III III a II0I 010 II0 III uui III 010 III I0I 0II 010 1110 II uii IIi - Questel

III III a II0I 010 II0 III uui III 010 III I0I 0II 010 1110 II uii IIi US 200801762 17A1

(19) (12)

(54)

United States Patent Application Publication

(10)

BOGOCH et al.

(43)

METHOD OF PREDICTING INFLUENZA OUTBREAKS BY CORRELATING AN INCREASE IN REPLIKIN COUNT IN SHRIMP WHITE SPOT SYNDROME VIRUS AND/OR TAURA SYNDROME VIRUS

(76) Inventors:

Samuel BOGOCH, New York, NY (US); Elenore S. BOGOCH, New York, NY (US); Samuel Winston BOGOCH, Oakland, CA (US); Anne Elenore BORSANYI, Brookline, MA (US)

Correspondence Address: KENYON & KENYON LLP 1500 K STREET N.W., SUITE 700 WASHINGTON, DC 20005 (21)

Appl. No.:

11/923,559

(22)

Filed:

Oct. 24, 2007 Related U.S. Application Data

(60) Provisional application No. 60/935,816, filed onAug. 31, 2007, provisional application No. 60/935,499,

Pub. No.: US 2008/0176217 Al Jul. 24, 2008 Pub. Date:

filed on Aug. 16, 2007, provisional application No. 60/954,743, filed on Aug. 8, 2007, provisional application No. 60/898,097, filed on Jan. 30, 2007, provisional application No. 60/880,966, filed on Jan. 18, 2007, provisional application No. 60/853,744, filed on Oct. 24, 2006.

Publication Classification (51)

(52)

(57)

Int. Cl. C12Q 1/70 C12Q 1/68

(2006.01) (2006.01)

U.S. Cl .................................................. 435/5; 435/6

ABSTRACT

The present invention provides a method of predicting outbreaks in influenza virus comprising monitoring concentrations of small peptides having defined structure in influenza viruses, and in particular viral pathogens of shrimp.

b 120

White Spot Syndrome Virus Replikin Concentration and H5N1 Human Mortality and Replikin Concentration

100

— • WSSV Replikin Concentration with

40

Standard Deviation —•H5N1 Human Mortality Percent

20

ao -- - H5N 1 Peak Gene

C; 1995 1997 1999 2001 2003 2005 2007

Replikin Concentration in Humans

b

20

Taura Syndrome Virus Replikin Concentration and H5N1 Human Mortality and Replikin Concentration

18 16 14 12 10

ao

8

Ar–H5N1 Peak Gene Replikin Concentration in Humans

6 4

—)( TSV Replikin Concentration with Standard Deviation

2 •–H5N1 Human Mortality per 10 infections

0 7 -2

ao

Patent Application Publication

Jul. 24, 2008 Sheet 3 of 17

US 2008/0176217 Al

FIGURE 3

2007 1" Qtr Year 2003 2004 2005 2006 HUMAN H5N1 Light Gray = Whole virus Replikin Concentration (Number of Replikins per 100 amino acids) Dark Gray = Replikin Peak Gene Replikin Count Uncolored Bar = Standard Deviation Black = % Human Mortality Rate (x 10)


Jul. 24, 2008 Sheet 4 of 17

US 2008/0176217 Al

Increasing Replikin Concentration ("Replikin Count") of Hemagglutinin Protein of H5N1 Prior to Three 'Bird Flu' 6 Epidemics.

El (1997)

U

E3 (2004) T

E2 (2001)

0

0

co. q C

Q q) 0

a E

0

U

c 2 a>

c . H5N1

1

1

I

oRj oS30 N

\ I

--,-

\ ) 003 ^9 oIQ o° oS^ o° o1+qo°§' qo°o I

I

I

J

cbcbc

FIG.4

I

I

I

I


Jul. 24, 2008 Sheet 5 of 17

US 2008/0176217 Al

FIGURE 5

Replikin Concentration vs Day of 50% Mortality of Shrimp Challenged with Taura Syndrome Virus

• Belize isolate 6 0

E • Thailand isolate

\° 0 ^

4 • Hawaii isolate

0 A

•Venezuela

M

❑

2

0 L

2.9

3

3.1

3.2

3.3

3.4

Replikin Concentration

3.5

3.6

olate

US 2008/0176217 Al

Jul. 24, 2008 Sheet 6 of 17


FIGURE 6

Replikin Concentration vs Cumulative Mortality in Shrimp Challenged with Taura Syndrome Virus 100 90

Belize isolate

80

Hawaii isolate

•

• Thailand isolate

70 60

• Venezuala isolate

50 40

1 30 20 10 0

1

2.9

I

3

3.1

1

I

3.2

3.3

Replikin Concentration

3.4

3.5

3.6


Jul. 24, 2008 Sheet 7 of 17

US 2008/0176217 Al

FIGURE 7 Cumulative survival of Litopenaeus vannamei per os challenged with TSV isolates: A: Belize; B: Thailand; C: Ilawaii; D: Venezuela.

100 90

100

e 90

A. Belize

80 70

B. Thailand

= 80 > 70 60 N 50 > 40 30 20 10 0

(Replikin concentration 3.5)

60 50 46 30 5 20 E 10 0 y


E U

U

1

2

3 4 5 6 7 8 Days after exposure to TSV

9 10 11

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Days after exposure to TSV

100 90 80 70 60 50 40 '30 20 V 10 0

n

100

C. Hawaii (Replikin concentration 3.3)

...............................................................................................................................:

:.

D. Venezuela

60 >


N 60 40 £ 20 U

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

1

2 3 4 5 6 7 8 9 10 11 12 13 14 15

Days after exposure to TSV Days after exposure to TSV

b

FIGURE 8

'4.1

Replikin Count = number of Replikins per 100 amino acids

Localization of 'Replikin Peak Gene' to pBl of Human H5N1 Virus: Comparison to Replikin Count in other Human H5N1 genes

D

GENE LOCALIZATION

n

S ies2 re +/-S.D.

A^

Mean

b

■ Seriesl

0 n

20

0

15

ao

10 Go

Nucleocapsid Matrix

pB2

Neuraminidase

pA

NS

Hemagglutinin pBl

5

CA

ao 0 '03---------'06

'03---------'06

'03---------- -06 '03----------'06

'03---------'06

03-------'06

'03---------'06

'03---------'06


25

Jul. 24, 2008 Sheet 9 of 17

'Reylikin Peak Gene' of H5N1 Virus: Activity in Four Hosts; Human Dominance

Count =number of Replikins per 100

20

US 2008/0176217 Al

HOST LOCALIZATION

acids

15 ::: Standard Deviation from Mean Replikin Count

10 H5N1 pBl Area Mean Replikin Count

61

'01 ('02)'03 '01 '05 '06

Goose

01---'02--'03---'04---'05--'06

Duc k

'01—'02—'03—'04—'05—'06

Chicken

Figure 9

('01 '02)'03 '01 '05 '06 (no data)

Human

b

FIGURE 10

25

Replikin Count =number of

Localization of 'Replikin Peak Gene' to Replikins per pg1 of Human H5N1 Virus in Indonesia 100 amino acids and Six Other Countries

❑ Series2

GEOGRAPHIC

+/-S.D.

LOCALIZATION

M

mean sl

20

Vietnam

15

Thailand Indonesia

ao

10

3apan

Russia

Egypt

China

ao

o

--

'03----------'06

^

'03----------'06

'03-----------'06

'03------------'06

'03-----'06

'03----------=06

'03---------'06

It

15

I

U) C.) 0

E

H2N 2-Epkiernic

10

Ow

H1N1Pandemic 1918

C 0-

c

H2N2•Pandemic 1957

I

H 0 00

CL

H1N1Epidemc

61

ci)

I-t3N2Eric

0

H3N2-Pandemc

E

1968

z ci)

o ±1910 1920 1930 1940 1950 1960

Year FIG. 11

1970

1980 1990 2000 2010


Jul. 24, 2008 Sheet 12 of 17

US 2008/0176217 Al

0 I

72 0 U

rJ

r

er

/

I """""...."""

Ln GCr

kp

c^ '

311l0) ui !ld,) 1

c\i

0

b

12.0

13 10.0 0 b

C

n

8.0

0

-Replikin Concentration (Std. Dev. bars)

6.0

-- ^ -Total U.S. (Reported) Morbidity (x1000)

4.0

—f—Total U.S. Mortality (x100)

2.0

West Nile Virus :eplikin Concentration 0.0

1999-2006 1

-2.0

)8

ao


Jul. 24, 2008 Sheet 14 of 17

US 2008/0176217 Al

3.5

FIGURE 14 Cl • 200]. Epidemic

• 2( )07 Epidemic

2.5

2

— —Replikin Concentration 1.5

Foot and Mouth Disease V irus Replikin Concentration Per Year

0.5

(all serotypes)

[ii 1996 1998 2000 2002 2004 2006 2008

N

U

ry d.

N rl

vm

n p cm .. < :.o

of

t0 U

iUvQ

n o-'

\ 0 0

c C

C N

N y C

W O

y

C^

W

w •

^ HH

1

v

1

'""""'lJJfilvv.Giiilfifillvviiiiiififi)lvv.Eilfififilvvvv.;

^7

,1

Nr °i•

p

'p roririrnmmwon n. i

n•

n' W

vaar^r^r^

CD CD

c

W

00

1

W W

V

riririiiidririririririiiidririririririiddririririririiddririririririid riririri ^

y O ^j

•

^ ^ ^

f

W W

1

W

f

1 1 f

y ^

[ O U i.w

q O

uvvmHH/., 1

W L C ^

.rruu. ^rrrrrr.r.rruu. ^rrrrrr.rrrruu. ^rrrrrr.rrrru. ^.^rrrrrr.rruu. ^rrrrrrrr.rruu. ^rrrrrr.r.rruu. ^rrrrrr.^

::::::::::::::...................... .

Lu H^ Z

W

Lu r^ l

W

cy

I I^

.mviaan

uai,;râuaûo^ ui,ry jd ^ b o

f


Jul. 24, 2008 Sheet 16 of 17

US 2008/0176217 Al

FIGURE 16 80

70 0 60 I—

z W

U

w

50

0

z H

$Replikin Peak Gene (pB1 gene area) 40


I-

w

H5N1 pB2 Replikin Concentration

30

U

in Humans

z

0

U Z

20

-H5N1 pA Replikin Concentration in Humans

J W

10 ,

0 2002

2003

2004

2005

2006

2007

2008

H5N1 Human Mortality percent


Jul. 24, 2008 Sheet 17 of 17

US 2008/0176217 Al

90

FIGURE 17 80

70

60

50

+ Replikin Peak Gene (pB1 gene area) 40


H5N1 pB2 Replikin Concentration

30

in Humans

20

A---,,

H5N1 pA Replikin Concentration in Humans

10

$\-,

0 2002

2003

2004

2005

2006

2007

2008

H5N1 Human Mortality percent

US 2008/0176217 Al

METHOD OF PREDICTING INFLUENZA OUTBREAKS BY CORRELATING AN INCREASE IN REPLIKIN COUNT IN SHRIMP WHITE SPOT SYNDROME VIRUS AND/OR TAURA SYNDROME VIRUS

[0001] This application claims priority to U.S. Provisional Appin. Ser. No. 60/935,816, filed Aug. 31, 2007, U.S. Provisional Appin. Ser. No. 60/935,499 filed Aug. 16, 2007, U.S. Provisional Appin. Ser. No. 60/954,743, filed Aug. 8, 2007, U.S. Provisional Appin. Ser. No. 60/898,097, filed Jan. 30, 2007, U.S. Provisional Appin. Ser. No. 60/880,966, filed Jan. 18, 2007, and U.S. Provisional Appin. Ser. No. 60/853,744, filed Oct. 24, 2006, each of which is incorporated herein by reference in its entirety. This application additionally incorporates herein by reference: U.S. application Ser. No. 11/355, 120, filed Feb. 16, 2006, U.S. application Ser. No. 11/755, 597, filed May 30, 2007, U.S. application Ser. No. 11/116, 203, filed Apr. 28, 2005, U.S. application Ser. No. 10/860, 050, filed Jun. 4, 2004, U.S. application Ser. No. 10/189,437, filed Jul. 8, 2002, U.S. application Ser. No. 10/105,232, filed Mar. 26, 2002, now U.S. Pat. No. 7,189,800, U.S. application Ser. No. 09/984,057, filed Oct. 26, 2001, and U.S. application Ser. No. 09/984,056, filed Oct. 26, 2001, now U.S. Pat. No. 7,176,275, each in its entirety. TECHNICAL FIELD OF THE INVENTION [0002] This invention relates generally to predicting influenza outbreaks through monitoring quantitative changes in the concentration of a class of peptide sequences known as Replikins in virus proteins, protein fragments, or genomes. BACKGROUND OF THE INVENTION [0003] Rapid replication is characteristic of virulence in, among other things, certain bacteria, viruses and malignancies. The inventors have described a quantitative chemistry common to rapid replication in different viruses and organisms. The chemistry of rapid replication described by the inventors is present in a family of conserved small protein sequences related to rapid replication, Replikins. An increase in the concentration of these Replikin sequences encoded in the genome of different strains of influenza virus has been correlated with an increase in the virulence of influenza. A correlation between increased concentrations of Replikin sequences and increased replication and virulence has likewise been observed in a range of viruses and organisms. Replikin sequences offer new targets for developing effective methods of predicting and treating influenza outbreaks. There continues to exist a particular need in the art for methods of predicting viral outbreaks. [0004] Influenza is an acute respiratory illness of global importance. Despite international attempts to control influenza virus outbreaks through vaccination, influenza infections remain an important cause of morbidity and mortality. Worldwide influenza pandemics have occurred at irregular and previously unpredictable intervals throughout history and it is expected that influenza pandemics will continue to occur in the future. The impact of pandemic influenza is substantial in terms of morbidity, mortality and economic cost. [0005] Influenza vaccines remain the most effective defense against influenza virus, but because of the ability of

Jul. 24, 2008

the virus to mutate, and the availability of non-human host reservoirs, it is expected that influenza will remain an emergent or re-emergent infection. Global influenza surveillance indicates that influenza viruses may vary within a country and between countries and continents during an influenza season. Virologic surveillance is of importance in monitoring antigenic shift and drift. Disease surveillance is also important in assessing the impact of epidemics. Both types of information have provided the basis of vaccine composition and use of antivirals. However, there has traditionally been only annual post hoc hematological classification of the increasing number of emerging influenza virus strains, and no specific chemical structure of the viruses was traditionally identified as an indicator of approaching influenza epidemic or pandemic. Until recently, the only basis for annual classification of influenza virus as active, inactive or prevalent in a given year was the activities of the virus hemagglutinin and neuraminidase proteins. [0006] The small peptide structure called Replikins has now been identified within influenza virus proteins and correlated with an increase in virulence. A Replikin sequence is an amino acid sequence of 7 to about 50 amino acids comprising a Replikin motif. A Replikin motif comprises (1) at least one lysine residue located at a first terminus of the motif and at least one lysine residue or at least one histidine residue located at a second terminus of the motif, (2) a first lysine residue located six to ten residues from a second lysine residue; (3) at least one histidine residue; and (4) at least 6% lysine residues. A Replikin sequence may comprise a terminal lysine and may further comprise a terminal lysine or a terminal histidine. A Replikin peptide or Replikin protein is a peptide or protein consisting of a Replikin sequence. [0007] Higher concentrations of Replikin sequences in the genomic code are associated with a variety of infectious agents including HIV, plant viruses, and a range of pathogenic animal and human viruses including flu viruses. Further, the correlation between the concentration of Replikin sequences in viral or organismal proteins and major outbreaks of disease is significant. Replikin sequences generally have been found to be conserved in both intrastrain and interstrain influenza viruses for as long as 89 years based on data going back to the 1917-18 flu pandemic. Concentration of Replikin sequences in viral genomes has been shown to increase prior to strainspecific flu outbreaks. [0008] Within the last century there have been three influenza pandemics, each strain specific: H1N1 in 1918; H2N2 in 1957; and H3N2 in 1968. The inventors have established that prior to each pandemic there was a strain-specific increase in the concentration of Replikin sequences within the strain. The strain-specific increase in Replikin concentration was followed by a decrease in Replikin concentration and several years later a rebound increase in Replikin concentration associated with a strain-specific rebound epidemic. The Replikin algorithm provided the first chemistry that correlated with influenza epidemics and pandemics. [0009] A similar correlation between the outbreaks of H5NI (Bird Flu) between 1997 and 2007 and the concentration of Replikin sequences in the viral proteins during each of those years has been demonstrated. Likewise, a correlation has been established between the global outbreak of SARS coronavirus in 2003 and an increase in the concentration of Replikin sequences in the proteins of coronavirus. In another study, Replikins in two strains of human HIV-1 virus demonstrated that the Replikin concentration in the rapidly replicat-

Jul. 24, 2008

US 2008/0176217 Al 2 ing strain was six fold greater than that of a slowly replicating strain. No instances of rapid replication have been observed in all the viruses and organisms examined wherein the Replikin concentration did not significantly increase as compared to the Replikin concentration in the dormant state. [0010] The highest concentration of Replikin sequences in an organism or virus that has to date been analyzed and reported is 111 Replikin sequences per 100 amino acids in the extraordinarily-rapidly-replicating parasitic protozoa Plasmodium falciparum (reportedly responsible for 90% of malarial deaths in humans) (herein sometimes referred to as malaria). P. falciparum has been observed to replicate 11,000 times in 48 hours during passage of the parasite from liver to blood in the host. [0011] It has been believed that changes in the activity of different influenza strains are related to random sequence changes in influenza hemagglutinins, which in turn are the products of substitutions effected by one oftwo poorly understood processes: i) antigenic drift, thought to be due to the accumulation of a series of point mutations in the hemagglutinin molecule, or ii) antigenic shift, in which the changes are so great that genetic reassortment is postulated to occur between the viruses of human and non-human hosts. The data provided by the inventors suggests that change in activity in different influenza strains, rather than being related to nonspecific random sequence changes, is based upon, or related to, an increase in concentration of strain-specific Replikins. Data were also examined for insight into which sequence changes were due to "drift" or "shift" and which were due to conservation, storage in "reservoirs," and reappearance. The data has shown that the epidemic-related increase in Replikin concentration is not due to the duplication of existing Replikins in the hemagglutinin of the emerging strain, but, instead is due to the reappearance of at least one Replikin composition from 1 to up to 59 years after its disappearance, plus (in theA strains only) the emergence of new strain-specific Replikin compositions. See U.S. Pat. No. 7,189,800 issued Mar. 13, 2007 (Tables 3-6). [0012] In monitoring Replikin sequences in influenza virus, the inventors have additionally identified a sub-family of conserved Replikin sequences known as Replikin Scaffolds or Replikin Scaffold sequences. Replikin Scaffolds were initially identified in conserved structures in particularly virulent influenza viruses. Included among these strains were the viruses causing the pandemics of 1918, 1957, 1968 and virulent strains of the H5N1 "bird flu" strain of influenza virus. Analogues of Replikin Scaffold sequences have since been identified in the virulent and rapidly replicating SARS coronavirus. See U.S. Published Application No. 2007/ 0026009. [0013] Scaffolding of Replikin sequences homologous but not identical to the algorithm of the identified Replikin Scaffold has also been identified in P. falciparum. Replikin scaffolding in general has been related to an increase in Replikin concentrations in pathogenic genomes where it has been identified. In P. falciparum, scaffolding contributes significantly to the very high Replikin concentration noted in the proteins of the protozoa. [0014] There is a need in the art for methods of predicting increases in virulence of influenza prior to outbreaks. There is likewise a need in the art for methods of preventing and treating outbreaks caused by virulent strains of influenza. Because of the annual administration of influenza vaccines

and the short period of time when a vaccine can be administered, strategies directed at improving vaccine coverage are of critical importance. SUMMARY OF THE INVENTION [0015] The present invention provides a method of determining an increased probability of an outbreak of influenza virus within about one to about three years following an increase in Replikin concentration in an isolate of White Spot Syndrome Virus or an isolate of Taura Syndrome Virus comprising identifying said increase in the concentration of Replikin sequences in at least one first isolate of White Spot Syndrome Virus or Taura Syndrome Virus as compared to at least one other isolate of White Spot Syndrome Virus or Taura Syndrome Virus wherein said at least one first isolate is isolated at least six months later than said at least one other isolate is isolated and wherein when said at least one first isolate is a White Spot Syndrome Virus isolate said at least one other isolate is a White Spot Syndrome Virus isolate and when said at least one first isolate is a Taura Syndrome Virus isolate said at least one other isolate is a Taura Syndrome Virus isolate, and wherein said increase in the concentration of Replikin sequences signifies the increased probability of the outbreak of influenza virus within about one to about three years following said increase in the concentration of Replikin sequences. [0016] In an embodiment of the method of determining an increased probability of an outbreak of influenza virus, said identification of an increase in Replikin concentration in said at least one first isolate comprises (1) determining the concentration of Replikin sequences in (i) a plurality of isolates of White Spot Syndrome Virus wherein said at least one first isolate has been isolated about six months to about three years later than said at least one other of said isolates of White Spot Syndrome Virus, or (ii) a plurality of isolates of Taura Syndrome Virus wherein said at least one first isolate of Taura Syndrome Virus is isolated about six months to about three years later than at least one other isolate of Taura Syndrome Virus. [0017] An embodiment of the present invention provides a method of determining an increased probability of an outbreak of influenza virus comprising: (1) obtaining a plurality of isolates of White Spot Syndrome Virus or a plurality of isolates of Taura Syndrome Virus wherein at least one of said isolates of White Spot Syndrome Virus is isolated about six months to about 3 years later than at least one other of said isolates of White Spot Syndrome Virus or wherein at least one of said isolates of Taura Syndrome Virus is isolated about six months to about 3 years later than at least one other of said isolates of Taura Syndrome Virus; (2) analyzing the amino acid sequence of at least one encoded protein or protein fragment or a combination of encoded proteins and/or protein fragments in each isolate of the plurality of isolates of White Spot Syndrome Virus or the plurality of isolates of Taura Syndrome Virus for the presence and concentration of encoded Replikin sequences; (3) comparing the concentrations of encoded Replikin sequences in the at least one protein or protein fragment or in the combination of proteins or protein fragments in each isolate of the plurality of isolates of White Spot Syndrome Virus or in each isolate of the plurality of isolates of Taura Syndrome Virus;

US 2008/0176217 Al

(4) identifying an increase in the concentration of encoded Replikin sequences in said plurality of isolates of White Spot Syndrome Virus or in said plurality of isolates of Taura Syndrome Virus over at least one time period of about six months or greater; and (5) predicting an outbreak of influenza within about one to about three years following said identified increase in the concentration of Replikin sequences in said isolates of White Spot Syndrome Virus or in the concentration of Replikin sequences in said isolates of Taura Syndrome Virus. [0018] In a further embodiment of the invention, the increase in concentration of encoded Replikin sequences in said plurality of isolates of White Spot Syndrome Virus or in said plurality of isolates of Taura Syndrome Virus over at least one time period of about six months or greater is an increase in the mean concentration of at least two isolates as compared to at least two other isolates isolated at a later time point of about six months or greater. In a further embodiment, the increase in concentration is an increase in the mean concentration of at least 10 isolates as compared to at least 10 other isolates. In a further embodiment, the increase in concentration is an increase in the mean concentration of all isolates available at a given time point as compared to all isolates available at another given time point, wherein said time points are separated by about six months or greater. In a further embodiment, the mean concentration of said plurality of isolates is increased over the at least one time period when the mean concentration of the isolates at a later time point is greater than the mean concentration plus one standard deviation of the earlier isolates. In a further embodiment, the mean concentration of said plurality of isolates is increased over the at least one time period when the mean concentration of the isolates at a later time point is greater than the mean concentration plus two standard deviations of the earlier isolates. In a further embodiment of the invention, analyzing the combination of encoded proteins and/or protein fragments preferably comprises all amino acid sequences available for White Spot Syndrome Virus or all amino acid sequences available for Taura Syndrome Virus at a given time point, such as, for example, all amino acid sequences available in a first year and all amino acid sequences available in some other year. In another embodiment, the combination comprises at least 100 amino acid sequences. In another embodiment, the combination comprsises at least 50 amino acid sequences. In another embodiment, the combination comprises at least 10 amino acid sequences. In another embodiment, the combination comprises at least 2 amino acid sequences. [0019] In further embodiment of the invention, the method of predicting the outbreak of influenza virus may further comprise: (1) identifying at least one Replikin Scaffold sequence present in at least one isolate of the plurality of isolates of White Spot Syndrome Virus identified as having an increase in the concentration of Replikin sequences as compared to at least one other isolate of the plurality of isolates of White Spot Syndrome Virus over a time period of about six months or greater or identifying at least one Replikin Scaffold sequence present in at least one isolate in the plurality of isolates of Taura Syndrome Virus identified as having an increase in the concentration of Replikin sequences as compared to at least one other isolate of the plurality of isolates of Taura Syndrome Virus over a time period of about six months or greater; (2) identifying at least one Replikin Scaffold sequence present in at least one isolate of a strain of influenza virus,

Jul. 24, 2008

wherein said strain of influenza is isolated within the time period in which the increase in concentration of Replikin sequences is identified or wherein said strain of influenza is isolated within said time period of about one to about three years after said increase in concentration of Replikin sequences is identified; and (3) predicting the strain of influenza virus in which the at least one Replikin Scaffold sequence is identified as the strain of virus that will likely cause the predicted outbreak of influenza virus, wherein a Replikin Scaffold is a peptide having about 16 to about 34 amino acids comprising (a) a terminal lysine and optionally a lysine immediately adjacent to the terminal lysine; (b) a terminal histidine and optionally a histidine immediately adjacent to the terminal histidine, (c) a lysine within about 6 to about 10 amino acids of another lysine; and (d) at least 6% lysines. In an embodiment, the likelihood of an outbreak of influenza is preferably greater than 50%, more preferably greater than 60%, and even more preferably greater than 75%. [0020] In a further embodiment of the invention, the Replikin Scaffold is a peptide having about 27 to about 33 amino acids. In an influenza virus, a Replikin Scaffold may refer to a Replikin peptide sequence comprising about 16 to about 34 amino acid residues, and in a preferred embodiment about 28 to about 30 amino acid residues. In a White Spot Syndrome Virus, a Replikin Scaffold may refer to a Replikin peptide sequence comprising about 16 to about 34 amino acid residues, and in a preferred embodiment about 29 to about 31 amino acid residues. In a Taura Syndrome Virus, a Replikin Scaffold may refer to a Replikin peptide sequence comprising about 16 to about 34 amino acid residues, and in a preferred embodiment about 29 to about 33 amino acid residues. [0021] In an embodiment of the invention, the method of predicting an outbreak of influenza virus may comprise the prediction of an outbreak of any strain of influenza virus. In a further embodiment, the method of predicting an outbreak of influenza virus may comprise the prediction of an outbreak of influenzaA. In a preferred embodiment, the outbreak of influenza A may be an outbreak of H5N1 ("bird flu") virus. [0022] Ina further embodiment of the invention, a plurality of isolates of White Spot Syndrome Virus may be obtained and analyzed for Replikin concentration or a plurality of isolates of Taura Syndrome Virus may be obtained and analyzed for Replikin concentration, or both in order to predict an outbreak of influenza virus. [0023] In a further embodiment of the invention, the concentration of encoded Replikin sequences in said plurality of isolates of White Spot Syndrome Virus or said plurality of isolates of Taura Syndrome Virus over at least one time period of about six months or greater may increase by one or more Replikin sequences per 100 amino acids, may increase by five or more Replikin sequences per 100 amino acids, may increase by ten or more Replikin sequences per 100 amino acids, may increase by fifty or more Replikin sequences per 100 amino acids, may increase by 90 or more Replikin sequences per 100 amino acids, or may increase by 100 or more Replikin sequences per 100 amino acids. [0024] The identified increase in concentration of encoded Replikin sequences in said plurality of isolates of White Spot Syndrome Virus or said plurality of isolates of Taura Syndrome Virus may occur over any time period including over one month or more, over six months or more, over one year or more, or over three years or more. In an embodiment of the invention, the identified increase in concentration of encoded

Jul. 24, 2008

US 2008/0176217 Al Ld Replikin sequences occurs over at least six months to about five years. In a further embodiment of the invention, the identified increase in concentration of encoded Replikin sequences preferably occurs over at least six months to about three years. [0025] In a further embodiment of the invention, the method of predicting an outbreak of influenza may predict an outbreak within about one month to about five years or more following the identification of an increase in Replikin concentration in a plurality of isolates of White Spot Syndrome Virus or in a plurality of isolates of Taura Syndrome Virus. In a further embodiment of the invention, the method may predict an outbreak within several months to about three years. [0026] In another embodiment, the method may predict an outbreak within about one year to about five years. In a further embodiment of the invention, the method may predict an outbreak within several months to about one year. In another embodiment, the method may predict an outbreak within about one year to about three years. [0027] Another aspect of the invention provides a method of predicting an outbreak of influenza virus comprising analyzing Replikin concentration in reservoirs for influenza virus. A non-limiting embodiment of the invention provides a method of predicting an outbreak of influenza virus comprising: (1) obtaining a plurality of isolates of a first virus from at least one reservoir of Replikin sequences shared by influenza virus wherein the reservoir of Replikin sequences shared by influenza is any source of Replikin sequences that may be shared with an influenza virus including any host of influenza virus, any food source of a host of the influenza virus, any vector of influenza virus, or any substance wherein the genetic information of the influenza virus may be shared, mingled, mixed, exchanged or come into the proximity of the Replikin sequences of the reservoir; (2) analyzing the amino acid sequence of at least one encoded protein or protein fragment or a combination of encoded proteins and/or protein fragments in each isolate of the plurality of isolates of said first virus for the presence and concentration of encoded Replikin sequences; (3) comparing the concentrations of encoded Replikin sequences in the at least one protein or protein fragment or in the combination of proteins or protein fragments in each isolate of the plurality of isolates of said first virus; (4) identifying an increase in the concentration of encoded Replikin sequences in said plurality of isolates of said virus over at least one time period of about six months or greater; and (5) predicting an outbreak of influenza within about one to about three or more years following said identified increase in the concentration of Replikin sequences in said isolates of said first virus. [0028] Ina further non-limiting embodiment, the reservoir is shrimp. In another non-limiting embodiment, the reservoir is a bird. In another non-limiting embodiment, the reservoir is a migratory bird. In another non-limiting embodiment, the reservoir is a chicken, duck, goose, or other domestic bird. [0029] In a further non-limiting embodiment, the method of predicting an outbreak of influenza virus further comprises: (1) identifying at least one Replikin Scaffold sequence present in at least one isolate of the plurality of isolates of said first virus identified as having an increase in the concentration

of Replikin sequences as compared to at least one other isolate of the plurality of isolates of said first virus over a time period of about six months; (2) identifying at least one Replikin Scaffold sequence present in at least one isolate of a strain of influenza virus, wherein said strain of influenza is isolated within a time period in which the increase in concentration of Replikin sequences is identified or wherein said strain of influenza is isolated within a time period of about one year to about three years after said increase in concentration of Replikin sequences is identified; and (3) predicting the strain of influenza virus in which the at least one Replikin Scaffold sequence is identified as the strain of virus that will cause the predicted outbreak of influenza virus, wherein a Replikin Scaffold is a peptide consisting of about 16 to about 34 amino acids comprising (1) a terminal lysine and optionally a lysine immediately adjacent to the terminal lysine; (2) a terminal histidine and optionally a histidine immediately adjacent to the terminal histidine, (3) a lysine within about 6 to about 10 amino acids of another lysine; and (4) at least 6% lysines. BRIEF DESCRIPTION OF THE DRAWINGS [0030] FIG. 1 illustrates a correlation between (1) the mean concentration and standard deviation of Replikin sequences observed in amino acid sequences of White Spot Syndrome Virus (WSSV) isolated between 1995 and 2007 that have publicly available accession numbers at www.pubmed.com , (2) the mean concentration of Replikin sequences in the pB 1 gene area of H5N1 strains of influenza virus isolated in 2003, 2004, 2005, 2006, and 2007 that have publicly available accession numbers at www.pubmed.com, and (3) the mean mortality rate for humans infected with H5N1 influenza virus isolated in 2005, 2006 and 2007. The data demonstrate an exceptionally high Replikin sequence concentration in WSSV in 2000 followed within three years by an increase in Replikin sequence concentration in H5N1 isolates (from 2003 through 2007) and a concomitant outbreak of H5N1 influenza in humans with rising mortality. [0031] FIG. 2 illustrates a correlation between (1) the mean concentration and standard deviation of Replikin sequences observed in Taura Syndrome Virus (TSV) isolated between 2000 and 2005 that have publicly available accession numbers at www.pubmed.com , (2) the mean concentration of Replikin sequences in the pB 1 gene area of H5N1 strains of influenza virus isolated in 2003, 2004, 2005, 2006, and 2007 that have publicly available accession numbers at www.pubmed.com, and (3) the mean mortality rate for humans infected with H5N1 influenza virus isolated in 2005, 2006, and 2007. The data demonstrate a higher Replikin sequence concentration in TSV in 2000 followed by a marked decrease in Replikin concentration in TSV in 2001 followed within three years by an increase in Replikin sequence concentration in H5N1 isolates (from 2003 through 2007) and a concomitant outbreak of H5N1 influenza in humans with increasing mortality. [0032] FIG. 3 illustrates a correlation between Replikin concentration in the H5N1 strain of influenza virus and human mortality from 2005 through the first quarter of 2007. FIG. 3 contains a graph comparing percent human mortality from H5N1 infections in years 2005 through the first quarter of 2007, mean concentration of Replikin sequences in the genome of H5N1 influenza strains isolated in 2003 through the first quarter of 2007 and mean concentration of Replikin

US 2008/0176217 Al

sequences in the pBl gene area of H5N1 influenza strains isolated in 2003 through the first quarter of 2007. Mean human mortality in deaths per 10 infections in a given year is represented by the black columns, mean Replikin concentration in the whole virus genome in a given year is represented by the light gray columns, mean Replikin concentration in the pB 1 gene area in a given year is represented by the dark gray columns, and standard deviations are represented by the white columns. [0033] FIG. 4 illustrates that an increasing Replikin concentration of hemagglutinin protein in the H5N1 strain of influenza virus preceded three "Bird Flu" Epidemics. In H5N1 influenza, the increasing strain-specific Replikin concentration (Replikin Count, Means+/—SD) 1995 to 1997 preceded the Hong Kong H5N1 epidemic of 1997 (El); the increase from 1999 to 2001 preceded the epidemic of 2001 (E2); and the increase from 2002 to 2004 preceded the epidemic in 2004 (E3). The decline in 1999 occurred with the massive culling of poultry in response to the El epidemic in Hong Kong. [0034] FIG. 5 illustrates a direct sequential correlation between Replikin concentration in isolates of Taura Syndrome Virus (TSV) collected from Belize, Thailand, Hawaii and Venezuela, respectively, and mean number of days until 50% mortality in Litopenaeus vannamei shrimp challenged with the respective TSV isolates on day zero. Statistical differences between the Replikin concentration for each isolate are significant at a level of pkyvlsgl lhlk .>r 1d•7.r,cukqRai:; :kkan :s ;k1 rlse; i i inkke . ,k2?> :'F g ihh ----------]ser.kitskdI_a2i 'FyiY1ai: . `>akr .^ :ntttcgegni:l i; : Y l: kprijV e tk9I .n:; ii rJ iS a, p ,:akrs; ^ nrty:9.. ........ .... knn t1krtn tn.>edililj:eji#ik k3snn Ttikr's o tngedlly:1j:eji}kf':'. k3s.>qn]_tr.>faaoi ylai Irrz -l.l. fldl',

acrnagykeaciheldckrifl1aqqgragaF3;

1971 2002 2000 2000 1968 1979-2003 1957 1957 2002 1959 2000 2005

H1N Influenza goose peptide H1N1 Swine Influenza Shrimp White Spot Syndrome Virus Shrimp White Spot Syndrome Virus H3N2 Human Influenza Pandemic H7N7 Influenza H2N2 Human InfluenzaPandemic H2N2 Human Influenza Pandemic H5N2 Influenza H5N1 Influenza Taura Syndrome Virus Taura Syndrome Virus

Residues identical to original 1917 Goose Replikin residues are shown in Amino acid substitutions

It... tgre3:

and.:

3,

any changes thought to be required for further spread from human to human, had been thought not yet to have occurred. However, the inventors observed substitutions in three H5N1 Replikin amino acid residues at position numbers 18, 24 and 28 of the Goose Replikin scaffold from isolates in Vietnam, Thailand and China in 2004 (see Table 1). Substitution at position number 24 has not occurred since the appearance of H5N1 in 1959 but was present in the last two influenza pandemics caused by other strains, H2N2 in 1957 and H3N2 in 1968, together responsible for over two million human deaths, and in a recent virulent epidemic caused by H7N7 (see Table 1). These data on substitution, combined with the rising Replikin concentration shown in FIG. 4, and the past correlation of such Replikin data with pandemics, predicted the small outbreak of H5N1 in humans in 2006 and 2007. [0110] It is important to note that an extra K has also appeared in the Replikin Scaffold of a 2006 strain of H5N1 in China (Anhui). This presence of an extra K both produces and signals an increase in the Replikin count within the Replikin Scaffold. The 2006 China (Anhui) strain has a Replikin count of 6.6 (as discussed below). A Replikin count of 6.6 is the highest ever observed for an H5N1 strain and is comparable in the entire A strain of influenza only to the Replikin count of the influenza strain that caused the 1918 Pandemic. Homologous Replikin Scaffold Sequences in Influenza, WSSV, and TSV [0111] The inventors have further established a relationship between virulent influenza virus and WSSV and TSV in the Replikin Scaffold portions of the viruses as may be seen in Table 2 below. Although there is extensive substitution, sev-

[0112] In addition, since many species, including but not limited to swine and birds, are known to provide animal "reservoirs" for human influenza infection, marine forms such as the shrimp virus can now be examined, with early warning diagnostic benefits for outbreaks such as swine flu and bird flu. While similarities of some influenza viruses were noted between species, and the transfer of these viruses interspecies was known, there was no previous quantitative method to gauge virus activity. The activity of Replikins in shrimp can now be monitored constantly for evidence of increased viral replication rate and thus emergence of epidemics that are likely to transfer to other species. [0113] A related example of virus reservoir activity in which the Replikin concentration was increased prior to an

outbreak was observed in corona viruses as a group. The Replikin concentration of the corona virus group increased markedly in 2002 before the outbreak of one of its members, SARS, in 2003. See FIG. 12. [0114] With high mortality for its shrimp host, White Spot Syndrome Virus can now have its Replikins examined as earlier forms of virus Replikins, or as parallel morphological branches, that in either case may act as reservoirs for bird and animal Replikins such as those in influenza viruses. The diagnostic and preventive uses of these Replikin findings in shrimp follow as they do in influenza and for other organisms containing Replikins. [0115] Advanced forecasts of influenza virus outbreaks are now conveniently achievable with Replikin concentration analysis using the proprietary software FluForecast® from Replikins, LLC, Boston, Mass. Such forecasts now may per-

Jul. 24, 2008

US 2008/0176217 Al 14

mit time for preventive public health measures to be mobilized and safer strain-specific vaccines to be synthesized, tested, and mass produced. Replikin Repeats as a Mechanism for High Replikin Concentrations [0116] The presence of repeat sequences of theReplikinsof the nucleocapsid protein of shrimp White Spot Syndrome Virus (WSSV) accounts for the unusually high Replikin concentration of 103.8. This Replikin concentration is much higher than the Replikin concentration of for example, influenza viruses, which usually range from less than 1 up to 5 or 7 and comparable, as discussed above, with P. falciparum. Interestingly, while the shrimp White Spot Syndrome pathogen is a virus, and the P. falciparum is a trypanosome, both spend an essential part of their reproductive cycles in red blood cells, an unusual host cell whether in shrimp (White Spot Syndrome Virus) or man (malaria), both are fulminating, rapidly-replicating diseases with high mortality rates of their hosts, and both appear to use the same methods of increasing their high Replikin concentrations to such record highs, namely, Replikin repeats and Replikin overlap. [0117] As illustrated in Table 3, examples of Replikin repeats and Replikin overlaps were found by the applicants in the above nucleocapsid protein of the shrimp White Spot Syndrome Virus. 497 Replikins were observed in the White Spot Syndrome Virus. Of those 497, the Replikins illustrated below in Table 3 were selected for their short sequences and high concentration of lysines which, as demonstrated throughout this application, is associated with high mortality. The chosen sequences are easier and less expensive to synthesize than the longer sequences that are not included in

Table 3. [0118] Table 3 illustrates intramolecular Replikin repeats and Replikin overlap in shrimp White Spot Syndrome Virus (WSSV) nucleocapsid protein (VP35) gene with a Replikin concentration (number of Replikins per 100 amino acids) of 103.8 (497 total Replikins per 479 amino acids). The nucleocapsid protein reportedly possesses thymidine kinase and thymidylate kinase activity. TABLE 3 Intramolecular Replikin repeats and Replikin overlap in shrimp White Spot Syndrome Virus (WSSV) nucleocapsid protein (VP35) gene with Replikin concentration of 103.8 Individual Replikins at Different Positions in the same Molecule, in order of appearance in the sequence 10) 23) 25) 37) 61) 72) 193) 307)

KooKo ^ No Vo ^K^ uSA ^ i;;'

K70 S 7 A7z

a??d?7

•160K161N162V 163K164S 165A

370) 462)

*Note in the shrimp virus the repeated use of identical whole Replikin sequences (underlined) and partial Replikin sequences (shaded) in different positions in the one molecule (each amino acid is numbered according to its order in the sequence).

