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Patent 2653811 Summary

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(12) Patent Application: (11) CA 2653811
(54) English Title: FILMS AND PARTICLES
(54) French Title: FILMS ET PARTICULES
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C08G 64/02 (2006.01)
  • A61K 47/32 (2006.01)
  • A61K 47/34 (2006.01)
  • C08F 20/26 (2006.01)
  • C08G 63/64 (2006.01)
  • C08J 5/18 (2006.01)
  • C08L 33/14 (2006.01)
(72) Inventors :
  • COLSON, YOLANDA (United States of America)
  • AZOUZ, SOLOMON (United States of America)
  • GRINSTAFF, MARK W. (United States of America)
  • WOLINSKY, JESSE (United States of America)
  • GRISET, AARON (United States of America)
(73) Owners :
  • TRUSTEES OF BOSTON UNIVERSITY (United States of America)
  • THE BRIGHAM AND WOMEN'S HOSPITAL, INC. (United States of America)
(71) Applicants :
  • TRUSTEES OF BOSTON UNIVERSITY (United States of America)
  • THE BRIGHAM AND WOMEN'S HOSPITAL, INC. (United States of America)
(74) Agent: GOWLING WLG (CANADA) LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2007-05-31
(87) Open to Public Inspection: 2007-12-06
Examination requested: 2012-05-24
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US2007/070159
(87) International Publication Number: WO2007/140483
(85) National Entry: 2008-11-27

(30) Application Priority Data:
Application No. Country/Territory Date
60/809,344 United States of America 2006-05-31
60/844,122 United States of America 2006-09-13

Abstracts

English Abstract

Published without an Abstract


French Abstract

Publié sans précis

Claims

Note: Claims are shown in the official language in which they were submitted.



We Claim
1. An oligomer or polymer having a repeat unit represented by formula XX:

Image

Wherein:
Q is selected from among O, S, Se or NH
G is selected from among the following structures:

Image

R2 is selected from among hydrogen, a straight or branched alkyl, cycloalkyl,
aryl,
olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon
chain of 1-50
carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,
arylsilyl, alkylaryl,
arylalkyl, or fluorocarbon chain is optionally substituted internally or
terminally by one
or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino,
mono- or
di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or
halogen
substituents;


114


R3 is selected from among hydrogen, methoxy, ethoxy, amino, a straight or
branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,
alkylaryl, or arylalkyl
chain of 1-10 carbons;
R4 R5 and R6 are each independently selected from among a straight or branched
alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, or arylalkyl
chain of 1-
carbons; and
R7 and R8 are each independently selected from among hydrogen, a straight or
branched alkyl, cycloalkyl, aryl, olefin, alkylaryl, or arylalkyl chain of 1-
50 carbons,
wherein each alkyl, cycloalkyl, aryl, olefin, alkylaryl or arylalkyl chain is
optionally
substituted internally or terminally by one or more hydroxyl, hydroxyether,
carboxyl,
carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,
thioester,
sulfate, phosphate, phosphonate, or halogen-substituents.


2. The oligomer or polymer of claim 1, wherein the oligomer or polymer is
represented by Formula XX':

Image

Wherein:
n is an integer from 2-750, and wherein each oligomeric or polymeric chain has
a
terminal group, the terminal goup being selected from among amined, thiols,
amides,
phosphates, sulphated, hydroxides, alkenes, and alkynes.

3. The oligomer or polymer of claim 1, wherein R2 is hydrogen or methyl.

4. The oligomer or polymer of claim 1, wherein Q is oxygen.

5. A composition comprising the oligomer or polymer of claim 1.

115


6. A polymer film or particle comprising an oligomer or polymer of claim 1.

7. A polymer particle of claim 6, comprising a microparticle or nanoparticle.

8. A polymeric particle of claim 7, wherein the particle has a diameter
between
about 2 nm and 1 micron.

9. The polymeric particle of claim 7 comprising a first volume at a first pH,
and a
second volume at a second pH, different from the from the first pH.

10. The polymeric particle of claim 9, wherein the second volume is 1X or more

greater than the first volume when the second pH is lower than the first pH.

11. The polymeric particle of claim 9, wherein the second volume is 4X or more

greater than the first volume when the second pH is lower the the first pH.

12. The polymeric particle of claim 9, wherein the second volume is 8X or more

greater than the first volume when the second pH is lower than the first pH.

13. The polymeric particle of claim 9, wherein the second volume is greater
than the
first volume and the change in volume is sufficient that the particle when
within a cell
during the volume change ruptures the cell or a cellular compartment.

14. The polymeric particle of claim 9, wherein the second volume is greater
than the
first volume and the change in volume is sufficient to cause the particle to
become
lodged, embedded, or immobilized in an anatomic location, such as a lymph
node,
airway, cavity, capillary, or other tissue.

15. The polymeric film or particle of claim 6, further comprising an agent.

116


16. The polymeric film or particle of claim 15, wherein the agent is a
biologically
active agent comprising one or more of an anti-cancer agent, an anti-biotic,
an anti-
neoplastic agent, an analgesic, an angiogenic, or an agent that promotes wound
healing.

17. The polymeric film or particle of claim 15, wherein the biologically
active agent
comprise one or more of asparaginase; bleomycin; busulfan; capecitabine;
carboplatin;
carmustine; chlorambucil; cisplatin; cyclophosphamide; cytarabine;
dacarbazine;
dactinomycin; daunorubicin; dexrazoxane; docetaxel; doxorubicin; etoposide;
floxuridine; fludarabine; fluorouracil; gemcitabine; hydrozyurea; idarubicin;
ifosfamine; irinotecan; lomustine; mechlorethamine; melphalan; mercaptopurine;

methotrexate; mitomycin; mitotane; mitoxantrone; paclitaxel; pemetrexed;
pentostatin;
plicamycin; procarbazine; rituximab; streptozocin; teniposide; thioguamine;
thiotepa;
vinblastine; vincristine; and vinorelbine.

18. A method of using the particle of film of claim 6, the method comprising
applying
to one or more of the following: (i) a surgical resection margin, (ii) within
a treated or
untreated tumor or cavity, (iii) a target site of disease away from a surgical
margin, and
(iv) a lymph node.

19. The film of claim 6, wherein the film is a single layered film.

20. The film of claim 15, further comprising two or more layers to form a
multi-
layered film.

21. The film of claim 15, comprising a first layer comprising a first polymer
of
Formula XX, and a second layer comprising a second polymer different from
Formula
XX.

22. The film of claim 21, wherein the second polymer comprises one or more of
poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycol acid),
polycaprolactone,
poly)trimethelene carbonate), polyester, polycarbonate, and polyamide.

117


23. An oligomer or polymer, or portion thereof, represented by Formula XXI,
XXII,
XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII,
XXXIV, XXXV, XXXVI or XXXVII:


Image

wherein:

118


Q' is independently selected from among O, S, Se or NH;
G', G1', and G2' are each independently selected from among the following
structures:

Image

or R1; wherein G1' and G2' are not the same;
R1' is selected from among a straight or branched alkyl, cycloalkyl, aryl,
olefin,
silyl, alkylsilyl, arylsilyl, alkylaryl, or fluorocarbon chain of 3-50
carbons,
wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkysilyl, arylsilyl,
alkylaryl, arylalkyl
or fluorocarbon chain is optionally substituted internally or terminally by
one or more
hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or
di-
substituents; or
R1' is selected from among poly(ethylene glycol), poly(ethylene oxide),
poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an amino acid, a
nucleic
acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a
polysaccharide, and antibody, a pharmaceutical agent, or any epitope for a
biological
receptor; or
R1' is selected from among a photocrosslinkable or ionically crosslinkable
group;
R2' is selected from among hydrogen, a straight or branched alkyl, cycloalkyl,

aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or fluorocarbon chain
of 1-50
carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,
arylsilyl, alkylaryl,
arylalkyl, or fluorocarbon chain is optionally substituted internally or
terminally by one
or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino,
mono- or
di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or
halogen
substituents;
x and y are each independently selected from an integer of 2-750;
a is selected from an integer of 1-25;
b is selected from an integer of 1-14;

119


c is selected from an integer of 1-14; and
each polymeric terminal group is selected from among amines, thiols, amides,
phosphated, sulphates, hydroxides, metals, alkanes, alkenes, and alkynes.

24. An oligomer or polymer, or portion thereof, presented by Formula XXXVIII:

Image

wherein:
Q' is independently selected from among O, S, Se or NH;

Image
G' is selected from among
R1' is selected from among a straight or branched alkyl, cycloalkyl, aryl,
olefin,
silyl, alkylsilyl, arylsilyl, arylalkyl, or fluorocarbon chain of 3-50
carbons,
wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,
alkylaryl, arylalkyl,
or fluorocarbon, chain is optionally substituted internally or terminally by
one or more
hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or
di-
substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or
halogen
substituents; or
R1' is selected from among poly(ethylene glycol), poly(ethylene oxide),
poly)hydroxyacid)), a carbohydrate, a protein, a polypeptide, an amino acid, a
nucleic
acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a
polysaccharide, an antibody, pharmaceutical agent, or any epitope for a
biological
receptor; or
R1' is selected from among photocrosslinkable or ionically crosslinkable
group;
x and y are each independently selected from an integer of 2-750;

120


e is selected from an integer of 1-8; and
each polymeric terminal group is selected from among amines, thiols, amides,
phosphated, sulphates, hydroxides, metals, alkanes, alkenes and alkynes.

25. The oligomer or polymer of claim 24, wherein R1' is selected from among a
straight or branched alkyl, cycloalkyl, aryl, olefin, alkylsilyl, arylsilyl,
alkylaryl,
arylalkyl, or fluorocarbon chain of 3-50 carbons, wherein each alkyl,
cycloalkyl, aryl,
olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon
chain is optionally
substituted internally of terminally by one or more hydroxyl, hydroxyether,
carboxyl,
carboxyseter, carboxiamide, amino, mono- or di-substituted amino, thiol,
thioester,
sulfate, phosphate, phosphonate, or halogen substituents.

26. The oligomer or polymer of claim 24, wherein R1' is selected from among a
straight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,
arylsilyl, alkylaryl,
arylalkyl, or fluorocarbon chain of 3-50 carbons.

27. The oligomer or polymer of claim 24, wherein R1' is selected from among a
straight or branched alkyl chain of 3-50 carbons.

28. A polymeric film or particle comprising a polymer or claim 23 or 24.

29. A polymeric particle of claim 28, comprising a microparticle or
nanoparticle.

30. A polymeric particle of claim 29, wherein the particle comprises a
diameter of
between about 1 nm and 2 microns.

31. A polymeric particle of claim 29, wherein the particle comprises a
diameter
between about 10 nm and 1 microns.

32. The polymeric film or particle of claim 28, further comprising an agent.

12l


33. The polymeric film or particle of claim 32, wherein the agent is a
biologically
active agent comprising one or more of an anti-cancer, an anti-biotic, anti-
neoplastic, an
analgesic, and angiogenic, or agent that promotes healing.

34. The polymeric film or particle of claim 32, wherein the biologically
active agent
comprise one or more of asparaginase; bleomycin; busulfan; capecitabine;
carboplatin;
carmustine chlorambucil; cisplatin; cyclophosphamide; cytarabine; dacarbazine;

dactinomycin; daunorubicin; dexrazoxane; docetaxel; doxorubicin; etoposide;
floxuridine; fludarabine; fluorouracil; gemcitabine; hydroxyurea; idarubicin;
ifosfamide; irinotecan; lomustine; mechlorethamine; melphalan; mercaptopurine;

methotrexate; mitomycin; mitotane; mitoxantrone; paclitaxel; premetrexed,
pentostatin;
plicamycin; procarbazine; rituximab; streptozocin; teniposide; thioguanine;
thiotepa;
vinblastine; vincristine; and vinorelbine.

35. A method of using the particle of film of claim 32, the method comprising
applying to one or more of the following: (i) a surgical resection margin,
(ii) within a
treared or untreated tumor or cavity, (iii) a target site of disease away from
a surgical
margin, and (iv) a lymph node.

35. The film of claim 32, wherein the film is a single layered film.

36. The film of claim 32, further comprising two or more layers to form a
multi-
layered film.

37. The film of claim 32, comprising a first layer comprising a first polymer
of
Formula XX, and a second layer comprising a second polymer different from
Formula
XX.

38. The film of claim 33, wherein the second polymer comprises one or more of
poly(lactic acid), poly(glycolic acid), poly(lactid0co-glycolic acid),
polycaprolactone,
poly(trimethlene carbonate), polyester, polycarbonate, and polyamide.

122



39. An oligomer or polymer having a repeat unit represented by Formula XX:

Image

wherein:
G comprise a first group that is convertible to a second group different from
the
first group at a pH at or below about 6.0;
R2 is selected from among hydrogen, a straight or branched alkyl, cycloalkyl,
aryl,
olefin, silyl, alkylsilyl, arylsilyl, alkylalryl, arylalkyl, or fluorocarbon
chain of 1-50
carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,
arylsilyl, alkylaryl,
arylalkyl or fluorocarbon chain is optionally substituted internally or
terminally by one or
more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono-
or
di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or
halogen
substituents; and
Q is selected from among O, S, Se, or NH.

40. The oligomer or polymer of claim 39, wherein G is selected from among the
following structures:

123


123


Image

41. A particle having a first volume and comprising and oligomer or polymer
having a
repeat unit represented by Formula XX:


Image

wherein:
G comprises a first group that is convertible to a second group different from
the
first group at a pH at or below about 6.0;
R2 is selected from among hydrogen, a straight or branched alkyl, cycloalkyl,
aryl,
olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon
chain of 1-50
carbons, wherein, each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,
arylsilyl, alkylaryl,
arylalkyl, or fluorocarbon chain is optionally substituted internally or
terminally by one
or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino,
mono- or
di-substituents; and
Q is selected from among O, S, Se, or NH; and wherein when the particles is
placed in an environment having a pH at or below about 6.0, the particle
increases in

124


volume from the first volume to a second volume that is more than two time the
first
volume after equilibrium is established.

125

Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

FILM.~.' AND PARTIC_~ ~ ~ S

CROSS-REFERENCE "1'O RELATED APPLIC:.ATIONS

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i~efiv exy of vii3 Ãou: agents tC3:: tT'C:i:tx'~~'iuÃ3t of d#,svi:1Sc'~' nd
L,o#:1dr~'iiot:5. InGÃ.i'en are
;~e pa:ic pol~'nlcl' based Ai.:3.iis, paS.tI#,."s.L=s,guls,'.in.Ã rGli.#toi.i
X~~
a t'~<} ~t' ~ . : - = .
t ) ?3;as,.#~.Ã':s, ,~iil~.~t processes fbÃ" i~:4iiYt'.n' of i~~eT~t;~. ri;';
:E:t~'`4~.4..`.1.Fz are p.3C?l\ t;7L.77i: f:1'3iC and
~.t:

p#3a`.1~.~:~i ~~i<f~ :~i à ~`~ LgÃl~ i:"I]`si~f~ ~~Ã3.~~, ~Li~F3 t~ t)Ã7i'`.=
(St #e:Ã3:'`..' `~~1~'a'z~~~Lt~t~: :{Ã~'zaf~s. ~~~t3 a Ei)S
2:3 shL'., w:ii':re il,,~ rd<'.'...~~ ~f fl.10 o1yL'= o" more iÃ.yY:'f.`ai:,
from the fiihI:3 or particle is .iT~nAi.ltt:d by a TAi
~:u~ _~' ' ~,codls~pradal-A#:, pc~lyn1et's.
+,::~t[zt.~, ~ x. Also provided .. ~
~.


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
l.t;: w7e:" <3s3i..~.:.. the Ea3'#1Ã~I~ .~t..Attlk~Gs t?~.i.~.:Ã3#.~#a~s t~r
P<3li.am,', s `~t.#\ #:i'~.*~ i.. ..~~'?~:~:EÃ tl'#1f."
~ .
:nted by Formula XX;
FR2

f+ v.,~ ~
..~.c.-" .\
t;Ãti

"1 .a3M OrP0l~M`.1.;PSs Q i~ :?dCdei3 ,fr'L.3~ m-no?~~0., Sg Sc, NIsa G .~s,i1-
lZ.+==tG~d
u ft:3#n w: on .~~e i?zlo`'i zg > E`u~,:~3.#'L4=

3. y,;

, ~.-=
~~1 t"'~~= , ,~=` 4
R }...\~- ..___ ...~ b~ =~
6 tD
R
R= Spli
~., .
a.=~ 1` ~ , ~. ~~ --Q
. ~r+ 1
jA ~-~~ j` ~=,~,i a r r,~~ ~ti

Rk R;j
f,
.: .: t~: ~
.
R?
= ...._._
~ ~k rt ~~ 13\
;'
i~ R4;,~ ~ I

<3 C~a
., .~ P,tr % =,'4

R^ .s sc:ea`A fr.s92a;r#md}ng h`edz'f.~gG'1: et-t sitI't33wTh[ (?I' br3ncheid
A1', cyWAti i . e:iil EIl,;=fz'#.?.,
1RFl. ,.1~,'a~ r4.lZ'izr~r c <~?k~''~i.~.~~j'E {r ~tw~~1a;~.Gy z~g , . ..
..^,3~~ L..i~a~r~iEa> r ~'~ =c.; . .. :;~~ ti .ih.~e~, or ~~~,
df~.r.~Z4~a~~:sa'}L~.~: ~.~:,..... ,

vx'hcxeis: f af_ii.3lkSA, cyZ.doa.[kyis ~~~yl, L.'rS`.'+fm si#yk
alk)'MyE.aaytd.4i, a{kf~ yl1 a.2wylaFkZ `.

o: fl#`at?aoi..'s?Si?on +,.l-icii#i, i:-, optionally sLi`i-)st#tut(:,d
li"~ternal3y or $e#'Iillnall ::3'v:" iy.:e Oi' mut'e
my' c~~rbo':vl, ctEFboxyC.stZ'.i, t:'cLt=.C;f}'i4'2tmidi., .tl:--ztno, #.nono-
or di-
hyd#o
c +
~'s.li3s:#.ru~ik~ i #,f3~i'li.~, r~~1.iC?4s~~L:~";, 7 .#~fiiF~:',
~3~'1~3sA~,#~3-lw. or halogen
is tiele;.Wcl. froiia aamng hvdrogL~#i, mo-d 3oxyf ot[zoxz' amino, a Stt
a.#g"h; or
~>_.~W.i Lbc]tFr..=~A~Z-'~:~ `ka!x'~ ~ . r~:l~;talk~~`. S,ay1, ~~l~..~a.a.<
Sil~r1. i~l~.ylsil~>,, t2#~~~~sil~~l, :~lY yJ;zy;. or ~:~~~vri~lk~'l
L.. : . . .. . .,. .

.5'


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
` {}: 1 ~5 L;.Rtb433:2:!. R,,v Rz.. mnE? R{, are independently w....iiGfa
&k;n. ..a.3om- a

I l z C?r i~rz::~a_ ~`<.:is~i3`, iy(.lL}<}.l~i~'S5 dli~r1 islL?~~3i tiil~t
c3~~!':J ~.~ 3, i~Lf~sÃ:)''3 aY~~ ~''~>~i 3, ~;r
:~~~~c.,Ik:~l s..,hm:i1; 5>f 10 L:&i'bi7ns, .lI?id R=; i33:?i`i R,~ ai:;e cc3Q
`a i#"tdo?iC.ÃEdei;tl) sc.3:s=L`+cG ftC`d};
MMOD~[~.iy~.tr\~,S'~.'=~2sf.3a +t.it'o::3i o.i s~?~~Siil'~.~~.~=~s Ci1t~.~lf:
i:yC=dl.~ci.i.~Cyk, Gi~i~4~~. rilEi'~rSC,.,'.i; ~.~;.
a,"'.1.ilktil ..,.ail;.ox 1-50 U;=:tbons, whereiti cach &lkyl ::ycl<?.Ãlkt],
a:i-y;. t,1cfd.., .lx, v;.~~ ryl, oi_?

e:l'z'`r iii2lki l Lh._zl.: internally or tei'`zI`s$Ilt$fly l;1y ome or F,3o.
Q ~~c,iv diomF'l,
bvdÃC'Sk>+i..tliir, Caibt`xf'3, cc3rbi.ZE:s:.-Lr., tiatb3x4`?;Sm1dC.=,
iiimii1o, iF.io:"io- or aI?"11tli;, ttiio;, thjoc;+t:'=r, 'wiafiiEtv.
(?htJ`phait; ph~~s'plIo"1at4, or hillo, g4"Il sÃ1b-stztuents<

z~yõ#:..yE`wiil,,~ ;k:iG Foi'fl:?#.lli:#
In s~?.3 ~i?.' i:Tiib3dii,:~,:..t the C, rl,.z},C?#~"'z~:I';~ or ~?L~s <

XX':

R2
# \ s
XK

~tfi.Tis.uÃ:aJ, n is a,l !Ã,, tt4:= [~Lifr31I~ 2 "?i~, i3i1<~ %3r A>
i~1i~7':~1~~ _iF~:= or pt~.~#:~
F:~ ~lls:'~1 ~:}~.~ ~Ã,C A:~ia?
..

xtLn31`n<1: gmlio, the ii:.Ã'la,iÃ`al gS,Lp being, 'aeie..=ted itlTiong
el1oasi
has

aF ~aidis, ~, ~~ z t3:~~ s. s c`. ~tYiki~`?~rÃ~~e,~s,, alkenes, and +.~i3~~'S,
~..~,:~~, 4 s. ~
'w"};ni;eh _.s~.~ect, iliU iiivei~~ion f"c;Itures oligo?.ir.er4 (.rr ~~~~~~-
IA,Ã.rs, OT x>c)rt,o,l.~-
;:`lorcof; ttizii {i,: .epr~,:,svnted by Forniu1t1 XXI, XXII, ~..XIIIY XXIV,
XXV, XXVI, XXVI x

xxviii, xxi.'k = xxx xxxt.;'2.xvSi y XXXF F 9., r}.xxiv, xxt1 vp:1.1R -1, V3
or Xõ~-"".='k 4..n.
4


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ti .= _~^ ~.. ~- ,. ~ .
~XV~=,=I
~.
~ '~= ` `il ~'~

~ ~.= ~ . . ti ~ ~~~k+~
\Vt),,~
?,'V. \ 't'`,~\ i ~S~-~ ~~ i=?~ .=~ t r y .
, ". ~ 1,= {' ~ =.r ~ ~.~. ~~Ã. ~ r y
X~,1,i :'

..E~.
~,.
; \ v..~ t~,-V i ~+4 Y ft=. ~ ~t.; :.
`= _\` i { }L.4i ^.` i u..~ .\.~ =, ~.~Y.i ::, . ~l .~ \r f,
\'( .

_-4
h r:;
.,.1 i, }. .. ~ ~. . V.~ . _.
xvtN'M

1 = vt

X'KxZ= r..
{ti= `7 ~.

In Gt.cl3 oh~i{Ã;3t-rs or p~,YI--vI"EIcI's, or pt"s2:loy34s, the3'eot Qr is
?tl:keperidlGtl1 'y St.aet;t+.~'~C.: rI'C5nn

~.f., C~:F i~~,4' ~. :3''~~,.~~=i:. ~ .=o,
aaImF'l4F 0, S :s.,, 't?:I' M l S;k' (3;f, and ,, :~7`G. ~.~f~.7 ~ #ils: ~,
~i=i3~. ~ ~ Ie~ ~ ~.~ "t3 ~i <.~731s3f1 ~': t ~
.{-~~~lowing ;~tmd"Ures:

-S


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
o~ IN

:ai:i{I cia ili'G: not the s.:e.i7}i3: 3~F is sC hai:-lI 31:E}FEx
:iFl:Y~3Fi#~? a s:i 'Ã4.ti or bÃ'a3 c,.#ed. :`+lkyEk
cyclcaalk;< aryl, tz1cfin sily`, alk4fls avl, aÃ'y ~lk::I, o: fl:.E.f
.;carlbztrl

V'haÃ#aoi`3 5(_)bar1,7o#2s >ho).c.w5ci-Fcti a`ki~l, cy\.1o(F~kylti = yl..o
e(}n.:Silylr,. Ltikl4l.sÃSL~lq

ES saÃ'yi3Hyl, c? kvdi.s,.1,rE.. au'x.ci.kyl or fli;.oFf3[;.ii'lbt3i7 chain is
:3ptioi':IN i3tern.,lly Ese-

ten;i,..F'Ã.iffly by omo C.?:. 11-mri' hyrArf.#i1.yl. layd'F'ox}`'-
\'.g...f~er, cm-boxZ}'."a Cf~ailboxvZ.steS"

,, : h"~}
:;tii#"bt?xt~.i~ax~t1:, :i.#?.I~..? Ã1i~?Ã~ii; or <~:ixStl~?T~ttu.~.i~
i3~Ila~ii~.i3, ti~Ã(.` ~~2is3~,.;i~:~.F = si.:lf"a , ..; E.~:`,E. ~.~?..~t~:=.
3'^,,'}s,}5> .~~1t:F~lczie, or ,~,Ã?(?<YeÃ.ii~3. tÃiI3['I~rt~; or ~~ zt is
4s.l4l:i.i Z. ~ y3Ã?:: ~}C}>4 (~..}~,Zzci"EZ'
i zt , .-
HlycE}l). poly3o:hylSne t3tSf e; piy;,`'ffiydrfsxi.'i#.c_1d)) a: a,
pIC?Ãi`.Fi'1; a

ptF(yp:pddc, a#l ta,.lair'li:? acid, a I7tade?i acid, a #?uel~.'t'?tÃdo,, a
pol.,v:i7ut:la.,4}aÃdl:=, any DNA C}i
RNA :'sf:jmm<`nl', a lipid, :Ã..?3i<3ly4..icU..>itii"1d`~..'y an
;:1T:1tÃbd}dnr'. a phtin?le.=.s.'(::].tF.ccii iaz,zF.3iY or any
,
~.~13t1?:}'t' 3~~E a :Y`tt~ tZ~;;#C%tf. Ã#,?Ã::i;?Ã~.~'!"; or ~'~l; .1s
~iw~~lS~.k;~_L~i ~..'ti~:3~F~. among i3
33~'}~3~.f;9S.'i~~1';~~f;.~~$1~+'s.~3I%'. t3
A43..11c1l':y crt3sti?1#}ktible gi'i3tap: R,};z iS :se.~ctL-d f;'f"sm
l`i17.~3iIL, I'1, a siI<3ag .t i?i'

bn.in`i la:df.1kS.yr'l., Lyf;lo~ -kyE. aryl, o3.4fim, silyl, tilky35$ly4,
.}ryAsiAyi, alkZ'}:#F==y a.4+ii3ky3:, o.#.
ihwaoatoF~ cht.:n ol. 3 :?:F , atboÃis. L.ach tixkyl cyc.loalk .~ ar, Y.
:,akfin, sfly:, a1k~ sfly=;

lti ~lcll\~ _ ~' > ~. ~ ~.. ~`~, or ~~it.?ii:z:~:{.'~.'{?:a t'. aÃI~' wh Ãia';
.n?i ;Yc 4t
t~Ã.I'~ i~1`~ <#.~ti~:~'s.i ,~'~`~; ~aÃ'õ ~,i or
t<`,nmfnal.) bi` i?>3(.= i:Ã' ;n'lriÃ: h-.drL'r\ v h\d>o4yetbCr, t:?. b431yl<
G.t6m4e:ita;1',

a`?1.:1A Ã27E?i~:~ or ~i Sif~`~~~t:.~u~.tie~ i.$3.'}~.il-ll~:s. l.~aii~?.~v.
t~..`53S s1i.I [2 ~4i~.E Y ~,)a~Ãi4~+p..e.l`~.E`.;
phi3`,'~.pa`età ~ ~te, or hi3.li?g,.-i'.Ã'l zsub4filue31t.`i: x and y a1'o
ez3eli ?,,3dc-pe#?d:.=~~~y -scles..'.,.wa frfzÃ'1-Ã. an
i=',.1toLL?'L`rZ3f 2 '.5is, a is 5e3`i_:tited fr:'DÃl:l an i3}ti.gfeI of ~ 2-
5v b is *e ,eL=t[:d &o#}'. :,#. :atcg ~.i (fi4 I

14 c ?.a an integer of > -14: wEad i;i:l't:b pZ?l1 rIC.riE:. tl.#.na#:ial
,c.;`: #l Fp issel'+`C:t:;t3

fi-Orn an^o:~g aÃ^~~nc.w, thiols, amides, -~~~~~sphates, ,t:iphatz4,
liydso_~ide4, nn.mis, alkumc:<,.
` ~~ ~,ix~'=Y.
a.lkvÃie.`> and

6


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
3.iA aTif.?~~~~3c'.I' iaspi::v, ttai:~ dF,L'i=latityÃ:e :~~i'`~~:.t.li'es
f?l1gC?'I.:as.f>i Z?z ''~3t`lymnw k:a, or jp~:tf Ãions'

:br:a"<.itle, T'C.-pla.s,~nitisd b4 Y ol"#311dia .=`R~t~XVITT:
n~
~~
t= ` ~~v F , ~ 'f ` .f ~.; ' ~ `~.
'
~
4:.
XX~ VIR

Ii3 Siac3; t"slagox'..1i:3':i or paltn3c >õ Or pC3ilIitt1s fl'i(:.=r4d, Q is
:3I.e1f3ng 0, S. Sc. or NH;

F_'r is s::lC:L=t~.~r: t ~~# a i5 1~.~..~::~w.:~ ? `u`- f~'~?d.Z ~ ~ :e~~iC~~i
~ 'S' t~~
.~.: from ~:i~~#5i.iti% F.\~:,=
L#

1..y~-AVA:~b:i.V~Yl.t~d~~iy olefin, st~1 iy tiilk~') i[~~~~~~. aJ~~lst~Yy
=1~5~~ ai yl.

<1:'A.3lkyl, or fluorC`Lat'b%.'iti tflit33ll of 3-50 cil. lbona3 3v'In#:.3tflZ
R:ziL31 3tkyA. xy{'lt`;a3i.yl, w `;i,

~x~ y` ~ ~ ~ :i s r~
:31~.=fi'T1. ~Sisyl, a~i~',: sl,vi, xords:~#yls ;:l~,` ttl.~I~'a, ail `33.:hj
~, l, C3:.` ~~Li:y,}4..c#~`,~,:1 E~~tci`~t :s C3?3~a(+17~:z~,
subgiWtol iÃcWII l3.y or ldVanki:$lly by one or i:I3:CSic hydlIoxyl, h
(s.,<;xw ethos ..=i:ii`buxi`i,

cait?Crx'So"te ., i'ti3i'bt?xy.aTliidc, m11no, a.iliant,aw #1' d1
si.ibsiTtutod ,i.i~ifl".i3; thdÃ3l , .h;t?eSie: ,
he.3~$d?E , ~3 1?3~'; 334+ ;~~'a'33ti~~.~{F3i i~cl, or halogen
substiliu+::.riE5: or R is ;i%luewd l'I;oITl anlJ.Fig
p<ii E #.`t.~s~:Z lent, `;bynCil po.y(tthyle:il& oxide), pof 4
(bj%dIo?i.yr#c:d);, a c.'aTbo;1' d..;.te, a
~c
Fi7`+at6:ti, a ~~t , a.. a,`:'e t~?? ~J~. ~:=, .-, #.i amino acid, a p~A. C:
~`dI i~i{~ pt~-, a :i~..f; l ei~.l.~Ã:~. '<l ~i~,, ~ ~~ ~?; i..lw=`(? , ~I;
a.. tt.., t ` .o-'
~: ~
: ., r
D%A t3rR;ZvA,s:.>~'.t]^:~:C:i'ti, a lipid, a pt)ly4accha3ridC', .ki, antibody,
c1p}i:i?'I',?acÃ:`uÃ1cii:l tfrfi=1.l`c, ar
k ~ selected ir'
any ~.j):~,,;q:?.. .i3.t` a .3ii..x{)} ~ii::~l l~.=tii~~[~3f or ~ ~ ~f is
5t:la~.~..tC~il fr(3ili Ll;.~~t>l~i`~ s i_ ~t1 E i: A..~SG.~.~w=.
or ionically L:ios,fiinkab3:i:' goi.Ã.p; x and y i3Re cxi(t 1nCipoTiZ`i4FaLlti
sC;i+:cte5:1 fimm an idatt;gz:i
i:d 2 '"i: iistilb.c=:i:d 11:'i?I7` an integer of 1 8> and i sakli r2L;li.3li
z`7i ianI'xik:l ;ro 1i:p :s
tiolec`i+.d ft:7m t:Fia Z?:i;ts zir#,:it;"~~`~'. tl.~ii?iS, 't1~3~a.El+.::i. ~
Ya~af)s~~~':atL.s, l1`4 dTi.?.tit~.t: =~J,. metals,
=- r
;:1lka..tcs. iikcnt:s and s; nmcs.

7


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
a.iloffieI aspect, Ãi,e, invention feaÃu3'0s r;]lIgi3nnea's or pobri'az'Fs
having a ;`e.pi.':<1t

unit by F'C3Pi i`.'Lzi#. XX.

ax~~ _
xx
111 `laCl] 'o1#wor pi3.,~;=rT.Fi'=~s G i.?.clud('.s a first group Ãb''sat is
Q~(}3 n.'z' rt.ill:' to a si.`=::.s.'sild

6 t f`Cxafk3 <3s.tftfLfueià Ef'0f73 thL >iaSà ~;I`lyi3:~.;5 at a ~.}~. at or
bf'lLS,,% about 6.0, such <3J :3 0l4fw` abE?ta
1551 or 45' R is '; LieC:Ã:;d Sra a,nfa7ag hyd:`i:_}4?e:i, asà cafghi or
branched .2a H?,'`l,
~ ycloMiky= a=yl, AQW, sdiAw alkylsh)l, ar,lstr)l, a.l.kyl.atyl, arylaikya
ori:ut? :?i<skm

4hi1in 4>:' 1 }ei E.`:aT=.3C3a4. A.2ai::h cEl`,`L\!'# (.yC:Soialkyi, arV`fi.,
ol;,fi#. 4elyl, cE MgyI`'il?`a iy_.i-dyi.
:alky3a:,-Z.:l, drjlaiky~ or fl:#C,i'f;i,tlrbt?r, chain is os?iit.)13c1al',v
siEbst:.Ã4_aEad.Fnte_'F'Iliclly or ti:.3ET.`a,.l1's.~flZ'
by ceo :3r mCiri;~~~krrf,.f'}'x3 ~}~ carU"(1xyB, L:arb(rxyt:"'.:\tF.r, amifao~

rnwvlE}^ or i.s 6ti. tal ;mÃI,i(~> 1:1i:ol, ,j41[)C ii rq 1tlfi:stU.
phi}sphalC, ph<3sp'"i~i n z3ti:. E?.i.
a#:? itiEliL;lr.,-~; and Q f:= se.e`,ti.teLi fir+i1i`a"i :1Tr3i:111g 0. S, S4,
~31 ,Nll .

1.11 z.a$?,a"`>he 'saspf.4L, !.h5 fcawrt:5 pix ÃiC:lCs having a, fi1:Ã.
MCafnt: and.
fnc.liid1;;"", an L`,:.I`oniet' o.having {?a'pLyatiaif.it tL.p1 e5ef`.4ed.?y
'u:"Ãi ,.fla i:.~.:

F=~ ~
1.

tÃ#'? such pw l#.i;:1c4, (,"i ill"Aldes a ldr:it t-~.,,ioup ii1'c.: is
c(?.BlYwL'>`Ãa~."?l2:' frit ., second group diffoa e1iÃ
f'(? n Ãlle fiA ia n:f i`.up at 3 IA'A ia.f frl` bel?:9L3' about 6M, S.a.E,::
<`s bilo';'i c:bi3i3t 5.5Y 5Ø o.,~ 4.5} R??
is solt.cticl .zi:E=:3 among h,ydz;t)g+,::3;, a tiogy, or b1m1ched alkyl,
t,yci.tstaFk~'Yl,
siI}`, a;ky; _ yl., arylsilyl, Ldk;hwv). <~z~vtaIkyl. u:Ã- flworoLarb.>n
chair; of 1-5.; LFaabon:~-

::iliEyS t V:%3oa.i\y~`a Y.'4'l, Z.id~.'.=fin;s tijiyi'., al2' yF4:lyl,
aI'yll'iiÃyi, t3i.kyacarr ciry#a3La_z3_,or

h<<dt'o<<yl hydror. J .<=ffi.. `, ca:boxyI, c,i rbox; csÃer, c.Cz:
bo~xy:Ã.ftdo amino, i;'i{371o- or Ci.3-

8


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
:bs,itwe;d wnum, :~iiol, Ã1hicrosÃei=, sulfate, pAio,~p1:at.e~ ~~~~~sphfn.itc,
or
~
:iubst.ft',ic;.nf =+, aÃnd Q is 4elect`o~i frL3st7. ,ai"i7t1iig 0, S, Se, or
NE';.. Welm, the paz #.ict.; is pl<3f'.:,'f,
ir, an aMv.irOMInen: 11.:ving <i pat :.tt .}r below about 6-0$ the pi=..~~~~le
tt,cr..a.-,.;~ In vx.zlurne

:iv-m the fitsl vE`ll3#:14; to :.- s4=oii12d v~.~lita"1e tb:it is Ti-l(33"e
tlaan tv'o ti.Tm~ theifÃ"st
equiil.>..iut:? s :;~tabl}s`hed,

p(3hn?'1eric, .<.ihn, oa .z3il.z ,.iL~.G~ Lill fTi{~ilC~~' ci11S`
(}K1~>?F3`li:'.=:' or t i'.z' i~o~~`~>'~.~~C~i.~

h0vn'mil. In .toiiE`e+ L.~~\f2A~v4+=.T~.tx3e pLTly.tRi4;5ic particles
lllzlude Ifia>r 3=\*.'l1.i%!l~l.~T at i, fii=.t i}id, <zm?
a se.,oni; vo~urne at a s;.:ct~~id pH, d;:k?it ftt?m the fh~3::n tliw first PI-
1, For C'marnp1c. tli~:.

Vecz fi~ 4 `: vs,:3luiõii:;= i,* IX or mt?;C.' tlii#.n tilC: first r'oewhti.i3
ft%C,' SC,cs3nd pH' ,s i<)w-eE10 ~:'=i~.~ the fin'A a, :iiaL:h cls 4X or n-
,,%3i`c greater t1tal=3 Oh+.' ~:? S. ,=iti3uITa4Wi1:.a: th1 sec.s;~kd p3 a lS

' ':: ..' < c y~::: ~~s~: ~}
lt~vvQi ,~` ;~~::`i the first ~~f:[. or 3 ~X i~:', " ~:r~~r~: w7rt:.~itw.z~
than tIi~: ~:~itit v~~li.,:no ~ ,~s~~.ra. :~ s... ; I I
is lowt;;ri;le, }r,sT PH.

A13,~,' .i:n or pi3:I.1c.10 L=iii: lncll.tde a L]i.~ra:pC.Y.4tlc ci:joi1t,
For ex<3=3..?.e, fl1L. i#..wt.,.lt cii:o
bti= a b:zi;lo M;.c;.illy ...d,.tive agent oC?b3;1pmS;.3'1g one or I1St3i'e of
<I.n x,, i.Ãz.t, il:i~.,unt3'-
sf='~~`
tr i.lÃ'~,'i~~t r~<. .',`i~ Za.:l##:~ <?i a ial agent _. ~E15.,
15 :.~.C `~ l &; an. Lin.,;^'` .~~. A ~~Zi~.;i'~w; ~ = ei3r ~ YcrL=sIC%, an
t: ~ ~i'~:.z. ~. ^~3#~. z.=..

;3't?ua3d hu<l,ng.

For cm:aipxe: ta#e pi.#.il,cles `..il,.a b:: used ft:i` applying to one <S.I'
D'it3ru of .he
' C? r a si~~+s%~:t~l r,=se~.iii;i t,iai'g"~1~, (#l) S=i'Et~ilil.1 f.~ i or
i:~ilt.~.~=c3~~'Ã~ ,t:ai:if3f:
foffla.brl; t`; .
?~
i;iS r y i`a.la3 a tc3.t'~,'L. ~~Ã.tt.. .i~. Ci'.lse.iist: :ls~~~' ~~'t3iTe a
si.#.i;Ff..ncil ilicil"g+:1, :litd (is), a t.a node.
20 ~i ~~1. ~ ~:aS,:F~'.= fs or a~y i~iiZ:<`~:Ia ~ ,~ Y have one or i,iorC
l<i~z.
'~~tax 45:
~zi.~ ~~:u.~~~.. a ~.~`~~.i~tc:t~<r or 1Ã;ti:~ t~3.iri wE.}0 Ã1~~;~c>it~c;t~:'
sa ,t.~c ~~ as less '.:i:in
i?: 1.j'+;~ ti.~.~a ~.0Ã.1 i~;.'..i{Y;~i~#_t:t~.i'S. For C;:1"ti1] slt. tii~'
~:;if~E3~.=,,i~S ~,iiE` :i
2'> i ~~zi~`i<32] ~~..t.~.~ . ~ ,=
. ~:r

clIziI1i4t.Li 3fiF:.E'vve4xn abt?%a I num aa".i{2 2 'Tnicit+i3s.

Any of the particles [:L.: onb3.:d herein can be applied at a iF:it ~ite,
s.d...,,.~ as a

25 surgical 3 nui1"Ãõ~ii .i:.ix ~i~'i`~'.i~z are 5;.<~i.Ti'~7'.(a by the to
tl. ;*4.%.t3~'nf~ 43,4= Ã~ t_st"^.'i >?x]i of .~,L, first
si tL, slac:.7 _'t", a Nip.~1 I1ir(ac. hi zE,3dii it is deS$mbl i.`. thcit
t:he v,.1;t:4ks iha = Ga d1e.0110ze:'
f3f lLsk `ta"1kn about 250 r#il.i7:`..il'a4=ti,:rs.; such as less than 100
nummGEe?".A'i or e!=t ri less +t.ham 5:;

In moF_lto., <t;ipec.i., di:, iitkiontic.}ia ti:attrcy app1vim" any Jelhnn or
pmk.iu:c duJc2 ibeta
w~õ~ 1-w,ei''3 to a 43~; i1sxT4?gST:tllreS 4tap~~.c;+, aI1d./C#i' adIlesiveS,

''s:ii ,.:iio'h+ tI1C, 1i'AVet7.t:Cv" features applying any fist2'i or
qy:iF'tii k f1[;"w,il;Ud
{'~1


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Ili:=r`4'#.;. to t>t.`.iipa1n, ri~ to .iltu hecllÃng m.=.g , to avo1dSSwca2
fs)"`i1.i.tt.i2Il.

Un~ ss, ~:pLc?fic defiÃ.Ãfion`i are pi'i)', tdL,d, E. g, s?s,
aÃ'ii.FÃ.c.3Ee:..~~ below, th4.
':izme?;cht1..'c used in r:{3n.loC:to;.3 with, and tl]'l lkbC?r:itt:: Y
Pd't?'4..t..=itWC', and Io-,.i.l.a::qll,~S of,
's.nG=e; ti?;,.,=ii a,h(.;3F:ti.ry, i.?i13L,'~`'1t::Ã;7zsti'y> synthetic
i?:Ã'fwi3k!Ã~'v obCmÃ.:?f:#"4 u?'zd ,edii<.naE <1nd.

,>~~: art, In Ã~~~:?i ;i=`4:Iii that
i..~l~."i~~'_ ~.i~:'~L,r~i~::~a E1~'?'e.I3 are those known i?a
.,
flac3.. 'ss a LIrafA,~ t3f d + fi..1.:::L3.2s I#:3i tr,rms ltci'e.5r thosc In
th15 ti.'.t.t:i? n pre va`I.
>~_Lt.`t~~ 'I'of;?~. <l.i`#.ei'Ili? a3ct.s, and
As .:si ?d heiemq th~:. ? ab~..~rf`+;`icltil)ITS for any }. r p.i<4 _õt~ ~

ot` t:.=ennpound~s .;funless inÃ...~ilci1iW o:-hÃ..?z.1'1:'se, in accord
w_1tl ;}:Ãcià v<?mmnwFl ti:i go:
ii::t.ed t.ibi}i"1,.viati.~;c.sn or sh>'. ~Et,!PA1r"IUIBOxanni.ison. oi2
BeE.YL,honica.

1I'942-944 (197;~?).
C
r''3.:, ~.;~L~:C ileE:.iF:, Ã:4t; C)f the siea?g3E`tc':' hl4'.$2.d#:.~ tho
Pli:ic3l ..lezC sp`v'clfiu,_ll~'

A4 Fd`?.:d herein, "or" ~ilt ~f3~ 'i#Ã1C~: Cx~tr? Unlt?4s stWtcd
t`..h%=rwsc. ;'urtht.".F~~.li3z"e; u,c;c
of the ti%'run "including" `lr't fl as 4>ti3t:~Ã' fo.?38} such as
"1mliie.ies," i::i;.c

lirdfir:g:
A s used h.i;i?=i, the. terms "treating" or "[roxtiT34nf'
w'I1L`;Ã.?n'3'?,#s': cit.:~er t+l b?ll-i
3 es~.~3?3?itii~'a= 'm1l P#'.3pr1y9c$xiti .-i7ca4Ã;;.i"es,g., dev']gi16l
tt'31`ililbit, :0knv or E'.c oÃAs~er o~N

zI2piu:"f3.i#3 u.?.niScs:sv<?r iIist?#`dvÃ, z:t:hÃL. .vc a .ta:1 or
p,.itO:;..icEl;;i fiS'`:"i of i:~y;;',pZ;:2n1 C>:~

d'": ' s'~:~, ili~vt . i. to ~; $ie, ,a a:~i~.ÃL ~ ~lH+ "`fV. ~~ ~ ;Si:3, i:
Ã" L.~tÃS'i: a z~.4 .:~4a= or a~; ort~cA :?? ;~-~Ã`
.~.. a`;r~.: ~~; ' ~. t ~iz~%

its syn`#pEo?its.

:~I?~ ~f'z`Ct't~T..i~:ti?., of t~SL~ sõ~xl'i~;3[C#3i'i:s i:pfi- particular
d.sE`+z:t." i?
As used .i`,3oa~-.: :,,a b:
<7.d3....I2a`tnat:oÃzi. ol i3 particular t:.(?inapiZl.ind or
phaan1i1CousTL;.?l 4:rlyipi``r`atton refers to a3iv
Y Gi:., ~ie$w~.~:i., ~+ #? w7s~'f, SSi}4~'iIÃg %~ f l3 ( 5:~3 ~ tMÃL~;1, of
<3.Ei ?.1~:~1A
3~hS~;~f~~iw; of r'.~:i~`y delay . . . .
L.:

C
s~iI1g ~jr iI<3n`ii:ai~. t:'t>at c<:i:'3 be 'c.'`sÃ_,b't.ÃtC'zd ito or
3~'3:+..~\ s3L~I~ ~3i.`i.#s Ã}.~ tt:l:i~i~~Ll~.i`4, li]

z:s..o6:ete-.t s,.dini.}.iat..ti:ctii#n rii.-IdIS: oC3m}*.]o:1xT.d or
c`1.,9mpos.ibou.

`~'~6 As used E'1cÃ'e:n, :a1i' `;~i`t7..., ` s1:b`eCÃ" is a }ltii":1i.tn or an
aÃ"1.Ãmdl, f:) 3i.:li.ly c, n]anb31al,
<EaLi3 .a,~ i: cow, h'..~.Fn, dC t;~, Li.t,p1-, 4hE'~ep. monk-C:ys or
i:)tl1i:.i' lixb)iaEto.y or t.t?.I-nt:=st.S..iLiS:i.l
s `
sZ:~:i%~~1i1l. As k.~e`.',i~ ~.?E'a'vil~, ~.i. term "patient" ~ includes '`s'
bÃAXn':.i 'c-1..`. ::i3.~.21zi~. sub)4?s:'ts,,
{
As i.\od hi`,,''ciF3, .:tL' :eÃ`Ã?I i$:=firl's t] a compound thi!.t
fa:.Ili~~te:i :,11.0
.riC:uÃ`p+:?rat?f3:'#: of mitt`itf"' t'f3]?:ipi3-i3i1d Irlti? cells or
tissL7C:=s, For oxi~mpic, d?:nr.; h. i.

f~_~.is'~~~~~ is it:,{?T:i.3i i3?~l; used t~.?'3"~~=I' tbr li',3pT'CSZ?];f
~:"t4izÃÃ?)itt.3: if of t,~.; t~sà f.?'5.'.~l1?::
ci}?'3)po.il ds Lt,.i``s or fi:?s":#e5.

~ ~~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

y i
As ~],:st =C~ '.,`.Z: tE'I1 ~`3~`'`><?:L'4L#t.i<;e`.il
iL{7`s~1~:3t~~;~a~Ff3:Fr:f refers t<7 a a{#f."f>3#?:.i'3.;
f:C?l]'iv<?i73]d or 5::Ã`1I1p3.?sit::<Jn i:F3p6bic of inducing a desired
;hc#"+:peut:c L..c:i:tsi{ tF:-'>:F.t~~mt.
wni3.hi i.:#7Ihi?f:xJ114i1t'~-r`, a p-hiFm7af'cf3t#L;:3l cC`?:3"1pC3FsÃtioÃr,
ci?nta]t::`, i3;t~ aC,i#vE: qgcx'ai, "O?fC:h #S

ffiFw i-ge;:ts flilF3t 3:{:i:ix'=.`ti t:w dE:sarr:,.f.: :hvfc{p'f-it2C:
e.f{C_ct. P}e .?harmL1w~&.al

0 can co1:tetFil ~a prodrug of the herf'i.{l, Ix3: ct.im3:1:
emb?da1c3+:'.F'tT's, a
'uhi3nmaf'.i:i3###;YFx if~ 3'~?~C`>~1`t~f lr LC3I?.~i11:I ^.I)i3L.+.F1tf'.=
tI1s.I'f"',dxC:fnr.t:;z s;;#s..b as, .:t3F L.xu{a?pley {.mhÃf:fs
and *~.xc.lpiunt:y.

As :,~wd he:i:i`r.'#, tht;li;m`t "thE~#".~.pC?ut?l%%'tl~~ ~f"Te<:;..vÃ;
i#.Falt#'i.#nt" l6as to .ka art"sE{t.23`Fi. of
a ph>z:533a ,~ ..~~ ~ ~~ ~~.I~:s,z cti~r#;"iI.t \ Z ~ ~*~.? {lE:.}ik3:.if.: a
:::f, '~s7if:i: S f~'i..~ r+; ?i.#{'#.:G: e'~.i:= r i~`
41~2{,, ~~ ;~fF~~.s~F<sY.~ f...

As f#`sedl, s eF"C'3'i# t13i`= tem, "~.~I':t3.?'#2'tai.vutct{.~ly
ai.'.cepfablf .efe*;:s f;;) a ~5oiÃ'z~ul<ItiF:Dii of
: f;i~t7~~i5:.i]t.~i i~3:F3. does not s1#rt1#~~4~>:1TFt~'~.~`
c`'~~~af)S.?c.#ti:= t"~?G ~~l#4>lf.~`si:`e{l .~ti.:t#S'#.i\', a

~~Fk.i 17.z%f C 3~3}?~i:l ziC:ilv 'v wad,=?# other properties of 0'lc
`~.'t:3Tt'#:pt3ii71d whi'.=Ã'i "hL so3'1-y:i?.Fl<1tzi'.Cx
cf3n1pi3::nd is tf` a 4:Il~jmt In t:ettdii.T oa"ibf?dii?1at;, a phs.3m 'lx{-
.e,.#..a4::ail`t
c.ica.tptablL fbmwlad4.'s3 F doc;3 >}ot cause s#~,~;ifican'e iFTit<li..-on to
a uFb eC;:

. .. . ~ ; .
r~y used ;?f~'+33.i?F~3~A::f;;2~tlt%CLItt.ull'1' acceptable derivatives
f'~~`i3 ~,:t5?:F?.~~;t.?F'1!~ 1#?c1#.1~:?v _,:;
axti not l#ll t < f~ `~ ..
õ ~: t.# 5, c~C:.f; t.stC:F`s.,
~ 't j;~ salts, asx~~.x~, f:~?#1. '3 eCh'.~.~:i, f:*~ZZ?3 "s. a $<aa.~s,
k~:::'i.. ' 2ls, 3t ~~~~?'~.F~~

r ~w '.
ai:'.ids, bases, solvi:te8, hy&,3ke`t, a'E~~YlaÃif'f#`:, or pr;,3dEftjgs,
t,tf,:a
.
S-iwh cif.fiwitve:: can be readily prwpatsd by t~~~~e of skill in tx?is arl
fisin~ x,?; min n?ut9.Fo;.~s
ffi:- such d,..~iv.btif.aa.-.+m~. The f:cainpoond.s pj(,,slucoP..d ca:i be
<~~~n-fim;;ferud to .F>.,:.naIs or

h# `.?i.tl:k 5>thikin Si1:l;ad,d:i1.:#x=il toxic i'~~f'c4t:i and either are
p}?#ir#:x<l.:=eutIcall~~~' a4tWG or . :;irf?
,?~?t3..~1~~. ~~~1 $1.15af 4F`3L`l:.?ti t.it',a:Qpt<1.?lf' salts 3t1t:lf1de;
but ilY"i; not :li':]Ãt4d to, t:nti.i'.aL S.?l>:<11
sv,,f .? aM bL.f n:v,HFf]'11ti;i e.o, 5:~-d:;ri.?pi;?;..a?nv, f:hPl3.tit.,
~;~` S~#~?411! S ; i i~FY ~:{At t+F:3 ?':?i~ .

i~l~`+~1 ?R ~>F~~f~ ~23i71x~t fi. Ls~~1 t`=tAi>t3{kl?.i#:i1~ ry~
\i.#2'imm"ES t, i3.4~htaFxo1:3#?3#Fac "iIFc.3 other

~`i?~.~~~=.S:tl?it.~?#Fz1F f., g~t';tc1i#?~. ~-'~~;:i3:1,~=z
}~}1f?Y~i',~~'2'~It1~?,#~Fa'. ~-F~3~1F<? ::~~~{3#`-,~"#L~Fif~.
f}1ok4Ylami?ls= and i;+fher altiyl#:mi w-`F, pip.F<--iZiFtf: and

illkah metal ':iS but :.3t?t ll#:i2EtEsi'- to lAtb""I:E.m,

poka-s"'#trii and 1t?d:ui]-iK %Fl[!w[b.in Z-wtii mwta( wl1w,1t.]., lf.tc7.t as
bNCnQ-it S{Eniil.f_, to bt].(`.{1:.#?i 44>.if-'#YFnn

and {71:Fa;T.i.;4.if{~Fa, .. 1.d-1:~#t#f?i`~ a31~.;::~~: .<1lfS. :aLi4.1'I.
as but #1(?t~. l..i?1.i.5:`,<> to :t;#.', .. ~~F.3~:i3 c?th `=s FT3oE.a;
Sk{>t:,.:
sF~,+s,~.'# ~ z$x but ` ^ t~ ~.i;=~t ~'= to sodium ttiT~~i~'C?#~~.# ~ Tr Z ~
~~Y..{,ti,? r t'~li$.<: and ? o .#.~ ~ i~ ~.~ FS..~ ~~ ~3:~Z~.~:r'~. also
~F;~t ..~.:~f~ eY, 'x~#`.-.tt~tl. `1 c3.i~~ #.i..t.
if?LWi.;:;1#;. bf;t not i{m#lfsfa t:?. S-.lt;, of 1'-rdi'1c.{t3.a c3:'l:ida,
~*`.s13Qh LIs b5.1ti3ot 1l1?'1#.trd to
;hy~LÃ"a~~:'z`F~f1F7t~.:k and .xili.3 s<1~t5 t~.~.f?i``~a:i7.tc acids, iu+i7
as but .,#ot l1mtsa:r. ::) 11


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
l:3ct:ates. Inals3 w6, tartrates, citrates, c14ivE5i'i3c3ti3ti, '`.'aucctTls.
tes. ~i e`, I c1::~S t'ale, a;v's ci:1C:~
fu_T+:m:i1tC:S, Ps3wirna:.Ei;:C'Eifii,:al9`v acceptable 4ators include, but
c`~..#'t: :1~.~t aÃT.".(2itiKdw, i:gktl, eifln.c,iyl.
alk`v:1yy 3, c `v:'yli '`i4tfi::oz3r' bly aTc1lk`v'l. 4~ t, "+~'. i.~k "*'
fi;3Eil,"E i ~'l t f.;;~r:iv.+ Cs~w.;~~,: ` `~:~if~:
~7C.~~i~f.v~'i?~#ii~+`3 i:~.~t,: ~?i:`~t{. ,. esters ~ <ai.x
groups, it ciudiiihj.; bu3.:niSt J:a.m,:t5.`d ti9, c~rbo,Xwyl1:c :lt.:id`?,
phosphoric acids, p }t,14c, 31PtiS

4:.dfCkni+:. acids, s&. fimai: acids and bs.?r;'}`.lIc acids. Pharmaceutically
ci4ceptai3,.L . '`~.'~i:.s3l QiI"i.::.'s,
1#.LlÃ.tek~ b1Ft i:Ãm rt3o": l117?3teci to, derivatives of foE'n.i'::#l'rl C
CZOR.r where R is ~3? ~='~ifog~.`Ii, L]lk;Y;,
>c.:r rwt ~\ >~ t ~ ~~{:....~SC?~.
;
cbt~tt.I,~`; i~;~`I?' aryl, }t~.::~>r~?>~~';i''l, cztf3lk'v, h`v~i:3't>aTs:l~~
.s*~~,> i'~~.l~ .~r ak1r .# <,i' ye: ~E>>~~.
~ , t
c~..e4t~tii::#le enol esters IIiL.iI#: , ;,?i#.Ã il.l't:
3?~)t2.#1..3.1~.5:=i~. tC?, ti~t.L~a~<iit~.v4~,`.~?a=..
P~?.O,.I#.~'1'e.~t..4ii t?4;.': :~lly i.1
;, r-mWa C -C(OC(O)R) wbx-e R ig hydrogen, alkyl, a1kenyl Ita~-)I,
heÃz:.r~>A1t7~11,

1i ~ > = `4';-' l~; ,~:,,.~, ~.tac. ,.`~`. ~ j i
~:~ ~.}~i:~~G~.~~:~`i; or 1c~~~~~.s~:~~;1~~;. :~'~r,~.~~~~[3
<~w~.:,.~~~~:t~.t~. ,>~~ wÃ'es
il;3d }1vd#.,..xeA are c,f3I:~~"' >3lt~:4:erof a i:=4,m?,pouT?d Wlth E?iri:,
or f.':'2S)-to4f?kv;le or w,.it:;=T mt..tl'':`.<;iF~C,a, ;iS
i.o about 100, or I to about 10, or one to about 2:t or -`, fiv^,li eÃ?

tt Alkk::;r :a? "<'3x#. >t31.?hafic hydiC?Cw1etxm FF.E>u"#;f wh,.:h. can bi
,.Si'.
a.z.#!'# ag, I i.i? about y`.3'+~a' ~~`~:t'bi?li atonas 1n the i:=hc, i11.,
w]d w1h.2E.h pI"i'.:#L. abli+ .`l, t%e

about 6 to about 50 'L'a1'~.'#t?Ã':ti iTi tt7e chain. ` Lt3wif.? alIfyl"
I'6er_7 to ;Ln atll:.' ` w,:'[3tlp having 1.
4i? Ilm"LIt 8 ci?R'bZ?.t# :1tiF11et, t" ftij?ca iilii\lee refe1' tC? :#t1,
at#kF ~# ti?up having about 10 to al;:>ut

carbon atoms. The .1kyl group mtl be optionally au`t'astimte,,J w=ith, m.% or
more alkyl
group s1,;m5fituunts W#.?;.d'i can be thÃ. S'L?nlk' or s#ffI,A'eI.:,
k}w,lcaf. "s.,3k4"l group ir3c~`a.1G.es x?nF.a7i?.'zI`a'l. } yt ^>o:S'La,
i.liki`x,`r', 'i'3:['ilE??a;.`, a.ki?l+3Li :lk~ltliai?.rZ.~thfi;t,

20 malkylo35.y. GErt-~.lky:i.F.ti[}> carboxy, nikoxyc#.3abt?nvl 'C3xv %',1ttE
t Lyi1tSalky-l i.bw=.if.; can b5:
t?p _io11:?.tly F;3sm;,'d along t:`e <3.lk;)''a chm3:i1 oI?.t:= %iI" more
3x4ra'e.., silicon, 3*:.~i1te`, i?-r
a~`
l~`,"+,.tiu# Z.,~ t #...~l5yes~..tWtt~.~23 # ' ? t'~.i~~x~:~y wherein
t~'#4?ii:tI~~~'~=d~ .naa 4 Ã-~".s~::L`tti~~i. { i.. ~ lf~t=5~~,.
ti\=F-iZi :-~~E ~5n~2~.~,',~~~ L~~s. 'Y L
ti;TF-

ala:yl, taBr3i3'ahL`dtt rLAC1` to an ilk4'3A gTi?1Ep in vwh]tih~ lowct akyl
`;r+.3L3~~~ s`alv..f:i as uactA`y l.
-, include
ithyl, or p'tt nyl. attached o a linear alkyl chain: :x4'1'npli]ri vmmps

m3..ffiyl, A`.'.ix?y.i.; i-prL?~~~.?'yL, n:'.bufyt ~~kftyl: n"'per#tyly
hepLyll, i;c yl. decyl, dode4yy.F.r vr#.i..SoJy.Fy
x g a..,:~ c?,.`'?t ., . . ,
.l~.~t~ .?~a..3~ ~.ibi3. or straight
~3.,~Lri:~iC~b o a` x s~ , ~rir, t~~'Zt~~ . ~ r~.. ~~~.# <~lkV'.[ groups
~#t.~.~..
,.~~a=~v 3.af..'C~3..S,.'i,~~i, ~-~ts~. v õ
~ ~~.~~ '~~~ 1 :~}
l 3, ~. i
ca~~~in.allky; gx.?La), ~ `a L.f 6 to ~ 50 ~:'{:~~?c?~~. and v:~~3 include the
lower .~lky` ~~,F. i. ~.
f~+~?%~~ ~~=F~ 3)~#y t.#lr z~?1~7 t %EE~ L'~ ib~"4`1~3~T:'s of if~~1CsL1~'.
1..' to 4r~.3(.1t 16 v:i~l`i:~,'.?`a.

