18/04/2008 17:46
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`ST-PN
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`(FAX) +49 241 5692655
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`P. 001/007
`
`I
`
`GRUNENTHAL GMBH
`
`GrOnenthal GmbH- 52099 Aachen- Germany
`
`Europaisches Patentamt
`Erhardtstraf.l,e 27
`
`80469 Munchen
`
`FAX
`
`Patent Application No. 05 770 026.2- 2103
`Our reference: GRA 3111-EP I ST-PN I RS-KN
`
`Reply to the communication according Article 96(2) EPC
`
`In reply to the communication according Article 96(2) EPC an
`amended claim set is provided on a separate sheet. We are confident
`that the examiner's objections with respect to the formal issues 1.1,
`1.2, 1.3. and 2 of the office action have been overcome by the
`amendments. Regarding the formal objections 1.1, we would like to
`emphasis that claim 2, 3 and 4 are dependent claims of claim 1 and
`that is stated in the description on page 2, line 19-25, that crystalline
`form A is best and sufficient described by the parameters recited in
`claim 1.
`
`Regarding 3:
`The subject matter of the present claims are regarded as being novel
`by the examination division.
`
`Regarding 4:
`The applicant provides with the enclosed "experiment 1" data that the
`novel crystalline form A is inventive over the prior art: The crystalline
`form B disclosed in 01 has the disadvantage that under the influence
`of pressure (which occurs e.g. in the manufacturing process for the
`drug tablet) polymorph B (crystalline form of 01) is transformed in a
`mixture of the crystalline forms A and B.
`
`The underlined problems can be defined in view of 01 to find a
`crystalline form which can be used in a manufacturing process of drug
`tablets. Surprisingly and shown by the data enclosed in Table 1 the
`crystalline form A claimed in the pending application shows stability
`regarding high pressure. There can be no mixture of polymorphs A
`and B detected up to the limit of quantification (LOQ) with the starting
`material B. The experiment shows clear evidence for a change in the
`
`--l'1-
`GRUNEIIITHAL
`
`Patent Department
`
`Date
`16 Aprii2DOB
`
`Your rof~<~ronco
`
`Your letter dated
`
`Our rofonmce
`
`Our letter dated
`
`Contact
`Dr Stowasser
`
`Telephone
`+49 241 569-2599
`
`Tolefax
`+49 241 569-2655
`
`E-Mail
`patents
`@Grunenthal.com
`
`EMAS
`Verified Environmental
`Managament, D-101-00034
`
`~
`~
`~
`0
`ill
`Re'l:eived at the ~"8'1i"Ap7"1~:'1'1ll'J!f'f?~'t5'f.1'~'g'kw"'r&f''7'"1h•'·•"m
`
`vgPs~n°JieP3e~:)ru~JFcgtirl1\~~~J1rb\:'i3E~~tl.}~~.f\Je~~e1Jf ~~~Jh~~~g~pi.-Psych. Wolfgang Becl<er, Dipi.-Kfm. Stefan Genten, Prof. Dr. Eric-Paul Pllques,
`Dipl.-lng. Sebastian Wirtz Sitz dar Gesellschaft Aachen Registergericht: Amtsgericht Aachen, HRB Nr. 3546 Ust.-10 {VAl): DE121737755 St.Nr. 202 5804 0019
`Bankverbindungen: Sparkasse Aachen, BLZ 390 500 00, Klo 181 80 04, BIG AACSDE33, IBAN DE20 3905 0000 0001 8180 04 ABN AMRO Bank N.V., BLZ 502 304 00,
`Kto 16 67 27 00 01, BIG ABNADEFFFRA, IBAN DE30 5023 0400 1667 2700 01 Ueferanschrift: ZieglerstraBe 6, 52078 Aachen, Tel.: +49 241 569-0, Fax: +49 241 569-3300
`
`Page 1 of 7
`
`Grunenthal GmbH Exhibit 2038
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`

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`18/04/2008 17:47
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`ST-PN
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`(FAX) +49 241 5692655
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`P. 002/007
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`--l"L-
`GRUNENTHAL
`
`modification of all form B batches exposed to pressure of 2 tons within
`only 60 seconds. All form A batches remain unchanged.
`
`In the case the amended claim set enclosed are considered to be not
`allowable by the examination division, a further official communication
`or, as an auxiliary request, oral proceedings are requested before any
`decision is taken other than the grant of the patent.
`
`Furthermore the applicant asks to postpone the amendments of the
`description until the examination division agreed on the amended
`claim set.
`
`Yours sincerely,
`Gronenthal GmbH
`
`:\/
`
`Enclosures:
`
`• Table 1 with experimental data
`• amended claim set
`• self-addressed envelope (by mail only)
`
`603W/08.04 F:\Pn\Patenle\KOR\Gra3111\GRA 3111 EP _0B0221_KN.doc
`2
`
`Received at the EPO on Apr 18, 2008 17:51 :57. Page 2 of 7
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`Page 2 of 7
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`

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`18/04/2008 17:48
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`P. 003/007
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`Table 1 (Experiment)
`
`There is clear evidence for a change in the modification of all form B batches
`exposed to a pressure of 2 tons within 60 seconds. All form A batches remain
`unchanged.
