Free Declaration - District Court of Delaware - Delaware

Case 1:08-cv-00166-SLR

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~~
Case 1:08-cv-00166-SLR Document 16-4 Filed 06/26/2008 Page 2 of 52
Paper No.
Filed on behalf of:
Senior Party Adams

By:

Oliver R. Ashe , Jr. , Esq. Greenblum & Bernstein , PLC 1950 Roland Clarke Place Reston , VA 20191 Tel: (703) 716- 1191 Fax: (703) 716- 1180 oashe~gbpatent.com

Jeffrey P. Kushan , Esq. Sidley Austin Brown & Wood LLP 1501 K Street , N. Washington , DC 20005 Tel: (202) 736- 8914 Fax: (202) 736- 8711 ikushan~sidlev. com

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES (Administrative Patent Judge Richard E. Schafer)

Human Genome Sciences , Inc.
Junior Party
(Patent 6

872 568;

Inventors: Jian Ni , Reiner L. Gentz , Guo- Liang Yu , Craig A. Rosen),

Genentech , Inc.
Senior Party

448; Inventors: Camellia W. Adams , Avi J. Ashkenazi , Anan Chuntharapai , Kyung Jin Kim).
(Application 10/423

ference No. 105 361 (RES)

~)E(G

~ P.
UI tl.-)

Sterne, Kessler. Goldstein &

L.L.C. ::nD

pposmg

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Appendix A to Adams Opposition 3
Interference No. 105, 361

Appendix A

THE EVIDENCE

Exhibits Cited
The following exhibits are cited in support of this opposition:

AX- I036
AX- I037 AX- I040

S. Patent Application No. 60/054 S. Patent Application No. 60/040

021 to Ni

et aI.

filed on 7/29/97.

846 to Ni

et al. filed on 3/17/97

u.s. Patent Application No. 60/046 615 , filed on 5/15/97.
Liu

AX- I046 AX- I048

et al. , Cell

87:565- 576 (1996).

Edelman

Antibody Structure and Molecular Immunology,

Nobel Lecture

(December 12 , 1972)

AX- I049 AX- I050

Yelton & Scharff
Sevier

American Scientist

68:510- 516 (1980).
27: 1797- 1806 (1981).

et al. , Clinical Chemistry

AX- I053
AX- I054 AX- lOSS

Curtiss and Witzum
Kehoe & Seide J Am.
Kabat

Clin. Invest.

72(4):1427- 1438 (1983).
181 (1 0): 1000- 1004 (1982).

et al. , Proc. Nat. Acad. Sci.

73:4471- 4473 (1976).

AX- I056 AX- I0S8
AX- I0S9

Novotnyetal.
Gruss

Bioi. Chem.

258:14433- 14437(1983)

et aI. , Blood

85:3378- 3404 (1995).
181 :985- 992

DeBenedette

et al. , J Exp.

(1995).

AX- I060 AX- I064

Mapara

et aI. , Eur. J Immunol.

23:702- 708 (1993).
The Pharmacological Basis of Therapeutics,

Goodman and Gilman

pp. 29-

, Ninth Edition (1996).

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Appendix A to Adams Opposition 3
Interference No. 105,361

AX- I065 AX- I 066 AX- I068 AX- I069 AX- I070
AX- I071

Nagata
Eischen

Cell

88:355- 365 (1997).

et al. , Blood

90:935- 943 (August 1997).
261 :345- 348

Rabizadeh

et aI. , Science

(1993).

Chapman

et al. , FEBS Letters

374:216- 220 (1995).

Beg

et aI. , Science

274:782- 784 (1996).
274:787- 789 (1996).

Van Antwerp

et aI. , Science

AX- I072 AX- I073 AX- I074 AX- 1075

Wang

et aI. , Science

274:784- 787 (1996).
et aI.

WO 92/01810 to Lerner

published on 02. 06. 92.

Chu

J Bio. Chem.

269(2):787- 790 (1994).
J Bio Chem.

Prakash and Timasheff
Feinstein

258(3):1689- 1697 (1983).

AX- I 076
AX- I077

et aI. , TIBS

20:342- 344 (1995).
371:321- 323 (1995).
178:2231- 2235 (1993).
81 :505- 512 (1995).
183: 159- 167
(1996).

Hofmann

et al. , FEBS Letters

AX- I078

Aldersonetal.
Chinnaiyan

J Exp. Med.

AX- I079
AX- I080

et al. , Cell et al. , J Exp. Med.

Hess

AX- I081 AX- I 082
AX- 1083

Sato

et aI. , FEBS Letters

358: 113- 118

(1995).

Liu

et al. , Nature

342:929- 931 (1989).
364:645- 648 (1993).
81 :495- 504 (1995).

Tsubata
Hsu

Nature

AX- I084

et aI. , Cell

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Appendix A to Adams Opposition 3
Interference No. 105,361

AX- I085 AX- I086
AX- I092

Brojatsch

et al. , Cell

87: 845- 855 (1996).

Declaration of Dr. Michael Karin.
Reed
Doctor American Journal of Pathology

157(5): 1415- 1430 (2000).

AX- I095
AX- I096 NX- 2004 NX- 2021 NX- 2022

et al. , Cell Death and Differentiation

10:621- 633 (2003).

Reed

et al. , Sci. STKE

2004 , re9 (2004).

USP No. 6 872 568 to Ni et ai , issued on 3/29/06.
Sheridan

et aI. , Science

277:818- 821 (1997).

Pan

et aI. , Science

277:815- 818 (1997).
60:47- 55 (1996).

NX-2053
NX-2064 NX- 2065

Ware

Cell. Biochem.

Declaration of John C. Reed , MD , Pho.
Chinnaiyan

et aI. , Science

274:990- 992 (1996).
6(12): 1669- 1676 (1996).

NX- 2066 NX-2072
NX- 2078

Marsters

et al. , Current Biology et al. , J BioI.

Tartaglia

267:4304- 4307 (1992).

Tartaglia

et aI. , Cell

74:845- 853 (1993).

II.

Papers Cited

The following papers are cited in support of this opposition:
Paper No.

Notice Declaring Interference , filed on August 31 2005.

Paper No.

Ni Substantive Motion 4 , filed on December 7 2005.

III.

Appendices Cited
The following appendices are cited in support of this opposition:

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Appendix A to Adams Opposition 3
Interference No. 105, 361

Appendix A
Appendix B

The Evidence.

Statement of Material Facts Relied Upon in Opposition.

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Appendix B to Adams Opposition 3
Interference No. 105, 361

Appendix B

STATEMENT OF MATERIAL FACTS RELIED UPON IN OPPOSITION

Counts 1 and 2 and Proposed Counts 3 and 4
75.

Count 1 is defined as " An isolated monoclonal antibody or fragment thereof

specifically binds to a protein consisting of amino acid residues
wherein said antibody or fragment thereof is an antagonist of the protein
1086 , ~ 33; NX- 2004; and Paper No. , filed on August 31 , 2005; Emphasis added).
" (AX-

76.

Count 2 is defined as " An isolated monoclonal antibody or fragment

specifically binds to a protein consisting of amino acid residues wherein said antibody or fragment thereof is an agonist of the protein ofSEQ ID NO:2. " (AX1086 , ~ 34; NX- 2004; and Paper No. , filed on August 31 2005; Emphasis added).

77.

Proposed Count 3 is defined as " An isolated antibody or fragment thereof

specifically binds to a protein consisting of amino acid residues

wherein said antibody or fragment thereof is an antagonist of the protein ofSEQ ID NO:2. " (AX1086 , ~ 35 and Ni Substantive Motion 4 , filed on December 7 2005; Emphasis added).

