(12) United States Patent
`Yang et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,357,891 B2
`Apr. 15, 2008
`
`US007357891B2
`
`(54) PROCESS FOR MAKING AN INGESTIBLE
`FILM
`(75) I
`t
`nven ors:
`
`R b t K Y F1 h_ NY (Us)
`0 er
`.
`ang, us mg,
`;
`Richard C. Fuisz, McLean, vA (US);
`Gary L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, McLean, VA (US)
`
`(73) Assignee: MonoSol RX, LLC, Portage, IN (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U'S'C' 154(1)) by 616 days‘
`
`_
`(21) Appl' NO" 10/768309
`.
`(22) Flled:
`(65)
`
`Jan- 30’ 2004
`P _
`P by t_ D t
`r1or u 1ca ion a a
`
`(56)
`
`(52) US. Cl. ................. .. 264/211.12; 264/260; 264/234
`(58) Field of Classi?cation Search ................... .. None
`See application ?le for complete search history.
`_
`References CIted
`U S PATENT DOCUMENTS
`'
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`a
`
`a
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`Us 2004/0258896 A1
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`Dec. 23, 2004
`
`(Continued)
`
`Related US. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`
`V1976
`2432925 B2
`(Continued)
`
`Primary ExamineriEdmund H, Lee
`(74) Azzgrney, Agenz, 0r FirmiHoifman & Baron, LLP
`
`(63) Continuation-in-part of application No. PCT/US02/
`32575, ?led on Oct. 11, 2002, Which is a continua-
`tion-in-part of application No. PCT/US02/32594,
`?led on Oct. 11, 2002, Which is a continuation-in-part
`of application No. PCT/U S02/32542, ?led on Oct. 11,
`2002.
`(60) Provisional application No. 60/328,868, ?led on Oct.
`_
`_
`_
`_
`_
`12, 2001, provisional application No. 60/386,937,
`?led on Jun‘ 7 2002 provisional application NO The invention relates to ?lm products containing desired
`60/414 276 ?legl on Sell 27 2002 provisional app1i_
`levels of active components and methods of their prepara
`Cation ’NO_ ’60/328 868 ?led on den 12 2001 pro_
`tion. Desirably, the ?lms disintegrate in Water and may be
`Visional application No 60686937’ ?led on Jun‘ 7,
`formed by a controlled drying process, or other process that
`2002 provisional application NO 60/371 9 40 ?led
`maintains the required uniformity of the ?lm. Desirably, the
`on Apr‘ 11’ 2002, provisional application NO 60/443,
`?lms may be exposed to temperatures above that at Which
`741 ?led on Jan 30 2003'
`the active components typically degrade Without concern for
`’
`’
`loss of the desired activity.
`(51) Int. Cl.
`B29C 47/88
`
`(57)
`
`ABSTRACT
`
`(2006.01)
`
`9 Claims, 33 Drawing Sheets
`
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`US 7,357,891 B2
`Page 2
`
`US. PATENT DOCUMENTS
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`5/1997 Horstmann et a1.
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`.... .. 427/372.2
`2001/0006677 A1
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`2004/0096569 A1* 5/2004 Barkalow et a1. ......... .. 426/660
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`
`4/1976
`2449865 B2
`3/1988
`3630603 (:2
`0 241 178 A1 10/1987
`0219762 B1
`12/1990
`0259749 B1
`8/1991
`0200508 B1
`10/1991
`0273069 B1
`10/1992
`0 514 691 A2 11/1992
`0250187 B1
`9/1993
`0452446 B1
`12/1993
`0381194 B1
`8/1994
`1 110 546 A1
`6/2001
`1 510 999
`5/1978
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`US 7,357,891 B2
`Page 3
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`W0
`W0
`W0
`W0
`W0
`W0
`W0
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`WO 91/05540 A1
`WO 92/15289 A1
`WO 95/05416 A2
`WO 95/18046 A1
`WO 00/18365
`WO 00/42992
`WO 01/70194 A1
`
`5/1991
`9/1992
`2/1995
`7/1995
`4/2000
`7/2000
`9/2001
`
`W0
`W0
`W0
`W0
`
`WO 01/91721 A2 12/2001
`W0 03/030881
`4/2003
`W0 03/030382
`4/2003
`W0 03/030883
`4/2003
`
`* cited by examiner
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`U.S. Patent
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`Apr. 15, 2008
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`Sheet 1 0f 33
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`US 7,357,891 B2
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`10
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`14
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`12
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`74
`
`FIG. 1
`
`70
`
`FIG. 5
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`U.S. Patent
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`Apr. 15, 2008
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`Sheet 2 0f 33
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`Apr. 15, 2008
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`Sheet 3 0f 33
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`US 7,357,891 B2
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`62’
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`58’
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`55
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`62
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`1
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`/ \56
`/ 54\\ N50
`
`N52
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`FIG. 7
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`U.S. Patent
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`Apr. 15, 2008
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`Sheet 4 0f 33
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`US 7,357,891 B2
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`U 26C bum.
