U 7444506
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`October 24, 2013
`
`TI~IS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`
`THE RECORDS OF THIS OFFICE OF:
`
`U.S. PATENT: 8,518,987
`ISSUE DATE: August 27, 2013
`
`By Authority of the
`
`Under Secretary of Commerce for Intellectual Property
`and Directbr of the United States Patent and Trademark Office
`
`T. LAWRENCE
`Certifying Officer
`
`Lupin Ex. 1001 (Page 1 of 36)
`
`

`
`US008518987B2
`
`(12) United States Patent
`Vermeersch et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,518,987 B2
`Aug. 27, 2013
`
`(54) PSEUDOPOLYMORPHIC FORMS OFA HIV
`PROTEASE INHIBITOR
`
`(75)
`
`Inventors: Hans Wim Pieter Vermeersch, Ghent
`(BE); Daniel Joseph Christiaan Thone,
`Beerse (BE); Luc Donne Marie-Louise
`Janssens, Malle (BE); Pier Tom Bert
`Paul Wigerinck, Terhagen (BE)
`
`(73) Assignee: Janssen R&D Ireland, Little Island, Co.
`Cork (IE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 276 days.
`
`(21) Appl. No.: 12/536,807
`
`(22) Filed:
`
`Aug. 6, 2009
`
`(65)
`
`Prior Publication Data
`
`US 2010/0204316A1
`
`Aug. 12, 2010
`
`Related U.S. Application Data
`
`(62) Division of application No. 10/514,352, filed as
`application No. PCT/EP03/50176 on May 16, 2003,
`now Pat. No. 7,700,645.
`
`(3O)
`
`Foreign Application Priority Data
`
`May 16, 2002 (EP) ..................................... 02076929
`
`(2006.01)
`
`(51) Int. C1.
`A 61K 31/353
`(52) U.S. el.
`USPC ........................................... 5141456; 549/396
`(58) Field of Classification Search
`USPC .......................................... 514/456; 549/396
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,413,999 A
`6,071,916 A
`6,096,779 A
`6,248,775 B1
`6,281,367 BI
`6,287,693 BI
`7,700,645 B2
`2013/0029945 A1 *
`
`5/1995 Vacca et al.
`6/2000 Askin et al.
`8/2000 Chikaraishi et al.
`6/2001 Vazquez et al.
`8/2001 AI-Farhan et al.
`9/2001 Savoir et al.
`4/2010 Vermeersch et al.
`1/2013 Phull et al ..................... 514/158
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`0715618 BI
`05-230044
`WO 95/06030 A1
`WO 98/56781
`WO 99/51618
`WO 99/67254
`WO 99/67417 A2
`WO 00/29390
`WO 00/47551
`WO 03/106461 A1
`
`6/1996
`9/1993
`3/1995
`12/1998
`10/1999
`12/1999
`12/1999
`5/2000
`8/2000
`12/2003
`
`OTHER PUBLICATIONS
`
`Gyseghem et al. "Solid state chara... "AAOS Annual meeting abs.
`(2009).*
`Gao "Physical chemical..." AAPS PharmSci. 3(1) p. 1-8 (2001).*
`Gyseghem"Solid state..." Eu. J.Pharm. Sci. 38 p. 489-497 (2009).*
`Vermeersch "Pseudopo..." CA140:47540 (2003).*
`International Search Report re: PCT/EP03/50176, dated May 16,
`2003.
`Giron D., et al., "Thermal analysis and calorimetric methods in the
`characterization of pulymorphs and solvates," Thermochimica Acta,
`Elsevier Science Publishers, Amsterdam, vol. 248, 1995, pp. 1-59.
`Borka L., et al., "Crystal polymorphism of pharmaceuticals," Acta
`Pharmaceufica Jugoslavica, Savez Farmaceutskih Dmstava
`Jugoslavije, Zagre, Yu, vol. 40, 1990~ pp. 71-94.
`Ghosh a.K., et al., "Potent HIV protease inhibitors incorporating
`high-affinity P2-1igands and (R)-(hydroxyethylamino) sulfonamide
`isostere," Bioorganic & Medical Chemistry Letters, Oxford, GB, vol.
`8, No. 6, Mar. 17, 1998, pp. 687-690.
`Gmnenborg A., et al., "Theoretical derivation and pracfival applica-
`tion of energy/temperature diagramas as aa instrument in preformula-
`fion studies ofpolymorphic drug substancas~" International Journal
`of Pharmaceutics 129 (1996) 147-158.
`Bym, S. R., et al., "Solid-State Chemistry of Drugs", SecondEdifion,
`1999, published by SSCI, Inc.. pp. 12-13.
`Seddon, K., Crystal Growth & Design, 4 (6), p. 1087 (2004).
`Braga, D., et al. "Making Crystals from Crystals: A Green Route to
`Crystal Engineering and Polymorphism", Chem. Commun., pp.
`3635-3645 (2002).