78.

Proposed Count 3 is the same as Count 1 , except Count

monoclonal" and Proposed Count 3 does not state the term " monoclonal." (AX- 1086 , ~ 36).
79.

Proposed Count 4 is defined as " An isolated antibody or fragment thereof

specifically binds to a protein consisting of amino acid residues

wherein said antibody or fragment thereof is an agonist of the protein ofSEQ ID NO:2. " (AX1086 , ~ 37 and Ni Substantive Motion 4, filed on December 7 , 2005; Emphasis added).

80.

Proposed Count 4 is the same as Count 2 , except Count 2 states the term

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Appendix B to Adams Opposition 3
Interference No. 105, 361

monoclonal" and Proposed Count 4 does not state the term " monoclonal." (AX- l 086 , ~ 38).

II.

Adams s and Ni' s Applications
81.

Adams filed Provisional Application No. 60/046 615 (" the ' 615 application ) on

May 15 , 1997. (AX- 1040).
82.

Ni filed Provisional Application No. 60/040 846 (" the ' 846 application ) on

March 17, 1997. (AX- 1037).
83.

Ni filed Provisional Application No. 60/054 021 (" the ' 021 application ) on July

, 1997. (AX- 1036).

III.

Level of Skill Possessed by a Person of
84.

A person of ordinary skill in the field ofTNF receptor research as of March 17

1997 and as of July 29 , 1997, would have been an individual who (i) had an advanced degree in

molecular biology, cell biology, biochemistry or similar discipline or had significant laboratory experience and knowledge of the literature in the field , (ii) was familiar with techniques for production of monoclonal antibodies and (iii) had experience in characterization and assessment

ofTNFR family
IV.

l 086 , ~ 39).

Antibody Tecbnolo2V as of March 17. 1997

Antibody Overview
85.

An antibody is a protein that selectively binds to a specific location on an antigen

(termed an " epitope ). (AX- 1086 , ~ 41).
86.

The general structure of an antibody molecule was well known prior to March 17

1997. (AX- 1086 , ~ 42 and AX- 1048 , Fig. 3).
87.

An antibody generally contains two pairs of polypeptides. (AX- l 086 , ~ 42 and

AX- I048 , Fig. 3).

g.,

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Appendix B to Adams Opposition 3
Interference No.

105,361

88.

Each pair of polypeptides contains one " heavy " polypeptide chain and one " light"

polypeptide chain. (AX- l 086 , ~ 42 and AX- I048 , Fig. 3).
89.

Each of the polypeptide chains contains " constant" and " variable " domains. (AX-

1086 , ~ 42 and AX- I048 , Fig. 3).

90.
Figure 3 of

A representative diagram ofan antibody of the IgG isotype is shown below.

See

Antibody Structure and Molecular Immunology,

Nobel Lecture , December 12 , 1972

by Gerald M. Edelman. The variable regions are shaded , while the constant regions are unshaded.
(AX- 1086 , ~ 42 and AX- 1048 , Fig. 3).
Fob (I)
Heavy PCA

Fob(!)

Chain

s-s
1v Sw---SIII
5 S

PeA

5 S-S

S

n---S
NHl

5 S

HI
S 5

COOH

COOH

Felt)
fig. 3.

Overall arrangemeIit of chains and disulfide bonds of the human yGt

Ell.

Half-qslinyl residues are I-XI; Ilight and heavy chains.

designates corresponding half-qslinyl

Fc(t) refer to fragments produced by trypsin, which cleaves the heavy chain as indicated
by dashed lines above half - cyslinyl residues VL Variable.

logous. The constant region oithe heavy chain
CHZ and CH3 , that are homologous to each other and to the C region of the light chain.
The variable regions carry out antigen- binding
effector functions of Ihe mOlecule.

functions and the constant regions the

91.

The constant domains of an antibody have a generally consistent and conserved
(e.

structure within each isotype

IgG) of antibody in a mammal , and playa role in certain

g.,

,~

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Appendix B to Adams Opposition 3
complement fixation), but typically do not playa role

immune system modulating functions

(e.

in antigen binding. (AX- 1086, ~ 43 and AX- l 049 , p. 510 , col. 3 , last m.
92.

The variable domains are amino acid sequences within the light and heavy
which vary between antibody molecules with different binding specificities.

polypeptide chains ,

(AX- 1086 , ~ 44 and AX- 1049 , p. 510 , col. 3 , ~ 2).
93.

The ability of an antibody to bind to a specific epitope is attributable to the

structure defined by the variable domains of the antibody. (AX- 1086 , ~ 44 and AX- I049 , p. 510
col. 3 ,

~ 2).

94.

Multiple antibodies can bind to one antigen yet exhibit distinct binding

specificities and cause distinct biological effects , as each antibody may bind to a distinct epitope

on the antigen. (AX- 1086 , ~ 45 and AX- I050 , p. 1798 ,

col. 1

, ~~ 2 and 3).

Observations on Antibody Issues of Relevance to the Interference
95.

Each antibody molecule in a monoclonal antibody molecule composition will

bind to the same epitope on the antigen used to produce the antibody. (AX- l 086 , ~ 51 and AX1050 , p. 1798 ,
col. 1

, ~ 2 , last sentence).

96.

Where the antigen is a cell surface receptor protein , such as a DR5 , the epitope to

which any particular antibody binds often will not correspond to a linear sequence of amino acids

found in the polypeptide. (AX- I086 , ~ 51 and AX- 1053 , Abstract and p. 1435 ,
97.

col. 1

, ~ 2).

As of March 17 , 1997 , a person of skill in the art would not have been able to

identify or describe the specific epitope that a monoclonal antibody will recognize on a DR5

protein antigen before the antibody had actually been produced and characterized. (AX- 1086
51).
98.

Once a reference antibody has been produced and identified , a person of ordinary

)).

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Appendix B to Adams Opposition 3
skill in the art could determine the specific amino acid sequences present in the two polypeptide

chains of the antibody. (AX- 1086 , ~ 55).
99.

Equipped with the discussed in paragraph 98 , a particular binding specificity can

be associated with a particular amino acid sequence and antibody structure. (AX- 1086, ~ 55).
100.

As of March 17 , 1997 and July 29 , 1997 , a person of ordinary skill in the art

would not have been able to define the amino acid sequence or three-dimensional structure of an

antibody necessary to cause the antibody to bind to a particular epitope on a DR5 without
structural information derived from a pre-existing reference antibody that exhibits the desired
epitope- binding specificity. (AX- 1086 , ~ 56; AX- 1055; and AX- 1054 , Abstract (" Certain
lottery- like ' aspects ofthese genetic processes add to the combinatorial possibilities that are

characteristic of the humoral immune system.
101.

As of March 17 , 1997 and July 29 , 1997 , a person of ordinary skill in the art

would not have been able to identify or describe the location of an epitope on a DR5 to which an antibody must bind in order for the antibody to act as an agonist or an antagonist of DR5 without
use of a reference antibody that exhibits an epitope-binding specificity that confers on the

antibody the capacity to act as an agonist or antagonist ofDR5. (AX- l 086 , ~ 57).
102.

As of March 17 , 1997 and July 29 , 1997 , a person of ordinary skill in the art

would not have been able to determine , using only a deduced amino acid sequence of a DR5
polypeptide , the location of an epitope on the DR5 protein to which an antibody must bind to

enable the antibody to act as an agonist or antagonist of the DR5. (AX- 1086 , ~ 57 and AX- I 056
p. 14435 , col. 2 , ~~ 2 and 3).