[0119] Replikin concentration was determined for the ribo nucleotide reductase gene in WSSV from Accession No

AAL89390. Accession No. AAL89390 discloses the amino acid sequence of ribonucleotide reductase translated from the total genome of a year 2000 isolate of White Spot Syndrome Virus made publicly available at Accession No. NC 003225. 1. The Replikin concentration, as discussed above, was an unusually high at 103.8. Additionally, the Replikin concentration of the Replikin Peak Gene of the protein was even higher at 110.7. The Replikin concentration of the Replikin Peak Gene was determined by dividing the number of Replikin sequences identified in the segment of the protein containing the highest concentration of Replikin sequences, 497 Replikin sequences, by the total amino acid length of the Replikin Peak Gene, 449 amino acids, to arrive at 110.7 Replikin sequences per 100 amino acids. See Example 1. [0120] The amino acid sequence of the protein publicly available at Accession No. AAL89390 is of particular interest because it demonstrates an overlapping of Replikin sequences that result in very high Replikin concentrations. The very large number of Replikin sequences present in the genome of the WSSV serves as a reservoir or vector for individual Replikins that are transferred or, via some other mechanism, otherwise appear in virulent strains of the influenza virus. This transfer or appearance of homologous Replikin sequences is seen in the Replikin Scaffold of the influenza virus and the Replikin Scaffold of the Shrimp White Spot Virus. [0121] The amino acid sequence disclosed at Accession No. AAL89390 was further observed to contain significant Replikin Scaffold sequences. The presence of Replikin Scaffold sequences in Accession No. AAL89390 was not unexpected since Replikin Scaffolds are frequently present in viral genomes when the Replikin concentration is observed to move above 3 to 4 Replikin sequences per 100 amino acids. The presence of a Replikin Scaffold and a Replikin concentration above 3 or 4 correlates with viral outbreaks or epidemics and is another clear association with the rapid replication states of the isolated virus. Replikin Concentration Correlates with 20th Century Influenza Pandemics [0122] As discussed above, Replikin concentration has been correlated with virulence in each influenza pandemic of the 20th century. See FIG. 11. This shared correlation between Replikin concentration and outbreaks and mortality in W SSV and TSV and influenza provides evidence that the Replikin structure is transferable or repeatable between these viruses. [0123] The correlation between Replikin concentration and influenza outbreaks is well established and unmistakable. Within the last century there have been three influenza pandemics, each strain specific: H1N1 in 1918; H2N2 in 1957; and H3N2 in 1968. In the reported amino acid sequences of the strains responsible for each pandemic, there is a strainspecific increase in the Replikin concentration correlated with the major pandemic within the strain, followed by a decrease in Replikin concentration and several years later a rebound increase associated in each case with a strain-specific rebound epidemic. The x-axis of FIG. 11 shows the year and the y-axis shows the Replikin concentration in Replikin sequences per 100 amino acids for each strain responsible for each pandemic. Note that within FIG. 11 there is a separate graph for each of the three strains. [0124] FIG. 11 demonstrates that frequently a one to three year stepwise increase is observed before Replikin concentration reaches a peak. This stepwise increase precedes the occurrence of an epidemic, which occurs concurrently with

Jul. 24, 2008

US 2008/0176217 Al 15 the Replikin peak. Thus, the stepwise increase in concentration of a particular strain is a signal that a particular strain is the most likely candidate to cause an epidemic or pandemic. H5N1 Influenza Replikin Concentration Correlates with Epidemics [0125] Replikin concentration has also been correlated with virulence in each outbreak of H5N1 influenza ("Bird Flu") virus between the initial outbreak of 1997 and the present. FIG. 4, for example, illustrates a correlation between each outbreak of H5N1 between 1997 and 2004. The x-axis in FIG. 4 indicates the year and the y-axis indicates the Replikin concentration (number of Replikins per 100 amino acids). The time periods for each epidemic of H5N1 are denoted in FIG. 4 by El, E2 and E3. In H5N1 influenza, an increasing strain-specific Replikin concentration (+/—SD) from 1995 to 1997 preceded the Hong Kong H5N1 epidemic of 1997 (El); an increase from 1999 to 2001 preceded the epidemic of 2001 (E2); and an increase from 2002 to 2004 preceded the epidemic in 2004 (E3). A decline in 1999 occurred with the massive culling of poultry in response to the El epidemic in Hong Kong. H5N1 Influenza Conservation of Replikin Scaffold in Highly Virulent Isolates [0126] There is concern that current high mortality H5N1 "bird flu" in several countries may represent an early phase of an overdue influenza pandemic. Analysis of Replikin concentration changes in H5N1 have suggested that H5N1 virulence is continuing to increase. A 2006 report nevertheless suggested that in the first probable person-to-person transmission of H5N1, "sequencing of the viral genes identified no change in the receptor-binding site of hemagglutinin or other key features of the virus. The sequences of all eight viral gene segments clustered closely with other H5N1 sequences from recent avian isolates in Thailand." Phylogenetic analysis suggested that from the absence of evidence of "reassortment with human influenza viruses" that H5N1 is not a new variant. However, the inventors disclosed in 2006, three changes in a specific H5N1 protein sequence at sites which had not been changed in the last two H5N1 epidemics and in fact had been conserved since 1959. See U.S. Prov. Appin. Ser. No. 60/808, 944, filed May 30, 2006. [0127] The results set forth by the inventors in 2006 showed that 2005-2006 virus data indicated clearly that 1) the mortality rate of human H5N1 was increasing markedly, and that 2) the first country in which this would be clinically realized would be Indonesia. Bayu Krisnamurthi, the head of Indonesia's avian flu control commission, reported in June 2007 the clinical realization of both of these two predictions (Canadian Press, Jun. 6, 2007). In his comments to reporters, Dr. Krisnamurthi stated that recent changes in the H5N1 virus seem to be increasing its rate and ease of transmission from birds to humans. The World Health Organization (WHO), which has not yet implemented Replikin concentration analysis and tracking that had predicted the increase in rate and transmission in 2006, reported that they had no evidence of these changes. [0128] Recent discovery of the Replikin Peak Gene have allowed prediction of the geographic location, as well as the gene location and the host animal species of each outbreak. See FIGS. 8, 9 and 10. The announcement by Dr. Krisnamurthi represents the first independent government confirmation of the success of these technological improvements. See,

e.g., U.S. application Ser. No. 11/355,120, filed Feb. 16, 2006 and U.S. application Ser. No. 11/755,597, filed May 30, 2007. Identification of Replikin Peak Gene for Targets and Prediction [0129] The inventors have identified a Replikin Peak Gene in an isolate of the White Spot Syndrome Virus (WSSV). A Replikin Peak Gene may be identified, isolated or synthesized for diagnosis, prevention or treatment of, for example, an outbreak of WSSV or an outbreak of a virus for which WSSV is a reservoir, such as influenza virus, by the method comprising: (1) obtaining a plurality of isolates of WSSV; (2) analyzing the protein sequences or protein sequence fragments of each isolate of the plurality of isolates for the presence and concentration of Replikin sequences; (3) identifying the protein sequence or the protein sequence fragment having the highest concentration of Replikin sequences in each isolate; (4) comparing the protein or protein fragment having the highest concentration of Replikin sequences in each isolate to the protein or protein fragment having the highest concentration of Replikin sequences in each of the other isolates of the plurality of isolates; (5) selecting the protein or protein fragment having the highest concentration of Replikin sequences; (6) identifying the amino acid sequence of the selected protein or protein fragment as the Replikin Peak Gene of the plurality ofisolates of WSSV; and (7) identifying, isolating or synthesizing the identified Replikin Peak Gene of at least one of the isolates of the plurality of isolates for diagnosis, prevention or treatment. The inventors have identified a Replikin Peak Gene in a ribonucleotide reductase gene of an isolate of WSSV. See Example 1. [0130] A Replikin Peak Gene is a segment of the genome or a protein or segment of a protein in which the expressed gene or expressed gene segment has the highest or a higher concentration of Replikins (number of Replikins per 100 amino acids) when compared to other segments or named genes of the genome. The gene or gene segment is known as the Replikin Peak Gene or Replikin Peak Gene Area. A Replikin Peak Gene has been identified in H5N1 influenza virus and an increase in concentration of Replikins in the Replikin Peak Gene of H5N1 has been correlated with epidemics, increased virulence, morbidity and human mortality. See FIGS. 11-13 and U.S. Provisional Appin. Ser. No. 60/898,097. Likewise, a Replikin Peak Gene has been identified in the VP1 protein of Foot and Mouth Disease Virus and has been correlated with outbreaks of the virus. See U.S. Provisional Appin. Ser. No. 60/954,743 (see FIG. 3 and Examples 1-4 therein). Further, a second Replikin Peak Gene has been identified in a fragment of the VP1 protein of Foot and Mouth Disease Virus and two particular Replikin sequences within the Replikin Peak Gene Area of the virus have been correlated with virulence of Foot and Mouth Disease Virus. See id. A Replikin Peak Gene has likewise been identified in West Nile Virus, Porcine Reproductive and Respiratory Syndrome Virus, Porcine Circovirus and Equine Influenza virus. See U.S. Provisional Appin. Ser. No. 60/853,744, filed Aug. 8, 2007 (FIG. 2 and Example 2 therein), and U.S. Provisional Appin. Ser. No. 60/935,816, filed Aug. 31, 2007 (FIGS. 1, 2 and 4). [0131] Identification of Replikin sequences as infectious units has allowed the inventors to identify isolates having higher virulence relative to other isolates and to focus attention on the geographic area of an outbreak of virulent virus (see FIG. 10), the particular host of hosts of an outbreak of virulent virus (see FIG. 9) and the part of the genome of a

Jul. 24, 2008

US 2008/0176217 Al 16 virus (see FIG. 8) wherein virulence mechanisms are located and wherein increased virulence may be identified and predicted. Identification of Replikin Peak Genes within viral genomes has improved the focus that is available to make these identifications and predictions of both virulence and mechanisms of virulence. [0132] Because the inventors have provided a method of focusing on particular units of a viral or organismal genome, the skilled artisan will understand the importance of looking for Replikin sequences in any portion of the life cycle or infectious pathway of a virus. For example, as described herein, the skilled artisan will understand that predictive and virulence-related Replikin sequences (or concentrations of Replikin sequence in Replikin Peak Genes) may be identified in reservoirs of influenza virus such as in WSSV and TSV. The skilled artisan will further understand that predictive and virulence-related Replikin sequences or Replikin Peak Genes may be identified in vectors of the influenza virus. The skilled artisan will additionally understand that predictive and virulence-related Replikin sequences or Replikin Peak Genes may be identified in hosts of the influenza virus or any other place where viral genes may be located or wherein viral genes may encounter genes of other strains of virus, other virus species, vectors or hosts. SARS Replikin Count Correlates with Epidemics [0133] An increase in Replikin concentration in coronaviruses also correlated with the SARS coronavirus epidemic of 2003. In particular, as may be seen in FIG. 12, Replikin concentration in Spike and Nucleocapsid Coronavirus Proteins preceded the SARS Coronavirus epidemic of 2003. In FIG. 12, the x-axis indicates the year and the y-axis indicates the Replikin concentration. The appearance of the SARS outbreak is shown by the shaded area in the graph between 2003 and 2004. The peak of the shaded area represents a total number of eight countries in which the SARS outbreak occurred in 2003. The solid black symbols represent the mean Replikin concentration for spike coronavirus proteins and the vertical black bars represent the standard deviation of the mean. [0134] FIG. 12 shows a remarkable constancy of low coronavirus Replikin concentration between 1995 and 2001 in the spike proteins, followed by a dramatic increase in 2002, one year before the SARS epidemic appeared in 2003. Replikin concentration of the spike proteins in SARS then returned to their normal pre-2003 levels (correlated with the disappearance of SARS). The return to normal pre-2003 levels of Replikin concentration is thus a quantitative virus structural signal of the decline of the outbreak. Replikin Concentration Correlates with Outbreaks in West Nile Virus, Foot and Mouth Disease and Equine Influenza [0135] In all viruses observed by the inventors, significant increases in Replikin concentration have been predictive of increases in viral virulence. For example, an increase in Replikin concentration has been correlated with outbreaks in West Nile Virus, Foot and Mouth Disease, and Equine Influenza, and is predictive of outbreaks in each of these diseases. [0136] FIG. 13 is a graph illustrating a correlation between Replikin concentration and morbidity and mortality in U.S. populations for West Nile Virus. FIG. 14 is a graph illustrating a correlation between the concentration of Replikins observed in the VP1 protein of isolates of Foot and Mouth Disease Virus between 1998 and 2006 and epidemics in the United Kingdom in 2001 and 2007.

[0137] FIG. 15 is a graph illustrating a correlation between Replikin concentration in the Replikin Peak Gene of Equine Influenza virus and epidemics between 1977 and 2000. The Replikin Peak Gene in Equine Influenza is identified as the pBl gene area. In years where the Replikin concentration increases in the pBl gene area of the virus, no concomitant increase in the pA or pB2 virus is observed. These data demonstrate a significant effect on virulence by an observed increase in Replikin concentration particularly in a Replikin Peak Gene. Vaccines, Treatments and Therapeutics [0138] The observations of specific Replikins and their concentration in WSSV and TSV proteins and their correlation with outbreaks in influenza provides for early production and timely administration of vaccines tailored specifically to treat the prevalent emerging or re-emerging strain of influenza virus in a particular region of the world. By analyzing the protein sequences of isolates of a virus for the presence, concentration and/or conservation of Replikins, virus outbreaks and epidemics can be predicted and treatments developed. Furthermore, the severity of such outbreaks can be significantly lessened by administering a peptide vaccine based on the Replikin sequences identified using the methods provided herein or Replikin sequences found to be most abundant or shown to be on the rise in virus isolates over a given time period, such as about one to about three years. Vaccine products against SARS Replikin sequences and H5N1 influenza virus Replikin Scaffolds have been demonstrated by the inventors. See, e.g., U.S. application Ser. No. 11/355,120, filed Feb. 16, 2006 (Examples 6 and 7). Replikin sequences added to the feed source of shrimp have likewise imparted measurable resistance to challenges with Taura Syndrome Virus. See Example 7 below. [0139] A peptide vaccine may include a single Replikin peptide sequence or may include a plurality of Replikin sequences observed in particular virus strains. Preferably, the peptide vaccine is based on Replikin sequence(s) shown to be increasing in concentration over a given time period and conserved for at least that period of time. However, a vaccine may include a conserved Replikin peptide(s) in combination with a new Replikin peptide(s) or may be based on new Replikin peptide sequences. Replikin peptides can be synthesized by any method, including chemical synthesis or recombinant gene technology, and may include non-Replikin sequences, although vaccines based on peptides containing only Replikin sequences are preferred. Preferably, vaccine compositions of the invention also contain a pharmaceutically acceptable carrier and/or adjuvant. [0140] Vaccines can be administered alone or in combination with antiviral drugs, such as gancyclovir; interferon; interleukin; M2 inhibitors, such as, amantadine, rimantadine; neuramindase inhibitors, such as zanamivir and oseltamivir; and the like, as well as with combinations of antiviral drugs. [0141] Vaccines may be administered to any animal capable of producing antibodies in an immune response. For example, a vaccine may be administered to a rabbit, a chicken, a pig, or a human. Because of the universal nature of

Jul. 24, 2008

US 2008/0176217 Al

17 Replikin sequences, a vaccine of the invention may be directed at a variety of strains of virus or a particular strain of

virus. Passive Immunity [0142] In another aspect of the invention, isolated Replikin peptides may be used to generate antibodies, which may be used, for example to provide passive immunity in an individual. Various procedures known in the art may be used for the production of antibodies to Replikin sequences. Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, humanized, single chain, Fab fragments and fragments produced by a Fab expression library. Antibodies that are linked to a cytotoxic agent may also be generated. Antibodies may also be administered in combination with an antiviral agent. Furthermore, combinations of antibodies to different Replikins may be administered as an antibody cocktail. [0143] Monoclonal antibodies to Replikins may be prepared by using any technique that provides for the production of antibody molecules. These include but are not limited to the hybridoma technique originally described by Kohler and Milstein, (Nature, 1975, 256:495-497), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today, 4:72), and the EBV hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). In addition, techniques developed for the production of chimeric antibodies (Morrison et al., 1984, Proc. Nat. Acad. Sci USA, 81:6851-6855) or other techniques may be used. Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce Replikin-specific single chain antibodies. [0144] Antibodies to any peptides observed to be present in an emerging or re-emerging strain of virus and combinations of such antibodies are useful in the treatment and/or prevention of viral infection. [0145] Antibody fragments that contain binding sites for a Replikin may be generated by known techniques. For example, such fragments include but are not limited to F(ab')2 fragments which can be produced by pepsin digestion of the antibody molecules and the Fab fragments that can be generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab expression libraries can be generated (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity. [0146] In another aspect of the invention, immune serum containing antibodies to one or more Replikins obtained from an individual exposed to one or more Replikins may be used to induce passive immunity in another individual or animal. Immune serum may be administered via i.v. to a subject in need of treatment. Passive immunity also can be achieved by injecting a recipient with preformed antibodies to one or more Replikins. Passive immunization may be used to provide immediate protection to individuals who have been exposed to an infectious organism. Administration of immune serum or preformed antibodies is routine and the skilled practitioner can readily ascertain the amount of serum or antibodies needed to achieve the desired effect. [0147] Replikin peptides, alone or in various combinations, may be administered to a subject, preferably by i.v. or intramuscular injection, in order to stimulate the immune system of the subject to produce antibodies to the peptide. Generally

the dosage of peptides is in the range of from about 0.1 µg to about 10 mg. In another embodiment, the dosage ofpepetides is about 10 µg to about 1 mg. In a preferred embodiment, the dosage of peptides is about 50 µg to about 500 µg. The skilled practitioner can readily determine the dosage and number of dosages needed to produce an effective immune response. EXAMPLES Example 1 Determination of Very High Replikin Concentration in Ribonucleotide Reductase from Accession No. AAL89390 [0148] Replikin concentration was determined for ribonucleotide reductase publicly available at Accession No. AAL89390. The amino acid sequence was translated from the total genome of a year 2000 isolate of White Spot Syndrome Virus made publicly available at Accession No. NC 003225. 1. The Replikin concentration in the protein was an unusually high 103.8 and the Replikin concentration of the Replikin Peak Gene of the protein was a yet higher 110.7. The Replikin concentration of the protein was determined by dividing the number of Replikin sequences identified in the amino acid sequence of the protein, 497 Replikin sequences, by the total amino acid length of the protein, 479 amino acids, to arrive at 103.8 Replikin sequences per 100 amino acids. The Replikin concentration of the Replikin Peak Gene was determined by dividing the number of Replikin sequences identified in the segment of the protein containing the highest concentration of Replikin sequences, 497 Replikin sequences, by the total amino acid length of the Replikin Peak Gene, 449 amino acids, to arrive at 110.7 Replikin sequences per 100 amino

acids. [0149] The amino acid sequence of the protein publicly available at Accession No. AAL89390 is of particular interest because it demonstrates an overlapping of Replikin sequences that results in very high Replikin concentrations, comparable to P. falciparum. The high concentrations of Replikin sequences provide a reservoir for transfer to influenza

viruses. [0150] In Accession No. AAL89390, the inventors identified a Replikin Peak Gene. A Replikin Peak Gene is the segment of a protein having the highest concentration of continuous, uninterrupted, overlapping, Replikin sequences. In the sequence disclosed below, the Replikin Peak Gene is underlined. The Replikin Peak Gene is observed to occupy most of the disclosed protein. The expansiveness of the Replikin Peak Gene across most of the amino acid sequence of the

protein is highly unusual and creates the remarkably high Replikin concentration. The amino acid sequence further contains significant Replikin Scaffold sequences. The following Replikin Scaffold repeats were identified in Accession No. AAL89390.

K66 KNVKSAKQLPHLKVHLDVKSAKQLPHLKVH 96 160 KNVKSAKQLPHLKVHLDVKGVKQLLH ^ 86 239 KNVKSAKQLPHLKVLLDVRGAKQLPH 265 K 303 KNVKSAKQLPHLKVLLDVRGAKQLPH 329 K K

K

Jul. 24, 2008

US 2008/0176217 Al

LEI

Replikin Analysis for AALS9390 PubMed Code: AALS9390 Description: Ribonucleotide reductase of shrimp white spot syndrome virus (WSSV): Isolated Year 2000 Source: Shrimp White Spot Syndrome Virus M 1 K 2 I 3 C 4 Qs I 6 S 7 S . P o T io L 11.^ 12 L 13 S 14 1 1s P 16 L 17 E.18 G.19 V 2 o Y 21 H 22 V 23 K24 Q 2 s L 26 L 29 H 28 L 29 K3 o V 31 H 32 L 33 D 34 V3 s K36 G.37 v38K39Q4 oL41L42 H43 L 44 K45V46 R47 L 48 D49VsoRs1G.52 A53 K54Q5 sNs6 P59W58Rs9K6oN61L 620.63 L 64 L6s K66K67 N68V69K70s7l

A72K93Q'4L95P' 6H77L 78K79V8oH81L 82D83V84K8sS86A87K88Q89L9oP9'H 92L 93K94V9 sH96L 97D98V99R'ooG'o1A' 02K103 0

Q 104 L 1os P 1o6 H1o9 L 1o8 K10

9 V11o R 111 L 112 D 113 V 114 K11s S 116 A119 K118 Q 119 L 12o P 121 H 122 L 123 K124 V 12s H126 L 127 D 128

V129R130G131A132K1330134L135P136H137L138K139V14oR141L 142D143V144R145G146A147K148Q149N15°P151W1S2A1S3

K154N1ssL1s6C159L1s8L1s 9K16oK161N162V163K164S16sA166K167Q168L169P19 oH171L 172K193V194H17 sL176D 1"198

K 199 G '8o V 181 K182 V204H2 osL2

°6 D 2

183 L 184 L 18s H 186 L 187 K188 V 189 R19o L 191 D 192 V193 R 194 G19s A196 K197 Q198 L 199 L 2oo H 2o1 L 202 K203 0

°'V2 o8R209G 21oA211K212Q213L 214P21sH216L 217K218V219H22 oL 221D 222V223R224G 22 sA226K227Q228

N229p23OW231R232K233N 234L 235C236L 237L238K239K24oN241V242K243S244 A245K246n247L 248P249H 250L 251K252V253

L

254 L 2ss D 2s6 V 2s9 R 2s8 G 259 A26o K 261 Q 262 L 263 P 264 H 26s L 266 K 267 V 268 L 269 L 27o D 271VV 272 R 273 G 274 A 27s K276 Q 277 L 298

P279H28 oL 281K282V283 H284 L 28sD 286V289 R288 G. 289A290 K291Q292 N293P294W29s R296K297 N298L 2990.30 oL3 o1L 302 K303

K304N305V3°6K307S308A309K310Q311L 312P313H314L31SK316V317L318L 319D320V321R322G323 A324K32SQ326L327P328

H 329 L 330 K331 V332 L 333 L

334 D 335 VV 336 R 337 G.338 A339 K340 Q341 L 342 P 343 H 344 L 345 K346 V 347 H348 L 349 D 350 VV351 R 352 G. 353

A354K3550356L357P358H359L36 OK361V362L363L 364D365V366R367G368A369K370Q371L 372P373H374L 375K376V377L378

L 379D380V381R3826.383 A384 K385^386N38'7P388W389R390 K3'1N392 L393C.394 L395L396K397 K398N399V400 K401S 402A403

K4

o4 Q4os L 4 o6 P 4 o9 H4o8 L 409 K41o V 411 L 412 L 413 D 414 V41s R416 G.419 A418 K419 Q42o L 421 P 422 H423 L 424 K42s V426 H 427 L 428

D 427V43OA431G.432A433 K434Q435Q436Q437Q438 C439C.44 OC441P442 L443 K444T445I446S447T448S449F 4S oT451H452 L453

L454L455C.ff s6L457Y4s8M4s'E.46OY461G. ff62K463 H464Q46sN466L 467Q468V467K49oM491W492 L473 N494l49 sT496Y477T478

S 479

Replikin Sequences in Amino-Terminal Portion of Peptide (1)

(2)

(3)

(4) (5)

H

22 V 23 K24 Q 2s L 26 L 27 H 28 L 29 K30

H22V23K24Q2 sL 26L 27 H 28L 29K30V31H32L33D34V35K36

H

22 V 23 K24 Q 2s L 26 L 27 H 28 L 29 K3o V 31 H32 L 33 D 34 V3s K36 0 37 V 38 K39

H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V35K36037V38K39Q4 oL 41L42 H43L44K45

H 22 V 23 K24 Q 2a L 26 L 27 H 28 L 29 K3o V 31 M32 L 33 D 34 V3y K36 0. 37 V 38 K39 Q 4o L 41 L 42 H43 L 44 K4s V46 R 47 L 48 D 49 V so R sl 0s2 A53

K H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V35K36037V38K39Q4 oL 41L42 H43L44K45V46R47L 48D 49VsoRs1052 A53

K 54 Q s5 N56 P 57 W 58 R 5 9K6 0 (7)

H22V23K24Q2 sL 26L 27H 28L 29K30V31M32L33D34V35K36037V38K39Q4 oL 41L42 H43L44K45V46R47L 48D 49VsoAs10.52As3 K54Q55N56 P59 W58R59 K6oN61L 62 C63 L 64 L6s K66

(8)

H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V35K36037V38K39Q4 oL 41L42M43L44K45V46R47L 48D 49VsoRs1052 A53

K54 Q55 N56 P 57 W58 R 59 K60N 61 L 62 C 63 L 64 L 65 K66 K6 ' (9)

H 22 V 23 K24 Q 2s L 26 L 27 H 28 L 29 K3o V 31 H32 L 33 D 34 V3s K36 0. 37 V 38 K39 Q 4o L 41 L 42 H43 L 44 K46 V46 R 47 L 48 D 49 V so R sl 062 A53

K54 Q55 N 5 6 P 57 W58 R s9 K 6o N 61 L 62 C 63 L 64 L 65 K66 K67 N 68 V 69 K 70 (10)

(11)

(12)

(13)

(14)

K

24 Q 2s L 26 L 27 H 28 L 29 K30

K24Q2 sL 26L 27H28L 29K30V31H32

K

24 n 25 L 26 L 27 H 28 L 29 K30 V 31 H 32 L 33 D 34 V35 K36 037 V38 K39 n 40 L 41 L 42 H 43

H28 b L 29K30V31H32L 33D 34V35K36

H

28 L 29 K30 V31 H32 L 33 D 34 V 3s K36 0 37 V38 K39

b

Jul. 24, 2008

US 2008/0176217 Al

19

-continued (15)

(16)

(17)

H

28 L 29 K3 o V31 H32 L 33 D 34 V 3s K36 G 37 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s

H28L 29K30V31H32L 33D 34V3 sK36G37V38K39 Q4 oL41L42H43L 44K4sV46R47L48D49VsoRs'G 2As3Ks4

H

28 L 29 K3o V31 H32 L 33 D 34 V 3s K36 G 37 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s V 46 R 47 L 48 D 49 Vso Rsl Gs2 As3 Ks4 Q ss N s 6 P s9

W s8 R s9 K6o (18)

H28L 29K30V31H32L 33D 34V3 sK36G37V38K39Q4 oL41L42H43L 44K4sV46R47L48D49VsoRs'G 2As3Ks4Qs sNs6Ps9

w s8 Rso K6o N 6i L 62 C 63 L (19)

H28L 29K30V31H32L 33D 34V3 sK36G37V38K39Q4 eL41L42H43L 44K4sV46R47L48D49VsoRs1Gs2AS3KS4Qs sNs6Ps9

W s8 Rs 9 K6 o N 6 i L 62 C 63 L (20)

64 L 6s K 66

64 L 6s K 66 K 6'

H28L 29K30V31H32L 33D 34V3 sK36037V38K39Q4 oL41L42H43L 44K4sV46R47L48D49VsoRs'0s2As3Ks4Qs sNs6Ps9 Ws8Rs9 K6oN61L 62C63L 64L6s K66 K67 N68 V69 K7o

(21)

H

28 L 29 K3o v31 H32 L 33 D 34 v 3s K36 G.37 v38 K39 Q4o L 41 L 42 H 43 L 44 Kos v 46 R 47 L 48 D 49 vso Rsl Gs2 As3 Ks4 Q ss N s 6 p s7

w s8 Rs9 K6o N 6' C 62 L.63 L (22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

K

3o V31 H32 L 33 D 34 V 3s K36 G.37 V 38 K39 n4o L 41 L 42 H43 L 44 K4s V 46 R 47 L 48 D 49 Vso Rsl G. s2 As3 Ks4 n ss N s 6 p sJ W s8 R so

K 6 o N 6 i L 62 C 63 L 64 L 6 s K 66 K 6 B N - v - b K 7o S

K

b

3o V31 H32 L 33 D 34 V 3s K36 G. 37 V 38 K39

K30V31H32L33D34V3 sK36037V38K39Q4 oL41L42H43

H

32 L 33 D 34 V3s K36 G. 37 v 38 K39 Q 4c L 41 L 42 H43 L 44 K4s

H32L33D34V3 sK36037V38K39 n4 oL 41L42H43L44K4sV46R47L 48D 49VsoRs'0s2 As3Ks4

H32L33D34V3 BK36037V38K39 b Q4 oL 41L42H43L44K4sV46R47L 48D 49VBoRs10B2 As3Ks4QS sNs 6Ps9Ws 8RS9K6o

H32L33D34V3 sK36037V38K39Q4 oL 41L42H43L44K4sV46A47L 48D 49VsoRs'0s2 AS3Ks4QS BNs 6Ps9Ws 8Rs9K6oN6'

K66

H32L33D34V3 sK36037V38K39Q4 oL 41L42H43L44K4sV46R47L 48D 49Vs°Ad0^ 2 AS3Ks4Qs sNs 6Ps9Ws8Rs9K6oN6'

L 62 C6 S

(31)

71 A72 K73 Q 74 L 7s p— H 77

K30V31H32L33D34V3 sK36

L 62 C 63 L 64 L6 s

(30)

64 L 6s K 66 K 67 N 68 V 69 K7o S 7' A72 K 73

L 64 L 6 s K66 K 67

H32L33D34V3 SK 360. 37V38K39A4 oL 41L42H43L44K4SV46R47L 48D 49VB°Rd0B2 As3KS4Qs BNs 6PS9Ws8As9K6oN6'

L62 C63 L 64 L6s K66 K67N68V69 K70

(32)

H32L33D34V3 sK36037V38K39Q4 oL 41L42H43L44K45W6R47L 48D 49VBoAsl052 As3Ks4Qs sNs 6Ps7Ws 5As9K6cN61

L62C.63 L 64 L6s K66K67N68V69K70S7'A72K73

(33)

H32L33D34V3 sK36037V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49V50Rd052 As3Ks4Qs sNs 6Ps7Ws 8Rs9K6oN6' L 62C63L 64L6sK66K67N68V69K70S7'A72K93Q'4L 95P96H 77L 78K79

(34)

(35)

K36037V38K39Q4 oL 41L 42 H43L 44K4s

K

36 tt.37 w38 K39 Q4o L 41 L 42 H 43 L 44 Kos v46 R47 L 48 D 49 vso R BkS2 AS3 KS4 A ss Ns 6 ps7 Wsb Rso K6 o N 61 L 62 c 63 L 64 L 6s

K 6 6 K6 7 N 6 8 V 6 9 K'I O S 'I1A 'l2 K 'l3 Q 'l4 L 'J S P 'l6 H 'I'I

(36)

K

36 G.37 v38 K39 Q4o L 41 L 42 H 43 L 44 Kos v46 R47 L 48 D 49 vso R si G s2 As3 Ks4 A ss Ns 6 ps7 Ws8 Rso K6 o N 61 L 62 c. 63 L 64 L 6s

K 66 K67 N 68 V 69 K7o S 71A 72 K 73 Q 74 L 7s P 7 6 H 77 L 78 K79 V 8o H 81 (37)

(38)

K

39 Q4o L 41 L 42 H43 L 44 K4s

K39Q4 oL41L42H43L 44K45V46R47L 48D49Vs oRsl052 As3Ks4QS SNs6Ps7Ws 5Rs9K6oN61L 62C63L 64L6SK66K67 N68

v 69 (39)

K90 S'

2 K73 Q 74 L 9sp 96 H 77

K39Q4 oL41L42H43L 44K45V46R47L 48D49VsoRs10s2 As3Ks4Qs sNs6Ps7Ws 8Rs9K6oN61L 62C63L 64L6sK66K67 N68

v 69 K9o S 71 A72 K73 Q 74 L (40)

9s p 96 H 77 L 78 K79 V 8 o H 81

H43L44K4sY46R43L 48D 49VSoAB70.s2A53K54

(41)

H

(42)

H

(43)

H

(44)

H

43 L 44 K4S V46 R47 L 48 L 49 V so R sl G s2 As3 Ks4 Qs 5 Ns 6 P s9 w s 8 R s9 K 6o

43 L 44 K4s v46 R47 L 4. ^ 49wo R sl ta.s2 As3 Ks4 Q ss Ns 6 p S7 w S. R so K 6 o N 61 L 62 L. 63 L 64 L h s K66

43 L 44 K4s V46 R47 L 48 L 49 V so R sl G.s2 As3 Ks4 Qs s Ns 6 p S7 W s 8 R s9 K 6o N 61 L 62 L.63 L 64 L 6s K66 K69

43 L 44 K4s V46 R47 L 48 L 49 V so R s' G S2 As3 Ks4 Q S s Ns 6 P S7 ta s 8 A s9 K 6o N 61 L 62 L.63 L 64 L 6s K66 K67 N 68 V 69 K 70

Jul. 24, 2008

US 2008/0176217 Al 20

-continued (45)

H

43 L 44 K4 s v46 R47 L 48 D 4 o v so R sl G. s z Asa Ks4 Qss Ns6 ps7 W s8 R so K 6o N 61 L 62 c. 63 L 64 L 6s K66 K67 N 6. v 69 K 7o S 71 A 72

K7 (46)

H43 L44K4SV46R47 L 48D 49VsoAs'G. s2 As3 Ks4Qs sNs 6Ps7Ws 8Rs9K6oN61L620.63 L 64 L6s K66K67N68V69K70S7'A72

K 73 Q '4 L (47)

7s p 96

H7'L'

8 K 79

H43L44K4sV46R47L 48D 49VsoRs'0s2 As3Ks4QS sNs 6Ps9Ws 8Rs9K6oN61L 620.63L 64L6sK66K67N68V69K70S7'A72 K93Q'4L7Sp76H77L 78K79V8oH81L 82D83V84K8s

(48)

H43L44K4sV46R47L 48D 49VsoRs'0s2 As3Ks4Qs sNs 6Ps9Ws 8Rs9K6oN61L 620.63L 64L6sK66K67N68V69K70S7'A72 K93Q'4L9SP96H77L 78K79V8oH81L 82D83V84K8sS86A87K88

(49)

K

os V46 R47 L 48 D 49 V so R sl 0 s2 As3 Ks4 Qss Ns 6 P s9 Ws8 Rso K 6o N 61 L 62 0. 63 L 64 L 6 s K66 K67 N 68 V 69 K 9o S 71A 72 K 73 Q 74

L7s P ' 6 H 'f'

(50)

K

os V46 R47 L 48 D 49 V so R sl 0 s2 As3 Ks4 Qss Ns 6 P s9 Ws8 Rso K 6o N 61 L 62 0. 63 L 64 L 6 s K66 K67 N 68 V 69 K 9o S 71A 72 K 73 Q 74

L 7s p (51)

6 H 77 L 7. K79 V 8 o H e1

K4sV46R47L48D49VsoRs'0s2 As3Ks4Qs sNs 6Ps9Ws8Rs9K6oN61L 620.63L 64L6eK66K67N68V69K70S7'A72K93Q'4

L 'Js P '6 H 'l7 L 7e K79 v 8o H .1 L .2 D .3 O e4 K8 s S e 6 Ae'I Kee Q .9 L (52)

(53) (54)

Ks4QssNs6Ps9Ws 8Rs9K6oN61L 620.63L 64L6sK66K67N68V69K70S7'A72K93Q'4L 9 sP96H77

K

s4 Qss Ns6 ) S' W sB R s9 K 6o N 61 L 62 C.63 L 64 L 6s K66 K6) N 68 V 69 K 9o S 71 A 72 K 73 Q 74 L 9s P 96 H 77 L 78 K 79 V 8 o ff 81

Ks4QssNs6Ps9Ws 8Rs9K6oN61L 620.63L 64L6sK66K67N68V69K70S7'A72K93Q'4L'sP96H77L 78K79V8oH81L 82D83V84K8s

S 86 A 87 K88 Q e9 L 90 P 91 H (55)

K

92

s4 Qss Ns6 P s9 Ws8 R so K 6o N 61 L 62 0. 63 L 64 L 6 s K66 K67 N 68 V 69 K 9o S 71 A 72 K 73 Q 74 L 9s P 96 H 77 L 78 K 79 V 8 o ff 81 L 82 D 83 V 84 K8s

S86A87 K88A89L90p9'H9

(56)

K

(58)

(59)

2L

93 K 94V 9s H96

6o N 61 L 62 `C G 63 L 64 L 6 s K 66 K 67 N 68 V 69 K9o S 71 A72 K73 Q 74 L 9sp96 H 77 L 78 K 79 V 8 o H 81 L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91

H92L 93K94V9 sH96L

(57)

90 p 91 H 92

97D98V99R'ooGlolAl

02K1o3Q1o4LlosP1o6H' o7

K6oN61L 62C63L 64L6sK66K67N6BV69K70S7'A72K'3Q'4L 7Sp76H 77

K60N61L 62C63L 64L6sK66K67N68V69K70S7'A72K93Q'4L 7Sp76H 77L 78K99V80H81

K

60 N 61 L 6X.63 L 64 L 6s K 66 K 6) N 68 V 69 K'o S 71 A72 K73 Q 74 L 9sp96 H 77 L 78 K 79 V 8 o H 81 L 82 D 83 V 84 K 8 s S 86 A 87 K BB Q 89 L 90 p 91

H 92

(60)

K6oN61L 62C63L 64L6sK66K67N68V69K70S7'A72K93Q'4L7Sp76H77L78K99V8 oHB1L 82D83VB4KBsS86AB7K8BQB9L9oP9'

H 92 L

93 K94 V 9s H 96

(61)

K 66 K67 N 6e v 69 K70 S 7'A 72 K '3 Q '4Us P '

(62)

K

(63)

K 66 K67 N 68 V 69 K7 0 S 7'A 72 K 73 Q 74 L 7S p 76 H 77 L '78 K79 V 8o H 81 L

(64)

K

(65)

6 H 77

66 K67 N 68 V 69 K7o S 71A 72 K 73 Q 74 L 7S p 6 H 77 L '7. K79 V e o H .1

82 D 83 V 84 K 8

5 86 A87 K88 Q 89 L 9o P 91 H 92

66 K67 N 68 V 69 K9o S 71A 72 K 73 Q 74 L 9s P 96 H 77 L 7B K79 V 8 o ff 81 L 82 D 83 V 84 K 8 s S 86 A87 K88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96

K66K67N68V69K70S7'A72K93A94L9S)96H77L 78K79U8nHB1L 82DB3V84K8s586A87K88Q89L90P91H 92L 93K94Y 9sH96L 97 D98V99R'ooGlolAl 02

Ki°3 Q io4 li 'os p io6 H i o7

(66)

K 67 N 68 V 69 K70 S 7'A 72 K 73 Q 74 L 's P '

6 H 77

(67)

