SHILPA PHARMA, INC.,
`
`
`Plaintiff,
`
`
`
`v.
`
`
`NOVARTIS PHARMACEUTICALS
`CORPORATION,
`
`
`
`
`C.A. No. 21-558-MN
`
`JURY TRIAL DEMANDED
`
`
`
`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 1 of 112 PageID #: 1656
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`Defendant.
`
`
`JOINT CLAIM CONSTRUCTION BRIEF APPENDIX
`VOLUME I OF III: EXHIBITS 1-6
`
`SMITH, KATZENSTEIN & JENKINS LLP
`
`Neal C. Belgam (No. 2721)
`Eve H. Ormerod (No. 5369)
`1000 West Street, Suite 1501
`Wilmington, DE 19801
`(302) 652-8400
`nbelgam@skjlaw.com
`eormerod@skjlaw.com
`
`Attorneys for Plaintiff Shilpa Pharma, Inc.
`
`OF COUNSEL:
`
`Michael R. Dzwonczyk
`Chidambaram S. Iyer
`Raja N. Saliba
`L. Roman Rachuba
`SUGHRUE MION, PLLC
`2000 Pennsylvania Ave., NW
`Washington, DC 20037
`(202) 293-7060
`mdzwonczyk@sughrue.com
`ciyer@sughrue.com
`rsaliba@sughrue.com
`lrachuba@sughrue.com
`
`
`Dated: June 3, 2022
`
`MCCARTER & ENGLISH, LLP
`
`Daniel M. Silver (No. 4758)
`Alexandra M. Joyce (No. 6423)
`Renaissance Centre
`405 N. King Street, 8th Floor
`Wilmington, DE 19801
`(302) 984-6300
`dsilver@mccarter.com
`ajoyce@mccarter.com
`
`Counsel for Defendant Novartis
`Pharmaceuticals Corporation
`
`OF COUNSEL:
`
`Jane M. Love, Ph.D.
`Robert W. Trenchard
`Allyson Parks
`GIBSON, DUNN & CRUTCHER LLP
`200 Park Avenue
`New York, NY 10166
`(212) 351-4000
`jlove@gibsondunn.com
`rtrenchard@gibsondunn.com
`aparks@gibsondunn.com
`
`David Glandorf
`Christine Ranney
`GIBSON, DUNN & CRUTCHER LLP
`
`
`
`
`
`
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 2 of 112 PageID #: 1657
`
`
`
`1801 California Street, Suite 4200
`Denver, CO 80202-2642
`dglandorf@gibsondunn.com
`cranney@gibsondunn.com
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 3 of 112 PageID #: 1658
`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 3 of 112 PagelD #: 1658
`
`JA-1
`JA-1
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 4 of 112 PageID #: 1659
`
`III III 0 II0 1101 101 0II II I0I II 0II II II 0I II
`
`US009266816B2
`
`(12) United States Patent
`Shrawat et at.
`
`(10) Patent No.: US 9,266,816 B2
`(45) Date of Patent: Feb. 23, 2016
`
`(56) References Cited
`U.S. PATENT DOCUMENTS
`
`5,604,229 A
`5,719,176 A
`5,952,316 A
`6,476,004 B1
`2006/0275357 Al
`2008/0311188 Al
`2009/0203798 Al
`2011/0105620 Al
`
`Fujita et al.
`2/1997
`Fujita et al.
`2/1998
`Fujita et al.
`9/1999
`Sakai et al.
`11/2002
`Oomura et al.
`12/2006
`Oomura et al.
`12/2008
`Oomura et al.
`8/2009
`Oomura et al.
`5/2011
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`WO
`
`10/1998
`0627406 Bl
`10/2004
`W02004089341 A
`5/2010
`W02010055028 A2
`OTHER PUBLICATIONS
`
`Durand et al.,"A new Efficient Synthesis of the Immunosuppressive
`Agent FTY-720", Synthesis 2000, No. 4, 505-506.
`(Continued)
`
`Primary Examiner — Clinton Brooks
`
`(57) ABSTRACT
`The present invention provides crystalline polymorphic
`forms of Fingolimod HC1 (I) and processes for preparation
`thereof.