`Kirk-Otluner Encyclopedia of Chemical Teclmology, "Crystalliza-
`tion", vol. 8 (2002) pp. 95-147 (2002).
`Vermeersch, H., et al. "Pseudopolymorphic Forms ofa HIV Protease
`Intdbitor", Caplus No. 1006987 (2003).
`"Defendants Lupin Lhnited’ s, Lupin Pharmaceuticals, Inc.’s, Mylan
`Pharmaceuticals Inc.’s and Mylan Inc.’s Joint Invalidity Contentions
`Pursuant to Local Patent Rule 3.6(b)", in the United States District
`Court District of New Jersey, Consolidated Civil Action No.
`10-5954-WHW-MCA, Nov. 18, 2011 (Redacted), 178 pages.
`"Hereto Drags, Ltd.’s Certification of Non-Infringement and!or
`Invalidity of United States Patent Nos. 5,843,946, 6,037,157,
`6,248,775, 6,335,460, 6,703,403, 7,470,506, and 7,700,645", Feb.
`10, 2011 (Redacted), 73 pages.
`"Lupin Ltd.’s Notification of Certification of U.S. Patent Nos.
`6,037,157, 6,703,403, 7,470,506, and 7,700,645 Pttrsuant to §
`505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act", Jun.
`3, 2011 (Redacted), 96 pages.
`"Teva Pharmaceuticals USA, Inc.’s and Teva Pharmaceutical Indus-
`tries, Ltd.’s Invalidity Contentions Under Local Patent Rules 3.3 and
`3.6", Nov. 18, 2011 (Redacted), 123 pages.
`Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Sys-
`tems", LippinCott Williams & Willdns, 7~n ed., 1999, 297-304.
`Bauer, "Pdtonavir an Extraordinary Example of Conformational
`Pulyruorphism", voL 18, Pharmaceutical Res., 2001, 859-866.
`Berstein, J., "Polyrnorphism in Molecular Crystals", Oxford Univer-
`sity Press, pp. 4-8, 2002.
`Brittain, H.G., "Polymorphism in Pharmaceutical Studies", Discov-
`ery Laboratories, Inc., 1999, pp. 205-208.
`Byrn, S. et al., Pharmaceutical Solids A Strategic Approach to Regu-
`latory Considerations, Pharmaceutical Res., vol. 12, No. 7, 1995,
`945-954.
`
`(Continued)
`
`Primary Examiner -- Celia Chang
`(74) Attorney, Agent, or Firm -- Woodcock Washburn LLP
`
`(57)
`
`ABSTRACT ’
`
`New pseudopolymorphic forms of (3R,3aS,6aR)-hexahydro-
`furo [2,3 -b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl]
`(isobutyl)amino]-I -benzyl-2-hydroxypropylcarbamate and
`processes for producing them are disclosed.
`
`Seddon "Pseudopolymorpl~. ,. "Crystal Growth & design v.4(6) p.
`1087 (2004) (2 pages from internet).*
`
`19 Claims, 18 Drawing Sheets
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
`
`Lupin Ex. 1001 (Page 2 of 36)
`
`

`
`US 8,518,987 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Center for Drag Evaluation and Research, "Guideline for Submitting
`Supporting Documentation in Drag Applications for the Manufac-
`ture of Drag Substances", Feb. 1987, 20 pages.
`Chemburkar, S.R. et al., "Dealing with the Impact of Ritonavir
`Polymorphs on the Late Statges of Bulk Process Development",
`Organic Process Research and Development, vol. 4, No. 5, 2000, pp.
`413-417.
`Chikaraishi, Y. et al., "Preparation of Piretanide Polymorphs and
`Their Physicochemical Properties and Dissolution Behaviors",
`Chem. Pharm. Bull., vol. 42(5), May 1994, pp. 1123-1128.
`Datta, S. et al., "Crystal structures of drags: advances in determina-
`tion, prediction, and engineering", Nature Reviews Drug Discovery,
`vol. 3, Jan. 2004, pp. 42-57.
`Ghosh et al., "Structure Based Design: Novel Spirocyclic Ethers as
`Nonpeptidal P2-Ligands for HIV Protease Inlfibitors", Binorganic
`and Med. Chem. Letters 8, Feb. 1998, 687-90.
`Haleblian, L et al., "Pharmaceutic al Applications of Polymorphism",
`J. Pharm. Sci. vol. 64, No. 8, Aug. 1975, pp. 1269-1288.
`ICH Harmonized Tripartite Guideline, "Specifications: Test Proce-
`dttres and Acceptance Criteria for New Drug Substances and New
`ping Products: Chemical Substances, Q6A", Oct. 6, 1999, 35 pages.
`Jesley, et al., "Organic Phase Analysis, II. Two Unexpected cases of
`Pseudopolymo~phism", Arch. Phnrm. Chemi. Sci. Ed., vol. 9, May
`1981, 123-130.
