United States Patent
`US 8,889,159 B2
`(10) Patent No.:
`(12)
`Clearyet al.
`(45) Date of Patent:
`*Nov.18, 2014
`
`
`US008889159B2
`
`(54) COMPOSITIONS AND METHODS FOR
`TREATING HEPATITIS C VIRUS
`.
`(71) Applicant: Gilead Pharmasset LLC,Foster City,
`CA (US)
`
`(56}
`
`(72)
`
`Inventors: Darryl G. Cleary, Chapel Hill, NC
`(US); Charles J. Reynolds, Greenville,
`NC (US): Miriam Michelle Berrey,
`Durham, NC(US): Robert G. Hindes,
`Skillman, NJ (US), William T.
`.
`rN
`S53
`cr
`isc.
`Symonds, San Francisco, CA (US);
`Adrian S. Ray, Redwood City, CA
`(US); Hongmei Mo, Palo Alto, CA (US);
`Christy M. Hebner, Belmont, CA (US);
`.
`ic
`;
`Reza Oliyai, Burlingame, CA (US):
`Vahid Zia, San Carlos, CA (US);
`Dimitrios Stefanidis, Mountain View,
`CA (US); Rowchanak Pakdaman, San
`Carlos, CA (US): Melissa Jean Casteel,
`Burlingame, CA (US)
`
`.
`
`References Cited
`5
`erean
`ees
`.
`U.S, PATENT DOCUMENTS
`3,798,209 A
`3/1974. Witkowski et al.
`3,852,267 A
`12/1974 Meyer, Jr. et al.
`RE29,835 E
`11/1978 Witkowskietal.
`4.814.477 A
`3/1989 Wijnberget al.
`936687 *
`je oo, Peauchamp al
`51 18.820 -
`B19) Tenet
`5,149,794 A
`9/1992 Yatvin etal.
`5190'349 A y 093 Basen 3 ‘ i
`ete
`a
`7
`~
`arenolé eb al.
`5,194,654 A
`3/1993 Hostetleretal.
`5,210,015 A
`5/1993 Gelfandet al.
`5,223,263 A
`6/1993 Hostetleret al.
`5,256,641 A
`10/1993 Yatvin et al.
`O8
`99%
`Chou
`et al.
`S97708 A a joa areal
`§.376,380 A
`12/994 Kikuchietal.
`3,405,598 A
`4/1995 Schinazi et al.
`SATLO4T A
`S/L995 Hostetler etal.
`Continued)
`FOREIGN PATENT DOCUMENTS
`
`
`
`(73) Assignee: Gilead Pharmasset LLC, Foster City,
`CA(US)
`M4
`S
`
`,
`CA
`CN
`
`2682230 Al
`10L108870 A
`
`10/2008
`1/2008
`
`(*) Notice:
`
`Subject to any disclaimer, the termofthis
`parent satand ees under 35
`S.C,
`ays.
`‘This patent is subject to a terminal dis-
`claimer
`‘
`(21) Appl. No.: 13/686,664
`nt.
`New
`Filed:
`Nov. 27, 2012
`yo Dehieet
`Prior Publication Data
`.
`US 2013/0136776 Al
`May 30, 2013
`
`(22)
`(65)
`
`(Continued)
`OTHER PUBLICATIONS
`GS-7977 structure provided by Chembest Research Laboratories
`Led.
`(biochembest.com/product, detail.asp?m2&id=1 178
`&classid! =65&nclassid=195). (last visit for this website was made
`on Jun. 27,2013)"
`World Health Organization (hereinafter ‘WHO’), “Pharmaceutical
`excipients-~an overviewincluding considerations for paediatric dos-
`ing.” (Jun. 2010).*
`Gane, E., “Future Hepatitis C Virus Treatment: Interferon-Sparing
`Combinations,” Liver International (2011) 3 (SL): 62-67.
`Gane, E., “Future Treatment
`for Chronic Hepatitis C:
`IPN or
`Ribavirin-Free Regimens,” Hepatol. Int (2012) 6:16-17 (Abstract
`#TCS 10-03).
`
`(Continued)
`
`(60)
`
`Related U.S. Application Data
`d
`Pri
`Examiner —Ernst V
`.
`Lo,
`.
`oer
`No. ay rani von o xron ;
`application
`of
`(63) Continuation-in-part
`PC'1/US2012/055621, filed on Sep. 14, 2012, anda
`458/8/4Rt Sxaininer — Kyung
`SOOK CRANE
`continuation-in-part of application No. 13/661,509, (74) Attorney, Agent, or Firm—Sheppard Mullin Richter &
`
`filed on Oct. 26, 2012.
`Hampton LLP
`ABSTRACT
`Provisional application No. 61/564,500, filed on Nov.
`(57)
`29, 2011. provisional application No. 61/707,459,
`Disclosed herein are a composition and unit dosage form for
`filed on Sep. 28, 2012.
`the treatment ofhepatitis C virus (HC‘V) infection comprising
`GS-7977 and at least one pharmaceutically acceptable excipi-
`ent, as well as methods for making said composition and unit
`dosage form. Also disclosed herein isa method of treating a
`subject, preferably a human,infected with hepatitis C virus,
`said method comprising administering to the subject for a
`time period an effective amount ofGS-7977 and an effective
`amount of ribavirin.
`In one aspect,
`the method comprises
`administering to the subject an interferon-free treatment regi-
`men comprising an effective amount of GS-7977 and an
`effective amount of ribavirin.
`In a particular aspect,
`the
`method is sufficient to produce an undetectable amount of
`HCVRNAin the subject forat least 12 weeksafter the end of
`the time period,
`Gilead 2004
`37 Claims, 3 Drawing Sheets
`I-MAKv. Gilead
`IPR2018-00126
`
`(51)
`
`Int. Ch
`(2006.01)
`A6LK 47/10
`(2006.01)
`COTH 19/04
`(2006.01)
`AGIK 31/813
`(2006.01)
`AGIK 31/675
`(2006 01)
`AGIK 31/4196
`—_—
`(52) U S Cl
`<
`.
`a
`CPO eosernsseen AOTK 31/675 (2013.01); AGEK 31/513
`.
`(2013.01): AGIK 31/4196 (2013.01)
`USPC eeeecsesetessenees 424/400, 514/86; 536/26.8
`reid of Classification Search
`one
`See applicationfile for complete search history.
`
`(58)
`
`

`

`US 8,889,159 B2
` Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`8/2004 Bhatetal.
`6,777,395 B2
`8/2004 Devos ctal.
`6,784,166 B2
`9/2004 Li etal.
