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T*
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T*
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T*
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T*
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T*
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T*
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T*
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T*
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T*
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T*
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[(detected)-341(using)-336.5(UV)-333(absorbance)-337.7(at)-328.8(214)-333.6(and)-334.7(280)-169.3(nm.)]TJ
/F6 1 Tf
9.9626 0 0 9.9626 313.0582 682.9227 Tm
[(Resu)-10.9(lts)]TJ
/F9 1 Tf
0 -1.7868 TD
[(Bio)-9.4(logical)-336.8(poten)-9.1(cy)-331.6(of)-339.2(differen)-7.9(t)-333.6(IFN-)]TJ
/F12 1 Tf
15.4897 0 TD
(b)Tj
/F9 1 Tf
.8877 0 TD
[(product)-6.9(s)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 323.0361 647.2628 Tm
[(Different)-535(assays)-532.2(were)-526.9(used)-530.4(for)-528.7(assessing)-534.5(the)-528.6(biological)]TJ
-1.1128 -1.2203 TD
[(activity)-309.1(of)-300.4(the)-300.9(different)-302.7(products.)-310.3(As)-299.9(the)-300.9(AVAs)-304.1(are)-303.6(currently)]TJ
T*
[(in)-411.6(use)-407.2(as)-411.8(a)-404.2(potency)-416.2(assay)-404.4(in)-411.6(various)-408.3(laboratories,)-414.1(we)-406.2(have)]TJ
0 -1.2267 TD
[(employed)-619.4(these)-618.3(assays)-620.7(using)-614.7(the)-617.1(2D9/EMCV)-615.2(or)-616.8(A549/)]TJ
0 -1.2203 TD
[(EMCV)-852.1(combination,)-851.9(which,)-848.8(although)-847.1(highly)-851(sensitive,)]TJ
T*
[(are)-474.3(laborious,)-465.4(multistep,)-474(and)-467.5(complicated.)-474.7(In)-467.1(contrast,)-472.4(the)]TJ
0 -1.2267 TD
[(reporter)-360.6(gene)-355.4(assay)-353.8(has)-358.3(a)-353.6(simple)-355(and)-353.7(easy)-352.9(procedure,)-359.6(short)]TJ
0 -1.2203 TD
[(incubation)-363.1(time,)-358.5(and)-360(a)-353.6(read-out)-362.3(based)-355.9(on)-360.2(IFN-)]TJ
/F4 1 Tf
20.9541 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
(stimulated)Tj
-21.5042 -1.2203 TD
[(soluble)-276.1(alkaline)-270.2(phosphatase)-279.9(production)-271.5(\()-82.7(Meager)-275.1(and)-271.5(others)]TJ
0 -1.2266 TD
[(2005\);)-437.7(such)-435.3(reporter)-442.8(gene)-431.2(assays)-437.3(have)-433.5(become)-440.1(popular)-434.2(for)]TJ
0 -1.2203 TD
[(assessment)-341.1(of)-332(biological)-337.1(activity)-334.4(of)-338.4(different)-334.3(IFN)-335.3(proteins.)]TJ
/F5 1 Tf
1.1128 -1.2203 TD
[(Antiviral)-442.8(assays.)]TJ
/F3 1 Tf
7.9479 0 TD
.012 Tc
[(Using)-485.6(2D9)-480.7(A)-2(VAs,)-484.1(individual)-484.7(p)4.3(o)-3.4(te)12(n)-10.3(c).1(y)]TJ
-9.0607 -1.2203 TD
.0122 Tc
[(estimates)-349.5(\()]TJ
/F5 1 Tf
4.8623 0 TD
0 Tc
(n)Tj
/F10 1 Tf
.7271 0 TD
()Tj
/F3 1 Tf
.9358 0 TD
.0124 Tc
[(1444\))-348.5(f)-.7(rom)-351.9(4)-347.5(to)-350.8(7)-353.8(i)2.6(ndependent)-348.5(assa)12.4(ys)-355.6(were)]TJ
-6.5252 -1.2266 TD
.0132 Tc
[(der)6.2(i)-3(v)6.1(e).7(d)-432.4(f).1(or)-430.1(each)-432.8(pr)6.2(oduc)13.2(t)-5.5(;)-432.3(the)-429.3(p)-.8(erc)13.2(e)-4.9(nt)13.2(a)-5.7(g)2.5(e)-435.6(o)4.1(f)-436.2(c)1.3(oefcient)-436.2(o)4.1(f)]TJ
0 -1.2203 TD
.0126 Tc
[(variation)-521.9(o)3.5(f)-519(e).1(stima)12.6(t)-6.4(es)-519.8(r)5.6(a).4(nged)-515.2(fr)5.6(om)-516.1(10.6%)-513.8(to)-521.3(2)12.6(1)-5.4(.5)12.6(%)-7.5(.)-515.1(The)]TJ
T*
0 Tc
[(i)-16.2(n)-9.7(d)-9.3(i)-16.2(v)-7.1(i)-16.2(d)-9.3(u)-7.7(a)-12.2(l)-401.9(p)-7.7(o)-15.4(te)-19.3(n)-16(c)-11.9(i)-9.9(e)-12.5(s)-393.3(o)-15.4(b)-10.7(t)-13.1(ai)-22(n)-9.7(e)-12.5(d)-395(w)-14.3(i)-9.8(t)-13.1(h)-395.4(e)-12.5(a)-12.2(c)-11.9(h)-395.4(p)-14(r)-7(o)-15.4(d)-9.3(u)-14(c)-11.9(t)-398.8(w)-7.9(e)-12.6(r)-13.3(e)-398.2(ex)-21(-)]TJ
