`into the hydrochloride salt at temperatures between —10°C and 10°C,
`
`30
`
`preferably between -5° C and +5°C
`
`(3) precipitation of Form XV at room temperature
`
`
`
`Page 22
`
`

`

`
`
`
`
`(4) recovering the precipitated 1—[4-(5-cyanoindol—3-yl)butyl]-4-(2-
`carbamoyl—benzofuran-5—yl)—piperazine hydrochloride solvate with
`tetrahydrofuran by filtration, and drying in vacuo at room temperature.
`
`Form X according to the invention has the charasteristic X—ray diffraction
`pattern as shown in Fig. 15. XRD pattern were recorded using a x-ray
`powder.diffractometer (Bruker AXS D5000) in transmission mode (Cu K
`alpha 1, PSD).
`
`The rat
`
`io of tetrahydrofuran to 1-[4-(5-cyanoindol—3-yl)butyl]-4-(2-
`carbamoyl—benzofuran-5-yl)-piperazine hydrochloride in said crystal
`of the invention in crystal
`modification is 0,5:1. that means the compound
`modification of Form II is a hemisolvate of 1-[4-(5-cyanoindol-3-yl)butyl]—4-
`(Z-car