1s.3l3iw'?ayl" re:var,I'4 to ,".l,Fa alkyl gr(x3'a3 ci7ntc'xli1in4.:.a~ least
i?T.?e R.ai'bt,I? E....`.'bo=3 di,fe,t?:e
.~~.c?nd: `l.':c a;:~,.~myl. grt+.~~~p can be opti.c:}iiully ;,mbsiituFt:.d
.3.i1ai oine or :-nore ;ak_4ri ,~;Aoup

12


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
si:~sfituenL-,~." a ,,,.cmp1,jy xitkenyI groups incitidc: vinyl, t1fly1, i.-
penten,,l, ~~cc,my3,
docleÃ.vriyl, ld-radec:t.d:tnyl, he~.st~adc.c-8-en=-l-yl. and hep.advc- 8.:

:Aak4'n'S r'c -,elk:e13 to ama ixlky`1 gt3up C;onai3:it1#.l"lg a i;.ubon
4.=zex`b<?n i:iple bf3...tS `he
yC3up i.<ln be (;ptio#:?ti;lly sFa~'.?vt3.t1tted with oriu or ;t7od-e
aLa.iiS`;. g`::ft31? ~=~S~1Lxi~:E~~h. <
zlkZils.; g
Erxemp1<3r: a:lkynyl g:~ours include efhy'nyl, pt'op<zr_gyl, a-pmit; tix:1,
dN<3nyx5 and
d;
.?E~C4..L~%~'ii +..~Sw~:E`a;, i$~.~k~`C!3''l groups ai1Glt~(~if.,~ ~}`=
lf}~4G1` i~i3k~raettl groups.
v = /

T;'+,:.lo";Ilkylr> 3'e rtõi'4 to a 31on-,`s?it,~mili.de mi?ni?, or
i23I1lficyw:1c i lt 3;i f':stC'r: of aE3o3:1E 4
to ~~boul 10 ,..:rbc3n aEoms. The cycloalky1 grckup, o4~~i bc :~~~~iont;ll~
pakba:;~y mmwair,xtcd>

Thi', t !'t:l2`c&.kyl group cm>. n s:i:?3:? optionally 4t.kbstit'.1teE.i with
an ilry: group stabstiti.iC:,i1t,
omfs .i'Ttd;ft3r 1,.k1'l'iic.. Representative mZ?i'!<?cyGl3c cy#':lt)eilkyl
ning4 l;i_,cl:adw Lvyi:.zi:2p..`'1ty;,
-L' t.~14x4 =_ t~,t -`:~a cy~ , .~`~.,l x~.~~ty'; '~,.si :11.l?~li~:fl:?~.L't
zJc c.'cl4s.~kyl rings i3'.iS..i.ide adzlrl3ilntv45
i:,E.a,3

octi2hyd,(Ei=?.a1li3131ZJI:~d.Vca""'ii]y cLx:,[}p"nÃii, S,lampha12e., and
iAotsaVC2.f'. -nmaly2.

-.``i.2yl?' ?C.f:+,'=d=s tt,? .xni1mn;t.it: cF.ibocy+.==ilc, radical
containing tibC?i#.t Sj to a:-xwr 10
E'r:nT.b#.}n aWan: I;3't'. E'try) group L.=aii Lil+ ~~~~~ionaxly 4~
bstiLuLt:C3. wiil2 linL i.1:y& g;roi>p
Y~,f L=ti7~{r'~'~.i i ~?~~~ si.'t~::'~bi` i..#w..~i.~L~:vS
1~. ~ } , ~ t ~ ~.~ c ~ixL. , sC3~.nY~.: or ~.~~~3 S~i.~:i~`L_.~t-.
~~f.tz~.3:=f:~ tLt3~~.i", ~
.~~i~i~.~ can

:ky.E 3l8en` 2 :1lk'i2yl4 31'{'>rl} arc~~kV, hyd:I=(:xy. AoxV, ai G'lo:'4:yx
aralkoxy, carboxy, .:fr(3y3
halo 'a>Lr\}+. tl'a.haiomeihyl< c5fbii(oy d.".~kox't'earbC:ny1, ai~~lo-
Nyeafbomyla.

i`Li:y, m4`K aicy?iu?l:11c). an3$`ai.#.rn;ni?; ci.3'~..?ui`[]:C]Yi=
:3:.ik'5lc:'FbamoyL C &;r1C.c: `i?ai ioyF, fS'fth1o.
it.~ky..ttist.` az~ yli;ne; and ..^ NRR`. wl1eT'C' R and WaF"c Z?C:b

c#:C} l, .3:l.~d ai adky: E?S.empl.:ry aryl gg"{_1ups include substituted or
u.:t~.:>l1bSthut...d phonyl .F:i~i
sWbs,aitiÃ:Ãed or un~~~ ~~~~~~~~od n.~~~~~thy1.

"<Yi.cZ.'::, õi.fLi4 :o aii T.'7upy b?b'l'1ciC;in alkyl is as pf;=Lvious.y
dw::iC:r#.i')ed=
ai:yl ;;romps cf?n1j.,yr.se alkyl of I to about 30 carbon atoniv. Exemp1a_q s
c:`s'j

4 t),#p e i?s.Jo i1"#:clI#.d.L- cfiL`,Z lCO'], pr43p+.1noy ,
2^mfi:dhylpfo})aIaZ?yl, bi.Etano'y5, a"iia. pah'n_it#,35,'"=

,f~.~ ` ~~~2a,~;; v) }` ) ry~~ ~ } x~= 9)~2S ~y~a t~ tc [\~ q ~ Y(`' ~}<
t~,`+;
~Z%.=i lii~L~.~~l11.t,'r t2ntYw"t4~`.-~ry.'k.~'- 4.~.rt)li Y
Y'4~.iS.6=L4+12:f1.~ Y~ 3~Lis ~.w~i. t,it.~ )'.'`tdY ~24s~'..1.a~:i.7.a
, 4i:mp~`ri. y aroyl ?4 ~i~ic=i~<~e ~3~'?~.IÃ~~'la and 1- and ..
t t;;
~! ;},!~23SZr ,~~1 C. ~~',..~.s .l 4~2}k~~l.. '" . ~_ p,~3'~~~.~i
~~1~.~:r~:z", alkyl is ~'~~r~;z'ic3:~s.y ~.~s~.aib4~.
,+.w ,.1''i~s.

.i :`c.ori3plarZ ,a.?,kovy' grE?i.lps- ÃI].cIL3iic nwIlhu-3.Z;~ ot'd7oxS`. F,,-
pFopi?xyq i-pÃ`opZ??;:.s, i"? bi7:i.?A1%, a#.~[3
;10~:t<3x s<.
' Arz loxi F` ~c;t-Qrs to an, aryl-0- t:r.3iip, whei-e::n tlic aryl ;~;~~LZu s
is ws ;slvv3fft~~ly
dcs;:nbed. E:.~~in:~lar; aryloxy gro-La7.)5 -includo pher:czxy x-id naphihoxy.

13


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
At.ky1Ã'bk't3'z F.'6c:'s ti, an alkyl-S")- group, whs:;I'..'Itd al.`h'.y3 is
as previously described.

Exemplary al.?~ylthxo, gÃo-u-p4 iriclzÃdc iiiot1iyltliiu ea~lyi~~~io, ~
~rop';=t.~io; and hivy:ul?ic3.
~t''M tis_a?f` 1'cf:.'i's to an a:4:=l--`*-- group, w1lerc1:: the a:1 e'.
gt'i3tap is as PreYit?:.#44y
dL;sc::bed. Exemplary <li'y?th S3 c._%i'oqt3s ?.i1c;.u~e t~~ic-iiyx NC>,;:n#.:
z3a-j?li hy.thÃiE,

AIsllk`u t':#`oNs to awaibiilk>p'! `?=ls`_?~t,"?_W ~.xf%h:dL:i~: i~;~~`3 and
.:lF i. aF4,: as prC v-toi3ti3y
s_i:esc:ribs,d. Exctnplary, t?nal.%.~~l .-~.~:~~?~ ztt:,~u~I~:1~~,Ã~.zt']t
~?liG-t~y~.~.~.~k'l. zi~'i~.~ . i~t-~~~tr~.yIt`~i~Ã}x~:'l.
AAalky,omy` rcf.wrs to an :ri,.1ky: 0-=-= group, wher~~~ii t1he w-a`ky; g:oyÃp
is as

prL.vli::u,s..y (Imsa:..~ib1^`.d, An i':Y.E}Ia:plzt.YS' aTillkyl<7Yt\% group
is bef7:'y1oxv4'.

ie:{ors W tit: arid1kyl==S.,.- f?'f~)q)y vhc..ewn the Leuro4i}RAsLSri

p:t;t'ÃZaus.y de?sLi`Tbed. An 4u:YC.113plc."y aralkylthio gd:}Lip is y?eÃ
?:yllmft3.

r Di.3lk4lC1.rn:no" !.er':i'.Ã`s to F.2i ' N3\1\' group, w_?ier:tà of R
t3.nii. R i"s
indepondor~~ly aÃi alkyl group as prei=iousI ; dea~ilibed. Exen =3la~~y al,. v
lw.uini:< gr.>ujps
inclade ;~:~d d'iet?:lzÃmino:
,,Pdkoxyct~~bony." reItrs tU a.n a~klyl-O__Ct:;Ã.... group. aI .oxycarbz?n;=l

'15 (g{r4tp4 itiUhudl'~. a'rwfh[3xycai'bi?nA 4ffioxYCaÃ'ba1nyl, bF
t?'lÃ?xycarbow f and t-
<

A>I3+~"tiyi~i~"bi~Ã;,`~~;ts refers t~.) `t#.Ii ~.I. ~'l-~~ ~~~:~- group. ..
Zr ~,: b
goups is z.ludle p}:enox:.r wad naphth<:.z:tyre:zÃrboÃ=lyl.

AF`il~kox,f.:=aibC3nYl' refers to a31 :~ra iYc:y~-O '~'l-~ ggrouk~p. An.
f:ktim}YFaiy
wralko;kye,arb,snyi gomup is 'he~'~azy1tAxyi:.azboT1yl.
"ti'[I~lmnloy1 " r;.1eri to an I[ .NWrCO-e gye>~~p=

" 'Jik}q'l{va~'fF1L=~~tl7Zs== '-et~'+r:`i'~i) ~.t F"r=:'~~!V^'^~~~~~
~T:'Cia~.~'4, `'a~.Crtia.:i~. t.i~.t+ ~3~. .~ and :'ci is
à and 3.~~-:_>~c~~ and Ã~~c.~, :>ÃAa..~= f~'Ã'R a:~c: R' is filk~ l a4
Pte}='iousl,= de;;crÃbetl
Ãeiers. to R-'RN--CO-- g~~wp, whemAt~ ~~~ch of R w`td Wis
ind~.~~~emi.~~~~ ly alkyl as ;z~reviz3iÃ;,d3 descifibezl.

>s A4ylt;:~y` res43t`:i to at'k acyl 0 grmlp, .xI1eE'ciÃ"P acyl isas "3.
e~'2~`E~},,~3' t~ai'.=SUIfb~.~E,
,

Sf Aic)'l(Wmfi,.oõ r4.lfVY~,~ boill..2 ck.t;yl NI`3.=.=` group, whe3.4'S.~~w
a4yl is 4~~p.1.`=e ~wi1.`y'+ty
ta~so-ribed,

:A>.o:}'..e.#.~~nÃnf? I6essi.o an aIoy:-N-J'1.. g(,) tFp, vvherC n aroyl is
as, pf.c-v&+:?uslZ'
d:;sc-rÃ~~fed.

14


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
A:kf`le:`3ao c x+~fQ~.s to zl s¾i'a1-:ilt or branched s¾3h'alGnt aliphatic
ll3 i~;:' ~.~~~?Z?:i g~'f?i.-Ip

,
tsZ?.31 : if, about ;.s~? carbon MCims. tIxhe aa~.'ylo33e g:'f)up can bt.
5u"t:7`i.}.,hr, br:...3L=hi;=+.i,
or f..yi:lii;;, '1135.'. .3 Hk~Jene ~""ioLlp '~,`i3I? ht~: also C?pt7:t3nwflly
1.11.>c3wir<.[tod w:ai(3 or substituted w7.m
01W OIr liltir4 ~~a:#k?y'l iIlx~~~e cilll. be opg:t%?I3ally 1_nS~.:B'WEi :
kmti :i1e

3Ikys.:,ii~= group f;:'ie or :n. : ~? i=~1 s?.tlphu:-, or su}DsÃ-Ailkef: or
:.ansub ÃAt#.?wd nitr t~~in
atoms. w~~~rc:i,: rhc. substiÃ-,writ is tx[kvi as prev:v~~~~y dG.sc-tibei:.
Ez>.:.J:11plary
alk , k aw g~i.':sps .#1L-ilEi2c $21f;thi'`Ln' f'lh;.`l`s,:i,iu (-..Cl+ CH{i
), p: t 2ylen:```.

WI E..:r:? " ~ G~Z c:is ~~+.'.X'S':~i.=.+#'`~ ~." ~~r,~`F4fi ,_~~~ ~~~. ~3.'--
~~_~ ~ -~::; ~ ~;.F i." t.*:.E~e ~u~k'3, ~.{S~:F.?..~, _...

f0 `+`t~(Ctfl wbwi,f=m n is m'I lnt1..wfF:r ftom iibi?ut. I to about 50 ianfi
n .>w an iz'.v .~ IRX~I
0 to <3b(? 1t'SOwl":eÃ`l..iIl each :sf '33': wn'=.~. Ii `. 2#+fe4~.'. a3C~~=Ã
;~~' L~1E

:.i~~cgi: from , to b:uk. 50 and R is l~.`~r'd~~?geÃz or all~ys, trtf ~1:~
1c.~~:.~:~~~xy

~1lat f:fllyaehnCi>iC}xt ~? 0..... ). AF3 ilikylE'.ne ;.T,.rt~"e.ip haL`f.
about 2 tC? ~M:33?m 3
ciA 'Don12Comsai14S oYiii fC{.nhor have 6-50 +ruboSdS.' 13z3i.^.' or :
hrlai&i' T# ci: to I311:3r1de, chlor1Lz[;', b?';3n1adc, or li)t.lck~,

The t+,'3-ni t a; fe#.?trr .#1:'f.,ll`a~acS w3thC3Ãlf. lim#~ afiC};t1,
1~`a~=i~:eC ilE~]i fl:~= ~ , .z~a311 a~, mi'mi'i3l
`upplC'ment +..Sub'..=iancC.4 ti4ed 'fc?':' the trf:.'atin'~G'" a..'~t,
~..)rLa-v'o' .tion, iiiaMno'?if',,crtra or nait.~~a~i
~.s.~~a.~ ~ffe4t. [tte 4tr11cE0.rs: or A`LIIiL`tiÃ:iTI of the body, or p?'(t..
of f.lwilw or ffi"~LsS, substances .

t>iu~. ~;s.wa11t,:i i sQco.i7:tL, b1{?:C`,gic:~~ly active i3r:t13f?re ai,'Ãi-
vC. Af[et t teyhaI'e bef.r p4af,t/d i::3 a
p}3'LP.Iite:ii'#?n,p=d phy\:iS,rlo-.~.Ca.[ CII.G'Erf?m-l?.L=nt.20 A tNo:be,.t-
.'v"', :lt,~,Ie't3t" rt..fi:.~rs to <li1 agent ti'ii.~.t is c~sl~.?abic f?f
c:?::cI daxo a biolo:.?IL;:.Il
GffG+:e.Tit vitro andior in l=`tS'o, -11'xc 'x3#i3i.of.?iS:=al eflCrci can be
M As t3s-C'd
herein, rf=fLrs it?so tf? a StAb;~ta1#:4~ that is lv~wd in cC?i3-r#cfi=t.t7Ã~
~vith `um

i~:~l~Ã.~'.8'~.f#, ti.:ii:}~+ l~'s$ ~a~. `~'~.4Ãõ3;.:4 f}.i
appl.lcilt z>t3>"# t. `.3fif~,t~:3`s't,~. ~~i in g nature, 4IE~:li e~ tz in
~?~ i ~ ~'-
~:F3~ is Z~

iEbm4=1wa' of a d.ESLa-so i#.i a ;.?'Lii;nt. Iõt7c bit};?.E`~ive zlgs?ncs, can
bE:'tie1:t?'i4z or pos# ,lvf~ y or
a.~ S= w3:s~~'~~~:i. ..:Z tlc ~~. ~.~ ' Fi~;~I1~ y~13~.'.:'i i3
.c ~+ ~~v~ ~i~~l'~=~ 't4k.Cuiti3ble '?1L.?%1Ct1-v+`.'. ag~ ~v~ 1. i(=~~.#:e<:
I`~
dlu;zs, cells, g:zscs and h`a :=Z?us prec~3isoi s { e;~., ~~ ~r ~#1t~~~~'1 4
Z?: ÃV?.3.~?3:= i~2: .i' . t~E t,
3`lloia;sT.F 4...n<'..'v':iT L'.s, growth fi1.E:toT'S, vitamins, 5tfro1ds:;
pf?lyanio`".y, mtidc? dC:S,
Ã3..#clS:otdt,ti, poka]uGlE.#)l-lfaes, 3nG Z`i,:ig:'tf.}4.1.c awe37.t;t,
`Ea.ci] as contrast agents tf`>r use ?!'>
ct,`>~n.t::tAlf3.i1. 4'w?ill magI?Ud<. = ri:ii?3a3'.it:c ;.mag1'ng',
uitTa4t`i.S.i1Cl, poS1t~.rL3r? 'tl]i5:^'.:f9.i

30 tf; apht , :.:Ã.Jf:i7putid ial nf`>gpph~', or other imaging :-noC .il3ty of
a pttf


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
"G[:31ctit i1:>3it 3'If3ls i.3w`x~E f ~ ~;~t:I2~:ri~llÃ% it?
#':~C3C.~l~.tit.L~t,.;~ 'c3x7~.~ ~~C?~.~'~,f2f.~.L.~~;,t?v,.=t ~Y
tie53x'1'#.;.bi3nuo3czc acid (DNAi :!?`tdi'ibt?i3.Lfi:lo1L~ c`-'~.ciCi (RNA
Ti3G lryf :E? <...tft i.l'lc#~t i'~c#2 cCIIi be
z;ii7ta'~.a by f`i?iotTc :heA`tF.c:3? ,{Ii.t`thf_ 3d'L~logy known to tia?.e
of ordinary skill in the art, or b4
~~iL I t of recombinant te+,..l1txoloÃzyj or by a tt?iTl~')f.Tlat.lof.i of the
,w4,s. Thw :I,NA <1:3d RNA

i:;'asi opt3Ã3.f'f<31lc+ ::07171prfS..= :.#?,111attirxil I]i!4=leofideS
f1.11d. can bC >"It:gIc ordaLFble4t3x3TiÃled.
<Genctic nulti> ia.l" z'i:.fers a1,o to sense ax?d anÃi..Se~~~e D1\1A. and
IP'NA; t:~a> :~,, a nu.:l-e;~?Ãi&

sequef..4=e ffi{.dS: vumplement~e~ryio Gf `peci-fifa sequeni':e of
aucFeoiidesin.DN; A wici.ll?i'
RNA.

The -vohme.`s pI'ci'r'f.d`a'(I hf_'#'e'C,ii. C:an bi:~tti:f3ii
'4G'di.h''u'aape .t.Le.fl~ and:E./L`.}.
For C-xam~~le; thc, poiy?'tien- in any:~orm described hor~:;iii can bca .a,e,t
#o pro#:aoie healing

and/or tFel.. #3-.fh#I73t disCi.je by t'c~.t'~.~x,,o:7i'Eg tIri.fg dt.'~lit
s.ry t*.:1 tt?LWE] e.fF..d f'e<';,tC?Ilt:l caA4;.'Rs. 17ht:
polymers hprL)vI3a`ei`3 hi.s4'h..i.:~a1'.2 also i3e used R)ra wifietV
t3Aai`,lpifL.`t;::ff)f'?s .i;fiQ i.f.3la'f..''`. bLZtnot
li3'Ih4t'.d tt}. :izi?di.,c:1t}n of []:iicY'i)- '3:#1d 1?ai1CiPPuatcle.s,
fihmv, i:.Ã?aiiug`, sf.1t.:e7, and
f:F'thi;pcL1aL :liai.k.r.t;is. S :Ic}i materials kat'f, be used to i`i~~pa;f`
<lt? f. ~jui't.d ;},'ga.i,, b(3:w.
;
i35 tl,i> ?~is4S +..t.~~:~Ã,3.'.= ~'~i3i~=~i??,f<=~'S
pitiZ~y~~'~:.f.~?~s;Ãc:.itl .:1w.z Lido ti:`c.t.'iicai: of 4i.t"l y.
:~

lf... or i1? .'.Z`;kmgly;.>eGe":;d In<llxgi'3aÃ..a.Ãi`s; p:eÃiz:awni:,nt of
mcllignatif'-t~s, or ot:"i:.Ã' :=t)aldildiia
as . Se:]sit..>.'.e:` ti? <1:i1.g3a]e#?: thE:napy of fiItxl`t''m''li.t`
x$4;Lnt atlcl-i as wit.I,#"u~+1..~1i>:1 rt 11,.1~1FC i'~>
avoidance of lt,?Ltf3 :w. Ãt71ii3l t1l`?d:'.= :F:fid.tastis`4=s. Ã$ug?,2-
w:1li3t1o3'T ?f local ,w.EFaE.: .3. c.~.l',:3g
and dd".(.'re<-f3e.ki. Piif~.-`c1.?;;n. ?1#ii.il#pulc;titrn E?f5tru4"t1.f3~..'
aTlct :'6b.7.E}i'1'Iial. se$r foi'.,`.:=at;t#ii. ;1F:43 fCiI=

2,~.,~`r NV tmifvElicait of pC?st"(Yp~.zil.ta re Pai2'f. 111 {,5,.:tc ii`.1
s`:mbotiiiiZ+::,i1.ts., .ti ' 3;?vE#eLx:
i7ef..it? :]t't, tawz to treat t;tizi'3cet'. .`ift` t':ifii3:'Iple, ti1G Pt-
?v27i,ov4 provided ht:t'eii`_ Qcifi bt. i.f;,,c:': to
~rf,at i';:i'.s,l`i.iy s'3~,o`~,~'~f.gnbiT...`fe_dy i'..g, lung, colon,
prf3sifite; pe]n,ca<'..5, or bteastU..Iit,S.:t'= Fo:."
+'.:Y.iai=Fi4`h'. :'.a3el2 #.i filf'i3. carrying i^rIiU o1".i2?f?Ii
flief'api=usic a"CiIta is i.7t1liZeC' E+.t.'f:.'~t ,, L>iYiee::`.

it oan bV iltiaplt`.\T.C ~9'`r[tLir'k_=dS:[2.kl.Of. glued in j.+laLe. e.g_
with 4Stvy.1fou1.+[yl att r4s2[Y..

'F_:e po`3,i'wi'S provided 'h#:`fi;il'l t;ail also be used to {e.i e o:"
w.;.''4' age:I... Tho agL=11``:
4 3#` be in any p1ha#.me:liõouti1:i1liy i;,e4.:cpt's.:C)lQ. J~,=4
lF=elf.fd`:i1g, w'rC ep:.<3ble
st3l J. A la e(; .t.f..-bf., of Ph,..;".'f'i1acLu:1.c.3a agonts are k`?Z3w{:i
in tbe ait e.tid <iy:.' ilil:lena~."+ak; i<?r
~

3;.fs~:= &I1 tlis,_ Pl,:.za-t?.<7.c::i:9l.U;:l c4?#'`.1P+.`~?id3at` t`3fq,,e
pol4'1"i3'Y;=i.c li1ata..Ail.i described hC'rC'.3m
Acceptable agents include, but ari Eif1t 11i7'i:Ybi'.d to,
4hemt?{he'apow,r:(..t`ef.t_, .:Ãrch a:+

f'>ldIiJsS'.=ns.tiif;`r4, ie''.f:~~~tor Mh1b.'iO1s and a,t~01.:3i~ .lt: t;
Iz#lt7:ian<.
~
:~i~?tjsul'si'f~zi i and ~i:t~izict i'~ iiM:l?~iS, as C4fE~Ihlili ,,
;~~{3~*~'~a ~~1.t)i'>5 or ?:<'Ã~~>CIi ~,ViL~f <,i'

1.Ã?


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
without the co-inC3;3Ipt3, aIok~ of tumor or pathogen t1t1t-i-gG'nFi to
zF'#.i,',recFsL tlaa tlF1.t,-;1vi7ph3st.10
response o..1 a Ãnewi:i of vacE:F.?<= devC.lt3.llmC'F3.t., IC;+L;a.1.l
c.#.Ili,.8tbC;di: aE?#::nt,a, an~ib.,t>Ii`v:'s, tÃ"'
a3,.EaleFi.= <iL3ds as c? niG4F?S of lc.3;,a~ ge1:ie 131eF`i1py,

thllt.~~s od.eni iSe dS.'.fFÃieds o L?. . as abova:, all tC.'~~,lhn:O%il "Fnd
` .t.Ãf#i.':L. terFa:s used

1-wF'i :FF `ilat e. `^-ii s.3mi: Ã?ci$ii i11g as Ct3IT1.iF.7otlly understood
by f3iw of S3T"dfF':i~li `r skill in .i"Fi:: a1~'T.
Ii"? i~'hicb z,:là n 3:nZ eT:=1wn b0o 3g3. Although methi)ds wad
.`:1ax,.=rAi:Fl`:+ NÃ.mffl.:P_d' or k.qi.:ivc..YIEa=.t, tf's
. Y=~ a be ~='~z., C al~. the a > r' .fi t~ ~ the a' ;fia. .?~: i::ÃA ~ aÃÃ<
those z~~:~t~F`Ã~i#E~Z~ :`3~F`::1, can ~?~ E1Si;~ ~i~:',~I~~. *,~~FI2~; i3.
,:~.t~-s;~~.l...~a',
~# . zi})`e methods w1d materials are described below, AU pa:?F1{vat#Ã?Ã S.
patent

iappl.FC;:itlÃ'+Ã,~, pat>.3=it:^s and t7th[ Ã' references m','li:tloI7cti.
Fi'FZ:i`a:Fn ..Fm= #rii..oF,~.~i}'.cltL.d by ..L :(.'=a"~C>.nc*w=
?1-3 their L.ÃFi ai`.~ty -undess noted ot3 C'.F :vlsv, tFl case of
i:3:Ifl7G>t? the i:'usint s`t~~tiSõ'.lfficalio`a`f,
fflc.udF3t,`, i i%fimF#.5ons, will Lo$3tÃ's.)3. Fn addition, the I7.latcÃi<.F
y.."Ãt.hoL%s. and .;}isa""ip4es
on1h' and m~~ intended Ii) bi: IiF l11n:;.

~~ .Ie:S;` la io=F1Z.e is i:i.c3E~.~t`:= to a URL or other suLll ldenfiÃ.ier
or iFddrcss. it
;.#Tld#. .F'Sw(?d f-a3:3~ suf h #deF:ti':1t Fc`,. can change iln.d
paFTt.cE3:aF' #:nxt? Int:.tFoIi on tl}o #.-'}.ti:Ãn;t.t. c:aF:3
i),, btiE i;qui= t:lcÃ_t:. F: FfS3nF7F3.tir3n can be R) iFÃ3d b-',
s4a.itrblrt"3r: tl3c
oF?3c and

~~efe1'"a Ã~~#:cc. thordez u~~='~#.i3e.F1i.:eti the availability and pLibl3t
4'.el.ssi'=Ã11Ãlti'::FoF
Fi R?rn.la`Ft?;:;.

tiL'E1nknui:Ci can be t7s`.=.~~ doi L~3iaFFIÃE:F~: "'zp:Fd-ww.,,
c:F'zi.:F2i:C>%Fl ctÃt'k:'i`i.':>,
phvF?'Iat3.+'..i..Ft.t_,.a, 2TI'vpi.#.Fi.1t#.o1, formulation &n.d delivery,
:#.Ãed, x1'i.c3t'.1`#ei3t :o-I= s-.tbj+.cts.

Standard :.o?:.:?~"#:F;.ÃqL#i.:s L.ctÃ: :: .FsotF -fi3r ii;=coTY1b3.F"#.<:=`o-
:i. ''s~NA, t1~~Ãr.3Ã.EFI~:i<3~ 1+ 4' .?fl3.i.'9 a, and
(Issu :` C1.#l.u3"e ;iI2d OL=ct3C:tpCk3"c``: ..Ff?" R4:i i a.i}.Fls and
Elu3`IficeA:Fon fci:=hnÃq`i.Fes cwi be pC3itbr%]'t`~.'l, t ,., using kits
a{,',cv;di;EaÃY to :E:i3sF..#fat':'F.R.Ff.F'~.'
" s ~C.'+,.:F~;~cf~,a~1:`s or c3:i i',=(~.I~'1I133:Ti~' FIC:n,'.oF~i~.~9]
ÃS~'~i'=C% 7]1 i`Ã~5,5 :a or as described herein. ~~Yhe
foregoing techniques :1.id prCr.edlll t..`i ;"f.-'.='I2'LL .'alt\' are
pe'fi3:7':r.ed zI.".:QC} d1;.a;:. to ct;IYvi.`.Ã"#hoÃFk.:3
mett,ods well 'known. in the ut aiid as described in various >,õerieF`a: axd
moÃ.. specific

1'cfGIvÃzi i^thw are cited and dF4i=Ee3'wd ihT()u ~?i4~iC=7:t ~3E i l~t 4
a:l?)..?. S'i '.g.
Swmbrook F.t F: , Molecular Clonangt A Laboratory M;wual (2~.i e,]. Cold
Sp.ÃFig Ha.F~boÃ'
Laboratory Pross, Cold Spr;iig Harbor, N.Y. (1989).
Other :uatt:#res an~d advantar;4s. of the ~n.vc;n#i:r,<: will bc: appa:c..~:
from Ohe
~~ following da;:,led wid ftom the clai:iris.

~ "f:,


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
BRIEF FIGU RE DESCRU"11O'~
FIG. 1. is.: :xa.' ~;~=~~~~~:~ ::~~<.~~~~i~~Yw t1~:~. ntÃiiib~.r of
~:~~.lIs..~t;:cr 4r~:~Ã~tyi?~:1?: vv#t~~ Ã)--
iyd#Z??%' c3"Ã#pti;tht i-Ãi3 loaded fi%:i71s, control fili?tS Svit'It3it ~
i.i i7`ri~Ã`i:3:S yC it:I?~~ J. ?4.ii1. ~~i:

~ IG. ~,' is a bzir graph shmving the nur:~bei o1"cclis Ã;eat.-~icritw:fli 1Ã3-

cfaded aihns, i;c3n.tz'f?1 ffiltnti witffiowt 10-hyd::oxvamp#othec~r,.
b'hm~.ik
a~l#?~~s, wic~. ,~~--h,~~~oxyc<3:uptotla

FIG. 3 is a >3ar sÃz1px# Sz?cm-ing ehe cyl+_](E=:gxi.C.ity of
a?E`?ly(`'a.~i:cÃ,~l f:=(? L.p:";31..sclo;ieI
111G 4 ik .i :)cir gÃ`a.q~)}1 haiii.]~A."1#3g ti?.c cytt'~toxÃ4ity of

nulnE>iluti+.-.C,` vv?ffi 10% paclitaxel.
FIG. 5 i:... bar ~,'~rap}i :=hi>wÃ~~~ the c~~tot:oxii:ity of poa~Q.l~sw>
iui?'Ã4]pi.:F"t2LlL's, W11,11 P~`ES ri.:fylati3Xt3l.

~ . ~. ;5 is a ~~i',3q?x? 4x]Etfi #1 g the release of
10~}p5'E~;t?hyi~c?#2;~3:i?~?#~.1Ã:
Iv 'p3J3yilau1 u. myÃ'Ã>itÃo, p$lmitac, or stearic ms,LcZ.=wl

1~1(_3. .77 .,a a ~i't1~3}l S}lOlWÃrlg _0-
hyiitCt:tiLYf:'mTttAollacc:nti,lw<Isi:= flt?n] poi.S{tite;1.rii=
gftlc>ol "A~`i.?:iT:es on pS.YiE.ari:muÃi.i "itrIps.

~ IGS, 8ai. and `~3'B, t1T:. '3+,:u1di.37g clectI'liÃ"~a m.t;ri}g.iph5 of I
lti~ded poly{st4a:ii, glx cea'.?l TF1G. 8A u1,ow-. Ãil~~

sug ~~~c:.~~ of the fi.m {su~le bL}r 3 -rniw:rc?vs), and 1`1G, SB shows ffic
fiAl:~~ in
(sccile :.3<`*i^ - I Oi3iAi. t'i3mS):

Ã'iijs:i ;drit3wt?g IvarbiE+le .`iwr^llÃFig 'si;.L wlai<,:3'uS pl-P:e.
h I\ , 9 i$: g

1 5G:10 is a gmphs}?l?wSng Si.ie do].TA~'L]'~~.'i~tY~.~l~.[ \}bsi.3..4~+.~..~
l)\t .v~7.4\~a [.fC>51.'~+ C.~7i~.ihy *t _ Ct

E~. i~ . v .s 1..~E:ckÃ~". :"viõ]~'`jy -at a ~Z t~~ 4a.S..'i~iss4'tA] S`.]a
?~12 t~~].
.
~~.` }' IG, l I is , "'zarm:,ng 41ectÃ;?n mac.raasc;?p<' (SA" M) of

FIG. 12 3.<? g?"ap of the d3.i.li2wtu of st,#:9i`~I' derived TnEÃ"o4phci'i==4
at viu'Ã.#:3uJ r:3ll:?;
Ã"aG . L? is it bc3Ã' g3'~pla 4i-if1wiJlg ti.#AI?or rttt]lÃ,121iC: in
2'^t'=.4'pon;iO ti? th#:;':I.oÃh41`F#.py-.
?otWkA 11z1110piia ].clf':5.

FIG, 14 is c3 beÃr z>'si`'~3,:1 Sl3t?w]I:g i'i1LC'i:#r Li"tlE1m- in response
Ii3 .si:ia]4Ã.a cs#`aci]us
2zoryri,c: ~~lm Ãn]p`,;yirttalion.

is


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
FIG. 15 t` iz R,3tiir gmph showing tlt<. percentage of hum1 s,.sps;3T.isG=
Ti7
;i? ad::f:i R04-1('PT aand uffle.?aded fil:~~?s.

k?:3~' '~il~>rh s~'a)~1'~Tl'~ G aa7~:L'caIICC1` activity of riiEa.l ~`s~: l I
.ra<$<>`~
~ I Ci. 16 ,4
c.. ~ ~ } r ,.
pa.;tc:os wzffi UrC (lun F ieinwGÃ') GC7al,? 'L'3.I'T'i).
nr3nE5
J'a~~. ~~; i3 i^a: i~ÃA. g3i~~~l': }}~f)s al~fS ~~aC t9 ti~'Ftb of
i~c.~G~.lti~.,.ysvt loaded 2]l'~~'2i?~)c?Iw~t ~'.~ :
s?:3cti.?thehomi# ciol;.5 in vitro,
FIG. 18 is z; bar gmpl: sh.~wnn;; tliic wita-caz~cet activity usf pac1:>axe:
I:4ad4r:
s><mopamiclt:~ ~~ ~ ~-., A459 Minn= hang cancer col1s in vitro.

DETAILED DESCRIPTION

Pl"tt4'1dQt> .1e1'i.'ii? %'.Teci7mp:3uS1dJ at.22d pd't?cG>scS to pr~par-'
b~mt;d fl3Yli:i.
paIEi.:la;',3, f;ld:;r ,A.xd :~lw teCi co;.11p(?s`fit331`'a, c3.I1d
~'`.riZ3C.E..S4ct fioF." d`l.l iv`r.'.i`n3 I'ki:.'=
following de;>c3.i~.~c~" 1i'3~ sy'nfhcsi;' of M3'f'fotnter units aiid the
pOcynmc?1:'si6i.l`: of Lhtsst'
_ <
i~lÃf nffi~~:G:~ z.1~13~.ti. Also ~;4tis~,'I'L~c'..La is ~~lL : ~ a1.~.t'~YS
of Pt`1:vi31Z:3"#:G S.`{'uL%3..E1L..y <hs.i a.Ici.''qvx:tto
t } .hef~. -} <
1a5z3`lS~? diIr1~Z~35.1~.#~Fl~#.s to '4L~':~:~t ~'i~'~'i?3~'I`<
Z3isi`~`~.tsC'.S a.::xL";
a }f1~a<)¾vt:xt{.]Z. i~~ ,s,>r 2s :A ~t t~:fG. y~`~ 5.A. V"t~1r>d4 :.?f C:.~
~c.=i.?L . . . . . . .
dis(?'k'd4 rs.

WL will first describe i 1t.1ya n1?no271Lr:S that a'an be i3sed. in .ia
ak#.ng ':~~E:= .w~:~w
z~.~olti`t]'.ers, as well as ?i1etlious of synthesizing the
s.3'?+:?t:?c?..7iens. Wev: i1l then (#t;,,i-c,'ibz'
.x?e~a`~~3;~s ~} ,~~~ 3 a.r ~~g and ~~:;r~x,F the pc?i>~~~ers. ~i:~?,~~ ~:
will describe Ã:?~: ~~: ~:~<~~if:tÃ~. of
fiflms and q<3C:f3 il's, as wi til. vs fliv i11i o3~P~:~T':.~~tli?Ta`~ of
agents 1:i1t(~ r]t}lfK:3~= :C: N~,`#..+`'a7xGs.
Finally, .~~ will di,;c~~~ the applic:~fic?ns c?.~~the po1yrn::~s and
ps:?lymer-ager:F
4.=oiv2ib}A. Viia~ I Monomcr Unitg

~~~:.$: As shown below, va?'lC?us vii?vl .ni)1?o1i1Gr units are disclosed
(ae?"i'i`.i.

t?JaZ?:3~`~'r %#.i7.Fts i#.Y'." l;1tiE:d to p'op:iTe pi3l~7T1i,'.i's5 a's
>Ct. . .~. 11 fiu'thLr dc`a"r,:l. buji3"t, V;~ik'i

t?nz>tnor ,,inits include cÃsrnpow:,dy of Fs?m-1111;1 1, lib ~1r~Q III.:
19


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
R,,

.~~

Q
QG r'e..
iv'h@.~~cadl Q wS >~Idk.'-'A~cn{.cn.tlv sS,iFi~,cted fTt3m wwonYti0, S. S{. or
NHr

C7 or 0 In{: $~ t g;:'=thS..:, ~.~.{'o st:lt,~`cted.ft't?fii among:
..r

~~~~`~-= ~,1~'~.
R,

R< \m i\ o

~ is, sc,e:.~ed frona amÃ.atig a Sar~i.~,Eit or bt=us .hod alkyl, evotoalk`
a'`yl, o,e ~.in.,
tizlrl, ,<l. yl, ]Y?, at slszlyl, alkyl~ry1 ary:Ialk} l, or'fhotocax-bc?>
chaÃ~i of - 5:_ car.~)c?ns,
wx`{eri:.$n L4E4 zi ;1~~Y `{<< t3c:E!.. W~ 1~v ~, i33i.v1s3T4r~.,
a.E,1~~:~5..-1.
or fl;.Io?:E3aYtli'bi.`.ia cha'erf is 3,?pt1on`2'.liy substituted iI1tC:mi::li
j' or ti.nninal ;.5' by o-tlw' {3r;I1C?I't;
hydt'oxyl i`y{ i{3 Sy''v'tfief , {=aeb<)a y'. l:a{'b55'S. "Un.I di.j .::k3hao;
m(.>uio 5;F (az^

libGtdb3ted .liu..i3t,, tthiC;l, th?tt{.4toI; sWfi?.+. phi.1sphat{'=,
pa'1i34pha{1 1t:{d, i3r f1{ o, u?"#.
I1awit's; or

R~, i; S..tC,dcd fi-t3a;I wn"zi?ny p3ly(S,. hti C:at', ~r?.ly;i3l)

l.aibE1hydratt:, a protein, polypC,pt1f1C.:, an 's.:T:l1Alo acid, a
t:ll:ck:1+:
~0


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
'c+;oli:, i:i>al].La%'.oF'.fdi4'., a ,"t3olyi2u`t'ieC3ti+;..~ie~ an't%. .'s.-
a,f'.1]eÃ:Ii::: material, such as a DNA +_i .~IN'A
5i= '71w:nÃ:, a .:p3:d, a :?[?lysacch<1Fide, ziFi :?t.tfit?ody, a
ph.intAcl:'.cutFc-ai agent, or any cp.itt)x3i;

1{)# a ``F#i3: t~,~-,Ff:i.ii receptor; or

R. `.~ vQ-k...Ã',~:d flam. a.tmo.-aÃ? i.: P~IC5Ã:t?E;I7)s5ltl7kciblt? or
ii:;n1E,a I.I ;y= c}c;~~N I : ?kah, I % gZ3up;
~ or

Fi.\, comprises a first ~.,f,.Fi:i..t) that i.s f;=o.F3,-vi:Ftlbl`s:., Ãfi a
second >i,[ap 3.1affF...i Fit ffo~;:~i the
a..Ãrià ~?~"(31t~? ,1; :a pfI a-à oTi3e`ow about (),0;

R.; i'~ ~&`vtÃ;d ITt)iF'i .{niE3ng hydrogen, a straight or :7.F":md:+:<d
a'kyl., {:y4.;loÃ1l-kyl . :3i'g'i,
{alC,fm,,, s>ly.Er aY ~~'il~S`t a13k~`~ls$iZ+l, e33~~:'.~ca~.~iY'.~ l')I~.
~3s~*i-~t3Ãi?~,.:FI~~.`~E?4~ i.:tÃ:~ C~. 1-50
' . . J . d .. ..
~y c"~. .v~~FL.>.~:;n ~~yc Cd`kZi ,~lq cy~., ~)i~b~Cy., ~~ryl., ~. 1l~:~~F~.,
~Flk~lh,i ~' ~~~l, ~~r>15i1 t ~tn~,yit~~~~f2,
FF~ en~. . ~ '~ _ ~

<a"+-l`lkyl 3f flÃat?ioz:ari10I, is optionally :ia.li7st#Ãtaod
Fnti`.F`'.,ali;}' or :on:l.ldwi.:y ~y +)ne f?`:
nao,FE: `;'}~'~F+3,{Z`~. ~?ii~Itia =Z't'':tCF ~.i1:i~?i 4"v x i
ill":`!s`~?~}`~'"itC':', Ed'FaF"btiyZ'i3~F'la~~`~, i3iTFi]~Fi)K ~:aFi.F#:f?
4:;i

iiF :~,,1>)s.#. F.tÃed amino, thiol, Th2oiaie.:', SiFlfaÃe.pj:){)sp,'3<"F:Ã<',
ph,.~owp:"FoF'1:,;Ã~.', or hka o:.Fi=I3

#;", efi..?i,A.ÃGiFt }Fol-r1 ayTai'}l.lg :.?.'.'tFi'.31; l`a,, or branched
alky, s :'Z.`.lo.lkyi <lrS'l, C3lZ:fin

sÃ:[~I, <~I~ ~r~~ia} l> ~.~ l~ilzr, i~lrtr~~~~~ l, ~r~,~I~3Ik~~l, or
~~Ã~.i?~~t~~.ar~)~.~~~ ~:l~.~..~ii of ~.~-:?,j i,~~Ã~-~r~)~~~,
3~,rhc.o-:<in alkyl, c4'`ioi$lkyl, a.I=Z%l.; olefin, 4alyf. alkyl;?S yl-
z).r\ l>.ilyi, .~ask'i'lary,, :1:Iy~llk;",J.
E3F r~E'xi?;.t?f ~F~'3<.3ai cha#r, is apt1oI1allJ' slabsÃ1t4.Fti;i~3
#IIter4iu"Hy or tf.vtlin.:3clyby- o#.ati= m' l.'FC3i'C'.=
ar:ydrC3i':'l 1{'f.~roxv'dhC'r, c<~Ã'bi5xyi, G.FTboxye5iea ',
{.t3.1'boxyF.#m:id(:, a.1F-n;i1:?.. ;'#1C,n{?- or di-

\ubst#t1:1:sta a#:r:ali.;. ffiFo..~ thioesÃa, s1FifaÃ4, p~'sf~:9sphate,
phti3splaf4nt`3.Ã<', or l.4iliL>,'=;kn~

I1, F,ciÃ.: 3? a i:=LA#^t-3poi321d t}fFonnF=;F~a 11 is sE..zei :ezt fti)F*.'~
e:lfEat3"!g a
cC)Imi,i?imi.. 4EatiwÃi i7el(?i`r:

.'~:~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
R R"?

SG
=~ S :3 N
-;
V 'Y
U Ni ;

t3 Hi

NG
ly
=
; i` ix s x eiE3 ~:3 k ~`'H
.a`hoai R's and 6 1'#:'f? :iiad'L'pGadl'.Ã`itly Sf:3,i'={.ieCa. :i4 deflllfi.d
}1ere1.a:

lu i.C;naal? :":mbc`d.l3-i'=~?.~lts, ~~-ie compound of Fti#.Ãlzi?ila Ia is z,
of FCZrf:nu.lc.i
IVt wzlf i'L Q ls oxygen. 11.1 4:>a#'lFÃ.tl3 C;ilibC>dII~.1t;Ã?t:i, the
i;mnp(~,E..`eI`.t`e o:..FCZII1'2alz. 11 is a

i'O;:~ pC`.ul.:. l:? FE7a7m; a V i?.''hC:t'~~ Q ii 81:i:fiiÃ'. I.['~.,
t,.eTt:'a'.8i cmboa.rr,l'.nti., ti:Fe mn'{:oE.F.d i,'A'
Fommla 11 3: a 'S ::fl7iP:'>u1le`: of F"L?rmL3l'il F't''!, where Q is St,`_ In
1..<;F"ti:ÃlI. C,FI`.b<.xt.~..,a~:v.'+i ve tht:

::_io~~-ipm:nd wa l?ftn-nula If is a compound of Ftx;-~~~~~, VII. where Q is
Nil;I:.

In ,rà h.er ca-ii;?oslim4nt>, a cz?mpf~undcz lffz3rmu1a I1 I is s, le~ ~~;d
rrcz:;. xnomg a
C<]mp3oun.i ;k.l'mul's? VIII,, tx X., o1' X.1, as show2i ill)oLC:. 13i_
c5,rt.3liri :..inbt3d.m+,:nt'+, t~'.e

30 ct;zrtpC~u41.3: t`+?: Fi`+i'in ula e11 &s 'c1::Ã)inpi3uI.d of `'3mufla
'L'11.1 txdht.'IÃ:` Q Ioxj'.SS'I^, b t;t:i:ili.Ã1.
4;m,boc~iimeÃ,Us, the conapc>~~~d ot'Fomuala II.( is a co.Ãllpound of 1"Onnula
IX, wljc;re Q ~~
sL~lftir. In ceat.ain ::Mlib:yd;:Ãni..nt4. the ct~~~ipound of FormuIa 1.1-1.
is a 4ompo,>nd of Formula
~õ ,, ,
;15. '4~.3i:'~'U ~ ~ 14 :~o. lÃc :~"~7.~~ttiMlil~L,tts. Ã~Ili i,t3mpÃ?u.F7d
of Forimifict I3I ts a L.mr;.pou#1d
iss Xa w;:`>4;ro Q 3s N11 1'1.

[z# C3#ti'r eI1~boteln',ti;3]ts, a C:=t.'?mpi.,~'u11d of Ff.'sr'i-mi:a It 1s
4t,.;ec .c;=.d firom a{:';o71g a

compound Ft?nmta~a Xi1, XilI, or XIV, as shown belc:sw:
?7


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
R"
i.. ;~\!2
SG OG

"Y y
~1.1 p ~~I11 ~ ~,
1b.
f iv
~Q`'z
H H
H
SG OG

xv 0 s
XVl 1. NH
where R' > ;tnid Zf wre :i?de:?enc.~ent`~ sclc>E:.ie41;~~ defined l.z.:rdn.

c?1?b>d.1i1"?Gnt5, ti-?.c ia`~mpfx?.IÃ"d of Formula I I i'sa wYin:'.+tiund of
:?
XII,

Xil 3. it? ci.A:,$i:ti ..I'? biy(,smU'#?ts. 1l3ccon'~pÃti3.,,?dofi ,,)I"Ã?-
iLIl.allis ~i 4.~?A:"tlTL?f?a?ci~.)..'' l`(srt??U.l:}
xiv.
A cf,rnpound o: Form~.~la III cm also ~.~~.: indepcm-donÃly wle;tw, `f: s3ri-
n, among a
conipf?und c?f;-omnalF~ XVY XVl;,. or XVlI, ,~~ ~hown above.

`j? >,:C..rwin t.`.l?~'"~7Cdl;'~3Y'i tC, each G F:rC?up is..clecieL% fr+.2-
m.amoi?,~~_, :.i ;;ilZti:p slwfivn
bC':1{:sw,

2 s


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
. :

R3R2
~ r u
~ /t l
.,....,.~x y...._.,\
f i
:"43 Rt
,r'_:-~= -' ~"'~=.,
t,t \fj A~ `f+

R:
Q
`4-R
i r

R`

~
whE.=p; Ã:::ath `tQ is i:1depenÃ;i<:i3dy selected #.oni a:'~luilg 0, S, Si.,
or Nii;

[1 s~:=?c~,::,: ~..E?k"1:~ i~.i"~~(?~i9 ~]'s'I'o;F~::O. m~tht3x4'',
ethC's:`s.y, `IEAI-4 (), c3. 'sti-a ~",ht or
btwicbM .~~kyl cytic3 lky=I., aryl, ~~lcfin; s<ly1, aMyhi~~~L aqAty:,
a'~~l4aiy , < raryta,kaiE
chWu of 4 `C: Qarbo-ns:;

R4 Llild R a.,i'C' ccit.:i ~.I'$~~~~ :I'L~i I:~~?v st~~=~~C~~
i:"~'=t1naI1It$ng a s;3" mt E}r br:3:zica1F'd
aI~~l~ c3:.lod:ko aryl, ~~iefhi, i;yl, alkzrlkl,z, aFyiSi:~14, Ay-,<uyl, t?t
;~ryla,ky t?
c=;arbÃ?ns; t:~ld

R, i i :idf.4ted f1";3sn among hs'de'3;yf.-n, a 4(raI4.~l;Ti or branched al
'p'l-

&i.:3 i:yL=zC?aailyrl, aryl, ol<:f#rl, i3lkfl`s3?'y3, i.'s~uyA<3.Fkyl m:iaaI-n
of 1-50 c..sidbÃ1ns, wherein kl;S::
24


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
<;,k~), ~:}~c~+_Ltlkyyiryk, olc.ttn, aI.k-,`1aAyl, or ,~it~yfialkcQl uh<~Iii
is op:'t\?nal^y subk:tt-0iec?
:n...rna:EA4 o:ermbnl:ly by afzc o-rmore:(lydr;zxyi, hyd-myeffier, cai-
bz}tiyl,

a'ar'#3CZxyLstC':i,, iwrbFxy':i:lid~.^', amino, mono- or di-substituted
a'lll:#o Ã.#Fol.
tl~loGst:er, suI1aw, phosphaai.<., ~~~izosphonats;, or halogen .~.5 h3 cutaln
i'.:`>lb(ri:lnwnts, Ã'=<,lS. F3 G f.;T'oE1p is sCõleeiLld ..1'~^~m
i?.llJi*il~? a gi(ii.ip

shown bi.1t,w:

Q ~.;R.
~ty F= .
c.-Iq
~\r ~ky
=~-f'J .Y~.rr
ll 1
~

~~.''`= '.,,~:_._~~i;;
tir

where ~~.>Cx~.'~~ ~. R~ ; ;ml ~ ,, ;3:~~ ~.<~~ ~ ~dL=` - ~:tlcit:~1t,; ; ~i
]l~, .~Ã.c,t~~i:5 <. .~s.'~,E'~~'e~. ~
ct~~7 >

IIl sso~~'tiliti. <?"I7.~.~+t1dim(.'? is, ea4dil G g;r#?EFp j:a
sG;lE~.'~ctC'.d fTs.`3m x3i2-3.i3Ã 1 $ ~gn,)up shC>vJI`~
~ 0 b0m3':



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ti F
-' :
- ti_~ .._;_ ~~-r=;
~.~= ~..

~..
R,

\ t
p-=. (.Y.r l~ ~~ ==~.v. -_-" \\
f~'f ! \
~.~ ~~ ~ ~ =~.
~.:

fu
.jl
. =
........ _ s:f i

}=-" ~ ,,\ .
F: \

R` R:, R. w ). 't337.C~ ~'i %#id ~~?s f rf <~ i ~ i~f i1[iF ~~ ~a~ ?t::`='t>

K
I rtii g~~'<2. i t '~;L~c .3 ^`~ ri t M siÃI.,
~~{{y ~, :~;~....~.,:..~. ~.s.3~?~::17t~f3.~.+'~'3 ~~:f`ik:. ~
~.~~~~3`~;.is.'d Z 's ~~iJ .. ~'~~4.~'~4 c~:.'~~, Cl ~.
si}; , t~lkyNi z'~ ~rylz Iy .aak~la:yl zxa`aÃyl alkyl Ch{ziya of I N10
w'af;roms: zand
4 :.1cUta'Ã~ S k .~ zat ~ll t~al~ ?~? {g x~i4~r~ ,.t`~~~C:n, :k#, : fE~: t ,
' riÃl.czlt`t:. L:i. R~5
., cv~-le~r:lk1`l, '_~t?':'
i~., ~~ :'? !,
ohA#?'d, i3lkL'li .F"yL it' ar4`IalkL cha:#.n t?f 1..50 d,:wbi>w, ry:ht=IvIn
t.heillk4l, incloslz?ivt alZ'ly
olZ.i'li3, tilkyli.t`yl i,i' anli#lk",': chain is optionally substituted Il1
,eY#:?:.dllR% c,a Ãt.F>?d::Gtlly.: R~

mw or Tnis,c IiVdi\,j'./,li hJ"dto^f,\f..:hi.)1 UGlrifo?}Y=i.
Z.^{YrV`\xyosCGD, ctArboTya:itzd\>> amino,
r

mt?`lo- :;i darsubsi::uwd alz`]lnw, i:L 3.C3l, :h1+L.titmq 5ulfa[S, p
f's5pt`.3W, pla4;3spy3t3l1ca:4, s.)r
,exl Ont S
czg

I.~ ce.i.t~in s:,m}?C?dim-tenÃ4, c.3::h G {3I'a`}1.i~3 i5 s( l?~t;.t~.~~
:~I~fTl ~:t:`~iÃ?l~,it a FE>~I,~~ :lzlL~~z
~ xv:
~r~lt~ _

26


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Q`
it i~
.... ~~ 1,
+ . ,
R4

".. t~
~!. ..........

a xQ
R~ R,,

<'i'I7l.~To cm.dl1. Qj R^, R4, RZ 5 as dot#.n'd hUree.11.

In ccm:i$t R, of F<3m1#.Zlil I gN sC:lwed fiC?F13. al:nt1.sg b'tdio',';f i7.
allk,vi, cZ=dl43<I=.kt 3, alkvic, dc`c2lk1; f:Ã yl, md hLt`'.IL?ar:4''l. h1.
:.e:ftc3.;1.: e?nbod::mt~ nts, R of

Fonurfla I :s s;:Icetid fr.?M rIMOV-9 Ct C2r3 alkyl, vv,=cloaikyl'., :_~ryl,
and In
~~rtum, embod'nie.. .s, ttts: ~~, ofForana3a, I is selcewd.faom am..a <w w;tiy
gso,,up :~1Aowr`
b~
df?w:

~~-


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
m~thyl
ethyl
~..__.
Ãsso p r<?py f
..\ :.~
. .. ., ~. ~=.,-r
~.

\,=. =,~'v . ~,lt:~~. ..'= . " _. ..
. _ '`.:\ .!"= i'\,= `
,.. .. .. . \.. . 'a: ..
y=~r.'4,~V ~==~ ~.:'~\\ : .
\=
i'\.= ~\= ='i-~.~
. v =\\.r~ . "v ==\_=r' .

"=. =,.. y . 4`l r ~` \~i =\

_" :~.\ :=\= .~'~ /~." -~-'~, e.'"+..=_
` =\:"\+,! ="\r_~~ ="`:': \.....:'~r . . If~ ~,~'. =.~~,. .-\,.
~ `\.~;, '~\.~;.. "\.~:-r \-..: =\,...r"l -!"\...::.r ==\:f . =`\:~r'. =,
~.:

}'. - . ,...,

~ \ti
: 1.=. y,.' r\.~' ., _
- _ ,.~:. f=="._
,: ==.\. ..,. = / J~`'~.
f =
\=s..
~
~_..... ~
iJ3C.
nY
...~ = =F1T~.i.
~
=~\:..: . ~~\

; \ \\\`="\~ ,.~^ +~~~
. ..Y r~....
r~ ..

ti~.~'


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
In curÃxair, 4m:sodirm-mts. R, of I{+}miila I is sclected fruÃYx aal<xn9,
all1,
i:aloaiky , 3.:eÃc.~rontl.(;:s 1c<<z>loalkil, zAlkylc.4'ckmtky=., tura=` and
'acÃoroaà yi, w:l::Ã`ein
::li: aliay, ha:[e,~ Jzks ;alkva, tvc1c?{iiky1. .~lky1c, ca~~~ ~lkyt, ~ y"k,
and h,.wawiryl axL.
ty,~~iona1h.,~u:nsfi'Wied, In oxqa:i-n miabodimmts, R, of Fo>~~iu1a -1 is
sclic~~d frÃ3a.n ~unEs:x
~ C# L ,~lkyl., wz.zn:in fl:ev;lk>>1 is <rpÃi4}nA}=su1~stittttod with ~~ ~lo,
01: NH ~'~TIÃz HA,

s37 (=001'1. ...7 csw`.F'tal.n iat"ibod1:r.t3eJTt;i, the Ru ; . : m..1d<Z. I
Fs Seemtee.l ffiri~m at~"loI1A,
?: .

my' W i:up Slii? w" bi ;low:
a,

29


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t?#4 .

: r. Ni-i.

. . .~
~OOH

~ ~~, r +-Y=`'~..
=/

,..c:
. \;;'' . . . ~ .

L) 0j
0+ ry~
V+
~.......~''~~.