0 -1.2266 TD
.0112 Tc
[(pressed)-510.3(a)-1(s)-514.9()85.2(milli)-5(on)-517(IU)-515(\()-84.1(M)-.2(IU\)/do)-4.2(se)85.2()-515.5(and)-516.6(r)4.2(epre)11.2(s)-9(e)-1.3(nted)-510.3(as)]TJ
0 -1.2203 TD
.0118 Tc
[(symbols)-305.7(i)-4.4(n)-307.7(t)11.8(h)-11(e)-304.2(scatt)11.8(e)-7.5(r)-311.4(p)4.1(lot)-311.1(\()11.8(F)-5.7(i)-4.4(g.)-307.3(1\))11.8(.)-314.1(A)-2.2(ll)-307.9(approved)-307.3(innovator)]TJ
T*
.0127 Tc
(IFN-)Tj
/F4 1 Tf
2.0802 0 TD
0 Tc
(b)Tj
/F3 1 Tf
.5627 0 TD
.0114 Tc
[(-1)11.4(a)-417.6(p)3.7(ro)-4(ducts)-407.2(h)-4.6(ad)-408.9(sim)-5.1(ilar)-406.6(GMPs)-407.2(a)-.8(nd)-408.9(showed)-408.9(consis-)]TJ
-2.643 -1.2266 TD
.0116 Tc
[(tenc)11.6(y)-675(b).9(etween)-668.3(the)-671.2(b).9(at)11.6(c)-7.1(h)-4.4(es.)-667.9(F).9(or)-672(example,)-667.9(t)11.6(h)-11.2(e)-664.9(GMP)-672.6(of)]TJ
0 -1.2203 TD
.0123 Tc
[(product)-772.2(A)-766.8(va)12.3(r)-6.9(i)2.4(ed)-768.4(between)-768.8(7.84)-764.9(and)-762.1(8).1(.5)12.3(8)-777.1(M).9(IU/dose)12.3(,)]TJ
T*
.0118 Tc
[(whereas)-463.7(t)-1.3(hat)-469.2(o)2.7(f)-469.2(p)-2.2(r)4.8(o)-3.6(duc)11.8(t)-474.8(B)-465.4(v)-1.6(aried)-465.4(b)1.1(etween)-465.8(8.35)-468.3(a)11.8(n)-10.1(d)-465.4(9)-.4(.16)]TJ
0 -1.2266 TD
.0122 Tc
[(MIU/dose.)-540.8(T)2.9(oget)12.2(h)-10.6(e)-.3(r)5.2(,)-540.8(the)-544.1(p)4.5(ote)12.2(n)-10.1(cies)-539.2(ranged)-540.9(f)12.2(r)-7.9(om)-535.5(7.84)-543.7(t)12.2(o)]TJ
ET
/Document /MC1 BDC
0 0 0 1 K
2 J 0 j .5 w 10 M []0 d
/GS2 gs
1 i
q 1 0 0 1 128.542 205.694 cm 0 0 m
16.458 0 l
S
Q
135.069 161.711 3.3339 3.334 re
f
.35 w
135.069 165.045 3.3339 -3.334 re
S
135.069 177.247 3.3339 3.334 re
f
135.069 180.581 3.3339 -3.334 re
S
129.961 177.956 3.334 3.335 re
f
129.961 181.291 3.334 -3.335 re
S
140.177 178.737 3.334 3.334 re
f
140.177 182.071 3.334 -3.334 re
S
135.069 183.916 3.3339 3.334 re
f
135.069 187.25 3.3339 -3.334 re
S
140.177 184.625 3.334 3.334 re
f
140.177 187.959 3.334 -3.334 re
S
135.069 194.202 3.3339 3.334 re
f
135.069 197.536 3.3339 -3.334 re
S
129.961 196.614 3.334 3.334 re
f
129.961 199.948 3.334 -3.334 re
S
140.177 196.756 3.334 3.335 re
f
140.177 200.091 3.334 -3.335 re
S
129.961 198.246 3.334 3.334 re
f
129.961 201.58 3.334 -3.334 re
S
135.069 199.522 3.3339 3.335 re
f
135.069 202.857 3.3339 -3.335 re
S
140.177 200.445 3.334 3.334 re
f
140.177 203.779 3.334 -3.334 re
S
129.961 201.296 3.334 3.335 re
f
129.961 204.631 3.334 -3.335 re
S
137.623 202.644 3.3344 3.334 re
f
137.623 205.978 3.3344 -3.334 re
S
132.515 203.425 3.3339 3.334 re
f
132.515 206.759 3.3339 -3.334 re
S
135.069 205.624 3.3339 3.334 re
f
135.069 208.958 3.3339 -3.334 re
S
129.961 206.05 3.334 3.334 re
f
129.961 209.384 3.334 -3.334 re
S
140.177 206.05 3.334 3.334 re
f
140.177 209.384 3.334 -3.334 re
S
129.961 207.256 3.334 3.334 re
f
129.961 210.59 3.334 -3.334 re
S
137.623 207.539 3.3344 3.334 re
f
137.623 210.873 3.3344 -3.334 re
S
135.069 211.796 3.3339 3.334 re
f
135.069 215.13 3.3339 -3.334 re
S
140.177 215.343 3.334 3.333 re
f
140.177 218.676 3.334 -3.333 re
S
129.961 216.407 3.334 3.334 re
f
129.961 219.741 3.334 -3.334 re
S
137.623 216.833 3.3344 3.334 re
f
137.623 220.167 3.3344 -3.334 re
S
135.069 217.116 3.3339 3.334 re
f
135.069 220.45 3.3339 -3.334 re
S
129.961 219.386 3.334 3.334 re
f
129.961 222.72 3.334 -3.334 re
S
135.069 223.785 3.3339 3.334 re
f
135.069 227.119 3.3339 -3.334 re
S
135.069 229.673 3.3339 3.334 re
f
135.069 233.007 3.3339 -3.334 re
S
135.069 235.632 3.3339 3.334 re
f
135.069 238.966 3.3339 -3.334 re