`
`1
`
`Method Description
`
`Instruments and Material:
`
`1.1
`Analytics:
`STOE STADI P X-ray powder diffractometer system; transmission
`geometry, Cu-Ka 1 radiation at 50 kV and 30 rnA, Ge (Ill)
`monochromator, position sensitive detector; omega-2-theta scan type,
`time/step 300s, preparation as flat sample, WinXpow software package.
`Balance for analytical quantification: Mettler Toledo MX5, Inv. Nr.
`28523.00
`Pressure Experiments:
`Intrinsic dissolution preparation devices according to Ph. Eur. 2.9.29 [1],
`purchased by Sotax AG, Basel, Switzerland
`Press: SPECAC, max. 5 tons.
`
`Balance for pressing experiments: Mettler Toledo AX205.
`
`Experimental
`1.2
`Approx. 50 mg of the sample material was weighed accurately into the
`intrinsic dissolution preparation device for the pressing experiment [1]. A
`pressure of 2 tons was applied to the sample material for 60 seconds. The
`bottom plate of the intrinsic dissolution preparation device was removed. The
`pressed sample was carefully taken out of the pressing cylinder where it
`formed a compacted pellet. The sample was placed on the sample holder of
`the X-ray diffractometer and measured according to the above described
`method.
`
`2
`
`Results
`
`Three batches of each of the two polymorphs were tested following the
`described experimental method and analysed accordingly. The batches were
`selected to cover a broad variety of batch types.
`
`Received at the EPO on Apr 18, 2008 17:51 :57. Page 3 of 7
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`Page 3 of 7
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`18/04/2008 17:49
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`ST-PN
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`P. 004/007
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`Table 2-1:
`
`Results of the Pressure experiments
`
`No. Batch
`
`I
`
`2
`
`3
`
`4
`
`5
`
`6
`
`A
`
`B
`c
`D
`
`E
`
`F
`
`Material
`for
`amount
`polymorph
`ratio
`determination
`[mg]
`
`25,2
`
`24,7
`
`24,5
`
`25,5
`
`24,8
`
`25,5
`
`Pressure/
`time
`
`Initial
`Polymorph
`
`Polymorph
`after pressure
`
`ratio
`
`2 t/ 60 sec B
`2 t/ 60 sec B
`
`2 t/ 60 sec B
`2 t/ 60 sec A
`2 t/ 60 sec A
`2 t/ 60 sec A
`
`:
`
`A
`
`70
`
`5
`
`96
`
`B
`
`30
`
`95
`
`4
`
`Form A only
`
`Form A only
`
`Form A only
`
`The results clearly show the instability of form B during an exposure of
`pressure. After only 60 seconds a significant part of form B already changed
`its modification to form A. Ratios vary from 4 to 95% of form A in the
`originally form B batches.
`All polymorph A batches however remain unchanged.
`
`3
`
`References
`
`[I] European Pharmacopeia, Version 6.0, Chapter 2.09.29,
`Intrinsic Dissolution
`
`Received at the EPO on Apr 18, 2008 17:51 :57. Page 4 of 7
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`Page 4 of 7
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`18/04/2008 17:49
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`ST-PN
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`P. 005/007
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`~ ~ ~ J 211.1..0~
`c;aA. 'lit\
`Ef' o!~~o o'Lb· 2.. -'2.:'\o'l
`
`1
`
`wo 2006/000441
`
`Claims
`
`31
`
`PCT /EP2005/006884
`
`1. Crystalline Form A of (-)-(1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)(cid:173)
`
`phenol hydrochloride showing at least X-ray lines (2-theta values) in a powder
`
`5
`
`diffraction pattern when measured using Cu K, radiation at 15.1±0.2,
`
`16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2.
`
`2. Crystalline Form A of (-)-(1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)(cid:173)
`
`phenol hydrochloride according to claim 1 showing in addition at least X-ray
`
`10
`
`·lines (2-theta values) in a powder diffraction when measured using Cu K,
`
`radiation at 14.5± 0.2, 18.2±0.2, 20.4±0.2, 21.7±0.2 and 25.5±0.2.
`
`15
`
`values) in a powder diffractiol!n:!JW!]leifH'IIrea1Me
`
`essentiall
`
`1·/ Crystalline Form A of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)- ·
`
`20
`
`phenol hydrochloride according to claim 1 characterized in that the elemental
`~----~·--~-
`. "~"":]./
`
`cells has a monoclinic form.
`
`4' ·~ Process for production of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride of crystalline Form /by dissolving the(-)-
`
`( 1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of
`
`25
`
`crystalline Form B in acetone. acetonitrile or isopropanol, leaving the solution
`
`to crystallize and isolating the crystals of (-)-(1R,2R)-3-(3-dimethylamino-1-
`
`ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A.