`6,787,305 Bl
`9/2004 Bryant etal.
`6,787,526 Bl
`11/2004 LaColla et al.
`6.812,219 B2
`5/1995 Britton et al.
`§ 420,266 A
`11/2004 Hong etal.
`6.815.542 B2
`6/1995 Kjell
`$426,183 A
`1/2005 Martin et al.
`6,846,810 B2
`9/1995 Chouetal.
`5,453,499 A
`5/2005 Boyeretal.
`6,897,201 B2
`10/1995 Schinaziet al.
`5,462,724 A
`6/2005 Watanabeetal.
`6,908,924 B2
`10/1995 Hostetlerelal.
`5,463,092 A
`6/2005 Schinazi etal.
`6,911,424 B2
`3/1996 Wangetal.
`5,496,546 A
`7/2005 Sommadossi et al.
`6,914,054 B2
`7/1996 Livak et al.
`§.538,848 A
`11/2005 Dempcyetal.
`6,962,991 B2
`7/1996 Reyesetal.
`5,538,865 A
`3/2006 Boyeretal.
`7,018,985 BI
`8/1996 Yarvin et al.
`5,543,389 A
`3/2006 McGuiganetal.
`7,018,989 B2
`8/1996
`Yatvinetal.
`5,543,390 A
`7/2006 Pietrzkowski et al.
`7,081,449 B2
`8/1996 Yatvin et al.
`5,543,391 A
`9/2006 Sommadossiet al.
`7,105,493 B2
`9/1996 Basavaetal.
`5,554,728 A
`9/2006 Carroll et al.
`7,105,499 B2
`3/1997 Draper
`5,610,054 A
`10/2006 Bhat etal.
`7,125,855 B2
`5/1997 Gruetzkeet al.
`5.633.358 A
`12/2006 Sommadossietal.
`7,148,206 B2
`5/1097 Dianaetal.
`5 633.388 A
`1/2007 Sommadossietal.
`7,163,929 B2
`10/1997 Testa et al.
`5,676,942 A
`4/2007 Eldrupctal.
`7,202,224 B2
`12/1997 Schinaziet al.
`5,703,058 A
`3/2007 Wagner
`7,217,523 B2
`1998 Gilbertet al.
`5,711,944 A
`9/2007 Cook etal.
`7,268,119 B2
`3/1998 Omer
`$,725,859 A
`12/2007 Schinazi et al.
`7,307.065 B2
`4/1998 Imakawa
`5,738,845 A
`1/2008 Olsen et al.
`7,323,453 B2
`4/1998 Greenwaldetal.
`5,738,846 A
`4/2008 LaCollaetal.
`7,365,057 B2
`5/1908 Hakimi etal.
`5,747,646 A
`6/2008 Beckeret al.
`7,390,791 B2
`6/1998 ‘Tam
`5,767,097 A
`9/2008 Clark
`7,429,572 B2
`8/1998 Hakimi ct al
`5,792,834 A
`10/2009 Wangetal.
`7,601,820 B2
`11/1998 Valtuenaetal.
`5,830,455 A
`10/2009 Sommadossi etal.
`7,608,597 B2
`11/1908 Dianaetal.
`5.830.905 A
`
`
`5.834.594 A 7,608,600 B2—10/2009 Storeret al.11/1998 Hakimietal.
`5,837,257 A
`11/1998 Tsai et al.
`7,635,689 B2
`12/2009 LaColla et al.
`5,846,964 A
`12/1998 Ozeki
`7,754,699 B2
`7/2010 Chun etal.
`5,849,696 A
`12/1998 Chretienetal.
`7,820,380 B2
`10/2010 Huang
`5.869.253 A
`2/1999 Draper
`7,879,815 B2
`2/2011 MacCosset al.
`5.891.874 A
`4/1999 Colacino et al.
`7,964,580 B2
`6/2011 Sofia et al.
`5,905,070 A
`5/1999 Schinazietal.
`8,148,349 B2
`4/2012 Meppenetal.
`5,908,621 A
`6/1999 Glue etal.
`8,173,621 B2
`5/2012 Duetal.
`§,922.757 A
`7/1999 Chojkior
`8,334,270 B2
`12/2012 Sofiaet al.
`5,928,636 A
`7/1999 Alber et al.
`8415322 B2
`4/2013 Clark
`5.942.223 A
`8/1999 Bazeret al.
`8,466,159 B2
`6/2013 Bernstein et al.
`5,980,884 A
`11/1999 Blatt et al.
`8,551,973 B2
`10/2013 Baoetal.
`5,990,276 A
`11/1999 Zhangetal.
`8,580,765 B2
`11/2013 Sofia et al.
`6,004,933 A
`12/1999 Spruceet al.
`20010034440 Al
`10/2001 Shepardet al.
`6,034,134 A
`3/2000 Gold etal.
`200 1/0038833 AL
` L1/2001 Rybaketal.
`6,043,077 A
`3/2000 Barberetal.
`2002/0008241 Al
`1/2002 Edmondetal.
`6,056,961 A
`5/2000 Lavie et al.
`2002/0058635 Al
`§/2002 Averett
`6.060,080 A
`5/2000 Kikuchi etal,
`2002/0147160 Af
`10/2002 Bhatctal.
`6,090,932 A
`7/2000 MeGeeet al.
`2002/0198173 Al
`12/2002. Schinazietal.
`6,130,326 A
`10/2000 Ramasamyet al.
`2003/0050229 Al
`3/2003 Sommadossietal.
`6.132.763 A
`10/2000 Fisher
`2003/0060400 Al
`3/2003 LaColla et al.
`6,156,501 A
`12/2000 McGall et al.
`2003/0096364 Al
`5/2003 Bakeret al.
`6.180.134 BL
`1/2001 Zalipskyetal.
`2003/01 19752 Al
`6/2003 Farmeretal.
`6,232,300 Bi
`5/2001 Schinaziet al.
`2003/0120071 Al
`6/2003 McGuigan et al.
`6.239.159 BI
`$/2001 Brown et al.
`2003/0 144502 Al
`7/2003 Pietrzkowskietal.
`6,348,587 BI
`42002 Schinaziet al.
`2003/0153744 Al
`8/2003 Mekouar etal.
`6,372,883 Bi
`4/2002 Attwoodet al.
`2003/01 76433 Al
`9/2003 Beaulieuet al.
`6,391,859 Bi
`5/2002 Schinazi etal.
`2003/0187018 A1
`10/2003 Llinas-Brunetet al.
`6.410.531 Bl
`6/2002. Llinas-Brunetet al.
`2003/0207922 Al
`11/2003 Neuneret al.