Monoclonal Antibodies Distin2uisbed from Polvclonal Antibodies
103.
By March 17 ,

1997 and July 29 , 1997 , a person of ordinary skill in the art would

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Interference No.

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105, 361

have considered it practically impossible to identify and isolate individual antibody molecules

from polyclonal antisera, or to determine specific functions possessed by an individual antibody

present in the polyclonal antisera. (AX- l 086 , ~ 58).
104.
By March 17 ,

1997 , possession of a polyclonal antiserum would not have

provided a person of ordinary skill in the art with a particular reference antibody that could be
characterized to determine its structure , or otherwise used to produce additional copies of that
particular antibody and , in particular , a person of ordinary skill in the art would have faced

problems obtaining sufficient quantities of a reference antibody. (AX- 1086 , ~ 59).
105.

This would have been particularly true when no techniques were known for

selecting the specific antibody out of a polyclonal antiserum containing many other antibodies

that bind to the same antigen. (AX- 1086 , ~ 59).
106.

As of March 17 , 1997 , a person of ordinary skill in the art would have been

unable to use a polyclonal antiserum to produce cell lines that would yield individual desired

monoclonal antibodies. (AX- 1086 , ~ 59).
107.
By March 17 ,

1997 , it was well accepted that monoclonal antibody compositions

offered several significant benefits over polyclonal antisera in diagnostic , therapeutic and

analytical applications. (AX- l 086 , ~ 60 and AX- I 050 , p. 1797 , col. 2 , section entitled
Polyclonal vs. Monoclonal Antibody.
108.

Because a monoclonal antibody composition is homogeneous , it will exhibit a

uniform binding profile and thus will induce a more consistent biological effect if administered to
a mammal or used in a cell- based assay. (AX- l 086 , ~ 60 and AX- I050 , p. 1797 , col. 2 , section

entitled " Polyclonal vs. Monoclonal Antibody.
109.

A polyclonal antiserum may exhibit diverse binding specificities and effector

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Interference No. 105,361

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Page 13 of 52

functions , because antisera contain many different antibodies , each having distinct binding

characteristics and isotypes. (AX- 1086 , ~ 60 and AX- 1050 , p. 1797 , col. 2 , section entitled
Polyclonal vs. Monoclonal Antibody.
110.

A polyclonal antiserum may induce many, often mutually exclusive , biological

effects when administered to a patient or used in a cell-based assay. (AX- l 086, ~ 60).
111.

The diversity in biological responses may also vary with each batch of sera tested

even when batches are derived from a single immunization of an animal. (AX- l 086 , ~ 60 and
AX- I 049 , p. 511 , col. 2 , ~ 2).
Structure of Cell Surface Receptors and Brief Overview of

General Observations on Cell Surface Receptors
112.

A given cell surface receptor may signal through several distinct signal

transducing pathways. In some cases , these effector pathways may act synergistically, in some
cases they act additively, and in some cases they may oppose each other. (AX- 1086 , ~ 61; AX1046).
113.

This is particularly relevant for signaling

known to have highly pleiotropic functions. (AX- 1086 , ~ 61).

TNFR Familv Overview
114.
By March 17 ,

1997 , there were a number of known members of the TNFR family,

including: TNFRl (also known

TNFR, TNFR60 , DR1); TNFR2(also known as

CD120b , p75- TNFR , TNFR80); LTpR (also known as CDI8 , TNFR3); OX40 (also known as
CD134 , ACT35); Fas (also known as CD95 , Apo- , DR2); CD27 (also known as Tp55 , SI52);

CD30 (also known as Ki- , D1SI665E); CD40; 4- 1BB (also known as CD137, ILA); DR3 (also
known as WSL- , TRAMP , Apo- , LARD); and p75 NGFR (also known as p75-NTR). (AX-

, p.

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Interference No. 105, 361

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Appendix B to Adams Opposition 3
1086 , ~ 63; NX- 2053 , pA8 , Table I; AX- 1058
29 and p. 2 , Ins. 28- 31).

3380 , Fig. 1; and AX- 1037 ,

p. 1

, Ins. 19-

26-

115.

By March 17 ,

1997 , it was known that TNFR family members and their

respective cognate ligands are associated with a diverse range of cellular mechanisms and
biological effects , including: cellular proliferation , induction or suppression of apoptosis

induction or suppression of other mechanisms of necrotic cell death , promotion or inhibition of
inflammation , activation of the NF-KB and JNK intracellular pathways , co-stimulation and

regulation ofT-cell activities (including CD4 memory T
functions , and activation and regulation of B cells and myeloid cells. (AX- l 086 ~ 64; NX- 2053

pA8 , Table I; AX- I046 , Abstract; AX- 1059 , Abstract; AX- 1078 , Abstract; and AX- 1060
Abstract).
116.
receptors " are

The ' 846 application discloses that the effects of the TNF

varied and influence numerous functions , both normal and abnormal , in the
and are " among

biological processes of the mammalian system "

the most pleiotropic cytokines

inducing a large number of cellular responses.... " (AX- 1086 , ~ 64 and AX- 1037 , p. 3 , Ins. 15and p. 26 , Ins. 5- 8).

117.

By March 17 ,

1997 , a person of ordinary skill in the art would have known that

TNFR family members playa role in the observed biological effects through
ligand-receptor binding characteristics , rather than through undifferentiated interactions between

TNF ligand family members and TNFR family members. (AX- I086 , ~ 66 and NX- 2053
Abstract).
118.
By March 17 ,

1997 , it had been shown that many TNFR family members interact

with cognate ligands on a " one receptor/one ligand" basis (e. , CD27/CD27L , CD30/CD30L

, p.

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Interference No. 105, 361

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Page 15 of 52

CD40/CD40L , 4- 1BB/4- 1BBL , OX40/0X40L (gp34), FAS/FASL), while others show more

complex types of interactions. (AX- 1086 , ~ 66 and AX- 1058
119.
By March 17 ,

3394 ,

col. 1

, ~ 3).

1997 , a person of ordinary skill in the art would have known that

other TNFR family members, such as TNFR1 , TNFR2 and L TpR , could bind more than one

ligand. (AX- l 086 , ~ 66).
120.
By March 17 ,

1997 , a person of ordinary skill in the art would have known that

certain ligands could bind to more than one member of the TNFR family. (AX- 1086 , ~ 66).
VI.
Requirements of the Monoclonal Antibodies of the Counts
121.

The antibodies that are the subject ofthe Counts are identified by reference to two

functional properties. (AX- 1086 , ~ 67).
122.

One of the functional properties of the Counts is that the antibody binds to an
(i.

extracellular domain sequence

amino acids

(AX- 1086 , ~ 67).
123.

This binding function can be evaluated without knowledge of the functions that a

DR5 polypeptide modulates or is involved in. (AX- l 086 , ~ 67).
124.

The second functional property of the Counts is that the antibody functions as an

agonist" or an " antagonist" of a DR5. (AX- l 086 , ~ 68).
125.

This requirement refers to the biological effect(s) or responses exhibited when a

cognate ligand binds to a DR5 in a setting where the levels of expression of the receptor are not

artificially manipulated. (AX- I086 , ~ 68).
126.

A person of ordinary skill in the art would have recognized that the terms

agonist" and " antagonist" had well accepted meanings by March 17 , 1997. (AX - 1 086 , ~ 69).
127.