`The application provides processes for preparation of crys-
`talline polymorphic forms-a, 13 and p. substantially free from
`process related impurities. The crystalline polymorphic
`forms of Fingolimod HCl (I) obtained by the processes
`according to the present invention having an XRDP pattern as
`per FIGS. 1, 3 and 5, which are useful as active pharmaceu-
`tical ingredient in pharmaceutical compositions for the treat-
`ment or prevention of autoimmune related disorder including
`multiple sclerosis.
`
`6 Claims, 5 Drawing Sheets
`
`(54) FINGOLIMOD POLYNIORPHS AND THEIR
`PROCESSES
`
`(75) Inventors: Vimal Kumar Shrawat, Karnataka (IN);
`Veereshappa, Karnataka (IN); Vinod
`Kumar Singh, Karnataka (IN);
`Prashant Purohit, Karnataka (IN)
`
`(73) Assignee: SHILPA MEDICARE LIMITED,
`Karnataka (IN)
`
`*
`
`Notice: Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 13/635,207
`(22) PCT Filed: Aug. 29, 2011
`PCT No.: PCT/IN201-1/000586
`§ 371 (c)(1),
`(2), (4) Date:
`
`Sep. 17, 2013
`
`(86)
`
`(87) PCT Pub. No.: W02012/070059
`PCT Pub. Date: May 31, 2012
`
`(65)
`
`Prior Publication Data
`US 2013/0281739 Al Oct. 24, 2013
`(30) Foreign Application Priority Data
`
`Nov. 25, 2010 (IN) 3563/CHE/2010
`
`(51) Int. Cl.
`C07C 213/10 (2006.01)
`C07C 215/10 (2006.01)
`CO7C 215/28 (2006.01)
`(52) U.S. Cl.
`CPC CO 7C 213/10 (2013.01); CO 7C 215/28
`(2013.01); CO7B 2200/13 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`IMOD]
`
`24000-11
`
`10
`
`. 1-.111 "111.-11,1111-T11
`
`20
`2-Thet9 - geale
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 5 of 112 PageID #: 1660
`
`US 9,266,816 B2
`Page 2
`
`(56)
`
`References Cited OTHER PUBLICATIONS
`U.S. PATENT DOCUMENTS
`2011/0229501 Al 9/2011 Jordine et al.
`2012/0184617 Al 7/2012 Gidwani et al.
`
`Kiuchi M et al. Synthesis and immunosuppressive Activity of 2-Sub-
`stituted 2 Aminopropane-1,3-diolsand 2-Aminoethanols 2000 J of
`Medicinal Chemistry, 2000, 43 (15), pp. 2946-2961.
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 6 of 112 PageID #: 1661
`
`U.S. Patent Feb. 23, 2016
`
`Sheet 1 of 5 US 9,266,816 B2
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`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 7 of 112 PageID #: 1662
`
`U.S. Patent Feb. 23, 2016 Sheet 2 of 5 US 9,266,816 B2
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`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 8 of 112 PageID #: 1663
`
`U.S. Patent Feb. 23, 2016 Sheet 3 of 5 US 9,266,816 B2
`
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`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 9 of 112 PageID #: 1664
`
`US. Patent Feb. 23, 2016 Sheet 4 of 5 Us 9,266,816 B2
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`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 10 of 112 PageID #: 1665
`
`U.S. Patent Feb. 23, 2016 Sheet 5 of 5 US 9,266,816 B2
`
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`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 11 of 112 PageID #: 1666
`
`US 9,266,816 B2
`
`1
`FINGOLIMOD POLYMORPHS AND THEIR
`PROCESSES
`
`FIELD OF THE INVENTION
`
`Particular aspects of the present application relates to the
`crystalline polymorphic forms a, 13 and µ of Fingolimod HC1
`(I) and processes for preparation thereof.
`
`BACKGROUND OF THE INVENTION
`
`Fingolimod hydrochloride has the IUPAC name as
`2-amino -242-(4-octylphenypethyl]p rop ane-1 ,3-diol hydro-
`chloride and have the following structure—
`
`5
`
`10
`
`15
`
`(I)
`
`20
`
`.1.1C1
`
`It is a structural analogue of sphingosine (II) which gets
`phosphotylated by sphingosine kinases
`
`25
`
`( )I I
`
`in the cell (specifically sphingosine kinase 2).