`6.420.380 B2
`7/2002 Llinas-Brunet et al.
`2004/0006007 Al
`1/2004 Gosselin et al.
`6,455,513 BI
`9/2002 MeGuiganct al.
`2004/0014108 Al
`1/2004 Eldrupet al.
`6,455,690 BI
`9/2002 Tam et al.
`2004/0023240 Al
`2/2004 Marliere etal.
`6,475,985 BI
`11/2002 Wagneret al.
`2004/0023901 Al
`2/2004 Cooket al.
`6,479,463 BI
`11/2002 Wangetal.
`2004/0024190 Al
`2/2004 Beaulieuet al.
`6.495.677 BL
`(2/2002 Ramasamyetal.
`2004/0059104 Al
`3/2004 Cookef al.
`6,509,320 BI
`1/2003 Wangetal.
`2004/0063622 Al
`4/2004 Sommadossietal.
`6,534,523 BL
`3/2003 Llinas-Brunet et al.
`2004/0067901 Al
`4/2004 Bhat etal,
`6,552,183 Bi
`4/2003 Ramasamyetal.
`20040072788 Al
`4/2004 Bhatet al.
`6.555.677 B2
`4/2003 Petrillo et al.
`2004/0097461 Al
`5/2004 Sommadossietal.
`6,573,248 B2
`6/2003 Ramasamyetal.
`2004/0097462 Al
`42004 Sommadossi etal.
`6,642,206 B2
`11/2003 Ramasamyetal.
`2004/0101535 Al
`$/2004 Sommadossi et al.
`6,660,721 B2
`12/2003 Devosetal,
`2004/0102414 Al
`5/2004 Sommadossietal.
`6,677,314 B2
`1/2004 Kleckeret al,
`2004/0L 10717 Al
`6/2004 Carroll et al.
`6,677,315 B2
`1/2004 Kleckeret al.
`2004/0142989 Al
`7/2004 Finzel et al.
`6,680,303 B2
`1/2004 Schinavi et al.
`2004/0142993 Al
`7/2004 Battistini etal.
`6,682,715 B2
`1/2004 Kleckeretal.
`2004/0167140 Al
`8/2004 Schinazietal.
`6,683,045 B2
`1/2004 Kleckeret al.
`2004/0171570 Al
`9/2004 Allerson et al.
`6,703,374 BI
`3/2004 Katki et al
`2004/0191824 Al
`9/2004 Dempcyetal.
`6,753,309 B2
`6/2004 Kleckeret al.
`2004/0214844 Al
`10/2004 Otto et al.
`
`

`

`US 8,889,159 B2
`
`Page 3
`
`(56)
`
`References Cited
`
`
`
`
`
`U.S. PATENT DOCUMENTS
`
`
`
`
`8/2007 Jonesetal.
`2007/0197478 Al
`9/2007 Shi
`2007/0225249 Al
`10/2007 Sahaetal.
`2007/0231318 Al
`10/2007 Betebenneretal.
`2007/0232627 Al
`10/2007 Rockwayet al.
`2007/0232645 Al
`11/2004 Babuet al.
`2004/0229839 Al
`11/2007 MacCossetal.
`2007/0265222 Al
`11/2004 Bhatetal.
`2004/0229840 A
`11/2007 Schmitz etal.
`2007/0265262 Al
`12/2004 Wang
`2004/0248892 A
`11/2007 Youngetal.
`2007/0274947 Al
`12/2004 Schinazietal.
`2004/0254141 A
`11/2007 Bhat etal.
`2007/0275912 AL
`12/2004 Olsenet al.
`2004/0259934 Al
`11/2007 Gentles etal.
`2007/0275930 Al
`12/2004 Li etal.
`2004/0265969 A
`11/2007 Bergstrom
`2007/0275947 Al
`12/2004 Rabi
`2004/0266996 A
`1/2008 Butora etal.
`2008/0021047 Al
`1/2005 Clark
`2005/0009737 Al
`2/2008 Bachand etal.
`2008/0050336 Al
`1/2008 Storeret al.
`2005/0020825 A
`3/2008 Clark
`2008/0070861 Al
`2/2005 Allerson etal.
`2005/0026160 At
`5/2008 Desaietal.
`2008/0108617 Al
`2/2005 Mekouaretal.
`2005/0026853 A
`6/2008 Bhatet al.
`2008/0146788 Al
`2/2005 Sommadossi etal.
`2005/0031588 Al
`7/2008 Simmenetal.
`2008/0182863 Al
`2/2005 Bravi et al.
`20050043390 A
`10/2008 Clark
`2008/0253995 At
`3/2005 Colonnoet al.
`2005/0069522 A
`11/2008 MacCoss etal.
`2008/0280842 Al
`/2008 Storeret al.
`2005/0075309 Al
`1/2009 Clark
`2009/0004 135 AT
`4/2005. Standringet al.
`2005/0080034 Al
`2/2009 Clark
`2009/0036666 Al
`4/2005. McPhee etal.
`2005/0090432 Al
`2/2009 Kimetal.
`2009/0041716 AL
`4/2005 Watanabeet al.
`2005/0090660 A
`3/2009 Simmenet al.
`200970062311 Al
`5/2005 Romineetal.
`2005/0096364 A
`4/2009 Simmenetal.
`2009/0105302 Al
`5/2005 Hathawayetal.
`2005/0098125 A
`5/2009 Hamilton etal.
`2009/0137521 Al
`6/2005 Sommadossi et al.
`2005/0124532 A
`6/2009 Raboisson etal.
`2009/0156595 Al
`6/2005 Bhatet al.
`2005/0130923 Al
`7/2009 Beigelman etal.
`2009/0176732 Al
`6/2005 Boyeret al.
`2008/0130931 A
`9/2009 Reddyet al.
`2009/0233879 Al
`6/2005 Sommadossi et al.
`2005/013B TIGL A
`10/2009 Seiwertet al.
`2009/0269305 Al
`7/2005. Castellino et al.
`2005/0148534 AL
`{1/2009 Schinaziet al.
`2009/0280084 Al
`T2005 Yang et al.
`2005/0154056 Al
`
`
`2005/0164960 Al 2009/0281140 Al=11/2009 Simmenetal.7/2005 Olsen etal.
`2005/0215513 AL
`9/2005 Boojamraetal.
`20097028114 AL
`11/2009 Simmen et al.
`2005/02 15614 Al
`9/2005 Singh et al,
`2009/0291902 Al
`11/2009 Cottrell et al.
`2005/0227047 AL
`10/2005 Chenet al.