S
135.069 245.919 3.3339 3.334 re
f
135.069 249.253 3.3339 -3.334 re
S
.5 w
q 1 0 0 1 153.371 201.084 cm 0 0 m
16.458 0 l
S
Q
159.898 154.759 3.3339 3.334 re
f
.35 w
159.898 158.093 3.3339 -3.334 re
S
159.898 163.91 3.3339 3.334 re
f
159.898 167.244 3.3339 -3.334 re
S
154.79 164.549 3.3344 3.334 re
f
154.79 167.883 3.3344 -3.334 re
S
159.898 174.267 3.3339 3.334 re
f
159.898 177.601 3.3339 -3.334 re
S
165.005 175.048 3.3345 3.334 re
f
165.005 178.382 3.3345 -3.334 re
S
159.898 180.155 3.3339 3.335 re
f
159.898 183.49 3.3339 -3.335 re
S
154.79 181.645 3.3344 3.334 re
f
154.79 184.979 3.3344 -3.334 re
S
165.005 184.625 3.3345 3.334 re
f
165.005 187.959 3.3345 -3.334 re
S
159.898 186.824 3.3339 3.334 re
f
159.898 190.158 3.3339 -3.334 re
S
165.005 189.662 3.3345 3.334 re
f
165.005 192.996 3.3345 -3.334 re
S
154.79 190.512 3.3344 3.335 re
f
154.79 193.847 3.3344 -3.335 re
S
162.452 190.655 3.3344 3.334 re
f
162.452 193.989 3.3344 -3.334 re
S
159.898 197.749 3.3339 3.335 re
f
159.898 201.084 3.3339 -3.335 re
S
154.79 197.891 3.3344 3.334 re
f
154.79 201.225 3.3344 -3.334 re
S
165.005 199.096 3.3345 3.335 re
f
165.005 202.431 3.3345 -3.335 re
S
154.79 202.218 3.3344 3.334 re
f
154.79 205.552 3.3344 -3.334 re
S
162.452 202.36 3.3344 3.334 re
f
162.452 205.694 3.3344 -3.334 re
S
159.898 203.992 3.3339 3.334 re
f
159.898 207.326 3.3339 -3.334 re
S
165.005 204.134 3.3345 3.334 re
f
165.005 207.468 3.3345 -3.334 re
S
154.79 205.481 3.3344 3.335 re
f
154.79 208.816 3.3344 -3.335 re
S
162.452 206.617 3.3344 3.334 re
f
162.452 209.951 3.3344 -3.334 re
S
157.344 208.249 3.3339 3.334 re
f
157.344 211.583 3.3339 -3.334 re
S
161.175 208.249 3.334 3.334 re
f
161.175 211.583 3.334 -3.334 re
S
159.898 209.171 3.3339 3.334 re
f
159.898 212.505 3.3339 -3.334 re
S
154.79 214.208 3.3344 3.334 re
f
154.79 217.542 3.3344 -3.334 re
S
159.898 215.201 3.3339 3.334 re
f
159.898 218.535 3.3339 -3.334 re
S
165.005 217.116 3.3345 3.334 re
f
165.005 220.45 3.3345 -3.334 re
S
154.79 219.386 3.3344 3.334 re
f
154.79 222.72 3.3344 -3.334 re
S
159.898 222.933 3.3339 3.334 re
f
159.898 226.267 3.3339 -3.334 re
S
154.79 223.075 3.3344 3.335 re
f
154.79 226.41 3.3344 -3.335 re
S
165.005 227.758 3.3345 3.334 re
f
165.005 231.092 3.3345 -3.334 re
S
159.898 229.673 3.3339 3.334 re
f
159.898 233.007 3.3339 -3.334 re
S
165.005 230.453 3.3345 3.334 re
f
165.005 233.787 3.3345 -3.334 re
S
.5 w
q 1 0 0 1 178.2 210.022 cm 0 0 m
16.458 0 l
S
Q
184.727 175.615 3.334 3.334 re
f
.35 w
184.727 178.949 3.334 -3.334 re
S
189.834 179.872 3.3348 3.334 re
f
189.834 183.206 3.3348 -3.334 re
S
184.727 200.587 3.334 3.334 re
f
184.727 203.921 3.334 -3.334 re
S
179.619 202.218 3.3344 3.334 re
f
179.619 205.552 3.3344 -3.334 re
S
189.834 203.992 3.3348 3.334 re
f
189.834 207.326 3.3348 -3.334 re
S
179.619 204.276 3.3344 3.334 re
f
179.619 207.61 3.3344 -3.334 re
S
187.28 204.559 3.334 3.334 re
f
187.28 207.893 3.334 -3.334 re
S
184.727 209.029 3.334 3.334 re
f
184.727 212.363 3.334 -3.334 re
S
184.727 217.116 3.334 3.334 re
f
184.727 220.45 3.334 -3.334 re
S
179.619 218.889 3.3344 3.335 re
f
179.619 222.224 3.3344 -3.335 re
S
189.834 219.67 3.3348 3.335 re
f
189.834 223.005 3.3348 -3.335 re
S
179.619 222.153 3.3344 3.334 re
f
179.619 225.487 3.3344 -3.334 re
S
184.727 226.764 3.334 3.334 re
f
184.727 230.098 3.334 -3.334 re
S
184.727 232.653 3.334 3.334 re
f
184.727 235.987 3.334 -3.334 re
S
.5 w
q 1 0 0 1 203.029 203.85 cm 0 0 m
16.458 0 l
S
Q
209.555 159.511 3.335 3.334 re
f
.35 w
209.555 162.845 3.335 -3.334 re
S
209.555 169.089 3.335 3.334 re
f
209.555 172.423 3.335 -3.334 re
S
