Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

Filing 325

DECLARATION re #322 Objection in Support of Defnendants' Opposition to Amgen's Claims Construction Brief by F. Hoffmann-LaRoche LTD, Roche Diagnostics GmbH, Hoffmann LaRoche Inc.. (Attachments: #1 Exhibit T#2 Exhibit U Part 1#3 Exhibit U Part 2#4 Exhibit U Part 3#5 Exhibit U Part 4#6 Exhibit V#7 Exhibit W#8 Exhibit X#9 Exhibit Y#10 Exhibit Z#11 Exhibit AA Part 1#12 Exhibit AA Part 2#13 Exhibit BB#14 Errata CC#15 Exhibit DD#16 Exhibit EE#17 Exhibit FF#18 Exhibit GG#19 Exhibit HH#20 Exhibit II Part 1#21 Exhibit II Part 2#22 Exhibit JJ#23 Exhibit KK#24 Exhibit LL#25 Exhibit MM#26 Exhibit NN#27 Exhibit OO#28 Exhibit PP Part 1#29 Exhibit PP Part 2#30 Exhibit QQ)(Fleming, Thomas)

Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

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UNITED STATES DISTRICT COURT DISTRICT OF MASSACHUSETTS ) ) ) ) ) ) ) CIVIL ACTION No.: 05-CV-12237WGY ) ) ) ) ) )

AMGEN INC., Plaintiff, v. F. HOFFMANN-LA ROCHE LTD, ROCHE DIAGNOSTICS GmbH, and HOFFMANN-LA ROCHE INC. Defendants.

SUPPLEMENTAL DECLARATION OF THOMAS R. KADESCH, PH.D. IN FURTHER SUPPORT OF DEFENDANTS' PROPOSED CLAIM CONSTRUCTION Lee Carl Bromberg (BBO# 058480) Julia Huston (BBO# 562160) Keith E. Toms (BBO# 663369) Nicole A. Rizzo (BBO# 663853) BROMBERG & SUNSTEIN LLP 125 Summer Street Boston, MA 02110 Tel. [phone] Leora Ben-Ami (pro hac vice) Mark S. Popofsky (pro hac vice) Patricia A. Carson (pro hac vice) Thomas F. Fleming (pro hac vice) Howard S. Suh (pro hac vice) Peter Fratangelo (BBO# 639775) KAYE SCHOLER LLP 425 Park Avenue New York, New York 10022 Tel. [phone] Counsel for Defendants, F. HOFFMANN-LA ROCHE LTD, ROCHE DIAGNOSTICS GmbH, and HOFFMANN-LA ROCHE INC.

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I, Thomas R. Kadesch, Ph.D., hereby declare as follows: I make this declaration in connection with Defendants' Opposition to Amgen, Inc.'s Claims Construction Brief in the above captioned action. I. INFORMATION CONSIDERED IN FORMING MY OPINIONS 1. This expert declaration is provided to assist the Court in understanding the science

and technology discussed in Defendants' Opposition. In forming the opinions set forth in this expert declaration, I have considered U.S. Patent No. 4,703,008; and the claims of U.S. Patent Nos. 5,547,933; 5,441,868; 5,618,698; 5,756,349; 5,955,422 and 5,621,080; (collectively the Lin Patents; Exhibit 2 to Kadesch Decl.), in the context of my knowledge of relevant literature and my academic and professional experience. II. ERYTHROPOIETIN 2. Human erythropoietin is a 34,000 dalton glycoprotein hormone. When produced

by a mammalian cell from a gene encoding human erythropoietin the secreted polypeptide has 165 specific amino acid residues. Figure 9 of the Lin Patents identifies each of the amino acid residues of the human (and monkey) erythropoietin polypeptide by an art-recognized single letter abbreviation. Figure 6 of the Lin Patents identifies the specific amino acid residues in the human erythropoietin polypeptide by an art-recognized three-letter abbreviation. (See Kadesch Decl. Ex. 3 ; Table 2-1 Abbreviations for amino acids). The first amino acid residue of the mature human erythropoeitin sequence is designated "+1" in these figures. 3. Example 5 of the Lin Patents contains a statement that FIG 6 thus serves to identify the primary structural conformation (amino acid sequence) of mature human EPO as including 166 specified amino acid residues (estimated M.W. = 18,399) . . . Sites for potential glycosylation of the mature human EPO polypeptide are designated in the Figure by asterisks. 2

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('008 Patent col.21 l.61 - col.22 l.2). 4. By inspection of the sequences in either Figure 6 or Figure 9, starting at residue

+1 and proceeding through residue +165, one can count the number of times each type of amino acid residue occurs in the sequence. The table below shows the number of times each of the twenty naturally occurring amino acids appears as a residue in the structure of mature human erythropoietin and the canonical structural formula of the side chain group which defines the residue. AA Residue Abbreviations Side Chain Structural Formula Occurrences in Human EPO 1. 2. Alanine Arginine A, Ala R, Arg
H2 C C H2 H2 C N H
CH3

19
NH C NH2

12

3.

Asparagine

N, Asn

H2 C C NH2

O

6

4.

Aspartic acid

D, Asp

H2 C C O-

O

6

3

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5.

Cysteine

C, Cys

H2 C SH

4

6.

Glutamine

Q, Gln
C H2

H2 C C NH2

O

7

7.