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`
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`m 26R ,oww
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`Apr. 15, 2008
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`Sheet 5 0f 33
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`US 7,357,891 B2
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`700
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`FIG. 9
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`Sheet 6 0f 33
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`7
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`700
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`FIG. 10
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`Apr. 15, 2008
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`Sheet 7 0f 33
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`US 7,357,891 B2
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`770
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`FIG. 11
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`100
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`Apr. 15, 2008
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`Sheet 8 0f 33
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`US 7,357,891 B2
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`7
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`700
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`FIG. 12
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`Apr. 15, 2008
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`Sheet 9 0f 33
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`7
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`70
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`700
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`FIG. 13
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`Sheet 10 0f 33
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`7
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`70
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`700
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`FIG. 14
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`Sheet 11 0f 33
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`US 7,357,891 B2
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`7
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`70
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`700
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`FIG. 15
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`Sheet 12 0f 33
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`7
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`FIG. ‘l6
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`200
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`FIG. 17
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`FIG. 18
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`Sheet 15 0f 33
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`FIG. 19
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`Sheet 16 0f 33
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`FIG. 20
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`Apr. 15, 2008
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`Sheet 17 0f 33
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`FIG. 21
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`Apr. 15,2008
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`Sheet 18 of 33
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`FIG. 22
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`Sheet 19 of 33
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`FIG. 23
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`Sheet 20 of 33
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`(22ax)A mum
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`FIG. 24
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`Apr. 15,2008
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`Sheet 21 of 33
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`US 7,357,891 B2
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`FIG. 25
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`U.S. Patent
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`Apr. 15,2008