K 67 N 6e U 69 K7o s 7'A 72 K '3 Q '4 L 's P '

6 H 77 L 78 K79 U eo H ei

(68)

K s7 N 6e U 6g K70 s 7'A 72 K '3 Q '4 L 's P '

6 H 77 L 78 K79 V 8o H 81 L 82 D 83 V 84 K 8s S e6 A87 K88 Q 89 L 9o P 91 H 92

(69)

(70)

K67N68V69K70S7'A72K93Q'4L7Sp76H77L78K99V8oH81L 82D83V84K8s586A87K88Q89L9oP91H 92L 93K94V 9sH96

K67N68V69K70S7'A72K93Q'4L7Sp76H77L78K99V8oH81L 82DB3V84K8s586AB7K88Q89L9oP91H 92L 93K94V 9sH96L 97 D98

V 99 R 'oo G io' Ai

(71)

K 7o

02 Kio3 Q io4 L 'os P io6 H io'

S 71 A72 K73 Q 74 L 9sp96 H 77 L 78 K 79 V 8 o H 81 L 82 D 83 V 84 K S s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K94 V 9s H 96 L 97 D 98 V 99 R1oo

G' ° 'A'°2

Kin 3 Q ' o4 L 'os P in 6 Hio'

9o S 71 A72 K73 Q 74 L 9s p 96 H 77 L 78 K 79

(72)

K

(73)

K 70 S 7' A72 K73 Q 74 L

(74)

K 7o

(75)

7S p 76 H 77 L 78 K '9 V e o H 8'

S 71 A72 K73 Q 74 L 9sp96 H 77 L 78 K 79 V 8 o H 81 L B2 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92

K70S7'A72K93Q'4L7Sp76H77L78K99V8 oH81L 82D83V84K8s586A87K88Q89L9oP91H92L 93K94V9 sH96

Jul. 24, 2008

US 2008/0176217 Al

21

-continued (76)

K

(77)

K

(78)

^

s Q 74 L 7s P ^ s H 77 L 7e K 79

73 Q 74 L 7S p 76 H 77 L 78 K 79 V 8o H 81

K73Q74L7sP96H77L 78 K 79 V 8o H 81 L 82 D 83 V 84 K8 s S 86 A87 K 88 Q 89 L 9o P 91 H 92 L 93 K94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1 A102

K 103 Qlo4 L ios P ios H ioz (79)

(80)

(81)

K

73 Q 's L 7S p 76 H 77 L 78 K 79 V 8o H 81 L 82 D 83 V 84 Kss S 86 A87 K 88 Q 89 L 9o P 91 H 92

K73Q'4L'sP96H77L 78K79V8oH81L 82DB3VB4K8sSB6A87K8BQ89L9oP91H 92L 93K94V9 sH96

K73Q74L7sP96H77L 78 K 79 V 8 o ff 81 L 82 D 83 V 84 K8 s S 86 A87 K 88 Q 89 L 90 p 91 H 92 L 93 K94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1 A102

K1o3 Qfio4 L ios p fi06 H i07 L 1o8 Kto (82)

(83)

(84)

(85)

(86)

H77L78K79V8oH81L 82

D 83 V e4 K ss

H77L7.K79VBOH81L 82 D 83 V 84 K 8 s S 86 A87 K88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R1oo G 1o1 A1o2 K103

H77L 78K79V8oH81L 82D 83VB4K8sS86AB7KBBQB9L9oP91H 92L 93K94V 9sH96L 97D9BV99A10oG.1o1A102K1o3Q1o4L10s

6 H 107 L io e K10

H77L 78K79Y8oHB1L 82D 83YE4KBsS86A87K88Q89L9oP91H 92L 93K94V 9sH96L 97D9BV99A10oD.1o1A102K1o3Q1o4L1oa

07 L i08 Ki09 V iio R ii1 L 112

D

113 V 114 Kiis

H77L7.K79VBOH81L 82 D 83 V 84 K 8 s S 86 A87 K88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R1oo G 1o1 A1o2 K1o3 Q 104 L 1os

P 1o6 H 107 L 1o8 K10 (89)

Q119 L 12o p 121 H 122

H77L 78K79V8oH81L 82D 83VB4K8sS86AB7KB8QB9L9oP91H 92L 93K94

P 106 H 1 (88)

11e

H77L7BK'l9Y8OHB1L 82 D 83 V 84 K 8 s S 86 AB7 K88

P io (87)

g Y no Ailt L ii2 D ii3 Vii4 Kiis S il 6 All7 K

9 V iio R ii1 L 112

D

113 V 114 Kiis S 116 A117 K lls

H77L7.K79VBOH81L 82 D 83 V 84 K 8 s S 86 A87 K88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 Y 99 R1oo G 1o1 A1o2 K1o3 Q 104 L 1os

P 1o6 H 1

07 L i0e Kio 9 V iio R ii1 L 112

79 V 8o H 81 L 82

113 V 114 Kiis S 116 A117 Kii8 Q 119 L 12° p i2i Hi22 L i23 Ki24

83 V 84 K ss S 86 A 87 K 88 Q 89 L 9o P 91 H 92 L 93 K 94 V 9 s H 96 L 97

K

(91)

79 V 8o H 81 L 82 83 V 84 K ss S 86 A 87 K 88 Q 89 L 9o P 91 H 92 L 93 K 94 V 9 s H 96 L 97 98 V 99 Rioo G io1 Aio2 Kio3 Q 104 L ios P io6 H io7 K D D L108 Klo 9Vllo R111L 112D 113V114 K11s S116A117 K115 Q119L 12 o P121H122

K79VB0H81L 82 D B3 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R1oo G 1o1 A1o2 K1o3 Q 104 L 1os P 1o6 H 107

L io8 Kio9 V lio Rii1 L (93)

(94)

(95)

(96)

D

98 V 99 Rioo G io1 Aio2 Kio3 Q 104 L ios P io6 H io7

(90)

(92)

D

D

112

D

113 V 114 Kiis S 116 A117 Kii8 Q 119 L 120 P 121 H 122 L 123 K124 V 12s H 1e6

K79Ve 0H.1Le2Le3Ve4Kos

K79V8oH81L82D83V84KssS86A87Kee

K79 V

8o H .1 L .2 L .3 V e4 K e s S e 6 A 87 K ee Q .9 L 90 P 91 H 92

K79V80H81L 82D 83V84K8sS86A87K88Q89L90P91H92L 93K94V9 sH96

(97)

H

(98)

H

(99)

H

81 L 82 D 83 V 84 KB s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K94

81 L 82

D

83 V 84 Kss S 86 A 87 K 88 Q 89 L 9o P 91 H 92 L 93 K94 V 9 s H 96 L 97

D

98 V 99 R ioo Gio1Aio2 Kio3

81 L 82 D B3 V 84 KK s S 86 A B7 K B8 Q 89 L 90 p 91 H 92 L 93 K94 V 9l H 96 L 97 D 98 V 99 A 10o G1o1A1o2 K1o3 Q104 L 1os P 1o6 H 107 L 1o8

K io9 (100)

H

81 L 82

Kid (101)

H

81 L 82

Kid (102)

H

(103)

K

(104)

K


D

D

D

D

D

98 V 99 R ioo Gio1Aio2 Kio3 Q 104 L ios P io6 H 107 L ios

D


113 V 114 Kiis S 116 A117 Klls


9 Viio R ii1 L 112

D

113 V 114 Kiis


9 Viio R ii1 L 112

81 L 82

Kid

D

9 Viio R ill L 112

D


113 V 114 Kiis S 116 A117 Kii8 Q 119 L 120 p 121 H 122 L 123 K 124

B s S 86 A87 K88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G 1o1 A1o2 K1o3 Q104 L 1os P 1o6 H107

ss S 86 A87 K88 Q 89 L 9o P 91 H 92 L 93 K 94 V 9 s H 96 L 97

D

98 V 99 R ioo G io1 Aio2 Kio3 Q 104 L ios P io6 H 107 L io8 Kio9 Viio R iii

L 112 D 113 V 114 Kiis S ii6 A 117 Kii8 Q 119 L 12o p 121 H 122 (105)

K

ss S 86 A87 K88 Q 89 L 9o P 91 H 92 L 93 K 94 V 9 s H 96 L 97

D

98 V 99 R ioo G io1 Aio2 Kio3 Q 104 L ios P io6 H 107 L io8 Kio9 Viio R iii

L 112 D 113 V 114 Kiis S 116 A 117 Kii8 Q 119 L 120 p 121 H 122 L 123 K 124 V 12 (106)

K

e s S e 6 A57 Kee Q .9 L 90 p 91 H 92 L 93 K 94

s H 126

Jul. 24, 2008

US 2008/0176217 Al 22

(107)

K

(108)

K

(109)

8s S 86 A87 K88 Q 89 L

90

-continued

P 91 H 92 L 93 K 94 V 9 s H 96

88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R1oo G 1o1 A1o2 K1o3 Q 104 L 1os p lo6 H 1o7

K88Q89L9oP91H92L 93K94V 9sH96L 97D98V99R'ooG1o1Al02K1o3Q1o4L1osP1o6H' 07L1o8K1o9VlloR111L 112D113V114 11s S 116 A117 K118 Q 119 L 12o p121 H 122

K (110)

K88Q89L9oP91H92L 93K94V 9sH96L 97D98V99R'ooG1o1Al02K1o3Q1o4L1osP1o6H' 07L1o8K1o9VlloR111L 112D113V114 K" S116A117K"8Q119L120p121H122L123K124V12 sH126

(111)

K

(112)

K

(113)

88 Q 89 L 9o P 91 H 92 L 93 K 94

.. Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96

K88Q89L9oP91H92L 93K94V 9sH96L 97D98V99R1ooG.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L 112D113V114 K11sS116A117K118Q119L 120p121H122L123K124V12 sH126L 127D128V129R13 oG13'A132K133Q134L 13sP136H137

(114)

(115)

H 92

L 93 K94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1A102 K1o3 Q1o4 L 1os P 1o6 H107 L 1o8 K1o9 V 11o R111 L 112 D 113 V114 K11s

H 92L 93K94V9 sH96L 97D98V99R1ooG.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D 113V114K11sS116

A117 K"8

(116)

H 92L 93K94V9 sH96L 97D98V99R'ooG1o1Al02K103Q104L1osP1o6H'07L1o8K1o9VlloR111L112D 113V114KllsS116 A' 17K"8Q119L120p121H122L123K124

(117)

H 92

L 93 K94 V 9s H 96 L 97 D 98 V 99 8 1 oo G1o1A102 K1 o3 Q lo4 L 1os P 1o6 H1o7 L 1o8 K1o9 V 11o R ill L 112 D 113 V114 K11s S "6

A'17K"8Q119L120p121H122L123K124V12 sH126L 127D128V129R13 oG131A132K133

(118)

H 92

L 93 K94 V 9s H 96 L 97 D 98 V 99 8 1 oo G1o1A102 K1 o3 Q lo4 L 1os P 1o6 H1o7 L 1o8 K1o9 V 11o R ill L 112 D 113 V114 K11s S "6

A117 K118 Q 119 L 12o p 121 H 122 L 123 K124 V 12s H126 L 127 D 128 V 129 R13o G131A132 K133 Q134 L 13s P136 H 137 L 138 K139

(119)

(120)

H 92L 93K94V9 sH96L 97D98V99R'ooG1o1A1 o2K1o3

H 92L 93K94V9 sH96L 97D98V99R'ooG1o1A102K1o3Q1o4L1osP1o6H' 07L1o8K1o9

94 V 9 s H 96 L 97 D 98 V 99 R 'oo Gio' Ai o2 Kio3

(121)

K

(122)

K94 V o s H 96 L 97D98Vo9R'ooGio'Ai 02

(123)

K 94 Q

(124)

Kio3 Qio4 L ios P fo6 H ' o7

V 9s H 96 L 97 D 98 V 99 8 1oo G 1o1 Alo2 K1 o3 Q lo4 L 1os

P 1o6 H1o7 L 1o8 K1o9 V11o R

ill L 112 D 113 V 114 K11s S "6 A117 K118

119 L 12o p 121 H122

K94V9 sH96L 97D98V99R'ooG1o1Alo2K1°3Q104L1osP1o6H'07L1o8K1o9VlloR111L112D 113V114K" S116A117K118

Q 119 L 12o P 121 H122 L 123 K124 V12s H 126

(125)

K94V9 sH96L 97D98V99R1ooG.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D 113V114K11sS116A117K118 Q119L120P121H122L 123K124V12 sH126L127D128V129R13 oG13'A132K133Q134L13sP136H137

(126)

(127)

(128)

(129)

H 96 L 97D98Voo R

1oo G io1 Aio2 Kio3 Q 104 L ios P io6 Hio7 L io8 Kio9

H96L 97D98V99R1ooG.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D113V114K11s

H96L 97 D 98 V 99 R1oo G 1o1 A1o2 K1o3 Q 104 L 1os p 1o6 H1o7 L 1o8 K1o9 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118

H96L 97D98V99R1ooG.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D113V114K11sS116A117K118Q119L120

P 121 H122 L 123 K124

(130)

H96L 97D98V99R1ooG.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D113V114K11sS116A117K118Q119L120 P121H122L 123K124V12 sH126L127D 128V129R13 0G131A132K133

(131)

H96L 97D98V99R1n0G.1o1A102K1o3Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D113V114K11sS116A117K118Q119L120 P121H122L 123K124V12 sH126L127D 128V129R13 oG13'A132K133Q134L13sP136H137L138K139

(132)

(133)

(134)

(135)

K1o3 Q104Liospio6H107Lio8Kio9

K103Q1o4L1osP1o6H107L1o8K1o9V11oR111L112D 113V114K11sS116A117K118Q119L120P121H122

K1o3 Q104 L 1os P 1o6 H 1o7 L 1o8 K1o9 V 11o R111 L 112 D 113 V114 K11s S 116 A117 K118 Q119 L 12o p 121 H122 L 123 K124 V12s H 126

K103Q1o4L1°sp1o6H1O7L1o8K1°9V11oA111L112D 113V114K11sS116A117K118Q119L120P121H122L 123K124V12 sH126

L 127 D 128 V 129 R13o G 131 A132 K133 Q 134 L 13s P 136 H 137

(136)

H

(137)

H

(138)

107 L io8 Kio9 Viio R ii1 L 112 D 113 VV 114 Kiis

io7 L io8 Kiog V1io R iii L 112 D 113 V 114 Kiis S ii6 A 117 Kii8

H107L1o8K1o9VH0R111L 112D113V114K11sS116A117K118Q119L120P121H122L123K124

Jul. 24, 2008

US 2008/0176217 Al 23

-continued (139)

(140)

107 L 1o8 K109 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124 V 12s H126 L 127 D 128 V129 R 130

H G 131 A132 K133

H107L1o8K1o9V11oR111L 112D113V114K115S116A117K118Q119L120P121H122L123K124V125H126L 127D128V129R130

G (141)

131 A132 K133 Q134 L 135 P 136 H137 L 138 K139

H 107 L 1o8 K1o9 V11oR111L 112D113V114K115S116A117K118Q119L120P121H122L123K124V125H126L 127D128V129R130 G131A132K133Q134L135P136H137L 138K139V140R141L142D 143V144R145G146 A147K148

(142)

H 107 L 1o8 K1o9 V11oR111L 112D113V114K115S116A117K118Q119L120P121H122L123K124V125H126L 127D128V129R130 G131A132K133Q134L135P136H137L 138K139V140R141L142D 143V144R145G.146A147K148Q149N150P151W152R153K154

(143) (144)

(145)

K

1o9 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o p 121 H122

b

K1o9V11oR111L112D 113V114K115S116A117K118Q119L120P121H122L123K124V125H126

K

1o9 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o p 121 H122 L 123 K124 V12s H126 L 127 D 128 V 129 R13o G131A132

K133n134 L 135 p136H137

(146) (147)

(148) (149)

(150) (151)

(152) (153)

(154)

K

11s SS 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124

K115S116A117K118Q119L 120P121H122L123K124V125H126

K

11s S 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124 V 12s H126 L 127 D 128 V129 R 13o G131 A132 K133 Q134 L 135 P 136 H137

K118Q119L 120P121H122L 123K124

K

118 Q119 L 12o p121 H 122 L 123 K124 V 12s H126

K118Q119L 120P121H122L 123K124V125H126L127D 128V129R13 oG131A132K133Q134L135P136H137

H

122 L 123 K124 V125 H 126 L 127 D 128 V 129 R13o G131 A132 K133

H122L123K124V125H126L 127D128V129R13 oG131A132K133Q134L135P136H137L138K139

H

122 L 123 K124 V125 H 126 L 127 D 128 V 129 R130 G.131 A132 K133 Q 134 L 135 P 136 H 137 L 138 K139 V 140 R141 L 142 D 143 V144 R 145

G146A147K148

(155)

(156)


H 6 146 A147 K148 Q149 N 1so P 1s

'W'5

2 R 1s3 K154

b

H122L123K124V125H126L 127D128V129R130G.131A132K133Q134L135P136H137L138K139V140R141L 142D143V144R145

G (157)

b

146 A147 K148 Q 149 N 1sop's1 W1s2 A 's3 K1s4 N1ss L 156 C 1s7 L 1s8 L 1s 9 K16o

H122L123K124V125H126L 127D128V129R130G.131A132K133Q134L135P136H137L138K139V140R141L 142D143V144R145 G146A147K148Q149N150P151W152R153K154N155L15 6C157L158L15

(158)

H

9 K'6 ° K '6'


G146A147K148Q149N150P151W152R153K154N155L156C157L158L15 9K'6oK161N162V163K164

(159)

(160)

(161)

(162)


H 146 A147 K148 Q149 N 1 sop1 s1 W 1 s2 R 1s3 K1s4 N 1ss L 156 C 1s7 L 1s8 L 1s9 K16 o K 161 N162 V163 K164 S ' 65 A166 K' 6' G K124V12 sH126L127D 128V129R13 oG131A132K133

K124V125H126L127D 128V129R130G131A132K133Q134L135P136H137

K124V125H126L127D128V129R130G.131A132K133Q134L135P136H137L138K139V140R141L 142D143V144R145G146A147

K148 Q149 N 15op151w 152 R 153 K'54 N

(163)

(164) (165)

155

L 156 0.'57 L 158 L ls9 K160 K'61 N162 V '63 K' 64 S 165 A166 K167 Q 168 L 169 P 1'° H 171 5

H126L127D 128V129R130G131A132K133Q134L135P136H137L 138K139

H

126 L 127 D 128 V129 R 130 G 131 A132 K133 Q134 L 135 P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V 144 R145 G.146 A147 K148

H126L127D 128V129R130G131A132K133 n134L135P136H137L 138K139V140R141L142D143V144R145G146A147K148Q149 b

b

N1sop's1W1s2R's3K's4

(166)

H126L127D 128V129R130G131A132K133Q134L135P136H137L 138K139V140R141L142D143V144R145G146A147K148Q149 Ni5oP151W152R153K154N155L15 60.157 L 1s8 L 1s9 K160

(167)

H 126 L 127 D 128 V129 R 130 G 131 A132 K133 Q134 L 135 P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V 144 R145 G 146 A147 K14. Q 149 NisoP151W152R153K154N1ssL1s 60.157 L1s8L1s9K16°K'6'

(168)

b

b

H 126 L 127 D 128 V129 R 130 G 131 A132 K133 Q134 L 135 P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V 144 R145 G 146 A147 K14. Q 149 N 1so P 1s1 W 1s2 R1s3 K1s4 N 1ss L 156 C.1s7 L is8 L 1s9 K16 o K161N 162 V163 K164 b

Jul. 24, 2008

US 2008/0176217 Al

24

-continued (169)

H126L127D 128V129R130G131A132K133Q134L13SP136H137L 138K139V140R141L142D143V144R14 sG. 146A147K148Q149

N 1no P 1s1 w 1s2 A1s3 K1s4 N 1sn L 1s6 c.1s' L 1s8 L 1s9 K16 (170)

o K161N 162 V163 K164 S 16 s A166 K16'

b

H126L127D 128V129R130G.131A132K133Q134L13aP136H137L 138K139V140A141L142D143V144R14 sG. 146A147K148Q149 N1sOplSlWlS2R1 s3K1 s4N1ssL1s 6c.1s' b L1s8L1s9K16oK161N162V163K164S 16sA166K167Q168L169P17 0H171L172 b K 173

(171)

K133Q134L13Sp136H137L 138K139V140R141L142D 143V144R14 sG146A147K148Q149N1s OP1s1W1s2R1 s3K1 s4N1ssL1s6 c1s7L1s8L1s 9K16oK161N162V163K164S16sA166K167Q168L169P19 OH171L 172 K173V174H17S

133 Q134 L 13s P 136 H 137 L 138 K139 (172)

K

(173)

K

133 Q134L

13Sp136H137L 138K139V14 oR141L142D 143V144R14 sG146A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL1s6

C 1s9 L 1s8 L 1s9 K16o K161 N 162 V163 K164 S 16 s A166 K167 Q168 L (174)

(175)

(176)

(177)

(178)

169 P 19o H171

H137L138K139V14 oR141L 142D143V144R14 sG146A147K148

H

137 L 138 K139 V14o R 141 L 142 D 143 V 144 R14s 6. 146 A147 K148 Q 149 N1so P 1s1W 1s2 R1s3 K1s4

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1 ^ oP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o

H

137 L 138 K139 V14o R 141 L 142 D 143 V 144 R14s 6. 146 A147 K148 Q 149 N1so P 1s1W 1s2 R1s3 K1s4 N 1ss L 1s6 C. 1s9 L 1s8 L 1s9 K16o

K 161

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1sOP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o

K161 N162 V 163 K164 (179)

H137L138K139V14 oR141L 142D143V144R14 nG146 A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL166C1n9L1s8L1s9K16o K161N162 V163 K164S 166A166 K167

(180)

137 L 138 K139 V14o R 141 L 142 D 143 V 144 R14s 6. 146 A147 K148 Q 149 N1so P 1s1W 1s2 R1s3 K1s4 N 1ss L 1s6 C. 169 L 1s8 L 1s9 K16o H K161N162V163K164S 16sA166K167Q168L169P17 0H171L172K173

(181)

137 L 138 K139 V14o R 141 L 142 D 143 V 144 R14s 6. 146 A147 K148 Q 149 N1so P 1s1W 1s2 R1s3 K1s4 N 1ss L 1s6 C. 169 L 1s8 L 1s9 K16o H K161N162V163K164S 16sA166K167Q168L169P17 oH171L172K173V174H17 sL 176D177V178K179

(182)

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o

K161 N162 V 163 K164 S 16 s A166 K167 Q 168 L 169 P 17o H 171 L 172 K173 V174 H17s L (183)

K139V14 oR141L142D 143V144R14 sG146A147K148Q149N1soP1s1W1s2R1 s3K1s4N1ssL1s6C1s9L1s8L1s9K16oK161N162

v 163 K164 S (184)

176 D 177 V178 K179 G18o V 181 K182

16 s A166K167Q168L169P1' °H171

K139V14 oR141L142D 143V144R14 sG146A147K148Q149N1soP1s1W1s2R1 s3K1s4N1ssL1s6C1s9L1s8L1s9K16oK161N162 V163K164S16sA166K167Q168L169P1' oH171L172K173V174H17S

(185)

139 V14o R 141 L 142 D 143 V 144 R14s G 146 A147 K148 Q 149 N1so p 1s1 W1s2 R1s3 K1s4 N1ss L 1s6 C. 169 L 1s8 L 1s9 K160 K161N 162 K V163K164S16sA166K167Q168L169P19 oH171L172K173V174H17 sL176D177V178K179G18oV181K182Q183L184L18sH186

(186)

K

(187)

148 Q149 N 1so P 1s1W 1s2 R 1s3 K1s4 N 1ss L 1s6 C 1s9 L 1s8 L 1s9 K160 K161 N162 V 163 K164 S 16 s A166 K167 Q 168 L 169 P 17o H 171

K148Q149N1n°P1S1w1S2R1s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16oK161N162V163K164S16sA166K167Q168L169P17 oH171 L172 K173 V174 H17

(188)

148 Q149 N 1so P 1s1W 1s2 R 1s3 K1s4 N 1ss L 1s6 C 1s9 L 1s8 L 1s9 K160 K161 N162 V 163 K164 S 16 s A166 K167 Q 168 L 169 P 17o H 171 K L172K173V174H17 sL 176D 177V178K179G18°V181K182Q183L 184L18QH186

(189)

1s4 N1ss L 1s6 C 1s9 L 1s8 L 1s9 K160 K161 N162 V163 K164 S 16 s A166 K167 168 L 169 P 17o H171 L 172 K173 V 174 H17s L 176 D 177 K V178K179G18oV181K182Q183L184L18sH186L187K188V189R190L191D192V193R194G19sA196K197Q198L199L 2 ooH 201

(190)

(191)

(192)

K1 s4N1ssL1s 6C1s9L1s8L1s9K16oK161N162V163K164S16sA166K167Q168L169P17 oH171

K1 s4N1ssL1s 6C1s9L1s8L1s9K16oK161N162V163K164S16sA166K167Q168L169P17 oH171L 172K173V174H17S

K1 s4N1ssL1s 6C1s9L1s8L1s9K16oK161N162V163K164S16sA166K167Q168L169P17 oH171L 172K173V174H17 sL176D 177

V 178 K179 G 18o V181 K182 Q 183 L 184 L (193)

(194)

(195)

186 H186

K16oK161N162V163K164S16sA166K167Q168L169P17 oH171

K

160 K161 N 162 V163 K164 S 16 s A166 K167 168 L 169 P 17o H171 L 172 K173 V174 H 17S

K16oK161N162V163K164S16sA166K167Q168L169 P17 oH171L 172K173V174H17 sL176D177V178K179G18oV181K182Q183

L 184 L 18s H 186 (196)

K16oK161N162V163K164S16sA166K167Q168L169 P17 oH171L 172K173V174H17 sL176D177V178K179G18oV181K182Q183 L184L18sH186L187K188V189R19oL191D192V193R194G19sA196K197Q198L199L 2

(197)

°H2

01

160 K161 N 162 V163 K164 S 16 s A166 K167 168 L 169 P 17o H171 L 172 K173 V174 H 17s L 176 D 177 V 178 K179 G 18o V181 K182 Q 183 K L184L18sH186L187K188V189R19oL191D192V193R194G19sA196K197Q198L199L 2 0oH2 o1L 202K2o3V2o4H2Os

Jul. 24, 2008

US 2008/0176217 Al 25

-continued Replikin Sequences in Mid-molecule Portion of s61 Ni62 V e63 K164 S 16s A 166 K167 Q 16. L ff6g P ' 7o H '71

Peptide

(198)

K

(199)

K 161 N 162 V 163 K'64 S '6s A '66 K'67 Q 168 L 169 P 17 o H i71 L i72 K'73 vi74 H17s

(200)

K161N162V163K'64S'6sA'66K'67Q168L169P17oH171L172K173V174H17 sL 176D177V178K179G18oV181K182Q183L 184

L 18s H '86

(201)

K

161 N162 V 163 K164 S 16s A166 K167 Q 168 L 169 P 17o H 171 L 172 K173 V174 H17s L 176 D 177 V17. K179 G18o V 1.1 K1.2 Q183 L 184

L18sH186L

187K188V189R19oL191D

192V193R194G'9sA'96K' 97Q198L'99L 20

°H2

01

161 N162 V 163 K164 S 16s A166 K167 Q 168 L 169 P 17o H 171 L 172 K173 V174 H17s L 176 D 177 v17. K179 G18o V 1.1 K1.2 Q183 L 184

(202)

K L 18s H186 L 1.7 K188 V 1.9 R 19o L 191 D 192 V193 R194 G 19s A196 K197 Q198 L 199 L 20o H 2o1 L 202 K 203 V 2o4 H 2 os

(203)

Ki 64 5 16s Ai66 Kl 67 Q 16e li i69 P i7 o H 17i L i72 Ki73

(204)

K

(205)

164 S 16s A166 K167 Q 168 L 169 P 17o H 171 L 172 K173 V 174 H17S

K164S16sA166K167Q168L169P17 oH171L172K173V174H17 sL 176D177V178K179G18oV181K182Q183L 184L18sH186

164 S 16 s A166 K167 Q 168 L 169 P 17o H 171 L 172 K173 V 174 H17s L 176 D 177 V17. K179 G18o V1.1 K1.2 Q183 L 184 L 18s H186 L 187

(206)

K K 188 V 189 R 19o L 191 D 192 V 193 R 194 G 19s A196 K1 97 Q 198 L 199 L 2 oo H 2 of

(207)

K K188 V1.9 R 19o L 191 D 192 V 193 R194 G 19s A196 K197 Q 198 L 199 L Zoo H 2o1 L 2o2 K 203 V 2o4 H 20s

(208)

Ki 67 Q 168 L 169 P 17 o H 171 L 172 K173

(209)

K

(210)

(211)


167 Q168 L 169 P 17o H 171 L 172 K173 V 174 H17S

K167Q168L169P17 oH171L 172K173V174H17 sL176D 177V178K179G18oV181K182Q183L184L18sH186

K167Q168L169P17 oH171L 172K173V174H17 sL176D 177V17BK179D1BoV1B1K1BoQ183L184L18sH186L 187K188V189R190

L 191 D 192 V 193 R 194 G i9s Ai96 Ki 97 Q 198 L 199 L 2 oo H 201 (212)

K

167 Q168 L 169 P 17o H 171 L 172 K173 V 174 H17s L 176 D 177 V178 K179 G18o V181 K182 Q183 L 184 L 18s H186 L 187 K188 V189 R 190

L191D192V193R194G19sA196K197Q198L199L 2 ooH 2 o1L 2o2K2o3V2o4H2es

167 Q168 L 169 P 17o H 171 L 172 K173 V 174 H17s L 176 D 177 V178 K179 G18o V181 K182 Q183 L 184 L 18s H186 L 187 K188 V189 R 190

(213)

K L 191 D 192 V 193 R194 G 19s A196 K197 Q 198 L 199 L 2oo H 201 L 2o2 K 2o3 V 2o4 H 2os L 2o6 D 209 V 208 R 209 G 210 A 211 K212 Q 213 L 214 P 21s H 2i6

(214)

H

(215)

171 L 172 K173 V174 H 17S L 176 D 177 V 178 K179

H17ilii72Ki73Ui74H17sLi76D177V178K179G18ovie1K1e2

(216)

H 171 L 172 K173 V 174 H 17s L 176 D 177 V 178 K179 G 180 V 181 K182 Q 183 L 184 L ies H ie6 L 187 K188

(217)

H

171 L 172 K173 V174 H 17S L 176 D 177 V 178 K179 G18o V 181 K182 Q 183 L 184 L 18s H 186 L 187 K188 V 189 R19o L 191 D 192 V193 R 194

G19sA196 K'9

(218)

H

Q'9

8L'9 20 o H2 o

'L202

K203


G19sA196K197

(219)

H


G'9sA'96K'97Q198L'99L 20 oH2 o1L 202K2o3V2o4H 2 osL 2 o6D 207V2 o8R2 o9G 21 oA211K212

(220)

H

171 L 172 K173 V174 H 17S L 176 D 177 V 178 K179 G18o V 181 K182 Q 183 L 184 L 18s H 186UB7 K188 v 189 R19o L 191 D 192 v193 R 194

G'9sA'96K'97Q198L'99L 20 oH2 o1L 202K2o3V2o4H2osL2

°6 D 2

°'V2 o8R2 09G. 21 oA211K212Q213L 214P21sH216L 217K218

173 V174 H 17s L ' 76 D 177 V 178 K179

(221)

K

(222)

K '73 V '74 H '7 s L '76d77 V 178 K'79 G 'eo Vie1 Ki 82

(223)

K '73 V '74 H '7s L '76 D '77 V 178 K'79 G 18o V '81 K' 82 Q '83 L ' 84 L 18s Hie6

(224)

K Ki 97 Q 19e L i99 L 2 oo H 2oi

(225)

K

173 V174 H 17s L '76 D 177 V 178 K179 G 180 V181 K182 Q 183 L 184 L 18s H186 L 187 K188 V189 R19o L 191 D 192 V 193 R194 G19s A196

173 V174 H 17s L '76 D 177 V 178 K179 G 180 V181 K182 Q 183 L 184 L 18s H186 L 187 K188 V189 R19o L 191 D 192 V 193 R194 G19s A196

K'97Q' 98 L'99L 2 ooH 2 o1L 202 K203V204 H205

(226)

K

173 V174 H 17s L '76 D 177 V 178 K179 G 180 V181 K182 Q 183 L 184 L 185 H186 L 187 K188 V189 R19o L 191 D 192 V 193 R194 G19s A196

K'97Q198L'99L 2 ooH 2 o1L 202K2o3V2o4H2 osL 206D 207V2 o8R 2 o9G21oA211K212Q213L 214P21sH216

Jul. 24, 2008

US 2008/0176217 Al 26

-continued (227)

(228)

K

173 v174 H 17s L '76 D 177 V 17. K179 G 180 V 1.1 K182 Q 1.3 L 184 L 18s H186 L 1.7 K188 V1.9 R19o L 191 D 192 V 193 R194 G19s A196

K197 Q19. L

199 L 2oo H 2o1 L 2o2 K2o3 V 2o4 H 2os L 2o6 D 207 V 208 R 2o9 G 210 A211 K 212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 220

H '7s L '76 D '77 V 1 78 K '79 G 'so V i e1 K '82 Q '83 L '84 L 1 8s H '86 L '87 K'88 V ' 89 R 19o L 191 D 192 V 193 R 194 G '9s A'96 K ' 97 Q 198

L 199 L 2oo H 2oi L 2o2 K 2o3 V 2o4 H 2os L (229)

2o6 D 2o7 V 2oe R 2o9 G 21o A 211 K212

H '7s L '76 D '77 V 178 K '79 G 'so V i e1 K '82 Q '83 L '84 L 1 8s H '86 L '87 K'88 V ' 89 R 19o L 191 D 192 V 193 R 194 G '9s A'96 K ' 97 Q 198

L 199 L 2

oo H 2 of L 2o2 K 2o3 V 2o4 H 2 os L 2 o6 D 2o7 V 2 os R 2o 9 G 21o A 2 ii K212 Q 213 L 214 p 21s H 216 L 217 K218

(230)

H '7s L '76 D '77 V 178 K '79 G 'so Vse1 K '82 Q '83 L '

(231)

H

(232)

84 L 18s H '86 L '87 K'88

17s L 176 D 177 V17. K179 G 180 V 1.1 K 1.2 Q1.3 L 184 L 18s H186 L 187 K188 V1.9 R 19o L 191 D 192 V 193 R194 G 19s A196 K197 Q 19.

L 199 L 2oo H 2oi L 2o2 K 2o3

H17 sL176D 177V178K179G'8oV181K182Q183L'84L18sH186L 187K188V189R19oL191D192V193R194G'9sA'96K'97

K'79G1.oV'81K'82Q1.3L 1.4LiesH1.6L'87Kiee (233)

(234)

K '79 G 'so V i e1 K'82 Q '83 L '84 L lss H '86 L '87 K'88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A'96 K '97 Q 198 L '99 L 2

(235)

K '79 G 1. K2

(236)

(237)

(238)

o V 1.1 K1. 2 Q 1 .3 L 184 L 18s H 1.6 L 1.7 K188 V 1.9 R19o L

191 D 192 V193 R 194 G19s A196 K197 Q19. L 199 L 2oo H 2o1 L 202

0 3 V204 H20s

K '79 G

1.o V 1.1 K1.2 Q 1 .3 L 184 L 18s H 186 L 1.7 K188 V 1.9 R19n L 191 D 192 V193 R 194 G19s A196 K197 Q19. L 199 L 2oo H 2o1 L 202

K 2o3 V 204 H 2os L 2o6 D 2o' V 2oe R 2o9 G 21o A211 K212 Q 213 L 214 p

21s H 2is

K '79 G 'so V i e1 K'82 Q '83 L '84 L lss H '86 L '87 K'88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A'96 K '97 Q 198 L '99 L 2 K 2o3 V 2o4 H 2os L 2 °6 D 2 °'V 208 R 2o9 G. 210 A211 K212 Q z13 L 214 p 21s H 216 L 217 K 21. v 219 H 220

oo H 2 o1 L 202

K' 82Q'83L'84L18sH'86L'87K'88

2 Q 1. 3 L 184 L 18s H 186 L 1.7 K188 V 1.9 R19o L 191 D 192 V193 R 194 G19s A196 K197 Q19. L 199 L 2oo H 201

(239)

K 1.

(240)

K '82 Q '83 L '84 L 18s H '86 L '87 K'88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A'96 K '97 Q 198 L '99 L

(241)

K 1.

L2 (242)

oo H 201

2 Q 1. 3 L 184 L 18s H 186 L 1.7 K188 V 1.9 R19o L 191 D 192 V193 R 194 G19s A196 K197 Q19. L 199 L 2oo H 2o1 L 202 K2o3 V 2o4 H 20s

o6

K 1.