`2009/0306007 Al
`12/2009 Wagner
`2005/0228013 Af
`10/2005 ‘Thurkauf etal.
`2010/0015090 Al
`1/2010 Tungetal.
`
`2005/0261237 AL=11/2005 Boojamraet al. 2010/0016251 Al 1/2010 Sofia et al.
`
`2005/0267018 Al
`12/2005 Blatt et al.
`2010/0022468 Al
`172010) Meppenetal.
`2006/0003951 Al
`1/2006 Mekouaret al.
`2010/0029008 Al
`2/2010 Rojas Stutz et al.
`2006/0004063 Al
`1/2006 Finzel ct al.
`2010/0035835 Al
`2/2010 Nagjes etal.
`2006/0014943 Al
`1/2006 Dempcyetal.
`2010/0081628 Al
`4/2010 Duet al.
`2006/0035866 Al
`2/2006 Cannizzaro et al.
`2010/0137576 Al
`6/2010 Stec et al.
`2006/0040890 Al
`2/2006 Martin etal.
`2010/0152128 Al
`6/2010 Attenntetal.
`2006/0040927 Al
`42006 Blake et al.
`2010/0173863 Al
`7/2010 Schinazietal.
`2006/0040944 Al
`2/2006 Gosselin et al.
`2010/0226885 Al
`9/2010 Albrecht et al,
`2006/0046983 A
`3/2006 Hudymaet al.
`2010/0227801 Al
`9/2010 Hopkins
`2006/0079478 Al
`4/2006 Boojamraet al.
`2010/0234316 Al
`9/2010 MacCosset al.
`2006/0094706 A
`5/2006 Panichet al.
`2010/0267785 Al
`10/2010 Wuetal.
`2006/0L10724 A
`5/2006 Burkhardt, Il et al.
`2010/0279973 AL
`E1/2010 Chunct al.
`2006/0110727 A9
`82006 McGall et al.
`2010/0286083 Al
`11/2010 Baoet al,
`2006/0122146 At
`6/2006 Chunet al.
`2016/0298257 Al
`11/2010 Rossetal.
`2006/0122154 A
`6/2006 Olsen et al.
`2010/03 16594 AL
`12/2010 Sommadossi et al.
`2006/0142238 A
`6/2006 McGuigan
`2011/0015146 Al
`1/2011 Sofia et al.
`2006/0166964 A
`7/2006 Hudymaetal.
`20110020272 Al
`{2011 Schubert detector te neces 424/85 .2
`2006/0194749 AL
`8/2006 Keicheret al.
`20110124592 At
`$011 McGuigan etal.
`2006/0199783 Al
`9/2006 Wang et al.
`2OE 10237621 Al
`9/2011
`Simmenetal.
`2006/0234962 AL
`10/2006 Olsen etal.
`2011/0245484 Al
`10/2011 Rossetal.
`2006/0241064 AL
`10/2006 Roberts etal.
`201 1/0251152 Al
`10/2011 Rossetal.
`2006/0276405 A
`12/2006 Albrecht
`2011/0257122 Al
`[0/2011
`Sofiaet al.
`2006/02765t1 At
`12/2006 Serrano-Wuetal.
`2012/0094284 Al
`4/2012 Lopatin et al.
`2006/0287300 Al
`{2/2006 Klein et al
`2012/0107278 Al
`$/2012 Berrey et al.
`2006/0293306 AL
`£2/2006 Beaulieuet al.
`2012/0245335 Al
`9/2012) Clark
`2007/0004669 A
`1/2007 Carroll ct al.
`2O12/G251152 AL
`10/2012 Brewington et al.
`2007/0015905 AL
`1/2007 LaCollaet al.
`2013/0029929 Al
`1/2013 Sofiaet al.
`2007/0024277 Al
`2/2007 Cech et al.
`2013/0102526 Al
`4/2013 Bernsteinet al.
`2007/0037735. A
`2/2007 Gosselinet al.
`2013/0102557 AT
`4/2013 Bernstein et al.
`2007/0037773 Al
`2/2007 Sommadossi et al.
`2O13/01025S8 Al
`4/2013 Bernstein et al.
`2007/0042939 Al
`2/2007 LaColla etal.
`2013/0100647 Al
`$/2013 Berrey etal.
`2007/0042988 Al
`2/2007 Klumpp etal.
`2013/0136776 AL
`5/2013 Cleary et al.
`2007/0042990 Al
`2/2007 Gosselinet al.
`2013/0137654 Al
`5/2013 Rossetal.
`2007/0049754 Al
`3/2007 Boojamnraet al.
`2013/0165401 AL
`6/2013 Rossetal.
`2007/0054842 Al
`3/2007 Blatt et al.
`2013/0165644 Al
`6/2013 Ross etal.
`2007/0060498 Al
`3/2007 Gosselin et al.
`2013/0288997 Al
`10/2013 Ross etal.
`2007/0060541 Al
`3/2007 Gosselin et al.
`2013/03 10551 Al
`£1/2013) Ross etal.
`2007/0087960 Al
`4/2007 Storeret al.
`2007/0 123484
`Al
`5/2007
`Bhatet al.
`2007/0135363
`6/2007
`Cook et al.
`2007/0 142380
`6/2007
`Beaulieuet al.
`7/2007
`2007/0155716
`Simmenet al,
`2007/0 197463
`8/2007
`Chun et al.