`Fingolimod being a sphingosine 1 -phosphate receptor
`(S1P-R) modulator, it binds to the SIP receptor on circulating
`lymphocytes, sequestering them in lymph nodes away from
`the CNS. It appears to be the first oral S1P-R modulator to be
`developed, which appears to reduce the number of inflamma-
`tory T cells in the circulation and CNS and in doing so, it
`reduces their potential to damage nerve cells.
`U.S. Pat. No. 5,604,229 is the first disclosure of the Fin-
`golimod and other related compounds. It has been found to be
`useful in the treatment or prevention of various autoimmune
`conditions, including multiple sclerosis.
`Mutz et al in W02010055028A2 reported various poly-
`morphic forms of Fingolimod hydrochloride designated as
`Form-I (at room temperature), Form-II (however at a transi-
`tion temperature of approximately 40° C.) and Form-III
`(however at a transition temperature of approximately 66°
`C.). Further, the patent application also mentions that
`approximately 107° C., Fingolimod hydrochloride forms a
`phase with lower crystalline order. However, other than ther-
`mal transition based forms, no exact crystalline form have
`been reported in the literature.
`In view of the existence of few known thermal transition
`based polymorphic forms of Fingolimod hydrochloride, there
`stills appears to be a need of novel crystalline forms, which
`are not only stable as well as convenient to scale up but also
`their processes provides improved yields & quality.
`
`SUMMARY OF THE INVENTION
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`Particular aspects of the present application relates to the 65
`crystalline polymorphic forms a, 13 and p. of Fingolimod HC1
`(I) and processes for preparation thereof.
`
`2
`The application relates to processes for preparation of crys-
`talline polymorphic forms-a, 13 and p. substantially free from
`process related impurities. The crystalline polymorphic
`forms of Fingolimod HC1 (I) obtained by the processes
`according to the present invention are useful as active phar-
`maceutical ingredient in phannaceutical compositions for the
`treatment or prevention of autoimmune related disorder
`including multiple sclerosis.
`Different aspects of the present application are summa-
`rized herein below individually.
`In one aspect of the present application, the present inven-
`tion provides Fingolimod hydrochloride crystalline Form-a
`characterized by X-ray powder diffraction pattern compris-
`ing at least 5 characteristic 20° peaks selected from the XRPD
`peak set of 10.51, 15.20, 19.27, 21.77, 23.12, 24.91, 26.14,
`26.46, 29.03, 33.47 and 35.46±0.1 20°. The said crystalline
`Form-a is further characterized by DSC isotherm comprising
`at least three endothermic peaks ranging between—
`a. Peak-1—Between 40 to 43° C.
`b. Peak-2—Between 65 to 68° C.
`c. Peak-3—Between 105 to 110° C.
`d. Peak-4—Between 270 to 280° C.
`In another aspect of the present application, the present
`invention provides process for preparing Fingolimod hydro-
`chloride crystalline Form-a comprising the steps of—
`a. Combining the Fingolimod hydrochloride with an
`organic acid
`b. Optionally heating up to about 40-50° C.
`c. cooling the solution up to about 0-5° C.
`d. isolating the crystalline Form-a
`In yet another aspect of the present application, the present
`invention provides Fingolimod hydrochloride crystalline
`Form-3 characterized by X-ray powder diffraction pattern
`comprising
`at least 4 characteristic 20° peaks selected from the XRPD
`peak set of 3.54, 7.07, 10.66, 15.35,
`20.52,21.43 and 25.10±0.1 20°. The said crystalline Form-13
`is further characterized by DSC
`isotherm comprising at least three endothermic peaks ranging
`between—
`a. Peak-1—Between 40 to 45° C.
`b. Peak-2—Between 65 to 70° C.
`c. Peak-3—Between 107 to 115° C.
`d. Peak-4—Between 265 to 270° C.
`In further another aspect of the present application, the
`present invention provides process for
`preparing Fingolimod hydrochloride crystalline Fonn-13
`comprising the steps of—
`a. Combining the Fingolimod hydrochloride with organic
`solvent selected from dimethylfonnamide, dimethylac-
`etamide, tetrahydrofiiran, 2-methoxyethanol
`b. Optionally heating up to about 40-50° C. followed by
`cooling
`c. isolating the crystalline Form-13 using another co-solvent
`by recrystallization
`In yet another aspect of the present application, the present
`invention provides Fingolimod Hydrochloride crystalline
`Form-p characterized by X-ray powder diffraction pattern
`comprising at least 4 characteristic 20° peaks selected from
`the XRPD peak set of 3.54, 8.65, 10.64, 12.49, 19.45, 21.38
`and 24.05±0.1 28°.