204.448 170.436 3.334 3.334 re
f
204.448 173.77 3.334 -3.334 re
S
209.555 178.24 3.335 3.334 re
f
209.555 181.574 3.335 -3.334 re
S
209.555 183.916 3.335 3.334 re
f
209.555 187.25 3.335 -3.334 re
S
204.448 185.334 3.334 3.335 re
f
204.448 188.669 3.334 -3.335 re
S
214.663 188.172 3.334 3.335 re
f
214.663 191.507 3.334 -3.335 re
S
209.555 189.803 3.335 3.334 re
f
209.555 193.137 3.335 -3.334 re
S
214.663 191.294 3.334 3.334 re
f
214.663 194.628 3.334 -3.334 re
S
204.448 192.783 3.334 3.334 re
f
204.448 196.117 3.334 -3.334 re
S
212.11 193.493 3.334 3.334 re
f
212.11 196.827 3.334 -3.334 re
S
209.555 196.472 3.335 3.334 re
f
209.555 199.806 3.335 -3.334 re
S
204.448 196.614 3.334 3.334 re
f
204.448 199.948 3.334 -3.334 re
S
214.663 198.103 3.334 3.335 re
f
214.663 201.438 3.334 -3.335 re
S
209.555 201.651 3.335 3.334 re
f
209.555 204.985 3.335 -3.334 re
S
214.663 201.651 3.334 3.334 re
f
214.663 204.985 3.334 -3.334 re
S
204.448 201.651 3.334 3.334 re
f
204.448 204.985 3.334 -3.334 re
S
212.11 203.07 3.334 3.334 re
f
212.11 206.404 3.334 -3.334 re
S
207.002 205.34 3.334 3.335 re
f
207.002 208.675 3.334 -3.335 re
S
210.832 205.907 3.335 3.335 re
f
210.832 209.242 3.335 -3.335 re
S
209.555 207.965 3.335 3.334 re
f
209.555 211.299 3.335 -3.334 re
S
204.448 208.249 3.334 3.334 re
f
204.448 211.583 3.334 -3.334 re
S
214.663 209.029 3.334 3.334 re
f
214.663 212.363 3.334 -3.334 re
S
204.448 210.518 3.334 3.335 re
f
204.448 213.853 3.334 -3.335 re
S
209.555 214.208 3.335 3.334 re
f
209.555 217.542 3.335 -3.334 re
S
214.663 215.627 3.334 3.334 re
f
214.663 218.961 3.334 -3.334 re
S
204.448 216.407 3.334 3.334 re
f
204.448 219.741 3.334 -3.334 re
S
212.11 216.833 3.334 3.334 re
f
212.11 220.167 3.334 -3.334 re
S
207.002 218.18 3.334 3.334 re
f
207.002 221.514 3.334 -3.334 re
S
209.555 221.869 3.335 3.335 re
f
209.555 225.204 3.335 -3.335 re
S
204.448 224.211 3.334 3.334 re
f
204.448 227.545 3.334 -3.334 re
S
209.555 227.899 3.335 3.334 re
f
209.555 231.233 3.335 -3.334 re
S
209.555 234.142 3.335 3.334 re
f
209.555 237.476 3.335 -3.334 re
S
204.448 238.541 3.334 3.334 re
f
204.448 241.875 3.334 -3.334 re
S
.5 w
q 1 0 0 1 227.858 207.61 cm 0 0 m
16.458 0 l
S
Q
234.384 166.889 3.335 3.334 re
f
.35 w
234.384 170.223 3.335 -3.334 re
S
239.492 171.642 3.334 3.334 re
f
239.492 174.976 3.334 -3.334 re
S
234.384 185.334 3.335 3.335 re
f
234.384 188.669 3.335 -3.335 re
S
229.277 185.476 3.334 3.334 re
f
229.277 188.81 3.334 -3.334 re
S
239.492 185.476 3.334 3.334 re
f
239.492 188.81 3.334 -3.334 re
S
229.277 186.257 3.334 3.334 re
f
229.277 189.591 3.334 -3.334 re
S
236.938 186.257 3.335 3.334 re
f
236.938 189.591 3.335 -3.334 re
S
231.831 187.604 3.334 3.334 re
f
231.831 190.938 3.334 -3.334 re
S
235.661 188.314 3.335 3.334 re
f
235.661 191.648 3.335 -3.334 re
S
233.108 190.371 3.334 3.335 re
f
233.108 193.706 3.334 -3.335 re
S
234.384 192.925 3.335 3.334 re
f
234.384 196.259 3.335 -3.334 re
S
239.492 192.925 3.334 3.334 re
f
239.492 196.259 3.334 -3.334 re
S
229.277 196.898 3.334 3.334 re
f
229.277 200.232 3.334 -3.334 re
S
234.384 198.672 3.335 3.334 re
f
234.384 202.006 3.335 -3.334 re
S
229.277 200.161 3.334 3.334 re
f
229.277 203.495 3.334 -3.334 re
S
239.492 202.786 3.334 3.334 re
f
239.492 206.12 3.334 -3.334 re
S
229.277 203.07 3.334 3.334 re
f
229.277 206.404 3.334 -3.334 re
S
234.384 204.559 3.335 3.334 re
f
234.384 207.893 3.335 -3.334 re
S
239.492 204.985 3.334 3.334 re
f
239.492 208.319 3.334 -3.334 re
S
229.277 205.056 3.334 3.334 re
f
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proof:pdf
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2008-04-17T14:19:15+05:30