`
`199 14474 At
`102008057284 Al
`0 180 276 Al
`
`Al
`Al
`Al
`
`DE
`DE
`iP
`
`10/1999
`5/2010
`5/1986
`
`FOREIGN PATENT DOCUMENTS
`
`

`

`US 8,889,159 B2
`
`Page 4
`
`(56)
`
`EP
`EP
`EP
`
`References Cited
`
`POREIGN PATENT DOCUMENTS
`
`0 350 287 A2
`L828 217 A2
`ES8tOor Al
`
`1/1990
`9/2007
`4/2008
`
`WoO
`Wo
`wo
`WO
`wo
`WO
`WO
`
`2004/002940 Al
`2004/002944 Al
`2004/002977 Al
`2004/002999 A2
`2004/003000 A2
`2004/003138 A2
`2004/007512 A2
`
`1/2004
`1/2004
`1/2004
`1/2004
`1/2004
`1/2004
`1/2004
`
`
`
`2/2004
`2004/011478 A2
`WoO
`3/2012
`2207 786 BI
`EP
`2/2004
`2004/014313 A2
`WO
`9/1993
`5.232039 A
`yp
`2/2004
`2004/014852 A2
`Wo
`4/1989
`89/02733 Al
`WO
`4/2004
`2004/035571 Al
`WO
`1/1990
`90/0053% Al
`WO
`5/2004
`2004/04 1201 A2
`WO
`LL/1991
`91/16920 Al
`WoO
`6/2004
`2004/046331 A2
`WO
`12/199
`OUI8S9I4 AL
`WO
`8/2004
`2004/065367 Al
`WO
`12/199]
`OVL97T2L AL
`Wo
`9/2004
`2004/080466 Al
`WO
`1/1993
`93/00910 Al
`WO
`
`
`
`
`WO 2004/094452 A2—11/200494/26273 Al 11/1994 WO
`Wo
`95/43090 Al
`$/1905
`WO
`2004/096210 AL
`11/2004
`Wo
`95/24185 Al
`9/1995
`WO
`2004/096234 A2
`11/2004
`
`Wo 2004/096235 A2—11/200496/15132 Al 5/1996 WO
`
`
`
`
`WO 2004/096286 A2—11/200496/32403 A2 10/1996 WO
`
`
`
`WO
`97/12033 Al
`4/1997
`WO
`2004096210 AL
`11/2004
`WO
`97/36554 AL
`10/1997
`WO
`2004/106356 Al
`12/2004
`WoO
`O8/E6184 A2
`4/1908
`WO
`2005/002626 A2
`42005
`WO
`98/17679 Al
`4/1908
`WO
`2005/003 147 A2
`1/2005
`WO
`9822496 A2
`5/1998
`WO
`2005/007810 A2
`1/2005
`WO
`99/0734 A?
`2/1999
`WO
`2005003147 A2
`1/2005
`WO
`QO/ESLO4 Al
`4/999
`WO
`2005/009418 A2
`2/2005
`WO
`99/32139 Al
`7/1999
`WoO
`2005/012327 A2
`2/2005
`WO
`99/32140 AJ
`7/1999
`WO
`2005/020884 A2
`3/2005
`WO
`99/43691 Al
`9/1999
`WO
`2005/021568 A2
`3/2005
`WO
`99/5962L AL
`Lis1999
`wo
`2005/028502 Al
`3/2005
`wo
`O9/64016 AL
`12/1999
`WO
`2005/037214 A2
`4/2005
`WO
`00/06520 Al
`2/2000
`WO
`2005/067900 A2
`7/2005
`
`wo 2005/072361 A2—8/2005O0/0953L A2 2/2000 wo
`
`
`
`Wo
`O00/37LL0 A2
`6/2000
`WoO
`2005/082144 Al
`9/2005
`
`WO 2005/087788 AZ—9/2005OO9L2E A2 2/2001 wo
`
`
`
`WO
`OL/32153 A2
`5/2001
`WO
`2005/095403 A2
`10/2005
`WO
`OL60315 A2
`8/2001
`WO
`2005/103045 Al
`{1/2005
`
`WO 2005103045 Al=11/2005O01/79246 A2 10/2001 WO
`
`
`
`
`WO 2005123087 A2—12/2005OV/81359 AL 11/2001 WO
`
`
`
`WO
`OL/90121 A2
`14/2001
`WO
`2006/000922 A2
`1/2006
`WO
`OMV9L737 A2
`12/2001
`WO
`2006/012078 A2
`2/2006
`WO
`01/92282 A2
`12/2001
`WO
`2006/012440 A2
`2/2006
`WO
`01/96353 A2
`12/2001
`WO
`2006/020082 Al
`2/2006
`Wo
`02/08187 Al
`1/2002
`Wo
`2006/029081 A2
`3/2006
`WO
`02/08198 A2
`1/2002
`WO
`2006/031725 A2
`3/2006
`WO
`O2O825— A2
`1/2002
`WO
`2006/035061 Al
`4/2006
`WO
`02/08256 A2
`1/2002
`WO
`2006/037028 A2
`4/2006
`Wo
`02/18404 A2
`3/2002
`WO
`2006/050161 A2
`5/2006
`WO
`02/32414 A2
`4/2002
`wo
`2006'063149 Al
`6/2006
`WO
`02/32920 A2
`4/2002
`WO
`2006/063717 A2
`6/2006
`
`6/2006
`2006/065590 A2
`WO
`6/2002
`0248157 A2
`WO
`6/2006
`2006/067606 Al
`WO
`6/2002
`O2/48165 A2
`WO
`6/2006
`2006065590 A2
`WO
`6/2002
`0248172 A?
`wo
`9/2006
`2006/09380!1 Al
`WO
`7/2002
`02/087287 A?
`WO
`9/2006
`2006/100310 Al
`WO
`7/2002
`02/057425 A2
`wo
`11/2006
`2006/116557 Al
`WO
`$2002
`02060926 A?
`WO
`
`
`wo 02100415 A2—12/2002 WO 2006/120251 AT 11/2006
`
`
`wo
`03/000713 A
`1/2003
`wo
`2006/120252 A2
`11/2006
`WO
`03'006490 Al
`1/2003
`wo
`2006/121820 Al
`11/2006
`Wo
`0301014 A2
`2/2003
`WO
`2007/002602 A2
`1/2007
`WO
`03/024461 A
`3/2003
`WO
`2007/014920 Al
`2/2007
`wo
`03/026589 A2
`4/2003
`wo
`2007/014921 Al
`222007
`
`2/2007
`2007/014925 Al
`WO
`6/2003
`03/081899 A
`wo
`2/2007
`2007/014926 Al
`WO
`7/2003
`03/0539890 A}
`WO
`
`
`
`
`wo 2007/015824 A2=—2/200703061576 A2 7/2003 WO
`WO
`03/062256 A
`7/2003
`WO
`2007/020193 A2
`2/2007
`WO
`03'064456 Al
`8/2003
`WO
`2007/027248 A2
`3/2007
`Wo
`03/068244 A
`8/2003
`WO
`2007/039142 Al
`4/2007
`wo
`037101993 A
`12/2003
`WO
`2007/039145 Al
`4/2007
`WO
`03104250 A
`12/2003
`WO
`2007039142 Al
`4/2007
`wo
`03/105770 A2
`12/2003
`ue)
`2007039145 Al
`A/2007
`WO
`03/L06477 A
`12/2003
`WO
`2007/065829 Al
`6/2007
`
`
`WO 04/000858 A2—12/2003 WO 2007/070556 A2 6/2007
`
`
`WO
`2004'002422 A2
`1/2004
`WO
`2007/076034 A2
`7/2007
`
`
`
`

`

`US 8,889,159 B2
`
`Page 5
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`Presented at the 47th Annual Meeting of the European Association
`for the Study of the Liver (Apr. 18-22, 2012), Barcelona, Spain
`(Poster #ILOL).