`Johnson et al., "indinavir Sulfate" Analytical Profiles of Drug Sub-
`stances and Excipiants, vol. 26, Academic Press, 1999, 319-357.
`Jozwiakowski, Water-Insoluble Drag Formation; Chapter 15: Alter-
`ation of the Solid State of the Drug Substance: Polymorphs, Solvates,
`and Amo~phnus Forms, Interphnrm Press, Jan. 5, 2001, 525-568.
`
`Matsuda et al., "Physicochemical Characterization of Sprayed-Dried
`Phenylbutazone Polymorphs", J. Pharm. Sci,. vol. 73, No. 2, Feb.
`1984, pp. 173-179.
`McCrone, W.C., "Physics and chemistry of the Organic Solids State;
`Chapter 8: Polymo~hism", vol. 2, eds. D. Fox, M.M. Labes, andA.
`Weissberger, Wiley Interscience, New York, 1965, 725-767.
`Salole, E.G., "The Physicochemical Properties of Oestradiol", J.
`Pharm. Biomed. Anal., vol. 5, No. 7, 1987, pp. 635-648.
`Ghosh, & al., Nonpeptidal Pa Ligands for HIV Protease Inhibitors:
`Structure-Based Design, Synthesis, and Biological Evaluation, J.
`Med. Chem., 39, 1996, 3278-3290.
`European Patent Application No. 10180831.9: Extended European
`Search Report dated Feb. 28, 2011, 8 pages.
`Japanese Patent Application No. 513292/04: Official Action dated
`Sep. 1, 2009, 3 pages.
`Ogata, "Operation of Chemical Experiment Procedures," K.K.
`Nankodo, 1963, 367-377 and 297-399.
`Lupin’s Detailed Factual and Legal Basis for Lupin’s Paragraph IV
`Certification that U.S. Patent Nos. 6,037,157; 6,703,403; 7,470,506,
`and 7,700,645 are Invalid, Unenforceable, and/or Not Infringed, Oct.
`1, 2010, 96 pages, Redacted.
`Mylan’s Paragraph IV Certification that U.S. Patent Nos. 7,470,506
`and 7,700,645 are Invalid, Unenforeceable, and/or Not Infringed,
`Oct. 1, 2010, 38 pages, Redacted.
`Plaintiff’s Response to Invalidity Contentions of Defendants Lupin
`Limited, Lupin Pharmaceuticals, Inc., Mylan Pharmaceuticals Inc.,
`and Mylan Inc. Concer~ing U.S. Patent No. 7,700,645 Pursuant to
`Local Patent Rules 3 AA and 3.6(i), Mar. 29, 2012, 62 pages.
`plaintiff’s Response to Invalidity Contentions of Defendants Teva
`Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries, Ltd.
`Concerning U.S. Patent No.. 7,700,645 Pursuant to Local Patent
`Rules 3.4A and 3.6(i), Mar. 29, 2012, 51 pages.
`
`* cited by examiner
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
`
`Lupin Ex. 1001 (Page 3 of 36)
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`

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`U.S. Patent
`
`Aug. 27, 2013 Sheet 2 of 18
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`US 8,518,987 B2
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`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 4 of 36)
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`U.S. Patent
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`Aug. 27, 2013 Sheet 3 of 18
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`US 8,518,987 B2
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`Copy provided by USPTO from the PIRS Image Database on 10(18/2013
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`Lupin Ex. 1001 (Page 5 of 36)
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`U.So Patent
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`Aug. 27, 2013
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`Sheet 4 of 18
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`US 8,518,987 B2
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`C16
`
`01
`
`C13
`
`,NIO
`
`08
`
`C38
`
`C37
`
`029 C24
`
`C25
`
`FIG. 4
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 6 of 36)
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`U.S. Patent
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`Aug. 27, 2013 Sheet 5 of 18
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`US 8,518,987 B2
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`FIG. 5
`
`FIG. 6
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`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex, 1001 (Page 7 of 36)
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`U.So Patent
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`Aug. 27, 2013
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`Sheet 6 of 18
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`US 8,518,987 B2
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`FIG. 7
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`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 8 of 36)
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`U.S. Patent
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`Aug. 27, 2013 Sheet 7 of 18
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`US 8,518,987 B2
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`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 9 of 36)
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`U.S. Patent
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`Aug. 27, 2013
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`Sheet 8 of 18
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`US 8,518,987 B2
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`FIG. 9
`
`iO0.
`~0.
`80.
`70~
`
`~o~oo ......... ~oo ......... ~’oo ......... ~ ~oo ......
`
`Wavenumbers (cm-1)
`
`FIG. 10
`
`100.
`90:
`
`70.
`
`20.
`10~.