1 s ~s;~ r
~ hte

~' ~. .. 2
NH
.=,~~^,,..
\
j



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
B. MeÃhod* of Syn#.hesdAng Nlavl '~~onomer Uitit~

~~ shoml i?eaf3w, ihZ. vinyl Y3:C?hTi?iT1eT tJ:niv descT`#bed }l..F's3.FI'
can, 4b'tlvhe;iz~~L by TC .=i3ctiIli.3. a cof31p-ox`:nCi of.FtJi1'1a[! 1Ftf?
pIf?v.dv a ct?'.'2pLrlsa'#E3 of i'oIalidli# I:

. ~.
I~
~.3 ~
...R.----------- -,_.._....~.__~._ .i =
\ ~\.

at ~l i l
Z..
`A,FL.: Gts

`11w. S,'. ~. " . ~ r~ ti>x jl.,eLe =~'~L''=~` and IZ? i~I~:=1'fs,C~ , ~~ ~tlt
s'`.=:s`~f: i IC:<_ "~ as i
c~~` ~, ~~j., f #, or ~'} :3Eiix ~f v4~{.=e~.~ C:l t:fi;"ied.
he:': w'a}.

and 1.6 is i:l lC av, gyo'i as --e
~,l or Br-
n a cc?mpound of F~.3rn-mla E~Q0, wI~crj`` Qand 6 .;rQ as deffi-;ed
h.feiTl, is d:,;:,L3lv+`.'<i:. in a s?lvs:ilt: tiucl? 41.s h.~.Z-aIlc,
bc..t~zt-?ea tE.3lllt.nc> diei'la~l ctK~er.
k_f:iayl ,.cetatc: ~~iddcf.i'ott,Ã:thanc. 1;4-d.ioxome, tolÃ4tffy~,.~rofar;m
(x`HF% acGtonc,
acotoaÃt-ndc (MoCN), (DNIF), z~irnet.hyl. sulto?ti'ideti oc:..fic acid, n-
t ,
~~L~t:3~f1f'~l. .SC)a;i~;:f>~`~i.~.InÃ}l. I~.~~".x'[:>-~~3c.i.l~.l.'+3,
:.`=~hi.EtE:1l= I138.-:ll#t.#.17.ol oT.6=atL:'.r. tE3'~~E:Iti:?.1#.:
S:i7,,bodl,.'}onx:~, a

Qompourid of Forn?ub.i l-lQG is ;:ii<:~~~lvi:.d in THF. To tffiis solution is
s~dd<. si t: l a. A yltjyl
haltda, suda k h:orde. En 4c.'tain crnbtizdynaen[s .: lsasc as a ti,x:kyi.
amine (e.g. lt: te`hy:al-tx,t1: ), is added to the I'e:i0toF: 1:F1:i?...tir4.
The rLyu . wih; product 'is, a
cCE-y3pi?;3i3d of FoF'3:3't3la i.

I'`., atnotheE' i'.m-bC5dimint, a ci"31pt.'su? id of Formula I is ~~
ies3:ored b4`n ac}i.ing %>

z:omn?:sb}~Ind o~.':Ffst::-lu[a s~~~QGJ. w~:czc Q and C3 are i.lefined: zt-i
ttbove;; with at ac.ry1
aI.h't'dn"dL;, `utfh as m4#h::t4;I'yl1k3 anhydride, en tiae pr4=>i=.Tii:~t: of
i3'3%;SLY s;.td'.= as tI'?ictiI'v[
m1%31e.

C. Me-th{sds of Poiym~.xrazing, V ~~~l IN'lonomer Units
As sbt;~.sn :)cI}.w, a t ..mpd1und c?i"Fc?a-niuls~ I can be pol,metizwd' to v
.e;d U>
comp.~~~nd{ & Fonnl~~ a XK

~:1


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~ i ..~`.
.~ =~; =~ r~~ + ~~... ~

X X 1>Y s1'op} 6~=
XXI pitti#ac :
hs+rt?phH:zÃs

l` . Y
.~"~.~.

\t::4. ~~`! `~ ?~ f{
, .. = . ;~
?~FL, - ------------r~'. 0~'

fr` . ...
-

{,)!-i vi-i
}~~~`'.C>F'fit:

lvhÃlv eaca, (2, (3, or (3 and tugz?lher; and ~~~ Mmo indt:~.~Ã;ndentl N
selected as defined
and r is ati ix~tc >e: from 2-750:an(I

~ 5.,:3ch p3 eL''113Lr1c tt.: il b143A i,fi~C?up is 4C'1cb'rwd #i'T'o:'f1
a:nJn`f wnmni:4. `,:b.iobõ i%:n1dZ`\.so
ph l.spa3atei hyd:t'oxi&,, a:kof1eSv and zflkya3.G:5.

A. iy .:iYE..thodi o. Z ;nyl p13%yrni...-ri: 1a-iion Ssnmvn i>.a. diC' arL Can
be,..:\'~,'d i or Lhis

#'L c c:7.i3Ã1, Fo> ,:~mwitpl a cun-ip{ ''14.`~ t?f Fon3-i4.1lt1 I i ari bL`>
F`cai:=tf-A wÃtt2 a ftt. .. '.".>lisc'sil
mit~<l~i~.a~. ;nC:lude ha3cF4en mo#ixutGL., Nucha4 C1.2, alCi eompownCfs~,
st,c.t .a4 2 , 2 ar:cxbini3 Ã:aetb:~lpaoyiioDibilc) {)VlBIN)> and org<Tn,c
puc?aidcs, ;;wh di 4-=
buty,pw:roxiz2o, Th;c> polyitkettzation canaIso be ~iu.:uced by !:ght an\~ a
ph.}.,zin:ifi: =oÃ';

,,-i one cn.t?i7Ã~imer:t, -a compound of Formula I is di;:4c}:vcd i.~ a
solvcnt:, so...l-; as
13_`x'.iT,o~ i>Ci'1cfiL. to1Cze.,a.:: ta3efl'-iyl Lti#.i:z, C:hlCiTC3fl)C=m,
tfiyl c;c;ft:3tF;;, dachlo>l>Ii C.'thc]Ido, 4r.

dho<3Nw>4 tt.v&hydr(~furf.Y.tA S=iiSBIZLicW.w1L2e, aAreto)fitl=L.t4' (MeCN)
\~+3~I~~~lPJ.'.~\1(~x~i~Y:fJ.6{i.='
.~,
7 2


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
(f)'~4F'), or dÃk~iofli,:1 s=.a't:3xicie, and re:actcd wiÃli A [BN to ~ri..'..
.-a u-sm~.~c>.und of Formula
xx.

In cca'ta.l3.Yn `~:'3:nbi1di.i`$ 'L':nts. the z?('bl:1`mf:3' of Formula XX is
hyCsai'ph~'~~.?a.c and i;=C)rmul:t:`s

P.H n3il:ve group. Cl grf~ups that mz> pF~ sunsitrve can besc1e::.iefl.frc?.in
aai:z?n~ ~.lr~:>

xYt'irraps dcsi:ribed he.rcxn. As ah.ow,~~ above, ~.,t?l.rnc.v~ of
Ft~rnn..ala:XMI 4.~m bw= Omaip6d lt:
a ~ ir~ ,~ ~~l:l , .r;=.~:zsc
group. A".3y- ?n;C'fla+3d aff acid ca4,,fly~,,t:d hydrolysis kais?wIn in 1hf'
art can be uSed, f6r this
Ãõt`I.ns~i?rÃnataE?i2.. For ctx<mapae, the 2irpdrf33Zs#s can E7e
r1.c1.a.zi.:d bv :a3:lia.irsi:ng ehe p;?l~'ant,.`:I~ of

Formula XX ~rac? a htitfi-c?w:h..aric aczd solution. The pti of ~he scAuÃion
be between
,~tifsr:, is ~:~~~~..c.a~ I ~ z~5. 3- >i.~c`
a
'1 ~)c and ` f 0 t~.l and `3.5. ~ .~, ;.t=i~:t~ G~~ ;~Ã.s~ii~~~~.nts, :1-~~.
pl-1 of ~.~n~. s<~1 (
Q~t:7npic. Ã'~c rsi-z can be b;::;<3vv about 6.0, A .5; 5 0, 4.5 oi: 4Ø In
c:ortmii Ãhe,

PIJ 4. >.? :5t.3L=.k' ~.:.11'.a,bod.II1-l<;nt5,~ thevIll sensitive group viln
bC: r'c.;aTlf?vZ.i:.i 1:::;.dS...r busi::
conditions Flnd'Err L=iin b:: cleta-vod +,a ry-m 3fical`i,%.
As shfl;.vn kt3ve, the hyz~~~~~Iffiffic poiymcr of Formula XXI czir, :ncroa>~
1113 SÃ21':e f11S

i'oT?lparod, tt> the Il~vdtoph$3i1#t. pi.)l~mncr of Ft:.1n13Li.G<a X-X. JRb:G
1.7:;f't'i:sL,d z*,i t'. (S;;) S,:.n1ib+:'.-
:7etw,ei:'n. L 5 :mtb `:'..0 or 2:'tt3a':: tll1'lc=`~^' [i3t'. C}i1,I3Lil
Slz`4.. (S 1). [n certain L.t..bs:`d amesIt~, One

Z.~ .. C aig' 1n ;1ity` L ? to S2 is L 'j~. ; '~: ~rvlirw'~~ ~ ~~" ~^....a{ ~+
~ ~~.~~.~iL~, ~.a.'g.,z., ~ ~., t i` =1 '' f';e and 3~~
,t+ a. i'.~.~ 3~! . ~~ . ~. ~~. _..:;y :a~n~.. , t'~ ~a~~4 ~~:- ~=1~ 5 ~.~\:
:E.
2 ,ind4., or 8 s.:n6.F 10 times, ffic origaana} size.

E Addi#~~~nal Y9='~uv~ ~~ioncsmiers,F Polyma:rizations,and Hydrolys.as,
CÃang~idorts

As ~hin~m below, a .:.on~po md_. ~.r., cotnpom.,d J., 21, 3. 4, 5, 6, 7, 8e 9,
10, 11, 12,
13, 14~ 15, i;r 16, 1spt> y7r.A.eil.' :4~i;~~: alone or in
C:.oml:sÃa'ltat.o1'l w,`.:h ians`_idaB,I Fa:{3#`to#:'aer, to fC7rm,
a po1"vnier, e:A, . cz.impound Ia. 2a, 3a, 4daa -5a, 6a, 7a, U, 9a, 10a, I I
a, 12a, 13a, 14ag

'=
1>.."+a, or 1~3 ra. Aa> KVtY i~3~>i#a~{`4rv~ti of ~?YF rl~c'~.~i,iiJ:' 7 S { t
i ,{ l~,a:xE;' .n s`,,. f>c~in bf:. > iÃNw,) e `e
,= r1.t~43'~~ described l~ ~tJa~ ~.~fK

tr_.nsft:rmatitan. For exaryiple, compf3fi~id 1, 2, 3, 4. 5, 6, 7, 8, 9, 10r
11. t ~ 13, 14, 15, mr
e ,. . . . ,
.~~? be r~.:~:0-'~.u(~s t='~~a~.A a 3:reo-~izdkal. 3lni.~F3its~~ 4ilt h as
(AMN ). I ~io rw.ardfi~g c;.}nnpound Ia, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a,
11aQ 12a, 13a,

14¾a. I 5-a, (:~ 16a is sts ric-rally a hyc;roj~h;:3bic poI~iner wl Ãh a p:+
szr:Ãmi,ive t a;?up. 1kily
AnofE-iod of acid c<a:wd'tr~c~f hydrolysis loi-[42wn i_rn t}3cm: cw xb% t3sLd.
to cleave Ã:3o pl-.

3C. ;>ta:isa[: vk g.r[3up, as d<.,st,ri:7ed ht?.i'k'tIl. Ea1zpm<3t1C Ivyd3
:alLs:r:4 ulo.ilt;., or i"n

For r~?:4:Fui'iple, compound


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
2a, 3a, 4a, 5a, 61a, t a., 8aa, 9a, 10xi, 1 Lt. 12a, l3a, 1.4a. 15a, or 16a
Qwi ,3:. ir:n,nc.=.;;ed
in t~ h-,"._{rodh1oric. a:;ic~ so~~~tiorr. 11c resulting ccwmpowid lb. 2b. 3b,
4b, 5b, ~ib. 9b, VAa
11b, 12b, ~ 3b, 14b, 15b, ai 16b is a hzrdmp~~lfic po1~lncr wani can increase
Ari si:r:

bt.:weei .i 1 .5 wA1d or mor(;~ li2?'1es fl3'l'% L7F'3r:iY3Ld size of
w?npo`ttnG I il. 2a, 3a. 4,i, 5a, 6a,
7a, 8a, 9a, 10a, I I a,'12atY ~3a, 14a, -1 5a, or 16a, respectAve] y. For
cxx~~-npl w., compound

I ~i, 1,i. 3a, 4a. 5a, 6a, 7u, 8a, 9a, I Wt, Ila, l2a, 13a, 14it, 15a, ft:-
16a can bG ~~)
mn _E..ldii'. ~,t~iuÃloÃ: f+3" wH,.Ãt?us pÃ'rI.od;4 of t1Ã&ie. Longer
p;I'Ãcids t)f exposure ca:'i kad to
itZ.#.'.`{t.well:fig A~te1'3'de`:bfiw methods of ziC:hTevivq; gi-f..el.oF"
g.+.;`i4't!'a.,l1L:.=31AQ aiiw,51ng :h

:oi 3:.1arc?.i..t'Z' ,ir'ec lCõk>e=.:-nG; thc ~T1-1 . `~.~~1L~ tl~9t'L'~. to
1'~i"ti'i.'.I'.1~1: ~.;."sil,t~: sti~~:~l`;~ i.~:,Ã be tt~.~-.i'~'~~<i
by =.Idd#.3'3f.; diff:3z3ctioni:~l czaf~~~ink~.?rs. Di1E3Flcl:aE1..3z cI'ossl1-
rkkt.'.?'s it3i:h3x.:i'. &11--<m:yliiW 4pe: =fLs-
<li"3d p`t?i td~~ et':?ash.Al x,` be-tweet-i =?iC3yinc;.t` chains fluil
fuabi:; 7e5E.7dl thi ;~#n s.3f i.i;o
p.:.EitzCli` t.`?t?-n Q." ::~an'sif?E:.

1, 2, 3, .i?ld 4 111d1vIdwilY i2te p(3lv123cd.izGii to fot'Ãn :%po ly i 7ie#
t? c~
e
e.o m p () u i ^d I a, 2 a , 3 a, :i n d- 4 11Y ws sho w n b c l(.) w:

v,T~4


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
f,.,~ R ~.:
..

QH QH
~> ,~,.=C}
la lb
~=ri

,..
R; 2 R:` R.

2a 2b
~

I` = "'`\ ~3 ~. E #Y
~s'rt,~.~= w.''-.,i` ~~t _.{'~ 3a ,~E~
~ `::

H. 43
R2
4a
15hcre each Q ,n;, R? R;, I)t". '`'`I.~.d tennmal ht:Ip zIie k:}dC3p~~n{ji.a.'
.' 4i teif:>:. as t;:~eft
(~ i',;i ~:=3Ã1..

C.:1F3# oui.i.` 5 and 6 are "B1ilivIdu3lly poliI3'wx`.i:r od tEs 1i`I,in :Ãpo~
i`#.1 LI', e.g,,
c
~ c~}it~,a?5311'{.I~~ 5a~ c3nE~ ~811, iti s.~3\"Ys~1 ~.~~.SC`1S':



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
r R,
, ..

a lo
:x---~~= y /, ~
;~l_-~Y~ / lw_:/~ ~^ri.
~ i ati3 5b
r
~,

R2
, ,

s ~ F HQ
i P 6 6a. H.~ 6b
P14
L?.'`leI k',. c.'dh Q<'{ R:?, R4. R. ~Etli{ t4=1ÃZdiIa.&I ;;,Ei':>l.p 3Ie
.i#,idC'pondGÃiil`T \(.lcf~:t4d as de.anS>i~.
Y

CCa2a'?p<a:l.tad 7 and 8 m4= Ã.ild1vidui1lly pC3ly#'a1i .S'"s'c't'd to ft3am a
po.yi23im t -g",
L+E,'s3`Ia.~`'J{)a.l`.ad 7a and 8a.~, as shown bo3.LJw.

R'!.
~ -Y~t -~.~ f,2=.

~ ~l = ' ~ /= ~ !~-... +f ~ ~"-, 4i
R4 H-/
Qf R
A R4
.~---~ `.,'~,=
=~
R,.
7
7a
Ã~-
~`}~_-
~~_ =~ ,'=~~~~
`~ ,.~....__~..

41,
i;. =:4~~'
8a
36


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~~ herc. cac:;Ii Q n, ~'~ , R<:_R;. and :.:nninal ~~~~ip :u~ ~~~depcadc. t`y
sel~.~;.ted as t1..fined
~~.~=r~::~~.

~'t.'f?anpC`und;g 9 <:illia 10 al''L'Y i1id;vldL1a(ly por'v:T3leTizt;c-I to fa
l~`na a ~]C~.~!`S~~a't, c w:.;
,:
com;?i3,3nd 9a and Itia, as shown Mowc

a f'~ i J \~F ;
rw ,
t
~ tc y ~
{ -- ta
V ~~ k~=Y'`G . \ ~i~..

-~ .. . ~.<.

~c3
t "~ \ ' . ,=v,. :^j 1..~. r
~ =
` .=G~. '.
_------ -- A.

r.=`~ ` ~C~ t,Yk~,#?P
R,,-
143

~NvhL.Ic eac:i ai, :.'~>.?, KI> R5. ;.3ndi tiyr#3i1rlial gt}t.~.~.;~ %11`i;.
11~.~kS.::3`t~n~`' ~t,?.+.',f~f~'.f~ as ~..c,iÃ;.if.'~'~~
Corripoul~~~ ~ I -ii1 i 12 we .In~~iv'1d;.I<ill-vpt,fyZ14t,dir:ei; Ef't ii?I'm
:s polSni:."r. O.g,;
_ ~..
co~~~pounL3.8..3 a and .1.2a, as sliow.~i beFms'.


-,:
,,
?i


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Jti`\o --------~ ,

{ Fiv
`{f

~ ~ ..' .
-.: ~ Cv a f.j: 2 17.
~~a {
-12b. i'.

where each t' R:., R4, Rr, R,~.ania t~rminal gmup a.?c se;e :ed s~s d.
fincol..
C._nipz?um1S 13 and 14 a,G: R-iÃ~ivzdua1ly pt31~raerizc:d to aimn a p:r~~~
rier. c.Ã_,.-

: s)i?lpomnd 13dl tznd .1.41t, as shown belC3w:

~
3


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Ã~=:
f... ~
R':
=,..-r
M ~r ~; s\
= - -- ---- ~.e õ~
,a

;\
R
R5
13 Q
R' 13b

, ~
i ._ i.t u ta
<Z.ts R.

+f~fi
f*Y!
R
" 14a 14b

wh,e1t!. each ~,,' z3 R-i, ;.~w4z ::~- med t1:17n-ii1:al gx't)tip aI'e,
Fz`t~lepond4'.¾-l'd sLI.ci4d a.~ d0fined
}:is`.'1'c:if.t,
;:'orzypounds 15 and 16 are In<lÃ3Fidua1ly poly~an~.1ri,xet1 to rann a pfr`
t1z:a, e.r;..
c#3mpi?faa?(i .~~a aa7Ca 4.6a, as shown tk;low;

39


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t'; ,'~ ~, r \~ ,f,? ------`A- ;it~
D 1 -- \. =s.;,~.
it;, Rs 3 ~r rZ
i_ .L:~ ~~3 lw6?
15b
P. 15sa

i _......y,. ,~.. .~..,, . ; ; .,
. ~3 . =.`:,,..

~G 1~~ ~~b
wa]ew eac3i Q Ia R^w R3t IR+., R., R . R,.aF?ci td;:~~I'nAt":ii:#l gt'43up

E 'i'inyl:~omÃ~~~~~y-me~s and Copolymers

a i'odt..d I3n are p?,'paretl bv p:;::v.T?C.? S!i'I?g a vi3`_?1pi_?E:nd c,,f

I~z}rzY~~~la I. In sonw c.rl-ib<.:?di ment=, compounds of Fonuu1a I car-L bc
cc>,=~~lyn"w:t:lzcd ~,.J;h.
.~.i?I
flÃ~~` vinyl ?~i3it~"#.i11.3i::f described ~"3<:Ã'E'i.Y7. or `t, ~'~':el in
~'~1::,~, c`~'. For +`.=?S:i~IIi~.~lC;, C,ripolli:.i I ciu:
be Umpi?l.t?2d 2, Compound 3 S.,<a.zi be L..{?'-p(>lp2:C.1'`.'iCet3 witÃi w?Zr

}via?i`.5known i'{?th ai"=t. orL'.:`ia?"npEZ.'.nn+alhyl.mC:dhav>vS'lat{ `.

Ir, t<thÃ,i +, .F=zlhi>diI7.?ents., any 5'E5mpoL.aid5 of Fo~`a`~~.L3l< I cwi
be i:<?-pt?lyflz't;lizoie ;? :ch

r, ~, t'l i Z e= s ~~ w ci to tt ~
xI7?' ~`1Ã ~~ i3.Z.'xll.Ã~ .?::'Ã~7E;t~ iit3e'11s ~3~ ~ 1#irlti%I3 in the
c.~~. ~f. ~?T"...+.~f'sff.` a .::s:fC~i?I~ E:i`~?Z~.l,i'7~ati;1'.
%i block 'ti>~~f?:~ 4I.~.Z~.`, a_lltC:~I1zi~:F]c, ,.opi3lynlG:1, or 'i
"1'<3.ft C.op..iy-nor wslng any mellt?dti
kilownÃI=` ?lla< Llr'..

hi iidd?i.ioa]itl t'.I'fAi.'~4:'3dTlz3eI3I4, c1.i'y' compound of I'i1i`'-
rII.El23 I L:;;Ã. ..tF :E3 ~?~?{.4".tFt ,~,;~=~:
w1thi :t27y- V:?'lYl nC?Ili?a:iC:.t" described hS:.Y'cISl or ~ti;,~Cywn in the
arE'i+? Y"4.ld :`~ lidwc3'`

h#ur; or Ut3?,":3i~ ~.?i?ain~?t3 ~t;;Ii^~õ i~.Tly' methods ,~.ili:~ '#i Pi~.t
s31~.

Any2<,Z?i5 of a Sli ~~.,lo mo:flt>E"Y3er ?'c(atFv4~ to 'sllxs.3dw;
2]'iC)ni?.I7?eT= cw1 bc t3sed W -fi.ti?'1:i3. w.
ffp.?lym...r< Difxue11t aatioS of Ã:-ic1iol3'?ei= fsntts i.?iipaT't
d?ffert.nE. pz'7:Lait.az w1d i'henÃcal
x t
~:3"'~37~7i;3'"~.ie`?'L43 the i~xl3'i~lE:]', ~~::'L?~~i.~~'~#~;'.s of
}zil:cros~i~ include, aiut :3~o ?~L?t :`.l: I,`~'[' ES`.~ ~il~:~l~;,iil.k


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t~an.sitiot~ ~om ~~~..t~:t~~Ãe, ~~a::l~E st>-~;~~Ã~~#Ia, s rt` t<~lIiji~:~,r,
flexi~iait~ ~:r ast ~~ ~ ti ~~l

hydf,'t?p.iio:,tcli'y, Y11us, by Ga.:'S:iiig Ã1101?0Td3.C:1:' ratios, it is
Pos+i:'~le :Cr c.iff<}rd i copt~lyrnei'

wiÃ~*i f1o4i.etfc'=>~racÃc:.-Hst.ics. For G~ample, introcaui,tion. (?f a
bul:4y hyd.o;Yhob1G side
:~~'t)i7p will. ako flIL ptYl'r.1n4i more hydq'tsphobÃC cEiii3 Ã4G.uivt the
rat: hy-df`i7lys1s.

GF, Additional Polvnug=~ ~~~~~~ as Polyc;sters, 1Poly~lthcc`s,
and:polvearbonaws
Ie

i1~1Ã~ ~3i3llc~ilai if? acids can be prepared ~~:4cf11'e~ÃI~y; ii? the
C~4suIi~1ti+J~1 ~~13 ~iji~tS~. 1~'~<t.4'. a' ,~St.
viAn be used to õ3'.iake ti153 filn3s, A:3i3I't7ik,,.sT r 'Lasõ and related
dLticrl.bL.d 3.'tc3"5..ix3p aÃ:d can be usvd e.g., iCS Ci`4'l2v41`\'<1Cio..z:
i{4õf ,>v4; g bitK3u li`i... cli;t:nt:i,

As ti~:E~sZ I.'i bf.ltJw, ffis. %hcrnF<:iÃ:x :: i.?"l,ietutE.S of :.?Yi.3Es
ÃleZv poly~.:iLg s ,m3.,Ã;:3g
F f;3-~nuhws XX r. XXH, 'iX; If, and XX iV:
f~,=
' r ~~ ~_ ~ .=~~~_ x?
`.~
XX I

4..: `

k'!~='~'+i~, r'``=~ r~,.uf,. ~.t~1'\. .r~> .
.. '{ ,'\ r. \. = ~'`l` ~rt ~'1.~~ ~ti~.:r'~ ~\'~ k~,
a:1 rtr ?,,
:.?ixIt

f; rl' fy'.?
I'v' .r .

r"~ .. . ,Y`1.F`= = '~ ,,,i d.i~' `'.,\,. "r ~~.~ .i r ` 7~ ~r
xxit5 !? ;
L=i,

c+,
~V

r ~ ~ r
: ~.:.~ + '~=v .r..=n~..~ : ~ ~. .~,-'.
`--4-~.,,.
1 '~ ~M.+ 4 ~ ti.~~f '..:r=' ~-.~ ..i,.
x: aiv ; i

41


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
w;iG;Ii:: ci.ch Q fS iF3dZ''pC'.ndiilil;' s~dccti::d from 's$ma.31?Ã:. (). Sõ
` )'i:., or N14:.

GY Z3i% and 62 arG l:~GIch indi.:p[`ndendy4iw,leS.:ti'.d fr<,`ii1 i:i:.no37&

or R.who'whi G:,' und Gi_, &-ro not ~~~c
" sa

Ri.' is :eclC:oti.'t. fi`{_}i~n among a sUil.lgalt or bI :I11d~ied M\%
L'y<,.toaa`4l cli' % _ <?ie'ik.z,,
A yi, t~lk)ds;Ial_ mry,sfl yl. alky'<ixyl, a:-y1alkzf) or flzxo>-txct~~bon
dhain of 3v50,
, t~. ....
tVhereÃi; t.is;.. alkyl, c~ ~:I~.~i~.lkyl, :x~?~ 1, c?lt;~ii~ :~~:'~, k~11~
I~i1~~I, . j l:~ilyl tl:~>~.~~I a~,.~-1, ;~r.'~~ilr~ :i
~ yl

hy(f-3.o,~~yl,, hyd oxyeth'4r,, ca.wbo~~yf ~,4i~~boxy1+::jE-cr,
carESoxya~~~~1.~iitioa2 Xint!, n.ono_ or i~:,,

`r1i,-)StÃt17ted 3a:~~irlEST thiol, thii>t..5:~.; sulfate, pa:C?Gph3n.A`:v,
oor ;1,'01o#r;o$]
3rfieili: i:S: cs:'

R,, ' is sZlZ'i:;ti;'.d fI'l?i?3 cxY3:3ng pC?ly(~thyii'.lle g.ity-col),
p53ly1c~~.~:y1a;'I,;' ox1dc3;
polrr~(hys?wotiykicizi)); a c,:rbohYdraw, a pri,?win, a polypoptli&~ an am;no
nid, a Pudci::
ac.d; ..~~~~ eofide, a pc?~yi.,mclcr?iidi, t3iiy DNA or RNA si~t~~un~i:t$ a
lipid,
~
p<~lys#?t.cha.i'i3'e, an fli:tibofsy, a phc3.i'rmaoci1tAC;i3.l c2vt:I3I, or
any vtiittt?~.3t. r.fi` a ~~li<;li)g14:.i7.l
A
.~5\.`\.~=~~i~?y, or

R~ is :tit 3o::E i3vd frolyi .iFru?7ig p1ht3tC}cross11nk-c1blC' or
1o1iicall`0 4Ã oswIinkableg-r.3lp;
t>:`

R, coIlipr,,:iZ:s a first group that is L`l)I1~;'~`(.ii`xlvic to, i`s
s't':l.t}nd ~i'i.'+%.ip the
fin4 group at a pa.s os or below about 6,0;

`c a` lw W'.4;.tcd fiau1-n a`il.bL}n' hydroge.n; a straight o.i~~ branched
alkyl Ut''Z'lIialkyl>

art1 oa fia., si,yl, adk aii.yi, arv'i:sily1õ adkj`xaryl, aryla~k)-=l; o.,
Al..ion)c<irt.ois chain of carbons. 1,11Z a.kyl~ cycxoalky'1, a.23.>, ~lt.
izv; silyl_ aikylsil}'1 aiy'ssilzl, a;ks atyx

:uy.ta3,tO"lt, t?.i' ::bcw3"i:1ccl::?ola chain is optionally 7ub.`a'+;i:n.itod
n:ntomad_5Z' f)a WT-i-ti,10.~~aly by s:1:'3C.'.=
cw mai`Z 3L'ilii;~~S53, h,`,rd13:;S:yChe-#'. ct.B.t'bt3xyl,
c.?E'btl?:y~.aS1iT, :%<libi:;L'G'ai'..Iide, n'loA3C3- i~FÃ'
di-;it3l,"Lfib,i~od ann`>nor }hatxl, thlt?L'.stc T, .: _e: <õtc,
j3hl3~plh:3ES;, 131it3sphi?I1.3tZ, (;: .3.ih~3gc'ii

412


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;S and v are t.."at.e}: selected fro.ITi m fntegE .I of a '>'`4~` and

wL.~#.`. ~'~,~i~~~~~.L=~:~% tor#:~:ii-n[kl 4fi;'ou-p isse3.ecl~~ froiii
aynovig an-fi:.e , i.#.nZ.~do;:
ph<yspbat4v. v~:phate5 xv; il~~~~~Ide,,,, noaIs, a1knos, alkenes, wad :lk.Ms.
A:.so prowis:=ed are wm~.~<?unds of Fo.rrÃaula XXV and XXVI. as belt?w,:
G{
~ ~~~~~, ~=

.i;~~`i` ~t ~=
G'
~j 'txvi
i .
:~}:tr u<#c~` Q. :} , S; !'q itl~~ .e#'#.7111^~i_~ ~.?Ã"~3.~p are
#is~:pi`,1~L3~:T~~E~;~ ~~a:?4~;~.~.d ~~~ ...l,3e~~~` ,1~:2~.':it2.
A >io provided are oompowids, of Fz?rmuia XXV11, XXVT,i, XXIX, and X-X'X a,,
.
; bozvii bek3~N-

4 -3


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

, %;2. ~~i ~ <S. : L~.=k~\ ~ f

l \ ~ L, f./` ~\,\ ~~~
i l.
MAI

~;'~ ,=;'.%r`~
= ~ ,.. ~.~:

``~-~~~ =:;=- =~= ~ ,
r ~
l1 f \ +'"~`
S ~ ~`=.F' x !

:KXX
iixix

Ladh Q% il.id teÃ`m.iwii v #'~~LF~~ Fi[i indt pe1xd4Y)tlSs .t C:i ;C: ~l
dÃ.:~fmwd
t ,-d;..h= ~=
3zt;
r3Ã:~ t=nd

3 ik suhk{:'iQd &'tTm an ÃntÃ:f?.er E?f 1-25:

Aas{? piovi6M ai'c cc?mpi3und.S of Formu1.i =KL XXXI 1, XXX . XXXIt='; and
XXXV. as show.n. btlcn.':

44


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Q'

XXX:t
~ ! ]
}

~ Ft ~ ~\ r~ ~\ r~n #p: G> :\ f t\ {,,
~R ~ `~i. ~ ;,! =,..-~` \~ ~"' ~`~, I ~,K .~{ ,,. ~ +~ ~ ''FF y
~' J~ ~...~~ ~}= ~, ~r ~.,A',

;K
~ ~~TV.. -~h, r{~~~~~-4 . .f~'~ ~~'~~ f'~~~'~. .,,..'`= ~.at~~'~ ~t~,.r
xA
( l~r
r
r.~.,'`3~'.. ~=r'`~.~ ~.,t~'~ y'`~ C~ ~~
b: 1`_a~ ~i.
X~ ...`~ . . -~, . 7,1. i.
~S_~s..~
r r+.- ,

L'K` G~'.' ~p?

'.E I;:,'t` v; and Wunini~l group aCC', IÃ1depe~.~dently scli,L.tQd as
de:.7.u.ti; and
b is Yo ccwts II'"oni ai-i Un:eget' of 1-14.

Also provkdef~ are compounds of Formula XXXVI and :C-*,,XZ'H, as s1::oNvai b;
lf?w:
XXXVÃ

.. .-. .r}~r


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
whoae cac : Q, (33`, R x, i', ytlici Ã'o nslinlal --yc};.tp aro as d;,'fim~~;

wid U is >oiQc:Ãed ali :ia:i~gcr of 1 -14:
l?i c::na;:n embod:mf:.~rzts, [Eic. (:3' of ['(:xmud<: XXI.-XXXVat is
sUlec>Ã.ci fii}orn
any group sI7vvk''~i b5:low;

vz`~~~~4 oaci: and R :' ati ii:i~a'~~~3~c~e~z~~~' as aefi2:ei1 Iwrd:~~.
\ f t ? " i ~
In i~'t:}~ ~~3".? X.;5.I.,

~XXVIa .s, inciop4n -izmt1;' sÃ.~ec~od fflo:7i aa-nc,qga ,.~'fpt?p shÃaw b
low:

46


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
methy l

e:"yl
~.......~

Es>r.3; ;"opy?

..- \\~~J .. =;, ~.. ,\'\ ~ \\'\
\\

-~,~ .. ='\\

= ~_rf'l ~. ~ . . =\~\!tr \ \1J . \\v ~\.~_ ~ \.
r~=\~ \ j-~` .. . I'.-'-..\\\ \\ %r\:` `f ""\\ .-`~\.\ .

...\\.r` ...'` `~
rr=i - ~i
,

.. _ . . ~ - . \ ,

- \. -=.\~ ~ .~.1 \~ .l-'
<,-
. st.\. .. . r-'

\.......~
I . ~le
~\f khe

LLL \, tG;~ r ~J\

In i'3 i.<33Fi C::i7:lbt?d:?-lent::?, ti.'=aL'h:R;', Q', G-+`, and G'
rsF<5?i,3 of c. tly of ~ ~ \1Cf. ~ C~ ) ,C
:`f.~.<~~`~i >~ i~:za~~;.~.Ã:t~..~ ~,. ~,~.~~r~, ~'t~~z~ r~a~~~a~~N a ,r~a~p
shown l~~;lz.~<~:

4"


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~ Cl
"~.

O ~r
,~ ~ '~~`~.~%`~`~-,. -'``~,.= ,. <....-.' `` ,
= _ ~ . ~ ~.
NRC
_ ``~...- :_=,~=- ~..f `~ ~:,?- ~. ~=:

...=r''-~~`~. i,: ~~`.,%~~~~ti:.;-' -. r ..'=s` . . ~ = ~'~ = `-`l1 =`'. ~~
~'
`~~ l; .=~`~ .i-..~~ !'~; v
~_:l)oi-i
0
7 ~~=
~ ~.;~}~`~~ ,"'~``5.F='"i ~ `~,

~OOH
's

0 0

1 j
; ' f?
~....... f
M~ NH^ -

``~~-''=~``~'rS~~~,.9~ ~
r-.
"~<:' =~;, ;

i ;~1 '~=~~.~Y~~rr ~`Yt~J ~~r-~'L~{.

\ 1" `~= _ ~ ~
s
~~H

4 S


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
I ,`, t,i~t:a`n ti=irabaztsj?liE.a1t`. oach R;' Gs;`<G at:cA Gr' isFf3t.1p of
x3.T ?S' i?: I'i?3'3-t71..I ,i xx ::.
4
XXXVII is i:=.idelmliai lfliv :aC.lt.cted fi'(y2`t7 a?-nt3n~g a group as
5ho,~xa
..\

?=~~ ~"~r
~I.. K

Q,
',t'. r `=,.- r.\r= . ~`,,.. `~'=`r
~r

+`,. := ~ ~'r~~.~
.. Yi ~ -=.~\ ' . . . ,~ . ~~'~;:~,` -,>~: - ,
~=

~t .... ,~
\
~

(=J

. 4~.,? =,..~ '}`~
Me
r
n1.` i ~1\ p
Q }
\~ ~J' =,` l ~
#k ~ ~ 0111
~...~--='`~,

vwberc eadx ~~.~` is ~:~C~~~~~=.t#~~ ,~~.~}'' ss.=1ecied ftom aniong 0, S; SQ,
or N111".
49


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~.~ S L~ dl~l ~:133~7E7Ea1.:l;t i1~3y each R. (',', G~'y and G4:aTM'C3L1pi?fmy-
of Fi?:'il:mlc.. X.X3-

XX'XVU is Indà peridently :wlected.firom ttziioiig ~t ~~.Foup tts beIow.

+^t? k:
~i: ~...

r'\
' ~..='f~~. ' ~..
\Fi C, H
L~r

-.2

-~r
. .. ~~,..:. 4~f1
\.~
~t.

zJ

~,i {wY `~ r
'`.

tmch Q' is a:;idipenda ntAy wixlc~~ from amoiig 0, S. Sc, or Ni-l.

Iil cCrta1I-: S:,znbZ3dÃr::wrYt4, S;E{E:.h Rj`. G. and G' g>t?up t?fa,:ny c?.
1";?r;x~ZEEl._l XXIv
G
X?SY XVI. is ia dE?px'nb~~~ ~ly aLls S tCd ftEjal3 :I37 oIlys a group a.-s,
slli.`w-n "!elE),,:i',

()


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~ ~. =\1~ r;,
~ . . ~a1 \ =\_ \ ~ .'t. .: \. .!\,.. .
Y~.

. : ?.:,. \ ~= ~ \. . . . ~, .
~r} ~!=1\. . ~`"\ :\..~. ~~
=`t~ .\,` "~.`.. .==\..\

\K, . l~va~}.~` ,.=\ . _
f ~ _.r . - -4Y v \\. , -~:\!=
. . - - ..;~}=.

f1' ,.-c:'=
1
Sai

..'v:i~~.\ %`=\:\
:. Y, r 'Y':=~. . \~,\...

.,' .
`~ . . .. ~\.\l

S i.a:= each Q 3s fiidwpor''C}.C.nO t .S'd'.i:ct~`.`.~.~d from among 0. S,
Se, f3i- ~'~iii:

fr ~r; 2 cJ t ` r :2r>l~$ } {r r ~ t ~ a> ~2= ~ ~= 1S( ( t CC Y>](t2i. i w ~-
V;_ayy.~ A 2 k.i~Yyt i~~fl}.n~:4.~~~~ r~ \.~4a~i..~.S ~~'r~ ~ *~hj,s.:~~~
Ci.ai\~ ~3 ~y ia~-} l C.}.~, i[iiY~\~~ 5~2.2.i-.. XX>
5.`^
XX_,'~ Y' II ?J :.i~.~E# .~ Irist I't~~Lr ~~ ~ti.~: ..~ : '~Ti3~1: s~'Jl
t3`lg a g~l.~,`, as shown ~~G..<3tr,~=':

51


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
CvH,
Q,
~. . ... . ,.
~'.K,4. .~..~ . .. ,~ p .~.

tiv:+

C'~--~'..~iH
"'Ãu

mE:
wh1.~~~.~ > ~' 3~ :~~ ~~{~l1.~.>o3~Cf3 ; Zrt ~ ft~ ~`'3~; or ~, .
each 2,~~ <...~'~ ~~.r ~.'f-~t~>:` L~ f~~i.'Fii~,~`~.~~1 among .. ;~;,

1lz i?.~<`F,` ,,~ of A.? #~~i :'S.~'i..l
-
~,;.~. R ~:rR ~3 ry.~a~^r 4~~~\ C.~' F-,r", a + . i
Ir, 1f.ova x ~~ .~l bL.>~ and ~Ã.i.~~.:c~~5:~. 4:~

XXXVf. .5 :.I#dt pi=#.^>iently' ~t= tv~ ~ ~. from aT?-T11:4: a g;0R.ip 'a"
shf3'4v3 bC S(t:t=`;

5 22


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;??ethv;
~_.... . ..

., ,\_~ .. .
-~.
...~y
~,-
. \'. A\ , +'\~==`+,\~`-. ~.

. . . ~..~.:''~
~ .. ~ \.. ~.,`

.. \;.+ \
=\l =\` \.\ ~_ ~\
\

~ \....... d
~'~C` .y ......
~47V

Y ~ \~v

..: '.

iL;,o pto\'idti, Iw C:s#;'.,#pf:wnd l)f Foii3el7h X~~XVH5, ils ;,f35'i
3be?f3'.4.:
5i


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;..~
.~~~.

' '~, ~,,`~ ~, = ~` ` t..
;=~>
u XXXs II.I
. f
`~ r~~ ~i~? ~ i' , , ;~ S and Ã~'.3"Iix7.~.~~, g~')E;:'3 s .< =~ ;aw e.z ,
~õ~
~ ~.~.`+,;~av ~ C ~ ~. ` ~: llrLai=~~?~Ã :41~.~~t `
..i..,i. a.. ..~ = ~.:...~~.,.L..C. ta.~ w~~.~F~t..~ E,c ei: _
aad i> i4 t!l~i:t. ~~ ~i'i;~~: 'c11'# r31t ~,~;~1' 5f 8,

IF.: v~iiinfta;~ embodiments, to i::(7.i.71pi?wds i,& Fz3t'awla XDXA`#rI3a
i:=a?, b(: a r~.Y;.k:m1;.
a block >_.t5pf#Iymer, aliem;:tting cc)z,E~ly'mer.:sr, a rfratlctrpacyme:

ai.:fm ~=,bC?d?i?1i9.n1, the t;=f?f?ym"Fid [}fFL:EiT-nl;.a? XXXVIII is a
c:?mp.?-ul#d of
:=o r3=3#e <a X:,~,-X2 X, es`

_~E.=
ta

~~i1 ..` .r=1 ;1'i r=. ...~.2~ r=~ ;<1
- ~ ~~..='~ `~-.;,-`='f i`.~. ` ~ +.`~~~. ..`ly}~r ``~~r...:<...1 `'~:.
1J-ti r
t i ~

Vi3.w "i: wi#w'h Q, O. X. y< ~I.I#'.; lS:t=:d'n:nal g#'tafsp ai`i.:
indC;pt;ndZ:nI.L tio_ReGtet ;::5 defined hi:n~m1.
i~ :n w.'erta:Ii-; umflb(sdltncÃ.`3~ flw cm=~.~ptnitli, of FE`õ$.Tl u,?~'t
XXXVIII :~: wiA:s.:ti'd
nor":~ 'I f}
i.. ~ a.
G~?~ f f~~Ã
rii ~~ '~I_., ~:~1, X1:1I, i >~' +. ~'LIhl. ii L s s ,z,3~bG;,._3<.~~~_
r r ~ i
54


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
XL
b
r }} }] i
{ rr # _

s ~.~ll~;= t
`L ti:Y. f

='r
i x '
t 3 + i =,~
x> il1 ~Q'v

~l -

' ~, e ~' = `
N

:~~_:~i: , = ~~ ~:

> hc :t`L~ c,..ch C: x: v. <.,nd te-m.in.:;l t à oÃ;p:) an xndopi'Ã:d~.'11t;y
stewied as +::t.f.n4J.

a.i ce?':'.3:1.1 ;mb+`iiT.t-&t.3t4, a compound of Fwniw...:sX;`5X%`a11 s .
.3cbvS:ted 3.if$i~~l
w.n~`.3T]g a ct;'?1?:.FL i~?kE~3 of ~"~ 1T~;a:f~ X ~rz'liE Ir ~~~ is (~xy
~.~'~, In :<Ã~i~I~? i I1?:?~.C~.~sl1,' n`~.s, a
==.y, t rr..~`Il is ?C. -.7~xS;>;~i~~ <a a lS_rf.s~3 rs'?LFf. ~' Ã r i~~z._ Y
F`~ ~~z~s+~3~~:~~~z. i?~ ., vs?M' ~~.>wz~ ~1~.~~'Y3 ~i~ 'c#~T~`?3~~ ia ~
i3:w ~~Il t:h~~za ::
wF , in c -r ~ 1 ic <> ~# < ,{ ,{ n e(:r;.:~~r.~.. a. ~ E ~
...4_'L.', ~ 4 tia~~~~~a:~ certain ``e';'3x~~ts+~h~,.""'...C`n .`~~i zx
<._.~ ~tz?%F i.`~ 3. XXXV :~:; F is .o31..t{.',d
=-~}.r -e s r c ciata~a= =rdn:~li~ Xa. ~1 r.:.~ i= ~ :'
~.1, ~; a L:~:iT~~??E.Ii~'t~ of Formula s~'~a4.:i'~.=" ~ is 4, ha
O:1#.c3d::

r mPoL>1ii1 of a > : ?lt.ta 4 ~X'Vlll is ~O ,. d c'Cs1u. amEmÃ, a ci
I;':pi3.#.I`t of Forn.wha X1:.1a..
4,~
)Y ~f `'`. { ~r 4 .: `i .i :

~~hA 4'VZ~vt-~A?t e~~~2C2\`$..fine.Skti,ti5v.., compound o~". FL,[Snuta:~
~XXVI+I. j,~ Lihi.,lt.ctGV\,e )]ona
,k 'r ~;f t ~. i~ ~;i:.
.~ ~l7g i CS.i. ~. ~%t !r :~~3~ 3 :~ ~ of ~ i. ,7 1~3,.~c i~ :S ~rLV~r, 7T
XLVI, L?I,~ ci5 J~'' at. v4sa1 s ,
. ` 3. ~. .+i'YZ C
<l r.C



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

fi ~'~`Rf,t ti.~=.r ` ~1r'' ~ ` i.~~,( ``ti=~ ~..~,: ' ~.
S

X: `
3i

0 : ~: ~`~. = ' `:. ~ .~ ~~

` =r~,~i ;'v
Ni#-}
3 $ ~
;:S> .4~..';:3:-<. Y X. s L:Ãf . it:t~ < !are z.E~{.~.iN~)v5Y'tli.i#~ >.~v ~
.L[~.4..~.L 2 as Ei'ai~1~va..3.i6,I=.S :~'Ã.
c..#Ãi3S)daauÃ`',~, a cf11 Ilp(1uTÃd i.+-rFd?n'iw~ aXXXV 1.1; is \e. E .L~.
3konrl

Ã~2,.E}e~lS a,.i i~,:;~t~?Il?.d of .~'i~;":E~~t.c; X~.:~3'. I.i C`~';:"~ti1#;
i:a3.-iFi;~~.l>`..ti, a v<,3 -2-1~~);~..~3t' S?.. ~ai,rÃ`Fnule3.
~T
XXXVIII . si.,?.,t;l:E:d ft?b3Ã k3a~loF~g a i:oli1poÃ3n#:a E?f.Ff#3anÃ.23a
XLV. .i^ c.._E.,,?,:Ã'1

4mlbt?d:+ w.#t`:. .co1'Ã:poulld f;f.1,01."e nuaa:XXXV1.111. is ~:s=i" f.ikin
LEÃz3Ã}i:h:. t,5.:3~ ttS~
FL1I j~ X,., V :.

11. ~~~~th~~~s of:~~~~~~~~ers of Fo~~~~~~~las ~.,t'~.J - XI=NI

A-faSe #.,~a\:vh(id of pi?.t4`n icriza4a.ion. 4aii tFC:i,isx'd to pnmiLa..e tE-
:ic poh'E`a4; ` ,, aM1Fi?~~~~ula.~~
XX1: . XI,.VI. ; or õxanap~e, polp-n;,r` of ! ox=mulus, XX1 ,XI_ Vl can bz,
prcp,.wc~ ~ ~ .at~: -p-
l7# F;-k?t)i'Ãl#.n- pt.tlymt'rF1<3.Iion, or 3~E.1i5?i
by
I
As Sho':=k'n belC3%,-, a polymer of FZ?nitl.`ix_. XXXVIII s.wi Jx;
pr3:.'.p.3.IE:d by
r . ~.
#i <]iZtZÃ`.:Ci< 33E;
~~:~iSf~~nt,.~'Ã~t~#.~tÃV?> t3. ;:: ~.c.EE,:#;t~~ .i7.?t?i~it>.o~' -.~ E~`. a
?d;"~3t?f3:?:Ie ,:.
=. 4~ ' . . . .

~~.,~.Lto~7 *:Ã1.-.E ~f ~- `'i)`. ry.Y\l\ 2 '~ es Ci s p1~MnPr !R>f...A ~(]~ i
3` ~''#.~i~E31e1 ~t.~'i~A''~~.kl~~~.fit.'I~`~.~~ ~.?. L:#~E12L.f, #.'.1.'
,. `~. ~..~. ~~'..f:.'Ly2 1. x ~~ . . . .
~ 4r

56


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
,,..
0 \S`...
. ~ ! p
r~~`
~ ~

i1

fJ O.ii 3 'I

t'4$id termna: gà 'oi1p 0.r~:= iI3tiL pendetarly :1el.'JL:tcd as (ac t1.3C:d
;`E 3.,2n.

Any :ani t}.iS1d of a:n`, z5pC .mi.ilg potymo{',}lataC3n can bo ;..~sedi for
th9;^ .. t..:aio#.; For
ox>.:l1v.Ã. `he ;,;1~ ffp~1I3I1~ pol`{E";:zz.iizt3dl:t'm iTla"S .7w
i.13:duc:,; ;3-v H
~?t%%l he Ãvth~ iÃE$~1. xIs O t
or2~ibt1d1l,u`_iit, t..e roacfiom zs t a..:ivot b:r a :llt:tal a=~~lalytiC,
Ã.t lF. 'Ms ` ;lG= , t.. ick.lt?l]
~
c..n be ?er:i$,"i-ned m,Ãt, i?i- 1..} dw pacsLF:ii~ of -a solvent, sliC>~'~a
as t5:ixt3e.

fj] di;..'tf, il E..dhe1, :12.~i rCSta:.= lif VL<i(V4' use@.s, iKor
w.}'tC2,?;i.pli., =}i4'r.\2~ic, \`t caA\Y\}aSat4'

al#olri.>z.~:~ar `,o, >2#irtc3l1<:. i.l`l?nf1me. (:;a . bG, I.1. .~;.
~....~.~. ~..~Yv I ."~y 1 ,~3K E 7~ ~.S. `~ :3; e. 1 `.~.
. . .. . . . , .. . . . . . . .

i#1y;w.onit' cc:nbfv used iz;Ã' the polymerization shÃ:>'rdi'3 abt~ve. As
s.aow'#1 b~ loi:t,
Eli,,. ..:i::mw c=::i3? J : a ,k f;riFive? six, or 2ifa'e'eFz m,..'1:E3bi;Ã;id
d'i'x'3g:

~",
_. ,


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
., ~.~
~= r : : _. .. ~
:\\ ':-, . .. -------_.W..W~,. ~j~,.., f=-f` .`ti. .=`'1,1 ~~'. f'~J...
`r~'~. .~;'; .
\ . '~ ` ~ ~:Lnf' \ .=t! . . ~.~.r v

i? ~7 F 7
r=~
\'.r..
~. _
~ ; r ./~ ~',..f . ~~ ,. i ,..~~ ~ .t ~...
,~,.. . . r ~
-........,. ~ , :
~'=~ ~4 t r:'~;.
-3-

='\`ti

rr,1 f
.,~
fE . ...............__-----3Ps~'

i~ =f= '~\-~,
r)

A~,
~i ' '~. r,^'~: . f`\, r=L?.{ + ~<-= r . ..... +,~. ..i~~ ==_~. . . -r`
.~`.`.`^''' + `'`. ..,~`, e,.~~ `~~~ ~

~ tt.~=~ c
~v",:Ã: ~ z=~ are tt: .i=. ~.. re ,~ i= e, ,.tii ,r.~1~..3. ~Ei. :~~~ :Ã#'~=
iÃFt ~_~f'1'1i:~Griit1~' w+..4+,:.L..t ,,z, dofiu:c?+:i ,
.t ;'..ii:,

As dzown %Ãbfj5tfi,'.. Compound 17 fti prepared by '.?E?lj`Ãrlet,;l: Ãg a
'bi.li`:%li?xt L?le'Ã....AZ?:
curbfyi-wZ. %'Wh oxt.:u.:", 2:-onw. CmT3t7C>1ti1i~ 18 ~~ ~~rep37cf b-,, .-
p:?l:ymci.z:l.n 2 be'n?t C.xy

L}.~~~L3 ii~r} 7 ~¾ p '~ as r
t`...i~ ~ ~_ :~~:?~3di1~tc ~~.~i~i ~.~~~.~~
~;r `.:'lr, Est x .. . } r.. ~~~,^ ~ i i ~^~.,=~:'G. ~,.\. L~.L3 A:. a },
o.~~:~4~.~c1,:by
tfxo..S l:'.3 t >.Atw; 'sà b;F.1't ~ 1o`4` ?,ly e e:Ã3l carbonate E=6'ilb tC
'#"ah4`dl +_, ? 1'~.~~1

L.yz ~r 5ili~.~ ~~~ ~~. ~`i ~~ . b3 ~ a ~ R bE.t ! e; l.. i~ s,
~ F :'~I~~~_. t ~Ã:i by F i ~;<"t'~iC=Ã'3~:I1~ a 't~ ~;E~~~ ~ .`su~ aÃ~?~
~..~~. ~<2aa<.. ~;_~~~, t. 3~LA;3al1-
}"Ã;nfi:;.