`Afdhal et al., Hepatology (2011) $3(1): 336-345.
`8/2007
`2007/088148 Al
`WO
`Asselah et al., Gut (2009) 58: 846-858.
`{2007
`2007;092000 Al
`wo
`Asselshet al., J. Hepatology (2012) 56: 527-532.
`8/2007
`2007/093901 Al
`WO
`Clark et al., Bioorg. Med. Chem. Lett. (2006) 16: 1712-1715.
`8/2007
`2007/095269 A2
`WO
`Clark et al.. J. Med. Chem. (2005) 48: 5504-5508.
`8/2007
`2007088148 Al
`WO
`Cotton et al., Mutat. Res. 285: 125-144 (1993),
`8/2007
`2007092000 Al
`WO
`Dienstag and McHutchison Gastrvenlerology 2006; 130: 231-264.
`1/2008
`20087010921 A2
`wo
`4/2008
`2008045419 Al
`WO
`F. Ruebasam et al.. Bio. Org. Med. Chem. Lett. (2008) 18: 3616-
`3621.
`4/2008
`2008048128 Al
`wo
`5/2008
`2008'062206
`A2
`WO
`Ge et al., Nature (2009) 461(17): 399-401.
`7/2008
`2008079206 Al
`WO
`Hayashi et al.. Genet. Anal. Techn. App 9: 73-79 (1992).
`7/2008
`2008/082601 A2
`WoO
`K. Ishi et al., Heptology, 1999, 29: 1227-1235.
`7/2008
`2008085508 Az
`WoO
`Kwo et al., Lancet 2010; 376 (9742): 705-7 16.
`
`WO 2008121634 A2=10/2008
`Lalezari et al., J, Hepatology (2011) 54: $28. (Abstract 61).
`
`WO 2008/142055 A2—11/2008
`Lindh et al., J. Infect. Dis. (20L1) 203: 1748-1752.
`WO
`2009/029844 Al
`/2009
`Mangiaet al., Gastroenterology (2010) 139: 821-827.
`WO
`2009038663 Al
`3/2009
`McCarthyet al., Gastroenterology (2010) 138: 2307-23 14.
`WO
`2009/052287 Al
`4/2009
`WO
`2009/115893 A2
`9/2009
`Moghaddarnet al., Hepatology (2011) 53(3): 746-754.
`
`WO 2009/120878 A2—10/2009
`Rauch et al., Gastroenterology (2010) 138: 1338-1345.
`WO
`20097129120 A2
`10/2009
`Sarrazin et al., J. Hepatology (2011) 54: 415-421.
`
`WO 20097132123 Al—10/2009
`Suppiah et al.. Nature Genetics (2009) 41(10): 1100-1104.
`
`WO 2009/152095 A2—12/2009
`Tanakaet al., Nature Genetics (2009) 41(10): 1105-1109.
`WO
`2010/042834 Al
`4/2010
`Von Wagneret al, Gastroenterology (2005) 129: 522-527.
`WO
`2010/075517 A2
`T2010
`Stuyveret al., Antiviral Chem. & Chemother. (2006) 17: 79-87.
`0)
`2010/075549 A2
`7/2010
`Sofia et al., J. Med. Chem, (2010) $3( 19): 7202-7218.
`WO
`2010/075554 Al
`7/2010
`Sofia, Antiviral Chem. & Chemother. (2011) 22: 23-49.
`WO
`2010/080878 Al
`T2010
`Paul J. Pockroset al., Hepatology (2008) 48(2): 385-397.
`WO
`2010/081082 A2
`7/2010
`U.S. Appl. No. 13/099.671, filed May 3, 201 1—-Claims as Amended
`wo
`2010075517 A2
`T2010
`WO
`2010112203 Al
`10/2010
`Sep. 4, 2012.
`wo
`2010135569 Al
`L1/2010
`US. Appl. No. 11/854,218,filed Sep. 12, 2007---Claims as Amended
`Jun. 28, 2041.
`WO
`20117035231 Al
`3/2011
`WO
`2011123645 A2
`10/2011
`US. Appl. No. 12/878.262, filed Sep. 9, 2010.
`WO
`2011123672 Al
`10/2011
`Sep. 1, 2011.
`WO
`2012/130862 Al
`10/2012
`Rodriguez-Torres et al., Hepatology (2009) 50(6): LLA (Abstract
`WO
`2013059630 Al
`4/2013
`LB17).
`WO
`2013059638 Al
`4/2013
`Nelson et al., J. Hepatology (2011), vol. 54, pp. $544 (Abstract
`#1372),
`Missiha, S.B.. et al., “Disease Progression in Chronic Hepatitis C:
`Modifiable and Nonmodifiable Factors.” Gastroenterology (2008),
`vol. 134, pp. 1699-1714.
`Zeuzem, S.. et al., “Review article: management of patients with
`chronic
`hepatitis C virus
`infection
`and
`‘normal’
`alanine
`aminotransferase activity,” Aliment Pharmacol. & Ther. (2006), Vol.
`24, pp, 1133-1149.
`Orita, M., et al. “Detection of polymorphisms of DNA by gel
`electrophoresis as single-strand conformation polymorphisms.”
`Proc. Natl. Acad. Sci. USA (1989), vol. 86. pp. 2766-2770.
`Poordad, F., et al, “Rapid Virologic Response: A New Milestone in
`the Management of Chronic Hepatitis C.” Clin. Infectious Discases
`(2008), Vol. 46. pp. 78-84.
`Myers, R.M., et al., “Detection of single base substitutions in total
`genomic DNA,” Nature (1985) vol. 313, pp. 495-498.
`Saleeba. LA., et al, “Chemical Cleavage of Mismatch to Detect
`Mutations,” Mutagenesis and Gene Disruption (1993), vol. 217, 286-
`295.
`and Linkage
`“Haplotype Variation
`al.
`et
`J.C.,
`Stephens,
`Disequilibrium in 313 Human Genes,” Science (2001), vol. 293, pp.
`489-493.
`J.G., et al. “Telaprevir with Peginterferon and
`McHutchison.
`Ribavirin for Chronic HCV Genotype 1 Infection,” N. Engl. J. Med.
`(2009), vol. 360, No. 18, pp. 1827-1838.
`Mitchell et al., “Bioreversible Protection for the Phospho Group:
`Bioactivation
`of
`the Di(4-acyloxybenzyl)
`and Mono(4-
`acyloxybenzyl)
`Phosphoesters
`of Methylphosphonate
`and
`Phosphonoacctato,” J. Chem. Soc. Perkin. Trans. 1, pp. 2345-2353
`(1992).