`~o°,~oo ......... ~o’oo ......... ~I~o ......... ~o’oo .... ""
`Wavenumbers (cm-1)
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
`
`Lupin Ex. 1001 (Page 10 of 36)
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`

`
`(9£ jo I,I, al~ed) 1,001, "x~B u!dn-I
`
`!i
`
`Absorbance
`
`

`
`U.S. Patent
`
`Aug. 27, 2013 Sheet 10 of 18
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`US 8,518,987 B2
`
`0
`
`0
`
`0
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`Copy provided by USPTO from lhe PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 12 of 36)
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`

`
`U.S. Patent
`
`Aug. 27, 2013 Sheet 11 of 18
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`US 8,518,987 B2
`
`eoueqJosqv
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`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 13 of 36)
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`

`
`FIG. 14
`
`~ = ’ =~ ....
`045 .........
`: : : : ..... : ~ : .......
`’ ’ :
`040
`’ ’ ’ i .... ~ ..... i ....
`Y!NA
`035 .....
`0,30
`’Ji
`0.25
`
`-0.05
`-0.10
`-0.1~
`
`-0.25
`-0.30
`-0.35,
`040. , ,, ,
`-045 ’!’
`980 960
`
`) ~ ’’’ !
`
`
`, , , l ~ ~ : :, , , i i i , , ,
`
`940
`
`920
`
`900
`
`880
`
`gO
`
`860
`Wavenumbers (cm-1)
`
`820
`
`800
`
`780
`
`760
`
`

`
`U.S. Patent Aug. 27, 2013 Sheet 13 of 18
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`US 8,518,987 B2
`
`FIG. 15
`
`32
`30,
`
`20 E
`18, -F--
`16
`15
`t0 40
`
`50 6O 70
`
`80
`90 100
`Temperalure(°C)
`
`110 120 t30 140 150
`
`FIG. 16
`
`101,
`~oo,~
`~. \",,, \o
`
`97: \~ ",.. \
`
`Temperature
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
`
`Lupin Ex. 1001 (Page 15 of 36)
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`UoS. Patent
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`Aug. 27, 2013
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`Sheet 14 of 18
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`US 8,518,987 B2
`
`FIG. 17
`
`26,0
`
`-25,5
`
`25,0 ~
`
`.24,5
`
`24,0
`
`I00
`
`99.8
`
`99,6.
`
`99.4’
`
`99,2
`
`99,0
`
`1.0
`
`Residue:
`
`1 99,65% lmin
`
`~(10,70mg) Residue:
`\ 99.45% 6rain
`(~o,68~g) ...........
`~ ’Residue: ......
`~ 99,36% 10rain (10,67mg) Residue:
`99,26°4 20min
`
`300
`
`600
`
`900
`lime (min)
`
`1200
`
`1500
`
`1800
`
`FIG. 18
`AdsorptiontDesorption Isotherm at 25°C
`
`40 50 60 20 70 ~0 90 100
`
`30
`% Relative Humidity
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
`
`Lupin Ex. 1001 (Page 16 of 36)
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`U.S. Patent
`
`Aug. 27, 2013
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`Sheet 15 of 18
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`US 8,518,987 B2
`
`FIG. 19
`
`Adsorption/Desorption Isotherm at 25°C
`
`...........
`
`..,... ....-....,--’.,....~. ;, - -,.- hydratatlon test
`
`io 2’0 ~o io go ~o fo go go
`% Relative Humidity
`
`FIG. 20
`Adsorption/Desorption Isotherm at 25°C
`
`.~
`, ~_..~_. Dried (1 hour at10°C)]
`’ First r~n
`I _~’~-
`
`1.0
`0,5’
`0.0’
`-0,5’
`-1.0~
`-1,51
`-2,(
`-2,!
`-3I
`-3,~
`
`-4,
`
`-5.oi
`-5,50
`
`8.0
`
`7,0
`
`6.0
`
`5.0
`
`3.0
`
`2.0
`
`1,0
`O,Oo-- ~b 2’0 ~’o ~’o ~’o ~’o io ~o ~’o ~oo
`% Relative Humidity
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
`
`Lupin Ex. 1001 (Page 17 of 36)
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`U.S. Patent
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`Aug. 27, 2013
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`Sheet 16 of 18
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`US 8,518,987 B2
`
`FIG. 21
`
`3000
`
`2000
`Wavenumber (cm-1)
`
`1000
`
`FIG. 22
`
`3000
`
`2000
`Wavenumber (cm-1)
`
`1000
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 18 of 36)
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`U.S. Patent
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`Aug. 27, 2013
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`Sheet 17 of 18
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`US 8,518,987 B2
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`FIG. 23
`
`-3
`
`25 50 75 100 t25 150 t75 200
`Temperature (°C)
`
`FIG. 24
`
`0,1969% I
`(0,01445mg)
`
`0.t086% II
`(0,007938mg)
`
`3
`
`2
`
`101
`
`100,
`
`99.
`
`96-
`
`Temperature (°C)
`
`~o ....
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 19 of 36)
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`U.S. Patent
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`Aug. 27, 2013
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`Sheet 18 of 18
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`US 8,518,987 B2
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`1.6’
`
`1,4-
`
`1,2-
`
`1,0.