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`Sheet 22 of 33
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`US 7,357,891 B2
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`FIG. 26
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`Apr. 15,2008
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`Sheet 23 of 33
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`FIG. 27
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`Apr. 15,2008
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`Sheet 24 of 33
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`US 7,357,891 B2
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`FIG. 28
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`Apr. 15,2008
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`Sheet 25 of 33
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`US 7,357,891 B2
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`FIG. 29
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`Sheet 26 of 33
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`US 7,357,891 B2
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`1223):) Rooum
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`FIG. 30
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`Sheet 27 of 33
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`US 7,357,891 B2
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`FIG. 31
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`U.S. Patent
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`Sheet 28 of 33
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`ESam33.3_3.<z%I_§_eEs§.g§_
`
`
`
`ooooo_oooo_
`
`89
`
`9:
`
`O 9
`
`oooF
`
`M21) Jd5'zooo‘NaI9K:>
`
`‘vNaeHINsu!wwn:>eor ZOLOH
`
`8oE(
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`U.S. Patent
`
`Apr. 15, 2008
`
`Sheet 29 of 33
`
`US 7,357,891 B2
`
`1101 02_JoeCumminsMHaRNA- Cy5|FN- 0002.gpr
`Map Chror Fun Keywords
`Genbank
`Common
`Normali. t-test
`p-\ Raw Control
`11
`ISG
`63217.5 743.905
`11
`H79534
`hemoglobin, epsilon 1
`84.981 0.0037
`ISG
`11
`13927.5 441.874
`11
`v-jun avian sarcoma virus 17 oncogene W96134
`31.519
`0.009
`ISG
`25923 1553.28
`CD69 antigen (p60, early T-cell activatil NM_0017812p 13
`16.689 0.0192
`ISG
`3612.5 236.618
`15.267 0.0168
`regulator of G-protein signalling 1
`AA017544
`1
`ISG
`2677.5 177.357
`15.097 0.0222
`ESTs, Weakly similar to 1207289A reve BF589173
`ISG
`20701 1878.21
`11.022 0.0271
`cold shock domain protein A
`AA465019
`ISG
`4329.5 499.333
`8.6706 0.0592
`nasopharyngeal carcinoma susceptibility AA504162
`ISG
`3699.5 472.107
`7.8361 0.0499
`interferon, gamma
`AA969504
`ISG
`25074 3256.69
`7.6992 0.0473
`nuclear factor of kappa light polypeptide W55872
`ISG
`920 119.623
`7.6909 0.0459
`early growth response 2 (Krox-20 (Dros( AA446027
`ISG
`7531 1020.01
`7.3832 0.0587
`phorbol-12—myristate-13-acetate-inducel AA458838
`ISG
`1770.5 241.591
`interleukin 8
`AA 102526
`7.3285 0.0485
`ISG
`7.0928 0.0503 33673.5 4747.59
`synaptonemal complex protein 1
`NM_00317
`ISG
`2963 444.246
`6.6697 0.0623
`v-fos FBJ murine osteosarcoma viral or NM_0052514q
`ISG
`AA669531
`10378 1589.94
`6.5273 0.0567
`Homo sapiens, clone |MAGE:3357927,
`ISG
`T49610
`ESTs
`8145.5 1289.05
`6.319
`0.0672
`ISG
`T621 00
`4008.5 654.478
`6.1247 0.0662
`NOGRW
`AA158035
`907 150.608
`6.0223 0.0642
`ISG
`TPFT47454
`5.7239 0.0691 11852.5 2070.69
`ISG
`H89563
`7907.5 1389.98
`5.6889 0.0698
`ISG
`T49086
`5575 980.557
`5.6855 0.0707
`ISG
`T57938
`7083 1277.32
`5.5452 0.0729
`ISG
`5.5284 0.0754
`6782.5 1226.85 malic enzyme1, NADP(+)-dependent,c
`ISG
`5.4536 0.0747
`6200.5 1136.96 betaine-homocysteine methyitransferasf
`ISG
`5.341 0.0847
`2714 508.147 guanosine monophosphatereductase
`ISG
`5.2945
`0.081612961.5 2448.12
`arriphiphysin (Stiff-Mann syndrome with
`ISG
`4844.5 917.408
`5.2806
`0.0802
`collagen, type Vl, alpha 2
`ISG
`9429 1796.04
`5.2499
`0.0796
`placental growth factor, vascular endoth
`ISG
`5.2416
`0.0799
`4123 786.592 ESTs, Weakly similarto hypothetical pro
`ISG
`5.1731
`0.0874
`1337.5 258.55 related to the Nterminus oftre
`ISG
`0.0872
`5.1566
`1234 239.304 KlAA0125 gene product
`ISG
`4.9288
`0.0875
`1567 317.926 cysteine and glycine-rich protein 3 (card
`ISG
`0.088
`13022 2657.27 IMAGE EST
`4.9005
`ISG
`0.0899
`4.8357
`8366 1730.04 K|AA0763 gene product