20 o H 2 o1 L 202 K2o3 V 2o4 H 20S

D

207 V 2 08 R

2

0 9 G 21o A 211 K212 Q 213 L 214 p 21s H 216

2 Q 1. 3 L 184 L 18s H 186 L 1.7 K188 V 1.9 R19o L 191 D 192 V193 R 194 G19s A196 K197 Q19. L 199 L 2oo H 2o1 L 202 K2o3 V 2o4 H 20s

L 2 °6D 2o7

V 208 R 2o9 G 210 A 211 K212 Q 213 L 214 P 21s H 216 L 217 K 218 V 219 H 220

(243)

H '86 L '87 K '88 V ' 89 R 19o L 191 D 192 V 193 R 194 G '9s A '96 K ' 97 Q 198 L '99 L 2

(244)

H

(245)

H '86 L '87 K '88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A '96 K'97 Q 198 L '99 L 2

oo H 2 o1 L 202 K2o3 V 2o4 H 2 os L 2 o6

(246)

H '86 L '87 K '88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A '96 K'97 Q 198 L '99 L 2

oo H 2 oi li 2o2 K203 v 2o4 H 2 os L 2 o6

oo H 2 o1 L 202 K203

186 L 1.7 K188 V1.9 R 19o L 191 D 192 V 193 R194 G19s A196 K197

D

207 V 2 o8 R 209

G 21o A211 K 212

D

207 V 2 o8 R 209

G210A211K212Q213L 214 P21s H216L 217 K218

(247)

H

'86 L 1.7 K188 V1.9 R 19o L 191 D 192 V 193 R194 G19s A196 K197 Q 19. L 199 L 2oo H 201 L 2o2 K2o3 V 2o4 H 2os L 206 D 207 V 208 R 209

G21oA211K212Q213L 214P21sH216L 217K218V219H 22 oL 221D 222V223R224G 22 sA226K227

(248)

H

'86 L 1.7 K188 V1.9 R 19o L 191 D 192 V 193 R194 G19s A196 K197 Q 19. L 199 L 2oo H 201 L 2n2 K2o3 V 2o4 H 2os L 206 D 207 V 208 R 209

G21oA211K212Q213L 214P21sH216L 217K218V219H 22 oL 221D 222V223R224G 22 sA226K227Q228N229P23oW231R232K233

(249)

K '88 V ' 89 R 190 L 191 D 192 V 193 R 194 G '95 A'96 K ' 97 Q 198 L 199 L

2 oo H 201

(250)

K '88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A'96 K'97 Q 198 L 199 L

2 oo H 201 L 2o2 K 2o3 V 204 H 20S

(251)

K '88 V ' 89 8 19o L 1 91192 V 193 R 194 G '9s A'96 K'g7 Q i98 L '99 li 2 oo H 2 o1 L 202 K 2o3 V 2o4 H 2 os L

K 212 Q 213 L (252)

K '88 V '89 8 19o L 1911g2 V 'g3 A'94 G '9s A'96 K'g7 Q 'ge L igg li

K 212 Q 213 L

2 o6

D

207 V 2 o8 R 20g G 21n A 2i1

214 P 21s H 2i6

2 oo H 2 o1 L 202 K 2o3 V 2o4 H 2 os L 2 o6

D

207 V 2 o8 R 2 o9 G 21o A 211

214 P 21s H 216 L 217 K21. v 219 H 220

L '99 L 2 oo H 2 o1 L 202 K203

(253)

K' 97Q' 98

(254)

K'97Q'9.L 199

L 2oo H 2oi L 2o2 K2o3 V 2o4 H 20S

(255)

Ki*o7Qi*98Lig9li2 oo H 2 o1 L 2o2 K203 v 2o4 H 2 ds L 2 o6

(256)

K'97Q'9.L 199

(257)

H2

D

207 V 2 o8 R 2 og G 2io A21i K 2i2 Q 213 L 214 P 21s H 2i6

L 2oo H 201 L 2o2 K2o3 V 2o4 H 2os L 206 D 207 V 208 R 209 6 210 A211 K 212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 220

oi li 202 K 203 v 2o4 H 2 os L 2 o6

D

207 V 2 o8 R 2 og G 21n A 2i1 1K 212

Jul. 24, 2008

US 2008/0176217 Al 27

-continued (258) (259)

H

2O 1 L 202 K 203 V 2o4 H 2os L 206 D 207 V 208 R 209 G 210 A 211 K212 Q 213 L 214 P 21s H 216 L 217 K218

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213L 214P21sH 216L 217K218V219H22 oL 221D 222V223R 224 G22sA226K227

(260)

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213L 214P21sH 216L 217K218V219H22 oL 221D 222V223R 224 G22 s A226 K227Q228N 229 p23 0W23 'R232 K233

(261)

H

2o1 L 202 K 2o3 V 2o4 H 2os L 206 D 207 V 208 R 2o9 G 210 A 211 K212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 22o L 221 D 222 V 223 R 224

G22sA226K227Q228N 229P230W231R 232K233N234L 23SC236L 237L238K239

(262)

(263)

2oi L 202 K 2o3 U 2o4 H 2os L 206 D 207 V 208 R 2o9 G 210 A 211 K212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 22o L 221 D 222 V 223 R 224

H G 22s A226 K 227 Q 228 N 229 P 23o W 231 R 232 K233 N 234 L 23s C. 236 L 237 L 238 K239 K 240

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213L 214P21sH 216L 217K218V219H22 oL 221D 222V223R 224

G 22s A226 K 227 Q 228 N 229 P 230 W 231 R 232 K233 N 234 L 23s C 236 L 237 L 238 K239 K 240 N 241 V 242 K 243

(264)

H 2 o1 L 202 K 203 V 204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213L 214P21sH 216L 217K218V219H22 oL 221D 222V223R 224 G22sA226K227Q228N 229P230W231R 232K233N234L 23SC236L 237L 238K239K240N241V242K243S244A24 sK246

(265) (266)

(267) (268)

K

203 V 204 H 20s L 206

D

2o7 V 208 R 2o9 G 210 A211 K212

K203V204H 2 osL 2 o6D 207V2 o8R2 o9G 21 oA211K212Q213L 214P21sH216

K

2o3 V 204 H 2os L 206 D 207 V 208 R 2o9 G 210 A211 K212 Q 213 L 214 P 21s H 216 L 217 K 218 V 219 H 220

K203V204H 2 osL 2 o6D 207V2 o8R2 o9G 21 oA211K212Q213L 214P21sH216L 217K218V219H22 oL 221D 222V223R224li22 sA226

K 227 Q 228 N 229p23o W 231 8 232 K233 N 234 L 23s C 236 L 237 L 238 K 239 K240 N 241V 242 K243 S 244 A 24s K246 Q 247 L 248P (269)

H 2 os L 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213L 214P21sH216L 217K218

(270)

H

(271)

0

b

2os L 206 D 207 V 208 R 2o9 G 210 A211 K 212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 22o L 221 D 222 V 223 8 224 6 22s A226 K227

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213L 214P21sH216L 217K218V219H 22 oL 221D 222V223R224G 22 sA226K227Q228 N229 P23 0W23

(272)

249H2

'R23

2 K233

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213L 214P21sH216L 217K218V219H 22 oL 221D 222V223R224G 22 sA226K227Q228 N229p23OW231R232K233N 234L 23SC236L 237L238K239

(273)

H

2os L 206 D 207 V 208 R 2o9 G 210 A211 K 212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 22o L 221 D 222 V 223 8 224 6 22s A226 K227 Q 228

N229p23OW231R232K233N 234L 23SC236L 237L238K239K240

(274)

(275)

2os L 206 D 207 V 208 R 2o9 G 210 A211 K 212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 22o L 221 D 222 V 223 8 224 6 22s A226 K227 Q 228

H N 229 P 230 W 231 R 232 K 233 N 234 L 23s C 236 L 237 L 238 K 239 K240 N 241 V 242 K243

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213L 214P21sH216L 217K218V219H 22 oL 221D 222V223R224G 22 sA226K227Q228

N 229 P 230 W 231 R 232 K 233 N 234 L 23s C 236 L 237 L 238 K 239 K24o N 241 V 242 K243 S 244 A24s K246

(276)

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213L 214P21sH216L 217K218V219H 22 oL 221D 222V223R224G 22 sA226K227Q228 N229p23OW231R232K233N 234L 23SC236L 237L238K239K240N 241V242K243S244 A24 sK246Q247L 248P249H2s oL 2 s1K2s2

212 Q 213 L 214 P 21s H 216 L 217 K218

(277)

K

(278)

K 212 Q 213 L 214 P 21s H 216 L 217 K218 V 219 H 220

(279)

b

K212Q213L 214P21sH 216L 217K218V219H22 oL 221D 222V223R 224622 sA226K227Q228N229p23oW231R 232K233N234L 23s c236L 237L 238K239K24 oN 241V242K243S244 A24 sK246Q247L 248P249H2s0

(280) (281)

(282) (283)

H

216 L 217 K 218 V 219 H 22o L 221 D 222 V 223 8 224 G 22s A 226 K227

H216L 217K218V219H 22 oL 221D 222V223R224G22 sA226K227Q228N229P230W231R232K233

H

216 L 217 K 218 V 219 H 22o L 221 D 222 V 223 8 224 G 22s A 226 K227 Q 228 N 229 P 23o W 231 R 232 K233 N 234 L 23s C. 236 L 237 L 238 K 239

H216L 217K218V219H 22 oL 221D 222V223R224G22s A226K227Q228N229P230W231R232K233N 234L 23SC236L 237L 238K239

K 240

(284)

H216L 217K218V219H 22 oL 221D 222V223R224G22s A226K227Q228N229P230W231R232K233N 234L 23SC236L 237L 238K239 K24 oN241V242K243

(285)

H


K24

(286)

° N 24

'V242 K243S 244 A24 s K246


H K 24o N 241 V 242 K243 S 244 A 24s K246 Q 247 L 248 P 249 H 2so L 2s1 K 2s2

Jul. 24, 2008

US 2008/0176217 Al

-continued

(287)

H216L 217K218V219H 22 oL 221D 222V223R224G225 A226K227Q228N229P230W231R232K233N 234L 235C236L 237L 238K239

K 24o N 241 V 242 K243 S 244 A 24s K246 Q 247 L 248 P 249 H 25o L 251 K 252 V 253 L 2s4 L 25s D 2s6 V 2s7 R 258 G 259 A 26o K261

(288)

K218V219H 22 oL 221D 222V223R224G 225A226K227Q228N229P230W231R232K233N234L 235C236L 237L 238K239K24 oN 241 v242K243S244 A24 sK246Q247L 248P249H25

(289)

K 2f8 V 2ff9 H 22 o L 22i fi 222V23R224G 225A226K227Q228N229P230W231R232K233N234L 235C236L 237L 238K239K24 oN 241 v242K243S244 A245K246Q247L 248P249H25 oL 251K252V253L 254L 2 ssD 256V257R2 s8G2 s9A26 oK261Q262L 263P264H 265

(290) (291)

(292) (293)

(294) (295)

K

218 V 219 H 22o L 221 D 222 V 223 8 224 6 22s A226 K227

H22 oL 221D 222V223R 2246 225A226K227Q228N229P230W231R 232K233

H

22o L 221 D 222 V 223 R 224 6 22s A226 K 227 Q 228 N 229 P 23o W 231 R 232 K233 N 234 L 23s C. 236 L 237 L 238 K239

H22 oL 221D 222V223R 2246 22 sA226K227Q228N229P230w231R 232K233N234L 235C236L 237L 238K239K240

H

22o L 221 D 222 V 223 R 224 6 22s A226 K 227 Q 228 N 229 P 23o W 231 R 232 K233 N 234 L 23s C. 236 L 237 L 238 K239 K 24o N 241 V 242 K 243

H22 oL 221D 222V223R 2246 225A226K227Q228N229P230W231R 232K233N234L 235C236L 237L 238K239K24 oN241V242K243

S 244 A24s K 246

(296)

(297)

H22 oL 221D 222V223R 2246 22 sA226K227Q228N229P230W231A 232K233N234L 235C236L 237L 238K239K240N241V242K243

s 244 A24 s K246Q247L 248 P 249 H25 ° L 2 'K2 52 H

22o L 221 D 222 V 223 R 224 6 22s A226 K 227 Q 228 N 229 D 23o W 231 R 232 K233 N 234 L 23s C. 236 L 237 L 238 K239 K 24o N 241 V 242 K 243

5244 A245K246Q247L 248P249H25 oL 251K252V253L 254L 2 ssD 256V257R2 s8G 259A26 oK261

(298)

H

22o L 221 D 222 V 223 R 224 6 22s A226 K 227 Q 228 N 229 P 23o W 231 R 232 K233 N 234 L 23s C. 236 L 237 L 238 K239 K 24o N 241 V 242 K 243

s 244 A245 K 246 Q 247 L 248 P 249 H 2So L 251 K2s2 V 253 L 254 L 2ss D 256 V 2s7 R 2s8 G 259 A26 o K261 Q 262 L 263 P 264 H 265 L 266 K 269 (299)

(300)

K227Q228N 229P230W231R 232K233N 234L 235C236L 237L 238K239K240N241V242K243S244 A245K246Q247L 248P249H 250

K227n228N 229P230W231R 232K233N 234L 235C236L 237L 238K239K240N241V242K243S244 A245K246n247L 248P249H 250 L 2 s1 b K252V253L 254L 2 ssD 256V257R 2586. 259A260K261Q262L 263P264H265

(301) (302)

(303)

K

b

233 N 234 L 235 0 236 L 237 L 238 K239 K 240 N 241 V 242 K 243 5 244 A 245 K246 Q 247 L 248 P 249 H 250

K233N234L 235C236L 237L 238K239K24 oN241V242K2435244A245K246 Q247L 248P249H2 soL 251K252V253L 254L 2 ssD 256

v 2s7 R 2s8 G 2 9 A260 K 261 Q 262 L 263 P 264 H 265 K233N234L 235C236L 237L 238K239K24 oN241V242K2435244A245K246Q247L 248P249H2 soL 251K252V253L 254L 2 ssD 256 V25'JR2s8G.2s9A26oK261u262L 263b264H265L 266K267V268L269L27tiD271V2"2R2'I3G.2'Z4 A27 5K276a2'J'JL 278p2'J 9H 280

(304)

K

239 K24o N 241 V 242 K 243 `55 244 A24s K 246 Q 247 L 248 P 249 H 25o L 2s1 K2s2 V 253 L 254 L 2ss D 256 V 257 R 2s8 `G L 2sg A260 K261 Q 262

L263 P264 H265

(305)

(306)

239 K24o N 241 V 242 K 243 5 244 A24s K 246 Q 247 L 248 P 249 H 25o L 2s1 K2s2 V 2s3 L 254 L 2ss D 256 V 257 R 2s8 G 259 A260 K261 Q 262

K L 263 P 264 H 265 L 266 K 267 V 268 L 269 L 27o D 271 V 272 R 273 G 274 A 27S K276 Q 277 L 278 P 279 H 280

K239K24 oN 241V242K2435244 A245K246Q247L 248P249H25 oL 2 s1K252 V 253L 254L 2 ssD 256V257R2 s8G 2 s9A26 oK261Q262

L 263 P 264 H 265 L 266 K 267 V 268 L 269 L 2'o D 271 V 272 R 273 G 274 A 27S K276 Q 277 L 278 P 279 H 280 L 281 K282 V 283 H 284

(307)

K239K24 oN241V242K2435244A245K246Q247L248P249H25o

`G

24o N 241 V 242 K243 5 244 A 24s K246 Q 247 L 248 P 249 H 2so

(308)

K

(309)

K 24 o N 241 V 242 K243 5 244 A 245 K246 Q 247L 248P249H 25 oL 2 s1K252V253L 254L 25 sD 256V257R 2586.259A26oK261Q262L 263 P264 H26s

(310)

K24 oN241V242K2435244 A245K246Q247L 248P249H 25 oL 2 s1K252V253L 254L 25 sD 256V257R 2586. 259A26oK261Q262L 263 P264H26sL 266K267V268L269L27oD271V272R273G 274 A27 sK276Q277L 278P279H280

24o N 241 V 242 K243 5 244 A 24s K246 Q 247 L 248 P 249 H 25o L 2s1 K 2s2 V 2s3 L 2s4 L 255 256 V 2ss R 258 G 259 A 260 K261 Q 262 L 263 D P264H26sL 266K267V268L269L27oD271V272R273G274A27sK276Q277L 278P279H28 oL 281K282V283H 284

(311)

K

(312)

K

(313)

(314)

(315)

243 5 244 A 24s K246 Q 247 L 248 P 249 H 25o L 2s1 K252

`G

K2435244 A245K246Q247L 248P249H 25 oL 2 s1K252V253L 254L 2 ssD 256V257R 2586. 259A26oK261Q262L 263P264H265

243 5 244 A 24s K246 Q 247 L 248 P 249 H 25o L 2s1 K2s2 V 253 L 254 L 2ss D 256 V 2s7 R 258 6 259 A260 K 261 Q 262 L 263 P 264 H 265 L 266

K 267 V 268 L 269 L 27o D 271 V 272 R 273 G 274 A27s K276 Q 277 L 278 P 279 H 280 K

K2435244 A245K246Q247L 248P249H 25 oL 2 s1K252 V 253L 254L 2 ssD 256V257R 2586. 259A26oK261Q262L 263P264H265L 266

K 267 V 268 L 269 L 270 D 271 V 272 R 273 G 274 A27s K276 Q 277 L 278 P 279 H 280 L 281 K 282 V 283 H 284

(316)

K 246 Q 247 L 248 P 249 H 2 so li 251 K252

`G

Jul. 24, 2008

US 2008/0176217 Al 29


K

246 Q 247 L 248 P 249 H 250 L 251 K2s2 V 253 L 254 L 2ss D 256 V 2s7 R 2s8 G 259 A26o K 261 Q 262 L 263 P 264 H 265

K246Q247L 248P249H 2 soL 251K252V253L 254L 2 ssD 256V257R 2 s8G259A260K261Q262L 263P264H265L 266K267V268L 269 L2'0D2'HV2'J2 R273L. 274 A27 s K2"16v2'J"l L

(319)

278 P27

9

H28

0

K 246 Q 24s L 248 P 249 H 2 so li 251 K252 V 253L 254L 2 ssD 256V257R 2 s8G259A26 oK261Q262L 263P264H265L 266K267V268L 269 L27 oD271V2'J2A273G.274A27SK2'16n2'J'JL 278P279H 28 oL 281K282V283H284

(320) (321)

H

25o L 2si K 252 V 2s3 L 254 L 25s

D

2s6 V G 257 R 2s8 G 2s9 A 26o K261

H25 oL 2 s1K252V253L 254L 25 sD 256V257R2 s8G2 s9A26 oK261Q262L 263P264H 26 sL 266K267

25o L 2s1 K 252 v 2s3 L 254 L 25s D 2s6 v 257 R 2s8 G. 2s9 A 26o K261 Q 262 L 263 p 264 H 26s L 266 K267 v 268 L 269 L 27o D 271 v 272 R 273

(322)

H G 274 A275 K 276

(323)

H 6 274 A275 K 276 n 27

25o L 2s1 K 252 v 2s3 L 254 L 25s D 2s6 e 257 R 2s8 G. 2s9 A 26o K261 Q 262 L 263 p 264 H 26s L 266 K267 v 268 L 269 L 270 D 271 v 272 R 273 L 278 p27

H 28 o L 281 K282

(324)

H 25 o L 2 s1 K 252 V 253L 254L 25 sD 256V257R2 s8G259 A26 oK261Q262L 263P264H 26 sL 266K267V268L 269L 270D 271V272R 273 G.274 A27S K 276 Q 277 L 278 P 279 H 280 L 281 K282 V 283 H 284 L 28s D 286 V 287 R 288 G 289 A290 K291

(325)

H 25 o L 2 s1 K 252 V 253L 254L 25 sD 256V257R2 s8G259 A26 oK261Q262L 263P264H 26 sL 266K267V268L 269L 270D 271V272R 273 G274A27sK276Q277L278P279H28 oL 281K282V283H 284L 28sD 286V287R288G 289A29oK291Q292N293P294W29sR296K297

(326) (327)

K

(329)

D

256 V 257 R 2s8 G 259 A260 K261 Q 262 L 263 P 264 H 265

`G

K252V253L 254L 2 ssD 256V257R2 s8G 259A26 oK261Q262L 263P264H265L 266K267V268L 269L 270D 271V272R273G274A275

K (328)

2s2 V 253 L 254 L 2ss

276 Q 277 L 278 P 279 H 280

K 252 V 253L 254L 2 ssD 256V257R2 s8G 259A26 oK261Q262L 263P264H265L 266K267V268L 269L 270D 271V272R273G274A275 K 276 Q 277 L 278 P 279 H 28o L 281 K282 V 283 H 284 K261Q262L 263P264H 26sL 266K267V268L269L27oD2'l1v2'J2R2'I3G2'I4 A2T 5K2T6^2U"JL 278P279H280

(330)

G 277L 278P279H28 oL 281K282V283H 284 K 261 Q 262L 263P264H 26sL 266K267V268L269L27oD271V272R273G274A27sK276 `Q

(331)

K 261 Q 262 L 263 P 264 H 265 L 266 K267

(332)

H

(333)

(334)

`G

265 L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G 274 A 27s K296

H26sL 266K267V268L 269L 27 oD 271V272R273G274 A27 sK276Q277L 278P279H 28 oL 281K282

H

265 L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G 274 A 27s K298 Q 277 L 278 P 279 H 280 L 281 K282 V 283 H 284 L 28s D 286 V 287 R 288 `G

G289A290K29'

(335)

H26sL 266K267V268L 269L 27 oD 271V272R273G274 A27 sK276Q277L 278P279H 28 oL 281K282V283H284L 28sD 286V287R 288

G (336)

289 A290 K 291 Q 292 N 293 P 294 W 295 R 296 K297 N 298 L 299 C 3oo L 3oi L 302 K303

H26sL 266K267V268L 269L 27 oD 271V272R273G274 A27 sK276Q277L 278P279H 28 oL 281K282V283H284L 28sD 286V287R 288 G289A29oK291Q292N 293p294W29sR 296K297N298L 2990.3OOL3 o1L302K303K304

(337)

H

265 L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G 274 A 27s K296 Q 277 L 278 P 279 H 280 L 281 K282 V 283 H 284 L 28s D 286 V 287 R 288

G289A29oK291Q292N 293P294W295R 296K297N298L 29903 ooL 3 o1L302K303K304N305V3 o6K307

(338)

H

265 L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G 274 A 27s K296 Q 277 L 278 P 279 H 280 L 281 K282 V 283 H 284 L 28s D 286 V 287 R 288

G289A290 K291Q292N 293

(339)

(340)

(341) (342)

P 2 94

R 296 K2 97

`G

H 26s L 266 K 267 V 268L 269L 27 oD 271V272R273G274 A27 sK276Q277L 278P279H 28 oL 281K282V283H284L 28sD 286V287R 288 K 291 Q 292 N 293 P 294 W 29s R 296 K297 N 298 L 299 0.300 L 301 L 302 K303 K3o4 N3os V 306 K3o7 S 3o8 A309 K310 K267V268L 269L 27 oD 271V272R273G 274 A27 sK276Q277L 278P279H280

K

267 V 268 L 269 L 27o D 271 V 272 R 273 G 274 A27s K298 Q 277 L 278 P 279 H 280 L 281 K 282 V 283 H 284

K267V268L 269L 27 oD 271V272R273G 274 A27 sK276Q G 277L 278P279H28 oL 281K282V283H284L 28 sD 286V287R288G289A290

K 291 Q 292 N 293 P 294 W 295 8 296 K297 N 298 L 299 C 300 `LG 301 L 3o2 K3O3 K304 N305 v 306 K30'7 S 308 A309 K310 Q 311 L 312 P 313 H 314

(343)

(344) (345)

K276 n277L 278P279H 28oL 281K282

K

276 Q G 277 L 278 P 279 H 28o L 281 K282 V 283 H 284

K276Q277L278P279H 28oL 281K282V283H284L 28sD 286V287R 288G289A29oK291Q292N293P294W29sR 296K297N298L 299 c3o0L301L 302K303K304N30xV306K307S308A309K310it311L 312F313H314

(346)

b

H

280 L 281 K 282 V 283 H 284 L 285 D 286 V 287 R 288 G 289 A 290 KK291

`G

Jul. 24, 2008

US 2008/0176217 Al

O

-continued

(347)

(348)

H28 oL 281K282V283H 284L 28 sD 286V287R288G289 A29 oK291Q292N293P294w29sR296K297N 298L 299c.3 ooL3 o1L302K303

H

280 L 281 K 282 V 283 H 284 L 28s D 286 V 287 8 288 6 289 A 290 K291 Q 292 N 293 P 294 W 29s R 296 K297 N 298 L 299 c. 300 L 301 L 302 K303

K304

(349)

H

280 L 281 K 282 V 283 H 284 L 28s D 286 V 287 8 288 6 289 A 290 K291 Q 292 N 293 P 294 W 29s R 296 K297 N 298 L 299 c. 300 L 301 L 302 K303

K304N305V306K307

(350)

(351)

H28 oL 281K282V283H 284L 28 sD 286V287R288G289A29 oK291Q292N293P294W29sR296K297

H28 oL 281K282V283H 284L 28 sD 286V287R288G289 A29 oK291 Q 292N293P294W295R296K297N 298L 299C300L301L302K303 K304N305 V306 K307S308A309 K3

(352)

H

10

280 L 281 K 282 V 283 H 284 L 28s D 286 V 287 8 288 6 289 A 290 K291 Q 292 N 293 P 294 W 29s R 296 K297 N 298 L 299 0. 300 L 301 L 302 K303

K304N305V306K307S308A309K310Q311L312P313H314L315K316

280 L 281 K 282 V 283 H 284 L 28s D 286 V 287 8 288 6 289 A 290 K291 Q 292 N 293 P 294 W 29s R 296 K297 N 298 L 299 0. 300 L 301 L 302 K303

(353)

H K3°4 N305 V 306 K3°7 S 3°8 A 309 K310 Q 311 L 312 P 313 H 314 L 315 K316 V317 L 318 L 319 D 320 V321 R 322 G323 A324 K325

(354)

K 282 V 283 H 284 L 28s D 286 V 28s R 288G 289A29oK291Q292N293P294W295R296K297N298L 299C300L301L 302K303K304N305 V 306 K307 S 0 9 K310 n 311 L 312 p 313 H314 8A3

(355)

K 282 V 283 H 284 L 28s D 286 V 287R288G 289A29oK291Q292N293P294W295R296K297N298L 299C300L301L 302K303K304N305 V306K307S308A309K310Q311L312P313H314L315K316V317L 318L319D320V321R322G323 A324K325Q326L327P328H329

(356)

K

(357)

(358) (359)

(360)

(361)

282 V 283 H 284 L 28s D 286 V 287 R 288 G 286 A290 K291

H284L 285D 286V287R 2886 289A29oK291Q292N293P294W295R 296K297N298L 299C300L301L 302K303

H

284 L 28s D 286 V 287 R 288 6 289 A29o K 291 Q 292 N 293 P 294 W 295 R 296 K297 N 298 L 299 0.300 L 301 L 302 K3o3 K304

H284L 285D 286V287R 2886 289A29oK291Q292N293P294W295R 296K297N298L 299C300L301L 302K303K304N305V3 o6K307

H284L 28sD 286V287R 2886 289A29oK291Q292N293P294W29sR 296K297

H284L 285D 286V287R 2886 289A29oK291 Q 292N293P294W295R 296K297N298L 299C300L301L 302K303K304N305V3 o6K307

5 3o8 A309

(362)

H284L 285D 286V287R 2886 289A29oK291Q292N293P294W295R 296K297N298L 299C300L301L 302K303K304N305V3 o6K307

S

(363)

310

308A3

09 K310 n311 L 312

P313 H

314 L 315 K316

H 284 L 28s D 286 V 287R 2886 289A29oK291Q292N293P294W295R 296K297N298L 299C300L301L 302K303K304N305V3 o6K307 S3°8A309K310Q311L 312P313H314L 315K316V317L 318L319D 320V321R322G323 A324K325

284 L 28s 286 U 287 R 288 6 289 A29o K 291 Q 292 N 293 P 294 W 295 R 296 K297 N 298 L 299 0.300 L 301 L 302 K3o3 K3o4 N3os V306 K307 D S3°8A309K310Q311L 312P313H314L 315K316V317L 318L319D 320V321R322G323 A324K325Q326L327P328H329L33 °K331

(364)

H

(365)

K

(366)

291 Q 292 N 293 P 294 W 295 8 296 K297 N 298 L 299 C 300 L 301 L 302 K303 K304 N305 V 306 K307 5 308 A309 K310 Q 311 L 312 P 313 H 314

K291 n292N 293P294W295R 296K297N 298L 299C300L 301L302K3O3K3O4N30sv306K3O7S308A309K310 n311L312P313H314 L315 b K316V317L318L 319D 320V321R322G323 A324K325Q326L 327P328H329

(367) (368)

K 297 N 298 L 299 C 300 L 301 L 302 K303 K304 N305 V306 K307 5 3o8 A309 K31o ^311 L 312 P 313 H314 K297N298L 299C300L 301L 302K303K304N305V306K307S308A309K310 b n311L 312P313H314L 315K316V317L318L319D 320

V 321 8322 6 323 A324 K325^326

(369)

b

L327P32 8 H3

29

b

K297N298L 299C300L 301 b L 302K303K304N305V306K307S308A309K310Q311L 312P313H314L 315K316V317L318L319D 320 v321R322G323 A324K325Q326L327P328H329L330K331V332L 333L334DD335V336R337G338A339K340Q341L342P343H344

(370)

(371)

K303K304N305V306K30'7S3O8A3O9K31O^311L312p313H314

b

K303K304N305V306K307S308A309K310 b n311L312P313H314L 315K316V317L 318L319D320V321R322G323 A324K325Q326 b

b

L327P328H329

(372)

K303K304N305V306K307S308A309K310Q311L312P313H314L 315K316V317L 318L319D320V321R322G323 A324K325Q326

L 327 P 328 H 329 L 330 K331 V 332 L 333 L 334 DD 335 V336 R 337 G338 A339 K34o Q341 L 342 P 343 H344

(373)

K303K304N305V306K307S3o8A309K310Q311L312P313H314L 315K316V317L 318L319D320V321R322G323 A324K325Q326 L327P328H329L330K331V332L333L 334DD335V336R337G338A339K340Q341L 342P343H344L 345K346V347H348

(374)

K

b

3o4 N3Os V 3O6 K3O'7 S 308 A309 K310 Q 311 L 312 P 313 H 314 L 315 K316 V317 L 318 L 319 D 320 V321 R 322 G323 A324 K325 Q326 L 32'7 b

b

P328H329

(375)

3O4 N3os v 3o6 K3o'7 5 308 A309 K310 Q 311 L 312 P 313 H 314 L 315 K316 V317 L 318 L 319 D 320 V321 R 322 G323 A324 K325 Q326 L 32'7

K P 328 H329 L 33o K331V 332 L 333 L 334 DD 335 V336 R337 G 338 A339 K340 Q341 L 342 P 343 H344

b

Jul. 24, 2008

US 2008/0176217 Al 31

-continued

(376)

K304N305V306K307S308A309K310n311L312P313H314L315K316V317L318L 319D320V321R322G323A324K325n326L32'7

P 328 H329 L 330 K331V 332 L 333 L 334 DD 335 V336 R337 G 338 A339 K340 n341 L 342 P 343 H344 L 345 K346 V347 H 348

(377)

(3.8) (379)

(380)

K304N305V306K307S308A309K310n311L312P313H314

K

b

307 S 308 A309 K310 n 311 L 312 P 313 b H 314 L 315 K316

K307S308A309K310 b n311L 312P313H314L315K316V317L318L 319D320V321R322G323 A324K325n326L 327P328H329

K

307 S 308 A309 K310 b n 311 L 312 P 313 H 314 L 315 K316 V 317 L 318 L 319 D 320 V321 R 322 G323 A324 K325 b n 326 L 327 P 328 H329 L 330

K331V332L 333L334DD 335V336R337G338A339K340Q341L342P343H344

(381)

(382)

(383) (384)

307 S 308 A309 K310 n 311 L 312 P 313 H 314 L 315 K316 V 317 L 318 L 319 D 320 V321 R 322 G323 A324 K325 n326 L 327 P 328 H329 L 330

K310n311L 312P313H314L 315K316

K

b

b

310 b n 311 L 312 P 313 H 314 L 315 K316 V 317 L 318 L 319 D 320 V321 R 322 G323 A324 K325 n326 L 327 P 328 H329

K310 b n311L 312P313H314L 315K316V317L318L319D 320V321R322G323 A324K325 b Q326L327P328H329L 330K331V332L 333 334 DD 335 V 336 R337 G 338 A339 K340 n 341 L 342 P 343 H 344

b

K310n311L 312P313H314L 315K316V o 317L318L319D 320V321R322G323 A324K325n326L327P328H329L 330K331V332L 333 L334DD335V336R337G.338A339K340n341L342P343H344L345K346V347H348

(386)

b

K 331 V332 L 333 L 334 DD 335 V 336 R337 G 338 A339 K340 n 341 L 342 P 343 H344 L 345 K346 V347 H348 K

L 385)

b

K

b

310 n311 L 312 P 313 H 314 L 315 K316 V b 317 L 318 L 319 D 320 V321 R 322 G323 A324 K325 n326 L 327 P 328 H329 L 330 K331 V332 L 333

L334DD335V336R337G.338A339K340n341L342P343H344L345K346V347H348L349DD350V351R352G353A354K355n356L 35'J b

b

P358H359

(387) (388)

(389)

H

314 L 315 K316 V317 L 318 L 319 D 320 V 321 R322 G323 A324 K325

H314L315K316V317L 318L 319D320V321R322G323 A324K325n326L327P328H329L330K331

H314L315K316V317L 318L 319D320V321R322G323 A324K325 b n326L327P328H329L330K331V332L333L 334D335V336R337 b

G 33 8A339K340

(390)

H

314 L 315 K316 V317 L 318 L 319 D 320 V 321 R322 G323 A324 K325 n 326 L 327 P 328 H 329 L 330 K331 V 332 L 333 L 334 D 335 V336 R 337

G338A339K340Q341L 342P343H344L 345K346

(391)

(392)

314 L 315 K316 V317 L 318 L 319 D 320 V 321 R322 G323 A324 K325 n 326 L 327 P 328 H 329 L 330 K331 V 332 L 333 L 334 D 335 V336 R 337

H 338 A339 K 34o n341 L 342 P 343 H344 L 345 K346 V347 H 348 L 349 DD 350 V351 R352 G 353 A354 K355 G

H314L315K316VV317L 318L 319D320V321R322G323 A324K325n326L327P328H329L330K331V332L333L 334D335V336R337

G (393)

b

338 A339 K340 n341 L 342 P 343 H344 L 345 K346 V347 H 348 L 349 DD 350 V351 R352 G 353 A354 K355 n 356 L 357 P 358H359L36 °K36'

K316V317L 318 b L319D 320V321R322G323 A324K325n326L32'JP328H329L330K331v332L333 b L 334D335V336R337G338A339 K340Q341L 342P343H344L 345K346V347H348L349DD350V351R352G353 A354K355n356L357P358H359

(394) (395)

K

316 V317 L 318 L 319 D 320 V 321 R322 G 323 A324 K325 n 326 L 327 P 328 H329

K316V317L 318L319D 320V321R322G323 A324K325 b n326L327P328H329L330K331V332L333L 334D335V336R337G338A339

K340 n341 L 342 P 343 H 344

(396)

b

b

K316VV317L 318L319D 320V321R322G323 A324K325n326L327P328H329L330K331V332L333L 334D335V336R337G338A339 K340Q341L 342P343H344L 345K346V347H348

b

Replikin Sequences in Carboxy-Terminal Portion of Peptide K325it326L327P328H329L 330K331V332L333L334D 335V336R337G338A339K340Q341L342P343H344 (397)

(398) (399)

K

325 b n 326 L 327 P 328 H 329 L 330 K331V 332 L 333 L 334 D 335 V336 R 337 G338 A339 K340 n341 L 342 P 343 H344 L 345 K346 V347 H 348

K325 b Q326L327P328H329L 330K331V332L333L334D 335V336R337G338A339K340 o Q341L342P343H344L 345K346V347H348 L349 DD350V35'R352G353 A354 K3 55n356 L3'' 5 P358 H359

(400)

b

K32SQ326L327P328H329L 330K331VV332L333L334D 335V336R337G338A339K340Q341L342P343H344L 345K346V347H348 L349D35°V35'H352G. 3S3 A3B4K35SQ3S 6L3S'JP358H3B 9L360K361V362L363L 364D36EV366R367G.368A369K370n371L 372 b

P373H374

(401)

(402) (403)

(404)

K32SQ326L 327P328H329L 330K331

H

329 L 330 K331 V332 L 333 L 334 D 335 V 336 R337 G338 A339 K340

H329L330K331V332L 333L 334D335V336R337G.338A339K340Q341L342P343H344L345K346

329 L 330 K331 V332 L 333 L 334 D 335 V 336 R337 G338 A339 K340 n 341 L 342 P 343 H 344 L 345 K346 V 347 H348 L 349 D 350 V351 R 352

H 6.353 A354 K355

b

Jul. 24, 2008

US 2008/0176217 Al 32

-continued

(405)

H329L330K331V332L 333L 334D335V336R337G338 A339K340Q341L342P343H344L345K346V347H348L 349D350V351R352

6.353 A354 K355 Q356 L 357 P 358 H359 L 360 K361

(406)

b

H329L330K331VV332L 333L 334D335V336R337G338 A339K340Q341L342P343H344L345K346V347H348L 349D350V351R352 6.353 A354K3ss^356L3s'7P358H3s 9L 360K361V362L 363L364DD 365V366R367G368A369K370

(407)

H329L330K331VV332L 333L 334D335V336R337G338 A339K340Q341L342P343H344L345K346V347H348L 349D350V351R352 6.353 A3s4K35sn3s6L3sUp35 8H359L 360K361v362L 363L364DD 365V366R367G368A369K370Q371L372P373H374L375K3I6

(408) (409)

(410)

K

331 V332 L 333 b L 334 D 33s V 336 R337 G 338 A339 K340 Q 341 L 342 P 343 H344

K331V332L 333L334D 335V336R337G338A339K340 Q341L342P343H344L345K346V347H348

K

331 V332 L 333 L 334 D 335 V 336 R337 G 338 A339 K340 n 341 L 342 P 343 H344 L 345 K346 V347 H348 L 349 D 350 V 351 R352 G353 A354

K355n356L 35'7 P358H359

(411)

(412)

(413) (414)

(415)

b

331 U b 332 L 333 L 334 D 335 v 336 A337 G.338 A339 K34e ^ 341 L 342 p 343 H344 L 34S K346 P34V H348 L 349 D 35O v 3S' R352 G.3S3 A354

K K3SS n356 L 35'7 P 3S8 H 359 L 360 K361V 362 L 363 L 364 D 36 S V366 R 367 G368 A369K370Q371L372 K340 b Q341L 342P343H344L 345K346

K

(417)

(418)

340 rv341 L 342 P 343 H 344 L 34S K346 v 347 H348

K340 b Q341L 342P343H344L 345K346V347H348L349D350V35'R352G353 A3S4K3S5Q356L35'7p3S 8H 359

K

340 ra341 L 342 P 343 H 344 L 345 K346 V 347 H348 L 349 D 3S

° V 3S' R 3s2 G353 A354 K355 b n 356 L 357 P 358 H359 L 360 K361 V362 L 363

H

H344L345K346V347H348L 349D350V35'R3S2G353 A354K355Q356L3S7p358H359L360K361

H

344 L 345 K346 V347 H 348 L 349 D 350 V 351 R352 G353 A354 K355 Q 356 L 357 P 358 H 359 L 360 K361 V 362 L 363 L 364 D 365 V366 R 367 b

H344L345K346V347H348L349D35°v3S 1A352G.353 A3S4K3SSQ356L3S'JP358H359L360K361V362L363L 364D365V366R367

6 368 A369 K370

(420)

72 p 373 H374 L 375 K376 n37'L3

b

H344L345K346VV347H348L349D350V35'R352G353 A3S4K35SQ356L35'7P3 S8H359L360K361V362L363L 364D365V366R367

6.368 A369 K370 Q371 L 372 P 373 H374 L 37

(421)

b

344 L 345 K346 V347 H 348 L 349 D 35° V 351 R3s2 G353 A354 K355

G368A369K370

(419)

373H374

b

L364DD365V366R367G368A369K370Q371L372P373H374

(416)

P

K376 V377 L 378 L 379 D 380 V381 R382 G 383 A384 K385

H344L345K346VV347H348L349D3S0v351A352G.353 A354K355Q356L357P358H359L360K361V362L363L 364D36SV366R367 G368A369K370Q371L372P373H374L375K376v377L378L379D380V381R382G383 A384K385Q386N387P388W389R390K391

(422) (423)

(424)

K

346 V347 H 348 L 349 D 350 V 351 R352 G 353 A354 K355

K346V34'7H348L349D35OV3S1R352G. 353 A3S4K3S5Q3B 6L3SUP3 S8H3S9

K

346 V347 H 348 L 349 D 350 V 351 R352 G 353 A354 K355 b n 356 L 357 P 358 H359 L 360 K361 V362 L 363 L 364 D 365 V 366 R367 G368 A369

K370Q371L 372p373 H374

(425) (426)

(427)

b

H

b

348 b L 349 D 3SO Y3S' R 352 G.353 A354 K3S5 n356 L 35'J p 358 H3S9 L 36O K36'

H348L349D3S°v3S1A3S2G.3S3 A354K355 b n356L35'JP3S 8H359L 360K361V362L 363L364D365V366R367G368A369K370

rt356 L 357 P 3S8 H359 L 360 K361 V362 L 363 L 364 D 365 V 366 R367 G 368 A369 K370 Q 371 H 348 L 349 D 35° V35' R 352 G. 353 A354 K355 b b b L372 P373 H374 L375 K376

(428)

H348L349D35°v351A352G.3S3 A354K3B5n356L3BUP3S8H359L 360K361V362L 363L364D365V366A367G. 368A369K370rs371

L 372 P 373 H 374 L 3S 'J K36 'J V 377 L 378 L 379 D b 380 V381 R 382 G383 A384 K385

(429)

b

H348L349D3S°V3s'R352G353 A3S4K3SBrt3S6L3SUp3S8H359L 36OK361V362L 363L364D36Sv366R36UG. 368A369K370Q371 L372P373H374L37SK376V377L378L 379DD38OV381R382G383A384K38SQ386N38'7P388W389R39°K391

(430)

b

H348L349D35°v351A352G353 A3S4K3SB^3B6L35UP3S 8H359L 360K361V V362L 363L364D365V366R367G368A369K370Q371 L372p373H374L375K376V377L378L379DD380Y381R382G383A384K385Q386N38'7p388w389A39 OK391N392L393C394 L 395

L 396 K397

(431)

b

H348L349D350V3S'R3S2G.353 A354K3S5n356L35UP358H359L36OK361V362L 363L364D365V366R367G368A369K370Q371 L372p3'3H3U4L37sK376V377L378L379DD380U381R382G.383A384K385Q386N387P388W389R39 °K391N392L393C394 D L 395

L 396 K397 K398

(432)

K355 Q3 s6 L 357 P 3 s8 H 3 s9 L 36 o K361

(433)

K

(434)

b

3s5 n356 L 3SU il 3S8 H 359 L 360 K361v 362 L 363 L 364 D 365 V366 R 367 G368 A369 K370 Q371 L 372 P 373 H374

H3S 9 b L360K361V362L 363L 364D36SV366R367G368A369K370

b

Jul. 24, 2008

US 2008/0176217 Al 33


H

359 L 360 K361 V362 L 363 L 364 D 36S V 366 A367 G368 A369 K370 ^ 371 L 372p373 H 3U4 L 3'JS K376

H359L36OK361V362L 363L 364D365V366R367G368 A369K370 b Q371L372P373H374L375K376V377L378L 379D380V381R382 6.383 A384K385

(437)

b

H359L360K361V362L 363L 364D365V366R367G368 A369K370Q371L372p373H374L375K376V377L378L 379D380V381R382 6. 383 A384K385Q386N387P388W389R390K391N392L 3930.394 L 395L396K397K398N399V400K401

(438)

H 359 L 360 K361 V362 L

363 L 364 D 365 V 366 R367 G368 A369 K370 Q 371 L 372 P 373 H 374 L 37S K376 V 377 L 378 L 379 D 380 V381 R 382

6. 383 A384K385Q386N387P388W389R390K391

(439)

(440)

H 359 L 360 K361 V362 L

6.

b

363 L 364 D 365 V 366 R367 G368 A369 K370 Q 371 L 372 P 373 H 374 L 375 K3'76 V 377 L 378 L 379 D 380 V381 R 382

383 A384 K385 Q386 N 387 P 388 W389 R 390 K391 N392 L 393 0. 394 L 395 L 396 K397 K398 N399 V400 K401 S 402 A403 K404

H359L360K361VV362L 363L 364D365V366R367G368 A369K370Q371L372P373H374L375K376V377L378L 379D380V381R382 G 383 A384 K385 Q386 N 387 P 388 W389 R 390 K391 N392 L 393 0. 394 L 395 L 396 K397

(441)

H359L360K361VV362L 363L 364D365V366R367G368 A369K37On371L3U2p3'3H374L37SK376V377L378L 379D380V381R382 6. 383 A384K385Q386N387P388W389R390K391N392L 3930.394 b L 395L396K397K398

(442) (443)

(444)

(445)

(446)

(447)

K

361 V362 L 363 L 364 D 365 V 366 R367 G 368 A369 K370 Q 371 L 372 P 373 H374

K361v362L 363L364D 36SV366R367G368A369K370Q371L3'72P3U3H3'4L3'SK3'76V3'7'JL378L 379D380V381A382G383A384

K385 Q386 N 387 P 388 W 389 R 390 K391N 392 L 393 C 394 b L K370Q371L 372P373H374L 375K376

(449)

394 b L 395 L 396 K397 K398 N 399 V400 K401 S 402,403 K404 Q405 L 406 P 407 H408

(451)

H3U4L37sK3'6v3''L378L379D38OV381R382G383 A384K38SQ386N387P388W389R390K391N392L393C394L395L396K397

v4°

b

°K4 01

H 374 L 375 K3'6 V377 L 378 L 3'9 D 38O V 381 R382 G383 A384 K385 Q 386 N387

p388 W 389 R390 K391

H374L37SK376V377L378L379D38OV381R382G383 A384K385 Q386N387P388W389R390K391N392L393C394L395L396K397 03 K404

b

H374L37SK3'76V37UL3'8L3'9D380v381A382G383 A384K38SQ386N387P388W389R390K391N392L393C394L395L396K397

H

374 L 375 K376 V377 L 378 L 379 D 38o V 381 R382 G383 A384 K385 Q 386 N387 P 388 W 389 R390 K391 N 392 L 393 C 394 L 395 L 396 K397

K398

(452)

b

H3U4L375K3'6V377L378L 379D380V381R382G.383 A384 K385

K398 N399 V 400 K401 S 402A4 (450)

b

370 n371 L 372 P 373 H 374 L 3'J5 K3U6 V 3'' L 3'8 L 3'9 D 380 V381 R 382 G383 A384 K385 Q386 N387 P 388 W389 R 390 K391 N392 L 393

K C.