`o.8-
`0.6
`0,4.
`
`0,2.
`
`0.0
`0
`
`2,00
`1,80
`1.60
`1.40
`1,20-
`1,00,
`0,80-
`0,60
`0,40
`0,20-
`0.00
`0
`
`FIG. 25
`Adsorption/Desorption Isotherm at 25°C
`
`--,.- Dded (1 hour at 10°C ~ ~ ’-
`---,,- First run
`"" ""Second run
`
`,/"
`//
`
`..
`
`10 20 30
`t
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`t00
`
`% Relative Humidity
`
`FIG. 26
`Adsorption/Desorption Isotherm at 25°C
`
`--,’,-..- Dried (1 hourat 10°C
`---.,’-- First run
`..,,--. Second run
`
`t0
`
`20
`
`30
`
`50
`40
`60
`% Relative Humidity
`
`70
`
`80
`
`90
`
`t00
`
`Copy provided by USPTO from the PIRS Image Database on 10/18/2013
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`Lupin Ex. 1001 (Page 20 of 36)
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`

`
`1
`PSEUDOPOLYMORPHIC FORMS OF A
`PROTEASE INHIBITOR
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional of pending U.S. application
`Ser. No. 10/514,352, filed Nov. 12, 2004, now U.S. Pat. No.
`7,700,645 which in turn is a national stage of PCT Applica-
`tion No. PCT/EP2003/50176, filed May 16, 2003, which 10
`application claims priority from European Patent Application
`No. 02076929.5, filed May 16, 2002, the entire disclosures of
`which are hereby incorporated in their entirely.
`
`TECHNICAL FIELD
`
`Tiffs invention relates to novel pseudopolymorphic forms
`of (3R,3aS,6aR)-hexahydrofuro [2,3 -b] fumn-3-yl (1S,2R)-3-
`[[(4-aminophenyl)sulfonyl](isobutyl)amino]- 1 -benzyl-2-hy-
`droxypropylcarbamate, a method for their preparation as well
`as their use as a medicament.
`
`BACKGROUND OF THE INVENTION
`
`Vires-encoded proteases, which are essential for viral rep-
`lication, are required for the processing of viral protein pre-
`cursors. Interference with the processing of protein precur-
`sors inhibits the formation of infectious virions. Accordingly,
`inhibitors of viral pmteases may be used to prevent or treat
`chronic and acute viral infections. (3R,3aS,6aR)-hexahydro-
`furo[2,3 -b]furan-3-yl (1S,2R)-3 -[[(4-aminophenyl)sulfonyl]
`(isobutyl)amino] -1-benzyl-2-hydroxypropylcarbamate has
`H1V protease inhibitory activity and is particularly well
`suited for inhibiting HIV-1 and HIV-2 viruses.
`The structure of (3R,3aS,raR)-hexahydrofuro[2,3-b]fu-
`ran-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl] (isobutyl)
`amino]-l-benzyl-2-hydroxypropylcarbamate, is shown
`below:
`
`NII2
`
`US 8,518,987 B2
`
`2
`including GMP (Good Manufacturing Practices) and ICH
`(International Conference on Harmonization) guidelines.
`Such standards include technical requirements that encom-
`pass a heterogeneous and wide range of physical, chemical
`5 and pharmaceutical parameters. It is this variety of param-
`eters to consider, which make pharmaceutical formulations a
`complex technical discipline.
`For instance, and as example, a drug utilized for the prepa-
`ration of pharmaceutical formulations should meet an accept-
`able purity. There are established guidelines that define the
`limits and qualification of impurities in new drug substances
`produced by chemical synthesis, i.e. actual and potential
`impurities most likely to arise during the synthesis, purifica-
`15 tion, and storage of the new drug substance. Guidelines are
`instituted for the amount of allowed degradation products of
`the drug substance, or reactionproducts of the drug substance
`with an excipient and/or immediate container/closure system.
`Stability is also a parameter considered in creating phar-
`maceutical formulations. A good stability will ensure that the
`desired chemical integrity of drag substances is maintained
`during the shelf-life of the pharmaceutical formulation,
`which is the time frame over which a product can be relied
`upon to retain its quality characteristics when stored under
`25 expected or directed storage conditions. During this period
`the drug may be administered with little or no risk, as the
`presence of potentially dangerous degradation products does
`not pose prejudicial consequences to the health of the
`receiver, nor the lower content of the active ingredient could
`3o cause under-medication.
`Different factors, such as light radiation, temperature, oxy-
`gen, humidity, pH sensitivity in solutions, may influence sta-
`bility and may determine shelf-life and storage conditions.
`Bioavailability is also a parameter to consider in drug
`35 delivery design ufpharmaceutically acceptable formulations.
`Bioavailability is concerned with the quantity and rate at
`which the intact form of a particular drug appears in the
`systemic circulation following administration of the drug.