`In yet further another aspect of the present application, the
`present invention provides process
`for preparing Fingolimod hydrochloride crystalline Form-p.
`comprising the steps of—
`a. Raising the Fingolimod hydrochloride temperature up to
`at least melting point but less than 130° C.
`b. Cooling the melt liquid
`c. isolating the crystalline Form-p.
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 12 of 112 PageID #: 1667
`
`US 9,266,816 B2
`3
`In further aspect, the Crystalline Forms-a, 13 and 1.t of
`Fingolimod HC1 obtained by the processes of the present
`application may be formulated as solid compositions for oral
`administration in the form of capsules, tablets, pills, powders
`or granules useful in the treatment or prevention of autoim-
`mune related disorder including multiple sclerosis.
`
`5
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is an Illustration of an X-ray powder diffraction
`(XRPD) pattern of Fingolimod hydrochloride-Form a, pre-
`pared according to Example-1
`FIG. 2 is an Illustration of a differential scanning calori-
`metric ("DSC") curve of Fingolimod hydrochloride, pre-
`pared according to Example-1
`FIG. 3 is an Illustration of an X-ray powder diffraction
`(XRPD) pattern of Fingolimod hydrochloride-Form 13, pre-
`pared according to Example-2 Process-A
`FIG. 4 is an Illustration of a differential scanning calori-
`metric ("DSC") curve of Fingolimod hydrochloride, pre-
`pared according to Example-2 Process-A
`FIG. 5 is an Illustration of an X-ray powder diffraction
`(XRPD) pattern of Fingolimod hydrochloride-Form 1.t, pre-
`pared according to Example-3
`
`DETAILED DESCRIPTION
`
`10
`
`15
`
`20
`
`25
`
`As set forth herein, aspects of the present invention pro-
`vides crystalline polymorphic forms a, (3 and g of Fingolimod
`HC1 (I) and processes for preparation thereof. 30
`Individual embodiments of the present invention are
`detailed herein below separately.
`In one embodiment of the present application, it provides
`Fingolimod hydrochloride crystalline Form-a characterized
`by X-ray powder diffraction pattern comprising at least 5 35
`characteristic 200 peaks selected from the XRPD peak set of
`10.51, 15.20, 19.27, 21.77, 23.12, 24.91, 26.14, 26.46, 29.03,
`33.47 and 35.46±0.1 20°. The said crystalline Form-a may be
`further characterized by DSC isotherm comprising at least
`three endothermic peaks ranging between— 40
`a. Peak-1—Between 40 to 43° C.
`b. Peak-2—Between 65 to 68° C.
`c. Peak-3—Between 105 to 110° C.
`d. Peak-4—Between 270 to 280° C.
`Fingolimod hydrochloride crystalline Form-a character- 45
`ized by X-ray powder diffraction pattern comprising at least 5
`characteristic 20° peaks selected from the XRPD peak set of
`10.51, 15.20, 19.27, 21.77, 23.12, 24.91, 26.14, 26.46, 29.03,
`33.47 and 35.46±0.1 20° is having X-ray powder diffraction
`pattern substantially according to FIG. 1 and DSC isotherm so
`comprising the endothermic peaks ranging between 40 to 43°
`C. (Peak-1), 65 to 68° C. (Peak-2), 105 to 110° C. (Peak-3)
`and/or 270 to 280° C. (Peak-4) is having DSC isothermal
`pattern substantially according to FIG. 2.
`The characteristic peaks and their d spacing values of the 55
`new crystalline Form-a are tabulated in the Table-1.
`
`TABLE 1
`Characteristic XRPD Peaks of Crystalline Form-a
`
`S. No.
`
`Angle (26')
`
`d Spacing Value (A.°)
`
`1.
`2.
`3.
`4.
`5.
