US007824588B2
`
`(12) United States Patent
`Yang et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,824,588 B2
`*NoV. 2, 2010
`
`(54) METHOD OF MAKING SELF-SUPPORTING
`THERAPEUTIC ACTIVE-CONTAINING FILM
`
`(75)
`
`(73)
`( * )
`
`Inventors: Robert K. Yang, Flushing, NY (US);
`Richard C. Fuisz, McLean, VA (US);
`Garry L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, Washington, DC (US)
`Monosol RX, LLC, Portage, IN (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 135 days.
`
`Assignee:
`Notice:
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21)
`
`Appl. No.: 12/102,071
`
`(22)
`
`Filed:
`
`Apr. 14, 2008
`
`(65)
`
`(60)
`
`(60)
`
`Prior Publication Data
`
`US 2008/0260805 A1
`
`Oct. 23, 2008
`
`Related U.S. Application Data
`
`Division of application No. 10/768,809, filed on Jan.
`30, 2004, now Pat. No. 7,357,891, and a continuation-
`in-part of application No. PCT/US02/32575, filed on
`Oct. 11, 2002, said application No. 10/768,809 is a
`continuation-in-part of application No. PCT/US02/
`32594, filed on Oct. 11, 2002, said application No.
`10/768,809 is a continuation-in-part ofapplication No.
`PCT/US02/32542, filed on Oct. 11, 2002.
`
`Provisional application No. 60/443,741, filed on Jan.
`30, 2003, provisional application No. 60/386,937,
`filed on Jun. 7, 2002, provisional application No.
`60/414,276, filed on Sep. 27, 2002, provisional appli-
`cation No. 60/386,937, filed on Jun. 7, 2002, provi-
`sional application No. 60/371,940, filed on Apr. 11,
`2002, provisional application No. 60/328,868, filed on
`Oct. 12, 2001.
`
`Int. Cl.
`
`(51)
`
`(52) U.S. Cl.
`
`................ .. 264/172.19; 264/212; 264/217;
`264/211.2; 264/234; 264/319; 264/344
`(58) Field of Classification Search ..................... .. None
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`307,537 A
`
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`(Continued)
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`Lazaridou et a1., “Thermophysical properties of chitosan, chitosan-
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`hydrate Polymers 48: 179-190 (2002).
`
`(Continued)
`
`Primary Examiner—Edmund H. Lee
`(74) Attorney, Agent, or Firm—Hoffmann & Baron, LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to film products containing desired lev-
`els of active components and methods of their preparation.
`Desirably, the films disintegrate in water and may be formed
`by a controlled drying process, or other process that maintains
`the required uniformity of the film. Desirably, the films may
`be exposed to temperatures above that at which the active
`components typically degrade without concern for loss ofthe
`desired activity.
`
`B29C 39/14
`
`(2006.01)
`
`191 Claims, 33 Drawing Sheets
`
`
`
`Page 1
`
`BDSI EXHIBIT 1026
`
`Page 1
`
`

`
`U.S. PATENT DOCUMENTS
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`U.S. Patent
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`Nov. 2, 2010
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`US 7,824,588 B2
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`Page 4
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`U.S. Patent
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`Nov. 2, 2010
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`US 7,824,588 B2
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 3 of 33
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`US 7,824,588 B2
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`6
`
`
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`
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`
`/,
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`
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`FEE. 7
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`Page 6
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`Page 6
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 4 of 33
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`US 7,824,588 B2
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`S[;"CT/0NC
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`SEC?"/ON5’
`
`SECTIONA
`
`MG.3
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`Page 7
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`Page 7
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 5 of 33
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`US 7,824,588 B2
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`700
`
`FIG. 9
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`Page 8
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`Page 8
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 6 of 33
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`US 7,824,588 B2
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`700
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`FIG. 10
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`Page 9
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`Page 9
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 7 of 33
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`US 7,824,588 B2
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`FIG. 11
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`100
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`Page 10
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`Page 10
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 8 of 33
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`US 7,824,588 B2
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`700
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`770
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`FIG. 12
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`Page 11
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`Page 11
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 9 of 33
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`US 7,824,588 B2
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`170
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`100
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`FIG. 13
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`Page 12
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`Page 12
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 10 of 33
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`US 7,824,588 B2