`The bioavailability exhibited by a drug is thus of relevance in
`40 determining whether a therapeutically effective concentra-
`tion is achieved at the site(s) of action of the drug.
`Physico-chemical factors and the pharmaco-technical for-
`mulation can have repercussions in the bioavailability of the
`chug. As such, several properties of the drug such as disso-
`45 clarion constant, dissolution rate, solubility, polymorphic
`form, particle size, are to be considered when improving the
`bioavailability.
`It is also relevant to establish that the selected pharmaceu-
`tical formulafionis capable ofmannfacmre, more suitably, of
`50 large-scale manufacture.
`In view of the various and many technical requirements,
`and its influencing parameters, it is not obvious to foresee
`which pharmaceutical formulations will be acceptable. As
`such, it was unexpectedly found that certain modifications of
`the solid state of compound of formula (X) positively influ-
`enced its applicability in pharmaceutical formulations.
`
`55
`
`SUMMARY OF THE INVENTION
`
`Compound or formula (X) andprocesses for its preparation
`are disclosed in EP 715618, WO 99/67417, U.S. Pat. No.
`6,248,775, and in Bioorganic and Chemistry Letters, Vol. 8,
`pp. 687-690, 1998, "Potent HIV protease inhibitors incorpo-
`rating high-affinity Pa-ligands and (R)-(hydroxyethylamino)
`sulfonamide isostere", all of which are incorporated herein by
`reference.
`Drugs utilized in the preparation of pharmaceutical formu-
`lations for commercial use must meet certain standards,
`
`Present invention concerns pseudopolymorphic forms of
`compound of formula (X) for the preparation of pharmaceu-
`tical formulations. Such pseudopolymorphic forms contrib-
`ute to pharmaceutical formulations in improved stability and
`bioavailability. They can be manufactured in sufficient high
`65 purity to be acceptable for pharmaceutical use, more particu-
`larly in the manufacture of a medicament for inhibiting HIV
`protease activity in mammals.
`
`Copy provided by USPTO from the PIRS Image Database on 10118/2013
`
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`US 8,518,987 B2
`
`3
`In a first aspect, the present inventionprovides pseudopoly-
`morphs of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furau-3-yl
`( 1S,2R)-3 -[[(4-aminophenyl)sulfonyl] (isobutyl)amino] ,1-
`benzyl-2-hydroxypmpylcarbamate.
`Pseudopolymorphs provided include alcohol solvates,
`more in particular, C1-C4 alcohol solvates; hydrate solvates;
`alkane solvates, more in particular, C1-C4 chloroalkane sol-
`vates; ketone solvates, more in particular, C1-C5 ketone sol-
`rates; ether solvates, moreinparticular, C1-C4 ether solvates;
`cycloether solvates; ester solvates, more in particular, C1-C5
`ester solvates; and sulfoulc solvates, more in particular,
`C1-C4 sulfonic solvates, of the compound of formula (X).
`Preferred pseudopolymorphs are pharmaceutically accept-
`able solvates, such as hydrate and ethanolate. Particular
`pseudopolymorphs are Form A (ethanolate), Form B 0ay-
`dmte), Form C (methanolate), Form D (acetoante), Form E
`(dichloromethanate), Form F (ethylacetate solvate), Form G
`(1-methoxy-2-propanolate), Form H (anisolate), Form I (tet-
`rahydrofuranate), Form J (isopropanolate) of compound of
`formula (X). Another particular pseudopolymorphis Form K
`(mesylate) of compound of formula (X).
`In a second aspect, present invention relates to processes
`for preparing pseudopolymorphs. Psendopolymorphs of
`compound of formula (X) are prepared by combining com-
`pound of formula (X) with an organic solvent, water, or
`mixtures of water and water miscible organic solvents, and
`applying any suitable technique to induce crystallization, to
`obtain the desired pseudopolymorphs.
`In a third aspect, the invention relates to the use of the
`present pseudopolymorphs, in the manufacture of pharma-
`ceutical formulations for inhibiting HIV protease activity in
`mammals. In relation to the therapeutic field, a preferred
`embodiment of this invention relates to the use of pharma-
`ceutically acceptable pseudopolymorphic for-ms of com-
`pound of formula (X) for the treatment of an HW viral disease
`in a mnmmal in need thereof, which method comprises
`administering to said mnrnm al an effective amotmt of a phar-
`maceutically acceptable pseudopolymorphic form of com-
`pound of formula (X).
`The following drawings provide additional information on
`the characteristics of the pseudopolymorphs according to
`present invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1, FIG. 2 and FIG. 3 are the powder X-my diffraction
`patterns of the Form A (1:1).
`FIG. 4 depicts Form A (1:1) in three dimensions with the
`atoms identified.
`FIG. 5 is a comparison of the Raman spectra of Forms A, B,
`D, E, F, H, (1:1) and the amorphous form at the carbonyl
`stretching region of 1800-100 cm-1 andthe region 3300-2000
`cm-1.