K3 98 N 3 99

(448)

395 L 396 K397 K398 N399 V 400 K401 S 402 A403 K404 Q 40S L 406 P 407 H 408

H

b

374 L 375 K3'56 V377 L 3'8 L 379 D 38o V 381 A382 G383 A384 K385 Q 386 N3.7 P 388 W 389 R390 K391 N 392 L 393 C 394 L 395 L 396 K397

K398N399V400K401S402 A403K404Q4 osL406P409H4 o8L4 o9 K410

(453)

(454)

374 L 375 K376 V377 L 378 L 379 D 38o V 381 R382 G383 A384 K385 Q 386 N387 P 388 389 R390 K391 N 392 L 393 C 394 L 395 L 396 K397 W K398N399V400K401S402 A4o3K404Q4 osL406P409H4 o8L4 o9K410V411L412L 413D414V41sR416G417A418K419

H

K

3U6 V377 L 378 L 379 D 380 V 381 R382 G 383 A384 K385 Q 386 N387 P 388 W389 R390 K391 N392 L 393 C 394 L 395 L 396 K397 K398 N 399

V400K401S402A403K404Q405L406P407H408

(455)

K

b

376 V377 L 378 L 379 D 380 V 381 R382 G 383 A384 K385 Q 386 N387 P 388 W389 R390 K391 N392 L 393 C 394 L 395 L 396 K397 K398 N 399

V400K401S402A403K404Q4 osL406P409H4 o8L4 o9 K410V411L 412L413D414V41sR416G417 A418K419Q42 oL421P422H423

385 Q386 N 387 p388

389 R 390 K391N 392 L 393 C 394 L 395 L 396 K397 K398 N399 V 400 K401 S 402 A403 K404 Q 40S L 406 P 407 H 408

(456)

K

(4577)

K385 Q386N387P388W389R390K391N392L393C394L 395L396K397K398N399V400K401S402 A403K404 o no o5L406P407H4O8

W

L 4o9 K41o V 411 L 412 L (4558)

(460)

413 D 414 V41s R 416 G419 A418 K419 Q42o L 421 P 422 H423 L 424 K42s V426 H 427

K391N392L 393C394L 395L 396K397K398N399V400K401S402A403K404 Q405L406P40'7H4 o8L 4O9K41OV411L412L413D 414

o L421p422

H423

b

K391N392L 393C394L 395L 396K397K398N399V400K401S402A403K404Q4olL406p40UH408L 409K41oV411L412L413D 414 V415R416G419A418K419Q42 oL421P422H423L424K425V426H427

(462)

b

K391N392L 393C394L 395L 396K397K398N399V400K401S402A403K404Q405L 406P407H408

V4 15 R416G419A418K419Q42

(461)

b

K385Q386N387P388W389R390K391N392L393C.394L 395L396K397K398N399V400K401S402 A403K404Q40SL406P407H408

L 4o9 K41o V 411 L 412 L (459)

413 D 414 V41s R 416 G419 A418 K419 Q42o L 421 P 422 H423

K397K398N399V400K401S402A403K404Q4 osL406P409H408

Jul. 24, 2008

US 2008/0176217 Al

M

-continued (463)

K

397 K398 N 399Wo 0 K4of S 402 A4 o3 K404 Q4os L 406 P 407 H4o8 L 409 K41o V411 L 412 L 413 D 414 V 41s 8416 G 417,418 K419 Q 420

L 42'

(464)

P4 22 H 423

K397K398N399V400K401S402A403K404Q4 osL406P407H4 o8L 409K410V411L 412L413D414V41sR416G417A418K419Q42o

L 421 p422 H 423 L424

(465)

K4

25 v426

H4

27

K398N399V400K401S402 A403K404Q4 osL406P407H408

398 N399 V 40 o K4o1 S 4o2 A403 K4 o4 Q 4os L 406 P 4o7 H 4o8 L 4o9 K41o V411 L 412 L 413 D 414 V41s 8 416 G417 A418 K419 Q42o L 421

(466)

K P42 2 H423

(467)

K

398 N399 V 40 o K4o1 S 4o2 A403 K4 o4 Q 4os L 406 P 4o7 H 4o8 L 4o9 K41o V411 L 412 L 413 D 414 V41s 8 416 G417 A418 K419 Q42o L 421

p422 H423 L 424 K42s V 426 H 427

(468)

(469) (470)

K401s402 A403K404Q4 osL 406P407H4 o8L409K410

K

4o1 S 4o2 A403 K4 o4 Q 4os L 406 P 4o7 H 4o8 L 4o9 K41o V 411 L 412 L 413 D 414 V41s R 416 G.417 A418 K419 Q42o L 421 P 422 H423

K401s402 A403K404Q4 osL 406P407H4 o8L409K410V411L412L 413D414V41sR416G417A418K419Q42 oL 421P422H423L 424

K42s V426 H 427 (471)

K404 Q4 os L 406 P 407 H 4 o8 L 409 K410

(472)

K

(473)

4o4 Q4os L 406 P 4o7 H 4o8 L 409 K41o V 411 L 412 L 413 D 414 V41s R 416 G417 A418 K419 Q420 L 421 P 422 H423

K404Q4 osL 406P407H4 o8L 409K410V411L412L413D 414V41sR416G417A418K419Q42 oL421P422H423L 424K42sV426H427

4o4 Q4os L 406 p407 H 4o8 L 409 K41o Y 411 L 412 L 413 D 414 V41s R 416 G417 A418 K419 Q42o L 421 P 422 H423 L 424 K42s V426 H 427

(474)

K L 428 D 429 V 430 R431 G 432 A433 K434 Q 43s Q436 Q437 Q 438 L 439 C 440 L 441 P 442 L 443 K444 T 44s 1 446 s 447 T 448 5 449 F 4s0 T 4s1 H 4s2

(475)

H

(476)

(477)

4o8 L 4o9 K41o V411 L 412 L 413 D 414 V 41s 8416 6.417 A418 K419

H4 o8L4 o9K410V411L 412L 413D414V41 sR416G417 A418K419Q42 oL421P422H423L424K42s

H

4o8 L 4o9 K41o V411 L 412 L 413 D 414 V 41s 8416 6. 417 A418 K419 Q 42o L 421 P 422 H 423 L 424 K42s V 426 H427 L 428 D 429 V43o R 431

G432A433K434

4o8 L 4o9 K41o V411 L 412 L 413 D 414 V 41s 8416 6. 417 A418 K419 Q 42o L 421 P 422 H 423 L 424 K42s V 426 H427 L 428 D 429 V43o R 431

(478)

H 432 A433 K434 Q43s Q 436 Q 437 Q438 L 439 C 440 L 441 P 442 L 443 K444 G

(479)

K410V411L 412L413D 414V41sR416G417A418K419Q42 oL421P422H423

(480)

(481)

K410V411L 412L413D 414V41sR416G417A418K419Q42 oL421P422H423L424K42sV426H427

K

410 V411 L 412 L 413 D 414 V 41s R416 G 417 A418 K419 Q 420 L 421 P 422 H423 L 424 K42s V426 H427 L 428 D 429 V 430 R431 G432 A433

K434Q43sQ436Q437Q438L439C.440L 441P442L443K444T44s1446S447T448S449F4s oT4 s1H4s2

(482) (483)

(484)

K

419 Q42o L 421 p422 H 423 L 424 K42S

K419Q42 oL 421p422 H423 L 424K42SV426H427

K419Q420L 421P422H423L 424K42sV426H427L428D 429V430R431G432A433K434Q43sQ436Q437Q438L 439C440L441P442 L443K444T 44s1446S447T 448S449F 4s oT4 s1H4s2

(485)

K419Q420L 421P422H423L 424K42sV426H427L428D 429V430R431G432A433K434Q43sQ436Q437Q438L 439C440L441P442 L443K444T44s1446S447T448S449F4s0T4 s1H4s2L 4s3L4s4L 4ssC4 s6L4s'JY4s8M4s 9E460Y461G462K463H464

(486)

(487)

H423L424K42SV426H427L 428D429V430R431G432 A433K434Q43sQ436Q437Q438L439C440L 441P442L 443K444

H

423 L 424 K42s V426 H 427 L 428 D 429 V 430 R431 G432 A433 K434 Q 43s Q436 Q437 Q 438 L 439 C 440 L 441 P 442 L 443 K444 T 44s 1 446

5447T4485449F4s

(488) (489)

(490)

H

423 L 424 K42s V426 H 427 L 428 D 429 V 430 R431 G432 A433 K434

K42sV426H427L428D 429V430R431G432A433K434

K42sV426H427L428D 429V430R431G432A433K434Q43 sQ436Q437Q438L439C440L441P442L 443K444T 44s1446S447T 448 6449 F4 s 0

(491)

oT 4 s1H4s2L4s3L 4s4L4ssc4s6L 4s9Y4s8M4 s9E460Y461G462K463H464Q46 sN466L 467Q468V469K470

T4

1H4 s2

K42sV426H427L428D 429V430R431G432A433K434Q43 sQ436Q437Q438L439C440L441P442L 443K444T 44s14465447T 448 S449F4soI4s 1H4s2L 4s3L 4a4L4ssC4s 6L4s9Y4s8M4S 9E.460Y461G.462K463H464

(492)

H427L428D 429V430R431G432A433K434Q43sQ436Q437Q438L 439C440L441P442L443K444

Jul. 24, 2008

US 2008/0176217 Al

M

-continued (493)

H

427 L 428 D 429 v430 A 431 G.432 A433 K434 n43s Q436 Q 437 Q438 L 439 c 44o L 441 P 442 L 443 K444 T 44S I 446 5 44U.r 448 s 449 F 4s0

T 4s1 H4s2 L

4s3 L 4 s4 L 4ss c 4s6 L 4 s9 Y 4s8 b M 4s9 b E 46o b Y 461 G462 K463 H464 Q46s N 466 L 467 Q468 V 469 K47o

K434^43sn436^437Q438L 439c440L 441P442L443K444.44sS446s447T448S449F4s°T4 s1H462

(494)

K434 b Q436 h ra436 fi o43'7 h o438L 439644 oL 441P442L443K444.r446I446S44'D.r448S449F4s Os461H4r2L4S3L 464L4syo.4 s 6L 4S7

(495)

Y4s8 b M4 s9 b E 46Oy461 b G462K463H464

(496)

H

4 s2 L 4s3 L 4s4 L 4ss C. 4s6 L 4s9 Y4s8 M 4s9 E 460 Y461 G 462 K463 H 464 Q46 s N466 L 467 Q468 V469 K470

K463H464n46 sN466L 467Q468V469K470

(497)

Example 2 Determination of Very High Replikin Concentration at Accession No. NP 478030 [0151] Replikin concentration was determined for a functionally undefined protein in the genome of an isolate of White Spot Syndrome Virus from 2000 made publicly available at NP 478030. The Replikin Concentration in the protein was again an unusually high 97.6 Replikin sequences per 100 amino acids. The Replikin concentration was determined by

dividing the number of Replikin sequences identified in the amino acid sequence of the protein, 361 Replikin sequences, by the total amino acid length of the protein, 370 amino acids. [0152] The amino acid sequence of NP 478030 is of interest because, like the protein in Example 1, it demonstrates an overlapping of Replikin sequences that results in very high Replikin concentrations comparable to the highly-replicating P. falciparum of malaria. These high concentrations of Replikin sequences again provide a reservoir of Replikins for transfer to influenza viruses.

PubMed Accession Number NP 478030 Description: Protein of unknown function translated from complete genome sequence of the shrimp

white

spot

baculoform

virus

(WSSV)

publicly available at PubMed Accession No.

NC003225.1. Isolated Year 2000 Source: Shrimp White Spot Syndrome Virus (Shrimp White Spot Baculoform Virus) M1K213C4QSI 6S7S8P9T1oL11T12L13S14 I1sP16L 17E18G19V20Y21H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V3 sK36G37

V 38 K39 Q 4o L

41 L 42 H43 L 44 K4 s V46 R47 L 48 D 49 V so R sl G s2 As3 Ks4 Qss Ns6 P s9 Ws8 R so K 6o N 61 L 62 C. 63 L 64 L 6s K66 K67 N 68 V 69 K 70

S91A72K93Q94L9sP96H77L 78K79V8oH81L 82D83V84K8sS86A87K88Q89L9oP91H 92L 93K94V 9sH96L 97D98V99R1ooG1o1A102

K1o3 Q 104 L 1os P 1o6 H1o7 L 1o8 K10 9 V11o R 111 L

112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o P 121 H 122 L 123 K124 V 12s H126 L 127

D128V129R130G.131A132K133n134L13sP136H137L138K139V14oR141L 142D143V144R14 sG146A147K148n149N1sOP1s1W1s2

R 1s3 K1s4 N1ss L 1s6 C 1s9 L is. LL 1s 9 K16o K161 N 162 V163 K164 S 166 A166 K167 Q168 L

169 P 19o H171 L 172 K173 VV174 H 17s L 176 D 177

V1 78K199G'8oV181K182Q183L184L18sH186L187K188V189R19oL191D192V193R194G19sA196K197Q198L199P2o

K 2o3 V 2o4 H 2os L

oH2

°'L2

02

2o6 D 2o7 V 208 R 209 G. 21o A 211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 22o c. 221 L 222 L 223 K224 K 22s N 226 V 227

K228S229A23 oK231Q232L 233P234H23 sL 236K237V238L 239L 24 oD 241V242R243G 244 A24 sK246Q247L 248P249H 2s oL 2 s1K2s2

V 2s3 L

2s4 L 2ss D 266 V 2s9 R 2s8 G 2s

9 A26 °K261Q 262

L 263 P 264 H 26s L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G 274 A 27s K276 Q 277

N2I8P279W28 oR281K282 N283 L 284C.28sL 286L 287 K288K289N290V291K292S293A294 K29SQ296L 297P298H299L 30 o K301v302

L 303 L

304 D 30s V 306 R3o7 G.308 A309 K310 n 311 L 312 P 313 H 314 L 31s K316 V 317 H318 L 319 D 320 V321 R 322 G. 323 A324 K32s ^326 ^ 327

n328n329L330C331L332P333L 334K33 s b r 336

1337S338T339534oF341T 342H343L 344L 34 sL346C347L348Y349M3s °EE3s' b Y3s2

G 3s3 b b K 3s4 H3ss n 3s6 N3s7 L 3s8 n 3s9 V360 K361 M 362 W363 L 364 N36S 1 366 T 367 Y368 T 369 5 370

Replikin Sequences Identified in Accession No. ABS00973 Replikin Sequences Located in Amino-Terminal of Peptide V 23 K 24 Q 2s L 26 L 27 H 28 L 29 K30 (1) H 22

(2)

(3)

(4)

(5)

H 22V23K24Q2 sL 26L 27H28L 29K30V31H32L 33D 34V3 sK36

H 22V23K24Q2 sL 26L 27H28L 29K30V31H32L 33D 34V3 sK36G37V38K39

H 22

V 23 K 24 Q 2s L 26 L 27 H 28 L 29 K3o V 31 H 32 L 33 D 34 V 3s K36 6.37 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s

H 22V23K24Q2 sL 26L 27H28L 29K30V31H32L 33D 34V3 sK36G37V38K39Q4 oL 41L 42H43L 44K4sV46R47L48D49VsoRs'Gs2As3 Ks4

Jul. 24, 2008

US 2008/0176217 Al

-continued

(6)

H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V35K36G37V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1G52 A53 Ks4 Q 5s N 56

(7)

P 57 Ws8 R s 9 K 6

H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V35K36G37V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1G52 A53 K54Q5 sNs 6P57W58Rs 9 K6oN61L 62 C63 L 64 L6s K66

(8)

H22V23K24Q2 sL 26L 27H 28L 29K30V31H32L33D34V35K36G37V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1G52 A53

K54 Q5s Ns6 p S (9)

H 22 V 23 K24 Q 2s L 26 L 27 H 28 L 29 K3o V 31 H32 L 33 D 34 V3s K36 G 37 V 38 K39 Q 4o L 41 L 42 H43 L 44 K4s V46 R 47 L 48 D 49 V so R sl G52 A53 K54 Q5s Ns6 p S

(10) (11)

(12)

(13)

(14) (15)

(16) (17)

W 58 R s9 K 6o N 61 L 62 C 63 L 64 L 6s K66 K67

K

W 58 R s9 K 6o N 61 L 62 C 63 L 64 L 6s K66 K67 N 68 V 69 K 70

24 Q 2s L 26 L 27 H 28 L 29 K3o

K24Q2 sL 26L 27H28L 29K30V31H32

K24 Q 25 L 26 L 27 H 28 L 29 K 30 V 31 H 32 L 33 D 34 V35 K36 G 37 V38 K 39 Q 40 L 41 L 42 H 43 H28 L 29K30V31H32L 33D 34V35K36

H

28 L 29 K3o V31 H32 L 33 D 34 V 35 K36 G 37 V38 K39

H28L 29K30V31H32L 33D 34V35K36G37V38K39Q40L41L42H43L 44K45

H

28 L 29 K3o V31 H32 L 33 D 34 V 35 K36 G 37 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s V 46 R 47 L 48 D 49 Vso Rsl G52 As3 K54

H28L 29K30V31H32L 33D 34V35K36G37V38K39Q4 oL41L42H43L 44K45V46R47L48D49VsoRs1G52A53K54Q55Ns6P59

W s8 R s9 K6o

(18)

(19)

28 L 29 K3o V31 H32 L 33 D 34 V 35 K36 G 37 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s V 46 R 47 L 48 D 49 Vso Rsl G52 As3 Ks4 Q ss N 56 P 59

H W 58 R 59 K 60 N 61 L 62 C 63 L 64 L 65 K 66 H

28 L 29 K3o V31 H32 L 33 D 34 V 35 K36 G 37 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s V 46 R 47 L 48 D 49 Vso Rsl G52 As3 Ks4 Q ss N 56 P 59

Ws8Rs 9 K6oN61L 62C63L 64L65 K66 K67

(20)

H28L 29K30V31H32L 33D 34V35K36037V38K39Q4 oL41L42H43L 44K45V46R47L48D49VsoRs1052A53K54Q55Ns6P59

W s8 Rs 9 K6 o N 61 L 62 C 63 L 64 L 65 K 66 K 69 N 68 v 69 K7o

(21)

H28L 29K30V31H32L 33D 34V35K36037V38K39Q4 oL41L42H43L 44K45V46R47L48D49VsoRs1052A53K54Q55Ns6P59

ws8 Rso K6o N 61 L 62 0. 63 L 64 L 65 K 66 K 67 N 68 V 69 K9o S 71 A72 K 73 (22)

K30V31H32L33D34V35K36037V38K39Q4 oL41L42H43L44K45V46R47L 48D 49V5 oR51052 A53K54Q55N56P57W58R59

K 60 N 61 L 62 C 63 L 64 L 65 K 66 K 67 N 68 V 69 K70S7'A72K93Q94L 95P96H77 (23)

(24) (25)

(26)

(27) (28)

(29)

K30V31H32L33D34V35K36

K30

V31 H32 L 33 D 34 V 35 K36 0 37 V 38 K39

K30V31H32L33D34V35K36037V38K39Q40L41L42H43

H32L33D34V35K36037V38K39Q40L 41 L42 H43L44K45

H

32 L 33 D 34 V35 K36 G 37 V 38 K39 n 4o L 41 L 42 H43 L 44 K45 V46 R 47 L 48 D 49 V 5o R 51 G52 A53 K54

H32L33D34V35K36037V38K39 b Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1052 A53K54Q55Ns 6P57Ws 8Rs9K6o

H32L33b34V3 sK36037V38K3984 oL 41L42H43L44K4sV46A47L 48D 49VsoAs1052 As3Ks4QS 5Ns 6p57ws 8As9K6oN61 L62

(30)

b

C63

L64

L65 K66

H32L33D34V35K36037V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1052 A53K54Q55Ns 6P57W58Rs9K6oN6' L62 C63 L 64 L65 K66 K67

(31)

H32L33D34V35K36037V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1052 A53K54Q55Ns 6P57W58Rs9K6oN6' L62 C63 L 64 L6s K66 K67N68V69 K70

(32)

H32L33D34V35K36037V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs'052 A53K54Qs 5Ns 6P57W55Rs9K6nN61 L 62C63L 64L65K66K67N65V69K'°S"A72K73

(33)

H32L33D34V35K36037V38K39Q4 oL 41L42H43L44K45V46R47L 48D 49VsoRs1052 A53K54Q55Ns 6Ps7W5BAs9K6oN61 L 62C63L 64L65K66K67N68V69K70S7'A72K'3Q94L 95P96H 77L 78K79

(34)

(35)

K36037V38K39Q4 oL 41L 42 H43L 44K45

K

36 037 V38 K39 Q4o L 41 L 42 H 43 L 44 K4s V46 R47 L 48 D 49 Vso R sl 0 s2 A53 K54 Q ss N56 ps7 Ws5 Rs9 K6o N 61 L 62 0 63 L 64 L 65

K66K67N68V69 K

' ° S'

'A72K73Q74 L '5

P7 677

Jul. 24, 2008

US 2008/0176217 Al 37

-continued (36)

K

36 G.37 via K3 o Q4 o L 41 L 4 z H 43 L 44 Kos v46 R47 L 4. D 49 vso R si G s2 As3 Ks4 Q ss Ns 6 ps7 Wsa Rso K6 o N 61 L 6 z c.63 L 64 L 6s

K ss K— N — v — K7o S 71A 72 K 73 Q 74 L ' JS p

(37)

(38)

K

39 Q4 o L 41 L 42 H43 L 44 K4s

K39Q4oL41L42H43L 44K4sV46R47L 4sD49VSoRslGso As3Ks4Qs sNs6pS7WssRs9K6oN61L 62c.63L64L6sK66K67N6a V69 K70S7'A72 K93Q74 L 7s P

(39)

S H 77 L 7. K79 v a o H al

K

'6 H "

39 Q4o L 41 L 42 H43 L 44 K4s v 46 R 47 L 4& D 49 vso Rsl Gs2 Asa Ks4 Q ss N s 6 p s7 W sa Rso K6 o N 61 L 62 c. 63 L 64 L 6 s K 66 K 69 N 6a

V 69 K70 S 7' A72 K73 Q 74 L 's P ' 6 H 77 L 78 K79 V ao H ai (40)

Hf3 L 44 K" s

(41)

Hf3L44K4

(42)

v4 s R4s L 4. N 49 U so R si G s2 As3 Ks4

V4E R47 L 4S D 49 V so R sl G s2 As3 Ks4 Qs s Nss p s7 W SS R s9 K so

H(3L44K"sV4sR4sL4.N49Uso R si G s2 As3 Ks4 Qss Ns s p s7 w sa R so K s o N si L s z C s 3 L s s L s s Kss

4s U4n R4s L 4a N 49 V so A si G s3 As3 Ks4 Qs s NsE P s7 W S s R s9 K so N sl L s2 C s3 L 64 L ss Kss Kss

(43)

H43 L 44 K

(44)

H(3L44K4nVs s

(45)

(46)

H43L44K4SV46A47L 4SD 49VsoRslGs2 As3Ks4Qs sNs 6ps7wsaAs9K6oN61L 62C63L 64L6sK66K67N68V69K70S7'A72K73

H

43 L 44 Kos v46 R47 L 4. D 49 v so R si G s2 Ana Ks4 Qss Ns 6 ps7 W sa R so K 6 o N 61 L 6 z c. 63 L 64 L 6 s K66 K67 N 6& v 69 K 7o S 71 A 72

K 73 Q 74 L (47)

H

H

7s p 96 H 77 L 7a K 79

43 L 44 K4s V46 R47 L 48 D 49 V so R sl G.s2 As3 Ks4 Qs s Ns 6 P s7 W s a R s9 K 6o N 61 L 62 L.63 L 64 L 6s K66 K67 N 6a U 6g K 7o S 7' A 7o

K 73 Q 74 L (48)

R4s C 4a N 49 V so R si G s2 As3 Ks4 Qss Ns s P ss W sa R so K s o N si L s z C s s L s s L s s Ks s Ks s N s a V s 9 K so

7s p 76 H 77 L 7a K 79 v &o H a1 L a2 D &3 v &4 Kas

43 L 44 K4s V46 R47 L 48 D 49 V so R sl G.s2 As3 Ks4 Qs s Ns 6 P s7 W s a R s9 K 6o N 61 L 62 L.63 L 64 L 6s K66 K67 N 68 V 69 K 70 S 7' A 72

K 73 Q 74 L 7s p 76 H 77 L 7 a K 79 V ao H ar L a2 D e3 V a4 Kas S a6 A87 K ea (49)

K4sv46R47 L4&D49VsoRs'Gs2 Asa Ks4Qs sNs 6Ps7ww Rs9K6oN61L620.63 L 64 L6s K66K67 N6&V69K70S7'A72 K73Q74 UJS P 'D 6 H "I "J

(50)

K4s

V46 R47 L 4. D 49 U so R si G s2 As3 Ks4 Qss Ns 6 P s' Wsa Rso K 6o N 61 L 62 C 63 L 64 L 6 s K66 K6' N 68 V 69 K so S 71A 72 K 73

Q l4 C lS P 76 H J l L Ja K J9 V ao H a'

(51)

K

(52)

K

(53)

K

(54)

4s Uss R47 L 4. D 49 U so R si G n2 As3 Ks4 Qss Ns s p s7 Wsa Rso K s o N s i L s z C ss L ss L s s Ks s Ks R N s a V s 9 K 7o S 71A 72 K 73 Q 74

L 's p

S H "I'D L 'Ja K'l9 u a o H a1 L a2 D a3 V q4 Ka s S a S Ae'J Kea Q a9 L 90 p 91 H 92

s4 Qs s Ns 6 P s7 Ws a R s9 K 6o N 6i L 62 0 63 L 64 L 6s K66 K67 N 6a V 69 K 70 S 7' A 72 K 73 Q 74 L ^ s P is H 77

s4 Qss Ns 6 p s7 Wsa R so K 6 o N 61 L 6 z L. 63 L 64 L 6 s K66 K67 N 6a v — K 7o 5 71 A 72 K 73 Q 74 L 7s p 76 H 77 L 7a K 79 v a o H al

Ks4Qs sNs 6Ps7Ws aRSg K6oN6'C620.63 L 64 L6s K66K67 N6&V69K70S71A72 K73Q74 L 7sp76H77 L 7 a K79V&oHa1C ao D 83V84 Kan

S a s A.7 Kea Q a9 L (55)

90 p 91 H 92

Ks4Qs sNs 6ps7Ws aRs9K6oN61L620.63 L 64 L6s K66K67 N6&V69K70S7'A72 K73Q74 L 7sp76H77 L 7 a K7 gV&oHa'C ao D&3V&4 Kas

S a6 A87 Kea Q a9 L 9o P 91 H

92 L 93 K 94 V 9s H 96

(56)

6o N 61 L 6z c. 63 L 64 L 6 s K 66 K 69 N 6& v 69 K7o S 71 A72 K73 Q 74 L 7s p 96 H 77 L 7a K 79 v &o H a1 L a2 D &3 v &4 K as S K H92 L 93 K94 ^ 9 s H96L 97 D9&V99R1ooGlolAl 02K1o3Q1o4LlO plO6H1o7

(57)

K

(58)

K

(59)

K

A &7 K && Q &9 L 9op91

s o N s i L s z C s s L s s L s s K s s K s R N s a V s 9 K7o S 71 A72 K73 Q 74 L 7s p s H 77

6o N 61 L 62 C 63 L 64 L 6s K 66 K 67 N 6a V 69 K70 S 7' A72 K73 Q 74 L 7S p 76 H 77 L 7 a K 79 V a o H ai

60 N 6' L 6u. 63 L 64 L 6 s K 66 K 69 N 6& v 69 K7o S 71 A72 K73 Q 74 L 7s p 76 H 77 L 7a K 79 v &o H a1 L a2 D &3 v &4 K as S

A &7 K && Q &9 L 9op91

H 92

(60)

K6oN61L62C.63 L 64 L6s K66K67 N68V69K70S7'A72 K73Q74 L 7Sp76H 77 L 7 a K79V& oHa1L a2 D 83V84 KasS86A&7K&8Q&9L9oP91

H 92 L 93 K94 V 9s H 96 (61)

K

(62)

K

(63)

K

(64)

K

(65)

66 K67 N 6a V 69 K70 S 7'A 72 K 73 Q 74 L 7s p 76 H 77

ss K6'J N sa v — K'lo s 'J1A 72 K 73 Q 74 L ' JS p 76 H 77 L 7. K' J9 v a o H al

ss K67 N sa V 69 K70 S 7'A 72 K 73 Q 74 L 7s p 76 H 77 L 7 a K79 V ao H ai L a2 D a3 V a4 K as S a6 A87 Kea Q a9 L 9o P 9' H 92

66 K69 N 6& v 69 K7o S 71A 72 K 73 Q 74 L 7s p 96 H 77 L 7a K79 v &o H a1 L a2 D &3 v &4 K as S — A&7 K&& Q &9 L 90 p 91 H 92 L 93 K 94 v 9s H 96

K66K67N6&V69K70S7'A72 K73Q74 L 7sp76H77 L 7 a K79V&oHa1La2D83V84Ka

D 9. V 99 Rioo G io' Aio2 K1o3 Q 104 L ios P io6 H 107 (66)

K

67 N 6a V 69 K70 S 7'A 72 K 73 Q 74 L 7s p 76 H 77

^

S&6A87 K&&Q&9L9oP91H 92 L 93 K94V 9s H96 L 97

Jul. 24, 2008

US 2008/0176217 Al

-continued (67)

K

(68)

K

(69)

K

(70)

67 N 68 V 69 K 7o s 71A ' 2 K ' 3 Q 74 L 's P ' 6 H 77 L 7. K 79 V e o H 81

l7 N s8 V 69 K 70 s 7' A 72 K '3 Q 'gUl P ' 6 H 77 L 78 K 79 V 8o H 81 L 82 D 83 V 84 K ss S e6 A 87 K 88 Q 89 L 9o P 91 H 92

67 N 68 V 69 K 9o S 71A 72 K 73 Q 74 L 9s P 96 H 77 L 78 K 79 V 8o H 81 L 82 D 83 V 84 K 8 s S 86 A .7 K 88 Q .9 L 90 p 91 H 92 L 93 K 94 V 9s H 96

K67N68V69K70S7'A72K93Q94L7Sp76H77L78K99V8oH81L 82DB3V84KBsSB6A87K8BQ89L9oP91H 92L 93K94V 9sH96L 97 D98

V 99 R'

(71)

oo G 1o1 A

102

K

105

Q 104 L 1os

P

106

H

10s

K70S7'A72K93Q94L7Sp76H77L78K99V8 oH81L 82DB3VB4KBlS86AB7K88Q89L9oP91H92L 93K94V9 sH96L 97D98V99R1oo

G io 1 A 102 K io 3 Q 1 o4 L 1os P io 6 H 107 9o S 71 A 72 K 73 Q 74 L 9s p 96 H 77 L 78 K 79

(72)

K

(73)

K

(74)

K 7o

(75)

S 71 A 72 K 73 Q 74 L 9sp96 H 77 L 78 K 79 V 8o H 81 L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92

K70S7'A72K93Q94L9Sp96H77L7BK'9V8 oH81L 82DB3VB4KBsS86AB7K8BQB9L9oP91H92L 93K94V9 sH96

(76)

K

(77)

K

(78)

lo S 7' A 72 K 's Q '4 L 's P ' 6 H I7 L Le K '9 V e o H 81

73 Q 74 L 7s P 96 H 77 L 7. K 79

75 Q 74 L 7S p 76 H 77 L 78 K 79 V 8o H 81

K73Q74L7sP96H77L 78 K 79 V 8 o ff 81 L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1 A 102 K103 Q 104 L ios P

(79)

(80)

(81)

10s

H io7

K73Q74L7sP96H77L 78 K 79 V 8 o ff 81 L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92

K73Q'4L'sP96H77L 78K79V8oH81L 82D 83V84K8sS86A87K88Q89L9oP91H 92L 93K94V9 sH96

K73Q74L7sP96H77L 78 K 79 V 8 o ff 81 L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1 A 102

K io5 Q 104 L los Pio6 H 107 L io8 Kto 9 V i1o R iii L 1i2

(82)

(83)

(84)

(85)

(86)

H77LseKsoVeoH8iL 82

115 V 114 K iis S ii6 A ' 17 K ii8 Q 119 L 120 P 121 H 122

D 85 V e4 K ss

H77L78K"I 9V8oH81L 82D B3vB4K8ss86A8"IKB8

H77L7.K79VBOH81L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94

H77L 78K79V8oH81L 82DB3V84K8lSB6A87KB8Q89L9op91H 92L 93K94V 9sH96L 97D9BV99A1ooG.1o1A102K103

H77L7.K79VBOH81L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L So p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G 1o1 A 1o2 K1o3 Q 104 L 1os

P 106 H 107 L io e K10

(87)

H77L 78K79V8oH81L 82D 83V84K8sS86A87K88Q89L9oP91H 92L 93K94V 9sH96L 97D98V99R1ooG1o1A102K1o3Q1o4L1os

P106H107L1oe Klo g V ifio R iii L ii2 D ii3 V ii4 Kias

(88)

H77L 78K79V8oH81L 82D 83V84K8sSB6AB7KB8QB9L9op91H 92L 93K94V 9sH96L 97D98V99R1ooG.1o1A1O2K103Q104L1os

p 1o6 H107 L 1o8 K10 9 V iio R ii1 L 112 D 115 V 114 Kiis S 116 A 117 K lls (89)

H77L7.K79VBOH81L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G 1o1 A 102 K103 Q 104 L 10s

111112D 115V114KiisS116A117Kie8Q119L12°pi2iH122Li23Kl24 p1o6H107Llo8Klo9VlloRlllLl 1

(90)

(91)

K79VBOH81L 82 D 83 V 84 K 8 s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G 1o1 A 1o2 K1o3 Q 104 L 1os P1o6 H 107

K

79 V 8o H 81 L 82

D


L 1o8 Kio 9 V 11o RC (92)

K

79 V 8o H 81 L 82

D

(94)

116

A 117 K ite Q 119 L 12 o

Pie

98 V 99 R ioo G io1 A io2 Kio5 Q 104 L ios Pio6 H io7 D 2

1H12


L io8 Kio9 V iio R ii1 L

(93)

112 D 115 V 114 K ees S

112

D

98 V 99 R ioo G io1 A io2 Kio5 Q 104 L ios Pio6 H io7 D 115 V 114 K iis S 116 A 117 K ii8 Q 119 L 120 P 121 H 122 L 123 K 124 V 12s H 126

K79V50H.1L.2N.3Ye4Kes

K79V8oH81L82D85V84KssS86A87Kee

(95)

K 79 V

(96)

K

(97)

H

(98)

H

(99)

H

eg H .1 L .2 D .3 V e4 K e s S e 6 A .7 K e8 Q e9 L 9g P 91 H 92

79 V 8o H 81 L 82

D

85 V 84 K ss S 86 A 87 K 88 Q 89 L 9o P 91 H 92 L 93 K 94 V 9 s H 96

81 L 82 D 83 V 84 K B s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94

81 L 82

D


D

98 V 99 R ioo Gio1A io2 Kio3

81 L 82 D 83 V 84 K B s S 86 A 87 K 88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1A 1o2 K1o3 Q104 L 1os P1o6 H 107 L 108

K io9

Jul. 24, 2008

US 2008/0176217 Al

3l

-continued (100)

(101)

81 L 82 D 83 V 84 KB s S 86 A .7 K 88 Q 89 L 9o P 91 H 92 L 93 K94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1A1o2 K1o3 Q1o4 L 1os P 1o6 H 107 L 1o8

H Kio 9 V"o R hs L si2 D 1i3 V ii4 Kiss

H81L82D83V84K8S86A87K88Q89L9oP91H92L 93K94V9 sH96L 97D98V99R'ooG1o1A102K1o3Q1o4L1osP1o6H' o7L1os

Kso

(102)

9Mso R ill L ii2 D 1i3 N ii4 K1is 5 s16 Ai17 Khe

H81L82D83V84K8S86A87K88Q89L9oP91H92L 93K94V9 sH96L 97D98V99R'occ.1o'A'o2K1°3Q1o4L1osP1o6H107L1o8 K10 9VlloR111L112D 113V114K" S116A117K"sQ'19L120p121H122L123K124

(103)

(104)

(105)

KGSSB6A87K88Q89L9oP91H 92L 93K94V9 sH96L 97D98V99R'ooG1o1A102K1o3Q1o4L1osP'o 6H1o9

B s S 86 A87 K88 Q 89 L 90 p 91 H 92 L 93 K 94 V gs H 96 L 97 D 98 V 99 R 1oo G 1o1 A1o2 K1o3 Q104 L 1os P 1o6 H1o7 L 1o8 K1o9 V''o A ill

K 112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o p121 H 122 L

KKSS86A87KB8Q89L9cP91H 92L 93K94V9 SH96L 97D98V99R'ooG1o1A102KIo3Q1o4L1osP106H' 07L108K1°9VpoR'1'

L

112 D 113 V 114 K11s S 116 A117 K'18 Q 119 L 12o p121 H 122 L 123 K124 V12s H126

(106)

K ss S e6 A87 K88 Q e9 L 9o P 9' H 92 L 93 K 94

(107)

K

(108)

K 8e Q 8g L 9o P 91 H g2 L 93 K 94 V 9S H g6 L 97 D 9e V gg Rioo G 'oi Al 02 Ki°3 Q i°4 L 'os p io6 H jo'

(109)