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`700
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`FIG. 14
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`Page 13
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 11 of 33
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`US 7,824,588 B2
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`FIG. 15
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 12 of 33
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`US 7,824,588 B2
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`100
`
`FIG. 16
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`Page 15
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`Page 15
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`U.S. Patent
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`Sheet 13 of 33
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`US 7,824,588 B2
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`FIG. 17
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`Page 16
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`Page 16
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`U.S. Patent
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`US 7,824,588 B2
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`Page 17
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`US 7,824,588 B2
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`Page 18
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`U.S. Patent
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`Nov. 2, 2010
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`US 7,824,588 B2
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`U.S. Patent
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`Nov. 2, 2010
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`Sheet 17 of 33
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`US 7,824,588 B2
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`U.S. Patent
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`US 7,824,588 B2
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`U.S. Patent
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`US 7,824,588 B2
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`U.S. Patent
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`Nov. 2, 2010
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`US 7,824,588 B2
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`Page 24
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`Sheet 23 of 33
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`US 7,824,588 B2
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`Page 26
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`Page 26
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`U.S. Patent
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`Sheet 26 of 33
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`Nov. 2, 2010
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`Nov. 2, 2010
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`12
`1513
`6.6706 0.0502
`4320.5 400.333
`nasopharyngeai carcinoma s0sc:ep11b1111y AA504162
`16
`158
`7.8361 0.0480
`3600.5 472.107 i111er1eron,gamma
`404066504
`12
`160
`7.6082 00473
`25074 8255.60 nuc1ear1ac10ro11<appa 11gh1po1y;5ep11de W55872
`14
`150
`7.6000 0.0450
`020 110.523 ear1yg.row111 res_0onse2{Kr0x—20 (D1051 AA446027
`10
`166
`7.3832 0.0587
`7531 1020.01
`phorboi-12-myristate-13-ace1a1e—induce1 AA458838
`18
`186
`7.3285 0.0455
`17705 241.501
`1n1er1euk1n6
`AA102525
`4
`166
`
`12
`15
`12
`.4
`10
`18
`4
`
`1
`111/1_00317
`7.0028 0.0503 33673.5 4747.50 synaptonemai complex pro1ein1
`5.6587 0.0623
`2863 444.246 v-1osFBJ murineosteosarcomaviralor N1v1_0052514q 24
`6.5273 00557
`10378 1580.04 Homosapiens,c1one11v1AGE:3357827,
`44660531
`17
`6.310
`0.0672 81455128005 E675
`740810
`17
`
`6.1247 0.0662 4008.5 554.478 c.5mp1eme11.1componen14-bindingpro1e 762100
`6.0223 0.0642
`007 150.608 pyridexal1pyr1dox1ne,v11am1n 85)=1<1nas
`424158035
`5.7230
`01118525 207050 ES7s,Weaklys1m11a.r1o ubiquitous
`TPF747454
`5.6889 0.0588 7007.5 1380.98 11ypo1he11<:aipro1e1n FLJ21617s1m11ar1c H80563
`5.5855 0.0707
`5575 880.557 EMAGE EST
`740086
`5.5452 0.0720
`7083 1277.32
`757038
`
`471550600
`5.5264 0.0754 67825122685 mal1cer1zyme1,NADP(+}-depender11,c
`5.4536 0.0747 6200.5 1136.06 betaine-homocysteineme111y11rans1e1’as1 756858
`5.341 0.0547
`2714 508.147 guan<3s1nemonop11osp11a1e reductase
`44405242
`5.2045 0.081512061.5 2448.12 amph1phys1n(S1111-Mann syndromewith AA620425
`5.2806 0.0802 4844.5 017.408 C-511agen,1ype V1,a1pha2
`Stratagene
`52400 0.0705
`8420170504 p1acer11a1g1‘ow1h1ac10r,vascularendoth
`/44130714
`5.2415 0.0700
`4123 756.502 E873.Weak1ys1m11ar1o11ypo111e11ca1pro 750026
`5.1731 0.0674 1337.5
`258.55 re1a1ec11c=111e1~11erm1nuso11:re
`474281057
`5.1556 0.0572
`1234 230.304 141440125 gene product
`1155343
`4.0288 0.0875
`1567 317.025 cysteine and giycine-rich pm1e1n3{card AA165050
`4.0005
`0.088 13022 2557.27 IMAGE EST
`T62805
`
`1
`21
`2
`5
`
`5:112
`5
`5
`7
`21
`14
`12
`1012213
`15
`11
`
`5365173004 KJAA0763 gene produci
`4.8357 0.0809
`4.7065 0.0872 12655 2580.42 z1nc1‘1ngerpro1e1n 81 {I-1FZ20)
`4.5765
`0.0851 4031.5 1054.54 Homo sapiens clone FLC0675 P140287’
`4.5575 0.0902
`1072 235.215 E875
`4.5351 0.1082 2120.5 467.477 hsiicase-moi
`
`AA775052 3p1er-:
`208304
`X
`/1.4062465
`22
`44.873507
`13
`4452147
`14
`
`4.5151 0.1015 2732.5 605.101 CC/4AT7enhancer51nd1ng p1o1ein(C/E8 AA043506
`4.5135 01008 00515 220703 E373.111o<1era1e1ys1m11artopu1a11veRa AA906155
`4.4582 0.1031
`056113408 R0118 (E C011 11omo1og)-11ke1
`41023500
`4.4506 0.1160 1911.5 420.458 helicase-moi
`471060444
`
`6
`20
`3
`14
`
`4.4227 0.1054 4090.51130.41 p11osp11o11paseA2, group\/11(p1ate1e1-as
`4.3605 0.1065
`6735154137 E57
`
`1165030
`1130012
`
`9252 2110.5 intermediate fi1amen1 protein syncoiiin
`4.3652 0.1052
`0525218652rela1ed1o1he1\11erm1nuso11re
`4.355
`0.1001
`4.3358 0.1075 10323.5 2381.01 prostagiandin-endopemxide syn1hase2
`4.3291 0.1096 5352.512C15.38 Ras-G7Pase adivating pmiein 3113001
`4.2285
`0.1‘a412949.5 3002.4 r1b0s0ma1p101e1nL15
`
`744486224
`711361586
`714544211
`411040381
`515434088
`
`1
`10013
`1
`4
`3
`
`1
`14
`7
`17
`
`1
`21
`2
`5
`0
`0
`
`6
`5
`5
`7
`21
`14
`12
`10
`15
`11
`0
`
`I3
`0
`22
`13
`14
`
`8
`20
`3
`14
`
`0
`0
`
`1
`10
`1
`4
`3
`
`15G
`16-?
