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Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS VI LLC

By: Jeffrey D. Blake, Esq.


MERCHANT & GOULD P.C.
191 Peachtree Street N.E., Suite 4300
Atlanta, GA 30303
jblake@merchantgould.com
Main Telephone: (404) 954-5100
Main Facsimile: (404) 954-5099
UNITED STATES PATENT AND TRADEMARK OFFICE
___________________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
___________________
COALITION FOR AFFORDABLE DRUGS VI LLC,
Petitioner,
v.
CELGENE CORPORATION,
Patent Owner.
___________________
Case No.: Unassigned
Patent No.: 5,635,517
________________________________________________________

PETITION FOR INTER PARTES REVIEW OF PATENT NO. 5,635,517

Petition For Inter Partes Review


Patent No. 5,635,517
TABLE OF CONTENTS
I.

INTRODUCTION.........................................................................................1

II.

MANDATORY NOTICES UNDER 37 C.F.R. 42.8(a)(1) ........................6

A.

Real Party-In-Interest Under 37 C.F.R. 42.8(b)(1) .....................................6

B.

Related Matters Under 37 C.F.R. 42.8(b)(2) ..............................................8

C.

Lead And Back-Up Counsel Under 37 C.F.R. 42.8(b)(3) & 42.10(a) ......8

D.

Service Information Under 37 C.F.R. 42.8(b)(4) ........................................9

III.

PAYMENT OF FEES UNDER 37 C.F.R. 42.103 .....................................9

IV.

REQUIREMENTS FOR IPR UNDER 37 C.F.R. 42.104 ..........................9

A.

Grounds For Standing Under 37 C.F.R. 42.104(a) .....................................9

B.

Identification Of Challenge Under 37 C.F.R. 42.104(b) And Relief


Requested ....................................................................................................10

1.

Claims For Which IPR Is Requested Under 37 C.F.R. 42.104(b)(1) ....10

2.

Specific Art And Statutory Grounds On Which The Challenge Is


Based Under 37 C.F.R. 42.104(b)(2) .....................................................10

3.

The Construction Of The Challenged Claims Under 37 C.F.R.


42.104(b)(3)............................................................................................12

4.

How The Construed Claims Are Unpatentable Under 37 C.F.R.


42.104(b)(4)............................................................................................12

5.

Supporting Evidence Under 37 C.F.R. 42.104(b)(5) .............................12

V.

SUMMARY OF THE 517 PATENT ........................................................13

A.

Lineage Of The 517 Patent ........................................................................13

B.

Description Of The Alleged Invention Of The 517 Patent ........................13

C.

Construction Of Key Terms In The 517 Claims ........................................13

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Patent No. 5,635,517
D.

Summary Of The Original Prosecution Of The 517 Patent .......................16

E.

Summary Of The Ex Parte Reexamination Of The 517 Patent ................16

F.

The State Of The Art ...................................................................................19

VI.

PETITIONER HAS A REASONABLE LIKELIHOOD OF


PREVAILING .............................................................................................22

A.

Each Reference Relied On For Grounds 1-3 Is Prior Art ...........................23

B.

A Person Of Ordinary Skill In The Art .......................................................23

C.

Ground 1: Claims 1 And 7-9 (Dioxo Analogs) Are Obvious Over


Piper And Kaplan .......................................................................................24

1.

Piper Discloses Dioxo Amino-Thalidomide Analogs Having Key


Functional Properties In Common With Thalidomide.............................25

2.

Kaplan Discloses That Thalidomide, Thalidomide Analogs, And


Other Anti-Inflammatory And Immunosuppressive Compounds
Reduce TNF ...........................................................................................29

3.

Summary: Claims 1 And 7-9 Are Obvious Aver Piper And Kaplan ......32

D.

Ground 2: Claims 2-6 and 10 (1-Oxo Analogs) Are Obvious Over


Piper, Kaplan, Agrawal, and WO 085 .......................................................37

1.

Piper Discloses Thalidomide Analogs Having Key Functional Properties


In Common With Thalidomide and High Structural Similarity To
Thalidomide .............................................................................................39

2.

Kaplan Discloses That Thalidomide, Thalidomide Analogs, And Other


Anti-Inflammatory And Immunosuppressive Compounds Reduce
TNF ........................................................................................................39

3.

Agrawal Discloses That Amino-Substituted Thalidomide Analogs


Retain Anti-Inflammatory Activity ..........................................................40

4.

WO 085 Discloses 1-Oxo Hydroxyl-Substituted Thalidomide


Analogs Having Activity In Common With Thalidomide .......................42

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Patent No. 5,635,517
5.
E.

VII.

Summary: Claims 2-6 And 10 Are Obvious Over Piper, Kaplan,


Agrawal, And WO 085............................................................................43
Ground 3: Claims 2-6 And 10 (1-Oxo Analogs) Are Obvious Over
Piper, Kaplan, Agrawal, And Keith ............................................................52

1.

Piper And Kaplan Point To EM 12 As The Lead Compound .................52

2.

Agrawal Provides Motivation To Aminate EM 12 ..................................54

3.

Keith Provides Further Motivation To Aminate EM 12 ..........................55

4.

Summary: Claims 2-6 And 10 Are obvious Over Piper, Kaplan,


Agrawal, And Keith..................................................................................56
CONCLUSION ...........................................................................................59

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Patent No. 5,635,517
TABLE OF AUTHORITIES
Cases
Graham v. John Deere Co.,
383 U.S. 1 (1966)...........................................................................................23
In re Deuel,
51 F.3d 1552 (Fed. Cir. 1995) .......................................................................46
In re Petering,
301 F.2d 676 (CCPA 1962) .....................................................................46, 54
KSR Intl Co. v. Teleflex, Inc.,
550 U.S. 398 (2007).................................................................................23, 47
Statutes& Other Authorities
35 U.S.C. 102(b) .............................................................................................11, 24
35 U.S.C. 103 ........................................................................................................ 18
35 U.S.C. 103(a) ....................................................................................... 11-12, 23
35 U.S.C. 156 ........................................................................................................ 15
35 U.S.C. 311-319................................................................................................. 1
35 U.S.C. 315(e)(1) ............................................................................................... 10
37 C.F.R. 42.6(e)................................................................................................... 61
37 C.F.R. 42.8(a)(1) ................................................................................................ 6
37 C.F.R. 42.8(b)(1) ................................................................................................ 6
37 C.F.R. 42.8(b)(2) ................................................................................................ 8
37 C.F.R. 42.8(b)(3) ................................................................................................ 8
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Patent No. 5,635,517

37 C.F.R. 42.8(b)(4) ................................................................................................ 9


37 C.F.R. 42.10(a)................................................................................................... 8
37 C.F.R. 42.10(b) .................................................................................................. 9
34 C.F.R. 42.15(a)(1-2)........................................................................................... 9
37 C.F.R. 42.63(a)................................................................................................. 13
37 C.F.R. 42.100 et seq ........................................................................................... 1
37 C.F.R. 42.100(b) .............................................................................................. 12
37 C.F.R. 42.102(a)(2) .......................................................................................... 10
37 C.F.R. 42.103 ..................................................................................................... 9
37 C.F.R. 42.104 ..................................................................................................... 9
37 C.F.R. 42.104(a)............................................................................................... 10
37 C.F.R. 42.104(b) .............................................................................................. 10
37 C.F.R. 42.104(b)(1) .......................................................................................... 10
37 C.F.R. 42.104(b)(2) .......................................................................................... 10
37 C.F.R. 42.104(b)(3) .......................................................................................... 12
37 C.F.R. 42.104(b)(4) ....................................................................................12, 22
37 C.F.R. 42.104(b)(5) .......................................................................................... 12
MPEP 2144.09(I) .................................................................................................. 46
PTAB IPR2012-00006 Final Written Decision (Mar. 6, 2014) .............................. 20

vii

Petition For Inter Partes Review


Patent No. 5,635,517
Coalition For Affordable Drugs VI LLC (Petitioner or CFAD)
respectfully submits this Petition for Inter Partes Review (IPR) of claims 1-10 of
U.S. Patent No. 5,635,517 (the 517 Patent) (Ex. 1001) pursuant to 35 U.S.C.
311-319 and 37 C.F.R. 42.100 et seq. The challenged claims relate to methods of
administering thalidomide analogs to reduce tumor necrosis factor alpha (TNF) in
mammals and the corresponding chemical structures of certain of those analogs.
I.