`
`10.51
`15.20
`19.27
`21.77
`23.12
`
`8.407
`5.823
`4.602
`4.080
`3.844
`
`60
`
`65
`
`4
`TABLE 1 -continued
`
`Characteristic XRPD Peaks of Crystalline Form-a
`
`Angle (20°)
`
`d Spacing Value (A')
`
`24.91
`26.14
`26.46
`29.03
`33.47
`35.46
`
`3.572
`3.407
`3.366
`3.073
`2.675
`2.530
`
`S. No.
`
`6.
`7.
`8.
`9.
`10.
`11.
`
`In another embodiment of the present invention, it provides
`process for preparing Fingolimod hydrochloride crystalline
`Form-a characterized by X-ray powder diffraction pattern
`comprising at least 5 characteristic 20° peaks selected from
`the XRPD peak set of 10.51, 15.20, 19.27, 21.77, 23.12,
`24.91, 26.14, 26.46, 29.03,33.47 and 35.46-10.1 20° and DSC
`isotherm comprising the endothermic peaks ranging between
`40 to 43° C. (Peak-1), 65 to 68° C. (Peak-2), 105 to 110° C.
`(Peak-3) and/or 270 to 280° C. (Peak-4) comprising the steps
`of—
`a. Combining the Fingolimod hydrochloride with an
`organic acid
`b. Optionally heating up to about 40-50° C.
`c. cooling the solution up to about 0-5° C.
`d. isolating the crystalline Form-a
`Combining the Fingolimod hydrochloride with as Organic
`acid comprise either mixing or suspending or making solu-
`tion with organic acids, selected from Cl to C4 carboxylic
`acid. In one of the particular embodiment, acetic acid is used
`as an organic acid for making Form-a. The combining of an
`organic acid may be carried out at ambient temperature; how-
`ever temperature may be raised to any temperature up to
`below 50° C., if desired.
`Any form of Crude or Pure Fingolimod Hydrochloride
`obtained by known processes can be used for preparing Form-
`a.
`The combined mixture may be maintained for about 1-2
`Jars, however, this time may be more, but, depending upon
`achieving the clear solution and equilibration to impurity
`profile compliance.
`The process related impurities, including unreacted inter-
`mediates, side products, degradation products and other
`medium dependent impurities, that appears in the impurity
`profile of the Fingolimod hydrochloride can substantially
`removed by the process of the present invention resulting in
`the formation crystalline form-a. A substantially pure prod-
`uct having purities more than 99% (by HPLC) can be
`obtained by the process of the present invention. In view of
`maintaining the equilibrium to the impurity profile compli-
`ance, the process requires quality checks, while raising the
`temperature, wherever required up to 50° C.
`Reaction mass can be cooled up to 25-30° C. and subjected
`to stir for about 1-2 hrs. Further cooling the reaction mass
`ranging between 0-10° C. followed by stirring for about 1-2
`hours may also carried out. The product may be isolated from
`the reaction mass by conventional processes including filter-
`ing and optional drying, which may be carried out at room
`temperature for the suitable durations to retain the crystalline
`polymorphic form characteristics.
`In yet another embodiment of the present application, it
`provides Fingolimod hydrochloride crystalline Form-(3 char-
`acterized by X-ray powder diffraction pattern comprising at
`least 4 characteristic 20° peaks selected from the XRPD peak
`set of 3.54, 7.07, 10.66, 15.35, 20.52, 21.43 and 25.10±0.1
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 13 of 112 PageID #: 1668
`
`US 9,266,816 B2
`
`5
`20°. The said crystalline Form-13 may be further characterized
`by DSC isotherm comprising at least three endothermic peaks
`ranging between-
`a. Peak-1-Between 40 to 45° C.
`b. Peak-2-Between 65 to 70° C.
`c. Peak-3-Between 107 to 115° C.
`d. Peak-4-Between 265 to 270° C.
`Fingolimod hydrochloride crystalline Form-3 character-
`ized by X-ray powder diffraction pattern comprising at least 4
`characteristic 20° peaks selected from the XRPD peak set of
`3.54, 7.07, 10.66, 15.35, 20.52, 21.43 and 25.10±0.1 20° is
`having X-ray powder diffraction pattern substantially accord-
`ing to FIG. 3 and DSC isotherm comprising the endothermic
`peaks ranging between 40 to 45° C. (Peak-1), 65 to 70° C.