L C-he.~~-i"- ~ ~~ckifficatio~~~ of ~~lviners of Ft~rmulas XXI - XLVI

a ol..>:Lrs i3;' Formulas XXI`.13.3,.VI, W;:3erei21 C1r 14 a protecting
~g*:'oup, can be
i
.i".F .i`~.:.1~:`sÃ'Ci t"} ~#
4t.il:zsiii Ã'l~?it; `<[~3i:; e~;.Mof1'?s ala:~~ p(:I3i.a"?i For t. tarn'~ic,
G' cea;-,
be wa,v p5+.`.tei;:``, g,?ii'ol,Ep known 11:i o-t7.; ail: hrl :tis1mC .
e:x3b'eDd:i]~ents.. f_3 is a Q[hcr or
~ rotL%ctII7 ` fyrC31ep, Any method knC1i3 n'#.?1 the art of sa?~'#.ing a
~4dc: i'<hc31l: 01"

pe >.Z{hf~a g~$.-}; to a ~2. p3.d.S 2w~c:~.=~' 7~.f~d~2 }=~~=~,, L:Z. > used
~~.a.'~r:.='l~ p k,~ f)=~ ~~~'q q S2~~,~.~ll.~,k ' ¾j~ V ~T~) =5=y ~c~~ of
.~X.i.
!\s S~`3=~ ~2k ~.y=~ ` =~4. N~_ I~Y. ~ZiLi~~. X.L;.J j,
e'F?.
~~~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t6r example, a #3f3hyz>.L.'F"= of Fi7i`Ã-ni:la5 :''i.xI Xj,VL bt.`= ~-
iiCjdÃfit;i~ to ?Ã~,. .. s'fd< ,tY?.EÃ
l ..f,`?;i am]of?g a straTg~~':~ 4)#'bI'a.~'.3chwd 's:lh.Gl, ~:=;iCle.""alk2 :
%E.i'y olGfin >3lky~sÃ.y:,

<3Tyl\dy . .Ãaii 4 li ~?l, Ã?`4ii~.lk~~-.~ CiI .~l,.[i~I`~~L"-.Ã~'}?i?F:1
~:~~.i2111 of ~j-5~i:wcÃ~`~`,'~,.,.,s, ~~ ~~:.. ~.. _ "'.~~ i:~~. ? l~i`,~~
_ =...

t yC.aoCnc3<yl, i.~.iyl,. Z?.Fn3FÃ`, sdyla ~~lkF i+1~,4. ,Ãyl41..0
alkd:.31'yl, arj'lalkli or f.uoF"ol,ubf)n
;~. . . ,F.i . . .
.'~. a.,~3.1I.:~ is ~?a~?`3C~Ic3#:?~' SwE:~`w'FÃF~t.:'t. ~#F:`~..#:'F.?+.3li~~
or t~:1'tI':i'#is'lll4' by i;.ne or .#3,m

h:~Ã1i.~~yr.Li=a~_Z.,}r ~..f~.i(~'{ `},,f.jS~'~. y
t- :~, >,~r~, ~'i2Y'~~.r`.lci. amino, mono- 3:3}.d~ sui,fJtÃaacuf

>I131#io, 3.hYE ' .33F.3eswt, `;i?i. aEi;'., pilt#s??h4itG`, phL? ..
y~~laÃ3'~ ,I~~., . ! s~. ' h{Ã,t3` ~~, _ ~` ~ > }._

Other ..ÃÃ~._ ;:1tà .. t Ãe'lIp` ccÃ#-, be >Lis ~._A fta?m a. +1-F.iJnt3
z.Flv`"E.l 'yiÃ.o'no gj3`C;+..31,j.
ioly(eth},e:xS,.o.K.d%);7oly(3~ydrox)'i?S,`.id), :~ C:=aI'bi:?h~t~i3.t~3., a
~~1+:tt~'d` a ;~f~ Z`~T{~,~~l~`i~~v, ~:t?.
õ
+.1'#Ã1:i7.`l. ,.16;a_ a F?Fkdc.ÃQ :Ãi:id i.l.i+ ...ot3df:q a any DNA or RNA
~~ 3 ?1CA3
' a
.#p:t3,

lzit31uggical i:_s;.op.ur_ Adia:FtÃ:>pm1lv', a haÃ;c;F.clnas 5idt: chaÃn cap,
be A~ac-orpo.atest into a

polZ~~'`meà of any one of ::oE'I'..3lrxh )Vys.i"..~i=.LVI. '."~F.t'L:h i s a
phC,:<3lni?tiskn,ÃC:bh~ {3i' ÃL?ni..c3.l;~.y
aos;ifiI:kcab3Ã:= Maemp,

i.l?i]e F:14ii:~(:sd of I:lZ:'dÃf' :I?.,',, a poly1:23'u``r f3f Foa~3~>nl.tl.~
XXXVIII below. Ta3o
beÃi.:;y: otl..er can ix L_lS..w i'ed tf) iÃ.ffi5?'d a hydroxyl ga .Zup, AaiZ
izF.i t~iod o% 4 f...ctv-lng a bcn1 S'l
ether kà i57}'i,, in t,w art i.'=ar, ?e F.1,`'s^d '~.i}Ã` "`.~.#J
ts'~.iS'~ti~t"# :'~Ã~sil. Ff'EÃ' v;~.a~.Ã, ~# the ~` `+. Ã
~ F:iI"ic i :7.~4., ~c~.t: a;3^`;:Ã'
Cm be ~ by ~%i~#g S
cleaved ~~c.l~~~:14:'. ~`3i''+arl:tso3 yo~~2ti `~wi >lm.r ..~'~v~uYC.tF,~`~
~..iL nt [pT ; qy`r{ t~: x:.t~~ c}~Vt. ' A~4=SY [)e}4~~.~f~ Y
J .+ JA_q~ 26~~2.iY~~a r1Z~_ ti:~. ~"~-~.,'z a i,}LwIffi #'i;actFiun l?,
;C:='il,t,i..n,s ft3 ari',dl#i;e the polymer of FC`.+I`.ln.ilc3
X<`i,5>.~~~'ill with a f:nt1"b'z-
'r..'.01 Za.~r\~w~=i~ ~,:r ..} ra~s~p Any Ã~,iet:.is}f.E C~...#`ei~.~i.tFl~.~.
[Ãn alcohol k~ Z~+'~` i: i' ? can a '+s<:~.Ã ~ .
. ~ t= ~:L ~{'Ã t,,:,3: ~.,~. ~t 3t.}.
Chi .uL<ll1i\1r2>. }ni:\)n.

1~.. {~ \~,... .\t
~ . i

w. \}
l&XC';

..........................'~p, ,
=~ `Y.
=~ .'~Y:;\C' ~1

M, Ã:#::' ci .~.poz,.n& shown a:.~ove ri y, i=, and the ternl:Fral. group,
arc. Ã .idc<pcnd:;s~~~~ Selected
s'. s >~~ <3> wd hczeFÃa.

59


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
, ...
. -.
>~5 shown 33C`.lE?~,~'õ ~~l. p<?l4:3S .l` ?:~. ~.'L~.'311"alcà XXXVIII
mZflt=i <'
i_
c(2 n, b~ Y ii~.`:> ~ tF. 3 ~ ~ y.~L 3 . ~ a ~. f.w 5le~W r with
vi:Ii'1.'1kl;i ~ ; \? is: 3_E f?' .~:~r1 '}'3~i Zr. ~,~.L :~; 1_- {.. k ~.
t~:,~`l
~: ~,3.~..~,,. x \= ,#:.I" E#~ r~~: ~
bi.my.iS.:Ãed s., %,':irboxt ixti~ ai~,tL such as ; EcF3ri: 3c:d, o:ec aei",
or t2 ae;ia: I3':
Z?:hLn n':=3t3d:#:ieI t , bw c13ii3ho; ds, IGELti d with 6 b<.1`l! 'lo?t.y-
.,e?zcl.:].?Fc c?cF:Ã, }wxc.t.na=fi14?de

L`tiF:oe,, C?F' ala~} .-:)v2~3~~3?ti}-~~~ 5<f~~Ã53 aGlC.. ~.11
t2l"f.t}`a.3S ÃtiT.*
i';%":3up ?~sa, ci?rb<?n< c+'>, ali? ester, Ã3T al CI1u.

~ _.=i
rxr =~;~.?' r
f;~' ~ -w ' ti`l ` `4 = ..
:ti

~ ~ ~ =~ ~ ,;

-.:i ~?=.Y" ,... 'Y-=.- ~=:` '~ +,,^~t
~ tl
.. t ~..c: .si..
`~=
..>~tj.,~~Yx,3i'lfi:. =~.

.4'i" t~'}-..r'.y` ~~ _'~. '= =
n ~=
, I F ~ .=`, i .

vn~
:~ ~.`.1`: ~ . ... .. .

1;i1 f.le ::d:?nwt?.7mh- . inf}w.,? ::bÃ}ve .',.. t e; and. tht~
tC".E'F3::3t..zl group are i1.,d5,:pcltle..it:> >t l;C;Eed

3 wLwi~~~ aLh+~~ h.~~. i.~..i4~ tf. is .~4%c4~~l.~cZ1 from ibii Sli~:s~~yYsa
of t'~i.t.~,
'.i

As >ht`iF:3 below, a p+?lS``:ai:i' o4:Sl1t<.#itiz7lg }..lydrom-4 }F +aAS'
i,a3: be n.,;,d#fie'Zi to
p.'dilce a po3yirwIw.i}?':t}i'I> l~ : :m1p;i, For exaiTmple: the aloti`h:?:
L'w] bQ, I:=,mi`.d ?i,ffi. a
s ,..bw'.YhY x3uf~ such as `'tea.l."#i, acid, ?lC:ÃG acid, or InyFitiuc
n;Ã.Ã. ?.l? o.hcw

.:~'t t ~4 5` ~ ~Z ~ .r2 '~ ~,
.,.a~ with ~rn ~~ i iz,t ~it3~Y~ 3 ~~, Ã ?c~, a u~ i ; ~i=fÃ: i?~(?i~iE>~f+
.,.t`3 i . Ã: .~E a?: a
w.:~:.}a`. !w ;LÃ

pIm4_...., ae.Ãd. ri;e bc'.r"t1'.yii}'S.y,?:'37:i5ni3"3C:?'Zx4vl, and h%ios:
p:'C,tCctaf:g r'"x3up"s

R 5 v:.ln be ml3wv `iA E3y' 3.r,LIhodti known in wi-f.t: art to pr>d:x: an
izlwhol, a Ã:'afbo} Z'be acid, Ex:`
~3:? unn1ÃiL ;isp L'QA .='0,y:



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
p fi

F:i:.ti_ - = .: ` : :YZ:i
:,.

=~~

1L
.n ti1S:;. 027. 3}:i)..tnd:i :i=1own %ib(3 ve x, Y'. 4} ~ and fl':c tc:i
i11al
wlvcLf:d a~'i %si '.#n;<3 h%iweiaI.

~ I M~~~~~ods of ~ ori-i$~~~g Particles aud.Fil.ms

v:?'{'ttzus :-ypi.y oI flm: e~f:f> pa1'fides can be ;.C3#1ned firf)m
pt#lpa:?C'.Ãs of Ft3.in.tahFs
h.X~XLVf. Astiht?;' :1 below, various t~pe;5 of fibus and p'i3wF.cl{'.s,
s`i.lchws m::ei0- (?.i'
.=iailt.'i'+''i?TtiS ~t:s. ~+ ~- ~+ ~.,{~ a . ~.i~i~ be #.71^.{~S 7?T3'
l+`$1~.+:.l~;o of "`l?IFT3`3~t~` .. ~X and ~k~N e 1, ~ f ~:I'3t;~
~. r .~:~~? ,3
. }'.II~.C.Ts,.. a~il:i`..4 .,:i3~ ~~a.It::I(:~lG.".s Cif Jv:~."3`t,.':C~
~:`t'.ii2 i:~'t~."#~ ~~?~,. '#lai.li~~, `L? #:.~'L`'d~.?i};: :i..4 ~`:C;i
iwt.~'
~'+i~ c, C.. f'
< i
t1`3;.~3mltc4, agma_s fh*>, polymt:rsll"1.:C:tEa'Ã; t(? j`)TFdCFI:e a
7NCZ'i2#L :'i:3S.'f.'nt i:3mnsE.EC,-'.X.

:l iy''mlvthod :-uw,ivn in ih3:aft can 'bi.; usi:d tf, {i3 w y=.<~,t [.t..~:.~
~r~~ L.n 3.~ } r. ~ ,. . 3.~~~ 't~ }~Ltarii..1~ ~i.,t.~-:. r~>. ~lu:.-
p
.~~~s;~.{~~.i'~'s;~+~:~.2$. ~
L=l~v~la~~;;~~L.3'l:i7.Ma~,4~r~if.,=..~`L.g~~~~~.

~I'S


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
i~,..

~ti ) .....__ M.i?.,nii~~i~i.~s#~.+.~.:

~;~' __:~= ~ ~' `
x ~ l

Q
s~XXVI I1
-.
1i1.~1i,'.~ L~.3~#1#At{3F.F.ii~:4s~']<3~~C~:1 iFi~~.3~,'L~, i;:F.L~~3~ Q.
~~', ~..F'. U. n R?; y, t=; ,AFId tQ_U:>,.}nid .~~~4.?ur? <EF';
1a,i.dÃpC:n<.:e1>t:y si,'lC`c$.:.d as dÃ:l7F"ifsd h3rrw.la3.

i'3iSth43ds of Mil.~F}:hx3Li

,>?cpo,.y"#ilc.F., described h,Q-iein can be [F4oC`~'e:fr peti.?dlFce,.
õ3.?.i4.i E.`=t:i`g tt-.;hn#.ques

LnL?wF:F ,n tl:.; art. Foà om3:npze, aus sh,?wn Li:.fE~ve, a p3;41#?er of
F:>> *?ur.: XX ~:= .:~XXV'I;
` dl stolveL; .h <da? {SÃ ` x.i# }c~l~ #:3~. ~~?F.c~1~<?Tl~ Fli~ y~~~~ `c
Ex4lL> ;
. ~ . .L)S 42#~4'~. L4~kz ~Vr {~:=; .<)::
{
.,,q.:1E',`+`3Lt4 SO..#,.:ii7;.1 iE2i, dct?L?sF'.ed i.?i3:i3 a solid surface,
such as a glass sufacii:, 4FF .ei:iF#:Fn
ithZ? ~.<<?tyme:F #s d`eSsolbM in 3 :iolve`: ukC)ng !.#`.'h ..<:F ;gf_l1f, `
?ch ?s 10=
i3:?d depp<FSItQd onto o, solid sL?rfsl+-t.., w.-#b:3.e as i4dc:Vs .#:#i E o,
l,"lf't
~
st_.1.'~.#'~'14 t}a~:,F# ~.~f' 3 3 ;i??Y~S.:~;1 i.i. c~b ~~Fy~:?f i.=.i~: to '
~~ ~ ~'~ .'< t,zi~ a ~.Z,~`ci'#~;~ '~#l~. F a L:e~~i~.t :~ 3
t .F#.F; iÃ~:;'1Ã~
tl.mpS:.na;l.F.i \ or pr't'.wuo, o# <li .l'i' vc#.t~'f~ or ~"t'(.~#.lL.~`C~
Z+? a .~;' ' ' j . ;
~. ~#I~LF'~3~' _~?rok s~:.:`.s, .:#.:
certain unboi`aimleIlà <. "h::= h'Fol\met {,i#li1ta43T1 is deposited t) 3t >
the so.1#.{ s::Ef,.Fy.L: -ws#ii,~ :3
# iQ.>?3 i.]?:="s}~ xt~3 i:. 1-i'~otheI 412t.i ilt~g~~'1r7 tLm.s, ) ~ .; G `,
>.
b~,yxF'c>
~ f~~ ~"=- . ~' ;}c}~tiÃ:~t ~.
onto `c}Fa. 4=diii ~mmk3s'::; ~::g., gls3M>. #`.lk:l, pL)l-vIlder.
c<)flaH;'.i>l,f p46:C;a'3'dh.#:-I.> . tt"L
llF+,.t,::l :Fa~`:e#a u.fla? 4cd.F~txid.. or :~#:: f:4..iE~sq .L~Ã#~e}~., a
J~~.i~i~ tffF õ ' ~f.cZ.FL:C?, 4L,i.~# #'Zs .} # xF~.'.EC, ~1~3' ~.
~'.

&vfcc, Fo#' w`1...?mplc, films E;=CIiÃ.ci1nw::;:3 polyuF3eF' 3;F
Fi.fi`?#Wul..XX or ;'S.XXVIII can i'Fx.
3i)FF:3'~.`~.i ioL t#' k32Nl,.?t:-r in <3F~i t3? Fl11ic i}:` aqueous
4<?lLsil7FS, i1`z

ijfgi3#.1.1c w:L; <'#.ciIwous S(?lut'#i ns.. and a;?~}l1# i`? the :s:fll-
#t#.#:?rz to a sa`. t
. ; :a1.e.
62


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~11 other imi?ix?inxI1.s, fillli:i cirn ttl1:]iI1<F a #3ol1m1ez of a oIm.3lz,
XX {.'X15XVIII
are fii:i:iii<'.'fl by.mc1fing ti:?epiS];o:-nZ:i. ThC.:.ii.?`.`lt5:d
pd_3ly~.iiwi can be i.~'~}pz.es to, a~^.53l.iÃa

su? f i e 4itt.xl. i'* g.a4: iother L'`=iriboc:zinr#..'`#ia.~'i, t}li:
pi#l'y'nner 3 s i::i7pl1L'`~l tt? a soa:i ssl`azi:#?.C.{.>
and is then ;n;.lti=:1 tc, ioIi`'3 a polynnwIic f:11l7.

13: ct;"ia?n ::~ibodin.i:nis, slibiltt<layered fihn5 are prepzs_.iti:i;; 1.
or exanr le, a
i".`o#ya.i3.tS. is d'::i`,E~~ited oI#t<? a 4i33.id suf-faGC, as described
abC?t'e tl`, pr?tt..#i:o.i fi.i#:''1. A second
ps`+3.y,m:urk ziAl.itFon Ã~ ttlLÃa ~t3e~.?f?si;'L's' o:7to tile first film.
Polymer fil`.~i.s is~ :. 2, t '), vt, 5 ct1'i.iz
6, (;.t. `?'lctn~' la'.,L,`s b:: A;31`odÃ..L:l:.d by this l`.ietb13i3t.. hi
t3i-iiUi {.i ?bE3'tl.inmits. u.ti.h p, ~~nls:,`z
ti .i# ::~ ~3~5?~..lti::~.:~~ ~'I'~?f7i i3 i3S3~ ri;.~~=~ f3~ ~`t7~al~i.:i~
:~~. ~;i' 1r;~.,~'i,~.~~~. ~I> 4i?.+L#;~la~.F ~ifi:~~ix.~~.Flf`i:?f,- ?F-
o4..aulÃ'3Z..:f'4 i`i'weudo a cl'-f-i"'eItz?t polymer, such as pi?iy(hai:.tl
a.4id), pt3ly(i? ycoiaC
.c
~?t}z~;~,~<3i.#..~, i.s.;? ,Sut,#.~4`~.;i..z~. cii:i<~ti.
~3t)3'v;vi1~?'CCy~~~.:~.{3?lf:.
7]C?~~?~~iir.^t~.#:~#~f:~~^='v't`~L:T"~3t~~:i~} A i i~'.ls;A:r
pozyea.;boi#wi i3`- ptiF = 1#.=x1de.

: #i.'~ .~. .. . ~' t ~5r
zi'.~ . '~r~s ;C~4 4ziY~. d ~'ir.3ers :=i~.#'#. 3:?C. :vfi.'E<:=+.=a<:i
to ~ :. i l Z y? . aS~. 't3'i., {. # ) .?`i Zxi:'.= rz.~.~G z~*
~~
i 3a w,, , ~ i

#'i?tQszo t3i,.`d#:et,~. .eb7t e4 h-i w.`iii:3 i.{#fft:Ti.t`Z
a,'t~;L`ntse:3:i":= :i'#ilud4d ;F#.i layers wnd i"c
a ~ t ~ aii ~ t, =. q c. ; in i'i ~a.C#w~ta s~. ~z;.a i~if:.t ,ilt~" `i~~.
For C.?S.cil~ -;~li., a .II'~tt ~~$L I#~ ~ti . ~3~'. #.~~~:#.t~", ,Iz a .i#.4
. ~ ~t? i'

E 3v-e?" di <Ã;trwd to mZ .tiL a rapid r ~.li..aS't' t;.g., within a iew hours
or sav i.#; 3i3 s; "+:.CoI'#ia
enr can .'.3i ,i3'e~A~:Jird #.il t3:. Lcoxl~ layc >F t.lesiga-3ed to
PI'oS'#.de e.'it,.at.Fea~. IG,.s'~'?st`AT'a''C?i;
i&
`- _ õ > .I
< t>I ~3L~:.~;., -w. `. `~. 5 ~~`C;<'.~... ~. .. '' ' < tE. .~~.ltE'=~"Il~iti
i`i:=~:~, an ~ `~i.~l. . ,t? ":ci+~~:3a''{~~~ can b',
~ ~ z # l~3 .'e`. `. #'E'~ '

ÃtaL<Ignti lii?t: :v i.lÃ.'t~ses:in4' zi.-i:1.iE, bilt tC; iT?Carly
`~ia.l".ty i'elea\Ã. 7..if agG .Es Iiw sue7SC"qLiia.i:`.

~':` #F'it::i ~i= r ~ by 1#'i Y.:'a'~i.tc-,#;.3 ~'i.~..~tTd#:~#~o ~sl, s:
~~c~~.:~'.aFi~#.'~%ll '~.~l.) z#li7 c z~ is j~Js'w`t.~.<2#4f,. ',r~ Lr'
.a.:#:g i:e"?#..LIu'~`i..l.i t3~ a z11L:C`~"I"# w?~e. lC5i i:x%i 'npEe;
u.i'{..tt`( 1111ct #s's='i#.il;;0 c_.#l be E.S:,i?

~ ~ i ~ ~~ ,a = 3a F ~,~t,. f( ri M+ i
~L; ~~:+~?~.s#~ <.;:li?a..~#Si~`i ~.~?#~?.t.#:~?ie:';
i~.~~~i.~'a.~~.'rs.i ~.~,`~i 31i.'~~t a~~ii16~# XX L.r. A 's~ 4_t\.:'4.
ti+~FF. !`#. ~..~. a ..w~ia#3i.
~~.

r~ ~-= ~' f~li::' s ~..,~ ` '.+>#~'~..L:i:=f T {~ `~ ~..~=}.~. ` `+
~ ...liz such <13. =3..4..'~ r`, The ~Tl: _E:I'~D~3i"ii2~:~` ~S:I'
#.1#~..:'t~a~ #i>d]~~ ~ at .,J a .,~ '* .~.: ~L1~~i:I1i..iz
iI% a cof...s.,s.lei manner to A"Yrly.l pa:ti,'=: 33s Sl3C:h as stripes
and:`i_?.i' &?ts. 'ri:e st?lvt'#it iS
Tet27E; wd bi cxa~,wL;l't$i`.:fn: T I11'.i 3meth[?d can be per.;t?maed with
more than .`a~#e i:s( i-y.i"3.Evr

~=:7l~iiia..<. ~c ~ i#4l5l u:i ,. ~3~`i t~.?za c.F'c ~ of q.~ii '~ ^i T~1~~
or .`~.X.:S.Z' 1:~~I c
~#I3: y'. :~. ~C.~=?iF:?~ a ~.}~vZal~~::,-cZ. ~ ce ~ ~ l~Il t.]. L.. .iE.:,~~i
:;wC:TiL s13L . ;?S 3 0}-;?Z+c~i~`Y\f :~ed ~~.rtS,3'#ls.~, i?1%i~? ~.?4.
fia~`~':'~1i.o ' onto a solid .'.#t facE,~.'~b' fl:'i:i

~ ~echmiqtth to ::ftbT'd a rt3_:f omC'i: ao-i=~ i containing ~.7~:.3~i, Such
~:~t~'ttzi'iiL,t~ can ~efi:~`:Te'~:'I~
~
l~3 ~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
#Is Ef3 apk<in>~ ~?1.~33i`4+,ai~`r.Ã3 .~~ ~:'u'`? ~Ã"IC~ ~:.ssLi~.;~s as
deiL'~n.33i= i by the pei1.,.f.: pal$Llrf? }f

at l\: ' iW\2 ~ ,~-"#, Y;t,h, a5 ~.~. a fi1i~~~i
` . .. . 5.,
Mt.Shod'\ of:~v~`~ak 'i?<fP;ra?L.;k4:"i

3fi.?f~ iC :?#.1F IC? a P;] x#3~:?~:#~ls.C~
'IYi?. ~3i3~ F?3i iLti \_L.?i=.`,rfbi..::7F'.#tiin i:'<S.iI bL'= t1SW to
t ~ . .
3,tsir.~; ?~. 2'iiz#:Ãs kÃ,sa?t=Z'n in fhQ <3rt: For t.x="s~mplG, a water 3in,
o.l, eli.Li::s3o.1 t#.:chi?Equo
s\:ribed bs `"AWnd &ad ;:o--"vorkf_.is' (see 1:d:(t:nza et al < AtIv.
Pol4ix..eà Si;15";6; -1``'
-,
A: ,=,a~ i, . s s i3a3t .> 3 ~, ~~zl`L'a'f3, a ~~li3r~>l. ~ ' 31+l. ?-'"~
,996). ~
~.~4 1 A. ,. t i:3 ~^~~C)~~'(? ~ =~`~.~x~ 3FSItt >avo. a ~t.?>.m4'r
is i, fL4iy? s i.le #3? using a \'f3TtS. .}nltiy device. 1:il
\:i'=.i't`t.l#.i. fi.ie
;i
i < ~
L:?,\~ is \si "'i in tli..' an ca r ~`r such ~1 ~ '\ 'S:=i ` ~. t~Ã
~.7 is~.t S~ ~t'-=: s~~s.. . ~~'.~ G~i i#. ~tz"iw_. ; hi'
z~oh.itr.ÃZ>;.? }'" i#.ÃC',f;=d in a 5% p(7ty-k'inyl #3lc(~hcil sE1:Ifi'al:#,a-
#`it and YC37'ttx.}.(, (C3r 5t`r+ycaAi.la ~i3.FÃg <
}:iÃi bfv tÃp sonicator) m3d 5$Ii'iLd ffzÃ' 16 li~.?im to ;~rc#%lu::4: F:-
r#t;aZ?p:ÃrE]clu1. Iffxc

~.t y ~Ã}1~~=:~..
mi4=Ã'o,"4?arf.C.C_t 3Ã'4 collected ;.i:"is`i'''...s}.1ed wTt:e3
d#T~ilAeia`d:kion>.:;Gt water and

T+. PÃ`#"3ducL: :3aa.3'Ã'.?sll`tÃ\.:t:.S, fsT:te oan if_?I exai31pl4_ me a
m:Ilit'=dE'si11uit>3i

pt?xy-,t-#.i:A.ir..<.#b':?Iz ÃT?iths3C?' (st`o, 4 g . Landfc-st[=r::'f GI/.,
N':<"1Cr<3i?';t?lmuies. 32:5222 ^, 19fr+k+ ).
Bi4flyn a :.32TEa~#?it;}i C~ I as C..f. 1,\'Til? ,f.Y{l 5=`; ~i~~'i>Ã~:#.il
initiator +'~ tls C> ~ t, 1 l
... -
^:7;#wt il~. t:#:7't~ #~ ~x.. :~`: x.~~

~mp1onÃti-ilt..) or fflbs;..`ed#t::iz:3d1lZ=e:2v
such :1:Z< i7ir.Xi:Ã7?w i3ei7:?'C.#:o' t3li.#t.=:3e, diethyl f.ho$ $
C;hlot;i..f?i`Ã:3., dhr.c'l :Li,C.~~:tÃ:t+::='

3..~~~^i e1#.f3:C:ii1.:, `tlÃ1 ~~~IF) bicLtot .<., ~(MCCN).
(DW), or fa3ld't:t:hyl SIlIl-C3?::iCz=e, f:i: C.S..itZf;a.l an nt,
`'suf..,.# as I.e,.(:fi:.:x4l >l õsl4Ãj d:Essol:'4d:d #.i-} th`\'.
S[3lvf;:$?r. Thf. ;,olvi'.iat is t`u.#.C?\ 4%La 4 i:i ao , ry
U~;?~?f~ r ~i~.;<3t' ?;a:%1tc ~`#S~~1L?s ~#.#.T?~:tÃ:l.ei:.~ Ã"i:=dllx~?Ã1s.
~~'~Z,~ 4'`sJi~.?i.,~ Ã;~,Ix.EÃ~':, .~ :?l$~:s..a with a

~Et1Ã?a 1.f.ÃF..~ ; Fi~.{ i t~:iTtEv 4t~t }k e#~ c~ C3~ ;~i[?1i +?~
i~?l~Etitfll ~~}f}~t C~`3 Ã~ ~cls ', 3IA `sà ~?ÃE#.~.~.:à zs; l..#df3n.
L,nSÃ~" ~:.a~~L,-flt.,= is ii'~?~~i'?.<i~.~:i~ Etii } .~'~. i. ' i ~ i a 2 ~
~" ~t ~ ~ W t L Sic3315:~ pulses ;~'#ti aL<i:Ã L, E3t,n}' snV2 Zvi.l} 30 ;~Z
of

power, w-hicb a+~)##.,~s ffiw.' mÃni\'.~~zÃ..~e`~iark <3sid allows the solvent
to ei'..#poic1.te. Tl1,,.`=
mimim'W`3:f,?n is .'siÃI1S':t=Ã"Ã"e~.~ iÃ.1.a? a iÃ.Ãdstu';:;''s: at 65
'Cft}Ã'
21 .?oi?vi:-e .i firce--ri3d1Ls:3 pC?lymer`z,..~.Ãti<J23. Optionally, the
:I:s...lfifà . Ã+t: d?; tI3:;#.'#.'~:

.z, ~~i Ãl~ ~. ~t~y~~.Kst 5 ~~~^~:; ` ;s~?~v~:~cts buffer, .v : _~.: .
i~~lfr~.i:. :~ rx ~ . <?~ .~ ~a~I 8 ~ ~~1~~:<,::F Zuiffer>

Nct1rb<?.aw iyL:.,4.I", sC?La:ÃEi.,v.l i,:ltri#..e :7L#r`atL e.i' fZ'.'c#
ti~=i,J d"svwJ, riW.rnf,3v= #%ce:i430 `<Ã% fc3'l:iaia and salts.

64


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Aft..e :1:Ft vi:a y #3aÃ>%3puft,dL~ ail, e?~=' produced by phi?W .,:i#i_F...
.Fi?:'#, For m<funpk~, a
nwTi~?i1E .? as O,,s.:3'=Ã.beCa li%F'e..: ci;f, be dAssol,. =::( .k"1 a
st)lvt.3t, st c?.# .:is ~ ~a c3 3t ~ be'{Ã zcF?.t;.

diethyl abE:>F Why[ e3#:=otatf:, C.'s.fchlf?foI?tctbief`s.L=$ ~~;3iz S4Fz#i',
(THF ~ :oi_t ~s Ã.i, ;#:L=i~-fg?1Ã~3~~~'y~s'~~ l.`~3, ~Ã:I?C7~ F~ ~~C's,
2Ii3f3'l#e~~ (DM2 i or

d#;i?C',thy: 4Fi.['i?.YC'.Fl3i:. II?. CfeÃ'tiI#.n embodiments, an agent,
5Faf4:i3 as px3:'t;=litiF:Cf'.~ is ..lso d.bSi::dJi;d
in dhe 4i;ai ef.e.: `F A3L:= <,ohr'ent is .ie-mC?-vC~d VÃfi ,"+`E?ei.s?. y
L'i'apCi<$iÃ(:>n t1.E1tÃi a i'Fsco.ati #?:l#lt?.il'c
>t.1.3:Ã:f81t:. ri':`a.': vIs.:=~.?us mixture is Ist.fxL'd vr#th a
S~l})#.?fl?F#.~ ~1'aF?~<# f'<fl#~ solw1 . ., scxLh :is
sF3d?F::mn doZ..';w'`. ; .#..Ãn a 63#.I. ~,:w ~.4oit.16CZJ?, The mÃ\.tllf L'
:`s' thC'.s1 sESÃt>ci'eic(> tor ?0
F'f:.t#Ã[Fli.'s 1s4:'=oon<? w1t,`F s2 sLZ'.i.FltlF d4 lclv) I4'#tb.?0 W
.`'b;'#tt#F 5.~.:~=

kF#id {3l1t>Zi'13'lg the solvent to pf.d;~i:F;.Fl v evapeSrel.:.E-. :..i34F,?
Y

pr'#`olÃtrtsEi.. .z3`e i,dd+.'.:ta to the 5.:3'?uEas.ÃiZl:. T-1hL'.'
nn.F3t#t!`e :4 thÃ::.n o;Ypi.?s!w=d icj H#,rM ftC?Ã?; FF.
soFf.i`Ge such as a fneÃ'c:.#.F' j t3rC l?1Ãi`:c while the solution is svi~mxi
vÃgof oF.:si.~ Ti?:` Fcmudtz?Fw;
pxfl"d.Fdws ~i~~ s:ÃaaLi.i wvemÃg"In ok3eFl to tho <k':I` to xFfli3w aY i'
:"eF-F3: sFI3:I';....'ro3s``i?i:a?: to
4vsfpoÃ'iiu.. Optionally, F_iIe ?t?~~Ã3i~F`iG i~3i3<?~~<3:.fS ~Ã'S are
tl'fc>i. dialyzed against a ~~".~u,,ft'i'.+?.

~ }~ . x .., a ~...i excess i y
: r~+ ''~~,..i14 ..~~ t;? iS .C:?F.f3 u a= .'~'S..L`t~#ii t3I3d salts.

~ e ~cs be a y "5 =lt~
~fi?=r:w3~.`>~; ~~1Ã't.C,.,.w: can also 3~.?`t. ~?f~ ~~?aev~S..d~ by a
~.?ft.C:=.~F~:Ei2tiC?Ia Ã^tl~.t.~7t~~a, For 4fimmp+e,

a potv#^iFa,F of Fi?F`113fahl XXXVaIa is t.~s.i`'s4i3l'L''cCs in a solvent,
sE3cF :4 ..l .: .: ... 1.h.~.: ...,~. .3..C`#.e~s
w a.h afl w gÃ,:13::; such as pe.lti,l1t&N.t:L I l?'''~.' '.^'.i]l`aFiF[3f7
#:1iidC>i:i~ to an aqfa.L;FÃo.e, `. Fà ~~Is I.fà f

,L d:.#t:C?7l. 33.1da e.Fs si?dluÃ?l l'.~.ittdC.l 4ri ;tf.Flfate in
s=S=';f~f.'.r, JIC `.'C:=.1'.[1 -Fn~,. mÃxtF:.3t-0 is ..uÃfs+..a~C'd :o,
p.{.xd?F%.. an The .1n.,:i,ttZ3`C: f~ sfir.i'i:.d while C?po: to the
at2't?oaps.::S. .ÃP c:=v:1p+,?rai`=
:~i.~. i ea.c>. . . ~ :a < 'F? .. ! r -~\~:=i., <f.>Ã~ x
s4 ~i.3F..k3 as ~,~Ã~:~~1lrri~#`~etx'#`ck`t~#V> ~~:f~= I"iHlt..~Z.ig ~
t~FÃ~F+~`~>.5::s are = z~~.a~.~.=d

t 'v ? ~`=
s:,3px.E-mii lyZa:aF=S z:,=dusl#'.w:i3:YF..C.F?i'<3I..F#Fe w3t1?
tf:tz't.%..i5vC.vx.i::S
4i#1'fat?t:;:i at,

x.. _ :s~ià t ~ 4Ã:~:~} ~~n't, the diameter ` ~ i.~i` the ~.fi x~.'~~.
af~F'Ã'f?~:: i.."J`" ~ ,: .g ~~.`~x~~:,~? a I f~ t, t..?:, iz: cÃ'ft:
c"1~+~ ~ C ~Ã:.. ~ *~ .Fi~~,

iO fn.Fcrf3 I5q e.g.a :?etweeÃf 1.0 l2t.f:i~ and I a1'Ficrfl:Ã1. ~evtvmI]
5~.~. .fm Yind I bt.t1iz:cefi
:eL`':.i'#: I and 50 F'n.lc?`oIF.`s.
100 ..1'i"f'f mltl 5(10 mm., or bC'l~:'

~ F~;;~tF#E FI t'Ff of i117 ~;fF .lf ~~ 1~?11I~ N":2?.~#"I4 Pt#Ft1s`.'.k-S

A`#S= faeffi(?F kÃÃov Ã1 in th iÃEt for o"3t:iFA}itflatif?g aF# ~ge:'3t
wFEilfÃ~ a P+? yf'f?oFf?:
pc3.~..=.elL L<i33 be used tfS folal a poa4":11S,:r:`agC:,13t vs)mpleA. For
C.a-,,,a:i31pl4, iF3l C,.l : nyFfF..sim;
Wi;bf?lqt..? :F4 usod, tt: fz?f'fT: pachum> containing pt1:t'~ici: s of
F?..7Ftiaa XX. A P;31y'Ã ^?et' i?f



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Fot't-nuia XXC".FÃ-. b~= di:~sowed ir, .. solvent, ;;u~ch as
di;e:hlort?mu?haneY in the pze~sefll;:e ofa:l

:a<' e.Ã-., s...C~l.s :9ii.~,~:it~.F,1~:?; ~~l-F.~
~?C1lX"aL~!'=`~3vFe:i'Iti~.i(r~. `~s`ti#?i-~it;.~.331 Fs +. ~?a:E k~.:~. A
sF~:F'~.t3.~:~F:kÃ~.Ã~
~. :. ,.

SZ#lEi.Toia, s:ach as 51,Ns p{3ly\tn3'` EcC3hnL is added to the and
the rLslÃlfi.li: ?t?lFÃt>E`Ã,, iti Y<Jr`~ex#~d fi3a a-b(?u: 15 ,3'1)FAi:Ãun;
followed by sÃ:n:tFk.: fE>F' FNnF? 16
bi.ZF.F,r:i. The rtisuifi:~g pi$r6c:C's ii:E'Zi colli_'.(`eÃir.'it w`sFSi-iod
witli. w<ilC,r, and 1}`i.3;3hi.FzeC:. Ii3.

E..LF-t<'diii r.=i3':kbod .'¾'3;x7ts, the m)GapJV101lat.Fi?n efficiency of
PaZ:litFxeE lbt #1h4 pwrt;#.:C:s t.SFi_,~ th'Fs
ti:i;l-lizÃL]aFE,.' is betwE'.=c'1=a 30-99%, hi another etlibC3dÃf?1s.'.F"i~
tbL' ~.~n4,<i3sL..,:itFo# efficiency o,"
Pn..cli ,aw'! by fihc Pi#ifia,los t3s;?,ii; this tecbn't;11iÃi: is
~.)i:tw+.;`m. 60-751.';i.

~llt .~e FFaF~.i'~~k`lc3 ~'=d .i#3It3PE3l''~eIfc IF ~ c1F3\a ?~cF TL~~1

Any 'CGA7mt can bV 2~5~'\y~S.~'V~Aii~~=W ~i,,ril~~~,i~. the polymer flSnn1?
and \J4l.F"L.n4.4~ d\.sZ.'5.i[iS.v'd

.i3ert'ii'#.. ., a>;' e,.&ixF'i3fq4, r: ;?i]ly'#nkF' fillF;"# or PartÃ.ciC:
LlL`sct"Fbed bebG#.s; :z,rF .Fs`iis?:`;3Z?s:_Fte a
pl.`ÃF3.ns.cU:iL.Fcaz a;;o?i: s..~,.ei~.tf#. f;ao.m a;:Iit?i.2tw (I)
F1m??zsteFi3id:?.: anEi 3.F3M3tiaai3 a.i=y i.E`"u::~

f NSAUDN,i i:i?zFlgsõ~,11'C, sud1 as t`Fic$Z3fcfEiie. 'rbi~3'I'ofGIln
~"~.Ct,apaof:,n~ :i13d n<l:pF:>xeI~_ ' # opiate
ii.?Ft;Fk3ha ..F1Fg-t`sFcs, such exs, L,otlE iT1e, fGk7lauy`l, h4'dF'on-
wrphoL)tn.,.i:=1d I;?t)i:ph-in = 81i

~ci~ÃE ~`~i~iL"= zÃ1~~3~~~ ~~~~, "'.,tz:Cr3 ..s a~~~ir11a (ASA) (L=nte33i:_
coated {'iSA)?. 2~~ l+ :}.ocker

antihi4lGF.~~~inW~s, such as c:vmas:h2o tÃ~~~~ terfen:~~ine, (5).a2 '
blt?Q:kcr k:ntÃh.s4amtnÃ.rs, .'iicl.

x.i ?:'.'i i7F1.:Fd3I1c and 1'iliilÃ3dFx3C' (6) SFla:l^.Tl 'cÃ:_3b\' Fgsuch
as
InliPAe`x3* 3, (Md ) iFnFi;i:Elcir:?`f3hii:: ?liiti-i`e3f~.'i::ikYS,`s,.,
s"e8t_h as and Ni:nC{ myc:Tl:,
20 (8) cFl'i~l~lÃFi :i~: i3nt,ibÃ(kt1ti. .:FÃ.`:+,Ã :m'oo.lv4ti. 4LFa'i: as
n1.F"1photC:#i.E tF^, sb> ciotr.i'n<i,z_'+,3..~.,

llF.Fct?i3:i..}lc, itett?Ls,i#.F;;Fziz.L.; (9) 12k<3c[:?lfdc a1ziFbF4?t"a. <-
i.Flfi f::fi~~:'SvC::i, ti.at,, as
azah,"wmyc_Fn ,.lF.:i bet;Ã-li3clti:FT? <xFsÃ;fbioL.c i3.$,3:i-FF,fev6i i;s,-
,
.
SF.FC13 as F3a?d (11) pse..,,iUM :Fi0bFotic 1uL:x3 as
n:..ciffir F3xai kfl.`i`.. p..=ii;.el.il7.i3 G. and penicillin V; (12)
quinolone ,.in`.ÃbiC3t.... ;~:Ãit:".

25 im\:ctivus. :Y7:FJh s?SL.'=iprofloxt'.2eiii <t-F.nd norfil)x[il-iA1, (13)
tvtriac\cliFio aunc.F.b>. fil-= anti"

3.i>rSõZ.ti.t ,}, .>.F+...., as do.~ycS`C.Fi`,4,, Ã'Ã.in'i;cy4linw, aIId teF:
<E'E yr:.v.iFfC : (14) t;nfit.#'.Y:.,=.~f'c#.fl{3tixS
's3mi -it:ÃfE'ct.i4'G~ such as isoniazid (INH). and d'zax'F`iipÃ,,r; (15)
aFnt3pF'C;tozoz3l wsFxi_='Z .., ti.,CFv`t.FCi,idille and C aps3:Fi`FC:,
L;6,Zr&ntFiFm.anei.l
antip?'Eit\?.Ii?3l z3Fi1i-.i#.1f\.i.tkv4s, such as u,:=hloJL?quÃI'k`v' a.#.id
s~3~5'11A3+ t~Lw:F27Ffii=.. (17)...k}Ã f=?`sõ3} Iti>;
Ft^t > [~5~ty..Ãi Te Y i?~.!=LÃ~~;s4= ts7 ~]tS =}L:;.-~s as , t* (~,e~s ';
sM~T't,~} Ã.V.\.}
[ttLtA ~,+j~! )}/t}iti~kLrn }-s(?y~ antiviral ~nti*.3y=i.i ~ {=A C;21SY .iy~
2.'=v \`~ s ~s 'Y t>
Fr C`~ &C?S~Cd\~. L~ LFLSY`:sF t~ \Ci C].igk,t'2t~~ ..1.F~An
~iCi
3 1J

c3`'s rFcyE,.lov_ii, waTzi.'.Fc:.ae7L'=#.r, i.Fz:Ãt'.rfi'Frf7:'.F alpha, and
huÃi:c3:Iit,.Ãdi.l.kG (19) <$lkZ`lx-3.t?i g wat n4t}")iwstFc

6 ;1


CA 02653811 2008-11-27

WO 2007/140483 PCT/US2007/070159 a1gC1~~.~. siÃt"3~ t)S ~.~ laT~~se~~~l(.t~Ã~
and ~:is~~. :;tÃ~~, (20) -nÃErcÃsouÃesà t~lk4l(xiis~g '111,611..v;_Ãi<asAic

aAy\-nYi'!Y SLYc#.]4#s cii1.!mF.vCiZl:~ (BCMj) (2 1) aÃJ.timehCibo Lo
CL.SS:i?i eZfp:.4vLicL2gVtF..~. .TuT.^ha+4.}.e

(22) p`orÃnnldine analog r.l:niii;l{:'=ti1blS.Siti' (?fl"sInL=op,_Es ts`s uaga
l-l`'s, 3.7t,i: as
fllxr3l{1u,uou,l (<.' FU-) and g4Ãiwii:1b i1LQ (2') h,`?ri:37101`1c`2] ;:51
..SY3t'Op..>`.s6..s, Ll.;~a s

1`,,.p".i?hLic. (Ã:Tt3 (24) viat:Ei':1l 43T1fink.oplx1stÃ.t;",s, StIc}. as
itSS..t..~~~x:YS..z, d.t3p.3sSdc (VIA46.), lI3'.eFf63.i'o1R>.'s~lpha
p.aGfitc:{ol, and tÃ'aInt;)iÃ: (,.Sa.+Rs:'s); 125}t

anLabamtc ..'.i>i.in4opi.a,4CmSJticik as 6Jl1:f.s.k~yciny d..{cF.imm>yZ:in,
dauno. L:Lrif.eiL:,
do.='~C\~rubit+;ny:JAia miifrml='1.~in (26) vi~ilLsac}ikalolid nG~~il.ur.;w
any~mmiA'a(stwc:`, such as

i iFÃblc.#:st3:#e .:3.iad vi72G.I "st1>io: (27) :luto.r,l:onnIF: agents,
tiS:ich as Ã#ÃE",:3t:3`.i+. =(2` `(3.i,Ã.dc1'Ã3J..x-It'.=x'_;:~
<'r.utt3.~',1t3t1i a i:lgio1tE. ~.. ~i3Z.h as ti?e#:lil'i.+p17...' iÃ.l3d
ti"Iht:'iy'pht n.idy~.; (291) >?Ã? _Ãm':asimriÃ'?ic

' C w _, . ~i?~.cÃl`
~~:%Ã
. :.zt~ I i5; ~.31 ~ ~ r~ . ~~.. t3~i`I'~?~,.,.J1 as c ?C and ~.~:3i +. ~ p 1
`r ~+~ #tj'~~:iÃi, (~ ~1' ~_l
:~3 ~1~..` ..1~=Ã'<~. :C= ~ y L.~i~..\, wi.wt:xl a E.
;v
il~,k <Yc ..ts, si4h <38 : ... ~~,c?E}i.: Ci t?,:rx">S t*eirytFli: <3~t, Y~
~iz7G. [: .: ~# ~:~?tJ~,.c~nl~s,i-
paà (,."~~~Ã;:-~~~i~?.?a~t#Ã:i~~=d~:~;, such as ,~Ã1c?~,w'~~irÃ~.; (;~' )
.- .

\'i;iG hi.[S pyi7iaSi>tigm.3Ã1LY (33) alpha'bt4iC=ki.Z tiESch
.a..4Ã::t.~~a. ~. 3y,i i~.f~iG= "Y- ,~y~.~.~~.~. ~ ~w.~v ~.~ U ~ a 4~.Y o-
as pn;im^=Ãn, (34) :fri'tr.i baf.Jf:ker s~~~V.~{ipafh~;F3~e~L,~vs. `s~~A.~1
~~~` ~,

=uxYCla)C>-~~~Z,.`a}~>.::i5.i.=~5~:?1.sWV..'S, as aSR7oter`}2 waia
dob(atLi1,i>t?L (36) GS..nhkJtas4uSCLr L(`r-..c_in.v, ssuch a^..

i;4pSi'1#.i t W:l}. p..wvi-N (ClC3~..~I6i?g.i'C.l. bisl:E.f{i3tt:') ett (37)
bÃ:ti';#-:Flockos `.~uoh iv4
i:l';LS`aiS;.%S. SFio,p op-anESloSe ('8) ca:5ci:Ãm tll:armel bli?ti;kt'#'
ca.E7t:c.Eiw f>nc',.zs ; o:o;. (~..`s n.itC.'d]::33:nC.`,

L~.i4.t V~iiklt~~3wi.~i>.2l; *3.J ~ 5?S.'Li~.~.i~l-' (~i1t1(Y.il~fi.fiiil,]q
.:M~~iy.:i>. as ix2~;sZ~xi.~Ã L'4' .S!\}.t~?^4t~b ~a~\ "1'4t }. 4~ }`? r
G~CtJ:~A23.it=

glycoside an>ia.rrh3~tbinik,sy sus.,la. rj\-, d,gc?xÃn, (41) class I . uch as
:;i.ocaz;:.,, ÃnuxSleta?.7i., pheI11 t<3i.1-I, ?Ã t3c-a3~:na13`iÃG.~e, and
pAn1dSne, (42) f.l4tss 1:1

such .,s :i.4i'<?loi, m;::opF'E?lS.Sl, p7~5.>-fyra:nol;13. tÃ1I7fSlol; (43.)
L:,S.i3sy III
:>tSl'.h as ai:i;.i<?daAf?ni:=; (44) ..-S-aws IV ;:Lke': as dalÃÃ 3zcm >t;
i'~.' ?..i
vC,l ;~.>t~ S2 # \' "~rtC. '~~si~`~.'i" .! .~<`4IÃ"a; (46) iiiÃ~?
"~ii.~I3 (451 i~~t ~;iS^~L>:f3~.:f`s&t.~ ,'y~iix Ã~~a k~i:~ ~i li:."~~ as i"fr
*'.~ ~. v'. . ti n-
4L9ii .`t:ftiSg unf y.me' imilib;:ti3" t'ACE is3h1bitt5; 1,lntSby~.^u.
ioÃ1Jti, us, such as i.x.zrtt;>pi .i and

immia-p:iA, (4-') betablt}ckcA antih.iporW.Ã1sive,i, Such, .:s amno4ol. and
p>opw.i+3lo;; (48) a._:lcSi#iS?-%h.Z.7n+.:l Mixt;:ksa.i' it,ntihypoXu,1;five
EMoat8, such t.Es firRxlÃE3t..`..'.q (49 central-acting ad:'e-nLk"gc
,,tÃitihypc3'te.ISiv;~~-S, Sucl1 ,.s c,lo?3Ãu. >m,' all >

mothyldopa: (50) dÃuuoc~io ~.~~6l~~y1wÃionwitre agents, suL}~ as 8rnÃ;<>ri&5 .-
:wr.~ fata:i.ie,
i.HC'I'ZI aÃ:t~ spironolactone; ~~~~~ pe-6p~i.o.,al v,;so.>flatoÃ>

i ~ pti.``tE."ii.srtvE..4, S:10h, as hZdIe1EAid:1#.3o w>Li minoxadl:t (52)
aTAiF."`pi'-rn:cs, sooh as
67


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;.~Ei71~z~3FC3r.3i e117i-~ ~}fi~~~ #e.:,~i`~: (53) b7`L, wl'#i; it,iZvSt;.EIIt
antilipemics, ; LEvEt'3 ;Es cl.:s~

(54) ~ ~~"IG- Z oA n%h.Q.asU Enhib:iLi.'sl` stti:"h as I~.~vc?.`.tt?~in aÃxs.a
p1.;vt3aiclt`;Ei; (55)
F:1L#tE'opL ., such t]s, zEmE`in n, dt;bEtWu11Ã3?1`r EzEd dc$p::Ee3]iF?C; 56i
i~,zixd.ac ~fycio`1;,::C:.

#.nolE"f;pt. r, 5::i<h, as fiiy+.~x:ns (51?) fliE`{3mb'i3rylacags.,nt:9 or
.~.'n':! ET3E'.5. :axF+. Ei?s ` JtC'.;,?la.s`5. ~ T}~~ ~.r,
'amme.`cEikiso, StF..r7wk zi:`s4t:a :1Fid i:lrt}zh#.xi'1 e: (58)
d.;r.eT?cj>o.z?gEu faw .3ts, stFoh n` co1L;:.31QR'>i:1
Inil:i.?x'1dil, tw:nt3111 Wi"R-Ai (',T)`~) dormatÃ?;s;i..v._,.#?;;ii<

%o.;b:cC;,.i.zw.,t`>id, <#.Eiti iE.f.ti;.:17.::#att?Av aoGni.t, sClcht tiS
bm=cfhi;<<'Srw and ; .. tioxbE:rwf#:stsor ~~_'. J ~t:t
~.~, 2
i1.i,.~fii iHS;v t;3p%Q~{13 :? zd1n.3`'L'`i;tvi.~s;, sLEch as amphotericin B,
f:;lo`zelmc^Z>.''f 3li;', m.ci?twt~lo, and
'61 ,2t,t;v:.,.k top:iml <`a:F7ta-iE7~ectZves. such i$4 ai:'trUl;34 ir'~Ã %)
tc.;#iu=.i.

': 0 czal E,,7eC`pzii_;,,.:t ;, Auo~' 35 x~.8::+)","f)'~i'wti.El (:?--FU).
(63) L'~ki'.'i.#EI`C. ~1~`a `EL; d T
z c c~:ta CEiili i;1 `s. EV a.`s
h3i.,ElÃ##.),sf..; (t.`'-xi-) loop d,uroi1cs, such as filrCr`sei7;idE, (65)
pfftas`3'`mn' sptzizir3gg d#.xli"x=fiLs. svia:i>
f`~~ Irian1tei'i I;f; ( i`3~f ~`~~ 3~:idf, a.~#:.~~',1s~:S, ttii;'? as
Z~.~.~~~ {' ;R~ .~ ,
EaiEE:i?4E:E,E C a~ L F E~~ E.i .~ as p= f3*:3f,',.E-at;e1dY. (68)
t:.E'1_ly.T`tE:,s such as RNil;ic 1nd.DNa_k't (69)

a.~e:1ts, SFa`'on isFi L'yI;lE:z`3ptT*a:int..,

5- rc`it.. ~<'i.rtn, (.70) c1nt1o n1t.i1 ;s. :eLEdI Fl4 ~~l:i?L=ilE2i
F~f~'.'<?L:(70 :i~AEq.,`Ii3.tt'.

c w tA ~ w `= ~ ;c~7 Z ' . #2 ~ 2~-
>14?+..Ã1~ti, r ~.~ r~4 `a~Ez#~":i:4~`.~'...c:~Ãi~t.. ~ t~.~~?j#."1+:
:::;E~p:amp
i:?.lIb`tt)r, iElti-okeI' `i,lge.n:'R, such ~$s t3mepxt'E;.~:ole> (73) Hj
`+,`_tloctiC`, ~2I~~E Ãc:iLr c gent4, 3u%i1
<~s LI :E:3~ ~'{\~E~.i::~, fE.EIa~~'Et.;.71;f, :iTf;:~.~.3d.E#3~:~, and
.x.':~.~'Z,'~Et~.E#.i:.'; (d 4) +~#<jt.s'~za33 5. such as
~) .li t ~ ~#~3 t=t ,
("5~, # TrZtr`s.iniAj ..>ti viit\T `.3.:`1.:f2 as ;:~~ItbdikmVi,=in. (76)
t.FpiLEti. a~,~,~,o#a:.sft a.n,.#avcv,+Fus :ns.7fhefi~.:?

20 ~~ such i~~ ;~ i,' :~) hi;f]Fi.ItC;poi%fiL <33v_ f:C I<iFc~ ilk.1 such i3s,
C,'# >'thl`+!pt`a~..;EIa, i` t i:st:An.E

(f_# CSI`) wnC S zÃt;nuI3.i?si#.lal (G \.I.-CSF)? ~~7~~ t(#i1f~ES~='t
'zf?il <F?fe.S7E , as Et`.'zia3#z..e3o Ph~I
fa{;tE?rS r H; (AHF 1 -10,,~; (79) f:ilt{coa,~~;`i3lwats, such aa -wnfarlE3,,
13C.Ps;t:"Ã.`.+, and i.EÃ`gatI'obal1;.
t801 growth F'f cLpii3:" 1I1hi'3hE}i>,~ such as LI'li.AIllxb :2:E1d,
M,0fetl8`zEbq (rt'.~~21'r ,E,??,3r.if~wÃi`IlÃs, s;ii=h
w" Fl`E ~.i3 w{ p(~'s: ~z;~) 1n..i t;z4~:Ela_`~, such cn ({i t"~) ~.,
`~~.'lt.:i ~;.~c.# 3~E<' 'E:,. >. '~"`v'lE
t"~E E:3s`.'.~1~ i3. I#.i._E~~IS: ,.~1r~~.Y~ E:`~, ~::
25 :#.S L.`strot":'fz ;E's.wt =3'R3gL'sC'1.1z; (S3) p"zJz ~ 1x17 ~~1..~', as
~.v v'()IE:a?"s,z;;:~t~'~:I `E:1~
~.t`rgi:<sf7=el (t46) s~A,^'ogeI]s s E..h. as i,:f?I3^jt`+y EEtti;d
::.SLmgC'.E J, d.i.'Ih`r l.11bC sta"e3l (DES)a v,W<3` .~.:i;;
(LstIad:ol, o4luof'o. i.:"1d i:.`stI'opÃpaiic); (87) fertility <$,,;<>F'EE"sr
such as i lorlt,A".+hs w hEl:`nf73i,
chorionic k;:?.'`.?..:+.FZa3.Fi}p..n (11W), and 1'S.3t;:=F:oET'f3piE:s; (8i))
r'zE3ra,hyE't#xid cz4-#=.'C'.E'ars .aLich~ i3~'s

t hEz3i EiifiEFE , (89; pizu' 3aE'y hormones, such as dk snFd1pr4 ss:EI1.
;~(?St =L=.dÃ, >3:{vz 1~~.iAA c3-Ild,

30 vi.#:i<)pr4s;sil:. (A~...~i.); {90} pi:?t.:.'C;st1F:s, such as
113edz[?xyliF"+Fk t:s:* on and
p`' )gC.Ste.o31i3; th t ['i?Ed hi?1iF'li3Ãte>; 4E.lL 3 as lC't' (9,2) 68


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
z ge11t.'>?,. suoh as f.3tez'fefon e3ctc3-~l 17 and ia"ltt.'fert7: ga1;:uml
I ii (93.) ;Ã#.iL~"::

as rtmalon,. I<?btrhÃ: iM, ÃWG, IGIM ai?<i xm~~~umo globuhn]V, 1VIC. ~~IV;
(94) waizdL.
local an~ ~thode4, such as ~i(iÃ3caine; (95) ost:or Ão:;zd t::?esthefics, s-
,Uch as bonzoua#ts.; anal,
.z>
~~I~SC.t?#.?~1S ~A ~~,i~t ?m:#sc3.#.lZ?"I&Oi:Qi.al +i."i:?,.tlcotite.'(?Id
ilt3ti^1.nfli?F3?'#?ia{toiy e:.g``_i3ts, sf,cih i3s',
'3t;tafa?{:tbaN+.?Ã?e, a.ixr:I.`ti.'i?nU. d.v.4.cll :C;~a?a;iC3'nU
hS'drt?(..oS'fi:iC3#?v, and
pri dy1l.::o#iv; (97) :-?3.[1.: m..1o4;k+'.>.l''~'.it:fl 'i#.nfi-i:1lhE-
n'4:I?i#.tt?f'L': l~b?I71E::3[3hai~~3Ã ~ } ~~, iF .'? 's:S

3Ãs'?Ão?pr3.11e, v.`dophi?spb:?#1:Ãa.ii;} alta ?n3eÃhot#"ta,xa.:C'.; (98)
m?.t,.ct?:.E,;,k~.'letG:. ,?=f?stt'Ã"of#;z?l
v

:?n`L? '~~~. ~li?.~:'tt~.~, drugs # .`4Spy i~ t ~+} >s~.2~.~5?5i~..~. t~ ~d v
2: a{~~ >~,?~ '.ai.~1. S~ !
,i~. L}?. ~~. a~A~:3~~ v'112~.'~=2 t C?:3 ~~t~~\.~;.~,i#.v~~E'.~i:a
~cE..~~l~?2~, ! ,f i~8C.=;

=t?~`~) .~}~+..i~,ti3: :ill.:at'<l.r E#'n~i:i:.i.i4, such <$.~
~?6,;~?'~L.~:i+~.lt3rtsie.?.. .#~ i;
dl 3 .e;?al .:< Z'= 00) Ti.Z'e.':s..'. ?Em7'omu1cula3' blocker skeletal
f`a]Lascl[', x'L'~3i3,.:3#3t... such as
pyYri (10 :'rri g;.rd~~.?e. t10 ~ ) iic `'..#.oEo=.,;ci~~ ~gentS, such [?S
'mMG di~~~~.~P,0, #~I lvo1x awLtii I-?~5,. r_.n3_[

t14lE:p?dÃ.i?e; 02) r#?"f~.:c}?ÃES':73y:; n ts, such as, c'41Ibatn<l1::.p1ne:
ga :?Sipi;tifin, i;?n-lo'f:i'?glÃ?e,

:?#:d vraep:i'"t)lL:= aL'.=idr (103) b1:i'bi'ti'lir#?ii s3;.#...2.3 as
I>:ia5.;..#.ieb.3..xb?tc.'tl ::.#.l-id
phtniLaf>m. 104) benzodii:nZopil?e :IÃ~~l oL}s:vu1sanRmfi ask.,fC?ns;zepamry
d3uiFfvpan-?, ;a2?L:15 lt~~rat.cp..`,`?, (10:9) a:#.E>:.1 pa?"k>oZ?i31#.in
awt.3`1t.: e, S#}.cl? <#k `i:i'c?r:?i?E:>ipi3i3c;.+ :t3dopxt, cw.7ddl?~`;:3.
~.ert ?..:do.. (306) ank`!"vt.'#'tiglZ t?k~iwn~~`.h~, such as mtiJS: ~iAnc,
oplt.c g.:Ãa:islt `s..ich ~as
md 7

r^C`,,a hyi: ;r ~ ~~.Z>lTI'~:Ã.l>=3~1~,>aÃ:, ~S?>~..~a 't>ciC?``v'I'ii~v
atl;~?S'?i?oT'j?cl~rtÃi?o, (108) op,ma..t~ ,av `~
va.=:,>..s: ?~'~. -. .. ~;,~;c.~;~?>?i.;`t.;.
ko.aÃ:1.Ã;:3,.

StÃE h, as a:tialE?:SoÃÃ.., 0 091} el+.'.ta b;.oLkCI' anti-giaÃ:#co:Ilt:l
i?ge#?ES,, 4ud;. as 111,-w1f)l; ~s 10) t:?;3.lot;.:%
aliii^g#:r:;EucE?3-na ?.g-OnLS; s3: c??. as p4lZ?t:tl.l'vt<iic; (I 11)
ophthalm.IL c3il:?'1.Ã?or',ly i:.os3&

tilÃrf?Iz?fCs ...ves, s,:.1~.~ii as Ã7e-aszÃ:?lf>iÃ:, neomycin, and
%t?'bFamyitl?, (112) E.3pl1E.iõ#. :].a;.c
such as ciprofloxacin, F:3o7"floxaiJhi, anduflt?a:al i.; (113)
3)

01,11di?:3:l.?3?i= '.:">or'E?ct?;?wI'i?ld ant? t1;flammt1tt?rr' ag!wea, s-uL:7
as C?L;k::.`:':1L:h.st`ne.: and
pliA>.3isC lo-z3e:, (114) opl7ffi#3lm#; nC}a1.`it%?i'o1d.i3S ia3"`zigS
(N;:.MDs) 4uch's:ti
d#e koff'7?a0.:: f I I 15# w,`6Tmi<L:=h+?t7c4, :~lit:h as d1[?z#.?p#.Ã?t:,
hi:Ilt>por#dt)>. and ni\pu.d<?IlG', (116.)