A representative definition of the terms " agonist" and " antagonist" is provided in

, p.

Case 1:08-cv-00166-SLR
Interference No. 105,361

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Appendix B to Adams Opposition 3
a widely used textbook , Goodman and Gilman , The Pharmacological Basis of Therapeutics
(Ninth Edition (1996), p. 29 bridging p. 30):

Drugs that bind to
endogenous regulatory compounds are termed receptors and do not mimic , but interfere with , the binding of the
agonist. Such compounds ,

which are

activity, but which produce effects by inhibiting the action of an agonist (e. , by competition for agonist binding sites), are termed 1086 , ~ 69 and AX- 1064 , pp. 29- 30).
128.
By March 17 ,

1997 , it was well known that many TNFR family members can

mediate intracellular signaling functions in cells. (AX- I086 , ~ 70; NX- 2053, Table I; and AX1065 , p. 357 , Fig. 1).
129.
Intracellular signaling results from binding of a cognate ligand

(i. e.

endogenous

agonist) to the TNFR family member residing on the cell surface. (AX- 1086 , ~ 70 and AX- I058
p. 3394 ,
col. 1

, ~ 3).

130.

The intracellular signals , in turn , can induce a variety of observable biological

effects in the cell. (AX- l 086 , ~ 70).
131.
By March 17 ,

1997 , it was further known that observable biological effects

exhibited by a cell in response to signaling induced by binding of a cognate ligand to a TNFR

family member in its endogenous cellular environment could also be induced through (i) use of agents that do not interact with the receptor or (ii) by artificially manipulating the levels of

expression ofthe receptor on the
991 , col. 3, ~ 2).
132.

1086 , ~ 71; AX- 1066 , Abstract; and NX- 2065

However, it was further known that such biological effects may not be the same

biological effects as those that result from binding of the cognate ligand. (AX- 1086 , ~ 71 and

NX- 2072).

Case 1:08-cv-00166-SLR Document 16-4 Appendix B to Adams Opposition 3
Interference No. 105, 361

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Page 17 of 52

133.

In view of these points , a person of ordinary skill in the art , as of March 17 , 1997

and as of July 29 , 1997 , would have understood that a monoclonal antibody that acts as an agonist
of a DR5 , would , when it binds to a DR5, activate the receptor to induce the signaling effects that

are induced when a cognate ligand binds to a DR5 that is expressed on the cell surface under
conditions that do not artificially manipulate the natural levels of expression of the receptor.
(AX- 1086 , ~ 72).
134.

A person of ordinary skill in the art , as of March 17 , 1997 , also would have

understood that a monoclonal antibody that acts as an antagonist of a DR5 would , upon binding
to an extracellular domain of that DR5 , inhibit the signaling effects that are induced when a

cognate ligand binds to a DR5 being expressed on the cell surface under conditions that do not

artificially manipulate the natural levels of expression of the receptor. (AX- l 086, ~ 73).

What is Needed to Describe a Monoclonal Antibody that Exhibits
Functional Properties

135.

By March 17 ,

1997 , and by July 29 , 1997 , a person of ordinary skill could

adequately identify and characterize a monoclonal antibody meeting the requirements of Count
or Count 2 by describing the structure of a DR5 antibody that is necessary for it to exhibit the
specific binding function that causes the antibody to function as an agonist or an antagonist , such
as the amino acid sequence of at least those portions of the variable domains of the light and

heavy immunoglobulin chains that are necessary to define the epitope binding specificity of the
antibody, or the sequence of a nucleic acid encoding such portions of the light and heavy chains.

(AX- 1086 , ~ 74)
136.
By March 17 ,

1997 , and by July 29 , 1997 , a person of ordinary skill could

adequately identify and characterize a monoclonal antibody meeting the requirements of Count
or Count 2 by describing a hybridoma or other cell line that produces a representative DR5

Case 1:08-cv-00166-SLR
Interference No.

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Appendix B to Adams Opposition 3
105, 361

antibody that exhibits the specific binding function that causes the antibody to function as an

agonist or antagonist. (AX- 1086 , ~ 74).
137.

To design and perform assays that could be used to identify monoclonal

antibodies meeting the requirements of Count 1 or Count 2 , a person of ordinary skill in the art
by March 17 , 1997 and by July 29 ,

1997 , first would need to know the consequences of binding

of a cognate ligand to a DR5 as it is expressed on the surface of a cell under conditions that do not

entail artificially manipulating natural expression levels of the receptor. (AX- 1086 , ~ 76).
138.

If observable biological effects in a cell are being used to characterize the

monoclonal antibody as an agonist or an antagonist of a DR5 , a person of ordinary skill in the art

would need to know the biological effects that are characteristic of signaling caused by cognate
ligand binding to a DR5 (in the case

from cognate ligand binding to the receptor (in the case of an antagonist). (AX- l 086 , ~ 77).
139.

Without knowing the biological effects that are characteristic of signaling caused

by cognate ligand binding to a DR5 , a person of ordinary skill in the art could not have attributed

the observable biological effects to an agonistic or antagonistic interaction between the

monoclonal antibody and a DR5 as it is expressed on the cell surface. (AX- 1086 , ~ 77).
140.

A person of ordinary skill in the art must have been able to correlate the

observable biological effects exhibited when a test molecule is incubated with cells expressing a
DR5 to interactions between the test molecule and a DR5 to ensure that the biological

consequences result from receptor-mediated signaling, rather than from other non-receptor
interactions with the cell.

See AX- I086 , ~ 78 and AX- I066 , Abstract , last sentence (" (tJhese

results indicate that antineoplastic treatments (e. , cisplatin J induce apoptosis through a Fasindependent pathway even though fas- and chemotherapy- induced pathways converge on

,~

Case 1:08-cv-00166-SLR
Interference No. 105,361

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Page 19 of 52

Appendix B to Adams Opposition 3
common downstream apoptotic effector molecules. "
141.

A DNA damaging agent could trigger apoptosis without having any effect on a

DR5. (AX- l 086 , ~ 78).
142.

If a person of ordinary skill cannot establish that the observable biological effects

result from receptor-mediated signaling, such a person would be unable to characterize a molecule
being tested as an agonist or an antagonist of a DR5 , as those terms require the observable

biological effects to result from ligand-receptor-mediated signaling (in the case of the agonist) or
inhibition of those signals (in the case
143.

1086 , ~ 78).

As of March 17, 1997 and July 29 , 1997 , a person of ordinary skill in the art could

not have screened randomly produced monoclonal antibodies or antibody- producing cells to
identify and select monoclonal antibodies that bind to an extracellular domain of a DR5 and act as

an agonist or as an antagonist of that DR5 if that person had not established an accurate
correlation between a measurable biological effect being detected through use of the assay, and

where the result of activation
79).
144.

1086

As of March 17 , 1997 and July 29 , 1997 , a person of ordinary skill would need to

know the identity of a cognate ligand of a DR5 to determine if a monoclonal antibody could

inhibit or reduce the signaling effects associated with cognate ligand binding to a DR5. (AX1 086 ,

~ 80).

The Descriptions in the ' 846 Application of A20nists and Anta20nist Are Inconsistent with Well-Accepted Meanin2s and Show that the ' 846

Application Does Not Describe A20nist or Anta20nistic Monoclonal Antibodies of a DR5
145.