`1013
`150
`
`1813
`NOGRW
`1513
`1813
`186
`1160
`
`1813
`1513
`136
`180
`15-13
`160
`1813
`1313
`156
`1813
`1815
`
`1530
`1513
`131.‘:
`1513
`160
`
`1513
`ESG
`ESG
`1673
`
`1813
`1813
`
`1813
`‘S13
`1:38
`ESG
`HSKP
`
`HS. 337%
`
`Page 32
`
`Page 32
`
`

`
`U.S. P
`
`atent
`
`Nov. 2, 2010
`
`Sheet 30 of 33
`
`US 7,824,588 B2
`
`1AA112979
`AA730815
`
`veeeinia related itineee
`
`coiiagen, type V111, eip11a2
`soiute carrier family 3 (activators of diba AASSO794
`beteine—hernoeysteine rnethyitraneferesi 158958
`STAT induced STAT inhtei1or3
`Nii1_=30395
`7-80 protein
`11458521
`eenilege linking protein 1
`AA115902
`cystic fibrosis trenenternbrane cenducfita NMJ0049
`nlernin 8, beta (ectin-binding protein-27 714488238
`lipoprotein iipese
`AA833835
`membrane protein 81 cheiinergic eynapt A/1859803
`KiAA0125 gene product
`1165343
`Heme sapiens ciene FLC0875 PR0287’ AA781508
`lt~11AGE EST
`755958
`
`14
`1
`11
`E
`..-
`17q25
`
`5:11-43
`7
`3
`8
`17
`15
`22
`
`caspaee 7, epopieeie-reieted cysteine pi 750828
`biiiverein reeuetaee A
`AA192419
`
`10
`7
`
`X
`
`RALBP1 associated Eps domain ceniair 772338
`tutier repeat associeterwith PC1'AlRE 2 752594
`protein phosphatase 3 (r'errner1y2B), ea 144682531
`meuee doubie n1inute2, human nemoie 4.4214817
`RNA binding motif, single stranded inter AA455629
`712% proiein
`AA908997
`E879.
`189980
`
`4
`121114
`12
`12
`
`tudor repeat esseciateiwiih PCTAiRE2 Stretegene pieci
`cempiement cernpenent 1, r eubcompor 759803
`guanine nucieetide binding protein (G pi
`l-130255
`duai specificity phosphatase 1
`iiiz1_00-441
`Epstein—Barr virus induce-.1 gene 2 tiyrnr 711123732
`revereipn-intiueing-eyeieine-rieh protein R28225
`E813
`R87218
`
`12
`19
`5534
`13
`9p13-1
`4
`
`4.2184
`1282.7
`5411
`0.1 38
`0.113 1789.5424.775
`4.2128
`0.1174
`15170 3935.2
`4.108
`0.1204
`4434 1085.9
`4.0832
`4.0739
`0.1198
`4373 1073.43
`0.1433 7193.51787.15
`4.0251
`4.0202
`0.1235
`15372 4072.42
`0.1234
`2452 814.782
`3.9885
`0.1273
`12993
`3283.8
`3.9587
`0.1318
`5513 1425.58
`3.9374
`3.8882
`0.1293 5779.5 148718
`0.1294
`1514 415.181
`3.8781
`3.874
`0.1303 11188.5 288807
`0.1344 11484.5 3028.98
`3.7918
`3.7797
`0.1352
`12188 3219.28
`0.1353 8575.5 2278.03
`3.7544
`3.7573
`0.143
`3153.5 839.193
`3.7535
`0.1371 12248.5 3253.17
`0.1404
`2549 715.295
`3.8982
`0.1442
`2901 795.331
`3.8475
`0.1472
`3147 858.748
`3.8225
`0.1577 1329.5
`388.57
`3.8072
`0.147
`515 142.972
`3.8021
`0.14
`7055.5
`1958.2
`3.5884
`3.5744
`0.1513
`2309 845.974
`3.5883
`0.1559 19005 532.905
`0.1588
`1220 344.552
`3.5407
`0.1527
`4877 1385.77
`3.5193
`0.1547
`775 221.358
`3.5011
`3 .5001
`0.1548
`889.5 254.130
`0.1559
`1889 541.038
`3.4914
`0.1825
`1984 571.888
`3.4892
`3.4552
`0.154
`4419 1278.58
`3.4448
`0.158811331.5 3289.58
`0.1583
`20335 5912.32
`3.4398
`01802 28322 7589.85
`3.423
`3.4083
`0.1579
`832.5 185.578
`1
`7885.5 2255.97
`3.3921
`at 7019.5 2071.23
`3.3891 -'
`3.3833
`1009.5 298.378
`3.3832 '
`5089 1498.28
`.