K iis S "6 A "7 Kii8 Q 119 L 120 p 121 H 122 K

(110)

es S e6 A87 Kee Q .9 L 90 p 91 H 92 L 93 K 94 V 9s H 96

88 Q 89 L 90 p 91 H 92 L 93 K 94 V 9s H 96 L 97 D 98 V 99 R1oc G 1o1 Alo2 K1o3 Q 104 L 1osp1o6 H 'o7 L 1o8 K1o9 Y'1c AiH L 112 D 113 N 114

K88Q89L9oP91H92L 93K94V 9sH96L 97D9BV99A'cot.'o1A'02K1o3Q1o4L1osP1o6H' 07L1o8K1o9VlloR111L 112DU3V1'4

K

HS 5 "6 A117 K118 Q 119 L 120 p121 H 122 L 123 K124 V 12s H126

(111)

K 88 Q e9 L 9o P 9' H 92 L 93 K 94

(112)

K

(113)

ee Q .9 L 9

° P 91 H 92 L 93 K 94 V 9s H 9s

K88Q89L9oP91H92L 93K94V 9sH96L 97D98V99R'ooG1o1Al02K1o3Q1o4L1osP1o6H' 07L1o8K1o9VlloR111L 112D113V114 K" S116A117K"sQ'19L120p121H122L123K124V12 sH126L 127D128V129R'3 oG131A132K133Q134L 13Spl36H137

(114)

(115)

H92L 93K94V9 sH96L 97D9BV99D1ooG.1o'Alo2K1°3Q1°4L1

H

osP1 o6H1o7L'o8K1o9V11oA111L112DU3VZ"4Kcts

92 L 93 K94 V 9s H 96 L 97 D 98 V 99 8 1oo G1o1A102 K1o3 Q lo4 L 1os P 1o6 H1o7 L 1o8 K1o9 V 11o R ill L 112 D 113 V114 K11s S "6 A117

K118

(116)

H92L 93K94V9 sH96L 97D98V99R'ooG1o1Al02K103Q104L1osP1o6H'07L1o8K1o9VlloR111L112D 113V114KllsS116 A'17

K118 Q119 L 12o p121 H 122 L 123 K124

(117)

H92L 93K94V9 sH96L 97D98V99R'ooG1o1Al02K103Q104L1osP1o6H'07L1o8K1o9VlloR111L112D 113V114KllsS116 A'17 K"8Q'19L120p121H122L 123K124V12 sH126L127D 128V129R13 0G131A132K133

(118)

H

92 L 93 K94 V 9s H 96 L 97 D 98 V 99 8 1oo G1o1A102 K1o3 Q lo4 L 1os P 1o6 H1o7 L 1o8 K1o9 V 11o R ill L 112 D 113 V114 K11s S "6 A117

K"8Q'19L120p121H122L 123K124V12 sH126L127D 128V129R13 0G131A132K133Q134L13Spl36H137L 138K139

92 L 93 K94 V 9s H 96 L 97 D 98 V 99 R 1oo G1o1A102 K1o3

(119)

H

(120)

H 92 L 93 K94 V 9 s H 96 L 97 D 98 V 99 R 'oo Gio'Ai 02 Kio3 Qio4 L ios P io6 H ' 07 L io8 Kio9

(121)

K94 V 9s H 96

(122)

K94 V9 sH96L97D98Vo9R'ooGio'At o2

(123)

K

L 97D9.Vo9R'oo Gio'Aio2K103

K'°3 Q'°4 L 'os P io6 H' o7

94 V 9s H 96 L 97 D 98 V 99 8 1oo G 1o1 Alo2 K1o3 Q lo4 L 1os

P 1o6 H1o9 L 1o8 K1o9 V11o A ill L 112 D 113 V 114 K11s S "6 A117 K118

Q119L120P121H122

(124)

(125)

K 94 V 9 s H 96 L g7 D ge V 9g A 'oo G'o' Ai02 Kio3 Qio4 L ios P io6 H 'o7 L io8 Kio9 Viio R ii" L ii2 D ii3 V ii4 K"s S ii6 Aii7 Klls Q 119 L 12o P 121 H 122 L 123 K124 V12s H 126 K 94 V 9 s H g6 L 97 D g8 V gg A 'oo Gio' A'02 Kio3 Qio4 L ios P io6 H 'o7 L io8 Kio9 Viio R ii" L ii2 D ii3 V ii4 K"s S ii6 Aii7 Klls Q

119 L 12o p 121 H122 L 123 K124 V12s H 126 L 127 D 128 V 129 R '3° G 131 A132 K133 Q 134 L 13s P 136 H 137

(126)

H96L97D98V99R'ooGio'Ai 02

(127)

H

(128)

(129)

Kio3 Q io4 L ios P io6 H ' 07 L io8 Kio9

96 L 97 D 9e V 99 Rioo G io' Aio2 Kio3 Q 104 L ios P io6 Hio7 L ioe Kio9 Viio R ill L 112 D 113 V ii4 Kiis

H96L97DgeVg9RiooGiofAi02Kio3Qio4Li°sPio6H'o7Lio8Kio9ViioRii"Lii2Dii3Vii4K"sSii6Aii7Klls

96 L 97 D 98 V 99 R1oo G 1o1 Alo2 K1o3 Q 104 L 1osp1o6 H1o9 L 1o8 K1o9 V11o R ill L 112 D 113 V 114 K11s S " 6 A117 K'18 Q 119 L 120

H P 121 H122 L 123 K124

Jul. 24, 2008

US 2008/0176217 Al

-continued

(130)

H96L 97D98V99R1ooG1o1A102K103Q104L1osP 1o6H107L1o8K1o9V11oR111L112D113V114K115S116A117K118Q119L120 p121 H122 L 123 K124 V 12s H 126 L 127 D 128 V129 R13o G 131 A132 K133

(131)

H96L 97D98V99R1ooG1o1A102K103Q104L1osP1o6H107L1o8K1o9V11oR111L112D113V114K115S116A117K118Q119L120 P121H122L 123K124V125H126L127D 128V129R130G131A132K133Q134L135P136H137L138K139

(132)

(133)

(134)

(135)

(136)

(137) (138)

(139)

K103Q104L1o5P1o6H107L1o8K1o9

K103Q104L1osP1o6H107L1o8K1o9V11oR111L112D 113V114K115S116A117K118Q119L120P121H122

K103Q104L1osP1o6H107L1o8K1o9V11oR111L112D 113V114K115S116A117K118Q119L120P121H122L 123K124V125H126

K

1o3 Q104 L 1os P 1o6 H 107 L 1o8 K1o9 V 11o R111 L 112 D 113 V114 K11a S 116 A117 K118 Q119 L 12o p 121 H122 L 123 K124 V125 H 126

L 127 D 128 V 129 R130 G 131 A132 K133 Q 134 L 135 P 136 H 137 H107L1o8K1o9V11oR111L112D113V114K11s

H

1o7 L 1o8 K1o9 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118

H107L1o8K1o9V11oR111L 112D113V114K115S116A117K118Q119L120P121H122L123K124

H

1o7 L 1o8 K1o9 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124 V 12s H126 L 127 D 128 V129 R 130

G131A132K133

(140)

H

1o7 L 1o8 K1o9 V11o R 111 L 112 D 113 V 114 K11s S 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124 V 12s H126 L 127 D 128 V129 R 130

G 131 A132 K133 Q134 L 135 P 136 H137 L 138 K139 (141)

H 107 L 1o8 K1o9 V11oR111L 112D113V114K115S116A117K118Q119L120P121H122L123K124V125H126L 127D128V129R130

G 131 A132 K133 Q134 L 135 P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V144 R145 G 146 A147 K148 (142)

H 107 L 1o8 K1o9 V11oR111L 112D113V114K115S116A117K118Q119L120P121H122L123K124V125H126L 127D128V129R130 G131A132K133Q134L135P136H137L 138K139V140R141L142D 143V144R145G146A147K148^149N1s0p1s1W1s2R153K1s4

(143) (144)

(145)

K1o9 V11o R 111L112D 113V114K115S116A117K118Q119L120P121H122

b

K1o9V11oR111L112D 113V114K115S116A117K118Q119L120P121H122L123K124V125H126

K1o9V11oR111L112D 113V114K115S116A117K118Q119L120P121H122L123K124V125H126L 127D128V129R13 oG131A132 K133n134 L 135 p136H137

(146) (147)

(148) (149)

(150) (151)

(152) (153)

(154)

K

11s SS 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124

K115S116A117K118Q119L 120P121H122L123K124V125H126

K

11s S 116 A117 K118 Q 119 L 12o p121 H 122 L 123 K124 V 12s H126 L 127 D 128 V129 R 13o G131 A132 K133 Q134 L 135 P 136 H137

K118Q119L 120P121H122L 123K124

K

118 Q119 L 12o p121 H 122 L 123 K124 V 12s H126

K118Q119L 120P121H122L 123K124V125H126L127D 128V129R13 oG131A132K133Q134L135P136H137

H

122 L 123 K124 V125 H 126 L 127 D 128 V 129 R13o G131 A132 K133

H122L123K124V125H126L 127D128V129R13 oG131A132K133Q134L135P136H137L138K139

H122L123K124V125H126L 127D128V129R130G.131A132K133Q134L135P136H137L138K139V140R141L 142D143V144R145 G146A147K148

(155)

H


G146A147 K148Q149N1so P15'W'52R'53 K154

(156)

b

b


G 146 A147 K148 Q 149 N 1sop1s1 W1s2 R 1s3 K1s4 N1ss L 156 C 1s7 L 1s8 L 1s 9 K16o (157)


G 146 A147 K148 Q 149 N 1sop1s1 w1s2 A 1s3 K1s4 N1ss L 156 G'57 L 1s8L1s 9 K'6 ° K '6' (158)

H122L123K124V125H126L 127D128V129R130G.131A132K133Q134L135P136H137L138K139V140R141L 142D143V144R145 G146A147K148Q149N150P151W152R153K154N155L156C157L158L15 9K'6oK161N162V163K164

(159)

H


G146A147K148Q149N150P151W1528153K154N155L156C157L158L159K'6oK161N162V163K164S'65A166K167

(160) (161)

K

124 V12s H 126 L 127 D 128 V 129 R13o G 131 A132 K133

K124V125H126L127D 128V129R130G131A132K133Q134L135P136H137

Jul. 24, 2008

US 2008/0176217 Al 41

-continued (162)

K

124 V12s H 126 L 127 D 128 V 129 R130 G.131 A132 K133 n 134 L 13s P 136 H137 L 138 K139 V140 R141 L 142 D 143 V 144 R14s G146 A147

K148 Q149 N 1so P 1s1W 1s2 R 1s3 K1s4 N 1ss L 1s6 c 1s9 b L

1s8 L 1s 9 K160 K161 N162 V 163 K164 S 16 s A166 K167 Q 168 L 169 P 19o H 171

Replikin Sequences Located in Mid-Molecule Portion of Peptide (163)

(164)

(165)

(166)

H

126 L 127 D 128 V129 R 13o G 131 A132 K133 Q134 L 13S P 136 H137 L 138 K139

H126L127D 128V129R130G131A132K133n134L13SP136H137L 138K139V140R141L142D143V144R14 sG146A147K148

126 L 127 D 128 O129 R 130 G 131 A132 K133 ti fl134 L 13s P l36 H137 L 138 K139 D14o R 141 L 142 D 143 Y 144 R14s G. 146 A147 K148 x 149 H b b N1s oP1s1W1s2R1 s3K1 s4

H

126 L 127 D 128 V129 R 130 G 131 A132 K133 n134 L 13s P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V 144 R14s G. 146 A147 K148 n 149

N 1so P 1s1 W 1s2 R1s3 K1s4 N 1ss L 1 (167)

C.s6 1s7 LL 1s8 L 1s9 K16 o

H126L127D 128V129R130G131A132K133n134L13SP136H137L 138K139V140R141L142D143V144R14 sG. 146A147K148n149 ssssss s ss o K161 N1s°P11W12R13K14N1L16C1' L18L19K16

(168)

(170)

H

126 L 127 D 128 V129 R 130 G 131 A132 K133 n134 L 13s P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V 144 R14s G. 146 A147 K148 n 149

(173)

o K161N 162 V163 K164 S 16 s A166 K167 Q 168 L 169 P 17o H171 L 172 b K 173

K133n134L13sP136H137L 138K139V140R141L142D 143V144R14 sG146A147K148n149N1s OP1s1W1s2R1 s3K1 s4N1ssL1s6

c 1s7 LL 1s8 L 1s9 K16o K161 N 162 V163 K164 S (172)

b

126 L 127 D 128 V129 R 130 G 131 A132 K133 n134 L 13S P 136 H137 L 138 K139 V140 R 141 L 142 D 143 V 144 R14s G. 146 A147 K148 n 149 H N1soP1s1W1s2R1 S3K1 s4N1ssL1s 6C1s9 b L1s8L1s9K16oK161N162V163K164S16 sA166K169 b

N 1so P 1s1 W 1s2 R1s3 K1s4 N 1ss L 1s6 C.1s7 LL 1s8 L 1s9 K16 (171)

b

H126L127D 128V129R130G131A132K133^134L13SP136H137L 138K139V140R141L142D143V144R14 sG. 146A147K148n149 N1soP1s1W1s2R1 S3K1 s4N1ssL1s 6C1s' b L1s8L1s9K16oK161N162V163K164

(169)

b

16 s A166 K167 Q168 L 169 P 19o H171 L 172 b K173 V174 H 17S

K133n134L 13sP136H137L 138K139

K

133 b Q 134 L

13s P 136 H 137 L 138 K139 V 14o R141 L 142 D 143 V144 R 14s 6.146 A147 K148 Q149 N1so P 1s1 W1s2 R 1s3 K1s4 N1ss L 1s6

C1s9L1s8L1s 9K16oK161N162V163K164S16sA166K167Q168L169P19 oH171

(174)

(175)

(176)

(177)

H137L138K139V14 oR141L 142D143V144R14 sG146A147K148

H137L138K139V14 oR141L 142D143V144R14 sG146A147K148Q149N1soP1s1W1s2R1 s3K1 s4

H

137 L 138 K139 V14o R 141 L 142 D 143 V 144 R14s 6. 146 A147 K148 Q 149 N1so P 1s1W 1s2 R1s3 K1s4 N 1ss L 1s6 C. 1s9 L 1s8 L 1s9 K16o

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1loP1s1W1S2A1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o K161

(178)

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o K161N162 V163 K164

(179)

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16g K161N162 V163 K164S 16s A166 K167

(180)

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1soP1s1W1s2R1 S3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o K161N162V163K164S 16sA166K167Q168L169P17 0H171L172K173

(181)

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o K161N162V163K164S 16sA166K167Q168L169P17 oH171L172K173V174H17 sL 176D177V178K179

(182)

H137L138K139V14 oR141L 142D143V144R14 sG146 A147K148Q149N1soP1s1W1s2R1 s3K1 s4N1ssL1s 6C1s9L1s8L1s9K16o K161N162V163K164S 16sA166K167Q168L169P170H171L172K173V174H17 sL 176D177V178K179G18oV181K182

(183)

K139V14 oR141L142D 143V144R14 sG146A147K148Q149N1soP1s1W1s2R1 s3K1s4N1ssL1s6C1s9L1s8L1s9K16oK161N162 v163K164 S16sA166K167Q168L169P19 oH171

(184)

K139V14 oR141L142D 143V144R14 sG146A147K148Q149N1SoP1S1W1s2R1 s3K1s4N1ssL1s6C1s9L1s8L1s9K16oK161N162 V163K164S16sA166K167Q168L169P1' oH171L172K173V174H17S

(185)

K139V14 oR141L142D 143V144R14 sG146A147K148Q149N1soP1s1W1s2R1 s3K1s4N1ssL1s6C1s9L1s8L1s9K16oK161N162 V163K164S16sA166K167Q168L169P1' oH171L172K173V174H17 sL176D177V178K179G18oV181K182Q183L184L18sH186

(186)

K148Q149N1soP1s1W1s2R1s3K1 s4N1ssL1y 6C.1l9L1s8L1s9K16oK161N162V163K164S16sA166K167Q168L169P17 oH171

(187)

148 Q149 N 1so P 1s1W 1s2 R 1s3 K1s4 N 1ss L 1s6 C 1s9 L 1s8 L 1s9 K160 K161 N162 V 163 K164 S 16 s A166 K167 Q 168 L 169 P 17o H 171 K L172 K173 V174 H17

(188)

148 Q149 N 1so P 1s1W 1s2 R 1s3 K1s4 N 1ss L 1s6 C1^9 L 1s8 L 1^9 K 160 K161 N162 V 163 K164 S 16 s Al 66 K167 Q 168 L 169 P 170 H 171 K L172K173V174H17 sL 176D 177V178K179G18oV181K182Q183L 184L18sH186

Jul. 24, 2008

US 2008/0176217 Al 42

-continued 1s4 N1ss L 1s6 c 1s9 L 1s8 L 1s9 K16o K161 N162 V163 K164 S 16s A166 K167 Q168 L 169 P 17o H171 L 172 K173 V 174 H17s L 176 D 177

(189)

K V 17. K179 G 18o V1.1 K1.2 Q 183 L 184 L 18s H186 L 1.7 K188 V1.9 R 19o L 191 D 192 V 193 R194 G19s A196 K197 Q 198 L 199 P 20o H 201

(190)

K1s4 Niss L is 6 Cis' L 1s8 L 1s9 K16o K 161 N 162 V 163 Ki64 S i6s Ai66 Ki 67 Q 168 L 169 P '7o H 171

(191)

K1s4 Niss L is 6 Cis' L 1s8 L 1s9 K16o K 161 N 162 V 163 Ki64 S i6s Ai66 Ki 67 Q 168 L 169 P 17 o H 171 L '72 K'73 V '74 H 17S

(192)

Kis4 Niss L is 6 Cis' L 1s8 L 1s9 K16o K 161 N 162 V 163 Ki64 S i6s Ai66 Ki 67 Q 168 L 169 P 17 o H 171 L 172 K173 V 174 H 17 s L 176 D 177 V K179 G 1.o V 1.1 K 1.2 Q 1.3 L 1.4 L ies H 186 17e

(193)

K 16o K161 N 162 V 163 Ki 64 S i6s A166 Ki67 Qi6e L 169 P i7 o H 171

(194)

K

(195)

K 16o K161 N 162 V 163 Ki 64 S i6s Ai66 Ki67 Q 168 L 169 P iz o H 171 L 172 K173 V 174 H 17 s L 176 D 177 V 178 K17g G 1eo Ui81 K182 Q ie3 L 1.4 L 18s H 186

(196)

K16o K16i N 162 v163 K164 S i6s Ai66 Ki67 Qi6e L c69 P iz o Hi71 L i72 Ki73 Ui74 H il

(197)

K

16o K161 N 162 V163 K164 S 16s A166 K167 Q168 L 169 P 17o H171 L 172 K173 V174 H 17S

s L 176 177 V 178 K179 G ieo Vie1 Kie2 Q ie3 D L184L18sH186L187K188V189R19oL191D192V193R194G19sA196K197Q198L199P2 0oH201

16o K161 N 162 V163 K164 S 16 s A166 K167 Q168 L 169 P 17o H171 L 172 K173 V174 H 17s L 176 D 177 V 17. K179 G 18o V1.1 K1.2 Q 183

L184L18sH186L187K188V189R19oL191D192V193R194G19sA196K197Q198L199p2 0oH2 o1L 202K2o3V2o4H2os

161 N i 62 V i63 Ki 64 5 16s Ai66 Ki 67 Q i6e L i 69 P 17o H 171

(198)

K

(199)

K 161 N 162 V 163 Kl 64 S i6s Ai66 Ki 67 Q 168 L 169 P 17 o H i71 li i72 Ki73 vi74 H17s

(200)

K L i.s Hie6

(201)

Ki61 N i 62 v 163 Ki 64 S i6s Ai66 K167 Q 168 L 169 P 17o H 171 L 172 K 173 V 174 H 17 s li 1l 6M77 V 178 K 179 G18o V 181 K182 Q 183 L 184 L 18s H186 L 1.7 K188 V 1.9 R 19o L 191 D 192 V193 R194 G 19s A196 K197 Q198 L 199 P 20o H 201

(202)

K 161 N 162 V 163 Ki 64 S i6s Ai66 Ki 67 Q 168 L 169 P 17o H 171 L 172 K 173 V 174 H 17 s L 176 D 177 V 178 K 179 G 180 V 181 K182 Q 183 L 184 L 18 H186L 187K188V189R19oL191D 192 V 193 R 194 G i9s Ar96 Ki 97 Q 198 L 199 P 2° o H 2 o1 li 202 K 203 v 2 04 H 20s

(203)

Ki 64 S i6s Ai66 Ke 67 Q 168 L 169 P 17 o H 171 L 172 K173

(204)

K

(205)

Ki 64 S a6s Ai66 Ki 67 Q 168 li i6g P 17 o H 17i L 172 K173 V 174 Hi7 s L 176 D 177 V 178 K 179 G 180 V 181 K 182 Q 183 L 184 L 18

(206)

K

161 N162 V 163 K164 S 16 s A166 K167 Q 168 L 169 P 17o H 171 L 172 K173 V174 H17s L 176 D 177 V17. K179 G18o V 1.1 K1.2 Q183 L 184

i 64 5 16s Ai66 Ke 67 Q c 6e L i 69 p i7o H i71 L 172 K173 Y 174 H 17S


K188V189R19oL191D192V193R194G19sA196K1 97

Q 198 L 199 P 2 oo H 2 of


(207)

K K 188 V 189 R 19o L 191 D 192 V 193 A194 G 19s A196 K1 97 Q i9e li 1g 9 P 2 oo H 2 o1 L 202 K 203 U 2o4 H 2os

(208)

K

(209)

Ki 67 Qs6e L i69 P i70 H 171 li i72 Ki73 v 174 H17s

(210)

Ki 67 Q 168 L 169 P 170 H 17i L 172 K173 v 174 Hi7 s L i76 D 177 V 178 K 179 G 180 V 181 K 182 Q 183 L 184 L 18

(211)

K L 191 D 192 V 193 A i 94 G i9s Aa96 Ki 97 Q 198 L 199 P 2 oo H 201

(212)

K L 191 D 192 V 193 R 1g4 G 19s A196 K1g7 Q i9e li 199 p 2 oo H 2 o1 L 202 K 2 03 V 2 04 H 20s

(213)

H

(214)

i 67 Qi 6e L i69 P 17o H 171 L 172 K173

H 186

167 Q168 L 169 P 17o H 171 L 172 K173 V 174 H17s L 176 D 177 V17. K179 G18o V1.1 K1.2 Q183 L 184 L 18s H186 L 187 K188 V1.9 R 190

167 Q168 L 169 P 17o H 171 L 172 K173 V 174 H17s L 176 D 177 V17. K179 G18o V1.1 K1.2 Q183 L 184 L 18s H186 L 187 K188 V1.9 R 190

171 L 172 K173 V174 H 17S L 176 D 177 V 17. K179

H17ilii72Ki73vi74Hi7sli176M77Vi7eKi79GieoVieiKie2

(215)

H 17i L 172 Ki73 V174 H i7s li i76 D 177 V 178 K179 G 180 V 181 K182 Q 183 L 184 L 18

(216)

H

H

H 186 L 187 Kiss

171 L 172 K173 V174 H 17S L 176 D 177 V 17. K179 G18o V 1.1 K1.2 Q 183 L 184 L 18s H 186 L 1.7 K188 V 1.9 R19o L 191 D 192 V193 R 194

G19sA196K' 97Q198L'9 9 p2 o o H2 o

(217)

H 186

'L202

K203

171 L 172 K173 v174 H 17S L 176 D 177 V 17. K179 G18o V 1.1 K1.2 Q 183 L 184 L '8s H 186 L 1B7 K'BB V 1.9 R19o L 191 D 192 U193 R 194

G19sA196K197

(218)

171 L 172 K173 V174 H 17S L 176 D 177 V 178 K179 G18o V 181 K182 Q 183 L 184 L '8s H 186 L 187 K188 V 189 R19o L 191 D 192 V193 R 194

H G 'gs Ai96 Kig7 Q'98 L ' 99 P 2o o H 2 o1 L 202 K2o3 V 2o4 H 2 os L 2 o6 D 207 V 2 o8 R 2 o9 G 21 o A211 K212

Jul. 24, 2008

US 2008/0176217 Al 43

-continued 171 L '72 K173 V174 H 17S L 176 D 177 V 17. K179 618o V 1.1 K1.2 Q 183 L 184 L 18s H 1.6UB7 K'BB V 1.9 R19o L 191 D 192 V193 R 194

(219)

H G 19s A196 K197 Q198 L 199 P 2oo H 2o1 L 2o2 K2o3 V 204 H 2os L 2o6 D 207 V 208 R 2o9 G 210 A211 K212 Q 213 N 214 P 21s W 216 R 217 K 21.

(220)

K '73 V '74 H '7 s L '76 D '77 V 178 K'79

(221)

K '73 V '74 H '7 s L '76 D '77 V 178 K'79 G 'so Vie1 K' 82

(222)

K '73 V '74 H '7s L '76 D '77 V 178 K'79 G 'so Vie1 K' 82 Q '83 L ' 84 L 18s H '86

(223)

K173V174H17 sL176D 177V178K179G'8oV181K182Q183L'84L'8sH'86L'87K188V189R19oL191D192V193R194G19sA196

K ' 97 Q 1ge L '9g P 2 oo H 201 (224)

K

173 V174 H 17s L 176 D 177 V 178 K179 G 180 V181 K182 Q 183 L 184 L 186 H186U.7 K'88 V189 R19o L 191 D 192 V 193 R194 G19s A196

K'97Q' 98

(225)

(226)

L'9

9 p2 ooH 2 o1L 202 K203V204 H205

17s L 176 D 177 V178 K179 G 180 V181 K182 Q183 L 184 L 186 H186 L 187 K188 V189 R 19o L 191 D 192 V 193 R194 G 196 A196 K197 Q 198

H 199 P 2oo H 2o1 L 2o2 K 2o3 V 2o4 H 2os L 2o6 D 207 V 208 R 209 G 21o A 211 K212 L

H17 sL176D 177V178K179G.18oV'e1K182Q1B3L'84L18sH186L 1B7K1B8V1B9A19oL191D192V193R194G.'9sA'96K197Q198

L 199 P 2oo H 2o1 L 2o2 K 2o3 V 2o4 H 2os L 2o6 D 207 V 208 R 209 G 21o A 211 K212 Q 213 N 214 P 21s W 216 R 217 K218

(227)

H17 sL176D 177V178K179G'8oV181K182Q183L'84L18sH186L 187K188V189R19oL191D192V193R194G'9sA'96K' 97Q198 9P2 ooH 2 o1L 2o2K2o3V2o4H2 osL 2 o6D 209V208R209G. 210A211K212Q213N 214P215W216R 217K218N 219L 220C221L 222 L '9 L 223 K224

(228)

H17 sL176D 177V178K179G'8oV181K182Q183L'84L18sH186L 187K188V189R19oL191D192V193R194G'9sA'96K' 97Q198 9P2 ooH 2 o1L 2o2K2o3V2o4H2 osL 2 o6D 209V208R209G. 210A211K212Q213N 214P215W216R 217K218N 219L 220C221L 222 L '9 L zz3 K224 K 22

(229)

H '7s L '76 D '77 V 178 K '79 G 'so Vie1 K '82 Q '83 L ' 84 L 18s H '86 L '87 K'88

(230)

H

17s L '76 D 177 V178 K179 G 180 V181 K182 Q183 L 184 L 186 H186 L 1B7 K188 V189 R 19o L 191 D 192 V 193 R194 G 196 A196 K197 Q 198

L'9 9 P2 0

(231)

(232)

(233)

(234)

H2°

1L202 K203

H17 sL176D 177V178K179G'8oV181K182Q183L'84L18sH186L 187K188V189R19oL191D192V193R194G'9sA'96K'97

K'79G'xoVie1K' 82 Q '83 L '84 L ks H '86 L ' 87 K'88

K'79G1.oV181K182Q183L 184U8s H 186 L 187 K' 88 V 189 R19o L 191 D 192 V193 R 194 G19s A196 K197 Q198 L 199 P 2oo H 201

K'79G'B0V1e1K'B2Q183L184L'8sH'86L'87K188V189R19oL191D192V193R194G'9sA'96K' 97Q198L' 99P2 ooH2 o1L 202 K203V204 H2os

(235)

(236) (237)

(238)

(239) (240)

K' 82Q'83L'84L18sH'86L'87K'88

K

182 Q183 L 184 L 18s H 186 L 187 K188 V 189 R19o L 191 D 192 V193 R 194 G19s A196 K197 Q198 L 199 P 2oo H 201

K' 82Q183L 184L18sH186L 187K188V189R19oL191D 192V193R194G.'9sA'96K'97Q198L' 99p20 oH2 o1L 202K203V2o4H 206

H'86L187K188V189R19oL191D192V193R194G.19sA196K197Q' 9BL199P2 ooH 2 o1L 202K203

H

186 L 187 K188 V189 R 19o L 191 D 192 V 193 R194 G19s A196 K197

H'86L187K188V189R19oL191D192V193R194G.19xA196K197Q'9BL199p2 ooH 2 o1L 2O2K2o3Y2o4H2 osL 2 o6D 207V2 o8R 209

G 210 A211 K 212

(241)

H'86L187K188V189R19oL191D192V193R194G.19xA196K197Q19BL199p2 ooH 2 o1L 2O2K2o3V2o4H2 osL 2 o6D 2o7V2 o8R 209

G (242)

14

P215 W

2'6 R 217 K218

210 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224

H'86L187K188V189R19oL191D192V193R194G'9sA'96K'97Q198L199P2 ooH 2 o1L 202K2o3V2o4H2 osL 2 o6D 207V2 o8R 209

G (244)

Q'3N2


G (243)

210 A211 K212

210 A211 K 212 Q 213 N 214 P 216 w 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224 K 22S


6 210 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224 K 22s N 226 V 227 K 228

(245)


6 210 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224 K 22s N 226 V 227 K 228 S 229 A 23o K231

(246)

K '88 V '89 R 190 L 191 D 192 V 193 R 194 G '95 A'96 K' 97 Q 198 L 199 P 2 oo H 201

(247)

K '88 V '89 8 19o L 191192 V 193 R 194 G '9s A'96 K'97 Q 198 L 199 P 2 oo H 2 o1 L 202 K 2o3 V 2o4 H 20S

Jul. 24, 2008

US 2008/0176217 Al

-continued (248)

K

I88 V189 R 190 L 191 D 192 V193 R194 G 19s A196 K197 Q 198 L 199 P 2oo H 2o1 L 2o2 K 2o3 V2o4 H 2os L 2o6 D 207 V 208 R 2o9 G 21o A 211

K 212 Q 213 N

214 P 21s W 216 8 217 K218 N 219 L 22o c. 221 L 222 L 223 K 224 K22s N 226 V 227 K228 S 229 A 23o K231 Q 232 L 233 P 234 H 23s

ll igg P 2 oo H 29i L 202 K203

(249)

K'osQi* 98

(250)

K'97Q' 98

(251)

0OQ198L199p2 ooH 2 o1L 202K203V204H2 osL 2 o6D 207V2 o8R 2 o9G21oA211K212Q213N214P21sW216R 217K218N219L 220 K' 221 L 222 L 223 K224 K 22s N 226 V 227 K 228 S 229 A23o K 231 Q 232 L 233 P 234 H 23s

L 199 P 200 H 2 o1 L 202 K203 V 204 H 20S

c (252)

(253) (254)

(255)

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G21oA211K212

H

2o1 L 202 K 2o3 V 2o4 H 2os L 296 D 207 V 208 R 2o9 G 219 A 211 K212 Q 213 N 214 P 21s W 216 R 217 K218

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213N214P21sW216R217K218N 219L 220C221L 222L 223K224

H

2o1 L 202 K 2o3 V 2o4 H 2os L 296 D 207 V 208 R 2o9 G 219 A 211 K212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K 224

K 22s (256)

H


K2 (257)

K2

28

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213N214P21sW216R217K218N 219L 220C221L 222L 223K224

K2 (258)

2s N 226 V 227

2s N226

V22

7 K228 s 229 A 23o K231

H2 o1L 202K203V204H 2 osL 2 o6D 207V2 o8R2 o9G210 A211K212Q213N214P21sW216R217K218N 219L 220C221L 222L 223K224 K22 sN226V227K228S229A23 oK231Q232L 233P234H 23 sL 236K237

(259)

H


K22sN226V227K228S229A23oK231Q232L 233P234H 23 sL 236K237V238L239L24oD 241V242R 243G244A24 sK246

(260) (261)

K

203 V204 H 20s L 206

D

2o7 V 208 R 2o9 G 210 A211 K212

K203V204H 2 osL 2 o6D 207V2 o8R2 o9G 21 oA211K212Q213N214P21sW216R217K218N219L 220C221L 222L 223K224K22 sN 226 V227 K228S 229A230 K2 31Q232 L 233p234 H23s

(262)

K203V204H 2 osL 2 o6D 207V2 o8R2 o9G 21 oA211K212Q213N214P21sW216R217K218N219L 220C221L 222L 223K224K22 sN 226 V227K2285229A23oK231Q232L 233P234H23 sL 236K237V238L239L24oD 241V242R243G244 A24 sK246Q247L248P249H2s0

(263) (264)

(265) (266)

(267)

H

2os L 206 D 207 V 208 R 299 6 219 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213N214P21sW216R 217K218N219L 220C221L 222L 223K224

H

2os L 206 D 207 V 208 R 299 6 219 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224 K 22S

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213N214P21sW216A 217K218N219L 220C221L 222L 223K224K22 sN226V227K228

H

2os L 206 D 207 V 208 R 299 6 219 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224 K 22s N 226 V 227 K 228

S229A23o K231

(268)

H

2os L 206 D 207 V 208 R 299 6 219 A211 K 212 Q 213 N 214 P 21s W 216 R 217 K218 N 219 L 220 0. 221 L 222 L 223 K224 K 22s N 226 V 227 K 228

S22

(269)

A230 K 231 Q 232 L 233

P234

H23s

L236

K237

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213N214P21sW216R 217K218N219L 220C221L 222L 223K224K22 sN226V227K228

S 229 A230 K 231 Q 232 L 233 p 234 H 23s L 236 K237 V238 L 239 L 249 D 241 V 242 8 243 G. 244 A24s K246

(270)

H2 osL 2 o6D 207V2 o8R 2 o9G 21 oA211K212Q213N214P21sW216R 217K218N219L 220C221L 222L 223K224K22 sN226V227K228 S229A230K231Q232L 233P234H23 sL 236K237V238L239L24oD 241V242R243G 244 A24 sK246Q247L 248P249H2s oL 2 s1K2s2

(271)

(272)

K212Q213N 214P21sW216R 217K218N 219L 220c221L 222L 223K224K22 sN226V227K2285229A23 oK231Q232L 233P234H 23s

K212Q213N 214P21sW216R 217K218N 219L 220c221L 222L 223K224K22 sN226V227K2285229A23 oK231Q232L 233p234H 23s

L (273)

236 K237 V 238 L 239 L 240 D 241 V 242 R 243 6 244 A24s K 246 Q 247 L 248 P 249 H 2s0

K218N219L 220C221L 222L 223K224K22 sN226V227K2285229A23 oK231Q232L 233P234H23 sL 236K237V238L 239L 240D 241

v 242 R 243 G 244 A24s K 246 Q 247 L 248 P 249 H 2s0 (274)

K218N219L 220C221L 222L 223K224K22 sN226V227K2285229A23 oK231Q232L 233P234H23 sL 236K237V238L 239L 240D 241 v242R243G 244 A24 sK246Q247L 248P249H2s oL 2s1K2s2V2s3L 2s4L 2 ssD 2s6V2s9R2 s8G2 s9A26 oK261Q262L 263P264H 26s

(275) (276)

(277)

K

218 N 219 L 220 0 221 L 222 L 223 K224 K 22s N 226 V227 K 228 5 229 A 23o K231 Q 232 L 233 P 234 H 23s

K224K22 sN 226V227K2285229A23 oK231Q232L 233P234H23S

K

224 K22s N 226 V 227 K 228 5 229 A230 K 231 Q 232 L 233 P 234 H 23s L 236 K237 V 238 L 239 L 240 D 241 V 242 R 243 G 244 A24s K246 Q 24'7

L 248p249H 2so

Jul. 24, 2008

US 2008/0176217 Al

-continued (278)

K

224 K22s N 226 V 227 K 228 S 229 A230 K 231 n 232 L 233 P 234 H 23s L 236 K237 V 238 L 239 L 240 D 241 V 242 R 243 G 244 A24s K246 n 24'7

L 248 P 249 H 2so L 2s1 K 2s2 V 2s3 L 2s4 L (279)

(280)

2ss D 2s6 V2s9 R 2s8 G 2S9 A 26o K261 Q 262 L 263 P 264 H 26S

b

K22 sN226V227K228S229A23 oK231Q232L 233P234H 23s

K22sN226V227K228S229A230K231n232L 233P234H 23 sL 236K237V238L 239L 240D 241V242R 2436. 244A24 sK246n247L 248 b

b

P249H2so

(281)

(282) (283)

(284)

22s N 226 V 227 K228 S 229 A 230 K231 n 232 L 233 P 234 H 23s L 236 K 237 V 238 L 239 L 240 D 241 V 242 R 243 6. 244 A 24s K246 n 247 L 248

K P 249 H 2so L 2s' K2s2 V 2s3 L 2s4 L 2 ss DD 2s6V2s9R2 s8G2s 9A26 oK261Q262L263P264H26S K

228 S 229 A 230 K231 n 232 L 233 P 234 H 23s L 236 K237

K228S229A230K231 b n232L 233P234H 23 sL 236K237V238L 239L 240D 241V242R 2436. 244 A24 sK246n247L 248P249H2s0

K

228 S 229 A 230 K231 b n 232 L 233 P 234 H 23s L 236 K237 V 238 L 239 L 240 D 241 V 242 R 243 6.244 A24s K 246 b n 247 L 248 P 249 H 2s° L 2s1

K 2s2 V2s3 L (285)

(286) (287)

2s4 L 2ss DD 2s6 V 2s9 R 2s8 G 2s 9 A26o K261 Q 262 L 263 P 264 H 26s

(289) (290)

b

K231n232L 233P234H 23 sL 236K237

K

231 b n 232 L 233 P 234 H 23s L 236 K237 V 238 L 239 L 240 D 241 V 242 R 243 6. 244 A24s K 246 n 247 L 248 P 249 H 2s0

K231 b n232L 233P234H 23 sL 236K237V238L 239L 240D 241V242R 2436.244 A24sK246 b n247L248P249H2s°L 2 s1K2s2V2s3L 2s4

L 2ss D 2s6 V 2s' R 2s8 G 2s9 A 26 (288)

b

o K261 Q 262 L 263 P 264 H 26 s

b

H23sL236K237V238L 239L 240D 241V242R243G244 A24 sK246

H

23s L 236 K 237 V 238 L 239 L 24o D 241V 242 R 243 G 244 A 24s K246 Q 247 L 248 P 249 H 2so L 2s1 K2s2

H23 sL 236K237V238L 239L 24 oD 241V242R243G244 A24 sK246Q247L 248P249H 2s oL 2 s1K2s2V2s3L 2s4L 2 ssD 2s6V2s9R2s8

G 2s9 A260 K 26i (291)

H23 sL 236K237V238L 239L 24 oD 241V242R243G244 A24 sK246Q247L 248P249H 2s oL 2 s1K2s2V2s3L 2s4L 2 ssD 2s6V2s9R2s8 G2s 9A 260 K261Q262L2 63 P264 H26 s

(292)

H

L266

K267

23s L 236 K 237 V 238 L 239 L 24o D 241V 242 R 243 G 244 A 24s K246 Q 247 L 248 P 249 H 2so L 2s1 K2s2 V 2s3 L 2s4 L 2ss D 2s6 V 2s9 R 2s8

G2s 9A26oK261Q262L 263P264H26sL 266K267V268L 269L 27 oD 271V272R2736.274 A27sK276

(293)

H

23s L 236 K 237 V 238 L 239 L 24o D 241V 242 R 243 G 244 A 24s K246 Q 247 L 248 P 249 H 2so L 2s1 K2s2 V 2s3 L 2s4 L 2ss D 2s6 V 2s9 R 2s8

G 2s9 A260 K 261 n 262 L

263 P 264 H 26 s L 266 K267 V268 L 269 L 27o D 271 V 272 R 273 G 274 A27

(294)

K 237 V238 L 239 `LL 24 oD 241V242R243G244A24 sK246Q247L248P249H2su

(295)