The discussions of agonists contained in the ' 846 application are inconsistent with

the commonly accepted meaning of " agonist" that was known to a person of skill in the art by

...
Case 1:08-cv-00166-SLR
Interference No. 105,361

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Page 20 of 52

Appendix B to Adams Opposition 3
March 17 , 1997. For example , at page 27 , lines 3-

, the application states that "

the present
ligand ,

invention is directed to a method for enhancing apoptosis induced by TNF- family

which

involves administering... an effective amount of DR5 ligand, analog or an agonist capable of
increasing DR5 mediated signaling. " And
, lines 31, the ' 846 application states that

inhibition or enhancement of the signal generated by the ligand indicates that the compound is an
antagonist or agonist of the ligand/receptor signaling pathway. " However , the ' 846 application

goes on to provide a list of potential agonist molecules that a person of ordinary skill in the art

would have considered inconsistent with these passages and misleading in light of the correct

understanding of the term agonist. (AX- I086 , ~ 83 and AX- I037 , page 27 , lines 3- 6 and 31- 34).
146.

For example , on p. 27 , lines 18- 19 the ' 846 application states that " by agonist is

intended naturally occurring and synthetic compounds capable of enhancing or potentiating
apoptosis. " (AX- 1037 , page 27 , lines 18- 19). It then states , on page 29 , lines 7examples of agonists include:
, that

TNF
suppressors (P53), cytolytic T cells

, transforming growth factor

neurotransmitters (such as glutamate , dopamine , N-methyl- D-aspartate), tumor
include chemotherapeutic drugs such as , for example , cisplatin , doxorubicin

bleomycin , cytosine arabinoside, nitrogen mustard , methotrexate and vincristine. Others include ethanol and amyloid peptide. (AX- 1037 , page 29 , lines 7- 19 and AX- I086 , ~ 84).
147.
By March 17 ,

1997 , it had been shown that many of the compounds that are

identified in the ' 846 application as " preferred" agonists either do not induce cell death through

apoptosis , or do not induce apoptosis through a selective binding to a TNFR. (AX- l 086 , ~ 85;

AX- 1074 , p. 787 ,

col. 1

, ~ 3 (" The cytotoxicity of cis plat
cross- links ,

of DNA adducts , which include DNA- protein

DNA monoadducts , and interstrand and
, ~ 2 (" Early morphological studies

intrastrand DNA cross- links ); and AX- 1075 , p. 1689 ,

col. 1

Case 1:08-cv-00166-SLR Document 16-4 Appendix B to Adams Opposition 3
Interference No. 105, 361

Filed 06/26/2008

Page 21 of 52

have shown that VCR (vincristin) destroys spindle microtubules... suggesting a specific
interaction between VCR and the microtuble protein.
148.

Because the compounds that are identified as " preferred" agonists would not

induce apoptosis through an interaction with a DR5 that mimics the binding of a cognate ligand , a

person of ordinary skill in the art would not have considered these molecules to be " agonists " of a

DR5. (AX- l 086 , ~ 85).

Identification of a cDNA and Deduced Amino Would Not Have Allowed a Person If An Antibodv. or Other Molecule. Was
149.

The ' 846 application provides no information derived from actual experimental

characterization or testing of a DR5 polypeptide. (AX- I086 , ~ 86 and AX- 1037).
150.

The ' 846 application does not provide any

had been expressed. (AX- 1086 , ~ 86 and AX- 1037).
151.
The ' 846 application does not identify a cognate ligand ofDR5. (AX- l 086 , ~ 87

and AX- 1037).
152.
At page 31 ,

lines 4 to 10 , the ' 846 application lists TNF

been identified in the literature prior to March 17 , 1997. (AX- 1086 , ~ 87 and AX- I037 , p. 31 , Ins.
10).
153.

There is no indication at page 31 , lines 4 to 10 of the ' 846 application , or

anywhere else in the ' 846 application , that one or more of the listed TNF family ligands that had

been identified in the literature prior to March 17 , 1997 is a cognate ligand of a DR5. (AX - 1086
~ 87 and AX- 1037 , p. 31 , Ins. 4- 10).
154.

A simple list of all TNF family ligands known as of March 17 , 1997 would

provide no guidance to a person of ordinary skill in the art as to which , if any, of the listed ligands

Case 1:08-cv-00166-SLR Document 16-4 Appendix B to Adams Opposition 3 Interference No. 105,361

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Page 22 of 52

was a cognate ligand of a DR5. (AX- l 086 , ~ 87).
155.

A person of ordinary skill in the art , as of March 17 , 1997 , would have read the

reference in the alternative to " DR5 ligands " and TRAIL to mean that DR5 ligand is most

a molecule that is distinct from TRAIL. (AX- 1086 , ~ 88 and AX- 1037,
156.

p. 31 ,

Ins. 4- 9).

Information that TRAIL is a cognate ligand of a DR5 was not reported in the

published literature until after July 29 1997. (AX- 1086 , ~ 88; NX- 2021; and NX- 2022).
157.

The ' 846 application does not report any data from testing

TNF family ligand , in particular TRAIL , to cells expressing DR5. (AX- l 086 , ~ 89 and AX1037).
158.
The ' 846 application does not describe any observed biological effects derived

from binding of any TNF family ligand to a DR5. (AX- 1086 , ~ 89 and AX- I037).
159.

The ' 846 application does not

that express DR5 and in which apoptosis or any other biological effects can be induced upon

binding of a cognate ligand or an agonistic monoclonal antibody to a DR5. (AX- 1086 , ~ 90 and
AX- 1037).
160.

As of March 17, 1997 , a person of ordinary skill in the art would not have been

able to determine if a given monoclonal antibody was acting as an agonist or an antagonist of a
DR5 by simply adding the antibody to cultures containing DR5- transfected cells and observing

the biological effect(s) the antibody exerts on those cells. (AX- l 086 , ~ 92).
161.

The lack of any information in the ' 846 application correlating apoptosis or any

other cellular response to a cognate ligand binding to a DR5 would have precluded a person of

ordinary skill in the art from doing so. (AX- 1086~ 93 and AX- 1037).
162.

The over-expression of a TNFR may potentiate signaling effects that would not

...
Case 1:08-cv-00166-SLR Document 16-4 Appendix B to Adams Opposition 3
Interference No. 105,361

Filed 06/26/2008

Page 23 of 52

otherwise occur upon ligand binding. (AX- 1086, ~ 94).
163.

Without information that allows a person of ordinary skill in the art to correlate an

observed biological effect to receptor- ligand signaling or inhibition of such signaling, a person of ordinary skill in the art could not have determined as of March 17 , 1997 and July 29 , 1997

whether the observed biological effect of an antibody was attributable to agonistic or antagonistic

interactions with the receptor. (AX- I086 , ~ 94).
164.
The ' 846 application contains no information that establishes that a DR5

overexpression assay was actually conducted. There are not any results of such an assay in the

846 application. An overexpression assay, standing alone , would not have been the preferred
method for demonstrating the apoptosis inducing activity of a new, previously uncharacterized

death domain containing TNFR. (AX- I086 , ~ 95; NX- 2064, ~ 25; and AX- I037).
165.

A person of ordinary skill in the art, as of March 17 , 1997 , would have known

that cognate ligand binding to death- domain containing TNFR family members was associated

with a variety of biological effects in the cell expressing the TNFR family member other than
apoptosis. (AX- I086 , ~ 98).
166.