`(Peak-2), 107 to 115° C. (Peak-3) and/or 265 to 270° C.
`(Peak-4) is having DSC isothermal pattern substantially
`according to FIG. 4.
`The characteristic peaks and their d spacing values of the
`new crystalline Form-13 are tabulated in the Table-2.
`TABLE 2
`
`Characteristic XRPD Peaks of Crystalline Form-13
`
`S. No. Angle (26') d Spacing Value (A')
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`
`3.54
`7.07
`10.66
`15.35
`20.52
`21.43
`25.10
`
`24.908
`12.494
`8.290
`5.767
`4.325
`4.143
`3.546
`
`6
`medium dependent impurities, that appears in the impurity
`profile of the Fingolimod hydrochloride can substantially
`removed by the process of the present invention resulting in
`the formation crystalline form-P. In view of maintaining the
`5 equilibrium to the impurity profile compliance, the process
`requires quality checks, while raising the temperature, when-
`ever required up to 50° C.
`Reaction mass can be cooled up to 0-30° C. and subjected
`to stir for about 1-2 hrs. The product may be isolated from the
`10 reaction mass by combining with co-solvent selected from
`ketone (C3 to C8) or nitrile (C2 to C4) or alcohol (C1 to C4),
`followed by conventional processes including filtering and
`optional drying, which may be carried out at room tempera-
`ture for the suitable durations to retain the crystalline poly-
`is morphic form characteristics.
`In yet another embodiment of the present application, it
`provides Fingolimod hydrochloride crystalline Form-µ char-
`acterized by X-ray powder diffraction pattern comprising at
`least 4 characteristic 200 peaks selected from the XRPD peak
`20 set of 3.54, 8.65, 10.64, 12.49, 19.45, 21.38 and 24.05±0.1
`20°.
`Fingolimod hydrochloride crystalline Form-pi character-
`ized by X-ray powder diffraction pattern comprising at least 4
`characteristic 20° peaks selected from the XRPD peak set of
`25 3.54, 8.65, 10.64, 12.49, 19.45, 21.38 and 24.05±0.1 20° is
`having X-ray powder diffraction pattern substantially accord-
`ing to FIG. 5.
`The characteristic peaks and their d spacing values of the
`new crystalline Form-pt are tabulated in the Table-3.
`
`30
`
`TABLE 3
`Characteristic XRPD Peaks of Crystalline Form-Li
`
`S. No.
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`
`Angle (260)
`
`d Spacing Value (A°)
`
`3.54
`8.65
`10.64
`12.49
`19.45
`21.38
`24.05
`
`24.905
`10.214
`8.310
`7.084
`4.560
`4.152
`3.698
`
`In another embodiment ofthe present invention, it provides
`process for preparing Fingolimod hydrochloride crystalline
`Form-13 characterized by X-ray powder diffraction pattern 35
`comprising at least 4 characteristic 20° peaks selected from
`the XRPD peak set of 3.54, 7.07, 10.66, 15.35, 20.52, 21.43
`and 25.10±0.1 20° and DSC isotherm comprising the endot-
`hermic peaks ranging between 40 to 45° C. (Peak-1), 65 to
`70° C. (Peak-2), 107 to 115° C. (Peak-3) and/or 265 to 270° 40
`C. (Peak-4) comprising the steps of-
`a. Combining the Fingolimod hydrochloride with organic
`solvent selected from dimethylformamide, dimethylac-
`etamide, tetrahydrofuran, 2-methoxyethanol
`b. Optionally heating up to about 40-50° C. followed by
`cooling
`c. isolating the crystalline Form-I3 using another co-solvent
`by recrystallization
`Combining the Fingolimod hydrochloride with as Organic
`solvents for preparing Form-I3 comprise either mixing or
`suspending or making solution with organic solvent selected
`from dimethylformamide, dimethylacetamide, tetrahydrofu-
`ran, 2-methoxyethanol. In one of the particular embodiment,
`dimethylformamade is used as an organic solvent for making
`Form-I3. The combining of an organic solvent may be carried
`out at ambient temperature; however temperature may be
`raised to any temperature up to below 50° C., whenever
`desired.
`As mentioned earlier, any form of Crude or Pure Fingoli-
`mod Hydrochloride obtained by known processes can be used
`for preparing Form-p.