Glutamic acid

E, Glu
C H2

H2 C C O-

O

12

8. 9.

Glycine Histidine

G, Gly H, His

H

9
NH CH N

HC C C H2

2

10.

Isoleucine

I, Ile

CH3 CH C H2 CH3

5

11.

Leucine

L, Leu

H2 C CH

CH3 CH3

23

12.

Lysine

K, Lys

H2 C C H2

H2 C C H2

NH2

8

4

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13.

Methionine

M, Met
C H2

H2 C S

1
CH3

14.

Phenylalanine

F, Phe

H2 C

H

4
H

H H

H

15.

Proline

P, Pro

H2C

CH2 CH2 N

8

16.

Serine

S, Ser

H2 C OH

10

17.

Threonine

T, Thr

CH3 CH OH

11

18.

Tryptophan

W, Trp

HC C C H2

NH H

3

H H H

5

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19.

Tyrosine

Y, Tyr

H2 C

H

4
H

H OH

H

20.

Valine

V, Val

CH3 CH CH3

11

5.

According to the teaching of the Lin Patents and what is understood by a person

of skill in the art, whenever a mammalian cell expresses a gene encoding human erythropoietin a polypeptide is produced having the side chains specified in the table. Each and every atom shown contributes to the essential structural attributes of erythropoietin expressed by a mammalian host cell. 6. A mammalian host cell that produces erythropoietin from a gene encoding the

human sequence will modify the side chains of only three specific asparagine residues and one specific serine residue. By a natural cellular process catalyzed by an enzyme, a hydrogen atom is removed from the side chain amide of asparagine (Asn) at positions Asn24, Asn38, and Asn83 and from the side chain hydroxyl of serine (Ser) at position Ser126. A new bond to a sugar residue is formed in place of the lost hydrogen. This type of post-translational modification is known as glycosylation. (Ex. 4). The Lin Patents expressly describe potential glycosylation of the asparagines, but not the serine.

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7.

The cysteine (Cys) residues at positions Cys7 and Cys161 can each lose a

hydrogen and form an intramolecular disulfide, an S-S bond, as can the cysteine residues at positions Cys29 and Cys33. (Ex. 4). The S-S bond formation process is reversible and

dependent on the particular conditions present. Disulfides are not fully described in the Lin Patents. 8. As mentioned above, secreted human erythropoietin produced by mammalian

cells is 165 amino acid residues. The sequence is the result of truncation of a longer sequence. The C-terminal arginine, Arg166, is cleaved from the premature polypeptide by proteolytic enzymes making the final residue of the mature sequence aspartic acid (Asp165). (Ex. 5). This cleavage is not reported in the Lin Patents. On the N-terminus, 27 amino acid residues are cleaved by the mammalian host cell from the premature sequence, making the first amino acid residue of the mature sequence alanine (Ala1). 9. Glycosylation, truncation of the pre-mature sequence, and disulfide bond

formation are the post-translational events that occur in the production of mature erythropoietin produced in mammalian cells expressing a gene encoding human erythropoietin, either known at the time of the patent filing date or subsequently discovered. 10. All other atoms of the amino acid residues, including all side chain atoms are

conserved and thus define the structure of erythropoietin produced from mammalian cells expressing a gene encoding for human erythropoietin. The N-terminal residue of erythropoietin produced by mammalian cells always has a free amino group (-NH2) which is positively charged under physiological conditions (-NH3+). The side chains of the residues derived from lysine (Lys) at positions Lys20, Lys45, Lys52, Lys97, Lys116, Lys140, Lys152, and Lys154 always

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have four methylene groups (-CH2-) attached to a primary amino group (-NH2). The primary amino groups are also positively charged (-NH3+) under physiological conditions. III. FURTHER TESTIMONY 11. If requested by the Court I may provide oral testimony at a hearing or at trial

consistent with the statements made in this declaration. 12. I reserve the right to supplement opinions rendered in this declaration as a result

of the testimony and opinions of other witnesses or other information which might exist and which may be presented during the remainder of discovery or during trial of this matter, including graphic or demonstrative materials not yet prepared. 13. I declare under penalty of perjury under the laws of the United States that the

foregoing is true and correct to the best of my knowledge and belief.

DATED: Philadelphia, Pennsylvania March 19, 2007

_/s/ Thomas R. Kadesch__ Thomas R. Kadesch, Ph.D.

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Index of Exhibits
Exhibit 1 Exhibit 2 Exhibit 3 Exhibit 4 Exhibit 5 Curriculum Vitae for Thomas Robert Kadesch. U.S. Patent No. 4,703,008, and the claims for U.S. Patent Nos. 5,547,933; 5,441,868; 5,618,698; 5,756,349; 5,955,422 and 5,621,080. Biochemistry (Lubert Stryer 2d ed. 1981) (1975). Por-Hsiung Lai et al., Structural Characterization of Human Erythropoietin, 261 THE J. OF BIO. CHEM. (ISSUE 7) 3116 (1986). Michael Recny et al., Structural Characterization of Natural Human Urinary and Recombinant DNA-derived Erythropoietin, 262 THE J. OF BIO. CHEM. (ISSUE 35) 17156 (1987).

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EXHIBIT 4

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AM-ITC-00072296

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AM-ITC-00072297

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