K

(297)

K

263 P 264 H 26s

246 Q 247 L 248 P 249 H 2so L 2s1 K2s2

K246Q247L 248P249H 2 soL 2s 1K2s2V2s3L 2s4L 2 ssD 2s6V2s9R 2 s8G2s 9A 26 oK261Q262L 263P264H26S

Replikin Sequences Located in Carboxy-Terminal Portion 2so L 2si K 2s2 V 2s3 L 2s4 L 2ss 2s6 V 2s' R 2s8 G 2s9 A 260 K26i (298) H D

(299) (300)

`G

237 V238 L 239 L 24o D 241 V 242 R 243 G 244 A24s K246 Q 247 L 248 P 249 H 2so L 2s1 K 2s2 V2s3 L 2s4 L 2ss D 2s6 V 2s9 R 2s8 G 2s9 A 26o

K 2— Q 262 L (296)

K276 n 277 N 278 P 279 W 280 R 281 K 282

of Peptide

H 2so L 2s' K 2s2 V 2s3 L 2s4 L 2s s D 2s6 V 2s9 R 2 s8 G 2 s9 A 26 o K261 Q 262 L 263 P 264 H 26 s L 266 K269 H2s oL 2 s1K2s2V2s3L 2s4L 2s sD 2s6V2s9R2 s8G2s9 A260K261Q262L 263P264H 26 sL 266K267V268L 269L 27 oD 271V272R 273 6274 A27sK276

(301)

H

2so L 2s1 K 2s2 V 2s3 L 2s4 L 2ss D 2s6 V 2s9 R 2s8 G 2s9 A 260 K261 Q 262 L 263 P 264 H 26 s L 266 K267 V 268 L 269 L 27o D 271 V 272 R 273

G274 A27 K276Q277N 278P279W28 oR 281K282

(302)

H 2so L 2s' K 2S2 V 2S3L 2s4L 2s sD 2s6V2s9R2 s8G2s9 A26 oK261Q262L 263P264H 26 sL 266K267V268L 269L 27 oD 271V272R 273

G 274 A27 (303)

K 276 n 277 N 278 P 279 W 280 R 281 K282 N 283 L 284 0. 28s L 286 L 287 K288

6 2s3L 2s4L 2s sD 2s6V2s9R2 s8G2s9 A26 oK261Q262L 263P264H 26 sL 266K267V268L 269L 27 oD 271V272R 273 H 2so L 2si K 2s2 v

G 274 A2'IS K 2'16 ra 2'I'I N 2'I8 P 2'I9 W 280 R (304)

281 K282 N 283 L 284 0. 28s L 286 L 287 K288 K 289

H 2so L 2s' K 2s2 V 2s3L 2s4L 2s sD 2s6V2s9R2 s8G2s9 A260K261Q262L 263P264H 26 sL 266K267V268L 269L 27 oD 271V272R 273 G.2'I4 A2'IsK2'16n2'l7N278P2'J9W28 oR 281K282N283L 284C28sL 286L 287K288K289N290V291K292

(305)

H

2so L 2si K 2s2 V 2s3 L 2s4 L 2ss D 2s6 V 2s9 R 2s8 G 2s9 A 260 K261 Q 262 L 263 P 264 H 26 s L 266 K267 V 268 L 269 L 27o D 271 V 272 R 273

G.2'I4 A2'ISK2"16Q2'J'JN2'J8P2'D9W28 oR 281K282N283L 284C28sL 286L 287K288K289N290V291K292S293A294K29S

(306)

K

2s2 V2s3 L 2s4 `LL 2ss D 2s6 V 2s9 R 2s8 G 2s9 A260 K261 Q 262 L 263 P 264 H 26 s L 266 K 267 V268 L 269 L 27o D 271V 272 R 273 G 274 A 27S

K 276 Q 277 N 278 P 279 W

280 R 281 K282 N 283 L 284 0 28s L 286 L 287 K 288 K289 N 29o V 291 K292 S 293 A 294 K29s n 296 L 297 P 298 H 299

Jul. 24, 2008

US 2008/0176217 Al

-continued

(307)

K252V253L 254L 2 ssD 256V257R2 s8G 259A26 oK261Q262L 263P264H265

(308)

261 Q 262 L 263 P 264 H 26s L 266 K267 V 268 L 269 L 27o D 271 V 272 R 273 G 274 A27s K 276 Q 277 N 278 P 279 W 280 R 281 K282 N 283 L 284 K c28sL286L287K288K289N 290V291K292S293 A294K29sn296L 297P298H299 `G

(309)

K

(310)

(311)

(312)

261 Q 262 L 263 P 264 H 26s L 266 K267

`G

H26sL 266K267V268L 269L 27 oD 271V272R273G274 A2755K276

H

26s L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G 274 A 27s K276 Q 277 N 278 P 279 W 280 R 281 K282

H26sL266K267V268L269L27oD271V2728273G.274A27sK276 Q 277N278P279W28 oR281K282N 283L 284C28sL 286L 287K288

(313)

26s L 266 K 267 V 268 L 269 L 27o D 271V 272 R 273 G.274 A 27e K276 Q 277 N 278 P 279 W 280 R 281 K282 N 283 L 284 0. 28s L 286 L 287 K 288 H G K289

(314)

H

K (315)

26s L 266 K 267 V 268 L 269 L 27o D 27 1V 272 R 273 G.274 A 27s K276 Q 277 N 278 P 279 W 280 R 281 K282 N 283 L 284 0. 28s L 286 L 287 K 288 289 N 29o V 291 K292 S 293 A 294 K29s Q 296 L 297 P 298 H 299 L 3oo KK301

H26sL 266K267V268L 269L 27 oD 271V272R273G2'I4A27SK2'l6Q2' D'JN2'18P2'J9w28 oR281K282N 283L 284C28sL 286L 287K288

K 289 N 290 V 291 K292

(316)

`G

H26sL266K267V268L269L27oD271V272R273G.274A27sK276Q277N278P279W28 oR281K282N 283L 284C28sL 286L 287K288 K289N290V291K292S293 A294 K295

`G

(317)

265 L 266 K 267 V 268 L 269 L 27o D 27 1V 272 R 273 G.274 A 27s K276 Q 277 N 278 P 279 W 280 R 281 K282 N 283 L 284 0. 28s L 286 L 287 K 288 H K289N290V291K292S293 A294K295Q296L 297P298H 299L3 oo KK301V302L303L 304D305V3 o6R307G.3 o8A3 o9K310

(318)

267 V 268 L 269 L 27o D 271 V 272 8 273 G.274 A27s K276 Q 277 N 278 P 279 W 280 R 281 K 282 N 283 L 284 0. 28s L 286 L 287 K288 K289 N 290 K V291K292S293 A294 K29sn296L 297p298H299 `G

(319)

267 V 268 L 269 L 270 D 271 V 272 8 273 G.274 A27s K276 Q 277 N 278 P 279 W 280 R 281 K 282 N 283 L 284 0.28s L 286 L 287 K288 K289 N 290 K V291K292S293 A294K295Q296L29'7P298H299L300K301V302L 303L304D305V3 o6R307G308A309K31on311L312P313H314

(320)

K

(321)

276 Q 2TI N 2'18 P 2'I9 W 28o R 281 K282 N 283 L 284 6 28s L 286 L 287 K 288 K289 N 29o U 291 K292 S 293 A 294 K295 `Q ff 296 L 297 P 298 H 299 K L300K301V302L303L 304D 305V306R307G308A309K310Q311L 312P313H314

(322)

276 Q 277 N 278 P 279 W 28o R 281 K282 N 283 L 284 0 28s L 286 L 287 K 288 K289 N 29o V 291 K292 s 293 A 294 K29s n 296 L 297 P 298 H 299 K L300K3O1v302L303L 304D 305v3 o6R307G.308A3 o9K310n311L 312P313H314L 31sK316V31'7H318 `G

(323)

K

(324)

276 Q 277 N 278 P 279 W 28o R 281 K282 N 283 L 284 0 28s L 286 L 287 K 288 K289 N 29o V 291 K292 S 293 A 294 K29s b n 296 L 297 P 298 H 299

282 N 283 L 284 0 28s L 286 L 287 K288 K 289 N 29o V 291 K 292 b S 293 A 294 K29s n 296 L 297 P 298 H 299

K282N283L 284C285L 286L 287K288K289N290v291K292S293A294K295 `Q G 296L 297P298H299L 30 oK301V302L303L304D 305

V 306 8307 6 308 A309 K310 n 311 L 312 p 313 H314

(325)

K282N283L 284C285L 286 b L 287K288K289N290v291K292S293A294K295Q296L 297P298H299L 30 oK301V302L303L304D 305

v (326)

(327)

306 R307 G 308 A309 K310 Q 311 L 312 P 313 H314 L 315 K316 V317 H 318

K288K289N 290V291K292SS293 A294K295Q296L 297P298H299

K288K289N 290V291K292S293 A294K295 Q 296L 297P298H299L 3 ooK301V302L 303L304D305V3 o6R307G3 o8A3 o9K31OQ311 L312p313 H314

(328)

K288K289N 290V291K292S293 A294K295Q296L 297P298H299L 3 ooK301V302L 303L304D305V3 o6R307G3 o8A3 o9K31OQ311 L312 p313 H314 L315 K316 V317 H318

(329)

K289N290V291K292S293 A294K29sQ296L 297P298H 299

(330)

289 N 290 V 291 K292 S 293 A 294 K29s Q 296 L 297 P 298 H 299 L 3oo K3o1 V302 L 303 L 304 D 3os V306 R 3o7 G.3o8 A3o9 K31o Q311 L 312 K P313 H314

(331)

289 N 290 V 291 K292 S 293 A 294 K29s Q 296 L 297 P 298 H 299 L 3oo K3o1 V302 L 303 L 304 D 3os V306 R 3o7 G3o8 A309 K31o Q311 L 312 K P313 H314 L 315 K316V317 H318

(332)

K

(333)

292 S 293 A 294 K29s Q 296 L 297 P 298 H 299 L 3oo K301

K292S293 A294K29SQ296L29'7P298H 299L30oK3O1V302L303L 304D305V306R307G308A309K310Q311L 312P313H314

(334)

K292S293 A294K295 b n296L29"7D298H 299L3OOK301U302L303L 304D305V3 06R30'G3 o8A309K310 ^311L 312D313H314L 315 b b K316V317H318

(335)

K

29s Q 2g6 L 297 P 298 H 2g9 L 30 o K30i

Jul. 24, 2008

US 2008/0176217 Al 47

-continued K295Q296L297P298H299L300K301V302L303L304D305V306R307G308A309K310Q311L312P313H314

(336)

K29S Q296L297P298H299L300K301V302L303L304D305V306R30'JG.308A309K310 b Q311L312P313H314L31SK316V31JH318

(337)

(338)

K 295 Q 296 L 297 P 298 H 299 L 300 K301V 302 L 303 L 304 D 305 V306 R 307 G308 A309 K310 Q311 L 312 P 313 H314 L 315 K316 V3i7 H 318 L319DD320V321R322G323A324K325Q326^32'7^328n329L330C.331L332P333L334 K335T336 1337S338T339S340F341T342H343

H299L300K301V302L303L304D305VV306 b R3O'J N G.308 A b3O 9K310

(339)

H299L300K301V302L303L304D305V306R307G.308A309K310Q311L312P313H314L315K316

(340)

(341)

299 L 300 K301 V302 L 303 L 304 D 305 V 306 R307 G308 A309 K310 Q 311 L 312 P 313 H 314 L 315 K316 V 317 H318 L 319 D 320 V321 R 322

H G 323 A324 K325

b

H299L300K301V302L303L304D305V306R307G.308A309K310Q311L312P313H314L315K316V317H318L319D320V321R322

(342)

G 323 A324 K325 Q326 Q 327 Q 328 Q329 L 330 C 331 L 332 P 333 L 334 K335 K301V302L303 L304DD305VV306 R307G308A309K310Q311L312P313H314

(343)

(344)

K

301 V302 L 303 L 304 D 305 V 306 R307 G 308 A309 K310 ra 311 L 312p313 H314 L 315 K316 V317 H318

K301V302L303L304D30SV306R30'7G.308A309K310 B ra 311L312P313H314L315K316V31JH318 L319D32 Ov321R322G323A324

(345)

K325Q326Q32'Q328r329L33OC331L332P333L334 b K33ST336

(346)

K

c 337x338T339S34 °F341T342H343

310 n311 L 312 b P 313 b H 314 L 31S K316

K310 b Q311L312P313H314L315K316V317H318

(347)

(348)

Q327 Q 328 Q329 L 330 G33l L 332 P 333 K310 Q311 L 312p313 H 314 L 31S K316 V 317 H318 L 319 D 320 V321 R 322 G323 A324 K325 Q326 b b b b L334 tr K33Ss336 1337S338T339R34°F341T342H343

(349)

K310 Q311 L 312 P 313 H 314 L 31S K316 V 317 H318 L 319 D 320 V321 R 322 G323 A324 K325 Q326 Q327 Q 328 Q329 L 330 C 331 L 332 P 333 L334 K335T336 i 337S338T339S340F341T342H343L344L345L346C347L348Y349 M350E351 y352 G353K354H355

H314L315K316V317H318L319D32 OV321R322G323A324K325

(350)

H314L315K316V317H318 L319D32 OV321R322G323A324K325Q326Q327Q328Q329L330C331L332P333L334K335

(351)

(352)

314 L 315 K316 V317 H 318 L 319 D 320 V 321 R322 G323 A324 K325 n 326 Q327 Q32. Q 329 L 330 c 331 L 332 P 333 L 334 K33s T 336 1 33'7

H S 338 T 339 5 340 F 341 T 342 H 343 L 344 L 34S L 346 C 347 L 348 Y349 b M 35° E 351 y352 G.353 K354 H355 n 356 N35'J L 358 n359 v360 K361 K316V317H318L319D320V321R322G323A324K32 5Q326n32Q328o329L330C.331L332p333 'J b L334K335T336 I I 337S338T339

(353)

5 340 F 341 T 342 H343 L 344 L 345 L 346 C 347 L 348 Y349 H 3S0 h E 3d y 352 b G 353 K354 H 355 K316V317H318L319D32 OV321R322G323A324K325

(354)

(355)

K

316 V317 H 318 L 319 D 320 V 321 R322 G 323 A324 K32s Q 326 ^327 ^ 328 Q329 L 330 c 331 L 332 P 333 L 334 K33s T 336 i 337 S 338 T 339 b b b b

S340F341T342H343

H318L319D320V321R322G323A324K32SQ326Q327Q328Q329L330G331L332P333L334K33S

(356)

318 L 319 D 320 V321 R 322 G.323 A324 K325 re326 n327 b n 328 Q329 L 330 C 331 L 332 P 333 L 334 K335 T 336 i 337 5 338 T 339 S 340 F 341

(357)

H T 342H343L344L345L346C347L348Y349 b M350 b E351 b y352 G353K354H355Q356N3S7L3S8n3S9V36°K361

(358)

K

(359)

32S Q326 Q 327 Q328 Q 329 L 330 C 331 L 332p333 L 334 K335 T 336 i 337 5 338 T 339 S 340 F 341 T 342 H 343

K325 n326 b Q327Q328Q329L330C331L332P333L334K335T3361337S338T339S340F341T342H343L344L345L346C347L348 Y349 b M350 E351 Y352G.353K3S4H3S5

(360)

(361)

H343 L344 L34 S L346C.34'7 L348y349M3s°E351y352G3S 3K354H3 S5n3S6N35'JL358n359V360K361 b b K3S4H3SSQ3S6N3SJL358Q3S9v360K361

Example 3 Determination of Low Replikin Concentrations in 2005 and 2007 Isolates of WSSV from Accession Nos. AAW88445 and ABS00973 [0153] In 2006 and 2007 White Spot Syndrome Virus (WSSV) has been observed to be dormant in shrimp. This continued decline of WSSV into "quiescent" or "dormant" levels in 2006-2007 is demonstrated in mean Replikin concentrations for viruses isolated during 2005-2007 that are very low as compared to years wherein the virus demon-

strated greater virulence, such as 2001. See Table 4 in Example 4 below. The continued quiescence in WSSV in 2007 may be contrasted with an observed rising of Replikin concentration in Taura Syndrome Virus Replikin during this period. [0154] As maybe seen from the analysis below, Accession Nos. AAW88445 andABS00973 have low observed Replikin concentrations. ABS00973 contains a single Replikin sequence in the entire disclosed amino acid sequence of 240 residues. The single Replikin sequence is underlined. The Replikin concentration of Accession No. ABS00973 is an inordinately low 0.5.

Jul. 24, 2008

US 2008/0176217 Al

Replikin PubMed

Analysis

Code:

AAWS8445

Description: Isolated

Year

2005

Source: Shrimp White Spot Syndrome Virus N3 G .4 As T 1 7 S 8 D o E io R 11 L 12 1 13 L 14 1 is L 16 D 17 K18 1 19 V 2o E.21 R 22 R 23 G. 24 V 25 S 26 N 27 L 28 S 29 E. 3o L 31 L 32 1 33 H 34 P 35 1 36 T 37

M' S

K38H3914oN41E.42 L43 L44 K4sN46T 47V48R49HsoGs1D52 R53V54Y5 sMs6K57 Ds8As9E.6oL61D 62V63 R64S 6sR66L 67 E.68D6917 o K71

K 72 D 73 C. 74 V 7s L 76 K77 A 7. 1 79 E. 8o K 81 Q B2 G.83 1 84 D 8s V 86 R .7 Q 88 1 .9 1 9o T

91 D 92 Y 93 L 94 A9s K96 R 97 K98 L 99.E loo Q 1o1 N 1o2 L 103

V104H105W106Y107R108P'o 9P11oI111S112C113T 114D11s I116D 117E118K119112°Q121Q122E123T124G125Q126V1276.128

R 129 C 13o S

131 V132 A133 T 134 Y13S N 136 L 137 R138 I 139 G 14o G141 D 142 D 143 G 144 E 145 F 146 T 147 R148 Y149 D 150 F 151 S 152 1 153

P154L1nG1s6D159F1s8K1s9116oT161A162K163L 164F16sR166 5167 I168N169D17 oE171D 172U173D174 A175V176I 177L178

V 179 5 18o R 181 S

182 D 183 V 184 V18s N 186 D 187 V188 L 189 S 190 F 191 E 192 A193 F 194 N19s R196 T 197 6. 198E199R 2ooV2°1V2 021203

F204F2 osN206V20712°8V209E 2106 211K2125213K214D 215

1 229 L

1 216 D 21'

1218V219C22 oK2215222R223Y224K22 sH226T227H228

23o N 231 G 232 E 233 5 234 A235 T 236 Y 237 A238 V 239 K24° R 241 1 242 K243 R 244 G 245 D 246 T 247 R 248 D 249 D 250

I

251 L 252 F 253

A25412ssT 2 s6A259F 2 s8K259E 260E 261

Replikin Sequences in Amino-terminal Portion of Peptide (1) H34P35136T37K38H39140N41E 42L43L44K4 sN46T47V48R49HsoGs1D s2Rs3Ys4Y5 nMn6Ks9Dn8As9E.6oL61D 62Y63R64565

R 66 L 67 E 68 D 69 I 7o K 'I 1 K "2 D '3 L."l4 v 'J S L 76 K77 (2)

H

34 P 35 1 36 T 37 K38 H 39 1

40

N 41 E 42 L 43 L 44 K45

H34P35136T37K38H3914 oN41E 42L43L44K4 sN46T47V48R49HsoGx1D 52R53V54V5 sMs6K s9Dn8As9E.60L6lD 62V63R64565

(3)

R 66 L 67 E 68 D 69 1 7 o K 71 K 72 D

73 C 74 V 7s L 76 K77 A7. 1 79 E.8 o K 81

K38H3914 oN41E 42L 43L 44K45

(4)

(5)

K

38 H39 1 4o N41 E 42 L 43 L 44 K4s N 46 T 47 V48 R49 Hso

H3914oN41E.42L43Z44K4sN46. 47Y48R49Hsoes1D52As3V54Y5 sMs6Ks9Ds8As9E.6oL61D 62V63R 64S 6nR66L 67E68D69170

(6)

K 71 K72 D (7)

73 C

' 4V

9s

L'

6 K 77

H3914 oN41E42L 43L 44K45N46T 47V48R49HsoG51D52R53V54Y55Ms6K57Ds8As9E6oL61D 62V63R 64S 65R66L 67E68D69170 K71K72D 93C94V' sL 76K77 A78179E8oK81

(8)

Hso G51 D s2 Rs3 V s4 Y ss M 56 Ks7 D s8 As9 E 6o L 61 D 62 V 63 R 64 5 65 R 66 L 67 E 68 D 69 1 90 K71 K72 D 73 C 74 V 9s L 96 K 77

(9)

HsoG51D52R53V54Y55Ms6K57Ds8As9E6oL61D 62V63R 64S 65R66L 67E68D6917 oK71K72D 93C94V9 sL 76K77 A78179E8oK81

C 74 V 9s L 76 K 77 A 78 1 79 E 8 o K81 Q 82 G 83 1 84 D 85 V 86 R 87 Q 88 1 89 1 9o T 91 D 92 Y 93 L 94 A 9s K 96 R 97 K 98 L 99 T 100 Q101 K71K72D 73 V'04 Hios

(10)

N' 0 2 L 103

D 73 C 74 V 9s L 96 K 77 A 78 1 79 E 8 o K81 Q 82 G 83 1 84 D 8 s V 86 R 87 Q 88 1 89 1 90 T 91 D 92 Y 93 L 94 A9s K 96 R 97 K 98 L 99 T 10o Q1o1N 102 K72 io3 V 104 H 1os

(11)

L

Replikin Zero

Sequences

in

Mid-Molecule

Portion

of

Peptide

Replikins.

Replikin Sequences in Carboxy-Terminal Portion of Peptide 212 5 213 K 214 D 215 1 216 D 217 1 218 V 219 C 22 o K 221 5 222 R 223 y 224 K225 H 226 (12) K

(13)

(14)

(15)

K

212 5 213 K 214 D 21s 1 216 D 217 1 218 V 219 0. 22o K 221 5 222 R 223 Y 224 K22s H 226 1 227 H 228

K214D 2151216D 2171218V219C22 oK221S222R 223Y224K22 sH 226

K

214 D 21s 1 216 D 217 1 218 V 219 C 220 K 221 S 222 R 223 Y 224 K225 H 226 1 227 H 228

Replikin

PubMed

Count

Code:

=

Number

of

Replikins

per

100

amino

acids

=

15/261

=

5.7

ABS00973

Description: Isolated:

2007

Source: Shrimp white spot syndrome virus ' D 2 L 3 S 4 Fs T L 7 S 8 V 9 V10 S 11 Al2 1 13 L 14 A is 1 16 T 17 A18 V19 1 2o A21 V 22 F 23 1 24 V 25 1 26 x.27 R 28 Y 29 H3o N31 T 32 V 33 T 34 K35.b 36 1 37

M

E.38T39H4oT41G.42N43144E.4sT4GN4"M48D49EsoNs1L52 A53l54P5 sVs6TS7Art8Es9VG0G.6lS62G. 63Y64 F6s K66M67 T68D69V7os71

F 72 D 73 S 74 D 9s T

76 L 77G 78 K 79 1

80 K 81 1 82R83N84G8 s

K86 S 87 D 88 A .9 Q 9o M 91 K 92 E 93 E 94 D 9s A96 D 97 L 98 V 991100T1o1P1o2V103

Jul. 24, 2008

US 2008/0176217 Al

-continued E.1°4 G.'os R 1°6 A1o9 L 108 E 109 V 110 T 111 V 112 G113 Q 114 N 11s L 116 T 119 x.118 E 119 G120 T 121 F

122 K123 M124 W 12s N126 N 127 T 128

S129R130K131I132N133 1134T13sG136M137Q138M139V'40P141K142I143N144P14SS146K147 A148F149V1s OG1s 1S1s2s's3

N 1s4 T 1ss S 1s6 S 1s9 F is8 T 1s 9 P 16o V 161 S

162 1163 1 D 164 E 1 6s D 166 E 167 V168 G 169 T 17o F 171V 172 C 173 G194 T 19s T 196 F 199 6. 198

A179P'801181A182 A' 83T 184A18sG1866. 187N188L'89 .19oD191M192Y193V194H19sV196T 197Y198S199G 200.E 201E 202.E 203

E 204 Replikin Sequences in Amino-Terminal Portion of Peptide ( 1 ) H 4o T 41 G42 N43 1 44 E 4s T 46 N 47 M 48 D 49 E so N sl L s2 Rs3 1 s4 P ss V s6 T s9 As8 E so V 6o G 61 S 62 G 63 Y 64 F 6s K 66 M 67.E 68 D 69 V 90

S 91 F 92 D 93 S 94 D 9s T Mid-molecule:

Zero

Carboxy-terminal: Replikin

Count

=

S6 L 99 G s8 K 99 1 8 o K81 1 82 A 83 N 84 E.8s K 86

Replikins. Zero

Replikins.

Number

of

Replikins

per

100

amino

acids

Example 4 Determination of Replikin Concentration in Publicly Available Accession Numbers for Isolates of WSSV from 1995 through 2007 [0155] Mean Replikin concentrations were determined for all amino acid sequences for WSSV with accession numbers publicly available at www.pubmed.com . The amino acid sequences were scanned for Replikin sequences of 7 to 50 amino acids comprising (1) at least one lysine residue located at a first terminus of the sequence and at least one lysine

=

1/204

=

0.5

residue or at least one histidine residue located at a second terminus of the sequence; (2) a first lysine residue located six to ten residues from a second lysine residue; (3) at least one histidine residue; and (4) at least 6% lysine residues. The total number of Replikin sequences was determined for each available accession number. The total number of Replikin sequences in each accession number was then divided by the total number of amino acid residues disclosed in the accession number. The result was the Replikin concentration. The mean Replikin concentration was then determined for all viruses isolated and reported in a particular year. Table 4 provides the results of the Replikin concentration analysis.

TABLE 4 WSSV Replikin Concentration byYear

Year PubMed Accession Number-Replikin Count 1995 CAA88950 18 CAA91970 59 No. of isolates: 2 Mean Replikin Count: 4.4 Standard Deviation: 0.6 Significance: low p < 0.10 1996 CAE17687 160 CAB03144 29 CAB03173 31 No. of isolates: 3 Mean Replikin Count: 6.0 Standard Deviation: 2.6 Significance: low p > 0.50, prey p < 0.30 1997 1998 ABA54417 48 No. of isolates: 1 Mean Replikin Count: 6.2 Standard Deviation: 0.0 Significance: prey p > 0.50 1999 2000 NP478030 361 NP478019 361 NP478001 361 NP477774 361 NP47775 6 361 NP 477753 361 NP 477809 361 NP477768 361 NP477523 361 NP477959 361 NP478053 361 NP478052 361 NP478051 361 NP478050 361 NP478049 361 NP478048 361 NP 478047 361 NP 478046 361 NP478045 361 NP478044 361 NP478043 361 NP478042 361 NP478041 361 NP478039 361 NP478038 361 NP478037 361 NP47803 6 361 NP 478035 361 NP 478034 361 NP478033 361 NP478032 361 NP478031 361 NP478029 361 NP478028 361 NP478027 361 NP478026 361 NP478025 361 NP478024 361 NP 478023 361 NP 478022 361 NP478021 361 NP478020 361 NP478018 361 NP478017 361 NP478016 361 NP478015 361 NP478014 361 NP478013 361 NP478012 361 NP 478011 361 NP 478010 361 NP478009 361 NP478008 361 NP478007 361 NP478006 361 NP478005 361 NP478004 361 NP478003 361 NP478002 361 NP478000 361 NP 477999 361 NP 477998 361 NP477997 361 NP477996 361 NP477995 361 NP477994 361 NP477993 361 NP477992 361 NP477991 361 NP477990 361 NP477989 361 NP 477988 361 NP 477987 361 NP477986 361 NP477985 361 NP477984 361 NP477983 361 NP477982 361 NP477981 361 NP477980 361 NP477979 361 NP477978 361 NP 477977 361 NP 477976 361 NP477975 361 NP 477974 361 NP 477973 361 NP477972 361 NP477971 361 NP477970 361 NP477969 361 NP477968 361 NP477967 361 NP 477966 361 NP 477965 361 NP477964 361 NP477963 361 NP477962 361 NP477961 361 NP 477960 361 NP 477958 361 NP 477957 361 NP 477956 361 NP477955 361 NP 477954 361 NP 477953 361 NP477952 361 NP477951 361 NP477950 361 NP477949 361 NP477948 361 NP477947 361 NP477946 361 NP477945 361 NP477944 361 NP 477943 361 NP 477942 361 NP477941 361 NP477940 361 NP477939 361 NP477938 361 NP477937 361 NP477936 361 NP477935 361 NP477934 361 NP477933 361 NP 477932 361 NP 477931 361 NP477930 361 NP477929 361 NP477928 361 NP477927 361 NP477926 361 NP477925 361 NP477924 361 NP477923 361 NP477922 361 NP 477921

Jul. 24, 2008

US 2008/0176217 Al 50

TABLE 4-continued WSSV Replikin Concentration byYear Year PubMed Accession Number-Replikin Count 361 NP 477920 361 NP477919 361 NP477918 361 NP477917 361 NP477916 361 NP 477915 361 NP477914 361 NP477913 361 NP477912 361 NP477911 361 NP477910 361 NP 477909 361 NP477908 361 NP477907 361 NP477906 361 NP477905 361 NP 477904 361 NP477903 361 NP477902 361 NP477901 361 NP477900 361 NP477899 361 NP 477898 361 NP477897 361 NP477896 361 NP477895 361 NP477894 361 NP 477893 361 NP477892 361 NP477891 361 NP477890 361 NP477889 361 NP477888 361 NP 477887 361 NP477886 361 NP477885 361 NP477884 361 NP477883 361 NP 477882 361 NP477881 361 NP477880 361 NP477879 361 NP477878 361 NP477877 361 NP 477876 361 NP477875 361 NP477874 361 NP477873 361 NP477872 361 NP 477871 361 NP477870 361 NP477869 361 NP477868 361 NP477867 361 NP477866 361 NP 477865 361 NP477864 361 NP477863 361 NP477862 361 NP477861 361 NP 477860 361 NP477859 361 NP477858 361 NP477857 361 NP477856 361 NP477855 361 NP 477854 361 NP477853 361 NP477852 361 NP477851 361 NP477850 361 NP 477849 361 NP477848 361 NP477847 361 NP477846 361 NP477845 361 NP477844 361 NP 477843 361 NP477842 361 NP477841 361 NP477840 361 NP477839 361 NP 477838 361 NP477837 361 NP477836 361 NP477835 361 NP477834 361 NP477833 361 NP 477832 361 NP477831 361 NP477830 361 NP477829 361 NP477828 361 NP 477827 361 NP477826 361 NP477825 361 NP477824 361 NP477823 361 NP477822 361 NP 477821 361 NP477820 361 NP477819 361 NP477818 361 NP477817 361 NP 477816 361 NP477815 361 NP477814 361 NP477813 361 NP477812 361 NP477811 361 NP 477810 361 NP477808 361 NP477807 361 NP477806 361 NP477805 361 NP 477804 361 NP477803 361 NP477802 361 NP477801 361 NP477800 361 NP477799 361 NP 477798 361 NP477797 361 NP477796 361 NP477795 361 NP477794 361 NP 477793 361 NP477792 361 NP477791 361 NP477790 361 NP477789 361 NP477788 361 NP 477787 361 NP477786 361 NP477785 361 NP477784 361 NP477783 361 NP 477782 361 NP477781 361 NP477780 361 NP477779 361 NP477778 361 NP477777 361 NP 477776 361 NP477775 361 NP477773 361 NP477772 361 NP477771 361 NP 477770 361 NP477769 361 NP477767 361 NP477766 361 NP477765 361 NP477764 361 NP 477763 361 NP477762 361 NP477761 361 NP477760 361 NP477759 361 NP 477758 361 NP477757 361 NP477755 361 NP477754 361 NP477752 361 NP477751 361 NP 477750 361 NP477749 361 NP477748 361 NP477747 361 NP477746 361 NP 477745 361 NP477744 361 NP477743 361 NP477742 361 NP477741 361 NP477740 361 NP 477739 361 NP477738 361 NP477737 361 NP477736 361 NP477735 361 NP 477734 361 NP477733 361 NP477732 361 NP477731 361 NP477730 361 NP477729 361 NP 477728 361 NP477727 361 NP477726 361 NP477725 361 NP477724 361 NP 477723 361 NP477722 361 NP477721 361 NP477720 361 NP477719 361 NP477718 361 NP 477717 361 NP477716 361 NP477715 361 NP477714 361 NP477713 361 NP 477712 361 NP477711 361 NP477710 361 NP477709 361 NP477708 361 NP477707 361 NP 477706 361 NP477705 361 NP477704 361 NP477703 361 NP477702 361 NP 477701 361 NP477700 361 NP477699 361 NP477698 361 NP477697 361 NP477696 361 NP 477695 361 NP477694 361 NP477693 361 NP477692 361 NP477691 361 NP 477690 361 NP477689 361 NP477688 361 NP477687 361 NP477686 361 NP477685 361 NP 477684 361 NP477683 361 NP477682 361 NP477681 361 NP477680 361 NP 477679 361 NP477678 361 NP477677 361 NP477676 361 NP477675 361 NP477674 361 NP 477673 361 NP477672 361 NP477671 361 NP477670 361 NP477669 361 NP 477668 361 NP477667 361 NP477666 361 NP477665 361 NP477664 361 NP477663 361 NP 477662 361 NP477661 361 NP477660 361 NP477659 361 NP477658 361 NP 477657 361 NP477656 361 NP477655 361 NP477654 361 NP477653 361 NP477652 361 NP 477651 361 NP477650 361 NP477649 361 NP477648 361 NP477647 361 NP 477646 361 NP477645 361 NP477644 361 NP477643 361 NP477642 361 NP477641 361 NP 477640 361 NP477639 361 NP477638 361 NP477637 361 NP477636 361 NP 477635 361 NP477634 361 NP477633 361 NP477632 361 NP477631 361 NP477630 361 NP 477629 361 NP477628 361 NP477627 361 NP477626 361 NP477625 361 NP 477624 361 NP477623 361 NP477622 361 NP477621 361 NP477620 361 NP477619 361 NP 477618 361 NP477617 361 NP477616 361 NP477615 361 NP477614 361 NP 477613 361 NP477612 361 NP477611 361 NP477610 361 NP477609 361 NP477608 361 NP 477607 361 NP477606 361 NP477605 361 NP477604 361 NP477603 361 NP 477602 361 NP477601 361 NP477600 361 NP477599 361 NP477598 361 NP477597 361 NP 477596 361 NP477595 361 NP477594 361 NP477593 361 NP477592 361 NP 477591 361 NP477590 361 NP477589 361 NP477588 361 NP477587 361 NP477586 361 NP 477585 361 NP477584 361 NP477583 361 NP477582 361 NP477581 361 NP 477580 361 NP477579 361 NP477578 361 NP477577 361 NP477576 361 NP477575 361 NP 477574 361 NP477573 361 NP477572 361 NP477571 361 NP477570 361 NP 477569 361 NP477568 361 NP477567 361 NP477566 361 NP477565 361 NP477564 361 NP 477563 361 NP477562 361 NP477561 361 NP477560 361 NP477559 361 NP 477558 361 NP477557 361 NP477556 361 NP477555 361 NP477554 361 NP477553 361 NP 477552 361 NP477551 361 NP477550 361 NP477549 361 NP477548 361 NP 477547 361 NP477546 361 NP477545 361 NP477544 361 NP477543 361 NP477542 361 NP 477541 361 NP477540 361 NP477539 361 NP477538 361 NP477537 361 NP 477536 361 NP477535 361 NP477534 361 NP477533 361 NP477532 361 NP477531 361 NP 477530 361 NP477529 361 NP477527 361 NP477526 361 NP477525 361 NP 477524 361

Jul. 24, 2008

US 2008/0176217 Al 51

TABLE 4-continued WSSV Replikin Concentration byYear Year PubMed Accession Number-Replikin Count No. of isolates: 529 Mean Replikin Count: 97.6 Std. Deviation: 0.0 Significance: low p < 0.001 2002 2003 2004 2005 AAZ29239 9 XP001681561 6 No. of isolates: 2 Mean Replikin Count: 2.6 Std. Deviation: 2.4 Significance: low p > 0.20, prey p < 0.001 2006 ABM92267 14 ABP01348 1 ABM64218 6 ABI34434 6 AB193178 4 AB193177 3 AB193176 6 AB193174 12 ABQ12866 3 ABD65308 2 ABD65303 1 ABD65302 4 ABD65300 3 ABD65298 1 No. of isolates: 14 Mean Replikin Count: 2.7 Std. Deviation: 2.5 Significance: low p < 0.001, prey p > 0.50 2007 2ED6L 1 2ED6K 1 2ED6J 1 2ED6I 1 2ED6H 1 2ED6G 1 2ED6F 1 2ED6E 1 2ED6D 1 2ED6C 1 2ED6B 1 2ED6A 1 ABQ12772 15 ABQ12773 3 ABQ12771 6 ABQ12770 9 AB069369 2 AB069368 2 AB500974 5 AB500973 1 ABQ44211 3 ABQ44210 4 ABP52058 4 ABP52057 1 ABP52054 5 No. of isolates: 25 Mean Replikin Count: 1.3 Std. Deviation: 1.2 Significance: low p < 0.001, prey p < 0.05

Example 5 Determination of Replikin Concentrations in 2001 and 2005 Isolates of TSV Publicly Available at Accession Nos. AAM73766 and AAY89096 [0156] The Taura Syndrome Shrimp Virus is less virulent than WSSV and the structure of the TSV Replikin Scaffold is less closely related to influenza virus than are the structures of WSSV Replikin Scaffolds. In year 2000, TSV had a Replikin concentration of 3.3. Between 2001 and 2004, TSV had a

lower mean Replikin concentration, as low as 0.7, and its Replikin Scaffold disappeared. In 2005 the Replikin Scaffold reappeared, with an increase in lysines and histidines, and a commensurate increase in Replikin concentration to 3.9, followed by an increase in TSV outbreaks in 2006-2007. [0157] Below is a comparison of the Replikin Scaffold identified in AAK72220 in an isolate of TSV from 2000 and the Replikin Scaffold identified in AAY89096 in an isolate of TSV from 2005. The TSV Replikin Scaffolds are also compared to two Replikin Scaffolds in H1N1 influenza virus in the 1918 pandemic and shrimp WSSV in 2000.

1918 H1N1 Human Influenza Pandemic 1918 H1N1 Human Influenza Pandemic 2000 Shrimp White Spot Syndrome Virus 2000 Shrimp White Spot Syndrome Virus kkvqanktrvfaasnqglalalrryylsfldh 2000 Taura Syndrome Virus AAK72220 kkacrnagykeaclheldcksfllagqgragah 2005 Taura Syndrome Virus AAY89096

[0158] The following analysis of Accession Nos. AAM73766 and AAY89096 demonstrate Replikin concentration analysis of amino acid sequences of isolates of Taura Syndrome Virus having publicly available accession numbers at www.pubmed.com .