`The combined mixture may be maintained for about 1-2
`hrs, however, this time may be more, but, depending upon
`achieving the clear solution and equilibration to impurity
`profile compliance.
`The process related impurities, including unreacted inter-
`mediates, side products, degradation products and other
`
`In another embodiment of the present invention, it provides
`process for preparing Fingolimod hydrochloride crystalline
`45 Form-g characterized by X-ray powder diffraction pattern
`comprising at least 4 characteristic 20° peaks selected from
`the XRPD peak set of 3.54, 8.65, 10.64,12.49, 19.45, 21.38
`and 24.05±0.1 200 comprising the steps of-
`a. Raising the Fingolimod hydrochloride temperature up to
`50 at least melting point but less than 130° C.
`b. Cooling the melt liquid
`c. isolating the crystalline Form-g.
`Any form of Crude or Pure Fingolimod Hydrochloride
`obtained by known processes can be used for preparing Form-
`55 1.1. The rise in temperature for the preparing melt of the Fin-
`golimod Hydrochloride can be slow in order to provide con-
`sistency and uniformity of the melt liquid phase. In a
`particular embodiment, melt temperature attained was 120-
`125° C.
`60 Simultaneously, it is essentially required to cool the melt in
`the successive lower rate of cooling in order to retain the
`characteristics of Form-R.
`Crystalline Form-µ can be isolated by conventional pro-
`cesses, which are not limited to scrapping, breaking, triturat-
`65 ing and if required conventional drying.
`In further aspect, the Crystalline Forms-a, P and j.t of
`Fingolimod HCl obtained by the processes of the present
`
`

`

`Case 1:21-cv-00558-MN Document 125-1 Filed 06/03/22 Page 14 of 112 PageID #: 1669
`
`US 9,266,816 B2
`
`8
`preparation of solid dispersion, wherever utilized in the
`desired dosage form preparation.
`Certain specific aspects and embodiments of the present
`application will be explained in more detail with reference to
`5 the following examples, which are provided by way of illus-
`tration only and should not be construed as limiting the scope
`of the invention in any manner.
`
`7
`application may be formulated as solid compositions for oral
`administration in the form of capsules, tablets, pills, powders
`or granules useful in the treatment or prevention of autoim-
`mune related disorder including multiple sclerosis.
`Different crystalline forms of the present invention may
`have one or more advantageous and desirable properties com-
`pared to the known Fingolimod Base, which are not limited to
`better stability, solubility and quality parameter leading to
`improved storage and distribution.
`The Crystalline Forms-a, 13 and II of Fingolimod HC1
`described herein may be characterized by X-ray powder dif-
`fraction pattern (XRPD) and Thermal techniques such as
`differential scanning calorimetric (DSC) Analysis. The
`samples of Fingolimod HC1 Crystalline Forms-a, 13 and
`were analyzed by XRPD on a Broker AXS D8 Advance
`Diffractometer using X-ray source-Cu Ka radiation using the
`wavelength 1.5418 A, however, DSC analysis were carried
`out on a Perkin Elmer Pyris 7.0 instrument. Illustrative
`examples of analytical data for the crystalline solids 'Form-a,
`p and If obtained in the Examples are set forth in the FIGS.
`1-5.
`In another embodiment, the Crystalline Forms-a, 13 and
`of Fingolimod HCl obtained by the processes of the present
`application may be formulated as solid compositions for oral
`administration in the form of capsules, tablets, pills, powders
`or granules. In these compositions, the active product is
`mixed with one or more pharmaceutically acceptable excipi-
`ents. The drug substance can be formulated as liquid compo-
`sitions for oral administration including solutions, suspen- 30
`sions, syrups, elixirs and emulsions, containing solvents or
`vehicles such as water, sorbitol, glycerine, propylene glycol
`or liquid paraffin.
`The compositions for parenteral administration can be sus-
`pensions, emulsions or aqueous or non-aqueous sterile solu- 35
`tions. As a solvent or vehicle, propylene glycol, polyethylene
`glycol, vegetable oils, especially olive oil, and injectable
`organic esters, e.g. ethyl oleate, may be employed. These
`compositions can contain adjuvants, especially wetting,
`emulsifying and dispersing agents. The sterilization may be
`carried out in several ways, e.g. using a bacteriological filter,
`by incorporating sterilizing agents in the composition, by
`irradiation or by heating. They may be prepared in the form of
`sterile compositions, which can be dissolved at the time ofuse
`in sterile water or any other sterile injectable medium.