INTRODUCTION
The 517 Patent is directed to a method of reducing TNF in mammals by

administering an effective amount of an amino-substituted thalidomide analog. The


structure of thalidomide is:

The claimed thalidomide analogs include: (i) modified thalidomide having


an NH2 (amino) group attached to the benzo ring (the dioxo embodiment); and
(ii) modified thalidomide having both an amino group attached to the benzo ring
and CH2 (methylene) in place of a C=O (carbonyl) in the phthalimide ring system
(the 1-oxo embodiment). In general, claims 1 and 7-9 recite methods of reducing
TNF in mammals by administering dioxo amino-thalidomide analogs; claims 2-6
recite methods of reducing TNF in mammals by administering 1-oxo amino-

Petition For Inter Partes Review


Patent No. 5,635,517
thalidomide analogs; and claim 10 is a product claim directed to the specific 1-oxo
amino-thalidomide analogs recited in claims 2-6.
During the original prosecution and a subsequent ex parte reexamination of
the 517 Patent, the assigned examiners were not aware of key prior art that
disclosed amino-substituted thalidomide analogs, including at least two analogs
encompassed by claims 1 and 7-9, that were administered to mammals and
demonstrated anti-inflammatory or immunosuppressive activity, both of which
were known to be important to the efficacy of thalidomide. The prior art also
discloses that other anti-inflammatory and immunosuppressive compounds were
known to reduce TNF, and that thalidomide and a variety of its analogs (including
some having high structural and functional similarity to the compounds
encompassed by claims 1-10) inhibit TNF production.
Petitioner asserts three grounds for invalidity: (1) claims 1 and 7-9 are
obvious over Piper in view of Kaplan; (2) claims 2-6 and 10 are obvious over
Piper in view of Kaplan, Agrawal, and WO 085; and (3) claims 2-6 and 10 are
obvious over Piper in view of Kaplan, Agrawal, and Keith.
Ground 1: Piper is a 1981 abstract that discloses dioxo amino-thalidomide
adjacent analogs1 AH 13 and AH 14, which are encompassed by claims 1 and

As used herein, an adjacent analog is a compound that differs from another by


the presence or absence of only one functional group. (Ex. 1007, 74.)
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Patent No. 5,635,517
7-9. The structures of AH 13 and AH 14 differ from thalidomide only by the
presence of an amino group at the 5- or 4-position of the benzo ring, respectively.
Piper also discloses EM 12, which was a well-known 1-oxo adjacent analog
having a structure that differs from thalidomide only by the presence of methylene
in place of a carbonyl in the phthalimide ring system. The structures of AH 13, AH
14, and EM 12 are:

Pipers study demonstrated that AH 13, AH 14, and EM 12 exhibit antiinflammatory or immunosuppressive activity in mammals. Piper also points out
that these activities are clinically relevant modes of action of thalidomide. Piper
was not of record during prosecution of the 517 Patent.
Kaplan is a U.S. patent published in January 1995, and discloses that
thalidomide and a variety of its analogs inhibit TNF production in humans, with
an express preference for EM 12. Kaplan also refers to anti-inflammatory and
immunosuppressive steroids that block TNF production. Kaplan was of record
during prosecution of the 517 Patent, but was not considered in combination with
the key disclosures of Piper.
Piper and Kaplan collectively show that the parent compound (thalidomide)
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Patent No. 5,635,517
and its adjacent analogs AH 13 and AH 14 all exhibit clinically relevant antiinflammatory and/or immunosuppressive activity, and that other anti-inflammatory
and immunosuppressive compounds were known to reduce TNF. Thus, before
July 1996, it would have been obvious for one of ordinary skill in the art to
administer dioxo amino-thalidomide analogs encompassed by claims 1 and 7-9
(e.g., AH 13 and AH 14) to a mammal with a reasonable expectation of
successfully reducing its TNF levels.
Ground 2: Agrawal is another 1981 abstract (published alongside Piper),
and discloses that thalidomide analogs in which the benzo ring is substituted with
amino or hydroxyl are preferred over those having nitro or carboxyl substituents
because only the amino- and hydroxyl-substituted analogs were shown to retain
anti-inflammatory activity in mammals. Agrawal was not of record during
prosecution of the 517 Patent.
WO 085 is an international patent application published in September 1994,
and discloses that thalidomide, EM 12, and hydroxyl-substituted EM 12 are all
anti-angiogenic. WO 085 was not of record during prosecution of the 517 Patent.
Piper, Kaplan, and Agrawal show that thalidomide, adjacent aminosubstituted dioxo analogs AH 13 and AH 14, and an adjacent 1-oxo analog EM 12
all exhibit clinically relevant anti-inflammatory and/or immunosuppressive
activity. Agrawal also teaches that amino-substituted thalidomide analogs retain
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Patent No. 5,635,517
the anti-inflammatory activity of the parent. Kaplan further teaches that
thalidomide and analogs thereof, including the preferred analog EM 12, reduce
TNF in humans, and that other anti-inflammatory and immunosuppressive
compounds were known to reduce TNF. WO 085 teaches that thalidomide, EM
12, and hydroxyl-substituted EM 12 all effectively inhibit angiogenesis.
Accordingly, these references show a direct link between structure and function
among thalidomide analogs. Thus, before July 1996, it would have been obvious
for one of ordinary skill to make the analogs encompassed by claims 2-6 and 10
(i.e., EM 12 with an amino-substituted benzo ring) for administration to a mammal
with a reasonable expectation of successfully reducing its TNF levels.
Ground 3: In 1981, Piper included EM 12 among its tested analogs and
found that it retained the anti-inflammatory activity of thalidomide. In 1995,
Kaplan emphasized the significance of EM 12 by identifying it as its most
preferred analog of thalidomide for reducing TNF in humans. From the teachings
in Piper and Kaplan, it is obvious that EM 12 arose as the lead compound in the
field. It would have been obvious to then make simple changes to the structure of
this lead compound in an effort to identify other analogs with similar or improved
properties. Agrawal and Keith provide specific motivation to make such analogs by
modifying EM 12 to add an amino substituent. Specifically, Agrawal teaches that
thalidomide analogs substituted with electron donating groups (namely, amino and
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Patent No. 5,635,517
hydroxyl) maintain the anti-inflammatory activity of thalidomide (which Piper
teaches is also an activity of EM 12), whereas analogs substituted with electron
withdrawing groups do not. Hence, one of ordinary skill would have been
motivated to make a structural modification that retains a key activity of the parent
compound. Furthermore, Keith teaches that both thalidomide and EM 12 are
essentially insoluble in water. Thus, adding an amino group to EM 12 would be
desirable as a means to increase solubility, making the compound easier to
formulate and also more bioavailable upon administration. Keith was not of record
during prosecution of the 517 Patent.
Thus, before July 1996, it would have been obvious for one of ordinary skill
in the art to identify EM 12 as the lead compound, easily modify it to add an amino
group at any one of the open positions on the benzo ring, and administer such
amino-substituted EM 12 analogs encompassed by claims 2-6 and 10 to a mammal
with a reasonable expectation of successfully reducing its TNF levels.
II.

MANDATORY NOTICES UNDER 37 C.F.R. 42.8(a)(1)


A.