`ISG
`4.7066
`0.0972
`12658 2689.42 zinc finger protein 81 (HFZ20)
`ISG
`4.6765
`0.0951 4931.5 1054.54 Homo sapiens clone FLC0675 PR0287'
`ISG
`1072 235.215 ESTs
`4.5575
`0.0992
`ISG
`2120.5 467.477 helicase-moi
`4.5361
`0.1082
`ISG
`0.1015
`4.5151
`2732.5 605.191 CCAAT/enhancer binding protein (C/EB
`ISG
`4.5135
`0.1008
`9961.5 2207.03 ESTs. Moderately similarto putative Ra
`ISG
`0.1031
`4.4582
`5056 1134.08 RuvB (E coli homolog)-like 1
`ISG
`4.4506
`0.1169
`1911 .5 429.488 helicase-moi
`ISG
`4.4227
`0.1054
`4999.5 1130.41 phospholipase A2, group Vll (platelet-ae
`ISG
`0.1065
`673.5 154.137 EST
`4.3695
`ISG
`4.3652
`0.1062
`ISG
`4.356
`0.1091
`ISG
`4.3358
`0.1075 10323.5 2381.01 prostaglandin-endoperoxide synthase 2
`ISG
`4.3291 0.1096
`5352.5 1236.39 Ras-GTPase activating protein SH3 dor
`HSKP
`0.11412949.5 3062.4 ribosomalproteinL15
`
`12
`16
`12
`14
`10
`18
`
`4 1
`
`24
`17
`17
`1
`21
`2
`5
`
`complement component 4-binding prote
`pyridoxal (pyridoxine, vitamin 86) kinas
`ESTs, Weakly similar to ubiquitous
`hypothetical protein FLJ21817 simiiartc
`IMAGE EST
`
`1
`
`AI361386
`AA644211
`AI040381
`AA434088
`
`10p13
`1
`4
`3
`
`AA775952 3pter—:
`298304
`X
`AA962465
`22
`AA873507
`AA521474
`AA043506
`AA996156
`A|023590
`AA069444
`H65030
`H30012
`AA486224
`
`_x[\_)_‘_x-Ao.>©oo.;><.o
`
`9252 2119.5 intermediatefilament protein syncoilin
`952.5 218.662 related to the N terminus oflre
`
`4.2285
`
`—‘—\I0_x—x|g—\_4_x—\|\3[x3_\_x—\_x_;_;__;_;___s0°"*‘—‘O—‘°°-'>0~>C>°°-l><»>l\.>‘3‘-’<>—‘<J'I3l\-74>-xio3<J1o3ooo1r\.>—x—~\|\I-l>—x.;;oo<3.n;r\3o5r\Jc>—-Ix)
`
`
`
`
`
`
`
`
`
`FIG. 33A
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`U.S. Patent
`
`Apr. 15, 2008
`
`Sheet 30 of 33
`
`US 7,357,891 B2
`
`ISG
`NOT ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`
`
`
`._n—\_;_x—x_x_x_.,_;.I>co$o-ucoNoomww-l>Oo\:oo§$:.‘°o°°\I<nc>\:o1_-—x.r>
`
`14
`14
`15
`15
`0
`12
`3
`
`0 1
`
`3
`
`14
`1
`11
`
`5
`17q25
`
`43
`
`7 3 8 1
`
`7
`15
`22
`
`10
`
`7
`
`5q1
`
`1AA112979
`vaccinia related kinase
`AA780815
`collagen, type Vlll, alpha 2
`solute carrier family 3 (activators of diba AA630794
`betaine-homocysteine methyltransferas( T58958
`STAT induced STAT inhibitor3
`NM_00395
`7-60 protein
`AA86521
`cartilage linking protein 1
`AA115902
`cystic fibrosis transmembrane conducta NM_00049
`filamin B, beta (actin-binding protein-27 AA486238
`lipoprotein lipase
`AA633835
`membrane protein of cholinergic synapt AA669603
`K|AA0125 gene product
`H65343
`Homo sapiens clone FLC0675 PR0287' AA781508
`IMAGE EST
`T55958
`caspase 7, apoptosis-related cysteine pl T50828
`biliverdin reductase A
`AA192419
`RALBP1 associated Eps domain contair T72336
`tudor repeat associatorwith PCTAIRE 2 T52694
`protein phosphatase 3 (formerly 2B), ca AA682631
`mouse double minute 2, human homolo AA214617
`RNA binding motif, single stranded inter AA456629
`TERA protein
`AA906997
`ESTs
`T89980
`tudor repeat associatorwith PCTAIRE 2 Stratagene placl
`12
`complement component 1, r subcompor T69603
`19
`guanine nucleotide binding protein (G pi H30255
`5q34
`dual specificity phosphatase 1
`NM_00441
`13
`Epstein-Barr virus induced gene 2 (lymr AI123732
`9p13-l
`reversion-inducing-cysteine-rich protein R26225
`4
`ESTs
`R67218
`BCL2/adenovirus E1 B 19kD interacting NM_OO405 14q11
`KlAA0440 protein
`AA417567
`14q24
`polymerase (DNA directed), gamma
`AA188761
`15q25
`tropomyosin 1 (alpha)
`W58092
`15
`ESTs
`AL520050
`mouse double minute 2, human homolo Al014368
`KlAA0226 gene product
`N36389
`ESTs, Highly similar to NK-TUMOR RE. AA279667
`mitochondrial ribosomal protein L37
`AA488652
`immunoglobulin lambda-like polypeptidl W73790
`K|AA0089 protein
`AA485401
`Novel human gene mapping to chomost AA488718
`damage-specific DNA binding protein 1 AA608679
`transcription factor 8 (represses interleu NM_03075
`aryl hydrocarbon receptor
`AA181307
`Homo sapiens NADH dehydrogenase (u AA608515
`isocitrate dehydrogenase 2 (NADP+), m AA679907
`defensin, alpha 5, Paneth cell-specific M97925
`von Hippel-Lindau syndrome
`H73054
`Homo sapiens cDNA: FLJ22783 fis, clol T59940
`small inducible cytokine A3 (homologou AA677522
`
`X
`
`12q
`
`4
`14
`12
`12
`
`12q14
`3
`
`1
`22
`3
`13
`
`11
`10p11
`7
`
`4.2184
`1282.7
`5411
`0.1138
`4.2128
`0.113 1789.5424.775
`4.108