`3.3739
`0.1544 12585.5 3724.59
`3.3830
`12959 3855.73
`3.3287
`1480.5 439.019
`0.1893
`3.3219
`2084 527.351
`0.1895
`3.3135
`13928 4203.45
`3.2888
`0.1719 8775.5 2858.47
`3.2838
`0.1728 7118.5 2157.29
`3.275
`0.173 17415.5 5317.55
`3.275
`0.1734 4833.5 1475.88
`3.2577
`0.1748
`3809 1185.57
`
`'
`
`14
`1
`11
`
`5
`17
`0
`5
`7
`3
`8
`17
`15
`22
`0
`
`10
`7
`
`0
`0
`4
`12
`12
`12
`0
`
`0
`12
`19
`5
`13
`9
`4
`
`14
`14
`15
`15
`0
`12
`3
`
`13
`
`10
`.7
`0
`15
`8
`3
`15
`17
`
`188
`1\iO"1' 13G
`13G
`18G
`13G
`13G
`13%
`186
`ISG
`130
`18G
`180
`18G
`186
`1530
`1813
`180
`18(3-
`181}
`18G
`1.813
`18G
`186
`180
`188
`1913
`136
`18G
`13G
`ISG
`18G
`1313
`HSKP
`ESG
`186
`13G
`18G
`18G
`HSKP
`18G
`13G
`180
`180
`18G
`186
`13G
`1813
`ESG
`1313
`138
`18G
`
`B012/edenovirus E1 9 191(1) interacting hili.i_OO405 14811
`t<iAA0440 pretein
`AA417887
`14824
`pelyrnereeeiDNA tiirected),gamrna
`AA188781
`15825
`treponryoein1 (alpha)
`W58092
`15
`E815
`A1520050
`rneuee deubie minute 2, human hemple 711014388
`1111317402213 gene product
`1138389
`E375, 1-iighty similar to NK-'t”Uh1QR RE. W79867
`niitechendriei ribeeernai protein L37
`AA488552
`imrnuneglebulin ienibda-iike poiypeptidi W73790
`10440089 preiein
`AA485401
`Novel human gene mapping in eherneet 714488718
`eamegeepeeifrc DNA binding protein 1 4.4508579
`trenscriptien teeter 8 {represses interieu 111403075
`eryl hydrocarbon recepipr
`AA181307
`Home eapiens NADH dehydregenase (u AA808515
`ieecitrete dehydrogenaee 2 ( N!-\.013+), rn AA879907
`deiensin, aipne 5, Panetn cellepecifie M97925
`von Hippel—Line'eu syndrome
`1173054
`1-temp eapiene C0114: FL322783i1e, clot 159940
`srnaii inducible cytokine A3 thorneiegeu AA677522
`
`121314
`3
`
`1
`
`3
`13
`11
`10p11
`7
`
`15
`8
`31125-1
`15
`17
`
`51$. 33%
`
`Page 33
`
`Page 33
`
`

`
`U.S. Patent
`
`Nov. 2, 2010
`
`Sheet 31 of 33
`
`US 7,824,588 B2
`
`2
`10
`
`4533-5
`
`17
`11
`1
`10
`7
`11
`17
`3
`5
`15
`5
`9
`
`12514
`4q22—1_
`5
`17
`
`19
`19
`1
`
`4.4025585
`5484 1988.29 1=1ornosapienscDNA: FLJ23259113, C151
`3.2511 0.1748
`1127154
`3.2509 0.1744 5253.5 1514.11 ribosornai prd1ein824
`790597
`3.2453 0.1759 7559.5 2328.57 E373
`787522
`3.2458 0175151255 4958.14 sin3—associaied pdiypeptide, 3014)
`7579570
`3.2259
`0.178
`818 253.498 pr51einkinaseC,io1a
`711201344
`3.2254
`0.178
`18430 5712.32 KiAA0150pro1ein
`AA529541
`3.2193 0.1784 23151.5 7191.38 ribosnrnai protein 813
`R89308
`3.2187 0.1784 22020.5 5841.53 503 acidic ribpsdmai protein 90
`41017388
`3.2125 0.1848
`1930
`500.78 euiraryotictransiation1nitia1ion1ac1or3,
`3.1794 0.1888
`21508 5795.28 aide-K515reduc1aseiarn1iy1, mern5erE A7-1701953
`3.1579 0.1857
`981 309.580 mucin5,gas1i1c
`U97598
`3.1525 0.1847 1101.5 348.301 casein irinase 1,dei1a
`4.1002538
`3.1514 0.1844 9115.5 2883.58 mitochondria! ribosoma1prd1ein
`L3H05820
`3.1497 0.185813505.5 4288.24 1108 1a-helix coiled-C511 rod homologue; R37025
`3.1487 0.1879 7727.5 2454.19 405 ribosomai protein S27iso1orrn
`44.155054
`3.1458 0.1907
`4831 1535.23 chem5kine{0-C 01011117950010!