Real Party-In-Interest Under 37 C.F.R. 42.8(b)(1)

Petitioner certifies that CFAD, Hayman Credes Master Fund, L.P.


(Credes), Hayman Orange Fund SPC Portfolio A (HOF), Hayman Capital
Master Fund, L.P. (HCMF), Hayman Capital Management, L.P. (HCM),
Hayman Offshore Management, Inc. (HOM), Hayman Investments, L.L.C.
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Patent No. 5,635,517
(HI), nXn Partners, LLC (nXnP), IP Navigation Group, LLC (IPNav), J.
Kyle Bass, and Erich Spangenberg are the real parties-in-interest (collectively,
RPI).
The RPI certifies the following information: CFAD is a wholly owned
subsidiary of Credes. Credes is a limited partnership. HOF is a segregated portfolio
company. HCMF is a limited partnership. HCM is the general partner and
investment manager of Credes and HCMF. HCM is the investment manager of
HOF. HOM is the administrative general partner of Credes and HCMF. HI is the
general partner of HCM. J. Kyle Bass is the sole member of HI and sole
shareholder of HOM. CFAD, Credes, HOF, and HCMF act, directly or indirectly,
through HCM as the general partner and/or investment manager of Credes, HOF
and HCMF. nXnP is a paid consultant to HCM. Erich Spangenberg is the 98.5%
member of nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is the
98.5% member of IPNav.
Other than HCM and J. Kyle Bass in his capacity as the Chief Investment
Officer of HCM and nXnP, and Erich Spangenberg in his capacity as the
Manager/CEO of nXnP, no other person (including any investor, limited partner,
or member or any other person in any of CFAD, Credes, HOF, HCMF, HCM,
HOM, HI, nXnP, or IPNav) has authority to direct or control (i) the timing of,
filing of, content of, or any decisions or other activities relating to this Petition or
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Patent No. 5,635,517
(ii) any timing, future filings, content of, or any decisions or other activities
relating to the future proceedings related to this Petition. All of the costs associated
with this Petition will be borne by HCM, CFAD, Credes, HOF and/or HCMF.
B.

Related Matters Under 37 C.F.R. 42.8(b)(2)

The 517 Patent is currently the subject of two patent infringement lawsuits
brought by Celgene Corporation against Natco Pharma Limited in the U.S. District
Court for the District of New Jersey, Case No.: 2:10cv5197 and Case No.:
2:12cv4571. Civil Action No. 12-4571 was consolidated with Civil Action No. 105197 on November 9, 2012. Additionally, pending U.S. Patent Application No.
14/156,325 filed January 15, 2014 claims priority to the 517 Patent.
C.

Lead And Back-Up Counsel Under 37 C.F.R. 42.8(b)(3) &


42.10(a)

Lead Counsel
Jeffrey D. Blake, Esq.
Reg. No. 53,214
Merchant & Gould PC
191 Peachtree Street N.E., Suite 4300
Atlanta, GA 30303
Main Telephone: (404) 954-5100
Main Facsimile: (404) 954-5099
jblake@merchantgould.com

Back-Up Counsel
Dianna G. El Hioum, Esq.
Reg. No. 52,949
Merchant & Gould PC
767 Third Avenue, 23rd Floor
New York, NY 10017
Main Telephone: (212) 223-6520
Main Facsimile: (212) 223-6521
delhioum@merchantgould.com
Ryan James Fletcher, Ph.D., Esq.
(Pro Hac Vice)
Merchant & Gould PC
1801 California Street, Suite 3300
Denver, CO 80202
Main Telephone: (303) 357-1670
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Patent No. 5,635,517
Main Facsimile: (303) 357-1950
rfletcher@merchantgould.com
Brent E. Routman, Esq.
(Pro Hac Vice)
Merchant & Gould PC
3200 IDS Center
80 South Eighth Street
Minneapolis, MN 55402
Main Telephone: (612) 332-5300
Main Facsimile: (612) 322-9081
broutman@merchantgould.com
Pursuant to 37 C.F.R. 42.10(b), a Power of Attorney is provided herewith.
D.

Service Information Under 37 C.F.R. 42.8(b)(4)

Service information for lead and back-up counsel is provided above in the
designation of lead and back-up counsel. Petitioner also consents to electronic
service by e-mail at RevlimidIPR@merchantgould.com.
III.

PAYMENT OF FEES UNDER 37 C.F.R. 42.103


Payment of $23,000 for the fees set forth in 37 C.F.R. 42.15(a)(1-2)

accompanies this Petition. The USPTO is authorized to charge Deposit Account


No. 13-2725 for any additional fees that may be due for this Petition.
IV.

REQUIREMENTS FOR IPR UNDER 37 C.F.R. 42.104


A.

Grounds For Standing Under 37 C.F.R. 42.104(a)

Petitioner certifies that the 517 Patent is available for IPR and that neither
Petitioner nor any RPI is barred or estopped from requesting this IPR because: (1)

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Patent No. 5,635,517
neither Petitioner nor any RPI is the patent owner; (2) neither Petitioner nor any
RPI has filed a civil action challenging the validity of a claim in the patent; (3)
neither Petitioner nor any RPI has been served with a complaint alleging
infringement of the patent; (4) the estoppel provisions of 35 U.S.C. 315(e)(1) do
not prohibit this IPR; and (5) the patent is not described in 3(n)(1) of the America
Invents Act and so is available for IPR under 37 C.F.R. 42.102(a)(2).
B.

Identification Of Challenge Under 37 C.F.R. 42.104(b) And


Relief Requested
1.

Claims For Which IPR Is Requested Under 37 C.F.R.


42.104(b)(1)

Petitioner requests IPR and cancellation of claims 1-10 of the 517 Patent as
unpatentable over the prior art for the reasons given herein.
2.

Specific Art And Statutory Grounds On Which The Challenge


Is Based Under 37 C.F.R. 42.104(b)(2)

IPR of the 517 Patent is requested in view of the following five


publications: (1) Piper et al., Int. J. Lepr., 49(4):511-512 (July 14, 1981) (Piper)
(Ex. 1002); (2) Agrawal et al., Int. J. Lepr., 49(4):512 (July 14, 1981 (Agrawal)2
(Ex. 1004); (3) U.S. Patent No. 5,385,901 to Kaplan et al. (Kaplan) (Ex. 1003);
(4) WO 94/20085 to DAmato (WO 085) (Ex. 1005); and (5) KEITH &
WALTERS, NATIONAL TOXICOLOGY PROGRAMS CHEMICAL SOLUBILITY
2

Both Piper and Agrawal were published on the same date on consecutive pages
of the same issue of the International Journal of Leprosy, but are presented
independently in this Petition in an effort to improve clarity.
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Patent No. 5,635,517
COMPENDIUM (Lewis Publishers, Inc. 1992) (Keith) (Ex. 1006).
Each of the publications listed above is available as prior art against the 517
Patent under pre-AIA 35 U.S.C. 102(b) because each was published more than
one year before July 24, 1996, which is the filing date of the earliest application to
which the 517 Patent claims priority. Specifically, (1) Piper was published on July
14, 1981; (2) Kaplan was published on January 31, 1995; (3) Agrawal was
published on July 14, 1981; (4) WO 085 was published on September 15, 1994;
and (5) Keith was published in 1992.
The following combinations of the above-listed publications render claims
1-10 of the 517 Patent obvious under pre-AIA 35 U.S.C. 103(a):
Ground
1
2

Claim Nos. Proposed Statutory Rejections


1, 7-9
Claims 1 and 7-9 of the 517 Patent are obvious under
35 U.S.C. 103(a) over Piper in view of Kaplan.
2-6, 10
Claims 2-6 and 10 of the 517 Patent are obvious
under 35 U.S.C. 103(a) over Piper in view of
Kaplan, Agrawal, and WO 085.
2-6, 10
Claims 2-6 and 10 of the 517 Patent are obvious
under 35 U.S.C. 103(a) over Piper in view of
Kaplan, Agrawal, and Keith.