`0.1174
`16170 3936.2
`4.0832
`0.1204
`4434 1085.9
`4.0739
`0.1196
`4373 1073.43
`4.0251
`0.1433 7193.51787.16
`4.0202
`0.1235
`16372 4072.42
`3.9885
`0.1234
`2452 614.762
`3.9567
`0.1273
`12993
`3283.8
`3.9374
`0.1316
`5613 1425.58
`3.8862
`0.1293 5779.5 1487.18
`3.8781
`0.1294
`1614 416.181
`3.874
`0.1303 11188.5 2888.07
`3.7916
`0.1344 11484.5 3028.96
`0.1352
`12168 3219.28
`3.7797
`3.7644
`0.1363 8575.5 2278.03
`3.7578
`0.143
`3153.5 839.193
`3.7536
`0.1371 12248.5 3263.17
`3.6982
`0.1404
`2649 716.296
`3.6475
`0.1442
`2901 795.331
`3.6225
`0.1472
`3147 868.748
`0.1577 1329.5
`368.57
`3.6072
`3.6021
`0.147
`515 142.972
`3.5884
`0.148
`7055.5
`1966.2
`3.5744
`0.1513
`2309 645.974
`3.5663
`0.1559 1900.5 532.906
`3.5407
`0.1586
`1220 344.562
`3.5193
`0.1527
`4877 1385.77
`3.501 1
`0.1547
`775 221.356
`889.5 254.136
`3 .5001 0.1548
`1889 541.038
`0.1559
`3.4914
`3.4692
`1984 571.886
`0.1625
`3.4562
`0.164
`4419 1278.58
`3.4446
`0.158811331.5 3289.66
`3.4396
`0.1663
`20336 5912.32
`3.423
`0.1602
`26322 7689.65
`3.4083
`0.1679
`632.5 185.578
`3.3921
`0.1691 7686.5 2265.97
`3.3891
`0.1631 7019.5 2071.23
`3.3833
`0.1653 1009.5 298.376
`3.3832
`0.1686
`5069 1498.28
`3.3739
`0.1644-12566.5 3724.59
`3.3636
`0.1671
`12969 3855.73
`3.3267
`0.1693 1460.5 439.019
`0.1693
`2084 627.351
`3.3219
`3.3135
`0.1696
`13928 4203.46
`3.2886
`0.1719 8775.5 2668.47
`3.2836
`0.1726 7116.5 2167.29
`3.275
`0.173 17415.5 5317.65
`3.275
`0.1734 4833.5 1475.88
`0.1746
`3809 1165.67
`3.2677
`
`FIG. 33B
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`U.S. Patent
`
`Apr. 15,2008
`
`Sheet 31 of 33
`
`US 7,357,891 B2
`
`ISG
`HSKP
`ISG
`lSG
`ISG
`ISG
`HSKP
`HSKP
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`HSKP
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`lSG
`ISG
`ISG
`lSG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`
`2
`10
`
`0 4
`
`2
`10
`
`4q33-c
`
`17
`11
`1
`10
`7
`11
`17
`3
`6
`15
`6
`9
`
`12q14
`4q22-(
`5
`17
`
`19
`19
`1
`
`6484 1988.29 Homo sapiens cDNA: FLJ23269'lis,clol AA026686
`3.2611 0.1748
`3.2609 0.1744 5263.5 1614.11 ribosomal protein 824
`N27154
`3.2463 0.1759 7559.5 2328.67 ESTs
`T90697
`3.2458
`0.17616125.5 4968.14 sin3-associated polypeptide, 30kD
`T87622
`3.2269
`0.178
`818 253.498 protein kinase C, iota
`T579570
`3.2264
`0.178
`18430 5712.32 KlAA0160 protein
`Al201344
`3.2193 0.1784 23151.5 7191.38 ribosomal protein 813
`AA629641
`3.2187 0.1784 22020.5 6841.53 608 acidic ribosomal protein PO
`R89308
`3.2125 0.1848
`1930
`600.78 eukaryotictranslation initiation factor3, A|017388
`3.1794 0.1888
`21608 6796.28 alda—keto reductase family 1, memberE AA701963
`3.1679 0.1857
`981 309.668 mucin 6, gastric
`U97698
`3.1625 0.1847 1101.5 348.301 casein kinase 1, delta
`Ai002588
`3.1614 0.1844 9116.5 2883.68 rnitochondrial ribosomal protein
`L3H05820
`3.1497 0.185813506.5 4288.24 HCR(a-helix coiled-coil rod homologue; R37026
`3.1487 0.1879 7727.5 2454.19 40S ribosomal protein S27 isoform
`AA156054
`3.1468 0.1907
`4831 1535.23 chemokine (C-C motif] receptor
`6N57964
`3.142
`0.1863 26450.5 8418.44 transcription termination factor, RNA po AA709143
`3.1396 0.1864
`8453 2692.42 breast cancer1, early onset
`H90415
`3.1297 0.1929
`648.5 207.207 mouse double minute 2, human homolo R80235
`3.1077 0.1934
`3570 1148.77 L-3—hydroxyacyl-CoenzymeAdehydrog T65407
`3.1074 0.1906
`18441
`5934.6 peptidylprolylisomerasec(cyclophilin( AA676404
`3.0865 0.1922
`6710
`2174 KlAA1001 protein
`H50253
`3.0789 0.1931
`1701 552.472 Homo sapiens mRNA;cDNA DKFZp564 AA404994
`3.0559 0.2033
`3388 1108.67 ribosomal protein 811
`AA461501
`3.0496 0.2079
`2771 908.639 RAD23(S.cerevisiae)homolog
`AAA476274
`3.0494 0.196318412.5 6038.06 splicing factor 3a, subunit 3, 60kD
`R17811
`3.035
`0.1981
`10403 3427.63 hydroxyacyl-CoenzymeAdehydrogenaO NM_00449 X
`3.0321 0.1983
`11859 3911.21 protein phosphatase2(formerly 2A), reg NM_00271 3q22.3
`3.0287 0.2097
`34258 11311.1 ribosomal protein S6 kinase, 90kD, poly R95841
`X
`3.0236 0.2007
`4435 1466.77 L-3-hydroxyacyl-CoenzymeAdehydrog T65407
`4q22-(
`3.0153 0.216918183.5
`6030.5 inhibitor ofDNA binding 2, dorninantneg NM_00216
`2p25
`3.0105
`0.201 12364.5 4-107.18 enoyl-Coenzyme A, hydratase/3-hydrox R02373
`3
`3.007
`0.2013
`831 276.355 alpha2,3-slalyltransferase
`AA181306
`3q13.