Adobe Illustrator CS4
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2008-05-15T16:23:06-07:00
Adobe Illustrator CS4
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2008-05-15T23:07:07-07:00
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T*
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59.754 504.964 490.167 .22675 re
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176.258 690.86 249.505 .22681 re
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59.754 673.172 490.167 .22675 re
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BT
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T*
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T*
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T*
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[(-1a)-435.8(peak.)-438.1(HSA)-436.1(eluted)-444.4(at)-436.3(1.61.8)-167.8(min.)]TJ
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[(ther,)-405.7(the)-402.1(major)-403.8(peak)-403.5(in)-398.9(this)-407(case)-404.7(appeared)-403.6(broader)-403(than)-405.1(in)]TJ
T*
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[(F,)-393(which)-390.6(besides)-392.8(2)-385.2(additional)-395.3(peaks)-392.2(revealed)-386.6(a)-391.5(broad)-389.8(peak)]TJ
0 -1.2203 TD
[(with)-527.5(a)-524.3(shoulder)-534.4(representative)-530.3(of)-528(the)-528.6(IFN-)]TJ
/F4 1 Tf
20.0057 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-524.3(monomer)]TJ
-20.5621 -1.2203 TD
[(\(Fig.)-344.5(3e\).)-344.2(This)-340(contrasted)-345.9(with)-344.1(the)-345.2(proles)-347.7(evident)-346(for)-345.4(prod-)]TJ
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[(ucts)-242.7(E)-236.9(\(Fig.)-243.4(3c\))-239.5(and)-239.8(B)-236.9(\(Fig.)-243.4(3f)-82.2(\),)-237.3(which)-245.2(showed)-239.6(a)-239.8(rather)-244.9(narrow)]TJ
0 -1.2203 TD
[(and)-328.4(discrete)-330.6(major)-321.6(IFN-)]TJ
/F4 1 Tf
10.6035 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
[(-1a)-328.3(peak.)-324.2(Product)-331.4(D)-323.9(was)-324.9(similar)-332.2(in)]TJ
16.8442 75.7738 TD
[(its)-327.8(prole)-327.4(to)-325.7(E)-319.1(but)-328.7(contained)-325.1(an)-325.4(additional)-325.8(very)-321.9(minor)-330.4(peak)]TJ
0 -1.2203 TD
[(\(data)-338.1(not)-335.4(shown\).)]TJ
/F6 1 Tf
9.9626 0 0 9.9626 313.0582 688.8187 Tm
[(Di)-8.2(scussion)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 323.0361 670.9604 Tm
[(Although)-355.8(biosimilar)-349.2(IFN-)]TJ
/F4 1 Tf
11.3307 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-347.3(products)-351.7(as)-354.9(dened)-347.3(by)-350.3(the)]TJ
-12.9999 -1.2203 TD
[(European)-416.7(Medicines)-417.3(Agency)-411.1(and)-410.6(WHO)-413(have)-414.5(not)-411.3(been)-412.3(ap-)]TJ
T*
[(proved)-368.9(anywhere)-366.9(in)-361(the)-364.2(world)-359.4(as)-367.6(yet,)-361.8(a)-359.9(number)-367.7(of)-363.7(alterna-)]TJ
0 -1.2266 TD
[(tive)-681.2(copy)-671.7(products)-680.5(of)-673.5(innovator)-674.9(IFN-)]TJ
/F4 1 Tf
18.1973 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-669.7(products)-680.5(are)]TJ
-18.7538 -1.2203 TD
[(available)-311.4(in)-310.4(South)-310(America)-311.7(and)-309.4(Asia.)-305.9(In)-309(this)-312.2(study,)-310.7(we)-305(have)]TJ
T*
[(for)-414.9(the)-408.4(rst)-410.2(time)-412.5(compared)-415.1(the)-408.4(biological)-413(activity)-410.3(and)-410.6(mo-)]TJ
T*
[(lecular)-330.3(characteristics)-328.3(of)-325.7(some)-324(of)-325.7(the)-326.2(available)-324(noninnovator)]TJ
0 -1.2266 TD
(IFN-)Tj
/F4 1 Tf
2.036 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
[(-1a)-322(products)-320.1(with)-325.2(those)-317.7(of)-325.7(approved)-319.2(innovator)-320.8(IFN-)]TJ