`51157954
`3.142 01853254505 8418.44 Eranscripiion termination factor, RNA po
`714709143
`3.1395 0.1854
`8453 2592.42 breast canr:er1,eariy onset
`1190415
`3.1297 0.1929
`5485 207.207 mouse doubie m1nu1e2,irumanh5mo1o
`550285
`3.1077 0.1934
`3570 1148.77 L-3—hydr5xyacy1-CdenzymeAdenydrog
`755407
`3.1074 0.1905
`18441
`5934.5 peptidyiproiyiisomeraseC(cyci5pi1i1in(
`714575404
`3.0855 0.1922
`5710
`2174 1117141001 protein
`H50253
`3.0789 0.1931
`1701 552.472 1-1omosap1ensmRNA; C1311/11}1{FZp554 471404994
`3.0559 0.2033
`3388 1108.57 riboson1aiprd1einS11
`44451501
`3.0495 0.2079
`2771 908.539 RAD2315.<:erevisiae)hdn1oldg
`AAA475274
`3.0494 0.195318412.5 5038.05 splicing 1ac1or3a, subunit 3, 5020
`R17811
`3.035
`0.1981
`10403 3427.53 hydrdxyacyi-Coenzyme71deiry<1rdgenaO N1vi_00449 X
`3.0321 0.1983
`11859 3911.21 proiein phospha1ase2(f5rmer1y 24), reg NM_00271
`3522.3
`3.0287 0.2097 W58 11311.1 ribosornai pretein S5 kinase, 90110, poiy R95841
`X
`3.0235 0.2007
`4435 1455.77 1-3-hydroxyacy1—CdenzyrneAdehydrog
`755407
`4q22—(
`3.0153 0.2159181-33.5
`5030.5 inhibitor of DNA binding 2, dominant neg NM_00215
`2,325
`3.0105
`0.201 12354.5 4107.18 enoyi—Cdenzyme A, nydra1ase/'3-hydrox
`902373
`3
`3.007
`0.2013
`831 275.355 aipi1a2,3-siaiyliransferase
`AA181305
`3:113.
`3.0008 0.2025 5225.5 1741.59 ribosdmai pro1ein. large, P0
`1173523
`12
`2.9975 0.2029 1848.5 515.589 ribnsornai protein 923
`H71557
`5
`2.9755 0.2073
`958.5 322.127 in1erIeukin4
`2.9751 0.2052
`13734 451525 E575
`
`44155517
`
`10
`
`2.9722 02155 49315 1575.02‘ hea1sndc1<10i<.D prdtein 1 iciraperonin
`2.9708 02058103555 3489.45 11174710471 gene product
`2.9575 0.2081
`2227 752.955 E973
`
`44445395
`44279023
`44.701025
`
`711222701
`2.9574 0.2105
`1197 404.749 nainuretic peptide receptor Cigiranyiaie
`1159150
`2.9544 0.2077
`31105 10528.5 in1er1eron(a1pha, beta and omegajirerse
`714757918
`2.9312 0.2107
`25030 858039 nuciear cap binding protein. 8014”)
`1120808
`2.9179 0.2125
`21755 7458.15 E575
`4.4457034
`2.9155 0.2135 21754.5
`7455.1 transforming growthfacior, betareceptc
`2.9145 0.2135
`5857 2352.58 1ySOS07713‘1-35300131007119i’7101’57i9p7010111 NM_01439
`2.9143 0.2153
`5172
`1774.7 hypotheticaiprotein FL85421
`4.4418724
`2.9133 0.2145 3530.5 1211.84 1(iAA0594geneprodirc1
`41553059
`2.9124 0.2132 55084.5 18913.5 perpxisome prdiiferative activated recap 1~iM_OO523
`2.9098 0.2135 5354.5
`2874.5 interferonregu1aiory1ac1or4
`4.4825491
`2.9025 02153
`17285 5955.35 siirnuiaied irans-acting 130151" 150 i<Da)-
`44083407
`
`14
`17
`
`5
`21
`9
`
`3
`3
`7d33
`
`5
`5
`11
`
`HG 33$
`
`Page 34
`
`2
`10
`0
`4
`
`17
`11
`1
`0
`7
`11
`17
`3
`5
`15
`5
`9
`0
`12
`14
`5
`17
`0
`19
`19
`1
`0
`3
`0
`4
`2
`3
`3
`12
`5
`0
`10
`
`14
`17
`0
`
`5
`21
`9
`0
`3
`3
`7
`0
`5
`5
`11
`
`185
`HSKP
`155
`130
`135
`155
`HSKP
`HSKP
`130
`180
`155
`130
`HSKP
`155
`HSKP
`130
`HSKP
`135
`180
`155
`155
`180
`I55
`H5118
`185
`180
`130
`150
`HSKP
`185
`185
`185
`90
`180
`80
`155
`185
`
`195
`155
`130
`
`180
`15G
`156
`185
`1813
`185
`1590
`130
`181.‘:
`ESG
`150
`
`Page 34
`
`

`
`U.S. Patent
`
`Nov. 2, 2010
`
`Sheet 32 of 33
`
`US 7,824,588 B2
`
`11704107
`0.2145 14884.5 5125.04 ribosemel pre1einL20nomp1eg
`i*~iM_~02187
`0.2154
`0530 3323.05 fibrinogen, gamina peiypeptéde
`0.215
`4567 1575.74 eukaryptic translation eiongeiionfactef AA020477
`0.2154
`705
`275.57 7ATAbexbind1ng protein 115?)-essecic AA077305
`0.2183
`5542.5 1040.34 a1anyi~tRNAsynt1ie1ase
`AA155571
`0.2155
`4473 1540.71 H-came sapiens agrin prec0rserrnF0lA.