`FIG. 6 is a comparison of the expanded Raman spectra of
`Forms A, B, D, E, F, H, (1:1) and the amorphous form at the
`carbonyl stretching region of 600-0 cm-~.
`FIG. 7 is a comparison of the expanded Raman spectra of
`Forms A, B, D, E, F, H, (1:1) and the amorphous form at the
`carbonyl stretching region of 1400-800 cm-~.
`In FIGS. 5, 6, and 7, P1 corresponds to Form A, P18
`corresponds to Form B, P19 corresponds to amorphous form,
`P25 corresponds to Form E, P27 corresponds to Form F, P50
`corresponds to Form D, P68 corresponds to Form H, P69
`corresponds to Form C, P72 corresponds to Form I, and P81
`corresponds to Form). G.
`FIG. 8 is the Differential Scnnning Ca!orimetric (DSC)
`thermograph of Form A (1:1 ).
`
`4
`FIG. 9 is the Infrared (IR) spectrum that reflects the vibra-
`tional modes of the molecular structure of Form A as a crys-
`talline product
`FIG. 10 is the IR spectrum that reflects the vibrational
`5 modes of the molecular structure of Form B as a crystalline
`product
`FIG. 11: IR spectrum offormsA, B, and amorphous form,
`at spectral range 4000 to 400 cm-~.
`FIG. 12: IR spectrum of formsA, B, and amorphous form,
`10 at spectral range 3750 to 2650 cm-t
`FIG. 13: IR spectrum offormsA, B, and amorphous form,
`at spectral range 1760 to 1580 cm-~
`FIG. 14: IR spectrum of formsA, B, and amorphous form,
`at spectral range 980 to 720 cm-I
`In FIGS. 11,12,13 and 14, curveA corresponds to FormA,
`curve B corresponds to Form B, and curve C corresponds to
`the amorphous form.
`FIG. 15: DSC Thermograph curves of FormA (curve D),
`Form A after Adsorption/Desorption (ADS/DES) (curve E),
`z0 and FormA afterADS/DES hydratation tests (curve F)
`FIG. 16: Thermogravimetric (TG) curves of FormA (curve
`D), Form A after ADS/DES (curve E), and Form A after
`ADS/DES hydratation tests (curve F)
`FIG. 17: TG curve of FormA at 25° C. under dry nitrogen
`25 atmosphere in function of time
`FIG. 18: ADS/DES curves of Form A.
`FIG. 19: ADS/DES curves of the hydratation test of Form
`
`15
`
`A
`
`FIG. 20: ADS/DES curves of Form B
`FIG. 21: IR spectrum of Form K
`FIG. 22: Raman spectrum of Form K
`FIG. 23: DSC curve of Form K
`FIG. 24: TG curve of Form K
`FIG. 25: ADS/DES isotherm of Form K, batch 1
`FIG. 26: ADS/DES isotherm of Form K, batch 2
`
`30
`
`35
`
`DETAILED DESCRIPTION
`
`50
`
`The term "polymorphism" refers to the capacity of a
`40 chemical structure to occur in different forms and is known to
`occur in many organic compounds including drugs. As such,
`"polymorphic forms" or "polymorphs" include drug sub-
`stances that appear in amorphous form, in crystalline form, in
`anhydrous form, at various degrees of hydration or solvation,
`45 with entrapped solvent molecules, as well as substances vary-
`ing in crystal hardness, shape and size. The different poly-
`morphs vary in physical properties such as solubility, disso-
`lution, solid-state stability as well as processing behaviour in
`terms of powder flow and compaction during tabletting.
`The term "amorphous form" is defined as a form in which
`a three-dimensional long-range order does not exist. In the
`amorphous form the position of the molecules relative to one
`another are essentially random, i.e. without regular arrange-
`ment of the molecules on a lattice structure.
`The term "crystalline" is defined as a form in which the
`position of the molecules relative to one another is orgaulsed
`according to a three-dimensional lattice structure.
`The term "anhydrous form" refers to a particular form
`essentially free of water. "Hydration" refers to the process of
`6o adding water molecules to a substance that occurs in a par-
`ticular form and"hydrates" are substances that are formed by
`adding water molecules. "Solvating" refers to the process of
`incorporating molecules of a solvent into a substance occur-
`ring in a crystalline form. Therefore, the term "solvate" is
`65 defined as a crystal form that contains either stoichiometric or
`non-stoichiometric amounts of solvent. Since water is a sol-
`vent, solvates also include hydrates. The term "pseudopoly-
`
`55
`
`Copy provided by USPTO from the PIRS Image Database on 10118/2013
`
`Lupin Ex. 1001 (Page 22 of 36)
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`
`US 8,518,987 B2
`
`data was collected between 4 and 60° 2-theta step size. Form
`A (1:1) has the characteristic two-theta angle positions of
`
`TABLE 1
`
`crystal Data
`
`5
`6
`morph" is applied to polymorphic crystalline forms that have
`of compound of formula (X), preferably the ratio is 1 mol-
`solvent molecules incorporated in their lattice structures. The
`ecule of solvent per 1 molecule of compound of formula (X).