`Olsen etal., *2’-Modified Nucleoside Analogs as Inhibitors of Hepa-
`titis C RNA Replication,” Programand Abstracts, 16th International
`Conference on Antiviral Research, Abstract No. 121. p. A76 (Apr.
`27-May 1, 2003).
`
`Gane. E, et al., “Once Daily GS-7977 Plus Ribavirin in HCV Geno-
`types
`1-3:
`‘The Electron ‘Trial’? EASL 47th Annual Meeting,
`Barcelona, Spain (Apr. 18-22, 2012)
`Poordad, F. et al. “A 12-Week Interferon-Free Regimen of ABT-
`4506+ ABT-333 + Ribavirin Achieved SVR12 in More Than 90% of
`
`Treatment-Naive HCV Genotype-l-Infected Subjects and 47%of
`Previous Non-Responders,” EASL 47th Annual Meeting. Barcelona,
`Spain (Apr. 18-22, 2012).
`Lewis. H., et al., “Second Generation Direct Antiviral and the Way to
`
`Interferon-Free Regimens in Chronic HCV.” Best Practices &
`
`Research: Clinical Gastroenterology (2012) 26:471-485
`Lawitz, E., et al, “The Effect of Hepatic Impairment on the Safety,
`Pharmacokinetics, and Antiviral Activity of GS-7977 in Hepatitis C
`Infected Subjects Treated for Seven Days,” Presented at the 47th
`Annual Meeting of the European Association for the Study ofthe
`Liver (Apr. 18-22, 202), Barcelona, Spain (Poster #1130).
`Zhu, Y., et al, “Virologic Analysis of HICV Genotype | Patient
`Samples from the Proton Study,” Presented at the 47th Annual Meet-
`ing of the European Association for the Study ofthe Liver (Apr.
`18-22, 2012). Barcelona, Spain (Poster #1217).
`Gane, E., et al., “Once Daily GS-7977 Plus Ribavirin in HCV Geno-
`types [-3: The Flectron Trial.” Presentedat the 47th Annual Meeting
`of the Furopean Association for the Study of the Liver (Apr. 18-22,
`2012), Barcelona, Spain (Poster # E113).
`Jacobson, I., “GS-7977 400 mg QD Safety and Tolerability in the
`Over 500 Patients Treated for at Least 12 Weeks.” Presentedat the
`47th Annual Meeting ofthe European Association forthe Study ofthe
`Liver (Apr. 18-22, 2012). Barcelona, Spain (Poster #1120).
`Cornprost. M. et al.. “The Effect of Renal Impairment and EndStage
`Renal Disease on the Single-Dose Pharmacokinetics of GS-7977,"
`
`OTHER PUBLICATIONS
`
`.-Claims as Amended
`
`

`

`US 8,889,159 B2
`Page 6
`
`Meieret al., “Cyclic Saligenyl Phosphotriesters of 2’,3’ -Dideoxy-
`References Cited
`(56)
`
`2°.3?-didehydrothymidine (d4T)—A=New—Pro-Nucleotide
`OTHER PUBLICATIONS
`Approach.” Bioorg. & Med. Chem. Lett, vol. 7, No. 2. pp. 99-104,
`(1997).
`Otto, M., “Evaluation of Nucleoside Analogsin the Hepatitis C Virus
`of
`Preparation
`“Mild
`al.,
`et
`Neidlein
`Replicon System.” Framing the Knowledge ofTherapeutics forViral
`[-Benzyloxyiminoalkylphosphonic Dichlorides: Application to the
`Hepatitis, IHL Press, First Edition, pp. 247-261 (2006).
`Synthesis of Cyclic Phosphonic Diesters and Cyclic Monoester
`Piantadosi et al.. “Synthesis and Evaluation of Novel Ether Lipid
`Amides.” Heterocycles, vol. 35, No. 2, pp. 1185-1203 (1993).
`Nucleoside Conjugates for Anti-HIV-! Activity,” J. Med. Chem., vol.
`Nifantyev et al., “Synthesis and Structure of Some Stable
`34, No. 4. pp. 1408-1414 (1991).
`Phospholane-Phospholanes,” Phosphorus, Sulfur, and Silicon, vol.
`Pierra et al., “Synthesis and Pharmacokinetics of Valopicitabine
`113, pp. 1-13 (1996).
`(NM283), an Efficient Prodrug ofthe Potent Anti-HICVAgent 2’-C-
`Novak, J. J. K., “Chireptical Properties of 2-Methyl-1,4-Lactones;
`Methyleytidine,” J. Med. Chem. vol. 49. No. 22, pp. 6614-6620
`Revised Absolute Configuration of 2-Deoxy-2-C-Methyl-erythro-D-
`(2006).
`Pentono-1,4-Lactones,” Collection Czechoslov. Chem. Commun.,
`Starrett, Ir et al, “Synthesis, Oral Bioavailability Determination, and
`vol. 39, pp. 869-882 (1974).
`in Vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-
`Novak, J. J. K., “Nucleic Acid Components and Their Analogues
`(Phosphonomethoxy)ethylJadenine (PMEA),” J. Med. Chem., vol.
`CXLIIL Nucleosides Derived
`from 2-Dcoxy-2(R)-C-Methyl-
`37, No. 12, pp. 1857-1864 (1994).
`erythro-D-Pentose,” Collection Czechoslov. Chem. Commun., vol.
`Stuyveret al., “Inhibition ofhepatitis C replicon RNA syathesis by
`36, pp. 3670-3677 (1971).
`B-D-2’-deoxy-2’-fluoro-2’-C-methI cytidine: a specific inhibitor of
`Oishi et al., “Asymmetric Dihydroxylation of Chiral Olefins. High
`hepatitis C virus replication,” Antiviral Chemistry & Chemotherapy,
`Control of Diastereofacial Selection,” Tet. Lett., vol. 34, No. 22, pp.
`vol. 17, No. 2. pp. 79-87 (2006).
`3573-3576 (1993).
`Stuyveret al., “Dynamics of Subgenomic Hepatitis C Virus Replicon
`Shih et al., “Preparation and Structures of 2-Dimethylamino-4-
`RNA Levels
`in Huh-7 Cells after Exposure to Nucleoside
`phenyl-1,3,2-dioxaphosphorinane-2-oxides,” Bull.
`Inst. Chem.
`Antimetabolites,” J Virol., vol. 77, No. 19, pp. LQG89- 10694 (2003).
`Acad. Sin., vol. 41, pp. 9-16, (Mar. 1994).