`3.0008 0.2025 5226.5 1741.69 ribosomal protein, large, PO
`H73623
`12
`2.9975 0.2029 1848.5 616.689 ribosomal protein S23
`H71857
`5
`2.9755 0.2073
`958.5 322.127 lnterleukin4
`2.9751 0.2052
`13734 4616.25 ESTs
`
`AA166617
`
`10
`
`2.9722 0.2165 4981.5 1676.02 heat shock10kD protein 1 (chaperonin
`2.9708 0.205810366.5 3489.46 KIAAO471 gene product
`2.9576 0.2081
`2227 752.966 ESTs
`
`AA448396
`AA279023
`AA701026
`
`1197 404.749 natriuretic peptide receptor C/guanylate A|222701
`2.9574 0.2108
`31105 10528.5 interferon (alpha, beta and omega) rece N59150
`2.9544 0.2077
`26030 8880.39 nuclear cap binding protein, 80kD
`AA757918
`2.9312 0.2107
`21756 7456.15 ESTs
`H20808
`2.9179 0.2125
`2.9155 0.2135 21764.5
`7465.1 transforming growth factor, beta receptc AA487034
`2.9145 0.2135
`6857 2352.68 lysosomal-associated membrane protein NM_01439
`2.9143 0.2153
`5172
`1774.7 hypothetical protein FLB6421
`AA418724
`2.9133 0.2145 3530.5 1211.84 KIAAO694 gene product
`Al653069
`2.9124 0.2132 55084.5 18913.5 peroxisome proliferative activated recep NM_OO623
`2.9098 0.2136 8364.5
`2874.6 interferon regulatory factor4
`AA825491
`2.9026 0.2153
`17286 5955.35 stimulated trans-acting factor (50 kDa)
`AA083407
`
`14
`17
`
`(DBO1
`
`3
`3
`7q33
`
`6
`6
`11
`
`FIG. 33C
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`U.S. Patent
`
`Apr. 15, 2008
`
`Sheet 32 of 33
`
`US 7,357,891 B2
`
`W94107
`2.9021 0.2145 14884.5 5128.94 ribosomal protein L26 homolog
`NM_02187
`0.2164
`9639 3323.08 fibrinogen,gamma polypeptide
`2.9006
`0.216
`4567 1576.74 eukaryotic translation elongation factor‘ AA620477
`2.8965
`0.2154
`798
`275.57 TATA box binding protein (TBP)-associc AA677306
`2.8958
`2.8936
`0.2183
`5342.5 1846.34 alanyl—tRNA synthetase
`AA156571
`2.8863
`0.2166
`4473 1549.71 Homo sapiens agrin precursormRNA,
`AA773358
`2.8816
`0.2172
`2119 735.348 ribosomal protein L32
`N53394
`2.8811
`0.2173
`1709 593.181 small inducible cytokine A3 (homologou AA416584
`2.8786
`0.2252
`2238.5
`777.63 ribosomal protein S29
`N93715
`2.8693
`0.2195
`2450.5 854.042 EST
`R06326
`2.8683
`0.2193
`11065 3857.66 Hemoglobin, alpha2
`T565282
`2.8641
`0.2214
`32368 11301.1 eukaryotictranslation initiation factor3,
`AA669674
`2.8618
`0.2324
`5644 1972.19 mal,T-celldifferentiation protein
`AA227594
`2.8557
`0.2232
`16526 5787.05 ribosomal protein L36a
`AA669359
`2.8552
`0.221
`521.5 182.648 RNA binding motif protein 9
`H03903
`2.841
`0.2242
`1422.5 500.711 hypothetical protein DKFZp547D155
`AL512758
`2.834
`0.2249
`4779 1686.33 modulator recognition factorl
`AA789301
`2.8274
`0.2277
`13507 4777.22 egf-like module containing, mucin-|ike,| AA157797
`2.818
`0.2328
`2764.5 980.998 asparagine synthetase
`AA894927
`2.813
`0.2269
`27172 9659.56 lectin, galactoside-binding, soluble, 1 (g NM_00230
`2.8106
`0.2354
`16494 5868.53 ribosomal protein L10a
`R01139
`2.8099
`0.2297
`25422 9047.41 ribosomal protein S24
`AIOO5519
`2.8059
`0.2316
`1637.5 583.599 ribosomal protein S6 kinase, 70kD, poly AA425446
`2.8059
`0.2283
`36245 12917.6 ribosomal protein L21