`AA773358
`0.2172
`2110 735.340 ribosoma1pre1einL32
`1153304
`0.2173
`1700 503.151 srnetiindueip1epyte1<ineA3ihernelegou
`704415584
`0.2252
`2238.5
`777.53 ribesema1pretein020
`N93715
`0.2105
`2450.5 054.042 E81’
`R05325
`
`5
`4
`7
`X7113.
`16
`1
`3
`17
`14
`
`16
`0
`2
`14
`22013
`
`2
`10
`7
`22
`6
`10
`17
`13
`8
`15
`15
`
`7555252
`11055 3557.55 1-1enipgleb1n.eiphe2
`02103
`32308 11301.1 eukaryoti-ctransiatipn initiation 1ae1or3, AA50057
`0.2214
`5644 1072.10 tna1,1-eeii differentiation protein
`M227504
`0.2324
`10520 5787.05 ribosema|pre1einL30e
`AA050350
`0.2232
`5215 132.648 R1\lA;1in-ding rnetttpretein 0
`1103003
`0.221
`1422.5 500.711 hypothetlcei prote1n0KFZp547D155
`AL512753
`0.2242
`4770 1585.33 medulafiorreeegnillen tectetl
`AA750301
`0.2240
`13507 4777.22 egf-iike meciule Cen1aining,n1ucln—1iKe,1 AA157707
`0.2277
`2704.5 080.903 esparagine syn111e1ase
`AA804027
`0.2328
`271.72 0550.56 iectln.ge1ae1osl0e~btn5ing,soluble,1 tg
`iiiit/L00230
`0.2260
`15404 5568.53 riE>osorrla1pro1einL10e
`R01130
`0.2354
`25422 0047.41 l1L't0SOt11a1p1010111S2~1
`711005510
`0.2207
`1637.5 553.500 rttmsemai protein S5 klnase, 701(1), poly AA425445
`0.2315
`35245 12017.0 ribosomal protein L21
`AA454743
`0.2283
`0.220 10155.5
`3625.5 iteatstiocktranscriptlen1ac1er1
`1~i1v1_00552
`0.2303
`11041 4242.32 111l‘0t11b0Sp071d1f11
`AA454630
`0.2335
`1770.5 537.552 nesepitaryngeeieeretnerna susceptibtiity AA04050
`0.2308
`150.30
`5500 ribosomal protein L30
`1454525
`5
`02314
`25378 0104,00 rtbosomal protein L05
`AA525534
`21
`0.2307
`1754.5 533.074 tetramcepeptide repeat ciemaln3
`AA007500
`0
`0.2372
`13155 5522.81 rlbosomei protein S10
`41511010
`1
`0.2364
`0032.5
`3244.3 iarnesyidipnosphate syntiiase (femesyi
`755700
`2
`0.2324
`15504 571205 xanthene dehydregenase
`P100503
`2p25
`0.2431
`5283.5 1000.56 inhi1:»itoro1D1\tA binding Zdeminentne
`i\li\r1_00215
`0.2520 40107.5
`15630 delta steep tnducing peptide, immuneree A5025432 X522:
`0.2333
`4250 1537.03 rnyeleiclllymphpld ermixed-iineageieuk. 44057425
`11
`0.2355
`0470 3420.01 epplipoprptelnt
`AF323540
`22
`0.230
`5131 1850.05 ELK4, ETS-domain pretein(SRF access 1151758
`1
`0.2352 45752.5 15632.4 zinc fingerpretein 01 (HPF7. HTF10)
`i\tiv1_~00343
`10
`0.2354
`05403 23 08.8 t1b0sema1preteinS23
`1473001
`5
`0.2366
`1053 303.050 edenyiate c3/c1ase21brain1
`1445141
`5
`0.2474
`7503 2750.53 res iiernoleg gene ferntty, rnemberfi
`AA405840
`2
`0.2373 21510.5 7834.44 inhibitor 01011.4 binding 2, dominant ne
`1\tiv1__00215
`21:25
`0.2544
`5356 1055.07 chemaklnetc-C nio1i0recepi<:>r7
`1i1v1_00183
`17
`0.2402
`521.5 100.551 EST
`1162914
`1
`
`X
`
`0.2425
`0.2301
`0.2471
`0.2400
`
`0.2505
`0.2458
`
`1053 385.000 hydrexymethylbifane synihese
`0355 232.705 nerve grpw1h factor, beta petypepticie
`1057.5 727.055 iigase 1, 01173., ATP—dependent
`54855 200776 E815
`
`4368.5 1612.58 SD35-in1e.rac1ingpt01e1n1
`0720.5 3501.45 stern-ieop iiiisiene) binding proiein
`
`R05321
`750316
`AA201715
`1153301
`
`1473241
`4.4620558
`
`11
`1
`10513
`5
`
`12
`4
`
`HG. 333
`
`_..:.