/F4 1 Tf
23.2114 0 TD
(b)Tj
/F3 1 Tf
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(-)Tj
-26.3476 -1.2203 TD
[(1a)-258.3(products.)-266.1(This)-257.8(analytical)-257(evaluation)-267.6(revealed)-260.1(considerable)]TJ
T*
[(heterogeneity)-510(among)-494.5(IFN-)]TJ
/F4 1 Tf
12.0452 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-499(products)-497.1(produced)-504.6(by)-495.7(dif-)]TJ
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[(ferent)-396.9(manufacturing)-400.7(processes)-393.5(around)-396.4(the)-395.8(world.)-393.9(Key)-392.8(dif-)]TJ
0 -1.2203 TD
[(ferences)-346.3(have)-338.7(been)-342.7(noted)-338.3(in)-342(the)-338.9(composition,)-344.2(concentration,)]TJ
T*
[(and)-467.5(activity)-460.9(of)-458.5(manufactured)-468.1(IFN-)]TJ
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15.8515 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-461.1(products,)-462.1(but)-461.5(how)]TJ
-16.408 -1.2266 TD
[(these)-441.2(differences)-435.5(impact)-438(clinically)-434.5(can)-432.1(only)-437.7(be)-434.3(assessed)-431.2(by)]TJ
0 -1.2203 TD
[(conducting)-703.8(appropriate)-694(clinical)-698.5(studies)-693.8(for)-699.5(efcacy)-695.1(and)]TJ
T*
[(safety)-341.2(including)-335.3(immunogenicity.)]TJ
1.1128 -1.2203 TD
[(Immunochemical)-712.6(analysis)-705.7(by)-704.4(SDSpolyacrylamide)-710.1(gel)]TJ
-1.1128 -1.2266 TD
[(electrophoresis)-248.5(followed)-238.9(by)-236.5(immunoblotting)-244.2(revealed)-241.1(that)-237.8(all)]TJ
0 -1.2203 TD
(IFN-)Tj
/F4 1 Tf
2.036 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-366.2(products)-364.3(contained)-369.3(in)-367.3(large)-362.1(proportion)-367.6(the)-370.5(mono-)]TJ
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[(meric)-329.8(IFN-)]TJ
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4.8054 0 TD
(b)Tj
/F3 1 Tf
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[(-1a,)-324.9(migrating)-327.4(at)-328.8(the)-332.5(expected)-328.4(molecular)-330.6(weight)]TJ
-5.3618 -1.2266 TD
(of)Tj
/F4 1 Tf
1.4416 0 TD
(*)Tj
/F3 1 Tf
.999 0 TD
[(1824)-162(kDa.)-571(In)-574.6(the)-572.8(absence)-576.8(of)-572.3(HSA,)-571.8(only)-570.5(one)-575.1(much)]TJ
-2.4406 -1.2203 TD
[(weaker)-328.5(band)-326.5(of)-319.4(38)-169.7(kDa)-321.5(was)-324.9(visible,)-329.7(probably)-324.6(representing)-328.8(a)]TJ
T*
[(minor)-330.4(amount)-327.5(of)-332(IFN-)]TJ
/F4 1 Tf
9.9396 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-328.3(dimer.)-323.8(However,)-331(in)-329.4(the)-326.2(presence)]TJ
-10.4897 -1.2266 TD
[(of)-294.1(HSA)-290.7(used)-296.4(as)-291.7(an)-287.4(excipient)-298(in)-291.5(the)-288.3(formulation)-294.3(of)-294.1(a)-290.4(majority)]TJ
0 -1.2203 TD
[(of)-509.1(products,)-512.7(slower)-509.4(migrating,)-507.3(multiple)-510.8(bands)-511.1(of)-502.8(varying)]TJ
T*
[(number)-260.2(and)-252.5(intensity)-254.4(were)-255(observed.)-255.9(As)-249.3(the)-256.7(anti-IFN-)]TJ
/F4 1 Tf
23.6667 0 TD
(b)Tj
/F3 1 Tf
.803 0 TD
(mAb)Tj
-24.4697 -1.2266 TD
[(does)-329.5(not)-329.1(react)-328.7(with)-331.5(HSA,)-331.6(these)-327.4(bands)-327.8(must)-329.5(represent)-336.4(IFN-)]TJ
/F4 1 Tf
26.1199 0 TD
(b)Tj
/F3 1 Tf
-26.1199 -1.2203 TD
[(polypeptides,)-247.1(probably)-242.4(as)-234.8(adducts)-241.9(with)-243(breakdown)-241(products)]TJ
T*
[(of)-755.7(HSA)-746(and)-752(aggregatesdimers)-753.1(and)-752(higher-molecular-)]TJ
T*
[(weight)-487.5(oligomersof)-493(IFN-)]TJ
/F4 1 Tf
12.2412 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
[(.)-483.5(That)-486.9(these)-491.8(bands)-479.5(were)-489(most)]TJ
-12.7913 -1.2266 TD