PubMed

Code:

AAM73766

Description: Isolated:

2001

Source: Taura syndrome virus M1P2A3N4PsV6E7I8D9N1oF11D12T13T14T1sS16G.17G.18L19 120p21G22G23S24V2sT26N27S28E29G30S31T32 I33L34M3sN36D39

1 3.p39 1 4o T

41 N 42 Q43 N44 V4s V46 L 47 S 48 K49 N so V

L72L73H74N7sD96S99W98T

79S8oS8lD

Y 104 E 1os I 1o6 S 107 L 1o8 P 10 9 D 11o D 111

82D 83E 84I

1

si T

s2 D s3 Ns4 L ss Fs6 Es7 Vs8 Q so D 6o Q 61 A 62 L 63 1 64 E. 6s S 66 L 67 S 68 R 69 D 7o V 71

8sG86T87T88M89T9oQ9'E

92Q93L 94A9sT96E 97F98N99Q'ooP1o1H1 02L103

112 V 113 R114 K 11s S 116 L 117 F 118 M119 S 12o N 121 K122 L 123 Al24 N12S 1 126 Al27 Y 128

M129R130C131D 132Y133E134V13sT136V137R138V139n14 oA141.r142P143F144L14SQ146G147A148L149W1soL1s 1W1s2N1 s3

K1s4M1ssN1s6A1s9K1s8Q1s9T'6° S1 61I1621163R164 b R16sT166L'67T168E169H17 oL 171R172S173 I174T17SS176F177P178

Jul. 24, 2008

US 2008/0176217 Al 52

-continued G "9 1 - E 181 M182 N183 L

184 Q18s S 186 E 189 A188R189A'9 0

1

191 T 192 L 193 S 194

1

19s P 196 Y 197 T 198 S 199 E 200 F 201 Q 202 V 203

F 204N205P2 o6R207N208V209N210N 211L 212N213S2141215R216L 219S218V219L 220S221Q222L 223Q224G 225P226E 229D 228

V 22

E 23

°S 231 A232 S 233 Y 234 5 235 1 236 Y 237 6 238 R 239 L 240 K241 N 242

1

243 K 244 L 245 Y 246 G 247 H 248 A249 P 2So 5 251V 252 T 253

°V271H 292 A273G294.E 29 sD 296E 299D 298 s254s255v256Y259P258s259T26°Q261S262G263Y264D265D266D267C268P269 127

S 299 S 28o K 281 Q 282 G.283 1 284 v 28s S

286 R 289 v 288 A 2.9 D 29o T 291 v 292 G. 293 A 294 v 29s A296 N 299 x 298 x 299 D 300 G. 301x 302 6.303

V304P30513O6L3 07s308T 309 I310A311K312P313V314S315W316V317S318G319V320V321S322N323V324 A325S326M327F328

G 329 F 33o S

331 K332 D 333 R 334 D 33S M 336 T 337 K338 V 339 N 34o A341 Y 342 E 343 N 344 L 345 P 346 G 347 K348 G349 F 350 T 351 H 352 G353

V354G355F 356D35'JY358G3S9V36Op361L 362S363L 364F365P366N367N368A369137OD371P372T3731374 A375V376P377E378

6.379 L 389 D

381 E. 382 M383 S 384 1 385 E.386 y 3.7 L 388 A389 n390 R391 P 392 y393 M 394 L 395 N396 R 397 y39. T 399 1 400 R401 ta. 402 G. 403

D 404.r40SP406D40'JV408H409G.410.r 411I412v413A414 D b415I416P417V4l8S419P420V421N422 F423S424 L 425Y426G.427K428

* 429 1 430 A431 K432 y433 R 434 T 435 L 436 F 437,438 A439 P 440 V441 S

442 L 443 A444 V445 A446 M 447,448 N449 W 450 W451 R 452 G. 453

*45414 ssN4 s6L459 N4 s8L 459R46 of 461A462K463T 464Q465Y466H469Q468C.469R47 oL491L 492V493Q494y49 s L496P499Y498

G.479 S 480 G. ^

D

481 x482 Q483 P 484 1 485 E.486 S 48'7 1 488 L 489 S 490 Q491 1 492 1 493 D 494 1 495 S 496 Q 497 V498 D 499 D Soo K50l G.SO2 1 503

s04 1 sosAso6 Fs 0s b P508S509V51oY511P512Ns

13 Ks14W51s o Ms16Rs19V518Ys19D520pS2' A A522 K523VS24 G.525Y526 T S27A528

529 C.530 A s31 P 532 G. 533 R 534 1 535 V 536 1 53'7 S 538 V 539 L 540 *541 P 542 L 543 1 544 S 545 A546 S 547 7 S48 V549 S 550 P 551N 552 1 553

V554MSSSY556P559W558V559Hs6

°W61S62N63L64E6V66A67E68P69G'

0T591L 592 A593K594 A59 sA59615996598

F 599Ns8 OyS81P582 As83 DS84VS 8sPs86E.587 Es88Ps89Ts9oFs 91S592VS93Ts 94 Rs9s As 96P599V598Ss99G.600T601L602 x.603

.604L6osL606Q609D608T6o 9K610V611S612L613G614E61sA616D 617G618V619F 620S621L 622Y623F 624.E 62 sN626T 629.E 628

T629G63oR 631R632H633R 634L 635T636Y637 A638G. 639L 640p641G 642E 643L 644G645S646C647E 648I649V6S °K6S1L6 S2P6S3

Q 6s4 G.6ss Q 666 y 6s9 S 6s8 1 6s9 E.

66o y 661 A 662 A663 T 664 S 666 A666 P 669.E 668 L 669 x 690 L 691 D 692 R 693 P 694 1 696 F 676 S 699 E.698

P679168oG.681P682 K683y68W68sV686T687 K688V689K69oN691G.692 D693V694V69ss696i69'ls698E.699E. "lo oT7 oL"Jo2vUo3

T 704 C 9os G 906 S 9o9 M 9o8 A 709 A91o L

911 6 712 G 713 A 714 T 91s V 916 A 919 L 918 Q 919 5 72o V 921 D 922 E 923.E 924 1 926 E 926 1 929 L 928

K729L73oE731S732D733F734E 735S736K737 A738P739V'40K741F'742T743P'J44G745N'46Y747T 748V749V75oT 751E'J52 A'J53

5 954 D 755 V 956 E 959 L 758 V 959 T 76o N

961 Q 962 D 763 1 764.96s V 966 N 769 E 968 H 769 N 77o P 991 R 992.E 993 H 994 A 99s G 996 1 999 D 998

E779E78Op78lp782V783K784R78ss786x787i788G789R790179lV792R793R"194v"J 9sA'J 96A'l''ly"l98v"I''P800N8oK802 L803

I 8o

4R8 °5R8 0618 °' D 810 L 811 5 812 Q 813 S 814 P 81s C. 816 1 .17 Y 818 P 819 5 .2o T 821 H 822 A823 G 824 L 826 D 826 Y 829 5 828 L 8 °8R8° 9

S825830D831T832S833T834M835L836T837T838M839G840E841Q842F843V844S845L 846R 847M848L 849.r8s 0A851R85 26853

S 854 P 8

ss V 856D 859

Q 879S88oL881V882 N

1 858 L 85 9 R 86 °G .61

D 862 L 863 V 864 T 865 L 866 b P 867 G 868 1 869 S .7o F 891 G 892.E 893 D 894 N 876 5 896 L 899 R 898

N8831 - i -s -Y88 7888 Y887A89oE8'Lr892 H893 G.894S89s 1896589 y898K899I 90oI901P9o2 K903

904 K9os G 906 D 909 L 9o8 Y 9o9 1 910 T 911 T 912 T 913 5 914 P 91s D 916 5 919 1 918 E 919 T 92o S 921 T 922 5 923 A924 Y 926 Q 926 F 929 D 928

T929N93oR 931A932M933H 934Y935I 936N 937T 9385939E 940N941P942M943A944Q945i946S947L 948P949Y9S 0y9S1s 952P953

A 954 E

9ss N 966 L 969V9s819s

9 D 96 °S 961

K 962 S 963 F 964 P 966 Q 966 L 969 5 968 D 969 L 99o S 991 1 972 5 973 N 974 L 996 E 976 R 977 T 998

E979N98oE 981Y982F983V984L98sA9865987A988G989D99°D991H992T993F994S996Q996L 997A998G999C1000P1oolA10 02

F '°

°3T'°°4F1oosGloo6P loo '

° A1o11 A'° °8 E 1009L'°'

`G

Replikin Sequences in Amino-Terminal Portion of Peptide (1)

(2)

(3)

H1o2 L 'r3 y 104 E 1os l 'o6 5 i09 L 1o8 P 1o9 D 110 D i11 1 112 V113 R 114 K11r 5 116 L 119 x.118 M119 5 12o N121 K122

K332D333R334D33SM336.r337K338V339N34OA341Y342E.343N344L34sP346G. 347K348G349. 350.r351H352

K

338 V339 N 340 A341 Y 342 E 343 N344 L 345 P 346 G347 K348 G349 F 35o T 351 H352

Replikin Sequences in Mid-Molecule Portion of Peptide

Jul. 24, 2008

US 2008/0176217 Al

53

-

continued

Zero Replikins. Replikin Sequences in Carboxy-Terminal Portion of Peptide K'729L 73oE731SU32D733 ^.'J34 E.'J35S736K737A738P739v740K741 ^.'J42 T 743p744 G.' 745NU46Y'74'J.y'J48V'749V'7S 0.r'J 51E.'J52

(4)

A753S754 D 755V7 s6E. 757 L758V759T 76 oN761Q762 D 7631764T 765V766N767 E. 768H769N770p771R772 T 773 H774

K729L730L731S732D733F734L735S736K'737 A''38P''39v''40K'41F'742T'43PU44G.4sN'46y74'T 748V749V''50T 751E'J52

(5)

A753S754 D 755V7 s6E. 757 L758V759T 76 oN761Q762 D 7631764. 765V766N767 E. 768H769

893 G 894 S 89s 1 896 5 897 Y 898 K899 1 9oo 1 9o1 P 902 K 9o3 N 9o4 K 9os

(6)

H

(7)

K89919ooI 901P902K903N904K9osG906D907L9o8Y9o9I91oT911T912T913S914P915D916S 9171918E919T920S921T922

S

923 A924 Y 92s Q 926 F 927 D 928 T 929 N 93o R 931 A932 M 933 H 934

Replikin Count = Number of Replikins per 100 amino acids = 7/1011 = 0.7 PubMed Code: AAYS9096 Description: Isolated: 2005 Source: Taura syndrome virus M 1A 2 S 3 Y4 Ys L ' N 7 1 8 K9 T io H11 N12 L 13 R 14 R

is T - P 17 G.1. A19 H 2o R 21 A22 F 23 Y 24 V 2s M 26 N 27 D 28 D 29 G. 3o E. 31 N32 R 33 1 34 Y 35 S 36 L 37

138G39T4 oL41R42R43A44P45A46F 47K48V49G50Ss1R52R53Y54KssSs6H571s8Ps9Y6oR61R62K63 A64T65V66A67E68L69C90

N

71 Q 72 L 73 H 74 D 9s R 76 V 77 L 78 P 79 F 80 A 81 N 82 P 83 Q 84 V 85 W 86 K87 E 88 V 89 1 90 S 91 E 92 N 93 K94 V 9s Q 96 P 97 D 98 S 99 M 1oo L 101 K102

A103A104F1osG1o6N107w108E1°9E 110W111P112K113D114K115V116 C117E118E119L120y121S122E123C124E125C1266.127

Y 128 V129 G 130 T 131 C 132 Y 133 V134 S

13s V 136 D 137 W 138 L 139 R140 P 141 n142 A143 T 144 K145 C 146 N147 D 148 C 149 1 150 L 151 K152

M153N154R155N15 6V157E1s8Y1s 9P160Y161H162T16311646.165V166 S 167G168N169V17°V171T172N173T 174D17s1196V1'9

Y 178 T 179 G 180 Y181 A182 D

183 V184 F 185 K186 C 187 E 188 K189 C 19o D 191 L 192 L 193 M194 G19s A196 W197 A198P 199N2o°D2 011202

P203 A204L2 o5T2 o6H207N 20812 o 9R 210S211S212Q213C214V215Q216F 217K218L 219P22 oT 221E 222N223L 224 A225A226R227

N

228 Y 229 V 230 L 231 L 232 0 233 E 234 E 235 1 236 E 237 R 238 E 239 N 240 1 241 P 242 V 243

1

244 F 245 n 246 D 247 Y 248 S 249 E 250 6. 251 N 252

V253F254T255C256R2S7I2S8V2S9S260G 261D 262L 263.E 264 A265V266G267T268A269S2' oNN 271M272Y273T 274 A27 sR 276D 277

V 278 A279 S 280 K281 S

282 L 283 L 284 D 28s Q 286 L 287 H 288 N 289 T 290 P 291 N 292 V 293 H 294 M 29s H 296 S 297 L 298 H 299 S 300 L 301 P 302

Y303E304N305F306P307C.308E.3 O 9A310L 311E312F 313 A314V315E 316Q317G318I319I32Op321p322V323T 324F325D 326E 327

V 328 F 329 A330 N331 D 332 E

333 Y334 V 335 1 336 T 337 1 338 S 339 C 340 S 341 b L 342 L 343 V344 V345 S 346 D 347 V348 G 349 P 350 T 351 ^ 352

A3S3V3S4A3 ssR356E35U A358A3S 9A36OK361R362 F 363 L364 K365M366Y367 D368Y369S37OA3'7153'72Y3'73P3'74S3'7 sT 3'76 b H377

M 37. F 379 T

380 L 381 S 382 T 383 L 384 P 385 ^ 386 R3.7 5 388 G.389 E.39o T 391 L 392 E. 393 L 394 A395 N 396 A397 T 398 L 399 N400 H 401 V402

N403 N4o4V4oSI4 O6D4O'J R408H4 o9D 410 b E. 411A4l2I413S414 N41SV416R4TJQ418N41'v42 oE. 421V422K423 L 424.r425D 426V427

S

428 R429 ^ 430 V431 G. 432 A433 M434 L 435 P 436 K437 V 438 E.439 T 440 V 441 1 442 DD 443 D 444 V445 S 446 S 447 7 448 L 449 S 450 S 451 x. 452

R453 G.454U V 45SL456D4S't K458I459S46oA461W462M463P464S465 ^ 466N467P468K469I47OI471D472 L47314'74K4'75E. 476.477

F478V479S480L481 x.482F483A484I48sL486T487 K488S489L490Y491P492i493i494Q49sG. 496I49'IS498S499Ys00AsO1Ls 02

R503 Ns04NsosLso6M5°9As08Ns 09H510L511T5 12 As 13Ls 14Ss15Es16Ws 17Ls18Ms19 `TT 52 o L 521 E 522 Y523 D 524 S 525 P 526 D 527

E 528E 529E 530M531P532S533T534H535G536F537M538D539D54 oL 541T542S543R544L545P546G547L548N549G55°Ass1Ks52

u553Q554Asss Ass6Ts57 Iss8Yss9E.s 6OS561I562 G.s 63 Ts 64 Gs6sfs66C.567VS68As6'L57OS571G.S7zl573 L 574557 sF 576I577

A578V579Ms8o Cs81Ls 82 Gs831584TsssDs86Ls 87 Ss88As89Vs9oTs91Fs 92 Ns 93 Ks 94 Ls9sLs96Ts 97QS 98Ss99S6o0L601V602

G 603 R 6o4 A

6°5 L 6 °6 V 6 °'G 608

V 6o9 R 610 S 611 F 612 K 613 D 614 V 61s F 616 F 617 6 618 1 619 W 62o D 621 Y 622 V 623 D 624 N 62s Q 626 V 627

c628E 6291630L 631Y632G 633K634S635R 636K637N 638L 639D 640L 641L 642K643E 644Y645P646S647L 648D 649S650L651L652

S

653 1 6s4 F 6ss N 6s6 Y 657 F 6s8 H 6s9 D 66o T 661 V 662 D 663 A664 N 66s V 666 L 667 1 668 S 669 C. 67o N 671 R 672 A673 A 674 C.67s E. 676 L 677

L678V679K680A681D682N683L684Y68s^68li G.68U Y688L689D690 K6'15li 921693 6694 L69sM696Hli 9U Rli98E.li99I'l0os'bls'loz

R 7o3 L 7o4 K 7os E 7o6 A7oe R 7o8 N s09 S e10 VG 711 K712 D

713 L 714 1 71s A 716 K717 A 718 Q 719 v 72o Y 721 L 722 T 723 C 724 G 925 D 726 6.727

S728R729V730P731P732V733V734V735Y736M737y7386739D740A741G742C743G744K745T746E 747L 748S749M'

° A ' 51 L '52

Jul. 24, 2008 5^

US 2008/0176217 Al

-COT1t11Auedy7D15a7z 63v464 p465 K966 K969 D76aV Y 96

^

s5 7s6 A57 V7sK7 9 a3

y3 824 MBZS s 8268820

479 79 oA991-r992D993 D494 'j

753D454 x7

9E§

gas

5786087K

^ ^ B ZZ a

I

s

17 817 D819 420 821/

7

o 7s Eas7w780 D7slGo BZ0 K Q

E 6o3Kao 4 p805N06p807 4

^

E80S

839 o4-V 841E342A843.r 844 C

^

8 3 8ÌaV87SK8O6DI471

s64 865Ra66Ls67D86aL66gCsgyovao1Y87v a62Fa 63 R

a 6o E61

sea E&1Ia6zÊa3 has

§ gi v

92 s93C+ B Eo GasEHsa 9Re9°K910a P K

338 939D940 A941 Q

R43 K

X965

X96 4

7^

H966s

L9 R

+98z E 9 a3 L 7a. 979898009 ri ^

1D1 3

103E p103

yo 3l3-0x§N 1DeB 1os 1 10-

0

`G

10§

^ §p

a 1060 V 71o5EE,3-o5y 3-096510=5

107 5

W

^

^

^

R o 1 s2a

111 7 N 1 q1E g

2 1133 113§

1o5K^

1126I11270y1128 S11z9A113o 111]4113 I 2 /^ 1153D1

146R114 ^

1149 K1150I115 B V114a 8

1143T1144 K11§5 C1

y1-

1171 ^

^

189 11888 1185 ^ 83-163 01184 R

y18 9

E 1a23I 122 4

1121 1122

11V7

1173 117§K1 C

175R

s

2140 121301

1012

Z

11

gz

1201 1202 R

i1g9D12oa

^

1 21 122 2

V

12171uEV121°H122aH ° S

1 21=51 21 0

2 1241 124

D

12 36 1237K1

P

23E E1239 Ei1240T

60v1?611262

1 y232rr1233v1234 H1235s

1350 1 ^

23 P

2 122 81229nEy23o Al D 12 2 6 012 2 C

16oy1161V

N

1y96 1197 p11gE

211A

Q^

U19C'1180D1181 L

1193 T 1y 9 §T y19s E

1207 1209 r1210 1 I 206012070

5711 15 EM1159

117711

SS1190 191 ^119

R1203v1204 Al205 81 v'

1146511

117

117zL

N

11aR

^ 15§ ^ 11ss

L

.1163V1164R1165Sn 66116,14" Gayf1169 A117o ff

112

H-y41 -•1142 113"011¢Oy 1136 1137 C113E X S 1162 ^ 35V

1110 y111I1112N R

5j,o34VD4C

3-3-2 413-2=V p

oa Ailoll

2

i113D1114F111s 61"6 K

6 os5M1asD 110 9 1o6N1107 xj1l09ld.p

1962

1761

096 1097 S1ogEAi og9 Qi

5 1o66Tyo67(^ yo6aI1o69T 109 oD loeygzo9zKzo93 s 3- o94 10 9E L1o63.p1 ossw1a6 M N108351os40

s1 Io4z E

1093- 1 108

1f`7a 1o71KzonzElov3 lo

1oaoKsoEaSyoE9I

10 °A1'40 s

1oss1os9y1oeap 1 0 76 g 3-°'B0

N

1047 n1049R10500

y1 o44D10§S yp§6L

1e 1o2a 102103-022 T

y034 s3-03501036F10371

4 3-n25p1f` z6N3o27510zaRzpz S

^

201 1002 996w997 F

Azo14 B10 1s s

yo 1 FN y0 p2 E 1o l P

g 3-D3QAl031NozD1p33G

L 1a 43

Ì4

1oy6 Y1o1701o1N1o19K

Q9a6 E

D3003W1oo4L1oo5 G1oo6D1ooz Flooa

EA 1023 1o2

97=579'J6Lo'J'J

v

90 9912'992993 9940 V

9

D loo9R

9

99a n999 ^}1oo0A

Q

P

949095O0a1N7s2

D

D 99

956 957095ag9e9R" gg4 5 98 5

E 941.p

K969 ^ 90o

967

61 96zV 963

o

S

94

fl

73

48

7 g44 9450946 A94 q D

M

33 934/9357 936L D

Ag 2°

g2o 9211922,r923p9z4E9z-1726

9220 93 E I

904 05K906rf 9O,QS,BH7o7O

32 E' 9300931090

ê 8 94 Ea95n896Kg97Is9a

914 915V914 X919091a.^919 VK

910 911 K

G^

9oz `d ^ e99L9oog9o1n

^ R

S

E.87s F a7 9 p R

Ss3 L9519s5E

950

a3spa3Es

^

x 757 Sae9A aBSD sa6

923 ^r 929

r s51

â

S09 rn 70E

.gs3pa54 Ks55as6Ia57

,N 903g

^ 8 pa §9 G8 '' 45 a§6b a4 7 N s4

gyl e1Ia13 8814 L71N716N S

1Aa32N833.r834Fa3I836 a2Tj 830 Ke 5789 8 5_B

7eo

995 496 997 179EV7"9O6o' Ss01 AEO2

61 76257 7 G

0

oz 3.IC74 p o77av E6N R

253825§125sp 1 N

A 2

1256 1257E125E5 P

1yg1

1 282

K

a 1290

^-'2S

Q 1273V1274V1275E127651217 121E 121-D 1 p0

5124311244012§D1246P1242 T124a p1249E1250Al251K

E1zs3

65 5 126 4 R1z

q 1267 z69 R 3-, 66D129 V

s6 I128 12

13p 6

- I

9s 1z96 ^ 1297 E`

22995129 9 0

Q 320

132yP13

22

1314 1315D1316E13178131E A1319 K1 N

1313 H 1312 310 1311E"'D1

130 , H

y30 9 Q3-

3oa

q 13255132681322 e32sp1329D13301r I

n1349D1350

3-7465134k

y 35 3 1351 1352N ^ j

136 2

b

T 137

1355 135651357 R135EN135913600136R

135 4 1 R

L

1381 1352

1375 1376jk137

2 ^13

6a 1369L1370Y1371 3-36951360' 3

73 73 137 40 G

F 1396 1397^139Ev1399S1400I 1401 A1402 1421 Ci 141Ev1419 rP1420 ^r

E,+1389D1390 013910139 N 1389 138 M

1370 13800 R y 13 1 EG

139§ 5 1395 13--

2 U363Y1364v1365p

3 Q 1335rP1336 D13371,133s C39T1340 E134161342

y3 ny332V1333E 1331 ` ^

571303R1304013o5K

I1323v132 E'

3- z

^

L

-

n 1301D1302

A 2 9 3 1 1 294 0

vyzea Elzs9S1z9oT1z

p1233e234 D1285 jj

7

1371 A V 1370 K

422

417 I

7

1415 1416 K1

14411442 K D

I 13a5 K.13860 ,,138301384 p 1403 K1404 ^+1405N140.r 140^R140a^1409H1410V1411K14121413 4^4s 1435 1436I143751a38 3- 39R440

j 143001431 E1432M1433G1434N 3-45 145rP1457 G145EM1459M146°6146161462 D

2

^,1423Y1424 E1425V1426D142211423 ^J142'I

y453p1454G

L

1401 1482 147

C145

51446 F1445 p1448.r144901450 1451 E145 L 1473 1474A1475 S 1476Dy477S 1

144371444 S144Y

1469 1470 A1471 K1472E 1494 ^

f(

1 y 4o2A93 ^

G1463R1464M1465 R1 466v1461 F1468s

Y495

14_ 0 ^r ^ I K149 1483p1484 Q1g85D1486F14a9v148a A1489

M

15oa ^,,15o9I

b1535

1906SbsU V p15o3E1sos K1so.K

^

r ^ 1499S

152 2 a 1520 521^ ^ M `d =17151ED1s1-C S

^1516E1

r.'1513 E151§E151s 1511/ ^1512 14

1517 R

1500

24971149

D 1496

154 2 1540 1541E

13

7 A153EK

3-5368153 34 S

2 N 1533 15

T1s5EI 15z9Vy3o01531p153 5 =96 Q 1=9' 2 z5 F3 ^1 54F 1555 A 7 py 52 q a

G12301sz4C15a5 426 19O 01543x1`'4401545 A1F461542 F1543 D1549G+1550.r1551 ^y

A15 5 R

1 1560 1561 E156`L

165 9 T

Jul. 24, 2 008

55

US 2008/0176217 At

^ lszv.flszsssv9F15soP15s1Hieaz

n

t lu 6 co 1ss5jLleC iss3G1co R

K

1595 1599K1oo.P16o1 Fya6o2

1szo1sz1R1soz

T

s 1s66Azs6aT156aP1s9T

a

61 ^ sL 6

V

6y 6za

1e2 2 4 161aF1619 P

R

g 1 e4oMy 64y ^('

I

1'1z 161_p S

64z

1636 163aK163s163 A 3s L

26 6275 1631 1632E1633N1634 L16

H1660 1

661V166

2

D

T

61629p 1

1656 16 sa C165aV'6s 9

r^16z 5 j^16 a 1649016525651 E1652D16s3

,.1623 A16a4P16a5 16z 6

V

M 1614 161sN1616 y6 ^

is as RlI56O15az515a s P1ss9y190 1s 91N1s9z

D 1

s 9 s A1s9s 1sg65zos

1s93

6

65s

016 s4I

16s1 E6a2 s U'6 9116 D 96 1694 V16 4 6

5K

02

01

y6 s 1699 Ssoo.r7 S17 16so 1651 S1syzD1sz3V16y4E R V 169z 1693 My694N169s 1696U16975 zW1v21J,zz Kss63R1664I16s L16eN166v Ay66a1669G Y 1s Q1739Ty ^ 1es9 1s92RR691Q 1a 1aK1 ^ 151s 51`116G N y ^ 39 1']4oI1741v1742

V1643T1644I(,445N16S6v1645E

L

1sa3 684I,68sT16a6G166Ì 16aaE

1jy1

1 `] 1z I(1 `113 G1`114 r

't36 HV 1`t3aE

s A1']03G1`t04F1205Py3 p61r130O r^ry30a S11'12911'l3 N731P1132D1`133

1 ^ as 17zF1

4

^

za l l^ zaV

D lzso 1as1V1a52Sas3 D

4aI1'J 49v D1, ^

^ R1a 6s R1

sa s4 G1z5s 1o56 F 1oaz L loy6Rya so Ylzzs Flyo9A2z ao y,415

E1 ^

1a 9s 1796F1zs7D1z9sD1z99K1822V1821Klaoa

69 Kz ^ aov 194

DNlsoa 5y5o9l1510 Gy1

1a16Y&19

^

N

8 D1839 F1a40 S1841N1842

^

9 1832D183I(1 a 34,j1E35I1a36 163 183

faos 11e o6O1eo az3R 826 1a K'1,1aza K^

1830 183

1 G

V

lash 5185'I lss s ^

1

yeso I

ael

1e9e 1e99 Sy9oo Gy9osN19oz

,472R1B7 aw E1e6aN1a69G1a0oL1aa1I

Ste , Dia94 N

^ p,^

1891 1s9

Y1s6361864 D1a6sjj 6

9a3A1924 Q

19 z5R192sE

C

19-B 1939N1a40^1941 A194^

C.1943I1944 F1945

Y 194

9^ 1936 F 193

3 `f

S33193R 619350+ 53211y

1949 194aD 1906 S 1?oM1 6G D

19za

i914I191sI1916F

6oNc19s1g1g6` 1965 5

19s9E19

4 1955 195K195^V

a

N

1 y91 191s ^r1919 `J1°zoY192

^

152 Gv1929F3°30P1931 M1 1927

^

1e_'

1909 91o1911Y191zN1913 i v

P1o3 y19

^

1s9s

2 Q159_

F

1sa4w1aesLleasMleazNleaaGlas9KzaaoV U 1 9 ° z llyoaN

1a6a

lsaz 1saxaa4TlSy Llaa6 Lzava i87 y1ea9Lyaso FlNleaz

^,1843D1a44G1a45s1&46L1940 N184a r^1843Q

Aisa3, ^

^

assY 1es9 Tyap0 D1e61

1as11g5zg1as3 Ryas4

N

24119os T19 os

y ^182 `

r 191sY1919 D18zo

^ ^ 161s

L1s1z ^11V

.N1493 ^

R1823I1824 ^j 182

^ 1az

^r149-Y 1a 14

199461995 X14 a6A19 a4 X19 as A1959L199oR1791R199z

T1ao3N1s24 R

K 1v 5o Ayz ss Ayys9T17°U''6

11a1Q1av2Asas3N11v4 Kizv ,

6a Ly ^ 6a

e6P1 ^

3 762

E1

^

j1 ^ y3K274 p1' 4 K1`l46D154'J('

D1o63E1a64

133 L '13 4 K

^ A1^ 2A1- VT ^9 4G19

K1996E1 990 yr194a ^

^ 1949D19s 2

s

1

981 1952

T

200 1 E

zao2

1996 1996T199,Fy99a L1999Z(z 000R R1 - L zozz V o D zoz 1M .N1963 Q1964K 96V 9eI196z 196a i991 5 1992y1993N1994E p1s 2 o19Ezaz s9Z,f °925 I 2 zolsRzo16N2o1y T 1965 P zo4a T 1^ sP 19s ^ P vz 19e4 196'6195 zo 1 zP zo13 p3 Q2o3aT2o39 za4oRzo4y1 C K198 3 S a10 za ll A ^ ^ zoos F H

2oa6 D Ezoo3Yzoo4 Lzo ø22

I

zao9W

zo33 Dzo34 Azo3s

p2 2p2 a Nzoz9lz

030 2 031A2

D

yz

36

Lz

o_ a

32

zo5s os6zoso g

2 os9 D C

ao 6o ^j

zosy l

zo62

^ 2ozsR'K o 4 0 2 as S ozsLz oo9D2°s°C2os1K oa so Ez KzoszNzos3 Yzos4F x zoos Ezo46p?p4''gaa o4aoo5l 2oLz 9 zloa Ez zo99 L21oo SzloyQ `rz D23Pj 4 zool zoazEzos3Az oy 4 C 20 ^ s Lz o ^ 6Hz o_ s Azo43sz F zo 90 E 2 F $ o 94.14zo 9s Dzpg6 zo63Kz o64 Azo6s Czo6Ro6sN2 o6apzos9 GroaoY zo9 K zo9z Gz93 Az

zo ^

K z oa6p 2

oas 2 osa Q2 os Q

9 G ro9o R

52083F228Ayzoas T40 ^41R42 R43 A44P45 A46F4`!I(48^49 ^5(1 z1o4 z1osl,zyp6N21o

D

Lz1o3L

Reh

P pZ't lOn O^ Pept1.de

^

a 39

32K71K63R33I34Y3ss36L39

quenceO liY.in S e E

ao Rzlpz z

Yi r5M 6Nz Ds9D6 56 sv l , sp Y

ea D69 CzoalQszLoxz4 ^

Se

, 4 GIs S Rs5 R5 y54K5s s

E s6 gsy saP59 Y6o R61R62 K63 6464V 6s I

aV49 Gso551RszR53Ys4j(5s s6H (

^

((4) Ks 55

s6K5

y I5 ^Psy Y6 R R66

K63 A64 T 6s v 6 6 A568U

ao A8 K2p8 Q84v8sWs6 Ka7

9a D8P 99 F

Asz Esa 69 CyoN Q D ( (6)

H^^ I a

59 E9zN9aj(94A64 T6sv66

96 P9v D9aS99M1ao Lsall(y oz 9e V1'ooLlo1 oz 93 K94 ^ 9s 4 Is P59 Z,eoR61R Qp 6D ^ a S K ^ 9s 9 91 91E92N93 Ka4• 899,S a3 B4 g5wa6Ka7EsaV a° I 90 S EOZN EaE ^ AelN sz P aQ a Nz4D7sRa6Uza LaeP72E 8o g5 ws61{es EsaVa°I9Dg 9122593K94 2V aoAelN' - P

Ea g

(71 (a ^

3H z4 DssR6Vva LasPzFso A1N82pa3 Q44v85ws6 Ka,

g^

^4 ^sR^6v^^Lê

(9 ) K D

P ^ 9F

Jul. 24, 2008

US 2008/0176217 Al 56


K

14s c 146 N 147 D 148 c 1 49 1 16o L is1 K1s2 M1s3 N1s4 R 1ss N1s6 V 1s9 E is8 Y1s9 P 16o y161 H162

K46914701471D472L4731474K47 E476T477F478V479S48 oL 481F482F483A484I48sL486T 487K488S489L490Y491P492 1493i494Q49sG4961497S498S499YsooAsol Ls 02 Rs 03 Ns 04Nsos Lso 6MS07Aso8Nso9Hslo

(12)

K634S63 sR 636K637N 638L 639D 640L 641L 642K643E 644Y64sP646S647L 648D 649S6soL6s'L 6s2S6s316s4F6ssN6 s6Y6s9

F 6s8 H 6s9 (13) (14)

K

H697R698E6991700S701S702R703L 704K7 osE. 7 o6A707R7 o8N 9o9S91oV911K712

Replikin (15)

637 N 638 L 639 D 640 L 641 L 642 K643 E 644 Y 64s P 646 5 647 L 648 D 649 5 6so L 661 L 662 5 6s3 1 6s4 F 6ss N 6s6 Y 669 F 6s8 H 6s9

Sequences

in

Mid-Molecule

Portion

of

Peptide

K7 osE 7 o6A707R7 o8N9o9S91oV911K712D 713L 714171sA716K717 A918Q919V920Y921L722

.E 9230.924G

72 sD 726G9275928

R'729 V'730 P''3IPU32V'J33 V'734v73sY736M'737y738G 739D 74 oA'741G.''42 C743G.'744 K74s T746 E747 L748S 749M7S OA7 S1L'JS 2

Q 7s3 D 7s4 H 7ss (16)

(17) (18)

(19)

H7ssF7s6A9s9T7s8K9s9Y96

H

(21)

(22) (23)

(24)

762E 963V964P96 sK766

7ss F 7s6 A 's' T 7s8 K 7s9 Y '6o F '6i G ' 62 E ' 63 V ' 64 P '6s K'66 K ' 6'

H7ssF7s6A9s9T7s8K9s9Y96 oF761G762E963V964P96sK766K767D'68V'69l99oy99lS9'2R 773K774

H

F (20)

off. 7616.

7ss F 9s6 A 9s9 T 9s8 K 9s9 Y 96o F 961 6 962 E 963 V 964 P 966 K966 K 967 D 968 V 969 1 990 y 771 S 772 R 773 K774 A 77S E 996 N 777 E 778 779 W '8o D 781 G 782 V 783 K 784

K 's9 y 76o F 761 6 762 E 763 V 764 p 76s K 766 K767 D 768 v 769 1 77O Y 771 s 7J2 R 773 K "I"I4 A'I'IS H.'I"I6 N 'I"I'I H.'I'I 8 F ''9 W ''8 V '83 K784 Q 78s 5 786 H 787

o D 781 G 782

K766K767D 768V769j7 toy771S7 J2R"3K774A77SE776N777E778F779W78 oD '81G'82v783K784Q'8Ss' 86H787

K

'67 D '68 V '69 1 S9

°Y

991 S 792 A 973 K 994 A99s E S96 N 979 E 9'8 F 999 W 98o D 981 0 982 V 983 K984 v 98s S5 '86 H T87

K004A99 sE 996N999E 998F 999W98 oD 781G.'82V983K'84Q98SS986H789

K004

`G

A99S E 996 N 999 E 998 F 999 W 98o D 981 0 982 V 983 K 984 `Q G 98s S 986 H 987 K988 1 989 1 990 A991 Y 992 D 993 D 994 V 99s L 996 ^ 999

1798V799D80oS8o1A802Q803K804P8 0sN806P807E808L809F810E811F8121813R814L81sN816N8175 818D819P82o`y82' Q822V823H824

(25)

H

8 s8 S 8 s9 A 8 so D 861A 862 F 863 R 864 R 8 ss R 866 L 867 D 868 L 869 0. 87o V 871 y 872 V 873 D 874 V 87s K 876 D 877 E 878 F 879 A88o R 881

i882V883 A884 G.88sS886K887G888H889R89oK891V892P893C894E89sn896K897 I898W899L900H901n902N903P90409os G G K9 06

(26)

H

8 s8 S 8 s9 A 8 so D 861A 862 F 863 R 864 R 8 ss R 866 L 867 D 868 L 869 0. 87o V 871 y 872 V 873 D 874 V 87s K 876 D 877 E 878 F 879 A88o R 881

1882V883 A884 G.88sS886K8870888H889R89oK891V892P893C894E89sn896 K897

(27)

K

887 0 888 H 889 R 890 K 891 V 892 P 893 C 894 E 89s n 896 K 897 1 898 W 899 L 9oo `H 9oi Q 9o2 N 9o3 P 904 G 9os K 906 T 9o7 Q 9o8 H 9o9 D 910

M 911 K912 H (28)

(29) (30)

(31)

913 E 914 1 91s t/ 916 A917 G 918 T 919 `y 92o K 921 1 922 T 923 P 924 E 92s T 926 A927 V 928 y 929 E 93o L 931 H 932

Ks87 G 888 H 889 R 89o K 891 V 892 P 893 C 894 E 89s Q 896 K 897 I 898 W 899 L 900 H 90i

K

887 0 888 H 889 R 89o K 891 V 892 P 893 0. 894 E 89s n 896 K 897

K887G888H889R89oK891V892P893C894E89s `Q G 896K897 I898W899L9tioH901n902N903P904'9osK9n6.90Ur9 o8H909

K887°888H889R890K891V892P893C.894E89J `rG a 896K897T898W899L9vnH9o1 `Q9o2N9o3P9°4 G.9osK906.I,90'7 `Q G 9n8H9o9D910 `G `G `G

M911K912H913

(32)

H

889 R 890 K 891 V 892 P 893 0 894 E 896 Q 896 K897 1 898 W 899 L 900 H 901 Q 9o2 N 9o3 P 904 0 9os K906 T 907 Q 9o8 H 909 D 91o M 911 K 912

H 913 E 914 1 91s V 916 A 917 0 918 T 919 Y 92 (33) (34)

(35) (36)

(37) (38)

(39)

° K921

H 889 R 89o K 891 V 892 P 893 C 894 E 89s Q 896 K897 I 898 W 899 L 9oo H 901 Q 902 N 903 P 904 G 906 K 906 H889R890K891V892P893C894E89sQ896K897

H

889 R 890 K 891 V 892 P 893 0 894 E 896 Q 896 K897 1 898 W 899 L 9oo H 901 Q 9ti2 N 9o3 P 904 0 906 K906 T 9o7 Q 9o8 H 909 D 91o M 911 K 912

K891V892P893C894E896Q896K8971898W899L900H90'

K

891 V 892 P 893 C.894 E.89s ^ 896 K897 1 898 W 899 L 9oo H 901 Q 9o2 N 903 P 9n4 G. 9os K 906 T 907 Q 9o8 H 909

K891V892F893C894E896 `Q896K8971898W899L9o0H9o1 `Q902N903P90409osK906T907Q9 o8H909D91nM911K912H913

891 V 892 P 893 0 894 E 896 Q 896 K897 1 898 W 899 L 9oo H 901 Q 9o2 N 903 P 904 0 906 K 906 T 907 Q 908 H 909 D 91o M 911 K912 H 913 E 914

K 1 91s V 916 A 917 G 918 T

919 y 920 K921 1 922 T 923 P 924 E 92s T 926 A 927 V 928 y 929 E 930 L 931 H 932

Jul. 24, 20 08

57

US 200810176217 At

–contin

ueC^ '

of 9o2N903p9o4G9 o 5K9 26 K92

e9sWa99Z9o99

(40)

Q

900 9aaH9a9 K906T Q

o1 9a2 03p9o4G9os

I

K9z Ie9awe99

9 L 9ooH

Q

N

g11 91zH9

904 9os K9 o6T9o

41)

0

914

^

A917 G91eT9y9y 9z 91s ^ 91s

Q9oaH9a9D910 M911K91zH913E I

92 Ie9aWe99 900fl20*Q9o2N9a3p (

13

Q9asH9a9D91oM K

^

G 9os 906T9o ^

K ( 42)

Y9z9 E93o L931H93z

zz ^ 9za

900H 90 zQ 02 (43) X89 Ie9tiwa99 L T K921 922T923 p9 24 E^

91y

91 z G9 18T9

H901 Q9 021YUOp904G90s K2 (44) go4G- K

o 921 19 y 9° g

9 oM911K91zH913 E914I91sV916 A91v

90 T 90 Qa9oaH90

D^

H901Q90259o39 (45)

4

K9 o5T 9

(()

H

TQ

^90 Q9oaH9o9D910 M911 g91zH913 E914I915V 916A G

oo

E93, 9318932

(48)

yl 909D

(49)

q19 918 T 919,r92oK921I922 T923p924 E92sT926 A924^92a^9z9

^ H90^ D^^1 M911j( 12"913

_o

K9°

(47)

Q9

916 91^G91aT919Y92oK9zy 1zH913 E914I915^ A

9y0 [Vj ° j(9

^921

H

16 91z G91aT919 Y9zo

926 9z ^

V9za1,9 z9 H

931 932 93oL H

^

(59) j{912H913Ei'914I9 15

11365113 ^

1 A91zGo1aTR19Y920K921I922T923p924g995T 30L 131L1132I1133G1134G1135

Vo 1145 `+11468114"1 tJ114 8 114 9 K.11'