`
`¢$CJ—.;J=-(.31
`--'~....kr\:«cz:-:»<34=>-~a<;:o..¢
`vx.:-_1E3l*\>c:s",\;.,-3:;
`
`rxz,..--n->-—-e--v-—-mcra‘-Jo3c_nr_x><;..:-\J©C5>
`
`WK.)
`
`HSKP
`lSG
`ESG
`HSKP
`ESG
`ESG
`HSKP
`186
`ESG
`136
`ESG
`156
`13G
`HSKP
`13G
`130
`15G
`18G
`18G
`1SG
`HSKP
`HSKP
`HSKP
`HSKP
`188
`188
`186
`HSKP
`186
`136
`158
`lSG
`13G
`136
`186
`13G
`15G
`ISG
`ESG
`HSKP
`NOGRW
`13G
`ESG
`ESG
`ISG
`156
`13G
`HSKP
`156
`13G
`18G
`
`2.0021
`2.0006
`2.8065
`2.8058
`2.8036
`2.8803
`2.8815
`2.8811
`2.8786
`2.8093
`2.8053
`2.8541
`2.8015
`2.8557
`2.8552
`2.841
`2.834
`2.8274
`2.818
`2.813
`2.8106
`2.8000
`2.8050
`2.8059
`2.8004
`2.7012
`2.7911
`2.7882
`2.7875
`2.7872
`2.7848
`2.7841
`2.7825
`2.73
`2.7720
`2.7700
`2.7528
`2.7587
`2.7508
`2.7405
`2.740
`2.7458
`2.7468
`2.7383
`2.7367
`2.7346
`2.7341
`2.7335
`2.7328
`2.7085
`2.7052
`
`Page 35
`
`Page 35
`
`

`
`U.S. Patent
`
`Nov. 2, 2010
`
`Sheet 33 of 33
`
`US 7,824,588 B2
`
`2.6924
`2.8917
`2.6644
`2.6819
`2.6717
`2.6661
`2.6423
`2.6422
`2.6344
`2.627
`2.6256
`2.6203
`2.6201
`2.6164
`2.6154
`2.6083
`2.6052
`2.6027
`2.5905
`2.589
`2.5852
`2.565
`2.5625
`2.5814
`2.5779
`2.5767
`2.5762
`2.5758
`2.5706
`2.5697
`2.5662
`2.566
`2.5627
`2.5475
`2 .544
`2.5415
`2.5377
`2.537
`2.522
`2.522
`2.518
`2.5169
`2.5169
`2.5121
`2.5087
`2.5082
`2.5026
`2.502
`
`35787 13284.8 nbosoniai protein 1.7a
`0.2484
`620.5 230.522 RNA binding motii protein9
`0.2458
`818.5 304.906 7179558, Ca++transporting, piesma me
`0.2488
`0.2832 5977.5 2228.84 nuoleareniigen 8p100
`0.2492 1025.5 3 83.343 serine 1oroys1eine} proteinese 11111101101‘,
`0.2511
`4589 1713.73 111-17
`
`H23421
`AA454881
`1193024
`AA447431
`1175719
`
`AA779404
`3830 1449.47 ribosornei protein 825
`0.2541
`1~i114_00283
`22780 8621.53 proiein fyroeine phosphatase, reoeptort
`0.2548
`41253281
`585.5
`222.25 z1nc1’ingerpro1ein 85
`0.2572
`748450139
`0.2598 2732.5 1040.17 enoiase 2, (gamma, neuronal)
`AA488826
`0.2803
`14783 5829.99 ub1oui1in~1i1<e1(.senirin}
`744158035
`0.2587 1594.5
`803.51 pyrkioxai(pyndoxine,v11ernin 88)i<inas
`1173590
`0.2531 2889.5 1018.88 imrnunogiobniin heavy cc-nstantrnu
`0.2627
`4298 1641.92 Human rnRi\iAtorK1.4AOQ99 gene, corn T58948
`0.2596
`8979 3433.17 60Sri1:»osornai p1otein1..30isoiog
`AA083398
`0.2808
`582.5
`215.88 generei1renscr1p1ien1ac1or11A, 1 (371<0
`1*~1i7i_01585
`0.2818
`1024 393.058 zinc finger protein 84 (HPF2)
`4.4922681
`0.2822
`1730 884.888 ribosomei protein 1.5
`1180831
`0.2758 7759.5 2995.33 cytoehromeo
`R52554
`0.2657
`814.5
`314.8 H1R(nis1oneoe11eyc1e reguietion deteci
`11794880
`0.2848
`889 343.875 Home eapiens cione 23832 mRNA seqo
`4.4418387
`0.2855
`2586 992.843 interieukin8{in1er1eron, beta 2)
`1498591
`0.2867
`4782 1851.88 brornodentain-con1eining2
`1172520
`0.2852 6480.5
`2510.5 1-iomo sapienseione FLC0875 P140237‘ R41407
`0.2884
`18317 8329.59 nin.1—re1a1ed1ransoript1ontacior3
`1187778
`0.2888
`5487 25407.1 ribosomal protein 823
`8173091
`0.2888 8790.5 2635.85 Peroxieomeieoyi-coenzg/meAoxidese1
`782985
`0.2885
`577 224.012 E873
`788698
`
`711351740
`02872189495 8593.59 iympnotoxin5e1a(1’NFs0per1en1i1y,me
`1128545
`02897379025 14749.8 E975
`0.2877
`2039 793.944 1rans1ooese oi outer mitoehoridriai rnem AA088722
`
`9
`22813