`Stuyveref al.. “Ribonucleoside Analogue that Blocks Replication of
`Stella, V. J., “Prodrugs as Therapeutics,” Expert opinion on therapeu-
`Bovine Viral Diarrhea and Hepatitis C Viruses in Culture.” Antimi-
`tic patents, vol. 14, No. 3. pp. 277-280 (Mar. 2004).
`crobial Agents and Chemotherapy, vol. 47, No.
`1, pp. 244-254
`Xiao-Ling et al., “Study on the Chiraliry of Sulfur in Ethyl (2S,
`(2003).
`3R,4R)-4,5-O-Isopropylidene-2,3-sulfinyl-2,3,4,5-tetrahydroxy-
`Wolff, M.E., “Burger’s Medicinal Chemistry and Drug Discovery,”
`pentanoate”, Acta Chimica Sinica, vol. 55, pp. 600-604 (1997).
`Fifth Edition, vol. 1, pp. 975-977 (1995).
`International Search Report issued in International Application No.
`Zon, G., “4 Cyclophosphoamide Analogues,” Progress in Medicinal
`PC TASS2004/01 2472 mailed Dec. 30, 2004 (4 pages).
`Chemistry, vol. 19, pp. 205-246 (1982).
`International Search Report issued in International Application No.
`Bhat et al. “Synthesis and Pharmacokinetic Properties of Nucleoside
`PCT/US 2005/0259 16 mailed Jun. 15, 2006 (2. pages).
`Analogues as Possible Inhibitors of HCV RNA Replication,” (Oral
`International Search Report issued in International Application No.
`Session V: Hepalilis C Virus, Flaviviruses), 16th International Con-
`PCT/EP2006/069060 mailed Jan. 30. 2007 (4 pages).
`ference on Antiviral Research, Abstract No. 120, p. A75 (Apr.
`International Scarch Report issucd in International Application No.
`27-May1, 2003),
`PCT/US 2005/032406 mailed May 8, 2008 (3 pages).
`Chuet al., “Isolation and Structure of SCH 351633: A Novel Hepa-
`Bartenschlager et al., “Nonstructural Protein 3 of the Hepatitis C
`titis C Virus (HCV) NS3 Protease Inhibitorfrom the Fungus Penicil-
`Virus Encodes a Serine-Type Proteinase Required for Cleavageatthe
`lium Griseofulvum,” Bioorg. & Med. Chem. Lett., vol. 9, pp. 1949-
`NS3/4 and NS4/5 Junctions.” J. Virol. vol. 67, No. 7, pp. 3835-3844
`1952 (1999).
`(1993).
`Bartenschlageret al., “Kinetic and Structural Analyses ofHepatitis C
`Chu et al. “Structure of Sch 68631: A New Hepatitis C Virue
`Virus Polyprotein Processing,” J. Virol., vol. 68, No. 8, pp. 5045-5055
`ProteinaseInhibitor from Streptomycessp.” Tet. Lett. vol. 37, No. 40,
`(1994).
`on
`pp. 7229-7232 (1996).
`azan et al., "Detection ofa Irypsin-like Serine Protease Domain in
`Phosphonomethyt Dipeptides and Their
`De TLombaert et al.,
`
`‘laviviruses and Pestiviruses,” Virology, vol. 171, pp. 637-639
`Phosphonate Prodrugs. a New Generation of Neutral Endopeptidase
`1989).
`(NEP. EC 3.4.24.11) Inhibitors.” J. Med, Chem.. vol. 37, No. 4. pp.
`Beaulieuet al.. “Inhibitors of the HCV NSSBpolymerase: New hope
`498-511 (1994).
`for the treatmentof hepatitis C infections,” Current Opinion in Inves-
`Edmundsonet al., “Cyclic Organophosphorus Compounds. Part 23.
`tigational Drugs, vol. 5, No. 8, pp. 838-850 (2004).
`Configurational
`Assignments
`in
`the
`4-Phenyl-1,3,2-
`Behrens etal., “Identification and properties of the RNA-dependent
`dioxaphosphorinane Series. X-Ray Molecular Structure of cis-2-
`RNA polymerase of hepatitis C virus,’ The EMBO Journal, vol. 15,
`Benzylamino-4-phenyl-1.3,2-dioxaphosphorinane —2-oxide,”
`J.
`No. L, pp. [2-22 (1996).
`Chem. Research (S). pp. 122-123 (1989).
`Calisher et al., “Antigenic Relationships between Flaviviruses as
`
`Goekjian Fluorinated©Marcocyclicet al. “Synthesis of
`
`
`
`
`Determined by Cross-neutralization Tests with Polyclonal Antisera.”
`Bis(indolylmaleimicdes as Potential 19F NMR Probes for Protein
`. Gen. Virol., vol. 70. pp. 37-43 (1989).
`Kinase C” J. Org. Chem. vol. 64., No. £2. pp. 4238-4246 (1999).
`Carroll et al., “Nucleoside Analog Inhibitors of Hepatitis C Virus
`[fernandez et al., “Synthesis of [lighly Functionalized Chiral Nitriles
`Replication,” Infectious Disorders—Drug Targets, vol. 6, No. 1, pp.
`17-29 (2006).
`by Radical Fragmentation of beta-Hydroxy Azides. Convenient
`Transformation of Aldononitriles into 1,4- and 1,5-Iminoalditols,”J.
`Eckart et al., “The Hepatitis C Virus Encodes a Serine Protease
`Org. Chem., vol. 69. No. 24, pp. 8437-8444 (2004).
`nvolved in Processing ofthe Putative Nonstructural Proteins from
`the Viral Polyprotein Precursor,’ Biochemical and Biophysical
`Hostetler
`et al,
`“Greatly Enhanced
`Inhibition of Human
`Research Communications, vol. 192, No. 2, pp. 399-406 (1993).
`Immunodeficiency Virus Type | Replication in CEM and HT4-6C
`Failla et al.. “Both NS3 and NS4A are Required for Proteolytic
`Cells by 3’ -Deoxythymidine Diphosphate Dimyristoylglycerol. a
`Processing ofHepatitis C Virus NonstructuralProteins,”J. Virol., vol.
`Lipid Prodrug of 3° -Deoxythymidine.” Antimicrobial Agents and
`68, No. 6, pp. 3753-3760 (1994).
`Chemotherapy, vol. 36, No. 9, pp. 2025-2029 (1992).
`ice, C. M., “Flaviviridae: The Viruses and Their Replication,” Fields
`Kucera et al., “Novel Membrane-Interactive Ether Lipid Analogs
`‘That Inhibit Infectious HIV-t ProductionandInduc