2 115 bo`,..nd.z,.`.s.,pint.. ,a ax:Ão yl#E:.':;:., sC?'.di:Iti4=4, aIiCa
hypnotics, sb.cIi w> d...k:'`epy3Y?'b,
p;'aL.C'pas3'1; (117) p#sy:h<t;A1.8t.F lan$ .; such as and a3e?il<?la?:c-, "
118) a..#fii:l:s5avE:=s; ::lu4h as et>deiI3't+: (119) ba?I1ohC?d#.a.awas
ar?ci~" t?:.'s,

tht:=C;phZ 5li3~~, 0 (-'} t?dI't;#?eÃ'#?'ÃÃ`, aLw.114t NZ?n~.~hod1la.'f[?''S,
such as x.lb?.et::rt?z, E12;i ~

3a ~~?s#'iI(C? i i:.[j."t.iC.oStt?'Ã3id tmb ??fl.. .yniT?alf9Ã'y :lhvll:i,,
yt.#t:.h ei:? ;(1,~~,'..2)
.a,3tiLaf?:es; ;I3d,., t.E'.1 fl#iTlazt.',ml c1.I:ld i?i.#l(??:(4 nc;: t 123)
hi::v.'y

:r?~ 3~~ . S~1t 3i ii, a à ~?~ ?~~. ;k?3à 4; f `~.^~) z~r.',ieÃ"T'[ .3'Ã~.
st~.~lSte .i1t:G'= ~3.:?1.[s~:.. ~i~::t t . ,~i:#t,;a as :~.1s.F3~F~s.?Ã1~#.,
69


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
f7.FltI'exmnt., z.nd nF~~C3fi }c; (;,2'') withdrawal sE.1bsl 3.#..+..w
clii3.IsL=. <?gi;m*x N?.Icl, as

(1 21Es) minerals, F;,ucl"i as #.3't1:`l, c<?lL:3uF-.i3, and i 3s ?eS;E.#.i3,
(1.27) v.itwi?z#.l B
i"~~rn:?;?F:#za~~3' , sL#ch as C 4'aTIC?Lobc$I m`.1ia (`t'3ti.#iT`xi? B 12)
w?lf niacin (3'X ,.i,7?;#: B3 i y ( i ) 8)
1'itt???F;.11 C cEfmpoi.F;':tdSY slid, as ascorbic t36d; (129) vitamin D
cÃ?r:"sp.m#wis, such as

<'...~le-#:`'#'id (13,01) vitc?miF. A, '4']taillii7..`.., <Ltid vitamin E
t.,iS.F'aip;ut#.ds; ~13 : i ;?C`.FSont^, stwh t4.'<''.
:'~ .k3.; ~ ? -. ?} <?F.?~#--~3~~(:~.~#F~~? i3r `4~"1~~< :~F.#t;.~5 eE:~
~?t`i3~~#11#1;:; ~ `? 3 '.~,.#?~#f#:~:=~f?z3F#~3,:.F..>F x#::~,t.~:~'~~~.
3` c1dd:t`.t}.:F to the fiE1rew;il~ the f:i#ilob3`F#.?g less t,oI'I..:3't`~
i.. dmub s can .k34i} be ...sF.'.~Fi:
S.`zrF'a[aliA i>yp,s,'3dlaif'. F .7 S3iI: estr .~a#.t)l vaatv.Ia:l% in t`;::
fimbffÃ;>i:

flui'bip.i't ..a.z3 tit??iiÃrn: i1..eÃm.,eCti3:#: Icvt)df.+pa; nafari,lin,
&ndGo1:3;fz?p#.i. F,?n.tzet', th:`
ft3il.s;i ;fFF dtw''.. :aFs i3lso be i.#.:;`~.'d: i'eco#:21biF';.:3:i3t
bet#.3 SrlF.:cc3#.?, bc.Z'a.i;c ?~` ~its#it~ ~(?~).# !1r
cmFtxIIt.F 3lc; bi3 v#ne Su;3E;'.xY??;.idL= d15:1'?'i1tF4C; the fm'itSh-MoII
c3c`F1p'n"'iikg

c~~"+#nephF i3c, and bovine collagen; recombinant b1mdI#' I3,IZ= , I
3:~T,:AaFEF:#.?;Yb',f:;
h,u,I??I? ,~F?fi ]FA.~: `-` :~#5~e1~`~t?~:~~~; FLirtt#?a~5~#Ft~#_i'#t
~:t1.1iF~.~~3 g~'?'s'i'tx? ~1~?~'fF'lt1~Fe .~.i:`:'?fiFi`1~?c;F~~t
=
155 'hi.ii2?;<3I1 hu.E t3:3:;;ol?i#:F (a f I.e ct?i?_ib #fic3.nà hLF3'm332
IF:eirei?imil F E#;-=1 GJ F - i.r?; i"ez?mb .2?.?Ã;;:
ii"#.t C!'?''.r l3ri ~c ii ? a, ;w'j'.i}z;.::l~s à i i? (G- -~~S F); <lhi :Iz
{ip ii3z'.; Ã:C'c o Fi?b Fh?wn i. ''1zyk- z?id JÃ#lr3'.#la `.:3??
hormone (r-T:"+H); and tt>po~r,4.,an. F%Frthwr still, E}FefE3alf3w1#iM'
..3:'3'a! v,xoa1.s i.`+Iol%:o;.,~ e,'=an be
uw3: :?.~g~ii? ='.,# ~?+~: #1??'; a.Fed4siiI3.~.C#i, t:teda61fi?l:; bleciÃztw
,i ;iulAawr human t,alS.:io#.,.v.i;
i'i#~3ili?'J3 3wi?~+ I~C3~2#~; ci.l$rbop3z<i.th`#; eiuF..~#a4lF?`;; di3Ã:
sF#3i?i3::win. dc#I..FI3e Fb#.c.iF.`e L:It{z,E,.i1xc:::

da?wsf3i7#s.l~j 1-i3:1; ~:,F?()L:1.n alpl1i1: d :C?p(?side (VP-16)
flu;3#"o^.#=rs;t.I,(.~ FU); F3?~:~:.5'rb'Ãe
Sc?dFEFr?'t = L.?'?trJ.i7F,4:i? si.#ff3>3., ÃntL;rfiI`ir#1 alpha;
hci.#p'r(:}iFt:t.

tnCi.hadCyi?w i'IL`i. . ,?1eflxw4:fi:s.itt'.= ;i:?diFta:s pacht~.#.,~e ;;
#"s:3n#ti: ll1e HCI; r 1z,.b.iz?wt...: : :1..~tlt.iu,`: iFI?i3
:r;d mal;h'}s = Z ZTS
= ., y: . ~ a .
.~x,~?~a, b~~~3,w, Aa#~: ~::SS.i~Ã`#3;?l;ti of ~.~ ~~ ,.=xa.E~i ,~h
Fl'#~l:i:C~LFfi:.al fFoF;~3 the abf3vi:
t,`'ate~f~x.F`L'..'a il'ly?3.#C~'=. {,t~) o`:ti #.i~#~.z~F:~f~`itr u such as
2#.IIch'~f:};y`4vi#iF'l~~#.~3itt?i~:+, ~;.'i#?.,~,'.$~~'`l?#.ItL`,`'s:
cytotoxic aF~~'rfi.as receptor F..~ 3.#b'.tis.'S. and F~I1J~ 3"~C2I~#~}+
i~~u4:C?F ;b) eint.F-tiUSs?Z t;',,,i such zis

dV:}.?i,ome~hoipiEan ~~`.v 4,t#5,7b#t?i?Flde,
FifJscaAf.a?~~vqca.bY'tap4'n\4}.iit,. c2C3G'W.

and .`=hloi`,:}llck:.,.#.F#Ãsl hvi.aC?c}?,t33fS:xi (c)
.@ii#:Fi?i:it$#?},vi?.e?r such as iFa<3leai:e.
pbwa3.il?i;t3y~~.sfl'~o-~ w.#:riFt4, pyt?hlm.lnC. maleate, G.3x5haFI:h1e
succinate, 3?'td p} C.FAyew.1i xt3i~`?1#:.#fi:"
i:..iÃ#`cite.y (d) dlicoF..g:;'A<3nts Si.'.'~.:.~~.? .%#q r~icd7ylE:ph'lyie
h.'tI~~aos"h:K?i' &

hydrt3<:h.s61d'1, a;:eeIktriS`~.."Phti>d.i'FnC,ah,rI.F"oddE7r1d. and
ep.ht1d'I'FIxC; (e) Z'i7t'F\3:3s ,.F..is.F;:lz?idS S:.#c;.i
Y`' Ã~
r


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
as codeine ph{~sph'i'StE. ~:=3:3#?#:ini. s13lfatL= and `1~a1t~5~zli1~; (`)
afit1Q.,aal s.3pplLmLiY`ts :4E$d as
pt`io3asnt1ml dlt3ni.,c, t.M4 L"'3101-Ide, {.c,aS.gE7a1l 4=a# b'#JTa.itcs
3na:t:i#bti..m.? {3x'#.{r~ amz3 i3t.aci a? r.: Af.
I?,;ac3l and ca,k;:iz?.i3L earth metal siilÃ5, i{?;:i fi.'x:Ã,A"#.;FigL:
I"SE.`F.3;ii such UJ
, . ,
~) i:Ei~.t7.~}i'#~~"{ w.
:?YiE~ i3FA:.3 ~3 ::~?#b a :i3:.:f..'.~I z~s N
~C~.~.~'a~3T'oC~i:ÃÃ{~si#1'lidi'> 1
~.L^=S anii: m's:l'c?c:*.Cit:~ss svich<
~ as ~~~1eaT~,'l-
at=4tci73-I`.i1o~~'{e .#, aS~~ ilfa i#.ili~ F 3E7 `rL~fi=al., # c~ ? ~
~~Gtit~: :i.~.~~)IE.`s>iiaFlws s31ti'
~ ~ ~~.
prop,a.Flolclmi,int u#" iycll-Mi~~ (k) as ggi.Ec?:,a`.'.1.,ch#.i';.~ (1),:ai,

~tai:ads ;msy'h l6 `r#.:EIma`~.~'flm tl j'i3t:'i;xid{y 2#33d 8?1ag11e4ruÃ`t,.
hyd'#'L ::idt'.$ (m) b;Io t`,t..l.c:a .s J,:ich a:i
p;`ptÃdL~s~ pt?lypLp{idy.s, paAclns and ili3:iilta acids, hormones,
.31lenfi.ic3t:.IJ or cL';okanesi #.ia~i
f ~ 'T `i'i.l .i4.:i:1.:., ~ 'c ~ i ~ ~ ~.=;?.#i~ac. ca~ ~ t23, ~ i-e
t3,t:EEi;da; such 4.<i t 1ilEei`lwla~,t t.#7S 1-18 3.31~:.1#~ ~ ~ r3 inU~.
a~'S aaii{
r, -i3~].s :,: #ii
i?,.:i.

: #lcalf3r;Li4s: ,.~<Nawi.'., DNi'i.`'sE'r~"; iE]tett`,=;Ii,14, I]`<)rIIl<?214
I{fle I:sIn`.j ='a`~.{1 "t731?n'`.`~ (LHRz l) `i.ia'IE'.i
F(;lcc1:Tt{;an hL7nnoIZC+ tS,,;fIiRl-Io-.timGfo3"#'?E..i#., y,.o15='u'#
=,3{,to B3.
fibrt3:?It3sà ,gowth a<tc:or 0't;iI-0ii turno: :ii..oto`i~ I'ac;;ot'- a1;)ha &
beta f Y NIT

4.~'~,
ialp.ha e~ bZtiz# iic'I'i`i', ts~.`aLtt:a (N~3F,~, growth hi?~~?i~~~>e
releasing factor ~_B1'f
growth `

<-3r ~'rT 5 fti.Lr . ~~:i,..~.~~, ~ '~3.:t~~=)> ~~ ~~wff.~lE~silgr'L~i=t`3
growth c: ~x`~.LE'i_.t~'E i'}7`~#.~ S r c <3T.~i ias i 2c.:: r*:~~ E{3,~
;r.\aEi~.~~=~~
~~E~t,:::71t.. t ~jF3 ..

5 hL p4tt{?wZ'tC`> groYvfl`E f+1d(.7i' (1'KF), 1i1s3_il`i2] growth factor
(IGF)~, Ii'1Z?ia4.E#n Mh#.,.'#tlng >;.~icAo;t ''
~;Ill. -2)0 bom.;. i3#oqphii gC,'I:C>1`.>i:: proteins 1 ~7 (...`.+mp 1-7)-.
sft.yli:E4_3st..atFl` flhL.3:1o1F::3-alA)lleE-;,

iE ~1~~xiE rõatt 3Olii"#., ~~Ã'r'~?C.To.S3ds. {a3s.inaEc1:je (SOD), ioi 5 fOac
..: A
Lc;.ll.# ai1i `., ANF, E.110 and ,inadin (I3) afFfi"iÃ:itt..+.t13'`t'
.lN;t'3'.IL' :wL.h """? AiTtt.fim`?;.3.~4. .`a16-
=i3~C i1ii~~ :wiE' ~~Ef:\ antisl~?ti~v4 imd t?n.ib#C+ticuv and kni oxyuv{.'to
l`C'#.i:x.'ag3z3bEl~.t..~ nitn'v' 01,
s,.ivc~-' wd&,.

a tlr$t fii:aItim; t:i;inpde4 l3fi3-anid c:.iti:.RoIivJ i}a L#S.C.a~.:;~
phi$nna..r'..'s:#cc'l agents
#i7ivAllde lw f(`la.3wxi.1=,~,..? th~;:+{'apC:#_3i1L~ s..atk.<,?'{.~ilLti;
's3F^t_lbolIc.ag ;) s. .a:.3L'.4ta3G3?i: c#tf...;3;s clnixis::i{as.
e'i1t. zasffi.1#a#.d1. agents, Lt#1~:i ~~C?~s3~.C ii;:{<~I :~= and aeltlvlf
.3#d i3gC.iFts,

:
S.~^'d`i.3a~i', Ya1Lc#E:a. ai1tiC:a~#: c-fii'. ~ c` ailtirti"a:11~+'..s,=stiSi
. s i`g~>cflt''`z a.i` n:;:i.~'.'t~. ai:ts F 3` =~ '~a
.`i~iif~ { t.;;L`i~~.:
ts.3##S~,3, a S~Ca#~~E:).. ~:.~~i }

.~~/.".~. :i#.#.$ ?,`:lE`~~, ~:~~,''il~.~, cl:Ã1~. t~s:`.". L:.rt:; 7
atFl~rtt7.i,C?.~~i~~~f{, c>~;L31~~S, ca:~~d 2'~.:5#af ci`,.~,:,rt ~~. t$~i}I
~~~~L:~:~+=:

and i ~c S i ~ ; r r= t ~ ' ~ r ~ r ttF = j } ~t~ ~ ~~ t =~. 4
ia{A~~. x .~i;a ~~4 c .l~}we~i`~i s..si# .i. .cÃ.# 1# ; c#;~i.{l....
ailt.i a'rlr?#.nail ~,Igs.,.E,Z.s iiT#t1 t'u`_i'Li$ves' kA7p!`.'fite
53..#.pp.re4sani:)., b olo3õ>i:a2s.
ce,.obE4~l d,iLao# 3.:o}!?nar~=' dilators, dei.-o #gusi-a'#'its, diurL6L-=`i i-
1`agpoisdv ag

ayffi3'+'_+pj,e:.iw a`:z'ri? 4x,3ctvtc~I'anl . I:Z'p4I'wt y+.:.iT.-.r.: w>s,
hypizoai#.ti, l>L'i*i3iz L''ci:m:c #ti,'ciats~, '#i;ta exchange t 5..::dF;.:i
.c..?i'c3txvos, t:;'~E1ae.';ii A,ar pz.cilia{'ilts,

i 7i.lcoly #`L.. agoE`#.ti, E>ouromtl.Eai;l.da{' d# uggs, pC'nphf:1i:El
vils~.)dil:e#.oi.:s; pychL3tr`.3ti:;r, Eod ?fives,,

71


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

s4itnulCbS?ts, tJi}rof.{'-an'1'. Li2ttY`fiYy-rt~id
ti~t~'.~..VntJaÃ.lt~.ltin+v relaxants, 41taS2 12i`.aL2d pi3').iLugs.

EmiFt3pl.` of spt.a.afic dS'ilg.i ffi;it. can be ti:ie'UIyiL'.li#de:
.i5pslra`?.nasf;, bE.:s-..~i~ixi-a,
E::i 3C:4;:.itci=Yi.3e., i:2.1.i'b(5pl3Ãii"i. S:'i?..f'in114fi"IC,'., 5::h-
l?':?71abui'::Fl, .Ispli3fin.

dilLiFrortPbii,'it7.:. dE.Yi'z32omar1, iif#co ,..:~el.

`s.lo.:Z?n#."32:i?:, <,w$?t?4edG:,, I-xoxÃ`s".idfi=.i6,', fl:ldaI'ibi1"ff.
., fl:iÃ?F..#i.i..:ii ihyi:i'3xy:,#.'::a_,

i0.54>.idb!`-Adi iJt..saS3L.ia2dZ.. AYSE.AoL'i=4'a3t,
5.~.~2F~iR~L3FDV,..12~4+r~~1.1t.=~Sl.'t,.iAf31S.1(! ~=',.mV.[pÃ?,-2At1a?.)

n?<?f:'i?.~,"it{?p.3a`i` ,~.? inetho.`re:5..%lt'., mitZ).iT?y:llf.
:Fl.itotan::, #:11t<":wntri?i?L, ps.fjhftca?:w~As
pL:mt?`t:it a?, pzi+.:t#n?ytii=i, pi-5.'.ili:xÃy-ed ?i'C?cui`ba:1i7?::,
rir.h?;`.a.:.bi.., Mo~f;.pt?i,+?L)a;.. te;? 'r,'`'43`i.1d.
$hi`Mm3i13ni, th:CZtq:a., v.it?plsistine, vi:?`.~hrfSfinL., ?:ild-
vf.Ili:81'cibFn<:, ..I'h4 E:=7::Eai?:..y pi,#e1`#"eC-j

drugs fos li)`.=.?.g ~'. ~I-zt;:'.',.a trccdtme1'?: is pi.EdIl.'ia?i'':ly
p`t.'l.i?'.ÃT='.:5.ed,

i Ãi?~te%un. (3:'deI'iva{ti5 iF{~th~,:4e.:i1e;,C'.=:?1xts,

; 1.ili'.::33os of <1.iIfii;wnc(~-? ; a,xtl#.?Eti3p~a!~wle agents are
Cw'?ptoffice:tns. ~ These dm,igS t?:I':;
,:i:'#ti;.lcqp..c.i k ~z5r vzrawof >lie3-r ability tL., ?li1.iib1t t(yp(ilso`l
#s`'.'.Fc1sG 1. is :i
p.aflt zilkslEo_.a isolated ffi).n t.ILL':4 7.,ldigent?ws to Chfiai3 a,iid
Pmdo`;s ;h.reof such z~s 9-

3l::1}~~:~?~?I~3~~A~GaF~, .`.~ ~?>~~ai ~1a?~~+?~a1~i i11. ~~~ ~~~'~E'7 4'
i?F:i~?~t?F~~t #~i= ::z#, ~ 1-
mei.i1yl#.>}eci::.i3iY.,~i3=l1,;3tÃ.;th<`%I"i, 9-i?.tP.'C?-IO..11
#l~~~d#~'.~:?C~?~'`t~~<~` 9-ckK.ii.`SC?..
~ ~~~ a f -~~`1.~.~ ? A t'~,`.~:.~ ?~~a ~ Y~ t::7131~?sL~3~i.~ t.G=a.~'1, ~~
$Ã'$.7.1i'~? ~ tt~, ~ ~ ~.?w~.~1~,`~~I?L~~i `~ti~? ` 4w $3~~?~3';~,Ã;~~y:a,
(C31.1.? 4722; C), and. other analogs (collectively 1'#,`.forred t"L? ht`
.1`4,',l3 tEs, G:Impt.5ffit:`dn dI Lg s:3

2 C. am. p,'.'yeiffly under study worldwide inrf;~oarC:h laboratories fell"
In4,x';2?'14i1t c3; k:cdoÃ?:,
by5 aai:, and t:;tiai..r {`.is:3cY<i`f.

Adi.aFi.:z' na;3y Ãile pilt3.i'm8:ccLttk4lal i, a:.t?t can bc a -
riid1c)st,".3s?fi1.C . -,'aic:'`; as

sbwnsw:S?i\:e or ~ ^i.Y'\r%~C~ ~ (l1a nul. (3ciure4< by ~.~ S ~ ~, ~'N}~=~Cy)
`?~~i
i5[ Et~.:a~)~~'S.S. = . ?~'4 .VD. }l x
(made b; :'ion), RSR1r (mado hy Alfos) THYN41TAQ1:, kftmi,Ic 11by AgoÃkron).

olai7.1dcilt?>e oT iirb lgÃ#-as:t:(m;?Ã?ufiac:'urcd by NyGt-n7.Ã.=d):
gadm>Ili>la?, tC:;mKph:"1:7. (I?.i:d~': by
1"a.amni:3c4clec:S): B*~~,.1DR/Br.t?xE7('. q:mado by NwPhurm)3 iFIdR
(1?:Eii::sc by Spa"'"-ia): CR24 12
~elke:l.~w= by ;.,..w=la Thi?3'isteÃ.`aiI?..)) JLIX (made by Te_iiap.il),,
c;gent'.~~. that im:n#.a~n:ix \ hypo:~;`aci-, and
`._;: Hkc.

The il.'`a.=.a.m ca#? ~.'?c selected fr`si:tl a :?PÃ?if7:,Ãs .illy ~.we:5'e
h,.i:3Jt.nC;c. 11..c biologically
uwÃix; :SÃ.#.bõiaunL, can be s.'=lef.ted from tli~` g1 ov-p Ce.1i;i1tiElng
t3f pi.'peit{i'.y, pE {y..; i.:p.xf..S,.`,*'.:
pa+.?ti3?.`>s, c.#.ii.?:T?Z xit`..idi'? polZ'h`,k':L'i`'.`xiiTif.Ãe~'`_''z,
growth fc1.S.;:i?'s. ht)rmnt5nwsw ll:~l i~ 2M s3~~~~~=:i2

....
r...


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

.fLtclZ?as, or M!ir#i34::[iZs, and pao-dS1.4{w+f.I#I weLL2F
t.~ÃSaboR.Si:.~iioi^ ss fl.W

b,,O1Ogia.a?:`Y Fa. t~r~ SU~~~~aDCU is a t.ic..FapeuF#e dni:; or T,Ãr, t
,?xef..mb}y a i>.rug,
.f:'f3i13 t~1C: 2~i:3[3~? ~:~fz141 ~F31`Ã~ l? f :IGI~#J~~~li'=~"~.3:tF.~,
zi`'+..ts and (?:.l?::a i'~Iat#t:;4'x.t+.i?.::Et;~
Ã,t..fz as p<.#S.aÃ:ta:tiel., iÃ:FÃtib#()ttiLS, .F3'.1t#i3.t.F74F3Iti
3#?L.Stht"t+'L:4, .3,.?fi~nchnn..~Fflas. ,.t.it;,.

.:l.F?d c,ntFf:i?i .qF..fl:mrs. 111 cC:~A2:1.Fi1 useful L#F3~3~)C~#F37F 3',`,
ffit= ~kk?t,# :3C'3_t~F~= i$?t#+ {
or pF'ÃS-E : ~,.tg t< <õaG.,L:cA Fro1''F tho gmntp consisting of
LlheF'?1ot~~.wi<.peÃ'Ã1:= -i.goiFts and, other
:3I.i`'iÃ;L'.E3patÃst#C.a :ti:3't;ii as pa+;=_jitc:mi:i, +:Itt'boph;tIrs and
c1:#plitu=?r 1,..tF"o4o:.#.zE.,a cilkj=3i:# :lF:1g
#xFi`.F#.t's.~~~4..e~.Fl: w,C,.~'i?".. staf.:.3i as a;EFl3.~F.F<~:~.1~3:
i~B~ya~;~J; ~~OS3aE):#i.Fc#. fw``'"~' U F ~1?# `'t:.'F#IL#...`.S_?.lF+.',
hi)#`mC3'#'i". .3Ã:tMoopli:`.iLsi s3.s, gi,31a#`oaFa. l(:.i:prmfit,3e, and
~.F~'.'?4Zx.#f:%n, -rC>.=q p~t,i>

?#`.>.:h#tt;::^ ;;LlC;,, e:Fs tii'lo:#..F:.``,, fs#.,fd,`=#]I Fb, s1:FtS:;3?t
S:SF' aFJFta-=-kz# :I1hib#t[3m 5.-#ch ia.,

na-uF-~sz's af~..~Ãr-coph?tÃc1, such asaldesit>13k1F1, InwrMAÃd1 .=~w,
doÃ..e`zi:lxcl...i7px??id:-, fVP 1~-~;,

in¾Lr'fZ::4EFiF alpha, pawlir.FxC+{, i.nFairefinoxi.i (ATK.=f'~.).

hi caFit'sk.?eI' iz?e b:t?lt?~4;.c<3llv acttvc iÃ.1b4tancL F?liviw=.c 's.34Ãd,
~.;::.`. YFIF~~laFu acid sequence cm b`' selected frti31'na s.lz oÃkg) any
DNA or RNA
. .
5~.'~~~:ei~IC;= I?~ i,~'#~Ã:<~11: ~.F#.:?E1i~FtTluÃx'Fs, ~.iz~, '~#olfif~,
.1ca~ly L~,clvve s. SsE,FnL.L. is a D~aA se;ixI?i:e

thLa wF4,.odesi-i o4nVfi4' w}1i2?ke2 ~,?t.,.(e4.LVd from
ti2.iifFt3(.:.=%uCaE?ase ge[[1. g4#:4'.i

z+'.f...#'i?i# L'Qin It.S11."'IjiILF#Ic6:., iaaa[i L:haoF`i3#':'1phorkol
zali..,~tt`. 's.:'a.E3a4`feF,v`if.'. Im, cert.%lm
c.~'iibo1%ija"3`w.st.s, iho biologically i1:d]v suti?4t~an<'e is a DNA
S'L':.quE.`~#lt wÃ.:i:ft f.`z:.z:=odes a a ;

a33
~o r > 'c c}t In a.~ckl:iF:t3;~`~..z ~'1:~.p~<):", a Jzu:l?:'L=s3#.. or a
t'~.di`i~^"t%1F':3.z tIaI~`'sc`I.i:f,F:= ~ <~.tsi1w factor. .3a c':`twFt

i;F.i:?oi3Ã azoi~t,~s thw b'1,t3lo"~~,:ic's3ll"', iFf;f F6 ~:
tii.IbSt,.3$lcl.. Iti a DNA ;s`a'.qF..5;.F7:ce flh:il G#.4oda::s a RNA
`'sE.,.ea..teil f#;(t:n tile gYO..p w:la.siÃ.Flg of a SG'R]4c RNA, ~il. :FEFb-
~n&~'~ ~~ N`,l, siRNA and a

r.! bi?i?-y-rn's::,

B#. 'C`:gFi.iElly c3ctF vk: tlgt..i'.:`i cE1:fm#3.i?l5.: for i.:so wat~''i the
aIWw zdL..sxeF'Fb<:.d
hQ.v1.n z31o3mk, w~thoi.'~': aii?'>itc1t:to1-F, #Fiedli.tdm=.::I:ts,
viIF:?mÃ:i3i+'; Tn7i#ex::?.l. s::pi?le..`f:.:.'.`1ts:.
=c a ; c
s~1.~?ti~<:a1L,e:s .,~.F.. fi>`i' E3~1~,. t.~::'i~~i#la~~ ,i'Ã:-.
p.Fiti?t.n'##CF3I, diagnosis, cure Ã#'~:IF~~~~\~.
. v ~~~``~... ~.,~ ~~t~..~~,t<~o3~<F.'' e S 1 i the ~structure ;F' i
f.,#:~~:#i(Ã'> i e of the ~3~Dcfkt2 #'!' Z.. ¾;3.: .
#a~7 ea.L.`i.~< {.~I ~'; ~ FÃ ~~F~ i.
4I'lFÃÃ;b ?;fi,t.o.;?':Ã' bFt?lo;? ci3lh a..t:iv'o ;2.F`>.1'3{??'C aG$.1vr.
after thf,'.-v.~t3C-C: been p%:t.ud in a
pfi:..L>i:t4;F.#`.F,..:=s'~``. phy; # "zf=#.i E;1`3vitiFÃ1ÃileI;.Ã',
t.T4svf3tt', i#cti'E6õ .c,gf'F,.ts. ,F?:F,C,.i?..3b?Q ff:t:F' EIse#.y1 the
i'ta iv c<?2].p<?s:{t.oTFti include 4Fd,Z~ ~':=t f;3.cmoI'a, sui:i3 as
tf'anSi[:f.F~"tI71.#i a growth fLFa.ois (TGFS),

~i .. , t platelet x ; e1'S ..~~_3~:: ' -~
a:.~} h3t~3:'Ã3~'SFi'il4. t~ ~7~. ~!'4t~.1 L~'ilti:tir#'s (F~l~'~i),
~3le1t~=+.~>~`F~'v~~ . .I:(_~ itFi: fiI:L#~. ~.. ~:~1a~~3C.F .?:F3
~~?Z+y~'t~~ a.a.F~.:Liirs (A CÃFS), (.t3#1IiLct:vi t1s-F1e 34=tIviiwd peptides
(CTAPs), ost<ot?en#S

Y.~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
wid ti`oloq z<..~~ llx' i.l's:ti:Q : ~f1~~1( 'z; ~ i1` 3.? @ ~ f
a,~.t".i~'i`1Ia~`~' ~: ;s f. \~Z, a ~Ã:~? `,a~.~ tt~ ;r3;. ;`L . lsl~~~'a) -
. ;!..
= r ; ~'fa~t, i~F1t~. z.E.

y( s\)}{- ~ f ~j? i~~~)C)v.t~~:}.:.t]~ ~ {~\1!C af5`)=~ \}t~) i tl j {}~`\~[!
{F ,) ~~)Y` <r~ j~a> L~.r J.:A~S. ~e S?.~lyS 4 C)4.1 t~~ti4~: C~.~w w=
_~~i~i S~R)_T\.~ R}~~~i.4 ~~]:bi1:[i~ 4t` '~`\{ .t1A.~t}:' ;,~[ ~^. M?f4,.4:t.

fi;#d~il~ax?t ~?LF.iI;IY} di:`:Fll~a.~t~E=Z% 4~i:E ?31'c+s are ~YIv~.
.~:I'~.:t~.. ~'rRa;:mb`r .=`,,,,, of 0::E TGF Si.ipo7",`-~.',5:;'le
famOv <~ndl.idG . te- ~`L.ti1-~~a"?.zs$C,1~~~.3I3..;. ~?rt?:Z .~'~ ~ } '.
;i'S.?tr example, k(.3.~i- b a t~.SS{
~ ~ta a~~~~~~s b,?,i'~ind..

'~i~fvF-~?Y,. bone morphogenetic pi.,t<:ims ffc~a-i~xamp`vz BN-I1-1-I, 8MPI .
BN3:.3" :i. BIMP-4.
BMP-S, ETNVIP-6, B'~.-`E'- BM;'-8. z~~~d.BMI'-9), s~epzr.Ij:-b.}T:Iiding
growth f..ctons-, fib;
ex,3mple librobltlst t?.lu~N.Ih ..#L'=~w31` t FGF;?. '.p1dL`m1al ~.~Ã'owt}]
f.aC'Ãox ~ EGI'; p.awltt dk:Iii`ed
yC ~ (1h ~ `~i..+..~ ~~ tj 'k . ~ ~s dXl~ ". t 'C4
~ihÃ.:Ã~..~ , Ã .. F~" and . t ,~J~v ~~i..~ It;~:4~ ,,I-:}~i~~.~t.1f~3:t~~:-
#~I~;iI"4) F~.?.~~3 E,~D> ~.x.:a tpae,
~,..C.~<
hi.>.i~~in A, anhibin 13), growth dlf.f:reiifiating.1actors (for example,
C=DFr :, andaLtivin,::

(io, example, AUtFvi.ii A.A+`..~~vi~.:i B. &i?i3. Activin AB),

K, ApplÃss3t.i~~~s for Polymer r Agent Compositions

a Elc t?[}l472-:t:.i' provided 1-:;3::1'c-.iii ciiil lic Litili.zt:d >z
,p:rYmf}:C; healing or tr:`aE or
i?7`it - ~ ~ ts~Ãc...~. ,`:#:. ~ ? } ~~i-3.1,~ Y i~.as,vl,o'f'i_ ~< ~x, to ;
C?L,.~3 and t.s~. `` Yi ~ c c~ *.,r~#lv..t>,~
~11t? .~1`s~:c:~;~ y~ i }~.... . . f:'i.~,. ~ 'ct,;vx;4
.
i
~B:"~ provided i?v`=.`e3.. ci1n, ...lso bS.: EaS:a fi37" i3'(='cli'l't:=ty
f~~ ;)i3>1 tt.l33~ ..~I~3%[t~ 7 S :ft,;f >14?t hs;,~i:4~i.:s
to, pa'?iu8...iOi: Ã}fr31ic-ri1- aund n<3`s11ps?rsTC:lt.S, filI31R, cf1ati>
,L;.`..; :tiE tur:ss.
cLiY.~ #`. E}l~~~?., ,i. `t3t:; 3al,. Ib4 pohT1ae:i's à <:r a;So e'3 used
ll. various tz;tlrt~i?i:

p8.ÃL?at..C?3is, iuC.:~~: as tissue FLug~nC,Itti:f-.lf?m Sl]Oh I:.citk t'Fbi~s
can be .ti5..=d h:. #.qp%.:3r anz
ap

i ~YCllp~ ~h: fi<>7 '~ I ~..:ti..=õ ~., õ ~:,, .,~3IlLq or ¾,~,:i4.,1ta
:t`a~ct, Other ta~;~';~ of the t?{tl4E7.'.~:~ ~:?.<2vIdtd he:r6?i ~:-
i42uta~..+

`irsilww.~, of <:l'ly.; late, Ei? pI'o;.1otasl1' xl"-i..al;d
#:ikalia;n'sin:ÃC=s or to 3.tzfii"1; 1'f .lkr:F'onG.: i3f
.~~.::t_ have bQS.'.1-i ;ur~ I`f)1'F'#(3`v'i'd or locally treated,
a?'C}?d.1s3:e of aoc:`rcgiZ?r`:fl
i?'ar3ph node '3i>t=tatit::sis, <11qi?'Zt;nEiltfr)n of local vr'43u?i$
hi'<3.lI3i.; :if2i3t <{em05 in ;.1.,f6::1.on,
?;ii3nliz3latia?n 3f sziI'if:;`:uI`' i11.d tIbt7.i,1mail scar
fi3."71stIt3on, and .bI= l:il trvc#t'..ieÃ.i ?fp<3`s':-

{ 1 p' i a:ive p#.ik.

i..a sL:??'.I]L eI.~"iii7t>dda3"1'nt:, ttze polyrr>Cr:i provided herein
t.,,,E s:sf.f..: to bwclt .riÃ:ct ,E'. For
emimF:3le hw pt7ly'a2C.1s pÃ`ov1kd herein b<.'.' tis:[1 to ari'i:d$. h2i1F;,,
i,s3lf}?<2, pr..zswt:,
pafw>va:zt?.rb14.ckst Z:,At.E:er., IthC`,'d i.:i'SLLil(~ also t~='~'~'
13sE'.~C~ z~ #t~'1~`Z:#3t'= .~T3i~rI~7.~r" z:> n:.t~>iil1. ..1`t,i?Ã;t:<?
r

tc?:gvtiretiiC.u.ii. thegraft, i"+uch:,:s lZ%mp(fhC~n-ia`i and
lLuSC.:l:.i'{.'.:.. The

po..4'?riG.?c ''a;.'t#clos c.z'r. be ,.7~e~tt.'.C. or indILI:iC:~ ~.'23t?
iS;` ari?l`aF.?t3 Iizt3AZcra3:?lÃ:= tfa>2C?r4 ~;) lL3Z:cttl.v
dL>iZ'er 3~Ã' 3;s. such <`zs, .hi>m:btA3<:Tti p-.,' or sensitizers, ("}:' i#
ie~w.Lf.t. or 11,.3a..sod a>.a.:1r the s..i:' of
tllo. (7pu.A#i]n 1F?a1tiToI4 to d{;.l#4ei' agS3r1.ts, St,l:h as
i.^ri`ft:Er~`'3iotiCs, -mlSti]vfiL=ti, o gi'wE i or

7 4


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
E:t. .t?lnlg i.he.ebZ r1L'o3d3Ila s,dC: (:Mf,>t#S 'i$4Sod.:z`a.zted with
sy<st{.'.:II`.ac Ciel>`c ai` Thi`,
P+'t.~y-Mi`;1'Ãc PtÃnIcks Pa E,sY'l:aed herch. ..'c?Y2 be adtt?inIstt?ed :l[ a
s1..C: of N,,wL.i'=Er' w?d; the

intent of ~,he paTl.cAe4 beiiig camed by the 1yFx?p.? fluid to lc?coregional
iaf3d..S, T~le
particles 4s:33Ã b&:."L'o?1ic tÃappiAi at i1hi; lymph Ãiodt'`i, a.~lobZ`f.i'sg
de,.#.v~,'ry of i#f.x,cats to tumor
5C'.C.fE+,~'i thL+, r,'~ .+ w's`~~,.dt$ 4+r z ~Ã;~Ã~~~ ~s3I Z' i?#1g~.~' ~iet
:tl l}'I3-lp\~ti;'l.tS that T~'lSr "`?rT i#' #~. .:.~` t {~' .N~:~ ~ a
~1 t1{-. 3~ ~C'3 . { ~~ E:C t??~?1`w :3 ' I?~, +3e:
Yltr&~ :i,LlI1dS;: tt.B.E:3.or cells and ?7:Ã~.t<'cl-#Y<E.I~.~'.c cells such
as or d-e?'#d??Ã:x<::cf,. IS. :3.:1d iha3s
dired. o3 un3i:en byi3ei'. v:Ã.rti4'..ies 5.aÃt: b{:: utilized to enhance the
i>iatr3~tiiiÃ.'

4wt `;C {~2 > < ~ ~'t -Z.q,r+<x 1 } )` <+r~ J! fy~ .yP } py-)5`.{ { . }~ ` }
:: ,c lt. ~ ~- {t ;S~~{ Y) T
..~'SiX.. a?il:c~$, L>i.._Ã,tA...S't.Ft.=~<Z.1b.t.~.. ~t+ C!~''+.C.f Y1~ lS
V`L5" Lt-S211.Vi ~ E!4 t.L~Z..(. v2-t.-~~ Y.~'i.~\. ~~[2-{ G+7i]..t.~~,

the Z,ell5 directly t?: b4` Ã.IpÃ'+;tfi.#..l3ti:3?tf ftw #.e.#.Ã''z:ui'#.c
Sy4ti',m iC:`'figi7.t ti>i Z.EF'l?:Ã1?`,

,?>>wy~;?Ã'>#tw p%;Ã'tÃi:.ii',s and fili?~~:s p;t.3v#ded herein can also i;le
<td12z.I:Eti`.uÃ'wi Ã'o
sÃ.ws Ly'h.."C. .E..W"?l?y :C=git;wi:1h is l:#i~-oly to occur. pi; ;Ecl[:'s
and -filmS .::..i3.i? ht'
i7dÃ?i::?'lls-t.i'><.d w; i:. c<3s whae, as a L.f3nsE;=qEl(''T7'+,:e x3f
qii&lh as CO.PD or Wfit,.,l??Ini1t33`"y
bor3., di4+ 3>i"..`. or sy>'``sw#?zii` ebw;"#li):i?.C,Ã'i#.py> poor #ilec?lÃ:
;1 lT'1ll result -i:l rni3ji3Ã'" i,;:rEi3pliccl:t#E:s"lti.
In, aditttt3n, i1h#- } ..+i't:#clo5 and fil#'i:t3 c<ti:i bc adl.i?.."rk? ~L'
ist[:3`f'S ~ :s. 3 r~.. m.3I .TFs (ià .. a 15 or or tt) s.tesff>llowÃ#.sg
local ablative ÃheÃa pY:`. F<?Ã. 'sÃpplÃcs:tÃo:tis.,

~
~ :iÃ. margin ?.a4
tÃ~.' P(?:y#..ei":e ;3,aõ ;i,clÃ' al'e prepared to sidniea"`~..'~ tf.? the
S..b gi~.: i or c' ~ LC. .~.:~L~,`'~~~.t..~~t:i within
the L't?na#.?.,e:+ .a#`d 33oÃimL`'''+e: of t.~'tie r?.<1sJ, In other
cmbZ?t,?'ÃI?'. ':?ts, the part..Ã~.;t3e ;i Or 11:171s,.
adhere to ¾he pe:.t_a:f:"d#E :ai, i:::.?n?li3gi'.; or cC?llagi=?l f3l":..hc
L.i'A>wry of ailt:-.c+,t..+.:Ã:r or
F7i?tx7ik:Snl<;4tiQ .w-e :l:i. i3-i oi.h4? aJl.".b;Jdinae1`ts, th.^ iiEI-r.;s
Cc`?:tl bz ,`.'..:43lw:d, 5:3 f.redv +.3'ld,'t::s"

24 .::aLwCOLii place Ltt

In t?.3:i'. the f1kC:3;i and pitft.C.fe hl;;.,lrA.Ã can b:`, used :.:-i
w== ttL ppht.;ti#?F:ls. hn such 'rl:i3. application, :}ic swofl.iTig
%+4`Ã}L#ct :.t?d with pH changes
c.Ãa be ::4d-v:>:Ai.i <L,t.`4.,#.11lf' i.iffl#:zt_ta. For 47a:'c'-:#.171~.~lv.
1 iili?y of the ::iC'.S yle:#tc poly-m.esR d.i;`ScribL'E?
~ - ^+-Z't
3t~*Y Y ti~~"~ =a3~ ~' +...~<~.r size
5 i ~,:.i#; a't>.? :~=~. i>Z ~.:~y~ to a ~1.``s;ail~. ~Ã.`v ~~,?r Ls~ i:~~~~
la.<.Ã'#:<!.'_ `~ 1,3 ~T~ :3E 3E.. e s ;~ :# ~ ,.~~? ,}ad .

25 ~ ~t~;~? ~X`{1'Si t~~..#~:~ < +.3 fill Lt'tÃ".~~t,~ ehi: saxe of
~~ i i'?C3 ' ?`N b:. = a~ ?.l;~t,t~ Z~.'Ãt~lZt;la,Ã t~:il;: > '~it~~:l,.s or
to ~, ,??ti o

iÃ4suc, if g., .Ã:~liAZ lips or dceks. Op7taE3.+`it#.ll4'`., the
pol'S'#'?,1el`` i.'(s:.ÃlLa deliver #> ,#;b*::{tic ct,,g+~:.'ÃA :s
s`31.,.odhÃti; oi iwciid t1`<`,":3L.a. In, st}4.3k et3'4bt?Z'f7TIeI1tSz fl-w
p:.`lyx3w.:y edsC.ad for ti..#c-li an
appliL;=afi13#Ã Y3A<:c ?..F . .."r`t~-E3i~ and 9i~ and 111`i~.

30 Any method Ã.sf iÃC?he1iikg particles to b1.ologÃu3n fis-S::ie can be used
`tt?,: t;t:S
4:tapl#Ã;.tsÃ#. Few np le; the pt?lst~ wric ~ ~~'~~~lU~ ~~~~~uct herein can be
...E3~.1:~:~.l ~r~~~#~.i~A
~~'


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Plu:'oiiic 1 :.w.7. .3: <3;:3otht''r Ã.`.TibÃ?i#in'.t;'.n i, the particles
a,".'c entIc.>3"a?`' ~4:~t;.]_i#l a ~t,.~.
h4dÃ`;3+~,7~,Ca, :WhEr43Yi.:õ \4..s.aii,E>e or :+llrw;#ci?l
I:Aal~S3#~:l.E7"?ZT?L strip ?-nc3d4= fi's.D pt'T`#ciFF'E.3_iÃ:FF:,

rE I k,.~~~'s vq iih."4k$ or o4tiC,'.r #i-latf'.='{'ii#lS t)I'pi1.rtfclf.s
3.izuFi C,i?v~ utilize a spL. ,E:'irFE :#C:h
}J .3Ti:fi#1 . ; ac3i n, to h14} S.:'a4e the:Ã'e.} t.hiÃdw=Ji t time at the
s:t-..

benefit ~'#'<"?I~:1 ~~.3E. Li`~, of the ~~.`,<rl;"~}1e?'3:;
en tidid#ÃiC?n. z>thL7 i:y~~L.J s3:.~'',i#~`MUÃ`~% can

pwrtÃcIe: wid f.~,ii.n'itidt.sliaÃb#;'.d l2vre#I.i. I'~oF ex-'iirnp3C%,
flinn_: and pa3't~iiõos i;_iia: f,,.t,iit:}Y,.?'1

`i iY tltiÃ.\icrie\> _E L ) i}jL ~~! ~(+ c> \ 3tSt;raty k ~{L.,.' Ft<at `~
ay+e <~ ~~ a Cl r. ~ J4}{r~~ t},f.. 2 wc)> )\.5~~w.) YsZ+ T i4.?i\:~ca of
iia~yty . a
vniÃ~ be L(:~..L~~~ L4kL ~yZ,4 ~ \ Tn4f~t{ i 3i1.x~- i ! 4.. The
CFS~

wn.&o; anz .=t.;Ls..nc;~ can i:?C'. :rT'oli,)ngto Ã"tid?#t.C the r#.s~. of
p<3st-n q,`i::'ili
'.:n..ed#Ã? .> b.#t.:. as ~: z???~tT.~.;'cs+s. 0~ficc'k InlL'.ct3+?Tl. Th};=s
f.31efl-l:.ir p .'ov}ies :.l}a alti.'.##..wi vw; tf?
ffis, use and risk of s4s:4~mn8i: .at7'i'fblo'Ã.ics. I'l1t films and
p.}:f'ÃI..le-s- can cmilc}i}? G}nwstl?Ctic=`,
43a.#,.l) a: local 'z.'>} 3}\:o :3a`aC.s:hLtÃcs, 5~'i'~ wu'E'..C?fif s, or
[}I2~a Tt~~~ }F:1}~ 7niJ"~ t!ag~= ilÃ\. ::Ã,;i:hk ::4

az,efZit. ~ iIs_ ~`..'~, ti? rC`~ ~c C~,1..~ t.l~i. }i1sE:i,. t1}3~.5. E]`~.
E. 1f ~?extlE.:i'~ `:, .~ 'a+ a:: i.is.. c. of such .~.Vx l ~~.~.:' ivZ\ z aY.
i`~~`s ~.a'=_~
titt:
f`.utor.i%ia:+ va:l `.Qdus`.:E. 3i:?.33)dlty stF S,i,.dili=y to
dt.4Ã}'F::#Ã#.i i#.i1d E:t3T1St;pa$ÃC;I`> E.,,..f:`"C.::i:;e th<'.
length E`,$ h:?`;'?.tal Si='s:iSs f<3'I pa..1e.23t5, ~md it.i.F¾iC:'}:.
C3vC;r`ct~l hei}ll.117..zi"e \f?5t'S>

151 Ia~ ceila}:.[1 t:n1:i{#d1~."'+eIlts> E~`a7o p[3lym4"I1c -fIlIIi4 :ii?s:i
p2#,i'taU.C.s a}t. in E:=w-~..i#.'Ovii:1a
i:Iqt[ef};us C}:" organic io.}#~~on5, or cS37nbii.Yul}loÃ"\ thereof }a ~~4}
aqt1C'=E?.,is }+)lut.i.l1s can be
sE,leCt..',d ki"t,m, .amL3.I1gl w::tiC::=1", bi.}..Fo ."ed sC3 ~x).:ti
ili.'ix''i},. 4<'dlFne. b2J'A~Itd `iaa`.#t.., s{3Ii.it}on.N of

a>$li.i acids, +~~~!iug:5y'.', si51i.ftAol}s t:.:.~`~o=itc} zl.1`f;>,
solutions is I

ci)I`z'i:1iÃ3z.'Ãit>i?:`t E;}' aixy ti'vE,' or more flwi'oE`.+f rri7i.'.
oI'gaTias. S:7?aty+}S"tw cc#n, h:'.<'wli:CÃ:E:=d f:`i37al
i':f.nn[3:i7.~-f DMSO. S..tr`a~~mZrlT. nwth<3j3C;~, T.Hi',
dIchlo#Y?37.FE?rh2.i3i`. DIVIkt`, 113=3diL: or l<?lE C:T}s.: or
cira7bÃfac irttfn'? t f3a;Jt"S'i? i:>, ayi;JrE' thf:#"L'o-f:

~ i3'= ps.'33Z i'%3C`'kc particles : a1U films a%iin E,a)ni::in w+. i~
:I4.'fic n-I6A w'f :`.s, `s. ,h,, ;`u}ciS::C: acid

. Y , = " ; . , .
ed'.., i l. E i?'ii,, \3 e#3 : ,'t , ~~';i:
4S.`.c:o~3E.i:',~, Such ?I`e<3~.t.:.1'.}~?lC can ~?;.'. ~lsf Ã~ to
~.IiÃ~Sfi.`+,'.:.:~.l..s <.3'F 3 ?>

polymerie part~~les, :.nd films can ctwit<1irt i} recepko-r :t..c;>:;t:i.z.ng
~; tai r>t't;.~ig tnzfÃ~.~Ãy,

~ y.. _ Y.~;
i.>A~ of .~ ~.'~,, iFceptf:r or
~.~ :~~ltf~~F~Ã.7 ~~)~,:. A~~. z r~t.t.~=~.=t; .iit;~ a ~.~.(i. or
:~~.t><<ratic~~~ or }~~ ,ibi!

s.1vBs'qExa3, antF"s.iGelli<.3l ar s::~.?l?%}iÃngF or apopototic $,?aEh`:3.}v.
-affiÃ.;,, dhe po: 5ii,4,.;c maÃt:Ã:'#.<l`
Cie;:E:.`,'.E' hkd .. c:a1-.', be i.#3+,.'C: to :+,,.livor nui l;.'=Ã:
:IL'ldhq%i4 ,iY..t:'.i tf_s :i E,z'.ll, or to EiE',.3it., .T

:2t L}'}i be t;'~#.I~.::~3+?t.+.'C~ }i? the i~a~BS;;lEii\ of a C,~::.al or
r..f3~.f.t iI'E}s;.`a('.~I~i~3:iC'i1 or E., c. ii.i'.x~?Ti
i'. it?Firk a such as ~~~I:?3E> a or specii.#c transcription factors.

The al:t ffi.3.3dJ of using ti?E> pE1lynn<:T'3.C: pi:"tlcic4 .}Iad fi`:Tl`i
dt.''sL'#"fbed ht:>e3:1 Ciin btf
~.4~~. , Y
t 4Cs \ SÃ'~az..}ta~~. A< ` S 2.~l4' or =F~~ti::li~ bu E:C?:i~'i~: i E?'~:'.
't'fi~i31"~; ~. X~ to ` Y '
.= ~~~~, v ~?~Il`~;L~ l'l~~l t,'3L?l. .,Sii.s~'~i\.ti 3E: ~:se.e . ..i
s~3#~~Ee
76


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
p<7:t.fn.1, 1."or exilmp3iy, +3ii:i'~tic,es c(3fi'?aa.11.lf3g; one Fypo of
ti:f.`.:Ã'z3peut.}c z1gcA:i be de sg11ed
.L3f~ results Ã;Ã' ffi3 p~iltf:le~s b's ir127Ãf`g fi'2~Ãa:~~?~?G{Ã at
:yx31pl:
nodes, ~=.hi::~f'w.. t}thE.~ pt:#itfcÃtes or fili-T#:~ that contain eishe:
the. or a dff-TeI`cz7f:
rhcÃ:3puÃfic, agent can be a:ppried to ,~t?~rgj4,:=3l #:t'1aTg:.Ãi.` or
:41.#.tuxc. s1::::5. It :`iÃ??~Ã~.(r `Fllh~.? t.3.i`=

TLcE??.T.Ã~.Ãt.C.~+.h. that ~~[~'.it à r.;~?aFi besides
c~aE~=f313st~1~.i'i~~si~`~lf ut F'J1E1 t'. g, cy3:f:ikrÃf i: 3'r=+1wth

~ 3 ~2~.~1 .f3 ~w.2': x~ itxffÃ',: 't~3 +'~Ã~.t:~, .;~c3.d'~ EF.4~`=Ei 7Ãf
a~`lt...~_~ .~.~.~`:r[zh ti?~:~ 4.tfi'l :~lf?<~s1~:li of

, p of ~)~f~ q
~~:~~i~.~.~`.1J:'. L:Z~%itf~.ÃfÃ:i~} a )`;~1r.~fd=t'
T'4I~Z:~~~Ã:(~~.3~\:=sC~~~i`'d,~~.2:~,~.'. or other i ~a i~.ex5tt! U<'fn. be
e.n~.a`'io'yC(j.
b3}t-lik} i ihi)d a.{Z.L'.ÃNl[.>o Ll<~il~we
~zk: ~?~3.y+`Ã:.r.<. ~Y:Ãic c}~;~f=ii,.1,..~, z~t~il..~~>sAAA..3TIFL

)-rov-1f.`..t3 can bS- used ..br:n viLrls :$n1~ ~~ ~~Z vivo ~` ~'.
a,.~.a,a"lw } ~ , ~< ~ ~tÃC;. faÃ.f Za:~i.~if a ~.le::~..tiC 4,s ki~i~,tlf;~_

Dpt'nkh#L` E?pf?:3 ti-fC, po1.ymos S6xff::d, ti1C`> rt1tF.. C3:`drtFc.,
,^:el.;-.s4.= can be Lai'.Ãi<.f?<,:'La or
<= .
Ã'fi1F~~i:.`=~::1<Ã.~'C'. II t?iC. ~~C?l~=~'t##~~"ti provided :3~:I~uiÃ`Ã
uCÃÃ?. b` Llso; ~.E:}?'
af~ii~i.ewj~''. C~Ã~LatiF '~ji:f.:LCry` after an if~..
F~ tia3 porff.)C.'1 of qu.:'v:lt.firo`..Ãf'a<e to peÃÃsift s:.Ã git~.a~..
b\.al:ng to
of.tJi.:i", I3a fl-wS... ~=Ã~]t }~7tt?~~5 dhe po.``ayme:ÃÃl: pc3f si{;lfi'.s,
p3'oa'':C.i(.d 1:etÃeM p.ias r:d'Gi %E dual

.i3e+.hanfs;Ã~i of dt'=lÃ'v'L.r,' ~-~'J.`sE:a`1:a dr..F1.:, is Ti,:=lL.=ased
ftol'':r the p+.:Ã`:,Ã+.:1.,x and :}'aC ;,arti=lvs. swell
to dSika.Pbfiif~;:= or destroy t_tl.: Coal or ci.llÃafsÃr c}mpartnir=rA
('g.. C'.nf...osom~.'). Aitean:afi?i `it''a
. a
~. ~ ;,.~ kcz~'~ 5~~~. :~~3C~ : - t)'~d, S. 1 ~, ~~~~ t ~
~~~.~ ~?;F~F a. r.~~ ~7Ã..~.`l~.= ,Ã}G:~~,+~ '' :l~le}~:=~~i:i~, or t3,~~
_~...~5<~. a f1f.,:TÃ~?~.;. s.r>L+,: at a
,:;.~ ~.<.~i.Ã z: ~ the :
c.a location . i? Ã3i_3 ~ t.xi'Ã.+,'. .f. t0~"1~c:+~.,?LC~x size ~ ~ ,i
i) ~. :ili:~ a~.klt#:=le, .w .3#.;3 ~3i~,
:., ~~=iz',lt?i ~
i3aÃticles can bL'ciAÃTi7t.= lodged {33. 3:`.anb'[.Ã.d`'i :a':th$;1 a L~
Ãvitj=', node, :`LÃ.b..Ã.,5^.5,:, be`3Tlch`sÃs,, or

....ap"llaxy and can be Lt:ed Ão cwclude blood tpow a4 :::.x.
C.rr'bs}li.~~It:oa~ .,gÃ_nà for ~~~ecding;
:Ãt4e =i'lw?v::1Ã:'_?fFS l`Ã..cl:foi~rii.1t"r'l?ns, or wJ-n;7'r,"
E.~'iE:vi.s=L3le33Ã:i`.2:.t3C?fà E3T 4kÃÃ:3 :?l, used to a3r.'.veIit
.ÃfÃ"flm% to a specific portÃ?,.'. {)f the It33.3g w* for tndos:Z3p1S; lLÃI
g..'Ztlam`', .k,'t.dtxf.`.=~Ãiz}Ã"f sÃ.lrf. zx :'`+l,
to a'.3Ã=e only twcs 4=xaÃa'pl(;> of potential e13e;i of Ii7f;a prtbpi`.rty- :
cÃ?1 b'L`
GÃ1mgred by pai L:.i1.Ã age firi?m an Czx,t~ont]u::i agent added to the
pixlyrnC'.Ã=1 a c.taÃi S S.E71~'ix i:1

z ors fty :n vesse,'l as :iul iyC:sLtt' iI? 3 .s+JheI72#c or :f'?f;:"ted
t:YsE3e or C:tv..4 t>z ~ `~fPl an
. ;...
.
olÃ1Ã3<fi1..3E.::3~: si.Ã0h ws an endC?sk?:mG=. ;??.3ch particles can
.....Sl b1:.
,

#:1cfÃa :~3:i#a=~ 1~~.~ to ?'k;li.il:eS3 agents thatH nI[3i1Ãpi7lÃ:ltL`
hc<lll.l~..g or fibrosis to faa: lstc;tc. pLÃ`Ã:3w13i=lA
or teInpoic.i''y clt3s;.::xÃ. ai,~~the oCciÃ:filt',d lÃ:3.ÃI3m;'.=fZ or
e,.`.Ãvlty,

G~.....i,Ã en,:t'hS.di:nUntts r3>?lht invention are directed t?3waÃ:tias
pt?lvEaS:Ã'li films thi-l.:
aa;, &~iLnw:d tCr deliver c1he-fnc~therapCutic agoiits locally at surgical
sites, ÃÃ7w,?Ã'~.~,:.`fs .iC'?n into the loxeC:t$oll mwuA".Jl. Thi:.'si:=
films c.ai~~c used, in Ã"-hc) Ã;'c.:Ã :ÃneIft E?l-,

77


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
cilili.;e7' pa':f.S:?3.ti, wl?eri . Laf:.llv3..x3#sg dtugs lt?c>3l`'s'y l~~~
t11L c,1dv:3.i3ti.lgC=. of >k~t3;aat>?u$ side t.`.={l-(C;ty
;: i. }.?i ~~.=`:'t\ at >i.aic~.
s.3 0, Z s #a.
~L.=tY .~ ~S Eõ t 2~ drug l.~ "7~ ~'e~'~', & F .iL~,=' ;\ 1 1n lf?~'1=' ho
ta~ 13~
~
~,i.S.=~Ã:~>C'~a.. ,~i: :.~.#y CF.ai~ ~.~L#.F.S~W i . ..

00,11Li:i1tAa'taf?:`#ti :hat ilou3d not othe vvi:iZ'. bo ub$e\ c.d- o-.Sue to
d.r`i.ig tox1c#t'y::=:, a ...c Riia3s,, can
i'et .<:Ese,as;eni:4a at .he site of S.:#.lga:ll-;v' and il~=C:
~'~i`:~Pl~'..~a4'~.l~S v:af:}.
St.r.'~ Lc.#_ii. i~. .~~ c~~''E.'i.lti~ of vl(#:i~~
prc2:C#.:clitZ ..<? t!#c `:np,,. Ã.ta-1ioia site and to :h ;, site of Ã.t]etaS
,,tt#= tumor g:'&swth. 'll3.c

:TI 3hun >.d : i?`14n.nui'ii: films f.,. : deliver one or ia14?t'i' :at'at#
iM:liet.ei a-gt:ils'K c.&, '..:ti d:st:.i.i:?ed
ht`.ra':-n, i.3at wai. a4. L3PO#.3 cci:`k:ui or 31ati-astC:tlc (:+.'.3Fs i.'-
ma1#l::ilg .3t the ,u#&.3 Ã 3: iIMLi14

aftf... 3.:.f.-mL:r oxi..;sio.i-#. is pS.rr3SJ."'imied, Thus i.?iC; fifltns
Can .eduE.i: the .'inv#L.ie;:>{-o of tumor

rS,c;.il"remaw at :v rC.a4=c:'i?3:a3 n?<3.i'~li% after removel of
cs7k'tZ.+,Ffsiis iS:iLFe.

~ ~ c ~ rli~,a ~h p.rr<? ' i~tÃa `4'~~ herein i.. ~ i.E..t. ability ~~ E~?
f..t. :..`;'; 3.c`s ;fG~' ~1..iW.? '`s
~ t ~ ?.;` ~~1{.'= . .~.
.~i3:.ii_:~ ~.~~

i'e filmS o.sil c-ov:? " tl3o choSi. W,:ll to :"t., ; dl1ot..isc~*
3i.;#;i';?`nn(t For C'xm.ipxe, t1w, pol;ri..3iri

such as InC.gi3thC.l ;.on3;%i or in C}th4'=l.' body +~::v+.vlt.ies fo-r
Zi:iti.LisGS such as :'t k'S,:Z?x3m4. In
add#;im; .1.~'. ?`<~~iT3I~'.1'3L f3I~37s ~:ilx'. #',x~s'l?:i'pi.ii3.'(:~ local
i#:ia...`:+~.~#L:~~-r or IV ~~:::`s:;t. t3~.\ and be
<Ssi~ ... Av '< a,A r113tv . ~'!-iE:;ll < a.i~a:=.st~)~1 for ;:~~~## lY ~'~
~i.'~i" cE. or i#?
ce.k: .t #' i~.&:
i ~ `w;:'`,_\.~.=ati:~~` ~i~. t~4 i~:i3c.i~,
~ Z
s. ~ ~ >. _ , . ~.

4 t~ = v~ + ' ' \ a ~~7 =: ~
~.~`õEt`.~'~iA ,.?tat`,.:ir agents in iP#'~~a~.r t:~? Fi3<?l~3{?:i3~t~,
>
a~#"`L:3~C+I?t iti A3a'.~''.i\33Y~iti.= ~.?# 9t,"'i~.3.Y15y.r~+/ 4
f\.(~~i71f3t1f?n.