`1
`2
`7
`
`11
`20p13
`
`12
`2
`21
`14
`1
`15
`14
`5
`1
`7
`22
`
`7
`8
`22
`1p38
`5
`17
`14
`
`7
`3
`
`Y
`8
`193513
`
`1
`
`169488
`0.2778 31810.5 12397.1 ribosomal protein S4, Y-linked
`44885464
`0.2722
`3307 1435.54 iymphoogne antigen 8 80iTip19)(, lo cos 5
`0.2773 3384.5 1320.72 grow111 arresiand 011A~darnege-indueib AA504354
`0. 2741
`924.5 383.408 iiypo1ttetica1pro1ein
`711079292
`02734
`19433 7846.34 adenosinedeaminase,51\1A—speoi11o
`AA600139
`0.2738 3852.5 1518.13 Homo sepiens cione 23832 mRi\1/-1 sequ
`1149250
`1
`0.278 10485 412.49 6100ca1oiurn—8indingproteinA11{ceigi N29374
`1
`0.2802
`27282 10808.4 guanine nucleotide binding protein (G711
`44487912
`6
`0.2771 7898.5 3131.84 Mi-10 oiaes 1 poiypeptide-reiaied seqnen N01_00593
`12824
`0.278411115.5 4414.48 2’.5‘-oiigoadeny1e1esyn1hetaee1 (40-48
`714148773
`0.2798
`47251 187737 CD88 antigen
`NM_00125 17813
`0.2781
`9155 383.748 101\13pro1e1n
`N82911
`5
`0.2823 20808.5 8283.18 splicing tector, ergininelserine-rioh2
`4.4454585
`17
`0.2802
`1017 405.389 guanine nuoieotide binding protein 10 p1
`4.4701554
`19
`02847 5064.5 2019.18 adenovirus 5 E174 binding protein
`144598473
`0.2892
`559.5 223.547 nypofneticai protein 111083038
`144978044
`0.2807 43177.5 17257.5 van Hippeiwiindeu syndrome
`R5417?
`
`7
`3p28-,1
`
`9
`22
`1
`2
`7
`0
`
`11
`20
`0
`12
`2
`21
`14
`1
`15
`14
`5
`1
`7
`22
`0
`7
`8
`22
`1
`5
`17
`14
`
`0
`7
`3
`
`0
`3
`19
`0
`1
`0
`1
`1
`8
`12
`17
`5
`17
`19
`0
`7
`3
`
`188
`190
`130
`160
`186
`
`HSKP
`180
`130
`166
`160
`NOGRW
`180
`130
`HSKP
`160
`160
`130
`ISG
`1813
`180
`ISG
`150
`166
`150
`166
`186
`130
`
`160
`196
`160
`
`HSKP
`180
`1613
`1513
`160
`160
`160
`160
`160
`1813
`190
`160
`130
`190
`196
`160
`180
`
`FEG 33E
`
`Page 36
`
`Page 36
`
`

`
`US 7,824,588 B2
`
`1
`METHOD OF MAKING SELF-SUPPORTING
`THERAPEUTIC AC TIVE-CONTAINING FILM
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a divisional of U.S. application
`Ser. No. 10/768,809, filed Jan. 30, 2004, now U.S. Pat. No.
`7,357,891, which claims benefit to U.S. Provisional Applica-
`tion No. 60/443,741 filed Jan. 30, 2003, and which is a con-
`tinuation-in-part of PCT/US02/32575 filed Oct. 11, 2002,
`which claims priority to U.S. application Ser. No. 10/074,
`272, filed Feb. 14, 2002, now U.S. Pat. No. 7,425,292, which
`claims priority to U.S. Provisional Application No. 60/328,
`868, filed Oct. 12, 2001, and U.S. ProvisionalApplicationNo.
`60/386,937, filed Jun. 7, 2002; U.S. application Ser. No.
`10/768,809 is also a continuation-in-part of PCT/US02/
`32594, filed Oct. 11, 2002, which claims priority to U.S.
`Provisional Application No. 60/414,276, filed Sep. 27, 2002,
`U.S. application Ser. No. 10/074,272, filed Feb. 14, 2002,
`now U.S. Pat. No. 7,425,292, which claims priority to U.S.
`Provisional Application No. 60/328,868, filed Oct. 12, 2001
`and U.S. Provisional Application No. 60/386,937, filed Jun.
`7, 2002; and U.S. application Ser. No. 10/768,809 is also a
`continuation-in-part of PCT/US02/325442, filed Oct. 11,
`2002, which claims priority to U.S. Provisional Application
`No. 60/371,940, filedApr. 11, 2002, U.S. application Ser. No.
`10/074,272, fled Feb. 14, 2002, which claims priority to