[(numerous)-444.6(and)-435.9(intense,)-438.4(particularly)-441.5(an)-439.2(apparent)-442.5(tetrameric)]TJ
0 -1.2203 TD
[(aggregate)-462.2(at)]TJ
/F4 1 Tf
6.0447 0 TD
(*)Tj
/F3 1 Tf
.999 0 TD
[(76)-169.7(kDa,)-457.2(in)-462.2(the)-459(noninnovator)-463.1(products)-465.5(with)]TJ
-7.0437 -1.2203 TD
[(the)-332.6(lowest)-325.8(specic)-323.8(activities,)-331.4(C1)-328.5(and)-322(F1,)-323(suggests)-330.6(an)-325.4(inverse)]TJ
0 -1.2266 TD
[(correlation)-256.8(between)-256.2(their)-254.6(formation)-251.5([presence])-259.6(and)-252.5(biological)]TJ
0 -1.2203 TD
[(activity.)-400.6(Further)-403(supporting)-400(evidence)-401.7(of)-395.3(adduct)-398.7(and)-397.9(aggre-)]TJ
T*
[(gate)-396.3(formation)-396.9(for)-396(products)-402.3(formulated)-395(with)-394.7(HSA)-398.2(was)-394.5(ob-)]TJ
0 -1.2266 TD
[(tained)-793.8(with)-793.1(reverse-phase)-799.5(HPLC.)-791.5(Additional)-795.5(peaks)-790.5(of)]TJ
0 -1.2203 TD
[(unknown)-285.9(protein)-284(composition)-290.6(to)-281.4(the)-282(major)-277.4(IFN-)]TJ
/F4 1 Tf
21.2892 0 TD
(b)Tj
/F3 1 Tf
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[(peak)-283.4(were)]TJ
-22.1175 -1.2203 TD
[(observed)-335.2(in)-335.7(both)-333.5(approved)-331.8(and)-334.7(noninnovator)-336.7(products,)-335.6(but)]TJ
T*
[(again)-516.2(were)-520.6(greatest)-518.8(in)-512.8(number)-519.5(and)-511.7(peak)-517.3(height)-514.6(in)-519.1(those)]TJ
0 -1.2266 TD
[(noninnovator)-343(products)-339(with)-331.5(the)-338.9(lowest)-332.1(specic)-336.5(activity.)]TJ
1.1128 -1.2203 TD
[(We)-422.6(therefore)-431.8(assessed)-424.9(the)-421.1(biological)-425.7(activity)-429.3(of)-420.6(different)]TJ
-1.1128 -1.2203 TD
(IFN-)Tj
/F4 1 Tf
2.036 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
[(-1a)-265.1(products)-263.2(in)-266.2(both)-264(AVA)-264.8(and)-258.8(reporter)-265.7(gene)-266.8(assay.)-261.9(For)]TJ
-2.5861 -1.2267 TD
[(this,)-340.4(we)-336.6(used)-340.7(the)-338.9(third)-333.6(IS)-335.7(for)-339.1(IFN-)]TJ
/F4 1 Tf
15.2445 0 TD
(b)Tj
/F3 1 Tf
.8915 0 TD
[(\(glycosylated;)-339.8(CHO)-338.3(cell)]TJ
-16.1361 -1.2203 TD
[(derived,)-715.5(coded)-703.5(00/572,)-711.7(assigned)-705.6(potency)-713.4(of)-711.4(40,000)-164.9(IU/)]TJ
T*
[(ampo)11.4(ule\))-239.2(for)-244.2(cali)13.1(bra)14.3(tio)12.2(n)-250(o)0(f)-249.8(bio)14.6(assay)19.2(s.)-250.8(Thi)15.4(s)-254.2(I)0(S)-247.2(has)-238.2(been)-241.5(sho)11.5(wn)]TJ
0 -1.2266 TD
[(to)-376.3(be)-377.4(sui)12.8(tabl)17.4(e)-379.3(a)0(s)-373.9(a)-378.9(ref)11.6(erenc)15.8(e)-379.3(sta)11.3(nda)13.1(rd)-376.8(in)-373.6(bioa)15.1(ssay)12.4(s)-374.4(for)-370.7(mea-)]TJ
0 -1.2203 TD
[(suri)12.1(ng)-703.3(the)-692.9(pote)14.5(ncy)-696.3(of)-705.1(cli)12.6(nic)12.8(al)-698.6(grade)-690.4(IFN)12.5(-)]TJ
/F4 1 Tf
20.2396 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-695(prod)11.1(uct)11.5(s)]TJ
-20.7834 -1.2203 TD
[(\(Mea)14(ger)-264.3(and)-258.8(Gai)17.2(nes)-263.8(Das,)-251.7(2005)14.6(\).)-262.6(We)-264.5(foun)11(d)-262.2(that)-256.8(the)-263(cal)16.6(culat)14.8(ed)]TJ
0 -1.2266 TD
[(poten)11.1(cy)-364.1(for)-364.3(each)-362.5(prod)11.1(uc)12(t)-373.5(was)-362.9(cons)12.2(iste)13.8(nt)-370.6(betw)12.6(een)-363.6(thes)13.9(e)-372.9(dis-)]TJ
0 -1.2203 TD
[(tinc)12.3(t)-285(assa)17.3(y)-282.6(typ)12.7(es.)-276(In)-277.4(bot)11.3(h)-281.6(AVA)-271.2(and)-277.8(repo)14.2(rte)11.6(r)-278.9(gene)-273.2(assa)17.3(y,)-279.2(non-)]TJ
T*
[(inno)12.2(vat)11.9(or)-401.8(IFN-)]TJ
/F4 1 Tf
6.6707 0 TD
(b)Tj
/F3 1 Tf
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[(-1a)-397.8(pro)14.1(duct)14.9(s)-406(C)0(1)-404.4(and)-391.6(F1)-402.3(had)-397.9(com)13(para)11.6(tiv)14.2(ely)]TJ
-7.2208 -1.2203 TD