Px ~i.~#' ~~~~~.#ir' r c :.i3:1t;.~r=i~i#a3 T}] a . ~# ai`,t1l~3 or
~`~`a~il#3f,: ~'" `{a, agents ~:t1ia Y be c.'3 - ~ ~~ ;.~ <. .,~x~ ~ `
. != _il#a, k ~#, s =~y. #YY tx solid
S:#'tf3L'=<. in a Q(_ri1.Eo<lC.'d 23:aTIF.ei' to ft5rr-i3 p#.3er.tt:,mS
51.1Evl7 as stripes z'kF-ld dof,,~: SailL`., or
multiple ig~m~m* ...".=.iii b3.. Ii>:f;:i?.-p4bi3:~-i.r Ifi mlyp'si4a.t#:m
tC) cia..l'#.3vve pze~.s54 tF.~"3.C.'Ã .peu:~~:#< d.>3#'i<L::.3r

of #undt.iple z ~,G3#ts siI7'1tIhmLC}l#sd"'. N'tt.xl#~ than one t)'`;)i> of
p\?lJ _3ii.:#' fit.,3i7. (.t.Ei., be u..4f., to
C \ >!z .Y v~ t' \i ~+; r .?~` t ~ t",rc. \
tune or t~=i;~`Y?"e)~ ~~3L ~z.~~~' of the Li1'E.i>~,. A ~ u3"~~'k~,:
4i',.3~3iY.f1?.3iE-.~~ the :ilE:~,#: :;3
,~~,is:.= t ;3ii:#.i~ i t \r ca t;i ;,#3I~:.. : a,:_ ~ `~3 ;~~~~=.i' a s
rel~:~~lso of the ".~?c~#~Ã(s).
the . r(~c:~

~a ~r,..k : t
E s..# e:?;ami s~r. a 'F1l`.~11 ~:~t}~11~3JSoC~ +~f a 'r `~ t. ti,i}~:t. iE`s
acid

Z qt ( Y+ r> .r~-.;tY ) t }t> e5>,~,r y2=Jt,)p <}~ry i~,je sr such \~ ( f}}{
?r''9 `Lq ft's t~` "`~T~
i:I{h t `.-,=~t=rtt.)!_.5"stl.L:ti.,sy-.`.]i3. i..ti.i% ~ \..=t~..t2S.2j~..~Cw
with GS''uit~? .. ~Fl~'~u'ta. i~<J b.,.^T.421 ~S 2:.F~.~F-f. ~aL~.S...., ..i,.

i3.nn.1e, .t::i:.dL The fil#..i can t>3ei1'iie cdRittt:c' W7th another
h3oltr'f1ler of ths<. Ss;ic.,e or i?1fft,,::'.:#?t
coz`.txpLrsifi>>'n 4hu.;`, does '^o`, contain J1`s: e:`3.3+,~,
fi3.i'i'f3i23.w`~_', <7.71:iilt3^le-# fi,.`:'Ld 3':lfn, tE?p

M i'i',# , Ahach Sxf3L.a .iiESt h%:vc t!'ke dI ~t`g, aLt as il
s.:i(:raa3i'.liil ~r`.tye E th~. . 1?.i, E 333tb~~~
fhc reli=aJL. ,e~~ ~hf C'a.+f'::t;f '.#'onn tl}o Li3ideri'r'tYtR #lf1.:,
bt7.t <3ti the 'iom .a!'er .#a`.g'i' .f?.eS, the ht;s`ioa7.i
lii:a. sisi1`t5 io `'Q.L,_ist:= fb3L= i.9::'3.z`? hn f.h7s, fashii3.i"#.,
delayed m3d controlled ro$eci~.~,e e,Dn =3cct;.te.
:30 i3.3d a.<i::3 bx to in1:Iitl w<3[u3.d hL':1<%1#'fk; li'. occur bt...b3.'z'
d...aJ.v5:r4' of

>#L=~`=~~3thaa:'J ~~.~.zv~`? can Ã~~~Y3.`.t 24'c3~1TI~3 a.~ i'sli:i~lv <3;i
f~z#.~.. 5:..`~'.+zf';. ,.SY..ioel.tt.v:=l~r' ~ x~:ak'[~~Iii
,. :

r; ~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
drugs "L'._.n be if,.ii,'t1~ed ti{;:q1#{:3-LiMly and i i~~lf?i ~'.I~i.iF:TÃ
~= E sr P:r=i?lC3;ilg ~l-iG` ef-f`+Yo. i?~ Ihi: other
drug or 2f`xott;~'~`vs "normal" C.i:=3~s from t"^,ie. to;$+..Io eff`v'ct u' of
tt1c second i~3iuf.: t?.. W `:'L`:sc-:i:e i'.f?llti
frtSnn the effea,"4 oL a Se{.>oI`Sd aÃ; :nt, for t'.xi:#;rnpz4 pI::-
tli'atmi*.34 widi tC?õc..tw c:i#.l 1i1Jl#.`

tt? :ii;=]t~ {#3Y3?o:til.u.il t:ells to aTitiwfi?liEe
+`;.lu."I7io1huc2p:i<`>.s iilEzi t`vt Wii:1iZ`a LC<:i;s xert?1::#;#.~
sust.::~}1
iC

Prov1do-d hi,.cl.';, can be LiSe-d tC? wor a#.tv G#.gi`=;?t. t~~~ aC,.3, ca#?
be
i.i any p.i.<rm?:icci&Qafl'uJ'a=::{..4`i.)t:.#i?f4 ff?~'"Su',;
inc3'i.#di'l~.;,.; ~i~~'t:a~l~::if-~u..~i.t4~~si ~~' ci`..'=#.C.~:~.::~~?,.C
,r^.a:t`; A
l#i i L nwm.i S a of ~3:Zt1ii#`. :li,t.4A4 i.#.i'7u k?1oI'i'.e]. #.n the #.irt
and 'i3,io z]..#;f'".i.. ,3lf; fÃ3:" t#.;ii.:: i#:`1
the ph<3 i]{i.i{ vJi3i#.#:l. l sz#'.1p{"'Si##o;K>h of i!ic ~.3<)lymt"lii:=
Mcitert`aik d:ser.ibc:d I'{eas..,.:n.

Ai,t:qAe#lfl#.. a.:,e-n~s are i.>.i:'aC:rtbzad i~ ~5:.x{I iflie$"W..`.13'1.
#indiscludi.. l.'t.t a.c T':ot bial'aFtCC, to.
i:=hLmÃJ}hi..:tgnu.Ãt== agC #?1s,. uiÃ;h as i"~E~iC?~~~1``:;i~ i=F , receptor
kfflh:butoi.S wii($ Ã3;..i#~~'s Oa"
ot.,e# ea:..#t# Ã?eitpic?.` v:t: {3.t=,.~,e
à L, rm`a nl7.tii modulators aiii: i?3oiaIvt igi'#3¾ .s:iC.i as ~ytok 3?tis,
gy,AWth factors or ,AÃ:rolds 4; .th (}z With13:3: tal4' or P<r"ihow;z'3'i
antit e%'3s et, ..:'15.,,;ti4e `.l?.e c.i7.ti ne{3i3li3''a~ri-it:= 3eSptF.ll-
sd'c3s a mf:illf:;i a?e v's,3.i.{.:1#.1:'.= & s`el{s3q37?T{, :-ft;

I ~ lo+Na;.a~.3.L>Ehot}c ah?t:nt5: anffl?i(>t:ii;s,r or nL3clo?c acids as a
m+::W~ of local Ãrcp-~t;= tY.E?i.r-ipy,
TI-10 b1i5li3gicall i .ii=t.;~ substances and agents are ti~ed trz amt3un1:
F.,.at a#.'o
,
. of ` .
:~.L."'~f~`#~:.#..#{õc_i~:`r t a~t=~~A~"i .~~ '~.?~ii: C'..1.vi~~tl~'iw
~~.Tx#.I`3#.2~'~t ~7~' a ~.3-~:i3 f a:SZ;afl `v active ,w.> .a.ince
will dqv;i`i.d: +`>#'~ thL `~,~,~.t1I'tIi:::ular ri3i3:eii.ib being i:EBk:d,
f#.1'a3C?i.E.i'#:t~? (?f ths' b#F3aot..:.it.zt>; t' active

S t')F~i-#f I Ft fife' tf? about {.,~e ~vk,. S;]i:a ~, ~ ~~ `{ u.#,}~ZF~$a.\
can 43G .a'~~"C.L, ~ ~ a`C C.#~3RS.:rI~C.a. .~a~?:~l e1~ 65% i# Ã.::~T.~ E1
desirable. ~E7 to

aio-~. `:~ . .<. =: .=~:
_ tcl:=;:i.~ ~ " c#:..+`~: s s
. ! ,{3s
~ ~.. ~ 4{ ia `i..i.<#..i..=eJ:
~~~ {,~>3=,,:i3c..si.is L'~'`OlJ 3t{. ~i~~t:iit~;at.`~:. I#?r' 4:i:~' : 3
c:~...E3
I'hw amount of druYd::~~ve#=::d per mea o ~ filwi iu~ per p_u-:icIc ;;.a; .i:
,}ezud z?x; t[:.c:
t}.C.:<lpt:.I.fc r>i t1.;e of tt#.c drug, r:, toxicity when dct#.vC.iC.d lo+:
`ffly, and the olin1oiil

i the patient E}f:if.~i?e i.i't.'.~'t~:~.S":3. ~..s~i~.= number E~a
G~i`ticSC.s or :'_?4~3"3.f of ~3'3t
.} m
1 ? =. a a ~ = ~t \ ~ .. . amount . q ..~~ fi
<~c~~i, _.....~ ti? a ait.4 is SL=l~~.ti:li taL,~t.#~ite:tllg on Ek~i:tC?~";i
~i~-F~.~s as i .) t A?c`. iiF71+:?tua~; of .~~+.'i:.

.{ rZ>r y~r f ~ ~ 7, '~:. 7 ~{] ~ f3 ~> .~.f. ? . t~~" ~. Zr :-#l t(f~.5{.=~~
~r S`~. t~~.~`w~
k3`~.Ã.i~ ~'Y~~ ~ i_.~.1~.~}c.iy~i{d~iC, "_.~ ~,~C.. ~.i~"#~~ ~~~A~~u x~i#
w'~= f. t:~C; t~,+4'=~~ the t ~: . . '

t b;''.ir~,i, ti'i':.ii3:.`.d. Tliu L`aevelz5pax#:ca`t i5.?~
f{tsQ and 4) tht . t:=h:13~.`,;,i3. C;l1.xra.i;E6:'iisz1e5 of the ~''i<i+.
,.'3

di;sa4 i::s ?.itie4.3 Ã5ii ;h t.4t'= p a? ain, t3tel,ti i s i"o1.EÃin:? l?r
pi`rit?I.rn4d by th~,?ti. 4k tEl L~.. li'~rl'i~ . ~iT"t. ~?;.
< <a
~~#,~i.e.~3:'i.t~lZ><F` v and L~J;~3C~t;. i?`i~',t~Tcl#`i~:. For ux~;iÃTi.~~i
l-'~, :?~.tZiG~~;~:? I. iiJ' and .% i C.
.. ,~:.,

pczrft:;'l':L l:m L'. i.il be iidr3 :"~i"=~t`.'1''c.'~~ to a ~~+:1{.~lf~::-#.Ã
i~. :3:I'~:~..

Tlhe rt'.lo:ise kl.nt .i5;:s of a ~;.i$'Ã:?z i`.FZf(';'i7ti:r fia'21 or
h?itrtÃo].Q i:an be fi.i:C. ~=,.d iiS:lÃ.3
atzk, #:+:G:`.' b-y".=,<3aL'lnrT; tl15:= i'L#txC? ~~'f l21t3nC,`m<'"1` units
i :iEb~bi by ::IiCS( ifv.nXY the side s;,;3.1#.s Ã1f
79


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
given 4?ti o.y:IIE:>. &Ã:, this ~..3<7.#'4.ns;<Y'r a fi3#37il'r, t3f
G(:pt'>ls''#7,.i.r." with #'.''lc.z;e kincfic;;
i'iiii_ bC' t!^2S.d ;.Ã} .i t S :?lA3m [>iiaic the d t'.l 1ves4' drf
tiC:veY'iil #eAffi.'.1'ei-`at dm g\ ?i i d: diS.' d ^t'4FrC7d
#'C,lÃ.=usr`~ k?no&:s. Ftr:' c:`i:iniplt:j 1,17.1:LiS.?23g 311f3?"e Si1C`
chains along ttxc "Foayi::i.cr ttic1,t uti

hy d'E>phÃl#c .T'.,d] eriÃ.nl<` ~~ . ht t;li" p~zy731~':Ã" I1:+3rS~`sZ tF` ~r
`.`:~.~~.'..#c m,`cF G:.: ca !d b''Ã"l. also
gone1%#lli Ã#`w-t.i..:ie the .t:,h'.asc à LiW~= of an agent ;'.E'C?[i3 thlG
p?Zl'c'3?i(:it

m S:E~#~`3.F.#.Ã#3 ~:::i~I3~?t?d~2~3:1C xtwi, i.ia&;= ~)+.3~.~'';x1~wa'2C:~
pt$rt3'w~'Aes or fiI1.;.3. Cir;.`xe:?{` rC:lc: s`i.: of
a,,gea`ts. The dL=s~.yUd Ã'Ã.'iei:lsi' can :;o1Ã"i.Ã.'IClL= wf-Ih~ i~'~
#,.#ni In
i'3..i1ai:`Ã Z'?'i1bt1d:1 7e7:is. drug kic]iv$ary is dl tl <.l' 33r a period
of ilpp.i'i3miT3aIi..Ãy 0-6 In other eii?:?E?ialt"1cutM, the drl3g ?s released
over a pG:riC?d of a. 6 wi~:ek4. hz aÃ#:i,Ã.i~er

i."11bod?.I1eL''"#1~< th .: drug is released weeks. over a ~?~'IiC3C~. of 2
(:ek5; Irl other c`1Zy.e1#,neÃ.tsy

m<, pa :1du's .~ by iFi:3?"S'iÃ4g the T:A3o of t;2iff#M#"e3?t.,m(?.3<?."Flf:.r
units dE':r.a?+

;"s)# a .c3t;,E3ttf .M0:80 of glycerol aÃ1:d caproic a.#h:id pt>lymo:"s and
Ã"C. *t3lt#$3g 1`:i3c"#`?.?ps31z3i;=le5 dh<3t :'4"ae<i`: dr1.3got'cr five
days.

Provided }1Ã'I'47,.# are p..:Ã'tÃde:i, i.Ãil;lUd1Ãig mu"C;rf..~pi.ÃÃ~icles and
In

i: a =~I,,.~3C2i~.l.c .l<zt~_S~C õl_ ~G size of t~Ii, a ~3i3l~'I7..f.f' ~ ~
particles ~.~.~=, ~`~ ~`~~ $" ~i..;iu..~i"~i.i~ `~?S..f? ;aÃ~.. 1~~~. i,,.%
C.3::;1.~? f>
...
- ~ ~
~.1~FÃls"'; #.~~

100 I]Ji; in dbwY`ÃZlea. III o#;l1C.r 4:1T bod1.~".`."3s:zaõi, 3,hÃ,. >ir':e,
of the pt3h{llatt#' pilit3+..c's t `S; bc-tv,;C:=i:':Ã1
0.02 . 0 iF., i ?a#.lc e'{'. In o:e}loÃ" i.,mbC)d1:n1:i."nts, flu ,-du of
tl`.::= pol'4, ;'DS;r

~3 #1i1C ~~= ~aF`c bl'-.i~ctnn 1-50 ?"?11L'=Ti3ilaG~~~ in d3ii3;.icCC'1".
Oflaer poi4`Ã'ias`,t.<z p>'l:.rcl<:S i,,. <3 larger
N i8 4~, 3'i.it uÃ'.;.pei.Ffi._ 'oIi`~..`=s, iEIch as where tw;^.T:of
r'egr:S`+4 th 1s pr4='viEir;,`:~. For

>.._`
{
p+. +~L trxZ titi.~ ~~c y ~a~r,r.~v'#~ C7~: size r ~,~~.. ' c ~:~~t~-=ti~ul
~g 4..i ~; :.. i<f,li ~.> ~~~~ii.3~
C~,\t=:~~~':E~. . . a~:}a.>t.~{~~#.i+.i`L:) ~f~,t. # ~.:~~a~ i.. at t~.
,~x`~i3:~kr . +~Yt~Ãa~,

~quau.ÃÃ#Wg or stapling has Q)C;C"LiÃ"#'~.'=id, f?Ã` within a Izi.iTVe or
treated i:i-. .ioi' Si#C;3 as .a;i. i.RbaeÃ:Wd
trs=vit't'Si;t.Ut#:da?"S` to md.ofr':,quenc5 ablation t}". other th<.#':ipy
.+,?I l=Vh`õ1 .:: a.Ã3t7a1`i:inci1u'S
c21';.t'r such a:~ occurs in :iq[1a#.m"u5 Ci,'ll t. a..io.i#1oI21`ci. P?<3c-
si`i7.i;?3:' of r`,olyuieFi.`.. p'i-1:Ã'fiC:"}G`.S
2 5 within oflhe?~ ~pont.-me~.?.~s ca,iÃ~~~s could be utilized to xcsii1. M
aclc.<r:~#s i.:a :it:: ca~ity;

C:=#d3ei wath i=L';~lGase of spcw'.ifi"S.. ;selcios#.'iig agents : #.Ãoh ws
m.#L 3i+-tido#"`, :Ior
do-x:rc'=yca..i# as cx: a`;ip>j~.5 or other 111?ti approach d?eTl .m .iit.fin-
:s
in ._`Es. , tie<3mntui'#1 E3f bu:.ut?=s d4`..'age :31 emphysema o.i'
1...fea,"fit3u, dIsG..lss;..s *u4h as

L yS:4. toi' :'-":{amplL'..

'I }iL new i?"?t;3"<3I3..i'2's :#i:d polymers can i3l5t2 be used to p,-
c~;':3ie bÃtrzl gF'c$dable
tr~TL~+?:i.S 3<5 ~~?.'?~ T7.~~~, f3i3~#i~#?1ti3~[C,13.~~ r z xd copt?ll'mi>Ã,
using s'"c~E~',is,iid ri :[ ;]I3Fqt1e4. ~?`.ic


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
olI.s ;?`11`~...'t . `34:3lymeI's> ll:c3t +a3~lks3~E ( 13~i i and
i.:i:rpf}l`Ji71ers c:an cont.3; n ..k~'3. .`-.t3& chains
~.tr,,:3Gis between i i) a .33t.'?n{.Ame.' f3: :3-?kcl'i`5u7f?lt'cid;.3;'
i,in`#t i.:ok'I ck.i?k#ng at 1s,-z7s,. one functional
~ide H #i ta r 12_ <3lky3 dma?A s ConIal .u ; 1-5 0 carbon tk?"?tS; w1 d,
?:#. :.wktskit >

[' 3 a sÃr:3uteiaa: 4' dkftZ.li.l':: 1':1 om"M4.I or :'k]acioft"kG>lC,i:lk3ttt
L.Ãiat. 132 's:=o>tain e.nbEfdid>1o? :; ti:tie
ca:k be clLk3tÃ.c solids Cxr t itÃ>oe:[2s'?.:< ~)3l;V~i. ir, v,.kl'o114
4mboan:>k1.?4'ilts,. the k2;atckkal;s j9ris,f;dcd he.e.k,` are ..?ydr4?pa?obkG
tF.k'
hyLE,'3phlli+;.. ~~:I3 ~?[hcl' ~.;Il:~t's(~11 ~~=I::tS a provided .1#',t`1n
u?k{xuigoÃ-.`_+ a :,l? ?ngt'. fr':bnn 43ch4J;:)hobiQ to tiyfb?"oph.`allc t?'`
:"k:.;+pon4o to a lrhang ?I:?pi'1. i':i

i ~t~r~ka? S,iI?b(`dzx71Ã:uis, :.Ix 7n clE,".f'C?mole`,::E"r:.7iG:k`
f.71e.',tk:.`.F1cl.3s Pxo.`{t3E:=`.d hf-.i=:'.n ..wG#s ~s} a :,#.n flxat
i.i4:+ .ab...l`.I::ti i?a, tlsõ`?fft:iy8 a a:'.LÃl oI' cÃ:llLllaT
i:r?mpt?nmeI`a:.

EXAMPLES

T,it; invention is further {lt`4crib`:;d. in 1.l1c ft?.lÃw:`i.kg d+_. I7.c::
~innlt ttle
C ~`e.T?k]k~,.
seopi` of t..~i:'v ?a`?Z G;T'?t:on described in the

~ f > .~iS`r~J l
6~ L~.t~it'if f3

t~{

~ a ---- `r
l
."~
~
T
t

:~ P~e.~.f:~Fi.~; ,,;. ~.~ =~~j~-~fii~"j,?~.~'~'.,?~~i.'+~5.}I`aP3i:~1~~"~~
'~.{ '3 ~-~`.~ÃfS;~.ilFa.,'~.^su'4"^{~'.~.I.f3`Ci:kikr. i'vas p.ep'~.:Feii

st ~. i'3c<3l.CCtn C ., 1~^' a p#-OvlÃff.kslr =' (`Lf ~El. ~1'a h . { 3 .~,~:
Z. ~; rY ~~ka,.k.. ,S: U
y=-
~` k`f~~7.7k,'`~ :~:=.i~a.~~ t ..<.. vC~
k1Q3:i7k'dFiv~g, a xs~~.3~~i:
1.`011~.~ .f 01t '?004), First = 1,1y :,-{=kS(hyriro:x~.'incÃi~z'1
)eÃ.~iaziG=a.ld'~? 4.t?..
wQrG dissolved in tcÃ:`ahydroiuk`ain, and 5 A rzic5loG.t<lar sieves

wL C 's3~i1~4~ i3~ a t~. 1 ~.:~Ihõ A c <1~r:k~~'~k~ :k3t'~.f)`a.k:`:kt
k.?f~i^tt33k.Ee~~i'G'`Sz.l~~i?x3.li. :L#i3 ::.~,~L>z :~.i3=Lat.':C~:
to tiie miilurc, and tizc rLii:c:ii3nw13:, allowed to pIs,3C:ci:=dut I"?:?,3nn
iempeI'fkltkle. Whc.i?~ Cie
m.tY~t?a3 .~,. ~?:~ ?.:f~flr-:<a-x;.f~kf%lxk~~13i]~= \=4 ~ '.<5 added ~ ti"I
~~eSGI.t:.s~ ., i the . L':i'~=:~ ~, t~iL~;.(;~+C.~vt?: 'cta
_..?~7.1:~#~..~ ~a.f;:, ~~ ~:st_; r
2 .; xi<. = ; i~cxe: ?omt?3'k; e us:Tlg IfiliÃ'11tio71. The solvent was
I'omc?vt'd- .'?_k r:>ia%'y
e+;kPo:iaÃli#fl u:i,dG>` "edw;:~d pÃCsst.,,c, i3:.ld fl:c residue taa
S4i3lvt,.d in i'r3is

~-..:~~G}E
` `x. at~~`~a L '`Z < .~` 1Ã. 1 :i~~s, <.~ .,k_.1w:~ , ~~'#. tl7 100 t~w3
i"v~i ~;`.*I s'?.~~ )F?t3), '~,..~t4 ~?`:~rf,.k .:i~:1i.# ` .
1k;~ .:z ~~~t~ ~s,~.~.

81


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over :uia3vdf"i5tt;, ; 43dla3Tn sc.aii:lEc?. The solvent wclssi153sequm"~k.,-
my3t.t'Cta usla3~ ~'s ~~.<I.ti'

ii apoi`atAi,?n L#Ã-W+u? reduced prL'1s#.Ile, and the residue L, 3s pu;.,.&d
using f:=hro I2'latoi(~ ap;-ti=.

~ ~Tcffi vl '4 14,6-:r~i-neffiox}`l?l3~n yl) `.,3 ;-5-di5x-miy1meflim<~l and
Ã~ ~~thylamun<::.~ wu.: dissolved in diehls.romGthuic and chilled to 0 'Ã_ :

chlf?'1dL was then added drop wi s% to 'rbL:= Blt1lixl-L3ri.. After m:x'Eng
Ã31 16 h., , ii. n'%.txfiiF'e lxas
then s;`asscd UaTf:e times with 100 in.'Vl pi'l 8.0 phosphate b'L'#ffi`.r
a."`1d f.....,ed oi`C:;x itnh,ct`::+13us
<
s. r r ` L~. f..~~. ~A.)~~ ~.~a~" a~
~iSi~il#.~~: J, W - ` # e1"8L ~~'i2 s `~l:#*t'q~.L i~tI~'.Ã'f tllf`''t t~
using E~~t. ~t pt> ar:_ w'.

rod~Ã;:~~:d ;',ris;5t re; m>d tffic residue, a: xI tbi: title ci3t~~ipt?und
was isolated ~is.,atg <~ihoa goi
} \t tIy~~(

~ 4Sta'ih.t`at.~'i F}~~i ` hv~ ob_.~~Z~..~~.~Y"~f3:~
-- --- S
r r ~ ~
,~ r \

(?i) 3~C:~:[: dissolved in i?~43. ^zz~f\\\ .t ~ i.1~I 2,9 .i e >:~. ; ~ ~,
.. C3i.~.~'C~<: ~~.. ~ ~ . ) aniLa
(03319 ,`~,., 1 t~? i.F i~~

sz1rrG.'.d afi 45 'C} foi I i. A#-th:ti EI:i-ne, toli.teE7.1,`. ( 1.0 i1:l.)
was 's.tld.v;` to the solution, ,ld
t3?hE#,'.,1G4me.` s r!-N distilled Ã.va of dae mixture at ~+~, C. :`I'f::Sh
ti?.iui.ili' was aiia(3.ed, and
d.dstltli4lY:<!h L..a.~ i.Ea e==` ~} t. ~.l`f ~~,~.et';'.:i. I i~is process
was repeated Fez3:~.~ :~s~,., was 't,~~õ+;':`Z'S; .:i#.
~Ãi1t.; ~~

in fii'F:ti: di :A.1;.%#te. SJd313m bii,iX,bfn1ate was added to yamwh flao
acid, t211iz fi..?:z..5~; 4fJdh: x?.
bFE.s:I`bt3nc.fto Te3T15:+ve% E;ivl..?g fils.-rai1L?n. T~~':ia l'om::i.llll?3g
to.i#..m<.`=mas 1::.mov~:~d: ~0.a ;"(?i: a'oi
;:V2p<;rafiitn, Ic: v>.nÃ; a sl#glztly yellow oil. 'T'his mixtuiri.= was Ãhm.
sopstrated tts:ng ~a~~:;=~:

g*.I t?'iF"f) Tn cbtY?g r t3p h S''; T b ?:, j?.f'C?du c : "+-v.:4 (Yb t a i~i
e d :f.`s a ~~L, 3t o s 33I ifs t 4 1.~ s'. ;'.o,.~4~.

3 a 3F~1~`~~ ' \ f' ho`, < ;3 7 Me~ > ...~f ` J l~q
-.,~ ......fi

(0.504 g, .2.42 :mn:?l) <.nd,

in`Lts3yl i:,.3?`lc (0,68 il,.l, 0.49 4.8 2T?1ilol) wci'i+ l.A.l,~sol)i`d à ?
and ch-d3::~:
92


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$.5, 0 :'`..~`: .{~ `t';i~,~.L~?'~'l.~t %`~'r~it'ii~'t-.`~ (~).r~s? ~'~~-r
0.:~7 :'~. 3.tr} ~Ti71Z ~.~' 3~'<7~ `t~~.`?C:Ãi ?t~tl.:~~".~~. drop
~Z ~~S to
fh.~`, niW#..aY=. Aft.t<:' 1I? xsng0b.r 16 hi3i.ii,"i, then3.;4.tuwo ~4as
then washed 100 .?..NI pH R;,?

p 1C?s~o;:e~~ ~'a.~f',~ ~~~Fa~.{iZ.~' (5~} xll::; X 3) wllt~'s dried over . j
r ~ ?~e~t'~:.LtZ~`a8 ' ` 3~c
~. v[~t3~1::..71 :~xat<f~.G, ..,7es?.,< a'ikt ii`as
4{.E?4eÃ,ue :dY^ .L'mtJ-v{'d using 3"S_3~ilii t c?zlptm3lbE,Fn uIidk-
r.rs::duced pF'i...~a,_.c, and the r?rt?t>txf
wa's isolated ki ?1~t SlIci3 gel at 83.9{' C;'1fi; la,

~ Sylthcsjs of ~ i b]4bc-,zvIOc2_..y....m+.:`,b t.`y'late
~ 1\ ta
0

fi.
. ;~
t
t,3......r---^''
`tt ~~~=

\tw.... .....+~:'

(OA5,mi.F.. 0,50 g, 3.8.nini?l) and ui1'+aF;.: .;ivJ._:e
K511,2 m ,. 0.371 .._
f, 3.73:I7:FY]i,~~ \i`C'3:"a dissolved 1#1 di.<b:o#'w,'riS3:banL', and cH_
4z~; to 0
~ ~~
.'~Ei~x: .:~a ~i'3~~~'~i ~F.~~i~_~.'i(f. 3 tm a 2 'r~a~3.:, `!F .. t was ;i
t1i{~ (~? cF.~a~3 3.i ft` to Y
. .. ~ ~. f ~ pi_r......+ ,`~ +. 9 . ~.C~.~~.~~~~.?f}'. L:~:3g.3 ~ C.~~Z:
~_(?cini.Siturt.. A> 3.urmix1?c7 for n. } 1 s#~~.`a..'= ~~~.ixo-t~.niC.' Z~~
i .+ t~7C~~ ~iL'el~. > .E~ EL ~ `40.;~ q~' ` r # t~>. St ~~ `>
~ z~ . .~?t?~.~.:~~~~?<3~~.
btJff\!2 = J;t~ ?~%>, X .i)Whit} dried ~l~~~~~`.r ~~2~~ ~ 1,. t~l'C)[~4' sE.i
~ SÃ~ ~i11 .~ 1i,.iC~L<:. s,1 ~ ~','i.> ~t was
;, ... . ~7~. ~ <3s
st-b:ii'q(1a,;fly removed u6`:.1#,F;ri?till,P evaporation t.Fndei'1ed`zced
pz`t.ss..#.c. and the p;'C}dLiC:t
Ww.`.a :3si?l...o-ed" using "I ?a, 2. gel 3tiztF3:t?aliAgwcphy at 8 > leld.

~{YciF~~~i ~ ~~Y3 ~#~5$'[??1~~?{i ~'~y'~~f~s {eti~iDllelZw i < a 3#iFic?if
~
yF!''~"ti,~.:f` `.~..f''..~ `~"~-Mr`f ~ f'=~{~ + v~` ```- ~' `?`{..

Ã624 .T?.<F, 3 Ia 11a1:~ ,.3~ ;i^L<~Y~?i3 <.4$t:s.ix '
24.~ .~; k.5: s`_'.~,y. . . .
'~``= ~i1~.x3 S$4 ~ t,i?:.F ~ :~:.it?~ # ~; ) a af;>. ~:::~i~ . ~ .f ..;.
: r ~>~' i 31 i?r Ã` 10,0 ~ ~~.~?~-~l~ in a 10 ,? ~. s~~t~;7 ..~. and
.-= .
~;^


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
:~~?bs~:q~,r ni~~~ ~,y~~~~u~~Ã~~:~i .;~,~. l~~.:a~~L d with ;~;~ three
trti?z:s. ~:~,:x~~~c?;~~i.~:~, t~~.e c t ::~~st

f=5 L. 0.02 ?l.:?:71ol) tt?L?slff 3ati:.+#113~_t%S~l?I ratto::z 50LS) Z'cEs in
a si.l.;..l
fl41i3C 3I. ..aUs. Tht? SC',bj4??k flask Ft`:bti PaTlÃally 511bma.rtsf=d. in
a th'wA?i{?5t.3t1ed oF.i
ba.Ã~~, preheated to 140 Toluene (400 x.FL) was added to the ~:.alai., st aiid
.ho. mixture

i=4}1s ?.1eC.t{:d v"I'a s4'i31g+`. :t? V>C mt>11E.1'2ic;[.sz. The
I'k.;.3C<tioE, was S.fl`red tt?{ 48 hours,
a'L.iT?E?t'{:d a'::om bt.cli, and. to .'f7i:+II`} te&71poaatUAC. The polymer :
<2:s, i?I4solvt,:d in
d~chloromethmo 0 s> m[..) and precipitated in. cold med=an~.~I. `Flie
sz~lveiit was {iecant,: .I

a31E .'',.lbst.ruendy dI..4.d by i.b`ip{.{Ã`atlt?;'?> ~11c
r%='iuffinr._~, polyin-c.I' foInitia L"=3.ffi`+.>.F a t .'`'sco{.E: `'~'1i
or wb_Ãtesd1d precipitate depending on the ci11`bt)$`iaw a(?,la-va .o?` f1s.
Ui?po 4net'..

'~t.lli~~ p'*;c 4, t;~'~: ~:[3r"3~#{;i) C') ittE'~ t~`o following ~:} 1{iil~i'
~4z'^. :, ~. ~~ ~.4, t' ~}. 1f)k;:.,~..~r?
~ ~ ~, e~~~a?a y~kc:= _i~3i?~t. .~ t~.Z:i~+t lx... ~.',

; ?i; iJ. `rk i;.501..00.

x;F.~.`k3I ` rLbIV ~>Vd1 Fx~
__ --___.__.~

~=~t.~ ~~,.~=r~,~,~,~.,,.~~~., ~ . ~ ~ ,..~,~~~~, ,tih~.,,..3 k~.
~ r
Pi3ly(~, .~~ r ~õ 2,022 ::?t#a:t4.3~.) was
~~.=E?:t,\~~C3~.t' glycerol 3

~: :~,~tl~.= a ~-~ i-~~i ,,~ ta~
~ia~~cik :=~~~.~`tl t .k- ~ ...L ~`#k Ã:'~,:_ ~ ci_r, c.:~ iis~:~?lt..<~r"~x~
taxi 1~.~3.a~t,~. 's Ãzis P~'t' t3i ~ . 10% ~,.' `]{ . ..~;`~~ (50 t CYZ and
20% p{:(0H (. (R) ?l.f,) were tliCn i}.f,d41d to the d.e3lsii:ioi7. The
rka.`:..ae

cv ac?tawd <;nd, puTt,ed wi-a., hydrogen thre-c tÃmm The fl,xsk was tfcr,
pwsw ~ .~ <:cd to ~> :3.~
psi 3<:th md sha-ki'>? f}?"' 24 3rit?is,?'S. T}?tL #"mi;tio?". n:E?xtF:E.1'c
.) c3ti a;..ri.. 4.i..t: ti1.`v'{.iLt3

Ceh#c: aiW the t.lter cakc v,:;~shcd ~=~:t~~ 50 nzL The st?I-vc:rit;~ wt.m
then

evaporated 'm S'Yidtl thw. 3.:'i-1al ~..~ol-~;n?ib:r.`, J1.E~. 1"('s:iid13.g
~..`oe;~11"41" fo;I?..r.} cF':~1e} a 'v`.st,..tu"~ ~s$l
or vv.hiÃe so:zti pÃ' .i:f-pau}it: depending :3'n t61c L,al"~.'?f?"iaf:t:`
s..i).: {: A`.t i. f the cC?pi? ? a?"Ye`:~'.

C a;poE-vmcs six ui'c -f3nnei~3 WYF'2 th~.' ~i.`.'HC?wÃn".,; cit'b(3llaie
il]i;ÃC. , ,r,:ci`,.ons. 0 f,5, 0. 10, `.~,220,
ii'k t; `{+., 0.50, 1.00.

Table I }.'t('3oi! 1i:CIiLatLY: 5hc C;;.?n-14"3osifi{1n, i-n('let.u.:.I w.i
?2:t, und thermal data of
~ ., t>.~ `L L= ~i ct.?po"1f'nmcisy whià n. [1.1$: 1.11 ll:itri.$tba=fi by
stritltuFt~E f(}}""`+.'3~4:>... ~s, bok:~`~' dw. _,.sWc. hy_:
Table 1, ( :i._= : ct7:prola.-t:)nt, CGI {,:abt>z7ate o'c`g,.yct:`,I'Z3~ ~ :~ -
_= f-mole p:.'~icent. +,:ub{r.Iu:t:'

84


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'n7=jt.:oF"n.cF' Tn po'cTnt i'11at1o11 to.C:i! F~~.~ :::1'f7Ã3lG por'.%flt
ci;abc3#ta`,.. 1>3:st,:?F:3.;r in i:op a`pt:'T:
s,:a;:_ ~i~~ :.ii"1~':Lxl~St.=.3 ~i~ ~~, ';Es.:Ct~

TABLE I

. ......... ---------------- - . ....... . ............... ------------------
. .................
molelulA ;:~r WeÃ~ ~~ ~en Aal Pavcà G=~~
--
"~I, ~~
~ =~.
c
s k=c ~~fl
~.~ ........... ..==........ -----_.._ ~.,.,,...~. ._.=___.... __ .. . _.
~___. ,_,_ w...~.,.f.~.,,........_............ -. .- .,- .. ,...<.:....:.
0 +~~ , ,;;.3~~E :..~J..2 ~r) ~ ,~~ `l. t j~^x Yi .~
J-. . . \ ~ ..' 6 Z -

c ,.. l.<..3 9(r-i,.t.Bn :0 11 61,700 13,300 1 .~~.M -54 ` ,t`~i .. 8 t. 1 10
11 5 7 ~0 0 1 2., . '0 ;: 1.t.`}~` -59 -11 ,r i':
~
Ciw '0 ;~Fa .:..jtF ~~ 6~7, 400 1~.},2~~ r 3. {~6 49 4 3 2 1, t
~ ~ t.'i r f... .;f=~_?~: 2 2;3 57,400 8.60#~i 1.96 : ~~'> 0 :I .' ` `
: ,,.
(:.'<i 10's~~ 110,100 ..;91 -47 .. 45

2.0 '010i4001 .9 6 -46 '5 :~~. .~.,.~

t. i:O t, 20 t ,¾3 NT; 20 68,700 101, ::) C.) 1,94 ~~~? `:s S
44
3 i.! 7 1 .E0ix 9~300 1.718 ,.43 3 Y 14
f. a. ..~~:b ~~~3`~Ei= ;~g~ 40 4.y e "' \e'?fi0 ?,9V0 1.94
~~, i-~i ~~ ? f=>"a~:a 100 1.00 104,000 _t,6t+t~.~ .~ 1. ~~ N i i?
-
s_.: t


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
:.

. t{ fr \
~1- r. \ ;:`~.~ =\, ! `\r t ~` .
lr \.`' \ ~` ^ \ _ __~ ~=~:

ff"-`. _>'==~~: r'~ . r \.. . \ ~.~ ~.
~_- r rY1 r;.;, .:f:~+ ...' =2 . =v ~,~.r ~... ! ''~-y~ ~:. \. t .
's. ~... ~ , `` =. ~~ .

,l \
.

(

111 ;>41!
~*.

86


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
------w -------- ----=-~-- - ------------- - - ----
=t
ti
1k........~ :~

i r ~ ,.= ; ~,
:.~'`~ 1~4~.:. ~_~~,.-.''r'~~.~ !.' õ~'~i~ r`~.w.~" u '~.~i'`/ ,,.~`

(1.0 _ 2:02 #t~:t~.<<~~>

nivf i:i{ts6v .....W (16{e+0 g, 3 13 nlmi.?o '<3A't<i (DMA,P) ((. i.f . 3
1,01
tn,mol) wei=o dissolved in IÃ~~ trrs'dichic:rÃsÃn.thani..

(DCVC.'.Z~ (UM) & 2.42 Ã#,z-n4.~~) was added to the reaction a`.{1#.:;5:'#uic
ciÃ: a `,4l# r 3ri:cÃpita:t'

- .. r i ,~ ; ~'b i q y, , r ~' ~y
aij Ãa~:.~;Ã:~Gi.~~': ~'~:{ti ;,~ t~i. rv ~._ ..:"~~P h~.>LÃ1;> cil
IÃ~t_'s3~t3 r.a~~.Y.~p4=~"i.it~.;;'c Ã..Ã~a:ia ~ Ã.~~3 t.? . : Ã

p) mtp.<iwm wt<.) ).oaC#.t.cd by fifltiCttiuii uY.Ãdi.he filCrList`.
'c..o.#i:4)2[LfCit\.=fi.i. 1,:#1.;

ionc::m,T<.S Z:d fiftt'aEe dissolved i,k diil--dot'onno.h.an-,c and ptr
cip:t>.~tcd in .:old n.<.caan;;l

(25 nIal t.~ .~:f' v33v:..~t was L:4,.Lamcd and sLÃi)Jequal$ s' {fi.-iC:i~
by evup(tlu.t2>m. ~'h;=
r"~=y~i~~.>l` pa?i ymer was a white solid pI'e.=1p1ts2tc.

imli_ 3b3lz ,S ~~ ~~~SSEc#ÃI~ ~L~t~ G<lÃ~~~Flx~4 +t3 c ~~r~L~ sti~C~a~f i

11{Ay(j)G"nGy1ox " glyLt,..fC.< . Ãia3 3ll~i~t tC1H# S :$~F]i't~.~itti~f?:i7 ~
(1.0 g. 2.02 ni.:no ) ,`i:oaÃ`.Ãc
.
acid :1>.~
;Ã+;`S` . 3,5.> ~m.31o';) .$F3ta DMt'3~ (0 123 g, 1:01. i7?-nol) t~i`re ..
54:3I.1..d Snz #.a~iL
ti;:

dry f~iunl;Z#.i.`#?':s't-lba#:.Z:. :.}~.~~C (UOO g, 2.:42 mYT2ol) was added
:.o the: roFli.'. :#.a}." :ET:id
a j>?'1it4 , Ãt~~ipitat.', f0mred: 'l]v ii21x`iLite was stirred fC`~i 24
13at#.?"4 at rowTÃ
à ntxer nafÃe ;:en, Vllac prz:::;ip.tatw, cox#tpc~wid was ist?iated_ by
filtÃa:i+.3n and S ,.;: ffiltiate ; as,
i f 1<~.Ã'23Ã t~ i;. #:4at cL>F1ct,'`nt1"a=:i+.i fitÃ#'e"li:o \`b+i.i:i
d1t5Ul'v~.'tid ii iÃ.tl.='tT.Ãro.i3tF.'.fi+,h'<`'s31i,. 'i1nd

prej :pft<3.'tt'.3i .ÃF; ...tyli3 n`_t..tii7143t (.c'.5 mL), H~IC:
4olvf;`..I.3t was dd;;=[.c..Ã'~tcd and Aiub:yequi'.>idy '=s~>.`#.t:=L3
by mapZ?,..?I;itia. T,I: "esi:tffiig was a w llie solid p;L.iiZic.t:f,e;

,~
`~s..,
~.

,~~'`%


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
=-~- ....... ..........~ _ ...õ-----.----.~,.,...,,,,,,~ .,............~.._

F`o 4,''(?lwt.?:t%IO3 yi,' glycerol i:1Ã~?i?i" i1~L u.t? i
i.i2:~3~17~%1?C3#?L} (250 0.43 Ilu?'li3lr w<3:.~,-,
d?ssi}IvL.d Ãn 25 m, L c+f py.Ã::di?:te and cooled to (} '(:.

3ra8 :?ddz_d t3:top by dTop< The ?,31x.#21'f: ~=~i casti::lÃ'I`i?d ff3> 24
ha.~?.Ers, c#i tx?Ã3i-?"#. :t~.a}Pe;'"At:eE'e tIF?f?er
?lltà s3gt:1#.. a ::.3v pva'.3d,T3t was removed t?#:1t3eT` vi3ct,.3??`[, i-
f1i.' i:3'Ã.tah~ p=E3df;GÃ w.z. d.?s-staIvf ;xI i:.?

Iai.:=Ifl1`.3roa?.`E.'.thim%'), and. precipitated in cold ~ i ={xy} Gi'
:~.i~.>,5 yx``~5,~ f~ r~F~ x.~ s't,i ~y?'''t-'..?? } ""~?~~~ \` t4\.4'1A i-
.t.~~k'
i~C t'4t~ ~ i#D. T, :

i3.nd s.<:#i:{:+eiji.:5::nfly &aL.d by : S'ftporat.tol3. 11u, e'f'sult1#?g
_lolym.:a was a 4i'h..t sE_tltd
precipitate.

E.Si.i3.17;i`5~lOA]T? T v F x_ ?) t el~ pol 4 ("'<?bl?7Fa?t< Of # 3al t Cia:
co L apfo t4t1?3ke
...... ......... ..........
- - -- -- -

f;
.

{
?~~ ~ ~f ~ `~~.=^ {~- -''f . ~"~.~ ~-'= +j ;,,} i ~~ ,+

~ jza

A'#? :i:?n3lts,'-C7zt,Fv1.3.:'ed c<3i.':<`lZ,mi'=:pC7ly(O ,.?'Ã1=:'#:tzai)-
hexiS,.-#-tD?z: :.C#i., 2-0ai ;. 3 dtf?x:?#t . ;_.
S=~ L4.+v',F' Li;?wf;~S i;?I'i?~i.i..Ãt?i`ia:}f ~3i?~ h3`C:~3i1I'~=E~ L~\ir?M
41~L`. ~.c33~C?:~~a-Ã1!; #?;:5.:~3t~t~';.

i;<< 171 j?~Ar r riJ ;{t<Ifs~' ~w:t.+~It itf #IF.ki'?::>:3G( .?t:':wf
~ ~ f~ rs??r'Ei/L~t +t13";t'?

i-yd,:Ãd (1277 g, 0,78 ?#?o").
(l. 5 g, 2.6 mmffl., 22 moI. % .t.)("(-' #0 129 ;;, 0,63

: :~`i~f.tl) were ~ v~ {~...t ~ : ?-,.ar, 3 4 ti 3<i
r~:,. , ut~., a. . ~ t~~5:~;.' ~ ~.i~ :~-ÃI~ t.~~=' .~. Z .:, 1'aw
m i ~ and ~x~` ~~_~'R (0,1032 rf +.2:` r~~

wi#.n wt?..zC'.`d at R 5 ,:<o#. .. s :l. The z)CU n`r1;: i.Ãh#'1-6.'.Ca and
li1G #izi.v.,.'1 t G'vil.,~ oIi=t Md, # iair
pÃodi.:c$ ws,S dli;so:ivi.6 Ã#`, f.i#.cb1oromCfau-?1t~ (10 mL) iÃx3d
prec;g31ti?.14d in c:5.i1 #:'?~'=~i3.iF.t?i.
,11s0 'a''#,?1w?-?3- ~A c3s d4'cwwZ:d and Si`~b4quf;i3F'ty fL['Yfad bn%
Lv%:pt33`a.EtÃo1: (85'!:r `tir..'td), Mh~':lÃt?:i'#

o., Phe i.An}:.f'sss<+.tL~~H=~:1Ã3Ãx w[is, deLL'.tmi):L'~by Ihe p1LsZ...~i?4~x
of :Mink, l:.2#.cCh\I.L':we group LaVares:t

#.:a;)flp as wf:=~l ws thC F'#?-iot= ~.~?'otC.i..itng Ã'1?Ãip 3`Sf,.a, .3.ih
p4;.t?ks t.n ttie
Ã'Z`2tL'Ct.Ã>?g ..

.. z NMR suC:c¾run~: [l.t 3. w%,#...I 19 (a?i 2H7 OCI--.k::)3 and 4.45 (s.
21:1. . .2'.,,#'.. r' ~8 cÃ?n:,
:t, :F?'fi ?3i~.#. ~ r=k~ f t ~3~"i ~~'.

8 IR


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
i.... i.C. C%;id ~r jL:v.3. {ft~ii-L`.t i~i ..rt i'f'=-f;L'~i~'trt~:+`..tLi~a
.: . ... ~% =. 2c t.1..~.f r~.7 i.^3.'.''.{i1r~i~?i.3.,r~F33:`.1~

11,3,: i:>qptshy3T.er (300 nig) was d'{:;~solt'ed in Ã1 -40 21 o.,pTj7w..
idi.w, `~16 mQ
and dry dj:31o;hyj sC3'~~2 Ã~`3<~v f,.24 r?1Q and the }:ci$a,3C?n vvm?'
sdmcd fC`a 90 P1.:i1. 1%

,~.+ 4L``i s t.Nswerc Z.`'<#.poi <3.led, UndL r'}'.ed1.3ced p. e3S,fSi`<

da4l-flo:Cmaothad3e ;10 IT3L# :?.d pi'ek.ip;;$at~.,dl in cold liielhG:n:3l,
Thest,.t`~~.:nE.i:.~~s dcoz33'i'#::d
and s}ibsL`i3uo`?dv' d"I`Qd by ei'apC?ziation (quaiit1tc3t11`E:~ JcW).
Complete dLp?"t>tecttm was
di,t+;F:xllnei: by à :e abs.ci:ce of the Fmoc protecting f...`=zÃ5tb' ~o-akS
ir, the El'I NINMR '`~ oe?:ruzn
a, 4. S<~

1_sc~r~ `uncrif,md:c~i N.}.V t'`aMoll te o G--- ---iTi?I-i:f~ --J
- -- -----------------------------
}+O

tr
4 7;J

r,,~`. ?c ~ `=_.

} ~. .:T f }1 f-<i,.
rr
~'4~^` .~~`4` f -..~'`'~. "f- +~~ ~''+=`,~"4.`'r ~'y.,.ir S.~-~.
t li f ~
y, t

se#f:

A -,xYa:i a'y xii.Z?hitl.^'di_#.; r'itl...ed c4:3polyia74.`.F c.c: >?-i;xÃ?

; ~r- r= ~ c l z ~ t ti~ r` `,' ~e'"
3 f~: xc~ ??yl E ti.. =T C? .--s=t?.~:i' rlt+;,<>~t~L ) i ~iS i 73t~:<'.511
.( ~ laSFt3 L.i ~s ~, ~ d ~?4.
r i ~ # ?EifS ;C>.F`L (W 0.38 -#.1'io]), bc.i7:1'yl :?:rt:+md.e ( :l'A ml
;+, a s {.>..ki), i`z-#?E$
p,otslt~tlEAm hydIo.'tkhn (113 g, M,.~:81 niC'1l) wL,r~E:, d1s:sL3Olveii:1Ft
tZ?l::C.Y+1C. #200 I xLi, Thi'.=
remior. fl::sk placed in, a 120 i,{v ImeSeded oil badiand :-s:.Duxed o4crMgxst
under

il Adug. ,n-,).t\=,.' A)rf..at.:.;v Y?412s.~~~~'~i. wj4\2i:~LF~i.FA=\S \i.~-
SiF~~. I ~M I-ICtS (300 S1F~-.~. 1.i.3e LS-}It:~cnae

20 i...traporat~.'.d f:?Dn and the pr#'.+dC1& <:o,i3.1=Wd .Ii3Ãg dichf
C3I<yTiC'th<ln:i:`= L3 -x 3f30'# "xlr) to .?ffÃ?.F'Ea a
#.:ixiia.e of nts`J.?o md d; t?!':.ltea :et` 6-i2ydlo?s`:y hLxiI-nEtILr
a(Cli`. ll?:~~ cI..It;'F~ p."t?Ci7::E wik~"'

4 apo:3.1fi4:.sted v,-i:3` I "I.N.1 sodium `~.`'t-vdro',ieds.,' (200 llAl_)
i:lEf~i :,1.?eth<knC?i (20() ext?"....t.:ted
i4Sth (HS:.I'di?:i=o.iY.4t~'':41.7c Ox 200 t11L):, and $h%si?lvt:ni was
o4ap+rtrctod l.1::de. Eod3ÃC<:d

preJsLa:f- to si~.}Zrd" kf;.;re 6"i3'vr,.zy1f,>xy f.ic.'~~.&noie ca6i,[
f72?4 vY,wEC3y qC NMR (CDCQ :38"
89


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
1.4; C ~y, 1w5 ~'~~.Ã,~ ~~:.:~~r;1_ t [I t4
11 -2 ~, 2 .rtk ' ?~ t ~:;''~~ ~`Ã I>~...~:~11}, 3,42_

-~ ~ ^~ 214, i .a y~ ~ . !r, .3 3 S
. ~, r~ (~r} 2a.q'~?`\~^ , a~7 .f4.^~t~'',
~.`37 ~.^ ~ ~~}lVK~3v~} ~. ~-'~3
..
2 ~

acid (OX' 3 g, Vr 8 ;2?nnC.~l);

23 `:iLA,`x, and. D,,kAP 0.26 Inin~.~i) were dI~solvE`:ki in .~'`~.: IN:: (20
ia'3L>, r''hL 5=3l1:t1on:
Was ;stirrxR~fs.'2 a1 2' i^E}r 18 h, TEwcD4.. E_, was i}F.tJ;:iC`ki'cll'#t}
ffic SoF1'Gl}t <. : s.}port.to>. T:,}E.'
m~so;.~vc d i;: diE.hac3rs n~:~eÃ~~at~e (10 n~Il,) and precipitated
ink :::olc=.:ineffianuÃ..
Th 0. sÃ1l va;:;;it Y='ti a4 dc5;',antcd ,.d subSErqueIAd w' d3'1#;d by t :
<`spL)-:<Ita;}n. (W:i; yiiul d'). AdEH ;EoÃ:i
~Cj oa d.Z;:ilcob:~c side i.'=hailt; was dekf,ri'#':ined by 1.1iC;
Pt`esirt`s:c of Ã1hoi;'1effi4<ieT#E t,,roLFp ..:s;ar<`..ti

-d;.i'. i' 4,t~.1` t~ +Ã` ~3iM~Lliõ~.~; g#'(r~.ly, 3s well t~ the t.,e~ 1 -
~i~,.ct`z c;';.'t, t}) ~~'~A ; il ; , ; .
3 3 ~?F ~3 ;~ tt131"l. ~~ ~?`{~ ~'r.~. ._ ~.~ ¾ .~4a>h ati
~~le Fi 'NITVIR spectsurn at ~33. l0N3.44 (m. 'H, OOH;)q ~a:}d 4.48-4,53 Ãs~
.1;
~
:~~:S~~s w:t~a.~;zv.
r

The coqx`ly1'11i., L.,?i>`'~.3 mg) wii;a dissolved in 50 n1L dxt
Ila3iÃj`+..'d:}

c~` Titl4.= '! ` .~.k 2?:T:e ~.,e ~ : $~it q i}\7i5qV ~ .f.2iiq
t~1..:1r~.}~nw+ was a/= ~t )~?t24~24~ti:=\~ ,+S 1 tS2S}-y } ~(~f._~i.~ y21 S:
2~ t ~' Z} {Z S~K y~
~... ~. .~n.i4~~ ~.~Z43.tiZ,~f~}5 l2. t VK 1l1`y~[:~a. f~ .2_Y~:~= times.
,?f~l4F
:e
: hE fla was P[ien pt ssaiz ud tE? 60 psi ~viffi hydrogen <iaid shaken for 24
hours. ~ 1

~:,'~0 icaii.lan I}:1.~'`i:tum !-v}s lKiiS:r.t> ti.:}'us.:gh C3,=. itr`:=
i:1.iit3 thS;i fi3tei Qako we:}sh~t:: ~r id v?0' i-n%.=
~t a rt~ .~~<3 ~, Q
t~3~:?~3.~L;FE~I~nv}i~~bz3L. ~~~z~s~ st;;vei:~:;i 33't~'~' t?lf:i3. i,4.~;
Egr.~tir~i ti~"4='1~:lt: ~i~'~.i~~ ~~I,l ,~3t3. ,~'.3wr

.`qac3s3EÃtt aE} v}`.'. ConiplF'.E~.'~ deprotection was d4$3rr21i1#1od by uhc
absenoo of the bcÃiI4''l
;vcac:;_Ãis y sup pcak~ in the H NMIZ. sp"Ã.rLtm at 4.~84;5s (s,
(m, 5:11
~
~=-~ ..
.:.

.~~ :~
\



CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
xa.~`iY' le ~Z2 ~Y~~fbx?'S.y31c <~L3Er FLllaL=ti~~i~u1EleLa ~~"(~li 4~zt~e?1
41~~ ttf
..............~.,................~............. -------
f3ic`~..'~1'l3.-UZ? E ip;"t3li3::l}Tle

_4~
r ~
r ~}$
q + `~- !r .~4.~,= `'ti. f. ~,}
:ix Z f +~ 1}i

A C,.:A'bz#xylzc, 1Cad d#.ri]lfizoi} copolymer ?,i?lCf(.1eSSi.~11ct;iC`,ic
s:,JE #11.?Ã t? ~w C3 tf ~,~
d.t3x.i?I? z ?) f't?f3i'+'i.Vzds $iyÃ?:hi.sÃ:r=acd using th,4 fibilo:tim?js
`teÃ?s,

~ Wi':f;i ]3 s {?ir?~ ~13='>..'tiF iW x'z`lf:i 1Ã3o3tf+~s?.',t'izvdr ester

DOW,_.X} "+(+F~t~wX3 (`- henf}': ff]i.M=rl.tC'. ( 10 mL, ^31i'.~. and :ldapi c
.1c3d (2 g5
I'Ãii?1) we,C, adided W owtai3,,~ (I Oix?.E.:). f3?I-#.em.lxtuif', wai
.i~.'t.ftix4d ,t?t' 4 h<)uÃS A 3 00 iTl.,; aI':
the CaudÃ: product Wa:i pui'ifii:d, via Sific.'s: chromatE},..',iaphy to viL1d
s clear, colorless lÃf;u1d
.;
~r
CH-COGH)Y 5.~)9 N 2:1-1, :(lhC;`f+~), "..:.':ii 30 t~u. 51-1V ~~rom<-btic;.

F+)r st.z.`1.c acid f'i~s:J;Ff.+ ~ "-(+].~f-~, 5 r~If3:xL3 ^,='i3 'Sdi:? Ãx
t. : t<'';"iJd.s>t1;'e'.c'}
lle4:i;n<'.d1fJ?= acid i13t?.,?t bi 3?Ii'1 ester q0.184 & E,, 18 Ã?'mnz:}l7,
p+3]`A : :~~h.'oLY ; ,:.`-
E~,t?~.~x's ` z~.~`3w= Lt3 ?: i e~?kt7zs i i.1)z~~~ i1-5 .~`'.{? 1umoi, 22
1'?3c?l % s. i?~ i3t;~ siv :3 DZ ~~ : t3. 1_=%'3

003) 3n;Ii3C?l), and DMAI? (0.032 g, 0.216 rTlf`a'.ml} were dl ty()l'v'ed, tI`
(20
iI?L~I. ~1.?~` ;]:.;,a:ii?.i'~ 4'w ~.~ s:k'37~:i.~ at ~~ a '~i~Ã` IS h. The
~.~`l..~w! ~~.,$o>c;s~ ii:'?:`~'~~': tiirlZ'ont
,

"L.vap\?roWfa, r3 Ã~~,: prCiZfu{::ZSiI~'"+. (.ki,S.st?iv~'<dIn {dit.=i
loÃarneithai:t' (10 n:i. and cf3:d rnoÃhr.~od. T}if: -~c}li'cra was decanic;zl
and subsequently dÃ'i.tx1 by ez:vwpt+m.zon, (83`J';.,

_yie:.lki). .ldd:ti:ii of v.,~~.c carbc~xyl:,: acid side Ã:has.n ~~~as, dete-
nm.;~~d bv ÃIae -p>osuc~:~ of tli.>
;?~z?iÃ:cÃi k~,;4roupi .4A=it:~ peaks iii the 11-1 NMR; pLci.:m-n a: ÃF6 (s; x
: f1hCH:~),

7 ' s -33

riti.++~ # lg ~?4'r ! tf3J.3 h[.:~~i:iTe.fJ[.` {E[ sd 2-:?I.U- ,`, `3 F:=
f ;sk;,=t,sE~f<i3xtz';

;.1f'w.` ,,'opi. df'.7't?" (NO .T]g) was dissolved la, 50 md, ihy, aC i?
trrt"~?~?l `, lc?Ã t: Ã?~.~?z.~ a
ParÃ' bo.t ~~ , w. I p : fl~~: ~. ~ (50 Ã? g' 3~<~(~C3~~)2.'~_: f.fi(. t?3g)
were ~ s+~ ~ a
i3~3.~.;if .}.~r.. ti, t~ts>.
91


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
iC3~t:t1(?I~ T .: .~"\..z.iC~t`'~fF~,. ~.z'11IS:~#.lt"`a~'= '4~'i?4
4'v'~e::~Ã:i~Isxat`s.ta~~~. and ~~1i .'~~ v 'd : ~.xq'Ã~ (~ti ~'.i_~ .3. Ca e
[?I ~t;t,

T;?~ .: ~-k ~;EeÃi ~~~~s..~.i~.e~~ [tJ 60 psi ~.~~iY1i, ~~~yc~r~~g~:.~i <~::~.
sI~~~G:t:? f~~r ~.~ hours. I~ ~:~:~
di<]ct?Lr?'4 r.i#x ;.t::If was a7ft-Qt`ill Ã~}T<?"iti''~? Celite and i'iiC
.filteF' cake i4' thx t 51-1 ??`ti._
c?`.ii:!'1I0'E:x.t1?Lt?ai:4,,:e. The ac7:v..t?w1 were theixa c;vi$~..~F.>l:
lLd to vit;d ?`liL- atn<Ãl ::#oiy,l?;.:'

(\F~.<?~?~#. <~ ~ t'.'w rt t~~,ixslot~: di~:~~-~~t~.Ã?~tst}t~.
<.~.te:~~ti#:~z:t:~ `~ ;' ~~-~~. >~bs~:a~c~' of ~.~:s. .:}~~:x fxs`
c~s
pffrÃ~.~ctin;; group pca~,, m ft3~ 1-.1 -N.N.-I.R. ~pec:.~rum at 5.06 tw, 21H,
PhCfl-,j, '7.A# ;-7 ? 3 z#::,
t3ao>3?wt3:c,
>.
axs?n~} e L # 4'f~~L11?lc 'Sv ~ v4~ ~~ Ã~?it}~ c3i~~? t 1Ã< s f1 r L t~)T~~x
~.? '
....... --------
,..

~;.=
? G i i

- atz

i hj'`a # i ?..di.t}a3an^2';JnC' and $'__G:.<;pri3-'s'h.fC1ll:3C.t{ snC: <.;
t:=i}'mb3ileta
W1th ii_#S# ~# mfit}:?> (to a L4?~i.l.l of 10,0 1I3:`f?ol) 1I? i.~ 10 I L
soi:?lc.A. flask t?E":t .I.1tieq(?eT.Al v
5 t <3<.u,atcv <nd R1?sxxitad with N t}.1TÃ:i: fi.12?Cs. Meanwhile, E;~c
ctaÃaly:;t 6,5 Ãx a_:..

0.02 #,n-mo3y ratio .;: 500) is eve.i'4iuatut: in a :?ina31 flask foi- 1,30
mit.t-t.tr,s.
'ffie ::<ch;<,nk flask is p&rÃ.~..x:ly sub-~~iea-gcbl in a Lbr.rmostatted. oi1
~.~ath, prc:u,; ,ed to <40 C.

Ti?..Li\.a.':e (400 i:s added to the itIÃwli`i4?s+ ;;;1'3ti e.hi., TI1??2tlae
13;ti 'tcd via to thi.:
?-~.f?:1?i~? _ 1^ i < bt.lm5.~ ~Ctt' 48 l?o#.1r5, i`ciTlÃ?ve\i '~.i~'m?#
f?[:4it a?.f`.Ã> 4 =i?3i':d .}_Y ri}t``i:i
.~I4. ~~l.t. I4ii'i::~.,+
1:0111peratur . 'IY'ie pc?ly^'?-lcA is dissolved in di~~~loromcfl=tm,e (10
n:_I.) and p;,.cipiÃated ir,

wid i~54.,=ltllv\JnL is d1:Wa};1edLi}[d f~SYl.}A Vl~~ by .ti l?c

f's;suffing pt>.T:i7:t.?` :`.nF3s a v1`cC3ll", Ol.l or white sol,d
prcõ_.px$.a\c C3ii;p:."'1d3.:?e. on the
t 21'bl?:?att! ci'i.nwn: of :.1`` L= vpC?lyn?c?.


92


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

r?" \r-''f a-..r ~.r''~J i '~:/- ~~`~ ~.r ~ ~~.'~~

1.~t~
~=
l ;t

l3i r yj, Zc1P1';`:t3ti4 ,~~ i~:.Ea ~
4n.LL.L3'C; :3A~3> .:< ,t t~= ~'3 `+ c ~:.C3J2L T Ã`s ~ .f~t3~ IÃ, 50 niL

dr, a F`arr b: i;le, I t)"N, 1'&{~~' #,50 m~,~ <~.~.~~ 20% 13t1' ~.)k ~ ;# ;
k. s ~ 3

,9 nag) i?i'e ad>; ed i(`? 3_ht: SL>ludi3Ã.: ThL ..4.e.ctfon .11l:Ã?b(,Ã,t'i:
t e'` .2ciÃ,_.tt an: p;1. tged 46ta3
hydfo.;.`,~,~'.I3 dl,cE i;:311QS. The flask is pÃ"v,~;St#x12L'.d to 60 p,,,3
~oi`ltffi hyd:'L~gen. and 1hi:\c:1 fb.` ?4
f3L3um Ã'w`.ait:i3z1.3nlazE:J';.e ÃS filtGt.`L:'i.ht?'agd3 Coliwe and the
fiRf:i &Ka r:.~s-hÃ.'f,` v,.its`z 50
Tf w sc?z 4 (:Tlts are evaporated to yà 'L'yci the final polymer.

F`S.aIT3 p]:~o 15 PoNf\t4adÃf. .3L13l t}lli3n ~~a?~~~11rt à C z #. e:f3"3 c~~
à ~t3i~ #
. """'____.&__.._.. ... .- -_, .._"____=_ _________ ________-.. - ..-. . . S~
. ...___._..~

~ ~--3+ \
~.

?. y 4~ t j
S FFF ~
~ i3ii

~ lvcct (? 1.~'..3i3, ~teaF,w zsdld

D'~IA1' w-~. dÃ~,Lolv<:d in t:)Ã~ i-t3_I_.d y DCC. is added to, the
rctic;ti,>n

and i3 white prf'.i.;Ãi)1.<.EtL i.i}rms, The .II`xl.{twe>s fit1m-d wZr 24'
i3mu3`S 3'+:ZZ?r3i

1M^, t.aitperi3.tuf'~~ unda 3':ii~,;i,4?;:n. The precipitate compound is
F:st3.,..to3.a by filtration and ti-ic
fiffictt:i': a?ila.L#3t1"atod, ra,`1,c +`.'.Ã3}`Is".eI3tS;attJd j-3i3~at.; is
dIsso~~a! ed;#i a~,~ ~eA43lti`fllc'~~3.1#1 and
pat:i',1;ÃSf`cat~.'-d 33 mRfluuat3l (25) ;rli.), _11"#.aw= ;iL?lbea:t is
decanted tind . 3i34c:{ Ã ci`.tlv, dried by

a:~ Ex, c mn 1L ...t F< `31`1G 1t F`I of F';C S?t3x l Ctlnec?zllaÃ>s' 11 LJA
N`1c:"o~,O4ÃF "1d i
B.Gc:b.4.tZ..b ab 3 p Si:Z' D.L. -Ia(..,~.Id k:,-LC3g, - kiy4{..;Ãd C ( I
a~.~GA~ 3,<'E1~."+c{'tC.b..... ?
ac;= a153dwht:eIi of paLl;t:Z2d . "I'hZ fahnita,.1.oi1 ttS.;ll_E-x.qu...4
l.is~:d to create P;.X}A

9V~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
'`_1C:=l'opii_u4.~4~~`s We2'e modified fI'o,Si Ediild3d. & ,^~lbo:i't`` 3t;
.`.3?d Wang `. :ii (1..:<3lul:ts #?i. ':~'?.,
At>v:. PC>, mw=f` Sd.. 15':6: 412?i}01Y tVai?.g s:" a.2's,, Chuo. l3hw~m BOz =
` Tok?ro,,

4. F 93:3,. ,> Ã'`}96) and ::.#.#.Uz,C'=kk a ifmaer in C3R C;12i.uf;stÃ71>
teti1ll11qi7G, First, 0.5 g Z? [ fi..~ 25 ,-11.=GA
,`~AbSi3d?..b:e Pi,E ya1'iZ',?" .:i-#ti'mao-ioi1:3l, B=#.1'I3lit:ghaTli.
Al:1bi1iI?>l) ts1blf:tE (thi: yc,'L.=...n:c~.i' i.llc vat.i4?
of l<lcfic acid to glycolic acid t1kt> S..owtaf' the i`~.'lea:*C".) were
d?gsz?lvW1>, 4..li.`i_:

<11ihlfiF"s.33.,#t :hx....t, (k?i~,~.~.,t.~ia Aldr1t:.=1). St. L'C?li-ds, MO)
i.s:ent; a vortexing dovi: L=, Afic . :t w,
<vas co:-npIote g dissolved, 50 m~~ of paclitaxel ffax( .> MP Biomec,ic:.i1
Irvine,
0011btYai ~) ;?rvt=iÃYt~~~y sol'Libi.i:.et~ in - 100 t.~i of zlinio _fiy .
s:#:lfi?a:du f DMS O. . :dac:t'

flatF i.?kizi... .Nli t. Z4 a:s e:~t~ded and fud`diei `a=3.~Ã"texod. M fl`}. =
fi1?fiI(,..tif3~n <?, x>:i?"tI.}i~~ PI,1 T.:~

beads only DMSO wa:: added. The st?lW.tm? :icis Pie;L'C.d i3't 10 ml t?f ~~>a
dly-vz:=1yl illoolol
Fai f,iL.:i...it. (Fi4i i..r) and T`:?.E'tl.:C~.`G: it}i' 15 I'i?lt?wtes (or
u`oi,icatcd using a probe fip CDn.catoq~
and Sfit`.cd ;tvL7?i# rhit, {I'he infc:E1p.Alt1cl^'.;s ws;;rti, i:=illlei,Ecx
ilnd washed Ãhmt. :.fliS.s it:. 50
nA. L.'>:td.is.#l,led:dt`,:,'i'r?niZed water. Following washing, Eilf'
IYOs~hÃ;'1.zOd
4 ftcc:?c st#:ed,; <and stored c3; 20''C ti) insure the qt~.?il1.Ãy
oflIaclit;xta. Fh4 e:,Ã::tipS..i`::{iÃ;n'.

~ 5 cffi.,ii':.i L y z.?;' ta:r?;?l by ~lie i?i#c.iY?pw.t?L;le:i was
Ã:tieterm#ncd to bÃ, 74~.5 4% by f IPLC
Niini>pF1.itis le5 Y.?V:.`#.`C3 prepared i-#s?.1?.v~ t3.I1.`aE?difiG'~,'tii}n
of a m;il_ie32`#1;l41oa

pt?ly?'.?xcicJ...:t.iot3 :i'l:i;;t}1,.\ ; :-;.'?'Ã(?u;iiy Iep<3TIi',L~.~
(L%171tilE',vi*,..i el t:it Mlzici'i;F`~..1tk4..3cu 32..5?2.y
~ 1{1'`~9)
< ..
(AIBN), a free tadiia; initiator, wenk .

Lii-s:ii,AZ'i..ta in xd.?1&C?w~~d by #"f:I~'A~#if`t'i:#l of th`~:~:ik, oo-
n¾.viil. t'owFY' cv>_iSC3nat.loa`
Ã.i?itii ii vi,.ic Ã:i:, . ?i:t#lf4 õ4~iil iÃ;~.~:=Ca,
.'~,t~'i:?.clt'~\'',3~'. ~~lb3t ~S7b'~ ~ ~. ?,i? .~#F:3iEi1Ã?~:'; ~~ ~a=I~
;,'~?r
A 3150t:ix--`ri.i]yimi:$hyl meth.ic?`y-lt!te, 0.: :? Iiig ttfpc ciit'clxe: and
22.3zo 214(2-

:3~~~~t?=<'E~ ~Z~~ :i?.?i~`.`?iL ,1 (.AIBN), a 'i'Le i"cadlv:;ll initiator,
.5.rei e

EtchC?ws:d by :"L.=Inl?vy?a of f:ie sÃ?l'S`=L'nft via `.'eoair:}' evaporation
i123c3i a Z isco i.`a,".i?i~~t Lit"C,',
rex?,.;aned. Tht.s.'IBtii,t.s i.7ixtuIc ~,viIS t11Ã;tZ FI3ixi.`d 3iii.i`#. %i
it3l{.fili?tr, of soti`>.v?:1 dodecyl
5..#ffato, a in 10 1-111M pl-I 8 13111i43sp:1ate btaMr. .. _}3Ii: miXE-ut"ie,
wati :hitõ`.,?i

sZf.tlccttÃ.d eÃ`z hour ~I si?.S.%Ã1'L.Er pulses with a 2 second x ?th 30, W
of power,
"C?#.`i`.='It.t'4w tili m a#.iein iit s:i?x?. and .i.:Elt4'4 iug T}1L~
Solve11t to uS`ipsi#";.1 ;:o:

94


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
tdaÃ..s!"s.`rreCi` oil bath and 4t1l-rE'.l at 65
'C $i#.i' 2' hi}s.ns to an#tie .te i.3e ~iGU^f~i2~#s ti~ p1?ly7:?lei?zaldt)n.
The ~<:'.~''14lt1ng

li3'#~i~ p~1T"tFt.~,S.:~ were ~~a~,:i3 i~#:il~~l.~'1~ Fgx.i?.i~ j~ 5 ~3 ~~
~~. { ~ phosphate }'bffi"r 4?4 s 1" two days tE?
it.nZ?ve L'<<3Q5s ;~t%!'fiat:tant md SÃ$~ts.

.:

1" k ml~i IL S, Syi#Ã 3. sik of Nia7lc)T} zs iit 1 , Ui#. pitmo
3p<<FÃ rÃl
1ec3.s Z>:14,.,?>lvk:d #F. by ie#?'F.ov.il +`?~~the soavea; via `.:,?tary
QvS,p<?>atx<)>:t:laÃÃ:.1. :isa.u;=t..i?tUT<.MItUAaf,od. A~terxiativelyY~~~~~;~

dioxa;~yhFsc .i'h; I Fsiei'aaf;rJ-Iate, wid ~.~. 25 tiag of pailitaxel was
dissolved {..?::hzi37"s?nif .ih?_Fnw', f.3llC3wed by ?`~.'nn<)vFti of tx:d::
Solv4=F-1t via aoial`~,` suvaFp+?`.`FIt.om until a

vISGi}L$` mI <:`i31'i, f.'::n7i1.if2Ã.=d, I i3-i:s viscous od was tiii::7.
mixed w=illh a :'s+,Axi.itFt?..7. +Fi,sod:ZurFi
dit.Jdt:cy.i -ndfiac, fl;.c s:~sa~.~fllze.ilg suÃ"iat~=~F:kAlt; z-n 20 anr4'`F
~Fy~~~1cF14 ~~# 1>i1~3 bEaffcT'. ~~.~#Fy F.'!"1#x`i:r:`.
was tih+.u. Si7n:c+..-t.;i`': foI" 3 0 31#31 Spuli:S L~iffi a 2 s i{ei+.y-;
w`_F 30 W of pw
oei f<?f'.i;si>g
I a} E.1c m1i:::8t}3.1k#t3n ;l;t. [il;:3wil.Fg t110 solvent to t.'?a#
ba;.3k .'vaA}[3.eAte. - ,?D: r14=t=1g ;,".:.3#1;...a.\#k:;n,
.'o`iiF'y and I VFny]2-pynol4dG}nc wesrc added to tiF.f: 'L:rnF:.Fi4Fo. .- g
LC.. flina3

E3? '.1'2 i.3m ..CF 2, 1#t~'~, ri:sped#.vi:l?R%; 111.i 's _F4 thi..n
eapo`iõdu;
light fi',.im "ca arc l;:iinp operating at 300 W for .~=' F::i`_lz i~~.~tÃF<
b;:tt,g yfÃi`E'od

e -LF?"~:?E `ly.r .:iiL.Sl~g pi} ;'nnel"#.{iiE~Ãi.si:. Following
~!!?i?.~3~rt?~~'?IG~Fr`cati,.+#1. .hc ;,1;#'t1;1c3 ;=:'`s.'=3`R:..'.
I.f?e
l~l~~)~ai333
~Eli~ic =<< L\~o":"f;~ t~'2f~.i', =C~:'~liv'~';L''~~ c`~fi':~st 5 f7e 4l
`r?i:~ ? i~l
b,,ffor s?5 <.i two d%iyaS to remove C;Ncoss- "-LF#fac1~Prtt aÃ;t salts.
~}>t+1pix~ ;it3si,~tC`~~ii
2~}

g, 1.2 num!3 wid bei-izoyI peroxide (21,6 m& 0,011 mr~iol.) _:vc=c dissolved
:n dry :~~lueric

(1{3 "ni...). The Ja:ik:'. as 4?t= U- l::Itl .d da`:iC. I"G'fifll"d w7.th.
n1t"f;gE:nAhii'. tha1e5 tv .: 4i23t4\e'e

o Y~p ~?6 .'#, r.^.~~li' #.?3iY turc `<1':3S t:S 17. S~ l-rS'd at 70 c'C R}?
14 .3(? r . The 4.`a r t 1'1t d w; J v,}1;S # i3
~b\e .eiZ~iG.~ v CLi.~~f.'~b !.ttF:~ :rf.f'..a~~.{~ ii~.CL~~F=~.i:~l was
'~i~1::s~~l~1~L~~F. :~1 C~~F._``l ,_ ~`5 7~ F ,):-~F~~iL.?

"'.z
. . . ; õ ..`~'"ili;F~ #\..~~
~:'+#. ~.+2 ~?i ~ l.::f., i". L:C`, ftJ i L3ltr.~ ~ ~ ` 3~ ii~.: :i'~I~, ~~'.
~'v 4~ L.i.~~. .F t a. `F.~.\. `;:..~3 `Ea ry `+'c3~:=Ea.aa..
,. .< .~i~= .v~a ~ .:i`s. solid t.,.i,

filtx.A:tt.#. T;te p.E'i?t7ui:t wa.. obÃai.3.ie,d as a whÃtf.' powder at 36-
5fF/i, yÃ6d.


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Na.:iopa.,: dF: l: s :3 G=r'.< prop ared by first d.t~sol`.'ing the pf?` i
n.,x;:, ('53.; A?-tg) :n i 1a-:C;.:

~.l .5: 3.7.{L) a1.2d dissolving sodiLary( d\1dl+c1l s(.alCaCe (50 nY,~,;,)
ii).i1lF~..~~t\.Ã.wzF~.Eid water (1() J.iÃ.~').

AltC.Ã"?`;.zit.=vZly, :~%aopi3..t..clb`:t w4ae prepared b' dIssC)a-vÃ1': j
:he pt Z''ilea (50 nng) and

pad:wxL, (0.: n-,~g) it: CYHI(.1. = ~~ .t? ~.r~_:~ ~~~ad rAissol~vii-iw;
;,,odiu:".n d;&.=S`~. sulfate (50 a.z~;:;b :a?
d6w2 .I ed water (110 I,1L.). ri'i#:: organic 4i3'~utPon was t~<,'?e#; <3ddc,
to the t2qFLo>~s 'szr,wfbcti:.Bne,
4L?l.WE1:>tl and ffi.s I":i3:iAwav 43'ta.a S'i;l:iwziied at 30 W of power
f[fi 5 Ã:llwu`?os w produce `:'l1c
+::.a~i.Ãr~'io:t5.. The Ã"3Ã.:Y~uÃ4 w-a.5 stirred wl31le opm to tt1c
ab31ouj?h'.3v overnight to eva~p{?A.3le
Hh5,,, '.:3.>;e"^'s Dialysis a il2"'-v'~Ã''iar.~ ~~' L't'~if.l i' Ji-
kS.i'1r~ ri 3.> ~lf>%:.~~i.> . t ~e r ~~i'i.: ,=,.
using ~ a ~:~ _ ~:"A~ ~.=~....i. ffw`sb>
Eaw ti? E.>3:.oi='. . Xce:?4 :Si:1.F"ffiL:Ulli:t; ''`+ian4"ip37#.acf.e.s,
dl2epaI"d Ll:i2ng t32s ` ux.o. rl\.: iat? 1t+;a~
swe 1 afi. pl, ., <

l~~ S~ ~ ~'%3~3 ! 3t5'1I ?f ~~t~SE,~~1~d'o:' x~~.t~t1~ L<~I~7 ~~c1~tZ GFs
e F 3r~~~ :~ ~~rat',s
Eacas?

aw

i]3~t lac3:t 4,y : i:i~I~~43~'i3 ;Et3T1~ }~Tlr4l': t~c3Fi~:~$ M '~w:'~'4
used for
Po t.`'(h~4Z~rZ?~.~=' ~{l}~-:b',i?? A;

:ht'' de;.ivL of p6...nitirexed. The f. bne<?iion tet;.hlliqI1o4 used to
create z.hi

i#tiJt;t:o' i? .13 {?ln. $:.. wziti;s fi:iz%ulSiC?n, *:i;4"ll'Ã1iquC'. I`Ma. U
of 20.80 j:3;: >Z { l~r`i~ ~3;~:

S ~' ~ ~.~`a~ C 4 ~~~~.+. z?: ~..<~~'~ ~::~s~3.~:~~.Ã~ ~.-
~::zt~~'~?]~~~.=~~~~~.~ c~is~c?l.`ed in -~ md_ d.cti;orÃ)meÃs;an:

Aldrzi>1"i. SÃ. LoudsY MOi using a ;v~ilextng deviac. A>.er th~po.yn::e: was
.i?mp1e"o;?y
d.Ã.s,oi :?cd" 50 :ing of pt'Ã?zctA'cxod pxs~viZ?7.~ly s7ltIbilà z':?=d ]i,
0r91% ~`~t'~'aK.. .4::;~ .aude: <1F-fd
K
.t~.llÃtVi::? I.Fi ttte f::1bi$ci3t.Ã.f332 C?foi332t2`oi' pi',?l"V~a~~~-dxoxy
glvreb,'.'>'.5F ci3.:'bi' nc.#:tecf3-<s..
C=F1pi<?iaGrY}314,'.) b,~~:.1d.' o31l'`d 0.9r'C I-N:iCI wi14 ai~dQst, Th:~
solution Was 2?l,,ic:rd ],t 1'.~ afx3 of 5%
poly`'viF:'y. alcohol :[?ÃfiaC.tua (f'i~ihea) and voaie-,F;:d 16i I
S.Fn.nl'a~~`i~'.?(ot so:;.iL=cif.C='.:.i uwl,,ga

p?F:b>vbil? 3w"Ãi:=aÃot') and sti;3ed The f:"liFw.i'opK3iicle.s v-c~t`o
ct?flQcÃid and. -w<zsE'?N`i>
Ãrll~:,:~ ~im~.s in 50 n1t ,Ã di.q:lled:`de,z?Di~ed water, Following thie
,TiiF::.zopw.Fx~.,~le5
,. . , .
L',Grt: ;.J`i3~.3~2?1~.Ã:fed ifP'4`.`.o1..+.' i>E'.1G[=! :wwStt:3iE:i~s, al -
"20` C t[.? 3Ã;.S[#:I'o whÃJ s:: bmKit'd o ;.3s;.;LZOiI`e?i.ciL
~_X,_$t~1 3:<? ~ ~ il~?I~L ~~~ Ã L3~ ~~t3~ ~~i~'t~~t3.'{~': ~,}tKt=::G`a~?~
Lr=1~~t3 ~_l~iõ L<? :a'L:cf 3n~3~c~i."~t1 i~3
_~`_______,.__. _...... -------------~ .. , __"~...._~ .- __ -_~_-__-_ _ .~
........_ --------=
~artldes 1`rth;..FI.1E3T4"4L1~'~~.._r ag
- - - ----------

;~,.~:~ 5~4:1~;~#'.=?~rL=C):Il. iF~.?~ J-~`i3i~?C??S~~:i' a~'~3d (0.005 g
19.5 Ã1#.'wl)~ p4?i

(1.5 g, -9.6 x3ltrliA., 22 .i`IFi?l % uEt~'bt3naÃÃ.;}.
}~: y~ao`i~.yli"r1t`.~,>.~ ~.~"~..) .'~=a i y ~"~ s~_f ~b~~..t;) ::~. Ã'(
:.. ~
i7 i7.6_ wu; ~~3(Ã~.4~3... ? d}, 0.26 ~~) ~.

96


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159

F ), fE }' aa~sir\ ,~. a;~ C~ ~i,i fl.i k"4 . f pa =~~~.M.:~r 1l. `5
hC~ti.~~`'s. ~1yvht. a D~-`~~7 'ar'i,:~.a i.~tCt 2 i ` ; ~~ >L~~ };ii,~:S i~v
"~ .:.. -..._ s4~i ~~i i'+.,. ` ~=~ ~i:~ ~,~.:.fC.=~'i't'.
Mf.._ f

+:.1t3:pib:Ea1t:.d (q!1?nifti3ti`v`` yi;ld): The t.,`:i'3:si~ae product
'6xdc2s -;'ed,b4i;`,..:i:d 1I"# ~~~LIM, pun~~~+.C:te
E1swa, ~y~fz ~ t 1'1 ~ a"} n?d t r t3 T1 iAa~?~f'i1~7}~ ~ }: i1:3i~ f
flIE3xIf'F` :1.. =v'l~"IE~~ ~,::)f:'Ioi=, f?5E.~i ~a a~ ~:
' x v:+~~~) 1f;-
~.t:~ S~ x:

o-.o9L 48 how"; tt~? L"ns:b:o, all residual unbound Za3ro w4:s, Ã't:alos'C-d,
C.Z_:ma:i33 i?C`rllnd i:op{+SL'IrWI'.~-~w-fi9::lL"'4 wU"`T'e prLpairt'i.t by
an
:.z apoÃ.atlt?an :':ac~~aod. Br~~ fil} a l ;~~ gof copo`y>n..:waa dts..ohcd
1.1'1112,0 inl.,

The S'[Ziutxt)n Wi:s', pourC:d into amil:du':`Ciof 200-m.. deionized water
0,5;C +E>'v SDS. ``~~1~.'. unui;iiZ'/n was stirred tC?I 5 minutes bE ;oro
being

~
yL~,.lioGft~ ~~ s ~:;3> 30 ;~1#~~i:~~:C;S, vkt7.~. z~~.Pi<.~.i.~" dialyzed
a~3r 3.~?a~,.if?~.ixTi3.i=~" ~4x. , ;;~.f3Lti'Cit~~ ~.:~y ' ? ~ ~ `~ tÃ.
remove tile SDS,

111'.' :3i3.nt5pi1lfic.t?= ko:.k 4i?i.`ai7iei (5 7Ilcg+_i7? l.) was
d7laES:xa to a fini3l ..Z?.`. i'=L;'3'tt, i3.tIf.~#F l3f'
0.0 1 i'i?;y z, with :~C'=lsii7. ;31'~~= I?t<=Ci ~iYl'a (Di.llbeccta s
Modified t aa?e*v M.'d1vi?l), A549
hllman hw ng cuE,.,I.'<':'~.?~l.a cells (.,Ã"$C'i`xi? TY1..~x CultÃar
~=~Z~~i ~~.C?T~._: ~t~c~ i.~~, ~, VA ) Lr .m4;
pif3 i:'..d Z3i3w a 96 v4f:,R piaf:`a. . .tfi i.3. dC`.T141t5` of 5,000
Ã;Gfl.:i.64 `,'"'.il and Fnt~.,.'.ub<.3:4ud t?'t`:=31.Iwx?E, or

until ~ = Z ~# 3f '~:=i>k~~l yu~.~<a acl." (
~~ ~ i~~~~i,:# i5:~?(..#.~ .~+ . i': ~~~~.. ~.=~25: a r ~ib:~~iuJ.~~ from
~."o:F:'wLl.." vf a1 i.4:~.i3.. i=~'::dG....6 :'L:pls. .a'+

w1d=': 1003.#l_ of 0:01 TI`at' ;l"z.~,. IlaalopanIt:.'le 5oliit#t3n auii, thv
colls w+'.f;` stibset.,.E..zafl}'

iÃ.t l.l'e`?c#.~~.:~ ~1'F~i? ~.~i~ ~?LI?~it.~:~:~ ~C?i= A~ ~fti:.i~"S> f~t~a~:
~1ci11f3A`3~;~1~'i~.:u :~~iF~E~.~.t3`i~.,l~.'~r`i:'- .,.::i dw3::lSr3'wf;:,
y 4
:~~;~. L.=L?~a ~bi~:i.'~ '~~,,~~~=t'~. i~1:'`C f~ i;~~~sC"~:.: s2E~.:i
~~~t~f.~a ~..s:'>. ~a~~~ ~i3~ t:~: eI'C::i'4: 3 a,~~'(.;
lf).:A1(4'4hf3te: , via a FII,"4 alil4'a..