Copies of Piper, Kaplan, Agrawal, WO 085, and Keith are filed herewith.
The above grounds for unpatentability are supported by the Declaration of Clayton
H. Heathcock, Ph.D. (Ex. 1007) filed herewith.

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Patent No. 5,635,517
3.

The Construction Of The Challenged Claims Under 37 C.F.R.


42.104(b)(3)

The terms of the 517 Patent claims are to be given their broadest reasonable
construction in light of the specification, as understood by a person of ordinary
skill in the art. See 37 C.F.R. 42.100(b). Petitioner submits, for purposes of the
IPR only, the constructions given in Section V.C. below. Any claim terms not
discussed herein should be given their ordinary meaning under the broadest
reasonable construction standard of 42.100(b).
4.

How The Construed Claims Are Unpatentable Under 37 C.F.R.


42.104(b)(4)

A detailed explanation of the unpatentability of claims 1-10 of the 517


Patent, including an identification of where each claimed element is found in prior
art relied on herein, is set forth below in Section VI.
5.

Supporting Evidence Under 37 C.F.R. 42.104(b)(5)

A listing of Exhibits is provided herewith, which identifies the evidence


relied on to support the challenges to claims 1-10. Section VI provides descriptions
and claim charts identifying specific portions of the evidence that support each
challenge. Provided herewith is a Declaration of Clayton H. Heathcock, Ph.D. (Ex.
1007) under 37 C.F.R. 42.63(a) attesting to, among other issues, the obviousness
of compounds discussed herein and their ability to reduce TNF.

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Patent No. 5,635,517
V.

SUMMARY OF THE 517 PATENT


A.

Lineage Of The 517 Patent

The 517 Patent, entitled Method of reducing TNF levels with amino
substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo and 1,3-dioxoisoindolines, issued
on June 3, 1997, from U.S. Patent Application No. 08/690,258 (the 258
Application) filed July 24, 1996.
B.

Description Of The Alleged Invention Of The 517 Patent

The 517 Patent is directed to amino-thalidomide analogs and a method of


reducing TNF in mammals by administering a dioxo amino-thalidomide analog or
a 1-oxo amino-thalidomide analog. (Ex. 1001 at 4:20-34.) The patentees alleged
basis for patentability is the purported discovery that amino-substituted
thalidomide analogs decrease levels of TNF in mammals. (Id. at 4:15-19.) Yet,
the 517 Patent admits that some of the claimed dioxo amino-thalidomide analogs
were previously known (id. at 4:58-62), and that the claimed compounds can be
prepared using methods that were known in the prior art. (Id. at 4:64-67.)
C.

Construction Of Key Terms In The 517 Claims

Claims 3-6 and 8-10 recite the following chemical compound names:
Claim #
3
4
5
6

Recited Chemical Compound Name


1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline
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Patent No. 5,635,517
8
9
10

1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;
1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;
1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline

All of the above-listed compounds recite an aminoisoindoline moiety.


Isoindoline is shown below with standard IUPAC ring numbering indicated around
the benzo ring:

(Ex. 1007, 100-03.) Consequently, 4-, 5-, 6-, or 7-aminoisoindoline would have
an amino group at the 4-, 5-, 6-, or 7-position of the isoindoline moiety. This ring
numbering was confirmed by the patentee in its Application for Extension of
Patent Term Under 35 U.S.C. 156 filed February 3, 2006 (Ex. 1011 at 2), which
identifies the compound of claim 4 by its full chemical name, common name,
proprietary name, and structure. Specifically, the patentee stated (in part):

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Patent No. 5,635,517
(Id.) Hence, the patentee confirmed that the claimed 4-aminoisoindoline moiety
has an amino group at the 4-position, according to the standard IUPAC ring
numbering described above. Accordingly, the chemical names recited in claims 3-6
and 8-10 should be interpreted as referring to the following chemical structures,
likewise in accordance with IUPAC ring numbering (Ex. 1007, 102-03):
Claim #
3

Claimed Compound
1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline

1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline

1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline

1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline

1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline

1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline

10

1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline

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Patent No. 5,635,517

1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline

1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline

1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline

D.

Summary Of The Original Prosecution Of The 517 Patent

The 258 Application was filed with ten claims on July 24, 1996. (Ex. 1012
at 15.) None of the claims were rejected. During a telephonic examiner interview
conducted February 5, 1997, the applicant agreed to correct a typographical error
in claim 7 by amending this claim to read each of X and Y is C=O instead of
each of and Y is CH2. (Ex. 1014.) A Notice of Allowance was then mailed on
February 11, 1997. (Ex. 1013.) The 517 Patent subsequently issued on June 3,
1997, without further amendments to any of the claims.
E.

Summary Of The Ex Parte Reexamination Of The 517 Patent

The patent owner filed a request for ex parte reexamination of the 517
Patent on April 20, 1998 (Ex. 1015), based on the disclosures in U.S. Patent No.

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Patent No. 5,635,517
5,593,990 (Ex. 1016) and its progeny (collectively, the DAmato Patents), U.S.
Patent No. 4,808,402 (Leibovich I) (Ex. 1017), and Leibovich et al., Letters to
Nature, 329:630-32 (Oct. 15, 1987) (Leibovich II) (Ex. 1018). According to the
patent owner, this request was filed because of a question raised by a nonadversarial third party, a potential licensee. (Ex. 1015 at 3.) The request was
granted on November 4, 1998. (Ex. 1019.)
In a February 22, 1999 Office Action, the Examiner rejected all of the claims
under 35 U.S.C. 103 as obvious over the DAmato Patents in view of Leibovich I
and Leibovich II. (Ex. 1020 at 2-4.) In making this rejection, the Examiner correctly
noted that the DAmato Patents disclose hydroxyl-thalidomide analogs and epoxythalidomide analogs that are very closely analogous compounds to the claimed
compounds. (Id. at 3.) For example, the DAmato Patents disclose the following
dioxo and 1-oxo hydroxyl-thalidomide analogs:

(Ex. 1016 at Figure 3.) The only difference between the hydroxyl-thalidomide
analogs of the DAmato Patents (above) and the amino-thalidomide analogs of
claims 1-10 (supra Section V.C.) is the presence of a OH (hydroxyl) group instead
of an NH2 (amino) group on the benzo ring.

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Patent No. 5,635,517
The Examiner further stated that the DAmato Patents recognize the
equivalence of hydroxyl, epoxy, and amino groups, and that one of ordinary skill in
the art would have been motivated to replace the hydroxyl group in the compounds
of the DAmato Patents Figure 3 with an amino group. (Ex. 1020 at 3-4.) The
Examiner also asserted that both Leibovich I and Leibovich II disclose methods of
controlling abnormal concentrations of TNF using thalidomide. (Id.)
In response, the patent owner filed a Request for Reconsideration on
February 25, 1999, arguing that the closest prior art disclosure was the hydroxylthalidomide analogs in the DAmato Patents, and that the DAmato Patents do not
suggest or equate amino compounds with the hydroxyl or epoxy compounds. (Ex.
1021 at 2.) In an earlier statement, the patent owner also argued that one of ordinary
skill in the art would have been faced with literally millions of possibilities to
approximate the [claimed amino-substituted thalidomide analogs] used in the
methods of and the compounds defined in the claims, and therefore alleged that
the prior art did not generically teach the claimed compounds. (Ex. 1022 at 3.)
The patent owner also asserted that neither Leibovich I nor Leibovich II mentions
thalidomide. (Ex. 1021 at 2.)
Accompanying the Request for Reconsideration was a declaration from
David I. Stirling, Ph.D. (Ex. 1023), a named inventor on the 517 Patent. Stirlings
declaration compared the relative activity of a dioxo hydroxyl-thalidomide analog
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Patent No. 5,635,517
(Compound 1) with that of a dioxo amino-thalidomide analog (Compound 2),
and concluded that both compounds inhibit TNF but that the dioxo aminothalidomide analog was over 10,000 fold more active. (Id. at 3-5.)
Relying on the declaration of Stirling, the Examiner issued a Notice of Intent
to Issue Reexamination Certificate for all ten claims on March 23, 1999. (Ex.
1024.) The alleged unexpected results considered persuasive during reexamination
are, in fact, irrelevant because: (a) with respect to claims to the 1-oxo embodiment,
Stirling is silent and provides no evidence of unexpected activity; and (b) with
respect to claims to the dioxo embodiment, Stirling did not compare the claimed
subject matter to the closest prior art (i.e., Piper, which discloses dioxo aminothalidomide analogs, including Stirlings Compound 2). See PTAB IPR201200006 Final Written Decision (Mar. 6, 2014) at 33 (To establish unexpected
results, the claimed subject matter must be compared with the closest prior art.). A
Reexamination Certificate subsequently issued on June 29, 1999 with no
amendments to the issued claims. (Ex. 1025.)
F.