`
`'S' ·/ Process for production of (-)-(1 R,2R)-3-(3-dimethylamino-1-ethyl-2-
`methylpropyl)-phenol hydrochloride of crystalline Form A according to claim p '+.
`
`30
`
`characterized in that during the process the temperature is kept below
`
`+ 40"C, preferably below+ 25"C.
`
`Received at the EPO on Apr 18, 2008 17:51 :57. Page 5 of 7
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`Page 5 of 7
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`18/04/2008 17:50
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`ST-PN
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`(FAX) +49 241 5692655
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`P. 006/007
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`WO 2006/000441
`
`'t
`
`32
`
`PCT/EP2005/006884
`-
`
`(.,·/Process according to Claim/characterized by dissolving (-)-(1 R,2R)-3-(3-
`
`dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form Bin
`
`acetonitrile, stirring the solution, removing insoluble residue by filtering and
`
`evaporating solvent leaving (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`5
`
`methylpropyl)-phenol hydrochloride of Form A to crystallize.
`lf
`¥Process according to claim /characterized in that (-)-(1R,2R)-3-(3-
`
`dimethylamino-1-ethyl-2 -methyl propyl )-phenol hydrochloride of crystalline
`
`Form B is dissolved in isopropanol at temperatures above room temperature,
`
`10
`
`preferably above 65'C but not exceeding 80 'C, after complete dissolution
`
`the heat is turned of and seed crystals of (-)-(1 R,2R)-3-(3-dimethylamino-1-
`
`ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A are added
`and thereafter the mixture is cooled down to :s; 15 •c, preferably :50 10 'C and
`especially :s; 5 • c.
`
`15
`
`~/Process according to one oflhe claims) to} characterized in that the(-)-
`
`(1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of
`
`crystalline Form A obtained is redesolved in acetone, acetonitrile or
`
`isopropanol, preferably in the solvent already used in the first step, optionally
`
`20
`
`is filtered to remove any insoluble residue and, optionally after reducing the
`
`amount of solvent by evaporation. is left to crystallize.
`4- ~
`~-
`j6.Process according to one of the claimsp toJ characterized in that in the last
`crystallization step the temperature is maintained at :so 15 ·c. m,:o:re~p~r:e~::e~ra~b::;IY~-;;--:-~L?'
`~ A- 5
`:s; 10 'C and especially :so 5 •c.
`
`25
`
`A 0 _;/.Process for production of crystalline Form A of (-)-(1 R,2R)-3"l.WW-=--(cid:173)
`dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride characterized by
`
`cooling (-)-(1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)- hydrochloride
`
`30
`
`phenol of Form B between 24 hand 168 h to a temperature between -4'C
`
`and -BO'C.
`
`Received at the EPO on Apr 18, 2008 17:51 :57. Page 6 of 7
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`Page 6 of 7
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`ST-PN
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`(FAX) +49 241 5692655
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`P. 007/007
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`wo 2006/000441
`
`PCT/EP2005/006884
`
`1111 :>{Process according to claim '!I characterized in that the cooling temperature is
`
`...., Gl·
`
`33
`
`between -10'C and- 60'C, preferably between -15'C and - 50'C, especially
`
`between -25'C and -40'C.
`
`5
`
`/\?..' 1:1
`.;1o
`.Jr· Process according to claim if characterized in that the cooling is carried out
`for a time between 24h and 120 h, preferably between 24h and 72 h,
`
`especially between 24 h and 48h.
`•
`t).CIOV~ ~ A-1
`1\ ?, f· Crystalline Form A o~2R)-3-(3-dimethylamino-1-ethy\-2-methy\propy\)­
`
`10
`
`phenol hydrochloride obtainable by dissolving (-)-(1 R,2R)-3-(3-dimethy\amino-
`
`1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B in acetonitrile together
`
`with active carbon, heating the solution to the boiling point, removing the
`
`active carbon by filtering, stirring the solution at a temperature below 40'C,
`
`removing insoluble residue by filtering and removing part of the solvent
`
`15
`
`leaving (-)-( 1 R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl )-phenol
`
`hydrochloride of Foim A to crystallize, redissolving the crystals so obtained in
`
`acetonitrile, removing insoluble residue by filtering and removing part of the
`
`solvent leaving (-)-(1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropy\)-phenol
`
`hydrochloride of Form A to crystallize.
`
`20
`
`25
`
`J!Lf.)lf.Pharmaceulical composition containing as active ingredient crystalline Form A
`
`of (-)-(1 R,2R)-3-(3-dimethylamino-1-ethy\-2-methylpropyl)-phenol
`hydrochloride according to claim 1 or ~nd at least one suitable additive
`;t .f., I :I -..J j( 'f
`,'1
`and/or auxiliary substance.
`.
`~~
`
`;ro. Use of the crystalline Form A according to claim ~for the production of a
`
`AG
`
`medicament for treating pain or urinary incontinence.
`
`Received at the EPO on Apr 18, 2008 17:51 :57. Page 7 of 7
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`Page 7 of 7