"t
?t~
~~
>'xaIa:pl*, 22: Ff?s3idl' 1t 'm E1~ N>iV(nt aÃi4 4id Lt~a~l3~it;~ S ~? ~ y
7?~~t34~{3 N<#no25f3I .1S l4~

nac à umo~? :'. erL' p3e~.'~<~~od by 6tÃ'3 emulSIoI'?=`si?l4 eÃlt:
ev.spE3raf?y>F. ;IZf,ffi,?t;,
fir1+.'tl'r p?i y(titi;wic acid was dissolved in 2() 11=11,

25 dissolved 1Ã.:: lm=0>?1l~ ~~idalE?!'oEnothat~c containing ePtl1o: I or 10
wt % i.`?aa.'l.ttExwl pw.i w6ght
tff pC?iyJ33S n Th`~'. ht)lutiC?#? S3 His poured iliti:3 a mt?'itL1TC'. of 200
1na., deionized wavr
i,.txat<tIT:1lig ;v.+`6 SDS. Ti1C?c-a:1ul3ioiI1'S~yas 1,0""5 m.+.nuti-".`s
bu:~3Y`4 "l.o.iTz#.?.
. ~~,~ nninutes, and xina.lly dialyzed for apprs?xun ..:,
~,f}i ; 3(# W ~~)
S.

97


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Nanoparticle ESj2itilF.illlg In Az #` B-Ll~ Not Nt..Ea ?" d CY+}#

:; ~~.r? , ,,,,..:,<=

.A S 'tl..n of ~.. ~. #~ ;at43t3z#~.Zi ~. r ~Ãil~;; C from i#l~>.:~... ¾;~ y
##? ~:?~. vf' '.} u;~~ v ~i.'Z
.~ ~c::#-~:3. a..>~i.:##3'~~7~~ ~~5 t.~. v ~#` t# 4,
.
oa ~.. 37 pC. TIw ~.~1umCltt'i' of the pa;tiz:lt,s ~~ <1w .hL'.:l I-
Ã:t.z'sÃ:"s'C'.'d a"

:, regular i:i:-nc iIA ,t.rval:i .:,yni? dvt#i,,a3'ili; 11,0pt
:it:'afti':'FIn:; (DLS), showing ht?w the pa.,A.#.dos
ncr4~<>c":-~~~ d .11 ' S q} za5 ~+a~1 J.z> 373 to ' ?+r v't each + : `. 3 {~~
~'tJ ~~~ 5~= ,a'}~ ~F ~ 4 !. Li j kt Sr~~~'r y
y.: ~~ L. ! ~i..= {.~ ljv? ~S{4...=, D.,~~~~L'~~~Z::~I.L \=' a ii~.F.' 4 ~
r`Svd.t. s

rt.=
ro 5 5"L'. 1Ct3T Ai4 b,t'~..i;.~~;~ Particle 4L4i:llta. S^g x ; '~'Ã1~":t,. I
~~~+ v 1i#ii Ir La:{~~:1 't *1~:~'~.=C', to near
. ~s iS ~ 'sc~,.~a C~~.~ic:~. ~

I tt#';?.?Ã, arYara:.=;t.#' ?-vas i?~'~se? i'+'d ~sctr Fi r 9'3. 1.n
addalzz?.3., t:a3e rci:'<#:~e of fic,c.2,4:iF-
1#~~?[ 1'<<cl4 L; bzC:t'vcd #zSii?.- UV 'Vi,, 5pectro4co;?L s:t <:
wlvt.;oÃ,gd-f o~
292 also indit'.:Yt##1g iepri2tect:+J+3 of the posv23:('r ti#d4': ~,grcZl.p4
(s,C. Fig. `:.?),

a.iCse :`?at"t.c>.e. are u3:'fi~d for controlled rf;,lca5e. r3pphcciti:3t?s
_.S 1v..;I ;.~s foi-
C ~ : ~ in ~ the ~ o Z > c t;'c~. 4 .,t ~, y of ?i'c
~
~.t.~,p~a~.ax~#~. ~;;3~3~1CaÃ.#i?i.õ~ #:~3 '`~l#~.~~ ~aA~. #1.~;F~.. ~~SL' li~
vC?~~1a~_~. :~#..:~~ li,t..#i~.t;~~?., U;i:s`z;'se
tdii. Siza,'c> Oi"tassue in!O Whsch xbaw~ pol"~ms'rs i?:'L. ttiji.L=ti:d.

F"x1mA 4, Nz3no-mirt1ClL ilnd SLv-dil1 J el`i)mA SLFfx` 4mYo~;
r
/ t n

......:, ~,+~
~~ t+
.?!/~r,=%\~

'2 ro ~si, .t} this ..=f?i:~~lC?$oa?E3 pv +3 v- vc S ~ described i .cv ~
e a~t~ 4~5~?~i:3 .~x4,~ 1:'e`t. 11L'S.~ ~.3..~ as s':~s~?=>,~ by .~tc.~~: 4<.
s. .<a. si: is
f;~..~lt3+.;k et tX:,; .ioumal of the CheT:1Tt;tia ~'i#f Fdy. 4433-4 ~ 19:96
3 3.
20, Slui:ol- uran SG ( I .<''XI) g. 3.46 mmcl' and

CN.2Ahyd)`#t...W (12 Y.V.tAv, 1.2 gqC`.2 }3.2õi1ioSY were dissolved til
Z?;riil.ikne(5 ZiS.) L.a.wl.. ww\..~\~W~i. ~:..`.
98


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
S_ .~I' 15 ra+3l'zrs. Then iv;l;o. (K<S M) k=vc,s 2Tld#:d, and Jki#a#`3 :aa.
65 (-,' ~' .I.`: :..+::)iltitl?w-:a

:>E?I :aai:?thLr .,'J .C?l3zs :aÃ'li", tl?oS1 at ':'L`.'td3m ie1nporrata.e3'e
i?1Cm#.ga'tt. 3hi mixture :'i 3s extF'.i]i_wd
with he:S.akf.cs i 7 .3!.L X 3,1 .,.d the combined hi'Ya:le:>
'w..>..#'c..ti.'ts vL eI'o tz?e#] -washE'd I M."
MO.. i: (15 ??1L X 33) iLI?Y.Ã. dic1E5nÃ:::4=d water (15 I31L), xbfl(ti,~iml
by d3"?,A#1N tFi'{ Y~'hc

Si?li'C:lÃt :vc3 < ionl3v+ d is$Ã?,: 1`a?ti#..~' ' e=b'%lp9:3?"at1'ri#av and
tbt_= Ãt.`.aT:ai1Tn a?;Y `~.'13`I'#.pf:}u:`1d was dried
#?#:dz:3 i"#ig-1? v< ct3aa.i#?. Fhe product was E?.:sta#.ned as :~ c4L.u oil
:a.Ã. ,'^r, } a 4s

N.?>nibptl3:xS:ics z%,'e-i`.'. Ã>?3'aF?3#'Ld fir<4m d1s.`.' resul'Ã..ÃI'3g
p,"?dt#.C=t by Ãia#:;ht?:`s dL.`tit.J ,}3c=Ã.l
lioa"eÃz1. As:Ã3aap3e ?..?~ ~~oo nii-ni pci~~~:1dvS was Cifl1:Ãted i31 0. 1 NI
~ICa anf3 mua1.1i ,.;Ã.Ytet.E at 25 'i_',
The :f.?ci#,acÃL:":`,? fll.I% p saft?::=:Eez,3 was thi.=n,.E"i]ea5u:Ãi.d at
1`t g?.:#laT.' t.,Tl..c i't'a:a.,;.'v:a.lS {.SÃ:I.i.~ dyndmzc

l~`x=?t ``+~'<3t.~.'.#'a~. c~ t.~Y~'{:E.~ iõ ~'+~' 3;xii~~.~.} iY 1 particles
;~~c~.~.i~.~~:tD ~ ~ ~ t >Ã~ i='`" over ' t ~~2l5~i~ (Fig. ~~ ~,.~ .. 'S: ~r
.:~,e~'t'p h.~~'~.e ~G~~~wt.,v .~"... 1"'lg. 12, h.:ow:> .a?m 43t::a PIJ S>f
aboL3.0a the particle size f?a9t3? about 200 I?ta"? Ã:L?

about 1600 ?'.tTi> t?t'a'T flX L:t~;%il'S`v' t'#.{, f&d:3w 24 hs;)urs, whereas
M. pl'I of about 3.0s li`ae
panÃ::=1c size is stc3blL etvcr the si$II.~. ##1't?:L`: pcIEC?&

E5i ~?i:i?,i?~ >~`~:. ~ ~ C2~~iÃ4<~~.~C?~a Ct~ s.7:Ãa?~r~L i.~Z=i.# i~.R
Ã.~o~i~1
--....... = _________ _~_____~~.~. ........~

wi:l'#:'. 4:.'t:+r: t?I?t#3 glass by dt.p##41;.1ng a pL7lSttei'#
:iola.ÃÃ.at??> ct3;t7.a3r7si.'d (`f
tat? 1E:d;vW .#A osrpi.?ly?'?#C..a" #i'.i5.:l.?.d.ll?g baÃi. #a[?t hin3tZ:d
e:t) p33l,r~(stea-ri:<i aC`.d ~=i~Ã ~?~?f a~E ~=i? ,s
t`=apÃ"}?jeiLtsyrw). dissolved i37. E`s.ti':3hytaaFi?fI:1:a`::i.:?. or
tC=3lÃ..i,,.7.a;.'=, wMn"ii: ta
Ã:.3ÃL;C3yy3 ilip'<. ?.?i:= sobvcut was removed by 5la?w i'.','~:poza.tii.$32
overnight i3?:.` dtti ri placed
under #=LdooW :`,#'(;ss1. rc for 24 hours.

"'Un niaÃion of ~1Iti 1av.;s'ed Pa, F _#~;

}y}fyai:iicc?rit_'. ;:a#....d ucÃI'~ f}:lik~<` fa~c ~ >3~?t~?~ifCaCp~at'~
~I~iT?l~ Z~ Le'ci #.d;'2c:"ixl b[:"f-~,3"'r,.+=..`in
,a%Ãd3 A po(5(lÃsG:fii.'-i>t?-glt aol1i

solution w a., Cipi?s1t~-'"I :3iltl; gl<#.44 using a `.iT.aerC?Sbl'Ãtl {i. Io
fZ`Ifll sfihn, A pt?l5tt',b:I4=
q ~ si,'~l:Ã 3 j lt7 ' ' ~~*~..rt.;, r~ t~:~ ~-,..:;3.3#aix~.w L.tz
=^i:i3~1~F~s`~~.~C:Ã1f:,'i.~:Ã~,%z~~l.~E.33'Ãi.#~"#i:ii~~.= ~#E.~ .,.f~i
'txi.~:.,_,.1t.i; ,l.ao
<ÃC.sf3

~`ri;:~~?l,.c:as~:ÃE3) film FÃ.Si~ÃiF? a Ãz?1S:=ri3`s5~=a'ta t>G~ to
~:EyI'I]~ a `~.~.z;Ã?i.: ,s.~=~?i", i3
, r k.

p;?I t'
?:3t?l`r`(s`LC.,aazC: i3i.a41 i ei:t?~~~~tÃ.i=1~~~4r,^r;-S=i:~7I~?~Ã:li ~t?f3~
+, fihm a.:s#:li.? a .I?.LrosL if`g:: $t. .:U.E-I:i? -all11:E.E, =
lfi{`m

99


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Em3m pai 2 _DevE? :C)n of Pt}l`rm:1 FYl#i4 on a ti=2iF f t <'

F>ed~`"ik~~

,~e~-i~:a~-:~:. ~~~?a,. `l_'.~:.~t~,r . crr tit~~~~.~;.t.~i by
~.~:~~~ui~tÃ:~; ~Ã::~~~a~>~~ac,.~ I .~.~{}Tz a:.;~~;~11:..sici :~~ ~~a~
:'.z~:~i~'x1~-~.'<3l S:i)p:l~`F~'l%',E 1TES,'3~?~ but not i.itl:k#ted to
"}.33l5ÃsLC;iL?`iv :i. 1d Uc11:bE?n,x:E.e ~co ~>

<.::3p`>olii4:,t(`P~S'=:#, dissolved in d3chl"Ã}rw`E"s[~than`s'.,
tetT'c`=Il"lydr4.3i.uIi:i3i or $i 6F:~I1`.:`=Y. usÃng a
::ynagc, Ihe Zb<.E:3= :I'eI11oS'i'.'.d ar Slow Lvc:poii:tzE?n 83vC:1n5ghi and
f.h;:f3 plcicQG',
'.~ndei t'e<F~.~L k:%~ ~~'i e"es-~.C: di.):x ~N hl+urs,

~att~ ~EL 7i ai o pi^kr"ht_>on 13if# P33I41`na F#it;l`>
::.. ~ - .....:.::._a-_ . _. _ . .. , w ______,.~,~ ........ .........
.....,._____.........~ ,.... ...
:~ iag, loxided polyfla4ric, ~~~~~~~~~ ~~~~~~~e. cast or ,;Ira4e<l.>ziic#
gla55 by dozo4Ãiing a.
yry loy~. r< , ~va k' 'ri-1<~n 1l'~=(x
I .~i3~~.r of ~ 1~[:3'~.~-.c3 i(: :lF.A i:[!~`~?1.1:i1Li'. C.i.= Y, z _tp3-
#~C~~ 1 ~~a. ,~ ~_ .7. T'r G::3~ la ~ and
us! õg a iYiicl'o` vniTage or c3i:;t'osCll dei ive, T'1~= sÃ;#h e:z.,. :L =;:s
E'%.,T,os'ed by slow 1~.vs~pors3fion overnight aFtd Ghei3 pl:~~.~,~.`J,
ti.ideE ?'<;ilticed pressure fo,. 24

h$:3 -ors.
~151

E maiiv i 29 12Cs3M3~~`ÃtsTl ant` Patti.`n3fi> L ()flvdn3x ca Iotb. L a'i IF`
~ Pov'EnL F1hns
a3t.Il ,~ lfi.~S~ ~ "` ~, p`y : ~'l~.n'; i'~~.I'c gj#~sS ~>.. ~ :3.~sl~~k~ i:l
.{v.; .~.= ~:6.i ~Y~E.e :i~~'l+a . . .

?:t3 i'rop#:'a1lia or 1r.iL"r 1sy...iie:;it by dt.pi?4iÃi#lg a p()lyme?.'
tiORIl-is?#. of PolL(4t:.c.ifi.: acid
t':a .;bi3I1=:ite ci;..c-C(`tAsro Iad.n;.) }?rtchlC3romethcÃnc..1nd i.? :>

coi,Eroli,,.d -n:a:eu>!.'r to t`.I'm '"~+a.tto;ilS suF:<l3 as Stiip`ws :_ITW
ta#4s. The solvent Y` w~, rt`fzlt.Seii by
s-lS.;i' QvapoI<::`t1.1 i>:vG.Yn?gN c'si7d #1he.~ ~~act-d iittd['i
.i"sa:ducQ: pFes:~uIL` ti,#Ã`24 hcDt;.t';. 113.14
1-u,::`tl3#,?z3 i a 3:.#.k,y be L;Sod w>fl1 T]?mn:= than E?t-IC P(`.lyn1a
s1~z.?~"':3ltaawi3iI`;sl}%.

Exwnpl1 30'. Rilsr?4c 43f 0?-I-IyLt~xaa3'it#thtidnfri 1T3

_ r 4 = r~':~iS:::":~t?. ~r..
A~ ~`,S;~<3 paZ~~3~l1L. ,;#.I.3-~34 ~6 ~',.e Q<.s:: onto glass a'kv i~~.
7C#`~.1~i1~r.t. <` ~'#tzlE3'.T~.
i:{)RxA7T18W f?f a3<,33y`c'r¾'#:l.~I acE[;3ie) (5 f?Ia',hloro5.31effi.-.Ike
(50 aL)s a72d 10--

i3` (100, t-`g)9 usiYig a I 3icrotiv=~ungt`:=. The so:LC%n_ was :'
.Tn(?t.''.d by ^^.alFL'`%
s~.' z3p.?::.et#:.sn :?voI' liight and flaoa] plaL.~=d :radi'i r4dt3i'.ed
pb'c.Sslirf' l-z?r '24 h#3a,s. An initial
bL2#'si was :`. i''ti.' fli¾., ..,"e 1: two Ãac34s, .i'c<C:.aaiIlg <3t a
.'<3.tt of aK)o[I.i 5 p`;.'da`:'.

f3r\.g'v.io).aded poi\=rSni.2` films wek-e6(}so Ci<sC }ri.ff:o gY...a.`.s by
dilpA}4`tin\ \; p:#3`imeA;
~
Si.?l::udi;F: E.o>;-x> $a.~oc, of ,.`t}:y,(wtE.lnic CFa ~?<?.i¾i.i 4c, ~
f;'sF.~~<3~ ~ÃC? 3'~ (.5 mg)

l. 0 :,5


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
(50 i.fL). 3d paGI 1,.::Lxe:`z (100 .#g); using a mtcroti).i.i?ga.?: fPhe
solvent was i41:a#c~Q.i, by
slow i: i aPife 23.~.~;)Tl "7 .~r n`=?h,ft and Ik?Q3i placed tiÃil.t'Ã
ro;Fur`ed prL:s`,"rL.u LSor 24 .i.~O....:>. i`Ew: resulting ,.7lx7iS 5,3:,ri:
hoi"i]iitses?ot#:. ~.d opaqljc,'+vÃtb :yi:Z.?d adh.`: cÃ'?G.a`.~ to dhe
g..'zl~~ su.?,,,`.Ã"i3.3o.

The fii.ti?s ri:ha5.`d rwxi?l over ~

of I i r o.348 l[ax fl Ã3m.
vI4tG`k?"ic <Ã i{F

Dt..i;?~Ãi;aded pi~lyEY3or fibus were cast onto w?lc{sw by depositing a p:tlI'
si}lut1011
r 1 P A~~~.> 4~, \ { ...
~:o~x~~?r;so~.? ~.f'~,~~<lz~(~tca~~:~. :a~:i~: (5 ,(50
"0 it ), i3:3t~3 (1~~0
~tes) , using <31zl,LT'?SyI.nge. Tb:S si?lL'Cw, 1Y as
:t:i?':<3v(d, by slow o4'`lpora=ttci?2i (a)4'G; night iFÃ:?t'?tiZ.en piaC;<'=d
under redz:wed_ p.c;~s"ii..c fb:-'.w' 4
f~f3urs: A 5lÃgak r.~~~l.i~ ~~~Ã"St was ht::'I~`a over ~~?~'. ?`EI'+~. t~#`~?
CiIZ's IC:~u'sl`:g wt ?Ãi:#tf t?e 1343 3i 3

occurred 43vf.'I:4t least 30 days ciE ., l'.:C `b z 4 cE3Y?`t3.<l::3f- Ec?le
of
.:e. ~9~, ~~I~tt ~^`
15 "t ~ltL~'nnl?`Z g ?
~ . l~f:' ~ ~:? 3 films r~ ,~a tl~~Ã~~c.r i:~i ~>~:. rt, cast if:t ttc. ~ ~,1
uh,1 by da;~c.~ t ~z~; a

`3+1ls.li?t..t. ,. 3>u;,Z?.? comprised of pi3 4(stf;13I'.Ã4 .={It'~~[J?:i1~G
4f3-'cr i c:~:?#i?~cE~ ~s?Ãi~ ~ ~~ '..3:~:~1.
..?..,hlomF.ieffi:;Ãef' ('?i p.L), c?ndpaL,lftiaxt,=l (100 l.E s~. i,$siTÃg
a ? t?lcxoi t E :i3 g?:.`. I'T':e st?.l~'e#':t
W<.,s N.ML+; u'.:d by sltw evaporation (wt:2' t71gh:: w`Ãd th#3i1 placed
under t'eC$ll.ed prÃ,s~,f2rc tf:~r
24 r3~'r"L~FS. a':'is'. 1`11t.);; weI'e, h(}1F'#'3u:2?.i?i15 i?. .3Ca
izpFzq#1e ?s`:'#ii gi?<;d U.f?.iw<:'4=i?.>e ti? fb.;::
20 <;`.iss s:tbsar:Ãt.:=. :The :iAnis t0casid ia:x{.~t ws-cr time.

aJx{~.3~pjl~> ~ Rx;~eaye o 104_Iy'AmNaPtfy 1~ cirl arorA.

?
D.-L1g^lt?a.#.E>C:d poly~.nt.i .:Ã.lkT?s w:I'C, cast Fsl.tt} h~li3ss by
.~e1?E?~i3'~1#.y~ `c~. p 3.:5'?'?A..I JF?l"t:i:1.3:~"~
25 Q[falpni`.,sed of poly(hydroxy -;S'GcrL.'l 4~:.?~>dÃt~~4 Gt~ ,: L.i~} C3~
sE ~~)T~< t (?m# ),

>~a-=?~~>Ã?;d>a3?o (:)0 pL); and IN?j'`dt`t7Ns?a?"1ptE:3t:ho4Ã.1 00 ig),
`ydLi~^ Ã Ãx=~C?4~?'Ãi,;`~=.
. i' ;o,ivei?t 1v<>q removed by slow avg1po?"at.of? over ;?zgj1'C and '> >2i
i.?i:>od 1f: F a #~.',c;L?ct.':d
jptos5`si3'L for '24 ho1rS> AI?.i.dfti3l burst was se.Ie ;3vG;Ã' tbv first
day. Ã`t,.,iowdig at a Ãi.lti= E3~~4
F3bz?i1tl8 l:Ã#.=`ta<Ar', Ct`.,3.#3:'`i.itl.1S T4'Ees,ÃaC' i?Ã;e-l..1#Ted
over 'ekt I :a:ii )?} &yS, bt.?gi 3=lÃ?-<lt a 1:"t.iti:=
to less than I ;.tG.N+c~3t' at aoliF' -%VLLk<i
30 i3Ã 3 #iif day and ~lo~~ ly decreasing

10~~:


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Y R : In Prt= Lt Turaor Cytoxicity wich iFc~ i' :;L L

Pt?`4(StLt3FFt aLTiE GxtFt~3Flaf~t` 4f) # ~ i `F1~xx# ~>i3~t,~~i~ t{2 ~
~i.:EF.I~;~
.. - ----- -
Lewiw Ã. fF~~_ Cucinoinz.~ (LLC) ceEl~ 'were washed wiÃx1 st:::r.fÃ:
ph.i,,q)h..Ftc buEkn-ed
s"~?m4 (aI~'=~~S) szsd tr~j3sinIz's-':f. The cells were tn"1.'C=ki counted
u`.aingi? b,,. C_#W:C;f+ ool.`ef..tt::F" t3nd

Y
3<3 S.4`~'i~?~ ]t t. 1~ `~ j~s<tall plates. ~.'i:,~l i t4 t,~ c;
{li,<'.i`3'ai<s :C ::iF.F{.. Y then
~~ i~C,\3`i` .~.~.., A`. :~~3 .i.'F"!~ S~:#`~s~~~F ::3iL..t
F~3ii?E+~i~a

~.. tn~3~1\ LZ... i:~Gl ~r.~~ ~ t: ~\L ~.:GF}..= ~.~w
treated qYt i it`:l i~- ?, = +}qT= t~3z . ..~4L~n~~.ra.x~-l"~ ~
1:~.F1ti3~."~3'~ .~.t,.,es `r# 1i) ~lik'+ t~]K :,Fa:;:
n `
3?f..iFu:~cl^.``yf.Fin.aed ne3.1oputlt..les (I % Paclffi.aAel) fo: ez ~.t~ e
da SperFod. A r~a3sF.J?vÃ. 4.t}nr:ri.'s''^.
ci`.+nl't1.FnL.d IF134 <.3r the ;,a.l.Fa3e LoI]Sf:=TAFi.kt;.;3n of i'M
pFo\c'.dvZ'a ao# t;.L:#.Fwd 5.:03:`, 1vv-h,~'+l`~.'. a
;34:"gafive i:=o:iia'tsll kwked r' BS, At :hG U<1vipleÃIF,?i. of t,'fF.. assay
:he cells Ly'4."G .,?~=Ã ~?F[~ i~
zv ith 5 "0 ~ :;r o i x x , 1, 11 i . Fo l~~~ ~I u i.~ =I'et:az <-3I iLj m Bro
na ;d e (-N -tIT, S ' g=n zF) d'=~~~I v e ca i n 11 B S

at "', "C .ba3" :3i?l:fr,.>. - l7'L: Fx3i;=d3.a w: 4 then ~sp.F4.atG;d and
1,00 of DMSO was ..{dfaf:d Ã#->
each w:..l.F¾, 11hC =?i,:Ã'L''.<.`'s were then E3i3vedc7f. a s+3'ikal3,~~.~
det='ic5~=. 10F-nÃf?t`s:C.s t...3d Ã`.i4 Fra.'ells
>#..n;~:~d pÃfp.;4y ~.i>~Ã"s'=`~~>~~"?~~IIF~M ~ :Ã~~ the n+.n2?*-:e':]
iwj..v1;_Fblo, :TF t11t; Z%s'ell frili~.:
;?lati:s wi.n. ptui:t`.d wi an ELISA reader 'tJ3-ict scanned at a
w%FvC:rt:=r?lgt}x o1 5. :.t #i#.: .

\
1 J!\ `w.} SY ={ C 1+-\ w~=yÃt: t3]'~~fx3 i:~ia.~ \: to values ~~`;?~3'~ F~.
`i 1';t; ~.i'Ti~+~. ] C2, y~Sar1.:.#~<~ K~ t". ~ t .~ ~z;~ 4~Fi. ~'tii]
..r :'~~3~~,r~=~~,]õ~~.i: ~'~,:1~::~ T~:~11~3[=i''I. .

cvÃua:i:;:3SecFiv was ob:iQõ"v'%a,d L;'?tl3 g17-: t 1TZp#i4! nanoparticles
(a:* a Col-rt i1t whereas
:aFSn.. i. t~.. '~.. J C~ ~ e[y ~ ~ [ ` 1'Y J ¾5~~1 ~~i :~~ Ã~~ ~~C 4 tls?C~
5
t 1r ' 4~ T . . . t= . . . . ..
Exi~~~,,o.4 34 Czf
---- ..a:..- - ---=--__~ _ - _ ~ _, _ _ _ .-__ --------- --------
20 1:101A(lau;i?v zlffil2Ãi Ly sÃoa1F'Ic) t~l"~:4rti3l fl#~Ff ~F E~~~ "tc#-

y Y
:0,3':
~s~~ah...i~,i.Fi~~'.d ~~i7l~~'f`:l[:F- .i.ea7,i ~4'+~::F'3~.. cast onto
\,:.`.~~1s+ by ~ e~..t-:':~a~1 }~ ~.~`~?`~.'F`'31.T :]?~.+i.It=

f.omp:'i~'+cil of pst Y E.(Ic3 #:r:c' l.fy-#7sti . 2)iFlII]Ftii". or
:~te=<7:;F1)

(50 LF ~ .~= and ('100 t 4;t, : s; n43 c.i

Thw +?~Jb{ A~~ was rem'c3vcd ~.~y'CSlow ev<3PC`>Ic3110# O:''i`,t 11g1-a and
Ã:^t..ii placed
25 1F1..de1 :<.duceL. 3:'c4_.1Fre ;<);i' 24 h{1u3":'i. An ]IkFtI:'r1.l
b`iFr.:i: was soC n. over tliF:, first di3v.;

1uC over at least 49
day-,, beginniFs.g al i.~nilie of 1"3 gh/day ud slowly S..tecroasing to
aL=....L. :3~'++an I ug1RLa'vr tFE.
xc3cF.r -w..cks :: Lc l'.Ãg. 6). F:IG. 6 sÃiows tbF.t increasing t1he
h;'dr<~pbiob3; ;Ãy of the po:yui:v.r

C~~,t.3~~3:~G release 157om Ãhi' petlyn.lt a's. Intl:i.FT1ed#.atc .F'elCilqc
lTrofle:. .4: fluoS4.vhi7wn. bC:
30 obtained by F:32>.F#:g or bli el dI1.gihe a olZd~.'1L=:'s:
3

1021.


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
à ?aat # iyzÃ.Iol ( t~ a~1t321i3$~ 4i? .itoiig) i.111P4rÃLudi3.Em S:r# 4
D#u.Fa;-Ii>a4MC,:d po.ymS.:r i1311:1, ivi::rL''. C.'cl:st ,3F.tC;pL.'.?
#c:3:#'tiiu#ii by dr.,3o5,.t n`.~~, a PL#[ v#I?i::`
sC)Ei#t3C3?F C?T3`FÃ?~~tn~ of pt?ly(4t+:.i.}:l'Fc i3i:id

and ~ ., . s - . . v =,
.ichli3'Ã'o#F?i..tb:3#i~-r, i'S? ~d.), i3f:Ls (100 ix~. ~ ~ a t t t.
L.%3a17 7~[.~~r:L~.lz? ;.F,_, L# JF;.::; .i 1as1~=~' 35~ #.,..t.

x The si?rv,=a was ''LF~~i.i~~~~=Ã3 by slow e Lii~?C?r;31~i?Ã~ overnight and
Ci~s di ~3~ Ft=ti=C~ iF7 dea J~tai ~'Cr
p "i'=ssun, w ' ~~.<`~- >3lii:#:F'~. t~3:? ._iiit?i l ~ri.ftF'st was seen over
illa`.'. ~'#r~.. day, .FL+;t3~~ ~~ `~TF 'y; ' ~ t~'. of
_ 2~. ,.~i'~ a i i{.

about 10' #r.4 i biy. CE3n3.F. #m# ru.ie<34 <?i G ili`.F'i d over at lec1,-
,?. 40 days, be~,aF.et?F~a4: lk :~ rate
of 3 :.Ie+i Fv :ihn'* 3y C'F':'=vai.:a~.~'`+inÃ.? to less than I F.itx`l~e.F~,
a.t .fÃ?L1Ã''~~j~i.=~'is (s~Ã. F'ik.: 7),
~.
~ r~
,u

Ex:i.-pp1e?6. Ce1l CF~lture and Ct~1 Assays

M>,.;ar.t?Ã;lc`a ~'~I 6 Ca?lt1 6 (hC:xTI#.1Fi lEF,.:; i,:?#'i=>.?'is3rn'c#):
A549 ~ ~#F#a ~F7 lung
c<#.Fti:zT.iÃ?: c#)ti -rnd LLC (#?luf'.,.1C L5'.~v#s Lung Carcinoma)
Z~~C;"'S., d..+.;1:bi.~#.tt=:d #.~ 'C. 5,.:~~~???
w .:}F MEM ÃwA,h 10`. ra .eÃt~l bovi.itn soraFm (FBS) ;s:id M;) essential
anitÃ>;:3 aõid-"i. - <

Pn~.~iicz. Ws.s ~:,;1ca,t`. ;gi:" L?I.,a,.2" Z'.'L'.F'r :l-ti eC. ?~ayi,
WhC.:n '#FoE. Lah1.RF'C;.d, all cell ?IS:`seb x ..:e#'s... stzb:l'i:C> 3rf
~~~~IN-1 I {Ãi efinti. i:?okia~a al. -"'O'tY s WiÃb 501,1r. FB& 401% JUIM 1
aFAd 1:0% :-'alneth.,y} . u13bxiel~

(D~~SO)>F,. i . . 1 .. . i x and = x ~ aiF ~Y' ~ Z, \ Y~ t
. .: t ~. lines were ~iF~~~siz~,Xed fIUI~ A~ cm ~~cFt( ~ i;a.~: ~~:~.ÃaC=~a
F.xli.t~ ~ : ;~'~~ ~?;<~t'S
i:#.nd ci?Ã'At,..C.wF..fii.aF~iC;I` of 30(10 C:elN per T=3'C'll, All cell
II#.aE.s we.t'i% c#.2lti.1.Fa:(3 10#.' z:i Yt3oi."#od of at
least three days .?ez#L?. e b6t?g feStL=d in cell '`~~~kE?l1fi:F"eat#on
a:ss:iys-

2kJ Tumor (. ei,iw w'L."ro washed with, <\, ti%? 4 i Ã~ ph},`7`p-h.Z r. `'-
bal-TGiC'd.. ti. i # so(TIa': kY) and
~'4Z ,)43n:z+ E~:.. TaFt. cells wC::F'C~ tbuÃ3 C:<?l.#.FIted I.::ilTI~' .F
Coulter C.'<#LIF.t:<':=#' i~,.#d p~':iEtE:Ci ?,.00+1

"1 ?:.` `?r~ 5si ~t~.::^. ~ (;s~lls ti~~~:. ~: 5~.r',~ll ;.t'~~:'~:,~ ~?~tGF'1
I~c ;:.~a.t ~ ,.Ã.i.s_z~ ~_~ ~~ _ 4~'.#
C:t,~.;~` ik's... ~ ~'. .. _. i'l
+

pi!z"=fitÃ?x. , i::7nlIL) or pfai;l?la:1'l loaded azFerÃ.p,.inFC.xC<:: the
a>c,'.)::`i &Ey. A
posr9.`.vÃ. cLsx33-.t.'o. %':f;nt23aIFi,'Ca 1.0% F!,-',S or til`.'~ sz3.I3"lf'
concentration of F.B:"i t).,o}dCd fo>
i.et .#.'.:~ Ck.is, '>~ ifflÃ: a ?FC".'atiSc i:o#tty`C)t lacked Fi}SS. At
4=t.te~Vfli:fioF2 of ..ee c1~say, the
cells wz<-re.,M:;ubG.t:ed wi}ll 50 41 of 1 x Thiazolv( B1ix Tdr;i.f...Fus?'i
BF:;Ã,i-ldc (MTT.