The State Of The Art

Thalidomide has been known since the 1950s, and was initially prescribed
for prenatal morning sickness until it was discovered to cause congenital birth
defects and subsequently banned in 1962. (Ex. 1007, 75); DAmato et al., Proc.
Natl. Acad. Sci. USA, 91:4082-85 (Apr. 1994) at 4082 (Ex. 1026)). The
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Patent No. 5,635,517
teratogenicity and other properties of thalidomide and its analogs was heavily
researched throughout the following decades. See Koch, Sci. Pharma., 49:67-69
(1981) at 1 (Ex. 1027). By the early 1980s, thalidomide resurfaced as a highly
effective anti-inflammatory and immunosuppressive drug of choice for treating
erythema nodosum leprosum (ENL). See, e.g., Sampaio et al., J. Exp. Med.,
173:699-703 (March 1, 1991) at 699 (Ex. 1009). By the early 1990s, thalidomide
and some of its analogs were also identified as an effective cancer treatment due to
their anti-angiogenic activity. (Ex. 1026 at 4082.)
In 1981, Piper disclosed the successful use of amino-thalidomide analogs as
anti-inflammatory and/or immunosuppressive agents in rat and mouse models,
respectively. (Ex. 1002 at 511-12.) In particular, Piper expressly disclosed AH 13
and AH 14, which are encompassed by claims 1 and 7-9. (Ex. 1007, 78-86;
Ex.1002 at 511.) Piper also disclosed EM 12, which is a non-aminated version of
the 1-oxo thalidomide analogs of claims 2-6 and 10. (Ex. 1007, 78; Ex.1002 at
511.)
By 1985, thalidomide and its analogs were widely known to treat a myriad of
symptoms and diseases. (See Ex.1028 at 171-213.) And in early 1995, Kaplan
disclosed that thalidomide analogs inhibit TNF, and recognized EM 12 as a
preferred compound for reducing the debilitating effects of toxic concentrations of
TNF-. (Ex. 1007, 90-93; Ex. 1003 at 3:56 5:39.)
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Patent No. 5,635,517
By July 24, 1996, the filing date of the earliest application to which the 517
Patent claims priority, some of the compounds of claims 1 and 7 and both of the
compounds of claims 8 and 9 had been known for over 20 years. (Ex. 1007, 7886.) In fact, the 517 Patent expressly admits this by stating 1,3-dioxo-2-(2,6dioxopiperidin-3-yl)-4-aminoisoindoline and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)5-aminoisoindoline are known. (Ex. 1001 at 4:58-63.) Further, since at least 1981,
these two compounds were known to effectively reduce inflammation or cause
immunosuppression in mammals. (Ex. 1002 at 511.) Thus, by July 1996, the
administration of dioxo amino-thalidomide analogs to reduce TNF in a mammal as
recited in claims 1 and 7-9 covered nothing more than the administration of known
compounds to achieve a readily predictable result. (Ex. 1007, 105-128.)
Additionally, EM 12, the non-aminated version of the 1-oxo thalidomide
analogs of claims 2-6 and 10, had been known since at least the early 1970s. (Ex.
1007, 76; Schumacher et al., Teratology, 5(2):233-40 (1972) at 233
(Schumacher) (Ex. 1030).) Reports of EM 12 effectively reducing inflammation
in a whole animal model had been known since at least 1981. (Ex. 1002 at 511.) In
fact, EM 12 had been considered a preferred compound for reducing the
debilitating effects of toxic concentrations of TNF- since at least January 1995.
(Ex. 1003 at 3:56 5:39.) Moreover, adding electron donating substituents (e.g.,
amino groups) to thalidomide was considered a preferred substitution that
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Patent No. 5,635,517
maintained the anti-inflammatory activity of the parent compound. (Ex. 1002 at
512.) Thus, by July 1996, the administration of 1-oxo amino-thalidomide analogs to
reduce TNF in a mammal as recited in claims 2-6 and 10 covered nothing more
than a simple substitution of one known element for another and a combination of
prior art elements according to known methods to achieve readily predictable
results. (Ex. 1007, 129-189.)
VI.

PETITIONER HAS A REASONABLE LIKELIHOOD OF


PREVAILING
Pursuant to 37 C.F.R. 42.104(b)(4), this Petition establishes that there is a

reasonable likelihood that at least one claim of the 517 Patent is unpatentable. In
particular, this section provides detailed descriptions and claim charts showing
how claims 1-10 of the 517 Patent are obvious under pre-AIA 35 U.S.C. 103(a),
including identifications of where each claim element is found in the prior art.
Underlying factual determinations in an obviousness analysis include (1) the
scope and content of the prior art, (2) the level of ordinary skill in the art, (3) the
differences between the claimed invention and the prior art, and (4) objective
indicia of nonobviousness. See KSR Intl Co. v. Teleflex, Inc., 550 U.S. 398, 40607 (2007) (citing Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)). The scope
and content of the prior art, the level of ordinary skill in the art, the differences
between the claimed invention and the art relevant to this Petition, and any

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Patent No. 5,635,517
objective indicia of nonobviousness are addressed for each statutory ground of
rejection upon which this Petition is based.
In assessing obviousness, the U.S. Supreme Court has stated that [o]ne of
the ways in which a patents subject matter can be proved obvious is by noting that
there existed at the time of invention a known problem for which there was an
obvious solution encompassed by the patents claims. KSR, at 419-20. The Court
has further stated that [w]hen there is a design need or a market pressure to solve
a problem and there are a finite number of identified, predictable solutions, a
person of ordinary skill has good reason to pursue the known options within his or
her technical grasp. Id. at 421.
A.

Each Reference Relied On For Grounds 1-3 Is Prior Art

Each reference applied in Grounds 1-3 is available as prior art against the
517 Patent under pre-AIA 35 U.S.C. 102(b) as set forth above in Section IV.B.2.
None of Piper, Agrawal, WO 085, or Keith was made of record during
prosecution of the 517 Patent.3
B.

A Person Of Ordinary Skill In The Art

A person of ordinary skill in the art at the time the 517 Patent was filed
would have had an advanced degree (Masters or Ph.D.) or equivalent experience
in chemistry, pharmacology, or biochemistry, and at least two years of experience
3

U.S. Patent No. 5,593,990, which is related to WO 085, was relied on by the
Examiner during the ex parte reexamination of the 517 Patent.
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Patent No. 5,635,517
in medicinal chemistry involving the research, development, or production of
pharmaceuticals. (Ex. 1007, 33-35.)
C.