[(lowe)11.1(r)-259.9(biol)17.4(ogica)15.8(l)-262.8(pot)14.4(enci)12.9(es)-260.4(tha)15.6(n)-262.6(was)-255.4(sta)11.4(ted)-250(on)-259.1(thei)11.7(r)-259.9(resp)15.7(ectiv)15(e)]TJ
0 -1.2266 TD
[(labe)11.6(ls)-308.3(\(be)14.2(low)-305.1(the)-307.3(lab)17.8(el)-313.3(stre)16.6(ngth)-302.5(of)-306.7(6)-309.3(MIU\))-300(and)-303.1(rela)15.3(tive)14.3(ly)-305.1(low)]TJ
0 -1.2203 TD
[(spec)10.8(ic)-347.3(acti)16.2(vitie)17.1(s.)-352(A)-361.8(bat)14.6(ch-to)12.6(-ba)14.6(tch)-350.9(vari)14.5(atio)12.7(n)-351.1(was)-350.2(also)-348.6(not)12.3(ed)]TJ
T*
[(for)-187.3(product)-179.7(F.)-184.4(In)-176.2(contrast,)-187.9(noninnovator)-184.9(IFN-)]TJ
/F4 1 Tf
19.2659 0 TD
(b)Tj
/F3 1 Tf
.5564 0 TD
[(-1a)-176.5(products)-187.3(D1)]TJ
-19.8223 -1.2267 TD
[(and)-492.8(E1)-489.4(had)-492.8(relatively)-490.5(higher)-495.9(potencies,)-495.4(but)-493.1(close)-493.7(to)-490.1(their)]TJ
0 -1.2203 TD
[(stated)-599(label)-598.9(strength)-595.8(of)-597.6(12)-593.4(MIU.)-593.3(Their)-598.6(specic)-595.7(activities)]TJ
ET
q
239.006 0 0 152.617 62.305 579.628 cm
/Im1 Do
Q
BT
/F14 1 Tf
8.9663 0 0 8.9663 62.022 562.8471 Tm
[(FIG.)-621.3(2.)]TJ
/F3 1 Tf
4.3818 0 TD
[(An)-618.1(immunoblot)-624.4(of)-616.6(different)-625.2(IFN-)]TJ
/F4 1 Tf
15.8958 0 TD
(b)Tj
/F3 1 Tf
.5564 0 TD
[(-1a)-619.1(products)]TJ
-20.834 -1.1128 TD
[(\(coded)-413.1(AF\))-410.5(using)-412.4(a)-410.5(commercially)-416.3(available)-412.5(IFN-)]TJ
/F4 1 Tf
22.3768 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
(specic)Tj
-22.9269 -1.1065 TD
[(monoclonal)-448.5(antibody)-445.2(showing)-444.1(variable)-448.1(composition)-448.7(of)-445.8(the)]TJ
0 -1.1128 TD
[(different)-435.5(products.)-436.8(Different)-433.9(IFN-)]TJ
/F4 1 Tf
15.1307 0 TD
(b)Tj
/F3 1 Tf
.5501 0 TD
[(-1a)-429.5(products)-433.9(\()]TJ
/F4 1 Tf
6.3988 0 TD
(*)Tj
/F3 1 Tf
1.0053 0 TD
[(20)-163.4(ng)-431.4(of)]TJ
-23.085 -1.1128 TD
(IFN-)Tj
/F4 1 Tf
2.0297 0 TD
(b)Tj
/F3 1 Tf
.5564 0 TD
[(-1a)-372.5(protein/track\))-380.4(were)-375.2(electrophoresed)-379.3(under)-381.4(nonre-)]TJ
-2.5861 -1.1065 TD
[(ducing)-482.9(conditions)-491.4(using)-481.9(4%20%)-481.8(Tris/HCl)-483.1(gradient)-482.8(poly-)]TJ
0 -1.1128 TD
[(acrylamide)-611.6(gels)-609.8(for)-610.9(1)-170.2(h)0(,)-607(followed)-612(by)-609.5(immunoblotting)-617.2(as)]TJ
T*
[(described)-261.6(in)-259.8(the)-256.7(Materials)-260.2(and)-258.8(Methods)-262.6(section.)-260.2(Products)-256.8(are)]TJ
T*
[(as)-380.2(follows:)-385.7(track)-383.8(1,)-381.8(B2;)-384.8(track)-383.8(2,)-381.8(E2;)-378.5(track)-383.8(3,)-381.8(A3;)-383.2(track)-383.8(4,)-381.8(F2;)]TJ
0 -1.1065 TD
[(track)-244.7(5,)-236.4(F3;)-240.8(track)-244.7(6,)-242.7(A6)-241.2(\()]TJ
/F10 1 Tf
10.2368 0 TD
()Tj
/F3 1 Tf
.7714 0 TD
[(HSA\);)-243.5(track)-238.3(7,)-242.7(A5)-241.2(\(no)-240.6(HSA\);)-243.5(track)-244.6(8,)]TJ
-11.0082 -1.1128 TD
[(C1.)-318.7(To)-315.6(control)-316.4(for)-320.1(specicity,)-316.2(HSA)-316(in)-316.7(amounts)-322.5(reecting)-318.1(the)]TJ
T*
[(levels)-369.3(present)-373.8(in)-373.6(different)-372.2(IFN-)]TJ
/F4 1 Tf
13.8156 0 TD
(b)Tj
/F3 1 Tf
.5564 0 TD
[(-1a)-366.2(products)-377(was)-369.2(tested)-371.8(for)]TJ
-14.372 -1.1128 TD
[(reactivity)-493.1(with)-489.6(the)-490.6(IFN-)]TJ
/F4 1 Tf
10.9829 0 TD
(b)Tj
/F3 1 Tf
.5564 0 TD
[(specic)-487.7(monoclonal)-492.7(antibody)-495.7(in)]TJ
-11.5393 -1.1065 TD
[(some)-652.8(experiments.)-658(No)-654(reactivity)-651.2(was)-653.7(evident)-655.9(\(data)-647.9(not)]TJ
0 -1.1128 TD
[(shown\).)-338.3(HSA,)-331.6(human)-340.3(serum)-335.9(albumin.)]TJ
/F6 1 Tf
0 36.3884 TD
(388)Tj
46.72 0 TD
[(MEAGER)-334.9(ET)-338.7(AL.)]TJ
ET
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