TNFa binding to TNFRl activates the NF- KB pathway, which can operate to

promote cell survival , and inhibit apoptosis, when it binds to its cognate ligand , TNFa. (AX-

1086 , ~ 98; AX- I046 , Abstract ("

while activation ofNF- KB protects against TNF- induced
, ~ 1 (" However, a dose- dependant increase in cell survival

apoptosis ); AX- I070 , p. 784 ,
was seen when RelA (NF- KB)

col. 1

was provided ,

with virtually complete protection at the highest

dose (Fig. 3)"); AX- I071 , Abstract (" (t)hese findings suggest that a negative feedback mechanism

results from TNFa signaling in which NF- KB activation suppresses the

); and

AX- I072 , Abstract (" (t)he activation ofthe transcription factor ... NF- KB by tumor necrosis factor

,~

Case 1:08-cv-00166-SLR Document 16-4 Appendix B to Adams Opposition 3
Interference No. 105,361

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Page 24 of 52

(TNF) ... was found to protect from cell killing
167.

The ' 846 application does not describe any antibody in terms that a person

ordinary skill would have found useful to identify and describe a particular agonist or antagonist
antibody of a DR5. The ' 846 application does not provide the amino acid sequence of the heavy

and light chains of an antibody, or a nucleic acid sequence encoding such heavy and light chains.
(AX- 1086 , ~ 99 and AX- 1037).
168.

The ' 846 application does not describe a hybridoma or other type

produces an antibody that binds to an extracellular domain of the DR5 polypeptide and acts as an

agonist or an antagonist of a DR5. (AX- 1086 , ~ 99 and AX- 1037).
169.

A person of ordinary skill in the art would not have considered the

' 846

application to provide a description of any particular agonist antibody of a DR5. (AX- l 086
100 and AX- 1037).
170.

There is only one reference to antagonist antibodies in the ' 846 application;

namely in a single sentence on page 27 , lines 16- 17. A person of ordinary skill in the art would

not have considered this disclosure to provide a description of any particular antagonist antibody

of a DR5. (AX- 1086 , ~ 101 and AX- 1037 , p. 27 , Ins. 16- 17).
The ' 846 Application Does Not Describe Techniques That Monoclonal Antibodv that Acts As An Al!onist or Antal!onist of DR5
171.
The ' 846 application does not contain any description of any assays or other

biological evaluations that involved contacting cells expressing DR5 with a cognate ligand of

DRS. (AX- l 086 , ~ 103 and AX- 1037).
172.

A person of ordinary skill in the art would not have considered the assays

presented in the ' 846 application to have described any attributes of an agonistic or antagonistic

antibody. (AX- 1086 , ~ 104 and AX- 1037).

Case 1:08-cv-00166-SLR
Interference No.

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Appendix B to Adams Opposition 3
105, 361
173.

In particular , the assays described at page 27 , lines 25 to page 29 , line 7 of the

846 application would not have provided sufficient information to allow a person of ordinary

skill in the art to
1037 , p. 27 , In. 25 to p. 29 , In. 7).
174.

l 086 , ~ 104 and AX-

The ' 846 application does not describe the use of controls

discloses. (AX- 1086 , ~ 104 and AX- 1037).
175.

In particular , the ' 846 applications fails to describe , for any of the assays it lists

an appropriate control to ensure , for example , that the biological effect observed in an assay is

specific to DR5. (AX- l 086 , ~ 104 and AX- 1037).
176.

The first assay, described at page 27 , lines 25- 33 (AX- 1037 , p. 27 , Ins. 25- 33), is

a melanophore screening assay as described in PCT WO/92/0181O. (AX- 1086 , ~ 105 and AX1073).
177.

The assay described at page 27 , lines 25- 33 identifies compounds that act as an

agonist or antagonist ofG-protein coupled cell surface receptors. (AX- I086 , ~ 105 and AX- 1037
p. 27 , Ins. 25- 33).
178.

A person of ordinary skill in the art , as of March 17 , 1997 , and as of July 29

1997 , would have recognized that DR5 is not a G- protein coupled cell surface receptor. (AX1 086 , ~ 105).

179.

The assay described at page 27 , lines 25- 33 would not have

ordinary skill in the art anything about apoptosis induction or inhibition thereof. (AX- 1086 , ~ 105
and AX- 1037 , p. 27 , Ins. 25- 33).
180.

The assay described at page 27 , lines 25- 33 would not and could not have

infonned a person of ordinary skill in the art whether an isolated antibody would act as an agonist

,"

,~

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Appendix B to Adams Opposition 3
or antagonist ofDR5. (AX- 1086 , ~ 105 and AX- 1037 , p. 27 , Ins. 25- 33).
181.

The assay described at page 27 , lines 25- 33 would also require the use of a

cognate ligand. (AX- l 086 , ~ 105 and AX- 1037 , p. 27 , Ins. 25- 33).
182.

The assay described at page 27 , line 34 to page 28 , line 3 , of the ' 846 application

focuses on measurement of extracellular pH changes caused by receptor activation. (AX- l 086
106 and AX- 1037 , p. 27 , In. 34 to p. 28 , In. 3).
183.

A person of ordinary skill in the art would have recognized that there is no

information in the ' 846 application that indicates whether a pH change is observed upon

activation ofa DR5 , or the nature of any such pH change. (AX- 1086 , ~ 106 and AX- I037).
184.

A person of ordinary skill could not have used the assay techniques described at

page 27, line 34 to page 28 , line 3 to evaluate an isolated antibody to a DR5 to determine if the

isolated antibody would act as an agonist or antagonist of that DR5. (AX- l 086 , ~ 106 and AX1037 , p. 27 , In. 34 to p. 28 , In. 3).
185.

To conduct the assay described at page 28 , lines 4 to 9, of the ' 846 application

the application discloses the receptor oocytes may then be contacted with the receptor ligand
and a compound to be screened , followed by detection of inhibition or activation of a calcium

signal in the case of screening for compounds which are thought to inhibit activation of the
receptor. " (AX- 1086 , ~ 107 and AX- 1037 , p. 28 , Ins. 4- 9).
186.

The ' 846 application does not show that DR5 ligation can cause calcium flux.

(AX- 1086 , ~ 107 and AX- 1037).
187.

A person of ordinary skill in the art could not have practiced the assay described

at page 28 , lines 4 to 9 to determine if an isolated antibody would act as an agonist or an

antagonist ofDR5. (AX- l 086 , ~ 107 and AX- I037 , p. 28 , Ins. 4- 9).

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Appendix B to Adams Opposition 3
188.

The assay described at page 28 , lines 10 to 15 of the ' 846 application , involves

detection of a phospholipase enzymatic activity. (AX- 1086 , ~ 108 and AX- 1037 , p. 28 , Ins. 1015).

189.

A person of ordinary skill in the art would have recognized that the assay

described at page 28 , lines 10 to 15 requires use of a cognate ligand , which is not disclosed in the

846 application. (AX- 1086 , ~ 108 and AX- I037 , p. 28 , Ins. 10- 15).
190.

A person of ordinary skill in the art would also have recognized that the assay

described at page 28, lines 10 to 15 could not have been used to determine if a cognate ligand of a

DR5 or an isolated DR5 antibody would induce DR5-mediated apoptosis because phospholipase

activity is not specifically correlated to , and is thus not indicative of, apoptosis induction. (AX1086 , ~ 108 and AX- 1037 , p. 28 , Ins. 10- 15).
191.
The assay described at page 28 , lines 15 to 25 of the ' 846 application , involves

measurement of competitive inhibition of binding of a labeled ligand to the receptor. (AX - 1086

~ 109 and AX- 1037 , p. 28 , Ins. 15- 25).
192.