Ground 1: Claims 1 And 7-9 (Dioxo Analogs) Are Obvious


Over Piper And Kaplan

The prior art references cited herein when combined disclose all of the
limitations of claims 1 and 7-9. A person of ordinary skill in the art would have
recognized this and had a reason to combine these prior art disclosures with a
reasonable expectation of success in arriving at the claimed subject matter. (Ex.
1007, 105-128.) To the extent patentee alleges commercial success to rebut the
obviousness of claims 1 and 7-9, no nexus exists between these claims and any
alleged commercial success.
Claims 1 and 7-9 encompass methods of reducing TNF in mammals by
administering an effective amount of a modified thalidomide having an amino
group attached to the benzo ring (the dioxo embodiment).
Claim 1 recites: The method of reducing undesirable levels of TNF in a
mammal which comprises administering thereto an effective amount of a
compound of the formula:

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Patent No. 5,635,517
in which in said compound one of X and Y is C=O and the other of X and Y is
C=O or CH2.
Claim 7 depends from claim 1 and specifies that each of X and Y is C=O.
Hence, claim 7 calls for a dioxo embodiment encompassed by the formula of claim
1, as depicted below:

Claim 8 depends from claim 7 and specifies that the compound is 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline. In accordance with the
above construction of key terms, the compound of claim 8 is shown below:

Claim 9 depends from claim 7 and specifies that the compound is 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. In accordance with the
above construction of key terms, the compound of claim 9 is shown below:

1.

Piper Discloses Dioxo Amino-Thalidomide Analogs Having


Key Functional Properties In Common With Thalidomide

Piper describes a study of thalidomide analogs and their utility as anti25

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Patent No. 5,635,517
inflammatory and immunosuppressive agents. (Ex. 1002 at 511.) Piper states that
[t]halidomide is remarkably effective in controlling erythema nodosum leprosum
(ENL) reactions in lepromatous leprosy, and that thalidomide has two clinically
relevant sites [modes] of action in ENL one anti-inflammatory, the other
immunosuppressive. (Id. at 511, left col.) Piper also describes an animal model for
each mode of action i.e., carrageenan-induced rat paw edema (a rat model of
inflammation) and splenic antibody or plaque forming cells (PFC) in mice four
days after i.v. immunization with sheep erythrocytes (a mouse model of
immunosuppression). (Id. at 511; Ex. 1007, 78, 110.)
According to Piper, 50 thalidomide analogs were screened in these two
animal models to determine the anti-inflammatory and immunosuppressive activity
of each in the tested mammals. (Id. at 511, right col.) Pipers results included the
findings that 4-aminothalidomide has anti-inflammatory activity and 3aminothalidomide has immunosuppressive activity. Specifically, Piper states: To
date, three [thalidomide analogs] are active in carrageenan (4-hydroxythalidomide
or AH 20, 3-hydroxythalidomide or AH 22, and 4-aminothalidomide or AH 13).
One, AH 20, is active in PFC and one, 3-aminothalidomide or AH 14, enhances
PFC. (Id. at 511, right col.)
The compound disclosed in Piper as 3-aminothalidomide is described in
the art using various terms, such as CC-4047 and, more recently, pomalidomide.
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Patent No. 5,635,517
(See Engelhardt et al., Recent Results Cancer Res., 201:359-72 (2014) at 359, 361,
Fig. 1 (Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a
derivative of thalidomide .).) (Ex. 1029.) The structure of 3-aminothalidomide
(AH 14) (i.e., pomalidomide) is shown below (Ex. 1007, 79-86):

Thus, 3-aminothalidomide (AH 14) is 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)4-aminoisoindoline, which is the compound recited in claim 8 of the 517 Patent.
(Id. at 80, 108, 122-126.)
The compound disclosed in Piper as 4-aminothalidomide is similar to 3aminothalidomide except that the amino group on the benzo ring is in the 4position, not the 3-position, according to Pipers ring numbering. The structure of
4-aminothalidomide (AH 13) is shown below (id. at 79-86):

Thus, 4-aminothalidomide (AH 13) is 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)5-aminoisoindoline, which is the compound recited in claim 9 of the 517 Patent.
(Id. at 83, 108, 122-126.)
For clarity, the different ring numbering used in Piper and the 517 Patent

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Patent No. 5,635,517
(which follows IUPAC standards, as discussed above) is illustrated below using
AH 14 as an example:

Piper: 3-aminothalidomide
(AH 14)

517 Patent: 1,3-dioxo-2-(2,6dioxopiperidin-3yl)-4-aminoisoindoline

Another thalidomide analog tested by Piper is EM 12, which was wellknown in the art before July 1996, as evidenced by Figure 1 of Schumacher (Ex.
1030 at 234), an excerpt of which is reproduced below:

EM 12 is an adjacent analog of thalidomide because its structure differs


from thalidomide only by the presence of methylene in place of a carbonyl in the
phthalimide ring system. (Ex. 1007, 74.) According to Piper, EM 12 is antiinflammatory in rats. Specifically, Piper states: Two compounds represent
changes in the 5 membered ring system of the phthalimide moiety and two involve
major alternations of the phthalimide system. Two of these, EM 12 and
glutethimide, are active in carrageenan. (Ex. 1002 at 511, right col.) As noted

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Patent No. 5,635,517
above, carrageenan-induced rat paw edema is an animal model of inflammation.
(Id., left col.)
In summary, Piper expressly discloses that AH 13 (the compound of claim
9) was administered to mammals and shown to have immunosuppressive activity,
AH 14 (the compound of claim 8) was administered to mammals and shown to
have anti-inflammatory activity, and EM 12 (an adjacent thalidomide analog
structurally similar to AH 13 and AH 14) was administered to mammals and
shown to have anti-inflammatory activity. Further, by expressly disclosing that
anti-inflammation and immunosuppression are clinically relevant modes of action
through which thalidomide controls ENL, Piper highlighted these activities as
important functional properties of thalidomide and its analogs. (Ex. 1007, 86,
117-119.) Hence, Piper teaches that AH 13, AH 14, and EM 12 have at least one
important functional property in common with thalidomide. (Id.)
2.

Kaplan Discloses That Thalidomide, Thalidomide Analogs,


And Other Anti-Inflammatory And Immunosuppressive
Compounds Reduce TNF

Kaplan discloses methods of reducing TNF by administering thalidomide


or an analog thereof (Ex. 1003 at 3:58-63; claim 1), and states that debilitating
effects of toxic concentrations of TNF- can be controlled in humans by
treating a human patient in need of such treatment with an anti-debilitating amount
of a compound disclosed in Kaplan. (Id. at 3:58-63.)
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Patent No. 5,635,517
Kaplan counts thalidomide and EM 12 among its preferred compounds. For
instance, claim 1 of Kaplan is directed to a method that inhibits the production of
TNF by administering an effective amount of a compound of the formula:

Kaplans claim 1 formula includes thalidomide when R is hydrogen and R is the


second (phthalimido, dioxo) moiety, and Kaplans claim 1 formula includes EM
12 when R is hydrogen and R is the third (phthalimidino, 1-oxo) moiety.
Kaplan indicates an even greater preference for EM 12 by also identifying it
among eight [e]specially preferred compounds. (Id. at 4:26-5:39.) Specifically,
Kaplan identifies EM 12 by disclosing the following structure and chemical name:

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Patent No. 5,635,517
(Id. at 5:31-39). It is noted that the depicted structure of 3-phthalimidino-2,6dioxo piperidine is incorrect because it shows a 7-membered azepane ring instead
of the named 6-membered piperidine ring. (Ex. 1007, 90.) A similar drawing
error appears in Kaplans Abstract, yet Kaplans text consistently refers to
compounds having a piperidine or piperidino ring, and never mentions an azepane
or azepano ring. (Id. at 91.) Hence, one of ordinary skill in the art would have
easily recognized this obvious error and that Kaplans 3-phthalimidino-2,6-dioxo
piperidine is indeed EM 12. (Id.)
Notably, none of Kaplans seven other [e]specially preferred thalidomide
analogs are covered by Kaplans claim 1 formula. (Id. at 92.) Hence, one of
ordinary skill would recognize that Kaplan considers EM 12 to be the most
preferred analog of thalidomide. (Id.)
Kaplan also discloses that both thalidomide and EM 12 reduce TNF.
Specifically, Kaplans Figure 3 shows that thalidomide exerts a selective effect by
suppressing only TNF- secretion [from] LPS-stimulated monocytes. (Ex. 1003
at 9:44-51; Fig. 3.) Kaplans Figures 5-7 show that EM 12 (referred to as
compound H) also effectively inhibits production of TNF. In fact, Kaplans
Figure 6 shows that EM 12 inhibited an even higher percentage of TNF than
thalidomide when tested in an ACH-2 cell line. (Id. at 10:52-58; Fig. 6.) Kaplan

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Patent No. 5,635,517
also states that TNF is associated with many conditions, and notes that markedly
elevated levels of TNF occur in ENL. (Id. at 2:56-3:2.)
Additionally, in highlighting the benefits of thalidomide and its analogs over
prior treatments for reducing TNF, Kaplan states, Heretofore, antiinflammatory
and immunosuppressive steroids such as prednisolone and dexamethasone have
been employed to treat the debilitating effects of TNF-. Unfortunately, these
therapeutic agents also block the production of other cytokines so that the patients
become susceptible to life threatening infections. (Id. at 3:50-55.) Kaplan thus
identifies a link between compounds capable of anti-inflammation and
immunosuppression and those capable of reducing TNF. (Ex. 1007, 93.)
In short, Kaplan discloses that effective amounts of thalidomide or certain
analogs thereof, including the highly preferred and structurally adjacent EM 12,
effectively reduce TNF in mammals, which in turn treats a variety of conditions,
including ENL. Kaplan also identifies other compounds with anti-inflammatory or
immunosuppressive activity that likewise reduce TNF. (Id. at 90-93, 120.)
3.

Summary: Claims 1 and 7-9 are obvious over Piper and Kaplan

Motivation to Combine the References: Given the foregoing, the


disclosures in Piper and Kaplan would have been easily combined by one of
ordinary skill before July 1996, because each one teaches the same parent

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Patent No. 5,635,517
compound (thalidomide) and various analogs thereof in relation to treating the
same condition (ENL). (Id. at 112-115.) Both references also teach the wellknown analog EM 12, and that anti-inflammatory and immunosuppressive
properties are important to the efficacy and activity of thalidomide and its analogs.
Hence, one of ordinary skill in the art would have readily combined the teachings
of Piper and Kaplan to develop thalidomide analogs having one or both of these
important functional activities for use in effectively treating at least ENL by
reducing TNF. (Id.)
Reasonable Expectation of Success: One of ordinary skill in the art would
have reasonably expected Pipers amino-thalidomide analogs AH 14 and AH 13 to
successfully exhibit the same activity as their common parent compound
(thalidomide) because AH 14 and AH 13 have high structural similarity to the
parent and also exhibit at least one key activity of the parent (i.e., antiinflammation or immunosuppression). (Id. at 116-117.)
AH 13 and AH 14 are adjacent analogs of thalidomide because their
structures differ from thalidomide only by the presence of an amino group at the 5or 4-position of the benzo ring, respectively. (Id. at 85, 117-118.) This
significant structural similarity is easily appreciated upon viewing thalidomide, AH
13, and AH 14 side-by-side, as shown below:

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Patent No. 5,635,517

Piper teaches that AH 13 and AH 14 each exhibits an important functional


activity of thalidomide (anti-inflammation for AH 13, and immunosuppression for
AH 14). In general, those of ordinary skill may expect compounds of high
structural similarity that have an important functional activity in common to have
other activities in common as well. (Id. at 118). Such a conclusion would have
been bolstered by the disclosures in Piper and Kaplan regarding EM 12. (Id. at
119). This is because EM 12 is an example of a thalidomide analog having high
structural similarity to thalidomide and anti-inflammatory activity (as does
thalidomide) that further shares thalidomides ability to reduce TNF. Thus, one of
ordinary skill in the art would have reasonably concluded that there is a direct
relationship between the structural and functional similarities of thalidomide and
its analogs. (Id.)
Further, by disclosing steroids that exhibit anti-inflammation,
immunosuppression, and TNF inhibition, Kaplan identifies another direct
relationship i.e., between compounds that are anti-inflammatory or
immunosuppressive and compounds that block TNF. (Id. at 120.) This
disclosure would have further encouraged one of ordinary skill in the art to expect
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Patent No. 5,635,517
anti-inflammatory or immunosuppressive compounds having high structural
similarity to thalidomide (e.g., AH 13 and AH 14) to effectively reduce TNF as
well. (Id.)
Given the foregoing, it would have been obvious for one of ordinary skill to
administer an effective amount of AH 13 or AH 14 (which are covered by claims 1
and 7-9) to a mammal to reduce TNF levels with a reasonable expectation of
success. 4 (Id. at 105-128.) The combination of Piper and Kaplan thus discloses
all of the limitations of claims 1 and 7-9. (Id.) The following claim chart shows the
limitations of these claims, and the disclosure of each limitation in the prior art.
Claims 1 and 7-9
1. The method of
reducing undesirable
levels of TNF in a
mammal which comprises
administering thereto an
effective amount of a
compound of the formula:

Ground 1: Disclosures in Piper and Kaplan


Piper discloses two clinically relevant sites [modes]
of action [of thalidomide] in ENL one antiinflammatory, the other immunosuppressive. (Ex.
1002 at 511.) Piper also discloses compounds of the
claimed formula in which each of X and Y is C=O.
Specifically, Piper discloses that 4-aminothalidomide
(AH13) had anti-inflammatory activity when
screened using carrageenan-induced rat paw edema (a
rat model of inflammation), and 3-aminothalidomide
(AH14) had immunosuppressive activity when
screened using splenic antibody or plaque forming
cells (PFC) in mice four days after i.v. immunization
in which in said
with sheep erythrocytes (a mouse model of
compound one of X and
Y is C=O and the other of immunosuppression). (Ex. 1002 at 511.) Piper also
4

Piper may inherently disclose reducing undesirable levels of TNF by


administering an effective amount of AH 13 or AH 14 because Sekut et al., J.
Lab. Clin. Med., 124:813-20 (1994) (Ex. 1031) discloses elevated local levels of
TNF in the carrageenan-induced rat paw edema model.
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Patent No. 5,635,517
X and Y is C=O or CH2.

discloses that EM 12 had anti-inflammatory activity


(i.e., active in carrageenan). (Ex. 1002 at 511.)
In each of AH 14 and AH 13, X is C=O and Y is C=O
(structures shown below):

The structure of EM 12 is also shown below:

Kaplan discloses EM 12 among eight [e]specially


preferred compounds that inhibit TNF in humans.
(Ex. 1003 at 3:58-65, 4:27-5:39.) Kaplan also
discloses, Heretofore, antiinflammatory and
immunosuppressive steroids such as prednisolone and
dexamethasone have been employed to treat the
debilitating effects of TNF-. Unfortunately, these
therapeutic agents also block the production of other
cytokines so that the patients become susceptible to
life threatening infections. (Ex. 1003 at 3:50-55.)
7. The method according Piper discloses AH 14 and AH 13, which each has
to claim 1 in which each
the formula of claim 1 in which each of X and Y is
of X and Y is C=O.
C=O. (Ex. 1002 at 511.)
8. The method according Piper discloses AH 14, which is 1,3-dioxo-2-(2,6to claim 7 in which said
dioxopiperidin-3-yl)-4-aminoisoindoline. (Ex. 1002 at
compound is 1,3-dioxo-2- 511.)
(2,6-dioxopiperidin-3-yl)4-aminoisoindoline.
9. The method according Piper discloses AH 13, which is 1,3-dioxo-2-(2,6to claim 7 in which said
dioxopiperidin-3-yl)-5-aminoisoindoline. (Ex. 1002 at
compound is 1,3-dioxo-2- 511.)
(2,6-dioxopiperidin-3-yl)5-aminoisoindoline.