S a 'ii7.<a) d?.,ti.3is'E:d FP, PB :r :Ft 3 7~. .+;#i two ht?1Frs. ~~'ht:
mccl?tl Xi=i{S ~h +.F, iaSp F`"E.F,wd a...id 100

kt ~ of DNISO wiis ad:dod to i.zxs:;b Y{ N~~. The pra[e. ~&=QF=c thicn. placed
on dt~V:CC 1-<3r
tt? 711.1,11utes amt the WcHs Ã:;~#rneÃ~ purple, cc?rrew~.~~.~ridxng witti
fria: aur.~be.,;; 3t ,iabl.e

b.iiewv#~l The plates wdirC: placed on a:?, :_:F..;ISA Tec#-dc.. `ii..
LrS.:ui`.3ed a. a

:i. wvi C F1 g h of 570 Iazn. J 1te absi7ti;c' V:.3.eC.iG:F were
"toF#elalFr.i..d to a lk:.2ii.svw?
103


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Ã.E3#`.ihe? Z?fJ:` .i'#e~'? ccIls. ':l1c dt:3se ikfpC1el1'~c},.~ei at
bi''?'#.cia 50#t3 s.JfeF.;.s are a.th~Es, or i_,D50,
was (ai1c. #lani i~ to be 3C$wCei1 I = Ek Ã;<4 i23I:, : ~
pp~'Li:Y.zCklzif:~=ly 1 ':~,:;~~L~ ~3~.i*:..i.;~Ni:1 i<?c:Zei:=~?

3 . .^s > to "s~l'.~`YIi.= ;~~~. = similar `,i~?al+~::l.uRlot G<r t \
~I?LL.>nt:~~.ffiiÃ":s .,in
4'r~`^, i1~4.Ul.S~i~33~ ;~ e: :;t:l;
~~.~.`=R~~~#.

~

; ' a 15iz tt~ Y^tin - tt?~.< ~=~'~ ~. a R =~.~=Ãry of t.1 ltaS.~ 'C
x?~.~,~:.i.'s zi~ #.IsÃ~
i,~r :7.i~?i .,r..t'E3.~'#.is~l ~~~=<~ . : ~ ~?, ~:~r.~i..;~ a~ were
i.:'i13;; ?
three '>Ã.:tao; ci..x llaes, Le=wÃ'~a" LonS: Carcinoma (LLC),
NlehunGimi1..>,ld {.'a:z+3 (14iFlaili?

C ;Y.C.er) \.Q:3 l1nE.':i We3'e plated a. 3,000 cells/well `ead-kd whe:i7:
ostcabe1Shei3. :Neft..:'S3d .`,?1 iTac-df:tl.
p<ai`_I?taxo3. Sikil`.5..' ,k.Ii1lt#.ni''i:; wC<i`c miafllata?'.t.~iod with
f.p::#.Ã :i.E go`t\ ti3 ;4Lw`z"ti
(`Cr"'.Ãm) wht;na`u t?thwõb WC..1'e scS'illlm, s;aI'vGd. (ÃloI3wg7o}Z Ãt3t.x3
cEa4turLS4. R'i. ,xf`s f.cl".
E31mw3' C:`l ; m-sl.-f<.t.;:iflon, was asSessei1. via MTT cÃ.i7t3i4's.i`i.
Data was X?hoEtt;C3 bv
f`.tix.3.1ilir.ext_ii.?f3 w, 1}}c pt?s.ef?rc: xa*.z,.i.i7ti w3t1Vi;.
Con$'E?l i:ultua`es, as O~'t3 :lÃ0 100?e i~~lubitlod?,
respectively. 15 1 Y1 C) n;~'. m a. reliably l.nhib ,tS gTowd7 of .1c I.M
melanoma, .i#?d Ct.#.l :a6 WmE)I'. <:~..`l i.i#i`\'.> 3T.

p.t}lffZ'.Ã'.h`.io;:Ãw~ I.:ll* data wa-, C?btai.i3eis. 1:1s1I`tgmioC~i.i's.`t
eC?f.ta1r3:Ã`g I fs':~t. i'BS, tposxfivC'.=
CL,c.'i#.ti.a(?.S J.

Ct. , i - `> ~ t c'w.., Ea~' Jikn' ~ i .e~:~ic~ of :?.I.k~i:~i "r.~#.C3?1
were +~ to ;ii t¾,4' the i~ a
Ãu~ 1-: on tumor ~ow*h. J. Ã,Ãmor cells were pl.itc.~Iat. 3000 ,,.o11s;';i e>.
mad l?osiÃi, ~~
aTlÃci ztpa

.C.'Y.0- i w.. ;`'ze i P= af '~ r a > r+ i used [T'iti A~, J j ~~t.=..
I t>,;4ti,z ii=~ ~~.,?~z.:l~~ i3{?~~ cultures ~~'~.ii ai~<k ~.l >. 1 z~ z:'~Ej
i~
gww th .iÃhI;?il{<,n. F: sg)ec$13'~ ly z: wus found tll:a~ the addlFit?I7 ol
zix~~tC#tii~ `c t.~Yf#?}4'
results .i.`a i#.;.?:l>ivÃt?z: equal to PLiclit:axeS ~~~.~IaGeÃ"Et?tll1oÃ;s 0

~~L ~'>>s ~~ia i?"'i.,4Gn+,:~= ;5f se.luÃ7~:t ricl1 J11ed1<`x, lT3h.`bb#t1oil
i1f tutnto:" r;#':iswt1i'it':A'' i?.C}r. ~?T=uti4~?'2t

)i=2tli'+,.onit-mS$~1/]V].`-r~~~ ~iZ:~l.l?~?A2}.,{1Ax'4~.~1L1A~~ ~~\? ~.L1.?$,
4\~'S.~\iS.i ?. };!F'i'~vfw~~~.2~:>~ t ~~4=1~ .t.=t]L:~.L+~,3
2`5 d~#:2t

i.i_Iad s`i'.t,,Uh in :a23 effective Tc? Ã;e~:~.Ã~.?.mi. Vine kcnÃ..tics of
:fic tiÃ~?tÃwtuaÃc?r :-e~pmÃ4e ~1 ~:t:~=c: by p3i.:t.it<xm..l ~l<.:Ã:~ded

3?3 cI'i v'u: ..C`.J .Ãi%tx +., ,a4s%i w .R?A' a potential Ini"J. effect" of
dill>_ :iLlek:ofiN a cell
p3.3l1Aeicaldon a,,wsay i:=o#.il,%i'7i?gPaC.l.1tc:x~.~l li}ildcd
msa;=IC?p:3T'tii.les and DN;`^O E:,'iklst.',?l?
3c, I#a.C.id:spe.#tt..l.Fe:s .isÃ:t?.g the `s11el.ai3i?InL..i cell lIt?L:
w.i.. Itx,,~i f<?r fivt consecutive days Ev#~t~:. a

plate ,Ã\ ~o>. < ~ .1 ilJsi:t ~. =Xi~:la ~> ~~ )#. ~Ã~ days } ~~~ 2 ~`
~~a4'lÃtK.x~:l . { ~S.) =i~d,~Ã~'~~.w!
~~. wY?zF ~w~-. ~=~'"~ analysis V'~

104


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
&nd worf: :;d0ed Ã'il 5tri'urn rich modia -a{,d individually on
tziFiatar coIl-; of the smi.?e pl,:Ftc, 'l`~-le rz:stFfts domorlstrate a do-
zt:w dopu~~deni : t~~i~?~~:<3 ~ .=:~t:~:
i1.: ad.F'flilFfs:;:Nik?F.~ of s`cFds:a:Ye b-LÃt little t.fil"fl~FL;i1ei ti?
?:i3h?b4ii'sa; ft?...

vim dose on {s av 2 ~ s, i.iw {.1 3. {.~Ã1~..; .5. l~'f..~.9~~~ ~ ~'` j 3ti
colia.~~~rm thl:{. ;Ft~-~+l1~,[i,5:4l ! '>,i.~~v.rY"r~:{~~l~~o~ ~ ~Ã..-.
.Cle:`
~ iii}ixbià aÃ.unci~~=~ wr.3l;,vÃr3 qu>.ckly Wiih littlc diffcronce .ir.
oi3r:h

1Ãi..i1<3I C;=yipf} =aFÃ'1',. This is ctSÃ1S.sttv11t with u ii13:Ã11L3.i:;:Fe
rL'a#:'.:3se +Ff C~ Llg i? ld 1:W21"s.3`i~'t
bui?'St

3~ 'R '.~ic~.#~+G ~ic~ii3Cl~~ ~.+ p~:ci3~tC+. ~~,tYC1.sl~
....._ ~_ _ __ .....

;3imopii.F~ic,~-5 YvVle cI"C'.a{t'C?ct as ds:'st:.r`sbi:'<:E.eÃ"C'.?Il wI:li
tb?4 add::tÃE?s3 i?:~ Y.?
t?F4Zt% i;3` t .:L;o#'t.4ci.:.lt N+,7n-;inii3.~l QE'll .[Ing c:1.F5cof A"t^+ff-
.: ce.as were \S...L'd:',tÃ.
onto a 96 Z't u:l p.c:te (20t..#00 oi,.[N Fvt:>laf and H3E.LFbaed o~-
(:t`:tight ~.¾~ `7, 'C .3iJi~3 5`1+) c::::bo.ii.
(sioxidv, F`a`o mLd1;i wt3:~ th+.;: 3oÃ'ncnk:d fttT:[]1 rho W<`.HN .F11i? :'t
phiced 'FZ`iF:h c. b'xFs_ti..ad. St:Il,:';;
-ollÃI3o.n u4s?tlaini ÃgflE..(?i"Z:=Sc`1.'33~ niÃnC]p`c3rtÃt:lex at a
:ok7E:i.'~~'2trFft.<2{a of 0 5. 3 oa 5
1i3tJ'{1'a~ ,
IC43-;1tti3ls not S.tÃ`~tai.Ã17nff li's.3l1C7pr3 }1des 13'~C,Ãe also
poI'for13iod. Afti'. at YY 'C

tFÃi d 5% ~.b.3,;?~~~ dioxide ~.~~{~ 0.5j1 , 2, or 4 i~~s:}.F`~^, t~#::~r{
(~v {:{.`; and

the cells wcà :t .L :43'Ei:, weL~~lFffei'i.C3 >~Fl~Ã~~3~:'tkFlia
F.~ia.F;.~y4t:#.~ with 100 #<~.

`~ritaF#. X ..OWI{ in 0:.~.3. M sodfL3nn h 1tzri>l.Ãdo. Mfouhua1Ã1 , thC Qs.l;
;ysc3.e
;'sz.i m~.'~:~ ~c :+t,*,. ~~~ -.,.1FonW,,Fv+~~??4npth 470
x3iit,i'.nnd4Sao3{'Sts;C~i F?Ã.~. 5 18 nI..3 `ai3i>

20 coF~'.i3i,`-.F.{;:P.g it? a standard i:=taI L o g:ivi;. the concentration
t:& I3~{1~:~)3{Ã:E C~:. ahs'
Thc cells iiC3~F w[a ;.F~%F~ c$y:?IS upt.3.k^v over fim~= il%3d.'L'1`";tli
decreased z? m'..1~,~.?=-lrtlc_Fe
i,oncoitr Foot;. .:i the buffm

I-tal.F=o
25 Ceii aiiie (MSrl`O-211 1-1) is fniaub~,k:t>ia f _1" C' with NAR:M
,.
(w.Lt"i 10% f4sa..ba?-v::3c s4roÃ'11 (FBS), I% ossc.t7.t.tal a?nd 3c? :>cI&,
i3_[id. ,%
w.th ',. ~(giutami-n_G (Per-i, Strep), F-3.2 HAM (ixi:h 10'.:n .fiBS a.Fi
P~ I. w~Ã ~, . K s and ~,. :~z
f~ .~,.~:~) and LN,11.:~:~ (~~~It:~ t~~"k3S ;~~~~~. 1% en/St.ep) Ã;ne:al~F
ri~,,pczs:.ve ;~ wiffi,
:~lo~;i~i~ i.b.'1..Eli`;w=s C>.#:3o[; ovC,'.:`yr' .b!=oC' :]'<3ys,
4d,%hc::i1IlC?t cultured, iFil a,N.ls#nF:u~i tr Nn.. :i:oT.~F: i>`Ã
30 R'.t+W: .ÃAE.. fF:?g Ãi.odha at -80, 'C (wi1}? 40% RIFMI aF{d H)t,
daF.w.hyl s.31f}_~xiz:e.

(DMSO)) Col.. 3ir{eta W3:.ro t{ypsa{'{1.: od f1C}na 15 cm plt3te:a and
`'~.`.t'ded FI,ei1 9{`.F 3x<t.~: pl;Ãi.us
105


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
of z000 c6h, per wL.l1.. All cÃ:ll were cu:tn;red t'or a TI>L~nod of at
least lti,Ge &,ys bdfibrk bviag Iest,;>f; in oe1l pr,_ali#eration. aSsavl-".

z
-c ~ zf.i~~L.F'Ii:.3i.t;~t I#i ~`?iFt3 '~'~L `~~~~SE?Ã~~af.3ÃF?Y1 :~F1 I2C5I F
`c.al #i I itilh ~.e'i#~t ~lF ~i.s `~t~`?r`
Ex;:t~~ !~: ~ ~~
;_ .~
0:11, ~v>,.rt~ washed with sterile pht.Ysplhatz:hFiffired Sa~ rio t.PBSt and
t.yps#,Fized:

r11':ic cells were thC.`:Ã: colÃ#i:.C.`l~ ,asiÃlg a ('C.iF:Ftti.Ã'
i;t)IJ33_te#.` :aF3d plated 3,000 L;el;:5 wc-fl #$, 96
> ~, p:ÃF S~Ls. (,;~~ls :Vs.'IE.. ,c = \d ''.3~ i..t~1T .. a ;;Y~~t t13i= =
24f3 ~` ~'Y',~."., i, ? ~ci ~.?4:t3~., ~` =~'
4~:x~:~i~~'`.~'~:~:c.Ãz ~?'i.t3 :4.,4:ted,
6~~~..

con ..E.ti}õ~~(hy#.F'+.rxy #..3ycerol 4i$i~3t3t?s3~~'Ell 2,-
L:Ã#~sEl3~z~~~6s'iswi #F-i#cri3p,1;:ldE:s t3-r VwnIL;;Ãi3xed
:C?a`LF` ik `~EeI3z ~z: ~ ~
~: a , i, dzoxy ,1,lyF:~:,Ã'm?l ~.:~li~.tl~.~`:~ iÃ~ s:-~::?~?tC?~~~~C?,7t~=l
:x?F~;Y'f3~`ci`. ~~~~.i~~i ~a?~' ~I~,:~i iFay:
A po':rtus~ cQ-F3.'#ol #;<(?#:wI1?e:a IFBS iliGhe S3FTF:te 4mFcC
.'#ixai:o.Elof FBS p.i+v1:i:#.d >sji"
r;:l."zitÃ:.d + aw;ls. whiiv a TF+. f' <I.t:vC: [:537-ft3'(3l lacked FBS,
r=i.tilie of ,..$k a.is>iF3.y ti-3e
cells w~~rc IÃ:cWbaÃed with 50 xd of I x ..('h:azoI y: B1ue I ctrzrzo:;ui::F
~'-~rom.i: o

tP?F+:F) d ?S,.o, h'S.d IFz ~I B S at 3:"C Ios";t1x' o b <`,Fli~'s. The
F.T.]...dzC: w ;:ts ili F-ià w:j,cktt:d c3=3d a0 0
al #~A DNI'. +O ~; a1 ,`=,ld{t.W to oc.C=f# w03, I'l1e ni<1lti:.h were thie31
p,.,.,S..f. a ;?Ti .Ã shaking ds.Z 7:-:L'

~ x i#ru;~'. and ~~ ~d >l=: s t.~...~;xe~l ~. . 1le, =ps3t~~ ~iaG to ~tY ~c
tlF,.:,.~ ~. :~3~? ?~ ~..,. ~~"~~.y , ~ i#~li.
'~c'' Ã~a~~ , =+ ~ : F ~>~, ~ :~.:~1 1~t'~. ~#~-F~:. s;

:1? lE#i~.i t.~Ã1i~Ã"ii~ #-~# s~i,:' ~, ~..~z. .~'a.L'. ~7l:i:~S.:~i 3<'e.tÃ.
~:3l:~F ~~.~ f3x-F an ~..~.,.~ St~i 3`5:`i~~t # ~<~iI s~ <~v1F?. ~ i3.~ a
Wavf.'.l''~`.~Ã':g~1-F of 5 .'f? nam. .rh4 absi11`~.~iFnce 4'alF#,cs were
i;:Ã}c*~t,nahzs.,d to values fi:t?#.:; a k1"ls:3wa'#
nc~r~~~s~:~ of ~t: ~~>.?c~~ ce1l~. 1'li~ cioGL of per.~ietrea~~~ at: :ih#c;-F
5~~~; of cells ~<f,~~::~:Ãl1~.~a
LD50, dete'f7Fa'#?'ÃeZ> to bi.' ~.~a1~~'eGt1 0.1-1;0 pgrnl:. A~~3~3
i3'.IÃ;#~{:Ux~ .? ~~.i#.3 <x ?f1f,},f?Fkt!
pY'..na+..rY'e:fi"? :L?:FdC.'~d ili.vÃ'o~.?ti:rt`acli.s1well or -_.100 ;,22i
0"opFÃn t.;l e'o.'h:f.r,`.3zbr of l: .le're nv+..6.'stiarv

to EdnIc :t. pt.'..al%L.#'Q.YLd concentrations and ::eli CiC:i#:F:}2,

~::.cFp7 oxLec?1`?fi_tzeL; tF fFtsT?? l lhns3;.
tFn T:t3.f} .Iwr#3tv Cell P~'i?lifa::.rat#on .r~~~,tw;

3'i.`.Vint.T ffli~F1s a:(?i1i:iFI111:1`; 10- 3`,
ydY't?X\%t`_=:.IYt"#.ptof.hGci:1", vva:...` cast s,2``itz?
,wlFo4 by ..f.'.pi;'Ma1I`g a P(5>'+`:TFer bi3lu ..Fw? S,'.oll?p:lsEd of
poIy(:i':ec#.Ie 3Lim1 LarbtZF?sti . #;.C? ;k
5:-2?.p.i?l.3Litti,Ã.') Z"= mg3 $,50 ,.Alvf and ' i~00 J:i:;;)

Films we"I.'`v= l:?tpt}F>+.'d t}? *Ulttl<'si`.ia3let f:UIV,`o- radiation
ovem3g}Ft :?r1F?A
to 57+i.?.:g plc3.C:=ed F#?Fi? 12. õ'-w`:. plates containing 3,000 Lewis
LF`tbg F_;.FFc#.ni.3#2#3 (L3....;....) cells
3s.. '~ tLa z~~ ~, ~ `x:s Y a ~'x ..~. incubated 4 for . ~FiÃ:ay e:t~~4~FÃ`~:
.. " =Fi, 1) c~., # 2.:
~~~ = ,~~~;, z_~~iÃ~t ~il~~F: a~ ~~F~, -

h.sx.. (Fig. }) i`rLF'#i3iiti eFllm~ then i1.:asc'F.yvd fi3i viability
F:E:dnIF1F.H ~E~.`~.r~ T :~f,::i?.h ~r },3:F'~?tC3Ã:#.?x5. Both
4~
'i06


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ix~~~su:-c: prov:ded c+~~ecfiive imbibition of t.un:or {.=c.'1 proIifer.a:aon
out to ~5 days
a#3:~ 1-b:c ,.mt..i#.du4zw= xpf`3:.im pefli+:)d co#a:inued to effts:nv4ly
k:3l., t:mi51 Leih, as late ~.~s, Day
30, B-t cE;#. Ar ctrisi3n,, exposure Ão films L<'3wa.1#eiFlg lit? dz wt,.',
ZuI.~t3:.3dt,d .:bna 3 '<.t31dea ':lAQ,
s4allfe exposure i;t?iid?1#C)n<i lp~. tlef:ltc:d I:FiJ {,.ytoir`jxic d'fcc.s
(tit(~ Fag. ; Ll"1a~ 3)These Fu4i.1l1s

#n{ii.~:~aaS.=thai;,`ur pol-YiiIei filF:ls cw:tliinit':g 10-=

4~f e.:=:n=i~,k :si.?,. w>:7.1a# ci.li;r for as long as Ãhi'ity days.

E"'l,it; 9 t. ~i2 .crrz ,' rrT{r T#.i#F s)T ~...N-tE~xiL~rt4'
~3i~~.~~c.14.a~~t~'.r.e ~(r~~G~.. ~~~li,i?.3i.t~'~.,.Ga~;n;
--- ------,~-.-

a"t. ` tualoi` z: tZ~{ a'..i~.f~;~ i,, ~'~~~3i'tÃ,t: ~_,~_.~.. ~~ and
1~.~...~~4rr .., ~ .~> :. ,~t~.~+-;c-x4~D0
?: =. ; #.ta~ Y' tkw:i
C3.e:';lÃ~
rn caI an~..~~ 3~ (I ~, -16); anus offichoma (~~~~~Ilan NA STC3-21I l. 1 '1),
b-r,:a~~ (b u1-n an M (" F") ] l-m Y.n,m,

'v4f'1pha:fea3. Ee3..:L.s1#nt:E (LMS05) t, ano5:r:i wer.: i=:uttur453 at 37
.'C./ 5% {O' ti. the aRpri;pr,.i`=.'C:=

in~.adia supp;anunt~.~ w-it;~ 10% I"e tl Bovine Ser~~in (FBS) and 1%
4;~th L-;;fi~ta;,nine, with Ãhe c=e,~-it:o~l. ot TVIEN"l ;~ic(fia wf~icli.
a:.of#ta'..i'icta I i~ssi:Ãlxlaj all:ino s?c1dt^; and I I~it~'IrIA.: of
bswi:'i`,' xeis'.:#fi.Y. 11..:wEi ..,~Jf :ezrt 'i"....

scc.ded at of IMOi) ; L:_.C. B 16; AJ,49MST~ 21 1114, NC'-1+460.), S.S`;?::
{NIM ) or 10,000 (UN4S05) col1s wJ1 i#-iti) {)6-wel1. aysmy plates -i.n,
f?.<I~~:A w ;.s:ab,tsla Oic
appt:;pr.atc it:.ntir etr.: ,iEattng dc=n4.ity. Cells ,~'c,rc;' :,'o-cul"utcd
fffit 7, days wiffi, paNliixt.SeE-
st7au~::.,a4 w;.Wd,{1nd;?aded :+-i]'ii=thyi ,~`^().4.;{3-t1 .iTi['t.F~4)xypl:
4i3vi }-i =3 dFZ>?<a#.e-5 i l :1l0$h,li

metha+'. -'late il,iÃtt?paificze:, ffalbI'1L:~2itioi:i, dS,.xit,-:1'1bf..d
t3b:#b=c',t. ~'~-4.fuZi'the 1ncubc~tiE3r, pLaI?_?d9
, e r v~ ~ = t ~ ~z-:~ Q
~t= z.~ ~ .~~4r.. ~.~y ; ~ xf~r viability :~.=~""1 :.~~~~~~'~~. .~~:~
~~~:~Ã':L~C, t .~=. ~ Ã~~~. ~~.W.u~..~~.agw of'v~ia~~le
cells using a P.. Sltftit. Co::i3'}t~ (culture cC?3?t.iai]ÃIbg no
n.x.iCxs1.A:tt+..ie4;) to, rep.a.` .#..:i3.t if.i 0 'u

vi :~.~ii.it4'.
~ i&, 1.6 4bo Js ;hw m;.c~lt for LLC and 17 Shows fc7r

cxpt;i'l#:ls:nts.?3'1d ÃndÃE.ate thzit pa..^=fitM.xtJl~lCIaCEtad, butnot
cell proliferation ior several dt-t_te-reait cancer Iitte~s at a
caÃ;.'cw=nÃ#'aÃÃonh as low l R+ mw<r#?;L

of A]~rA} t~#t A 1 Ei.a l3 32 ~IUaE 4 ((:={371ti1I!`:iig:ippr(.)xk.m<3tf'ly
100 Fig n.3..: of .E'<S:lv``aila;<~l, LAJ.Isf'.:~te1
witb, the IC.~(e of }?'. .<a peiL.=aft.tixt'l,+. 1`SG. IS :~bL?ws the
anta'ci:a`:icor activity o.C pat:l.iti~xei

l.,t<3dC:=d ?1<1:3opc3l..ciC': w"#ta7 LLC' cells in vft1`L?P =('ll(:s[;
i"#..sLalt: ;F:ld1c;3:te tA :1t. l3 #: po:STI i:?'`.^`.

~i..; c s e~i~e s(A e that c : ~ =,.l .i#$~ I an :~# ~ ~:.-i:c ` - `. can r
t~'v`>i v.`l,.<. F
~ C <xc, ~,='."i3'~,:.3 ~.t3t?l_C.~x'~#i` :~N?~. zi ~' :#l"
VrLfncVrr.ryell>>fo. .5uhta nt:ktp].+.t,to\!s of S.ti)..te, Ai*iy~a
w`:bV3:4=!~'4 }2{~yi#K.}.i\fit3Wt.unden43s.= offfic"

107


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
x xq>j 4 L3. Ql..ad]ti:E3gfitif3i1 of ml4,d'C) E~ k.....- ? ii
~ ^ ~....,., .. --- ~.

To ;L? ~'~ 5 '~~~<l~'L'. iÃal i"53~3iEi'~;i: =~1 `rkt:<icz3d71eltt to 1 lung
it silii, p%di`d c 1 cs s:v~=:
suEpLiIdi<.Ã. iii. Afimi?i3.i4 .:'vF-1 27 or water e1.11t~i f'=aci3 5t?(utl~al-
t was pad3dWd C;i?tt? th~o Ff3..~dc
7i#i.us4 R1# gs. h< t`.1e:<,3i..fingo,Y

~.r=~e' t y~.._õ j ~= ~ ~'~.a :'x
pleural ~~irdC~e ~iit cta'i~'+:' d.ltf r~t3:i~?C> ~t+,.r15.3+.~:~ ii:~i~ the
percent of i3't~f#~:..i.,~F diavi`{:3;3~#.itlt\ vl., 4
i3i.'ti.i'mx#le.d a.:#81.id..; a 'L`.+o.ilftfi,;; i:i.;vinier. Ati(;r a one
bot3..:' exposure tt5 PBS ~v$'ttiT?.w ilit' ?iAng,
thL' 4up~.'t"Ãaa';aÃ`z? ~'~Ss; rL'??dt?vi'd and cou.`itud foI' adhvs[',nt
m:cropartdc:es; wC'.rc

tht> t.fug;Ay fi?Esed tC? avoid cS)L1naT.:7gadRdE'.4d3'#"1 to f17i'a.
A73.3..e dc]t:~,.S..i flh4Yz lud.1,w, a:w i.?L` i.'tmt ,?i:P
?ruz<.rt?pa1"t.z.,S~- : dhoT.'#.'t?g to lui1`~ WaN ou,11d by 'cd`<aaoi;g tho
d'd?.FÃ:i~.~4:'1 of .n'icri?parE3.Jle:*

I rG`.G,..:iF'=d to .:he s3F,~e:i'~.lsZ$I.3.~1t. It was rdEfi.f~ that t}-
iGd'i; is a nnl#i;h .:1gl;.u pe7`4c.7t ~ft:ai..a3mon`~
~89.9 1 0) of :';?3.i1'r~,:,pa.tFcles loaded in .PlLii't3:71c NF12;
Y:.~,r.x3:t "vk#t..i tl:?w a? ~{?f`~1~ .Gti;
gel .

< ~.~... ~~
.i?` ` ` "~~~.~ if. :3 : (28.3 " 2~~~~. .a ~ ]a '~S'~'7~.` ?`~~
t~.?~o4L,~,.tkie.11.n:nti ~~t ~;t d~.3,,~
,~3 ~~''~3'~.s..:" }..S"``n'.l'~i'.5. ~ ~ f'z ~~(:i, in is
;tto-it#.5t#i::ally >;t,t?;#,`#m?i I ' 4051 and indicates that
:?..dfl'iS..:ii\'e:, such as NT>.27 g~.`l o_tn tÃssuo, Such as :tili<}
tiss.,:.

~~ ~ 4. 1'~,~ti Tii~t~~Ã + ~': ~'~~
=___==___ _._ , .... ...~.... ........~A ......... ~~___~__
~-__=_

( j(750,000) were .~~~ Y \ t
H Carcinoma cells (fF~~.S.,1 Vb:~~1+d wafla os v, ibmm.[51D
A14~=~.~,=.`3 i..1.~'n
a . - . `. ii']iz~~~ ~':.:t~:-3`a.~:Ãt~.~.~;l lf~?.<~.~~~c. ~ ~x~iGr,~p~i~-
Ãi~.le.s _<~i~ac:~~t<~:~c~?c~sl,~ ~:~-. ~.:~7e`~~,f~ ~~~l~ce. It is

:=itell i.;>aa:ei7.#.\ItL'`'d that this ;%tmi}r iit3Se I'C'sl\ilts :d1
a4bcE'slGdnct71:#:i tumor i.s:3dE3.1e. .v1$?7.II` 1
20 week wrt.l? Ã'::lpdd w;;'i?wah. requiring 4;~L%'#fii;e, witit7ed3 2- 33
wecks, tii t1'3e t3.ne following
.ir?,s.cfioii it 3r1i3'+ R)wid tt14tt t?aMor size Wck5 slgi7d#tcF. ,i;aly
dc'~.~.'e._.sex? in ..Eni.:r?<.hs Ymo;vii :~:.
LXX colihand vs. iirLi. s..ell5;2.oI3e. AE: c3.t.ai:cC;;

l`kiit~li}.;~ ~=~.'=?y~.~Ii,:~.~ 3.8 0-9 `~.[`3s sx'`i~~dt~bis ~.1:~:.3 i~
i,~~ ~: ~~a3~~7 P._'+vaA
, , ,.
y ~ r ~ =. ~ ~ -\ 1 \.,.. -} ~; ~ 1'~ - ..: '~ ~ l i~ ~y p 'S l (l
t3w.t ld..~? z..a ,+sx.#,:~.a~3 ~..1~.. (tt} d~iZ.~L~ j i~~ i~zli~t~ ~ .~~- ~
,~ ~I i3~1:~ (Day > : ~. i_ .05).
r
25 'I'~~c naajo..ty of PIT_tA-pac::.oxe~ loaded micropanicl:e treaml animals
developed

minimal ?<.vrdei'icc. f.5f :tm.aod or gyC?wrh. Nc; toxicity ffioi:f

ni. fE,'d. 'flhlts> the data suggests that locally df;li ; t,Ã {.G
ohe1;,isiht.T~:ipy
via d'I3i::ri3piSl3'<,lks Uan, deter ~~:Ã.'= gowa and i
.:ie:i.`~ab?1sha:i2C;1:t of 1i.mg ca3"+ ..i):< .d'..; :Jx ' e :oI:i".z.
: us3C . taz`i;=aiis I~dC~t Gi. C3f twmor b3`T3pSiit?EtAtii?f?,

30 Fc33Fd'dca .t.'C2 i)-11.ciEbpk1.i'taGi't':4 were 1 5 ~.i.:n in
d.1cEI:iC.te:`;, t:#,i?(?th, and 3aQk pu.io'~ity
'~ aiw~~'stix4 that they will ;Y1r3i11t{32Ã': i? d~:li3t# x'G`l~' l l?d3
5i3s3r fa;?=.LL? ii=aF <:i~4 a ~??~?y ~+~.iÃ~;.~a tJ~.
`~~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
tFII;f:', If 1,. ..>itF3'?r'e1t4~ti tP?;i~. 4UI~.?ci t?-liF?t?r~:.d4~il I
s:;~'i'~ia~:s .:1 ti3e 5-10 zl?z .~~.?ii:l: :S
~. ~. .

;stEl:x<1.tC:d to be abF.gi. a .` .i?.icF`l}paitxc" {:s per cell, .{z,l a"
c{.Y_It *jwÃ;t:ià ; K
aF~~ nF of ':oiz...:tt; ueUs a:Id
r.:.
;~~.tÃ:..?#.~'.i?:ii..i .iei:AE:Ã~Ci, z'FiÃ~.i+3w343.1ti:i;::5
C~C.',F'F"#t51:i;~~..cit4~ 1~~]itt a C~C`,~~'. of 1i~~t: f.33#.ffiÃ3?;i
mF+.:i'z_Jp(I.dÃl :le,`~s
i't?.iil'pictL'I <` inhibits gÃ'mvth iunf4 iS1a.?l.;ii3;.11ent C?fÃ'FfffFt?a
Ã."cflk 71'1"a3I Ã&a;at3.on ta;s.zyS ..;,id z,r^;

~ Si'tJ i`?jixdEf.a:^ hc3ve iiz>o d`4'i.i3{3I?strai+'.d that the GC?iltaC?l
PLGA #.F-F1La{3'hSc rtFi ii <?iv. IFt.'~~:`~i and
~..
ti iffi{ywFt a k 4:Ã =.; vr, tumor 3?Fi.3wth.

E;Sis~~1 TaS ~, ~~.`~.na? TL1IF.zÃ)7 ~' q~7{?i7s4 C?f F3II?E3`ifAl'tl L~`r
if#ZSS~ ~clt?t# ~i3ij t# le 1k ~`E f I# t3
~--_ -- --- ------------ - ~--~-~---- ~------ -- -...___ .........,...
I.t`.I- fe..f'fii<:t`,S` of eftG:ÃTFf?t>1eF'G1py^lC?:id>õd F3imoptinJLles
f`>Es,n Exea..7Fple 3~
wer~ ~~valz.a"'vd i,: WÃ.l1-{~~tablistled sabcutaneou4 tumox models.
~.lot.s::. 11..C or hurn;:t:#
NIS''lO-2 _ 11-1, 0-atia::~T CeiÃ. 1:i-nek wore impiaiiz-<:d ii~~~i (,57BL6;~Y
a-espt.s.:Ã:ivelT.'.

S?.lsi?e}'1sF{?f?:", were with {ai11.m l?i? af.d
iFiu:3i?p._;::.AÃ.:`?L:s#iaii? tho
s:. w#t7Ã. .imans.:3tl i lFs.`.*iFes of the bc-.ck C3: :,?,i(:i:: 13t?ih
A3:t.". ` ,h"`2:5 Ã.:It`r `, Z,~ ti,?'i?$.~ ~?c'~~. :Ek,a.,?Sil;
~ ...; UFd
sli:?w" # 2.5 I.33L'F`53f4'7 i3 p.mr':'.d) 'llC?se~'_, of
'aiiÃ?oÃ:+e$z'tzLlE.\ `e .`L.ic e'4s.luia'tZ-'& A"ziii:'#EFh,

??jected W?~:,i: i,a.`#?i?r cczh-, a.oni,?.n PB~'s, tt3f?-if?T tv7fli
Iz.$E:I:.ficial dE-xie;, Ei;.e,.f?...z.,ed f::3I,ctic,:ni3i
Tumor Ã3~ lc?~iÃ~:~.~~ 3:~?1`. f.;#.i~l{:~~l.F,u~l
{;:~~1?~i~~~'1!:.~~}t71asI~f~C:_~ I:~G1nC:p3rirt~K ~ae:i k4,'.{ i:~`}z. ~i:~
controls. .r$:'`ir~

was m;3ni:i.;I'4d :?ÃtrL'i.#..lkly, and i:1.F-#.lfTlais wC:I`Ã; 1h ~:*.-
i.Il.>r~,h` r(.'clchcd 2 cm if? >. zÃ.:, As
2#ikmti.. aitf''.~d 'K#i.
~.
.' B bM3da :he high ilml I.{.~w doses oia pai: i.iiaxt`u`.E^3.63<ldE:<i
fid8.cbiE3llz$l
,?c.#1+3~3,.1`FL1~4 ,ikll#.~7?~ted w;:?'FÃ.FT gt'i~tt'ffi 1n flF?ii'e (~.3 =
~.~.}4?OS`?Y), and were F"?3i#if ?Ilt)"e

6FlCc`i2b e iF.:.?in even the pi3+,..,,ta?k.a:.l-loi:fdi:`,d b3.It Sat?Y?-'t
x;?.inSF%e Ã'z:li;ligp..1.fiG=les. Thi`=se d'c`#.t;.;
i.rctiTev dk.311.s`s.S;tA:3ts;~ that the v3t3 tu.?1C?r Ã..ffs'r.=t;> of
Piichiw".0-1Ã3:#-d6;;d a{F# :zi~???t:a
niFlli?;?{arlit.,:i:;j s~..i:? }:ss t ii.;'~? t#'aa=a3s:t;.tes to ~{k~7?~ ;,;
iG~ F~FÃ3 7~x ~#F ~#r~i t' <r #?1r`~~`# ii', F s~ (.<,
~ {

EC 1m3lu' 4i5' Ad7t;~,,.T Fl..7i ~a~' of St1beti~c~l7es.3~is ~~l~lyIF3k F
#fT3? n`.zi..#tsF e~zs f 3 ~~
,........~.--- ___
~._. _. ......... ........

i~.*,:: r+ "t ~ .'~:{-l > .~~.',.~ ~.i~a " 3Ã:"# '~ aà 2..,i3
2 :,lz 1'": ~ ~~.i-71'~t1. G2t i.C,t:~ f ?i iyE- ~ ci71+`..~`~Fi`, i~i~.~`y# F
'} :F '~t t'K`z] ~ .cl:`l t\ ;~``~'`~; ~.:;r
evaluated using i.Ã. Sub i,.3t.x:1{.[,ia:s ti]n14,?I` n?C}Q'.Ql, After lni-
~uobitsn . ..t ,..;~e..~r#aa.; ~..~:? + .Bi.<:E?
K ;
:il?#.~;i.'~ ~~C?a. \iaÃ~Z C:.i<z :F.J.d :?k:i~#'? EiF:i the back of the
F'I?.f e.::i(wiaw prC ;:'pod li, a ha s..FFon. .`al;.
i#?:.s;:{3:i z?: i,.:'`s :'.nz made bc:.weGn thC shoulders :iFe J.t#G :. 17.0
;S:\ 1 ti =.~{it'
d.li#'+'wA i.F;.ir. sY:tr, L?sz?c.'t @ed with ti pii3.d''C?f sterilized
tweezers t(? :t7.c3..'3."w a s.l.i`z.=t.#i>..,Fed.~t,E.:1

I?o2'kF:t. A }.4:ct;' of Gif#'ffI Ãzed" pttl ZiZ?s.:' fi I l'n dn{:d i.'+$? a
ps'.'E1~--iirda:.iy2e strip (i?,S x 08 cm)
wft~s inserted into the st1bÃ.:i..4a#?{:=Ãstts pC3e.ket with Fhu drug-loaded
sÃdt, Ã,Ffthe fiII>? }`,lnod
109


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ijpward .i.,nv:FrfYs ii-ic ,L,,d t~-ie IF.cisif?n was closed with 54) sutuF-
os. Nfi,x wen~
:110-nit~~red ~inz.~i futiv recÃ~~ven-A from anesthe5ia., given :wui.~gegic~
and w..:~0 housed un a

SPF ispe4~ific pAFl:-lorren 'guiudl4: "LFnirna.E facility. Two1}:zFYs worti
adF.(.fwCid healing KZs>,t: f4fi?ai 750,000 I~at~ilJt= LLC tL~iTlit# s~o=ll
`~"'T f~7~:`w` i~ C3 s17 = ~..:Fitixy i?:3 ti':q)
of t}ic 1mp1ara:~C'~ fi`f-t3 'i'#,, a 27-guage n4i'.dlL,
~ r . .
TF:.~i:si`i ;~i2::'i'c'~F5 iF';t3.F1tt33'~iF 3~~'s`.'t;3s~~' ~3=[3~~.
z.EF#iY.:Fl;~ ii~~.T~.z"#.tChec].I3Fz:f. Fl.tFl:i3õi?x'i
'2 a=f`? ff. 4 .{e. Funr39.i,F` .,1o~`rtb. didn<3t occur oL\w:c,p \?`
ap{.3I` moA :.flh":ts >.Cs<difod w.Fi.,1
30bllw L~ ~": ~ {5~~'~:i}i1~~?`~E~~;1~"=41~ (10 1-icPT) ÃI~' any of ffiÃ?:
C>.%p..:'Ãmon,.:i` m..u (:`s'i.o #` :-3g. 14).
Th:h is #.x ci37?t.a#.sa ~.t~~ the tlli7:31?Y g7"owti3 ihF3t ocC"L.rn':_l
directly on ~he 1..:11oi$ZieiE
pC3l4':x#tF fflam IF': over 7 -5;#:t3 of th:, aIa?lIl'c3ls tested. .. .,a:aU
\:fw'i' r

~(,"~'T ,.oFE cli~d polymer alli11s did develop tt#:I~..ois w.Ftii delayed
fbl,E)'Z:-up bF> theso EFF3n+3i"s
w4.:Ti. &Iwc t`ti .iF ti.le p,F FphC.#"=y of the pocket :iF,~d away ffim~.i
the filiFl it, ei'; ~s>.i` Fig. I.'~?).
:Fddit#t?:i tt:" '.b,. delay iF:: tumor appearance, Ih~.`'~s'C; F.i:Fl.F::t3TJ
W'L``,i `t. sFtx;i-1FfiCi.1.nt.,i. , iF..iS.l.,eF' in .#"I,e
(p ~~, 5K ui~Sx:':'i312~, ~s:1c`3.it) `t i 14~ :~ Ã-~: f> 3 "f~1ti; Y-l 5.~`
~Ã~-(~~ 3 films st;'>i=`~..I.L~:~ .Fi~:~~~ t =C?t ~ ;C.~~~.YÃ.~t.\
ÃA : ~Str y, l:l y"~ ~ 3`;La
13 Wni)r i-r1Z3d~.'l.

?`3r > ~ ' ?: N..3~ {.~.. ~'l~F.`' . x 4 In ti4'}`xt?~.~Ft~ Ht¾t2:~a~gI1~~~
tl~F~t~ 1'~`~.s:~'~.ca i) ~. S~~.~?w~' Ã ~~'ti1~t~=~> <~
~~~ .

PC`i.i'F:?#c: fihnS were subcutaneously <,.inplaF'::ied ;3'.'3 flir:i.= bi1&
of finFc~:=

3~ ~r ~ rc ~. ~ . .~~3` under %IFFt.~:;:F':t:.~3i3 as described ~`~Os~.1:1.
~`~t_c3li E:E1i ci~ :;sMe~;~~a[~ i:.3L~~fvC;E#.i?E,.:I: that
~:..

ccci~~~.t~ `. ~~ s{'II'l lt :~s~:d i~t~lyin:F -~ilFa?~, u>~1.~?a~3ec~
:~t~1yF~icr iil.Ã~s or s~~<2>3a . t, cFy ~xI~c.~
pockets ivi.re ~"',=['Ã:pwFF'('.(3 btJ.t Flt) film wi$.>i I3'F'1pliu]3.C'C.. 1-
~ll #.F-4. iJFt`.a3~i were
closed 1i Tta? 5-0 ;iut-u. ~,'. Th+`..# L`, was i1o t=,:4.Fduii.:t:'. t)f
w)EFnf.Si drõlul;.L;cx`.t.,~. early or lt3 w (::[l) to

s t.iq:;> :n u:iF.tF#':al's mat received lC?.:3ded or un:oi.:.dGd .iil.IT7s.
In adE..#ti~`f.]. ~.'1`~.`F"e w~'e~ Iz(?
25 dF.~".zL''re.Fai.:e ;r, 5"`."yfh`'I'f2%: or <L'ouF-id <r`,o-
3pC<i3:1:3.F2ci; ami3Ã:gc#.Flx"."11;3.l;s witi] r~'.Fhns 4CtÃ':sCIs s,.F.#nn,
Exc]ini~~~ ~~ Lote:il Dii1tF R<xe<zse of `>F 3eFxl.anc43us Pt7`ynFc 1`lffiF ~
F
.....,.. . . -- a... ... .. ...
, .#~` ii? ~a il drug .~.lft~.;ii1 of ~ .3Ek~~,: ti,~<?C~:=tz '
p:sl.,,:F`F3:=:w
. ~'~,, i'~Fti(:. ~g~. SEI.~i;=.l~i~'~~E~~~~' IT,1~"~~i3~1~:~ .x~ .
30 `Fi1m5 :'~~ 1'41,0 ;.x.Fs ex< ~~~ned. PolyFner fitrns were sF'abcutarwouSly
Fn .??.Am..z`. on ~~aeback
tsf C57BL/6 F1>iL'.5: LIFFfseT.':7;IleSt.ti.3eSF3:35 desL-t7bed abt')iCl. At
weekly ;,nteF r w:s

~ 10


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
implilntx3bon of t..ie.'; fllms, 4h,: s+.:rrt?uT1dL$'1g tissues Weis
?1a2"vf:swLa. Tlhe:L' #.3:~`~3.w;:r ?it..;':0 t:,::3::
in a filsi>iozl 's: w<? r ur+3_"+:I tA34 fi';FII and s`s?q,,il:i7(1a`.illy SC
gpli;I1.tt:d cl. 3::-rITri d#4taFlcÃ. .'i

, aY~ ..sYO 3`i \>m t.i Lb 2. k i d 2Sq thus pro} h 4.i F. L Atf i~ saw
fo[Si.J sc ts`me1 i F.at }ra}} oi:ts i.iii 1.f!_i r Lici)Ca.~ Ad

S_F1acefiYSn:. awriv fi.-L>na the dI33-3i;i3ded fii.E#n. ThC.> concentration
lF',, the w:?.I~ d1ilt<'.=d at tzi4~
t'a.`ik1;#s dusiafiLes was dheI% fx3+e:}i Iss[1o se FInL'..=Ilt L.#:?i:-Lg 1
. aPF_:C for t1hC:.
ti,?ct:Ãc i~I3i.:,; of fl `~"LL4~. The k'.`t"i:ldIt;$1t of drug
t.(3nm;2tr$i:=.#o!? Y-v1t:h1#> z. 2 cia'. t.iamnacF of

Y' > t Y '~+'Yr~,T = + ~{,Y
the :,La:~~.~.~ ~i3"t~~<~ film , ;<~~e tlaplotted to L..~Ã~~blisf~ t?~~.
ci~=ti~~ r.L,lL,xs.~ ~.r~~c.~ :~~.z~ ug,
<31st?,l?utim': zia;.o '.hi:= surrounding tissues in }'s'e'o.

1.:K.'t1mpIti. 4~-.~: _ t#.ML?3= Roc1:#1'?''moL Model of ~#3'Ã3L ~~~i z~4=~
Lfti L~II'i~3 R>.5~cfi%~~,'+13
J'J)o svqppt`cs.,_~joji of twnor rey.urronie, by drug..toarJc.d
nar,op.;r:iclz, an_~~ dlru~,:,_

loitded pol:.m~I fiims bit'C', also being examined a SsiF'#.g a well
L..s;..3~.`ll:.4wd .>t. 14ve,`r tE.J,ET:li>a:

to fA~4~ <~it~r( S1> ~'`~ >
mZ?C3i:i (Qc'r.Ci:3? ., .ai, A-n#aTho#'ai` Surg 80.1046'?i., 2005). ~?g1.,
Fl:ct; c3,1~=L: :a:.
4

tuA`.1oi' model w,.l..t,'w:=d if`: Iv7SiLLi1plC3 4,13, 750,000 Ã:Ã.1{ti' z_-
C.la`.s 4x'ac iitier..:'..=tsi

and i?flowl.'Yl to T ~p..e tumor wi3_ti 4,kC`3;'iL~lftL'..Aa y #"e:iZ:ctt+i fl-
1_I'mijL a LO
i,'.Ii1 #n~~:is.L?i3 p;...all~l ti, tils,'- tu711i3rand ght``. enuTc: ttu21o,
is removed and ¾}.''o-s; Fn4isiC3I1+.?z`.sefa
in control a$1in#:i.iks. Uffli..taded. or drug-loaded tlr.znopartli:le4 C)>
Po:ymer fi.tTis xl"S; applied
C).bÃL3 the I#...zl:,:i' bed Lt~ L ti~ ~ ~ i.illE=#l~r#~ animals and the skin
#:EaLis,<31.: `, :hiF2]_.3.a..y ?..Io,,wd.

Aniu-mada arc a..sL.sm1 b.wockIy.fL>> ele#ice of recu::-ent tumor gamwill
v;lAi ,..h our pil:z~
st.aL.#Qw h3! e di.=mof']s ratei, occurs aggressively in i_431ArC3l animals
"h.#t do nitt i`ew.t.'~fW
s~ru4,..}k,i,.sdod or P#.Zayme.#' fi9:~ls.

Exs_Lit7olu 50 +TFi IniFÃxJI1t~33#Ec7l '4~L sL~a}1~ ~iL)i~i~^ ~`~~~i# i # with
_ ________` :......... ._.---__T~
Pt3.vx~tax4''3"Loa'`l~F'4S.i Nl.

t ~' 3.h: abia~+` ~ i'~ r ~,~t #,A#~L~~ ~ c) v>`~ ;3r~~.~ed ?s #~L$s~t{3~
~.rfiUle :i to > ~ ` ii . ~.~.iit,=ii~ the Cr#'ow"i, ..r ?,{'..~,
. . wi#;am, tumL?;:
~~~

ca;IbS :lE t.i%o wilhii? 01"#e >.3iil'i3pe7'xii>I#.cal ii.lv7td' has altso
bot'.II us 11`", <l I~~i..3'lI1t~:
mo{.Ftii~of vi''olle'3iiabiished :!~i vivo t{.i,L,~$ nno~ ~?.#r~: : f=` t
.<..tr, J
t~L ~ ~1~.~I~.,:it>: ,
Tht'.fai:ca5.1i~vati4 SL1rK,. 1:32.117 9-88. 2006). Cultured
Y1iL:=sC,tuiG~~io#;.>i3u#.1:L`:: <;+,.il`~5
million M:? ,YO 21 11 ~'t .AY; :::o-iJ:tjGt .:d witl? '"a,.3a%=,tdtmt.l $ngc
dLd ftiF3a.oR"'Eal a`cini)pc3rfi.cli?S

6u1a3L?.Y ce.l5 alone in P13S L?. tEiT:I3r with identical dt5:,4:, of loaded
i1L3nf..nia.aZnz,# (1)t>z}--

? Y ~


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
: xpa1?sÃl+ a z3ai?opbl#fit res ;ie.i1'ed <i i i?iitif?li for ttl..Tit?iig
QF~ic>ty %1,,ml IIFmf?pafticle tt>x-jL'#.Ã'~~~
t-s;~~-s~:~::~i z~ ~:I >=.

1e 51: ~EMf?fFAÃ.~3s

L~-~y \?l~.._l;3aftW }.IoFfkiFc. fi.'f:.%.L=.F were cast otiiS..J gSLi4Js by
~~epL?sal.[ Zt.f .~i poL;,`iIiV't r;+oluhi\}I~

comprised ,?i'pUl,1(stC,.ik':.C ~u~~Ji??227~f` `dJ t. t ~~?C?~fl~~C?~<L~ i
?'#? ~~ C~; 4~~,~?,,:>Ã1?M:.1:.Ã1~= L ?~3 pt)~i:#Ci Ã~.v~~4Ca (100 ~#g).
t25EIru a llaliriivY"Ãrx~t
~,O. ~ a`.1+,: .`9ok-Qr.. 4u ?C. ~i'~ ('SÃ.
by il.t3w ev<$p<1:;Ãii3. over n7,+.,,ht, i1Ã'id then placed
Llnde;'.rL`ducei.,?xC.~s:".uI~fo.. 24 x:<3ua^s.
Prior ii;r. i'{Ti23Ela:g, the Fll`l1s wf?t'e, ci3:3l:i:d 't4>tl7 7 lIi-n of
At3lPd. The ;.3hms e4 erc #:;=?.aaged

is'^~?iYt` .1'#;,'ti .mi.11'... 01wi"o>? microscopy. f-l1e Starfal=C:s of the
fl~im i3.ppearQd 4`.zE~oEYkh atsi
~.`~oi'o1:i5 w,l~i fibrous-like i3'?ictm+Ni3:tu?'ff.'. As s}.lowt-}.iv'3 Fig,
S. cri.yS-:?Cddoal Ãnl":s;es tsEso
revealed a D0,11--POri3US il-Aer'iOr With Csfii;isÃent :hÃckiiusies tha'oi:ag -
.oW. dl.. l,:agxh
of 15 Examplo 52,~~

~~~~~~~~~~~~ IZzr scanning electron microscope ~SENP :n.,,a~.~mg were
prop4~rec by

w li Ãir~g a smp~e o~~`3' undSpa-mlicles, .s? a C:tni..eI:?,Ã.Tat.Ãor, :Jf U5
`Ã"'ig':alL waih dojE3Ã?iFed"11
wW.'e;a, A 10 ul. pd.?rt#i.Ã: of the d1h:Ã.Ld-sar-aplL rvil5 tht:n. placed
iSF:: a Clown ai?E.n.ÃI3:an "s-Au"Z
fl'#e sa3?'fpies were coated 4<.t}? 15 Ãiza# 1 t~,~~!' of
.: -

Au~"Pt. Sc7r?lpli.:-, we1'.i.. ;:hF:i3 1 .3. 'L;~'d~ i~.Ã~a a Zeiss ~?~,~P3.
40VP ~..,c:i~. ..~] ~ ;~~.i
L.
>~~f E.3C:d'ii.ltz~? t`i lt~.{t,:;:3: of ~l ~ r The image in ?. I ~i
;d~34'k~~s pz;.F.~i,:~f'\ fe<3'1'l''a abmi .C? ;'.~~Ã,=.`
microns SZl Ã:3G= pmt;:i t4S e3etwC;ei1 5 :3:[ld 20 `zI1lC:3.`i3ns.

N5i; Cf}x3t<3~~ ~i?.z} e~'~~~1~t1~`LÃ1c:?~

c glass t= ~ '' and . . .
p;3>y-ÃI?er films Weri`.- ust i#;at~> ~5:x~3:+t1".~.~~~ .~~#Ã~ the contact
c3:~7~rlt~ ;S~~~i';.s~:~~# ~'AI~~'i
W.Ã.'_e deÃei-mined i3.,,ÃEa4~ '3 L'nti}i.t .9.,:3'.t.?;~v
:~Ef;Ã~..7L?:.~~LÃ.1.~'`. ~.~:E.#ll~t.c.'~~. ranged .~:~4F#i:i 75 1J.:~~t'.
. . . .. +,- ~

i`or i ;iai?`P.ti=, `hc i ol'1Ã<1vb aF~,oõ1Ã' of p4.?~.y4`v't~.~1i'i4~ acid 4-
~.Ã"~~i31~i~tt.n. ::.;3 C C.a,4Ft~?c:LÃixe~~ i t3'il~
I i SK "Ã,aiw t:'Z?z3tt:C:t aiigiw~ of grl<.s':i is about 35r .


112


CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t
._--- --~ --------- --------- --------- ------__
Th a':?-:ial trt.t:n.'s#.F.ioI:?s' of ead? Po:,``,dl??Cr were
mi.:i`bsu1't:Ã.3 iÃSIL?<~r t iftZ.ra'..' ..1a. 4t,aTin.S.ng
i=~low il2t"tI'N. P?lymii5 Q{ mpt?st'd of <: ca(?rf?Aai tt?tli- <?ird
beEl'!Zli??ti~v a1'~~c{~` tzI ~:Ã?rbz?maie
m[3nC)i.ne.iS we.n~ formed v.'1th t1`si:.= ~fi.~,lli,;wÃng carbonate mole
Iftc,ctFiTI? _. 0,05. 0. 0.20,

; V".~f ~ ~ v 0,401, r).J~( 4.1,.LL t ~f )s\t Yi itf zo1 k~i !c}=~+~ y~cj\~k.i
`q*~i.~s l. '} 41,c {<i~'4ta }[ C~~)={~ 'y .,i .) ~= t~~A E t~.l #. `~yF ()q ~
2
s~,,.' Sl~. 1.00. Y~{-'fliixy~ ¾ LV-4FS~~Z-:2.Cl.C y~k:t?.f}.~~~ `~i.l'~'~ l-
<i.i).Zl

>~"ejtlliw;~;oÃ;i~rt~I<?~.i..'~=> lc.ia`FG:~~. {~S"?~3I;;1 2! ~s~ti 5~'sC
::Usa:a?E#iL. and f3i..ha a,.i1x741l,s'Y:7cx ~1,~...4= a.Ttt?IphoI:I's.

0`rilER EMBODIME NTSS

It. is to i?e ui?:day>t #oif thF:twh.i>``.e the ~nvt:nt1o#` has .zi;m -
dest.Pibei. j.. ~. Lcl.l.t_:t?D.
E'e'i:':T t:xt; dci:ffliEt> theri.~C-yf, til-hf! lz?IF=gt?iS-1g descttpI"it?ta
is 1`:w: ded to iflustriite
and Il ~. If.:.,~?: t~>?~. ~iC~~:?~~t~ of tz?a, i>?~~'~s`I,l~t.?Ã?~~,
~tr~Yli:~'? Ã~ <~:;tin.t; by tiAc scope of dFo qlpeTtded
Cla:if;s. OÃ:#i;rt#*pect", 'wdvw%ts, and mi3d.ific'c?t7.or'iS
c#.i't;witl.i?.E? flIke swpe of :lw

1olIt?zvir?g claims.

113

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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2007-05-31
(87) PCT Publication Date 2007-12-06
(85) National Entry 2008-11-27
Examination Requested 2012-05-24
Dead Application 2015-06-02

Abandonment History

Abandonment Date Reason Reinstatement Date
2014-06-02 FAILURE TO PAY APPLICATION MAINTENANCE FEE
2014-06-23 R30(2) - Failure to Respond

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $400.00 2008-11-27
Maintenance Fee - Application - New Act 2 2009-06-01 $100.00 2009-06-01
Registration of a document - section 124 $100.00 2009-09-11
Registration of a document - section 124 $100.00 2009-09-11
Maintenance Fee - Application - New Act 3 2010-05-31 $100.00 2010-05-04
Maintenance Fee - Application - New Act 4 2011-05-31 $100.00 2011-05-06
Maintenance Fee - Application - New Act 5 2012-05-31 $200.00 2012-05-18
Request for Examination $800.00 2012-05-24
Maintenance Fee - Application - New Act 6 2013-05-31 $200.00 2013-05-29
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
TRUSTEES OF BOSTON UNIVERSITY
THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Past Owners on Record
AZOUZ, SOLOMON
COLSON, YOLANDA
GRINSTAFF, MARK W.
GRISET, AARON
WOLINSKY, JESSE
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Claims 2008-11-27 12 673
Description 2008-11-27 113 8,061
Drawings 2008-11-27 18 861
Cover Page 2009-03-30 1 24
Claims 2009-04-01 7 184
Claims 2013-10-10 4 80
Abstract 2013-10-10 1 15
Description 2013-10-10 113 7,878
Assignment 2008-11-27 4 99
PCT 2008-11-27 3 159
Correspondence 2009-03-26 1 25
Prosecution-Amendment 2009-04-01 9 266
Assignment 2009-09-11 12 416
Prosecution-Amendment 2012-05-24 2 50
Prosecution-Amendment 2013-04-12 3 114
Prosecution-Amendment 2013-12-23 3 116
Fees 2013-05-29 1 163
Prosecution-Amendment 2013-07-30 2 50
Prosecution-Amendment 2013-10-10 14 523