`AA464743
`2.8004
`0.229 10155.5
`3626.5 heat shock transcription factor1
`NM_00552
`2.7912
`0.2303
`11841 4242.32 thrombospondin1
`AA464630
`2.7911
`0.2335
`1779.5 637.552 nasopharyngeal carcinoma susceptibility AA94059
`2.7882
`0.2308
`15639
`5609 ribosomal protein L39
`N54526
`2.7875
`0.2314
`25378 9104.06 ribosomal protein L35
`AA625634
`2.7872
`0.2307
`1764.5 633.074 tetratricopeptide repeat domain3
`AA007509
`2.7848
`0.2372
`18165 6522.81 ribosomal protein S10
`Al611010
`2.7841
`0.2364
`9032.5
`3244.3 farnesyl diphosphatesynthase (famesyl T65790
`2.7825
`0.2324
`15894 5712.06 xanthene dehydrogenase
`R09503
`2.78
`0.2431
`5283.5 1900.56 inhibitor of DNA binding 2, dominant ne
`NM_00216
`2.7726
`0.2529 46107.5
`16630 delta sleep inducing peptide, immunorea AB025432
`2.7709
`0.2333
`4259 1537.03 myeloid/lymphoid or mixed-lineage leuk. AA057425
`2.7628
`0.2355
`9476 3429.91 apolipoproteinL
`AF323540
`2.7587
`0.239
`5131 1859.95 ELK4, ETS-domain protein (SRF access H61758
`2.7508
`0.2362 45752.5 16632.4 zinc finger protein 91 (HPF7, HTF10)
`NM_OO343
`2.7495
`0.2364
`65463 23808.8 ribosomal protein 823
`N73091
`2.749
`0.2366
`1083 393.959 adenylate cyc|ase2(brain)
`N45141
`2.7468
`0.2474
`7583 2760.63 ras homolog gene family, memberB
`AA495846
`2.7468
`0.2373 21519.5 7834.44 inhibitor of DNA binding 2, dominant ne
`NM_00216
`2.7383
`0.2544
`5356 1955.97 chemokine (C-C motif) receptor7
`NM_00183
`2.7367
`0.2402
`521.5 190.561 EST
`N62914
`2.7346
`0.2426
`1053 385.069 hydroxymethylbifane synthase
`R06321
`2.7341
`0.2391
`636.5 232.798 nerve growth factor, beta polypeptide
`T56316
`2.7335
`0.2471
`1987.5 727.086 ligase I, DNA,ATP-dependent
`AA291715
`2.7326
`0.2409
`5486.5 2007.76 ESTs
`H63361
`27085
`0.2505
`4368.5 1612.88 SC35-interacting protein1
`H78241
`2.7082
`0.2458
`9726.5 3591.45 stem-loop(histone) binding protein
`AA629558
`
`X
`
`5
`4
`7
`Xq13
`16
`1
`3
`17
`14
`
`16
`8
`2
`14
`22q13
`
`2
`19
`7
`22
`6
`10
`17
`13
`8
`15
`16
`
`6
`21
`6
`1
`2
`2p25
`Xq22.:
`11
`22
`1
`19
`5
`5
`2
`2p25
`17
`1
`11
`1
`19q13
`5
`12
`4
`
`5
`4
`7
`0
`16
`1
`3
`17
`14
`0
`16
`8
`2
`14
`22
`0
`2
`19
`7
`22
`6
`10
`17
`13
`8
`15
`16
`0
`6
`21
`6
`1
`2
`2
`0
`11
`22
`1
`19
`5
`5
`2
`2
`17
`1
`11
`1
`19
`5
`12
`4
`
`HSKP
`ISG
`ISG
`HSKP
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`HSKP
`HSKP
`HSKP
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`NOGRW
`ISG
`ISG
`ISG
`ISG
`ISG
`ISG
`HSKP
`ISG
`ISG
`ISG
`
`FIG. 33D
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`U.S. Patent
`
`Apr. 15,2008
`
`Sheet 33 of 33
`
`US 7,357,891 B2
`
`9
`22q13
`1
`2
`7
`
`11
`20p13
`
`12
`2
`21
`14
`1
`15
`14
`5
`1
`7
`22
`
`7
`6
`22
`1p36
`5
`17
`14
`
`H23421
`35767 13284.6 ribosomal protein L7a
`2.6924 0.2464
`AA454681
`620.5 230.522 RNA binding motif protein9
`2.6917 0.2458
`818.5 304.906 ATPase, Ca++ transporting, plasma me N93024
`2.6844 0.2488
`2.6819 0.2632 5977.5 2228.84 nuclear antigen Sp100
`AA447481
`2.6717 0.2492 1025.5383.843 serine (or cysteine) proteinase inhibitor.