`term pseudopolymorphism is used frequently to designate
`Solvates may also occur at different levels of hydration. As
`solvates (Bym, Pfeiffer, Stowell, (1999) Solid-state Chemis-
`such, solvate crystal forms of compound of formula (X) may
`try of Drugs, 2ndEd.,publishedbySSCI, Inc).
`5
`in addition comprise under certain circumstances, water mol-
`Thepresentinventionprovidespseudopolymorphsof(3R,
`ecules partially or fully in the crystal structures. Conse-
`3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1 S,2R)-3-[[(4-
`quently, the term "FormA" will be used herein to refer to the
`aminophenyl)sulfonyl] (isobutyl)amino]-l-benzyl-2-hydrox-
`ethanolate forms of compound of formula (X) comprising up
`ypmpylcarbamate,
`to 5 molecules of solvent per 1 molecule of compound of
`In one embodiment pseudopolymorphs are alcohol sol- 10
`formula (X), intermediate solvates crystals, and the mixtures
`vates, more in particular, C1-C4 alcohol solvates; hydrate
`thereof; and optionally comprising additional water mol-
`solvates; alkane solvates, more in particular, CI-C4 chloroal-
`ecules, partially or fully in the crystal structures. The same
`kane solvates; ketone solvates, more in particular, C1-Ca
`applies for Form B through Form K. In case a particular
`ketone solvates; ether solvates, more in particular Ct-C4 ether
`solvates; cycloether solvates; ester solvates, more inparticu- 15 "Form A" needs to be denoted, the ratio of solvation will
`follow the ’~Form A’, for instance, one molecule of ethanol
`lar C1-Ca ester solvates; or sulfonic solvates, more in particu-
`per one molecule of compound (X) is denoted as Form A
`lar, c1-C4 sulfonic solvates, of the compound of formula (X).
`(hl).
`The term "C~-C4 alcohol" defines straight and/or branched
`The X-my powder diffraction is a technique to characterise
`chained saturated and unsaturated hydrocarbons having from
`1 to 4 carbon atoms substituted with at least ahydroxyl group, 20 polymorphic forms including pseudopolymorphs of corn-
`pound of formula (X) and to differentiate solvate crystal
`and optionally substituted with an alkyloxy group, such as,
`for example, methanol, ethanol, isopropanol, butanol,
`formsfromothercrystalandnon-crystalformsofcompound
`1 -methoxy-2-propanol and the like. The term "Ct-C4 chloro-
`of formula (X). As such, X-ray powder diffraction spectra
`alkane" defines straight and/or branched chained saturated
`were collected on a Phillips PW 1050/80 powder diffracto-
`and unsaturated hydrocarbons having from 1 to 4 carbon 25 meter, model Bragg-Brentano. Powders of Form A (hl),
`atoms substituted with at least one chloro atom, such as, for
`around 200 mg each sample, were packed in 0.5 mm glass
`example, dichlommethane. The term "Ct-Cs ketone" defines
`capillary tubes and were analysed according to a standard
`solvents of the general formula R’~(~----O)--R wherein R
`method in the art. The X-my generator was operated at 45 Kv
`and R’ can be the same or different and are methyl or ethyl,
`and 32 mA, using the copper Kct line as the radiation source.
`such as, acetone and the like. The term "C1-C4 ether" defines 30 There was no rotation of the sample along the chi axis and
`solvents of the general formula R’~R wherein R and R’
`canbethesame or different and are a phenyl group, methyl or
`ethyl, such as, aulsole and the like. The term "cycloether"
`defines a 4- to 6-membered monocyclic hydrocarbons con- peaks as showninFIGS. 1, 2and3 at: 7.04°-+0.5o,9.240_+0.5°,
`taiulngoneortwooxygenringatoms, suchastetrahydrofurun 35 9’96°-+0’5°’ 10’66°-+0"5°’
`11’30°-+0’5°
`12’82°-+0’5°
`14’56°-+0’5°, 16’66°-+0’55 17’30°-+0’5°’
`13"80°-+0"5°
`and the like. The term "C~-Ca ester" defines solvents of the
`18’28°-+0’5°’ 19’10°-+0’5°, 20’00°-+0’5°’ 20’50°-+0’5°’
`general formula R’~(zO)~R wherein R and R’ can
`21’22°-+0’5°’ 22’68°±0’5°, 23"08°-+0’5°’ 23’66°-+0’5°’
`be the same or different and are methyl or ethyl, such as
`25.080-+0.5°,
`26.28°±0.5°.
`27.18o-+0.5°,
`25.580±0.5°,
`ethylacetate and the like. The term "Cx-C4 sulfonic solvent"