A person of ordinary skill in the art would have recognized that the assay

described at page 28 , lines 15 to 25 , requires use of a cognate ligand of a DR5 , which is not
identified in the ' 846 application. (AX- l 086 , ~ 109 and AX- 1037 , p. 28 , Ins. 15- 25).
193.

A person of ordinary skill in the art could not have used the assay described at

page 28 , lines 15 to 25 to determine if an isolated antibody would act as an agonist or antagonist

ofa DR5. (AX- 1086 , ~ 109 and AX- 1037 , p. 28 , Ins. 15-25).
194.
At page 28 ,

lines 26- 28 (AX- I037 , p. 28 , Ins. 26- 28), the ' 846 application refers
J. BioI. Chern.

to an assay described in a publication by Tartaglia and Goeddel

267(7):4304- 4307

(1992). (AX- I086 , ~ 110 and NX- 2072).

, p.

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Appendix B to Adams Opposition 3
195.

The Tartaglia paper describes research performed on the TNFR family member

TNFR1. (AX- 1086 , ~ 110 and NX- 2072).
196.

One assay disclosed in the Tartaglia paper involved screening transfected L929

cells to detect cytotoxicity resulting from addition of anti- TNFRl
1086 , ~ 110 and NX- 2072).
197.

A person of ordinary skill in the art would have recognized that the TNFR

transfected cells were treated with cycloheximide in the assay. (AX- l 086 , ~ 110 and NX- 2072).
198.
By March 17 ,

1997 , a person of ordinary skill in the art would have known that

cycloheximide inhibited activation ofthe anti-apoptotic
inhibiting the (innate) NF- KB pathway in the cells which would otherwise block apoptotic

activity. (AX- l 086, ~ 110 and AX- 1046).
199.

A person of ordinary skill in the art would have recognized that the assay

described on page 28 , lines 26- 28 of the ' 846 application required use of the cognate ligand of

TNFRl as a control. (AX- l 086 , ~ 110 and AX- I037 , p. 28 , Ins. 26- 28).
200.

A person of ordinary skill in the art , by March 17 , 1997 , could not have used the

assay described on page 28 , lines 26- 28 of the ' 846 application to determine

antibody would act as an agonist or an antagonist
, Ins. 26- 28).
201.

l 086 , ~ 110 and AX- 1037

The assay mentioned at page 28 , line 29 to page 29 , line 6 of the ' 846 application

is a competitive binding assay that requires use of a " TNF- family ligand" and the candidate
compound. (AX- l 086 , ~ 111 and AX- 1037 , p. 28 , In. 29 to p. 29 , In. 6).

202.

The assay mentioned at page 28 , line 29 to page 29 , line 6 requires use of a

cognate ligand of the DR5 to measure the degree of competition in binding between the test

, p.

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Appendix B to Adams Opposition 3
molecule and the cognate ligand. (AX- 1086 , ~ 111 and AX- I037 , p. 28 , In. 29 to p. 29 , In. 6).
203.

A person of ordinary skill in the art , as of March 17 , 1997, could not have used

the assay mentioned at page 28 , line 29 to page 29 , line 6 to identify an isolated antibody that

would act as an agonist or an antagonist of a DR5. (AX- I086 , ~ 111 and AX- 1037 , p. 28 , In. 29
to p. 29 , In. 6).

A Person of Ordinary Skill in the Art Could Not Have Predicted That A TNFR Familv Member Will Induce Apoptosis Based on The Presence of a Death Domain
204.
By March 17 ,

1997 , a person of ordinary skill in the art would have known that

death domains " are sequence structure motifs involved in protein- protein interactions and are

found in the intracellular regions

, including FADD (MORTl), TRADD
, PELLE , TUBE , DAP- kinase

RIP , Ankryn , the ankryn-related proteins UNC- 5 and UNCmyD88 , N5 , p84 , pRb , NF- KB2/p100 as well as some but

(AX- 1086 , ~ 112; AX- 1076, p. 343 , Fig. 2; and AX- 1077 , p. 322 , Fig. 1).
205.

A person of ordinary skill in the art would have understood that death domain

structures are not exclusive to the TNFR family, and that the presence of a death domain structure
in a newly identified molecule would not , standing alone , warrant classification of the molecule as

a new member of the TNFR family. (AX- 1086 , ~ 112).
206.
By March 17 ,

1997 , a person of ordinary skill in the art would have understood

that the mere presence of a death domain structure in a protein does not reveal the function or
activity of the molecule, and in particular , does not reveal that the molecule will induce apoptosis

upon ligand binding, or even playa role in apoptosis. (AX- 1086 , ~ 113).
207.
By March 17 ,

1997 , it had been shown that several death domain-containing
344 , Fig.

proteins were not implicated in cell- death induction. (AX- 1086 , ~ 113 and AX- I076

)).

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Appendix B to Adams Opposition 3
2 (" so far there is no evidence implicating the ankyrins , myD88 , TUBE , PELLE or NS in celldeath induction
208.

Before March 17 , 1997 , it was well established that the biological effects

exhibited upon ligand binding to TNFRl , Fas and DR3 varied. (AX- l 086 , ~ 116).
209.
The ' 846 application at page 3 , lines 7- , states " TNFR- l can signal an array of
KB. " (AX- 1086,

diverse biological activities - many

~ 116 and AX- I 037 , p. 3, Ins. 7- 9).
210.

Before March 17 , 1997 , TNFR

TNFa were known in the

art to be associated with different biological functions ranging from cell differentiation and

proliferation to inflammation to apoptosis induction. (AX- l 086 , ~ 117 and AX- l 046 , Abstract,
sentence ).

211.
binding ofTNFa

Before March 17 , 1997 , it had been established that activation

ordinarily blocks apoptosis. (AX- 1086 , ~ 117).
By March 17 ,

212.

1997 , a person of ordinary skill in the art would have been familiar
TNFa

with various work, which showed that activation

binding under physiological

conditions , does not result in apoptosis unless additional , artificial measures are taken to inhibit

the activation ofNF- KB by the same ligand-receptor interaction. (AX- 1086 , ~ 117 and AX- 1046).
213.

Several studies published before March 17 , 1997 , had demonstrated that
KB pathway, which was known , before March 17

activation ofTNFRl served to

1997 , to inhibit ligand-mediated apoptosis. (AX- 1086 , ~ 117; AX- 1046; AX- 1070; AX- 107l; and

AX- I072).
214.

A person of ordinary skill in the art by March 17 , 1997 , would have understood

that cognate ligand activation

)).

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Opposition 3

105, 361

predominantly promoted cell survival , through NF- KB activation , rather than inducing apoptosis.
(AX- 1086 , ~ 117).
215.
By March 17 ,

1997, it was known that Fas receptor could induce proliferation of

certain cell types, in addition to an ability to stimulate apoptosis upon binding of a cognate ligand

FasL. (AX- 1086 , ~ 118; AX- I 060 , pp. 705- 706, Fig. 6; and AX- 1078 , p. 2233 , Fig. 1).
216.
By March 17 ,

1997 , it was known that Fas ligand activation of the Fas receptor

recruited the intracellular adaptor molecule F ADD and that F ADD was not

initiating the activation of the NF- KB pathway. (AX- I086 , ~ 118 and NX- 2065 , p. 990 ,

co!. 1 , ~ 1

Activation ofCD95 (Fas) recruits the... molecule FADD. Although the central role ofCD95 is
to trigger apoptosis , TNFR - 1 can signal an array of diverse biological activities , many of which

stem from its ability to activate nuclear factor
217.
March 17 ,

Another TNFR family member referred to in the ' 846 application , DR3 , had , by

1997 , been shown to

NF- KB pathway. (AX- 1086 ,

~ 119 and NX- 2065).