`N75719
`2.6661
`0.2511
`45691713.73 11H7
`AA779404
`2.6423 0.2541
`3830 1449.47 ribosomal protein 825
`2.6422 0.2548
`22780 8621.53 protein tyrosine phosphatase, receptort NM_00283
`2.6344 0.2572
`585.5
`222.25 zinc finger protein 85
`Al253261
`2.627
`0.2596 2732.5 1040.17 enolase 2, (gamma, neuronal)
`AA450189
`2.6258 0.2603
`14783 5629.99 ubiquitin-like1(sentrin)
`AA488626
`2.6203 0.2587 1594.5
`608.51 pyridoxal(pyridoxine,vitarrrin B6)kinas AA158035
`2.6201
`0.2581 2669.5 1018.86 immunoglobulin heavy constant mu
`H73590
`2.6164 0.2627
`4296 1641.92 Human mRNAfor KlAAOO99 gene, com 756948
`2.6154 0.2596
`8979 3433.17 60S ribosomal protein L30 isolog
`AA063398
`2.6083 0.2606
`562.5
`215.66 general transcription factor HA, 1 (37kD NM_01585
`2.6052 0.2616
`1024 393.058 zinc finger protein 84 (HPF2)
`AA922661
`2.6027 0.2622
`1730 664.688 ribosomal protein L5
`N80631
`2.5905 0.2756 7759.5 2995.33 cytochromec
`R52654
`2.589
`0.2657
`814.5
`314.6 H|R(histone cell cycle regulation defect W94880
`2.5852 0.2648
`889 343.875 Homo sapiens clone 23632 mRNA sequ AA418387
`2.585
`0.2655
`2566 992.643 inter|eukin6(interferon, beta 2)
`N98591
`2.5825 0.2667
`4782 1851.66 bromodomain-containing2
`H72520
`2.5814 0.2652 6480.5
`2510.5 Homo sapiens clone FLC0675 PR0287' R41407
`2.5779 0.2664
`16317 6329.59 runt-related transcription faotor3
`N67778
`2.5767 0.2666
`5467 25407.1 ribosomalprolein S23
`N73091
`2.5762 0.2668 6790.5 2635.85 Peroxisomalacyl-coenzymeAoxidaseI T62985
`2.5758 0.2665
`577 224.012 ESTs
`T88698
`2.5706 0.267216949.5 6593.59 Iymphotoxin beta (TNF superfamily, me A|351740
`2.5697 0.2697 37902.5 14749.8 ESTs
`H28545
`2.5682 0.2677
`2039 793.944 translocase of outer mitochondrial mem AA088722
`2.566
`0.2778 31810.5 12397.1 ribosomal protein S4, Y-linked
`T69468
`2.5627 0.2722
`3807 1485.54 lymphocyte antigen6complex, lo cusE AA865464
`2.5475 0.2773 3364.5 1320.72 growth arrestand DNA-damage-inducib AA504354
`2.544 0.2741
`924.5 363.408 hypothetical protein
`AL079292
`2.5415 0.2734
`19433 7646.34 adenosine deaminase,RNA—specific
`AA600189
`2.5377 0.2736 3852.5 1518.13 Homo sapiens clone 23632 mRNAsequ N49250
`1
`2.537
`0.276 1046.5
`412.49 8100 calcium-binding proteinA11 (calgi N29374
`1
`2.5228 0.2802
`27262 10806.4 guanine nucleotide binding protein (G pl AA487912
`6
`2.522
`0.2771 7898.5 3131.84 MHC class I polypeptide—related sequen NM_00593
`12q24
`2.518
`0.278411115.5 4414.46 2',5'-oligoadenylatesynthetas