`Pharmaceutically acceptable excipients used in the com-
`positions comprising Crystalline Forms-a, 13 and t of Fin-
`golimod HCl of the present application include, but are but
`not limited to diluents such as starch, pregelatinized starch,
`lactose, powdered cellulose, microcrystalline cellulose,
`dicalcium phosphate, tricalcium phosphate, mannitol, sorbi-
`tol, sugar and the like; binders such as acacia, guar gum,
`tragacanth, gelatin, pre-gelatinized starch and the like; disin-
`tegrants such as starch, sodium starch glycolate, pregelati-
`nized starch, Croscanuellose sodium, colloidal silicon diox-
`ide and the like; lubricants such as steatic acid, magnesium
`stearate, zinc stearate and the like; glidants such as colloidal
`silicon dioxide and the like; solubility or wetting enhancers
`such as anionic or cationic or neutral surfactants, waxes and
`the like. Other pharmaceutically acceptable excipients that
`are of use include but not limited to film formers, plasticizers,
`colorants, flavoring agents, sweeteners, viscosity enhancers,
`preservatives, antioxidants and the like.
`Pharmaceutically acceptable excipients used in the com-
`positions derived from Crystalline Forms-a, 13 and j.t of Fin-
`golimod HC1 of the present application may also comprise to
`include the pharmaceutically acceptable carrier used for the
`
`10
`
`EXAMPLE 1
`
`Preparation of Crystalline Fingolimod Hydrochloride
`(Form-a)
`
`15 Charge 10 ml acetic acid at ambient temperature followed
`by slow addition of 1.0 gm of Crude or Pure Fingolimod
`Hydrochloride obtained from any source in round bottom
`flask under continued stirred. Raise the temperature up to
`about 40-50° C. and maintained for about 1-2 hrs. (This time
`20 may be more, however, depending upon achieving the clear
`solution and equilibration to impurity profile compliance).
`Cool the reaction mass up to 25-30° C. and stir for about 1-2
`hrs at 25-30° C. Further, cool the reaction mass up to 0-5° C.
`and stir for about 2 hrs. Filter the reaction mass and isolating
`25 the crystalline product after 12 hours of drying at room tem-
`perature.
`Yield 0.36 gm
`XRPD as per FIG. 1; and DSC as per FIG. 2
`
`EXAMPLE 2
`
`Preparation of Crystalline Fingolimod Hydrochloride
`(Form-13)
`
`Process-A:
`Charge 3 ml DMF at ambient temperature followed by
`slow addition of 2.0 gm of Crude or Pure Fingolimod Hydro-
`chloride obtained from any source in round bottom flask
`40 under continued stirred. Stirr and maintain the solution for
`15-30 minutes to ensure clear solution. Slowly add 30.0 ml
`acetone at ambient temperature in about 1 hour time. Cool the
`reaction mass up to 0-5° C. and stir for about 2 his. Filter the
`reaction mass and isolating the crystalline product after 12
`45 hours of under vacuum drying at room temperature.
`Yield 1.37 gm
`XRPD as per FIG. 3; and DSC as per FIG. 4
`Process-B:
`Charge 3 ml THF at ambient temperature followed by slow
`so addition of 2.0 gm of Crude or Pure Fingolimod Hydrochlo-
`ride obtained from any source in round bottom flask under
`continued stirred. Stir and maintain the solution for 10-20
`minutes to ensure clear solution. Slowly add 60.0 ml acetone
`at ambient temperature in about 1 hour time. Cool the reaction
`55 mass up to 0-5° C. and stir for about 2 hrs. Filter the reaction
`mass and isolating the crystalline product after 12 hours of
`under vacuum drying at about 45° C.
`Yield 1.51 gm
`Process-C:
`60 Charge 5 ml 2-Methoxy ethanol at ambient temperature
`followed by slow addition of 2.0 gm of Crude or Pure Fin-
`golimod Hydrochloride obtained from any source in round
`bottom flask under continued stirred. Stir a