218.

By March 17, 1997 , the predominant signaling associated with ligand binding to

DR3 was not known , as a cognate ligand for DR3 had not yet been identified. (AX- l 086 , ~ 119).
219.
By March 17 ,

1997 , the death domain-containing TNFR family member, p75

NGFR , had been shown to inhibit apoptosis upon binding by its cognate ligand , NGF. (AX- l 086
~ 120).

220.

Rabizadeh

et al. explain that " expression ofp75 NGFR induced neural cell death

constitutively when p75 NGFR was unbound; binding by NGF or monoclonal antibody, however
inhibited cell death induced by p75 NGFR. " (AX- 1086 , ~ 120 and AX- 1068 , Abstract).
221.

Chapman reports that" .. . cell

, p.

,~

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Appendix B to Adams Opposition 3
reversed rather than caused by ligand binding. " (AX- 1086 , ~ 120 and AX- 1069 , p. 216 ,
222.

col. 1).

Despite the presence of a death domain that had a sequence identity of
, apoptosis was not induced in the

approximately 27% to the death domains
same manner upon agonist binding

(i.

NGF or agonist antibody) to NGFR. (AX- 1086 , ~ 120

and AX- I 069
223.

216 , co!. 2 , ~ 3. 1).
The ' 846 application provides little discussion regarding the p7S-NGFR. (AX-

1086, ~ 121 and AX- 1037).
224.

The ' 846 application does not contain

based

sequence comparisons ofa DRS sequence to the NGFR sequence. (AX- I086 , ~ 121 and AX1037).
22S.
The ' 846 application does not discuss the biological effects induced by ligand

binding to NFGR that had been reported in the scientific literature by March 17 , 1997. (AX1086 , ~ 121 and AX- 1037).

226.

Before March 17 , 1997 , researchers (including Dr. John Reed) had identified a

region within the intracellular domain of CD40 that shared some structural similarity with other

known death domains. (AX- 1086, ~ 124; AX- I 080; and AX- I081).
227.

It had been reported , prior to March 17 , 1997 , that CD40 had an intracellular
31 %)

region that shared sequence homology with the death domains
and Fas (39- 41%). (AX- 1086 , ~ 124; AX- 1080 , p.161 , Fig. 1; and AX- 1081 , p. 113).
228.

Prior to March 17 , 1997 , it had been suggested, that CD40 played a role in cell

survival and cell proliferation , and protected against apoptosis in certain cell types. (AX- l 086
124; AX- 1082; and AX- I083 , Abstract).

229.

As of March 17 , 1997 , knowledge that a TNFR family member contained a death

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Appendix B to Adams Opposition 3
Interference No. 105, 361

domain would not have provided a person of ordinary skill in the art a basis for reasonably

predicting that the receptor would induce apoptosis upon cognate ligand binding. (AX- I086,
125).

~

Mechanisms of Apoptosis Known bv March 17. 1997
230.

It was known by March 17 , 1997 that in order to stimulate an intracellular signal

upon ligand binding, a TNFR family protein needed to recruit certain intracellular adaptor
proteins. (AX- 1086 , ~ 126 and AX- 1065 , p. 357).
231.

It was known by March 17 , 1997 , that signaling by TNFRl was mediated by an

intracellular molecule known as TNFRl-associated death domain protein (TRADD). (AX- I086
~ 126).

232.

By March 17 ,

1997, intracellular signaling by Fas was known to be mediated by

direct binding of a distinct different adaptor protein called Fas-associated death domain-

containing molecule (FADD). (AX- 1086 , ~ 126; AX- 1084 , Abstract; and AX- 1079 , Abstract).
233.
By March 17 ,

1997 , it was known that the identity of the intracellular adaptor

molecule recruited by a receptor makes a critical difference as to whether (i) apoptosis is induced (FADD and caspase 8), (ii) apoptosis is inhibited (RIP and NF- KB), or (iii) some other cellular

signaling pathway is activated (TRAF2 and JNK). (AX- 1086 , ~ 127).
234.

Which signaling pathway or pathways would be activated or what resulting

biological effect would occur could not have been predicted based on comparisons or alignments

ofreceptor (or death domain)

1086 , ~ 127).

Sequence Structure Identitv or Similaritv TNFRs With Death Domains
235.
The ' 846 application provides a sequence alignment of the DR5 amino acid

sequence to those ofTNFRl , Fas and DR3. (AX- l 086 , ~ 128 and AX- I037 , p. 5, Ins. 8- 13 and

g.,

g.,

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Appendix B to Adams Opposition 3
Figure 2).

236.

The ' 846 application reports that "the DR5 polypeptide ofthe invention shares the

greatest degree of homology with human TNFRl , Fas and DR3... " (AX- I086 , ~ 128 and AX1037 , p. 6 , Ins. 29- 30).

237.

The ' 846 application suggests that a death domain is present in DR5 , and

comprises amino acids 324- 391 of the DR5 sequence. (AX- 1086 , ~ 129 and AX- 1037 , p. 9 , Ins.
13- 18).

238.

The ' 846 application notes that because the domain was predicted by
(e.

graphics , the amino acid residues that constitute the domain " may vary slightly

by about 1 to

15 residues) depending on the criteria used to define the domain.
1037).

Id.

(AX- 1086 , ~ 129 and AX-

239.

The ' 846 application does not provide any analysis regarding the identity or

conservation of specific amino acids within the putative death domain. (AX- 1086 , ~ 130 and AX1037).

240.

By March 17 ,

1997 , certain amino acid residues in the death domain were known

to be crucial to the activity of the death domain ofTNFR1. (AX- 1086 , ~ 130; NX- 2078 , Table 2;
and AX- I 085 , Fig. 4B).
241.
The ' 846 application does not identify any amino acid residues within the DR5

putative death domain from which a person of ordinary skill in the art could have predicted, as of
March 17 ,

1997 , or as of July 29, 1997, which , if any, intracellular effector molecules

FADD or TRADD , would directly interact with the putative death domain. (AX- 1086 , ~ 130 and

AX- 1037).
242.

A person of ordinary skill in the art would have understood that the function of a

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Appendix B to Adams Opposition 3
DRS and its mode of action could not be predicted from a sequence comparison of it to TNFRl
Fas and DR3 as of March 17 , 1997 , and as of July 29 , 1997. (AX- 1086 , ~ 131).
243.

A person of ordinary skill in the art would have understood that the capacity of a

given TNFR family member to activate the NF - KB pathway upon binding by a

would have a very strong bearing on its ability to induce or inhibit apoptosis. (AX- l 086 , ~ 131).

VII.

The ' 846 Application Did Not Teach a Person of

Make and Use an Experimentation
244.

The information provided in the ' 846 application would

sufficient information to a person of ordinary skill in the art to produce an isolated antibody that

binds to an extracellular domain of a DRS and acts as either an agonist or as an antagonist of
DRS , without having to engage in an undue amount of research and experimentation. (AX- 1086

~ 132 and AX- 1037).
VIII.

Observations on U. S.

Provisional Application 60/054. 021. filed Julv 29. 1997

24S.

The information added in the ' 021 application relative to what is contained in the

846 application includes: an example showing that overexpression of DRS in the absence of a ligand results in cell killing in MCF- 7 and Hela cell lines; an example showing that