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Patent No. 5,635,517
D.

Ground 2: Claims 2-6 And 10 (1-Oxo Analogs) Are Obvious


Over Piper, Kaplan, Agrawal, And WO 085

Claims 2-6 and 10 encompass methods of reducing TNF in mammals by


administering an effective amount of a modified thalidomide having an amino
group attached to the benzo ring and methylene in place of a carbonyl group in the
phthalimide ring system (the 1-oxo embodiment).
Claim 2 depends from claim 1 and specifies that X is C=O and Y is CH2.
Hence, claim 2 calls for a 1-oxo embodiment encompassed by the formula of claim
1, as depicted below:

Claim 3 depends from claim 2 and specifies that the compound is 1-oxo-2(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. In accordance with the above
construction of key terms, the compound of claim 3 is shown below:

Claim 4 depends from claim 2 and specifies that the compound is 1-oxo-2(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline. In accordance with the above
construction of key terms, the compound of claim 4 is shown below:

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Claim 5 depends from claim 2 and specifies that the compound is 1-oxo-2(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline. In accordance with the above
construction of key terms, the compound of claim 5 is shown below:

Claim 6 depends from claim 2 and specifies that the compound is 1-oxo-2(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline. In accordance with the above
construction of key terms, the compound of claim 6 is shown below:

Claim 10 is an independent product claim that recites, A compound


selected from the group consisting of 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline, 1-oxo-2(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline, and 1-oxo-2-(2,6-dioxopiperidin-3yl)-7-aminoisoindoline. Hence, claim 10 encompasses any one of the four
compounds recited in claims 3-6.

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Patent No. 5,635,517
1.

Piper Discloses Thalidomide Analogs Having Key Functional


Properties In Common With Thalidomide and High Structural
Similarity To Thalidomide

As discussed above, Piper discloses that anti-inflammation and


immunosuppression are important functional properties of thalidomide that are
clinically relevant to ENL. (Ex. 1002 at 511, left col.) Piper also found that three
adjacent analogs of thalidomide exhibit at least one of these properties in mammals
i.e., anti-inflammation in rats for AH 13 and EM 12, and immunosuppression in
mice for AH 14. (Id. at 511, right col.) Piper further discloses two other adjacent
hydroxyl-substituted analogs (4-hydroxythalidomide and 3hydroxythalidomide) that were found to exhibit anti-inflammatory activity as
well. (Id. at 511, right col.) Hence, Piper teaches at least five analogs having high
structural similarity to both thalidomide and each other, all of which exhibit key
anti-inflammatory or immunosuppressive activity. (Ex. 1007, 137.)
2.

Kaplan Discloses That Thalidomide, Thalidomide Analogs,


And Other Anti-Inflammatory And Immunosuppressive
Compounds Reduce TNF

As discussed above, Kaplan discloses that effective amounts of thalidomide


or certain analogs thereof, including the highly preferred and structurally adjacent
analog EM 12, reduce TNF in humans, which in turn treats a variety of
conditions, including ENL. (Ex. 1003 at 2:56 - 3:2; 3:58 - 5:39; Ex. 1007, 138)
Kaplan also identifies other compounds having anti-inflammatory and

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Patent No. 5,635,517
immunosuppressive activity that reduce TNF. (Id. at 3:50-55.)
3.

Agrawal Discloses That Amino-Substituted Thalidomide


Analogs Retain Anti-Inflammatory Activity

Agrawal is an abstract (published alongside Piper) that describes a study of


the structure-activity relationship of several thalidomide analogs, and teaches a
preference for amino-substituted analogs. (Ex. 1007, 139.) Agrawal used the
same two animal models as Piper to assess the anti-inflammatory and
immunosuppressive activity of its tested thalidomide analogs. (Ex. 1004 at 512,
left col. (The anti-inflammatory and immunosuppressive activities of these agents
have been determined by utilizing the carrageenan rat paw edema test and the Jerne
plaque-forming cell (PFC) assay in mice, respectively, at various dose levels.).)
In conducting its tests, Agrawal studied the effects of certain substituents,
and states: The electronic effects were analyzed by synthesizing analogs
containing NO2, COOH, NH2, or OH groups. (Id. at 512, right col., part b.)
Agrawals results revealed a preference for analogs with an amino- or hydroxylsubstituted benzo ring based on the finding that [t]he agents containing the
electron donating groups such as 3 or 4-hydroxy and 4-aminothalidomide retained
the anticarrageenan activity, whereas the analogs with electron withdrawing groups
such as 4-nitro or 4-carboxy were not active in this assay system. (Id.) Agrawal
also confirms Pipers finding that AH 13 (4-aminothalidomide) is anti-

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Patent No. 5,635,517
inflammatory. (Id.) Hence, Agrawal concludes that anti-inflammatory activity is
retained when the analog is substituted with an electron donating group, such as
amino or hydroxyl, but not with an electron withdrawing group. (Ex. 1007, 8789, 139.)
Agrawal also refers to a widely recognized motivation among those of
ordinary skill in the art before July 1996, by stating that its study was conducted
in an effort to develop an analog of thalidomide which may be effectively
employed in the clinical management of erythema nodosum leprosum (ENL)
occurring in lepromatous leprosy. (Ex. 1004 at 512, left col.; Ex. 1007, 88-89.)
That is, Agrawal exemplifies a goal that motivated significant study in this field
long before July 1996, which was a desire to identify thalidomide analogs that
possess beneficial anti-inflammatory and/or immunosuppressive activity but not
the grievous toxicity of the parent compound. (Id. (This effort has been directed to
design and synthesize analogs which may not possess the toxicity of thalidomide,
manifested by teratogenicity and peripheral neuritis.); Ex. 1007, 88-89.)
Agrawal also encourages those of ordinary skill in the art to build on its
results and develop additional thalidomide analogs with a reasonable expectation
of success by stating, The results [of Agrawals study] suggest that modifications
in the parent thalidomide molecule can be made which retain the anti-inflammatory
and immunosuppressive activity, but yet may be expected to alter the neurotoxic
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Patent No. 5,635,517
and teratogenic properties. (Ex. 1004 at 512, right col., last paragraph; Ex. 1007 at
89.)
4.

WO 085 Discloses 1-Oxo Hydroxyl-Substituted Thalidomide


Analogs Having Activity In Common With Thalidomide

WO 085 discloses methods of inhibiting angiogenesis using thalidomide or


an analog thereof. (Ex. 1005 at 1:20-25.) The disclosed analogs encompass a
variety of compounds, with a preference for EM 12, N-phthaloyl-DL-glutamic acid
and N-phthaloyl-DL-glutamine anhydride. (Id. at 14:8-12.) Other disclosed analogs
include epoxides of EM 12 and hydrolysis products of such epoxides (Id. at 16:1-3;
17:15-17), including hydroxyl-substituted EM 12 (shown below), which is a
hydrolysis product of an epoxide of EM 12 (id. at 17:5):

Hence, WO 085 teaches that each of thalidomide, EM 12, and 3-, 4-, 5-, and
6-hydroxyl-substituted EM 12 inhibit angiogenesis. Further, WO 085 highlights
EM 12 by demonstrating in its Example III that EM 12 is a more potent inhibitor
of angiogenesis than thalidomide. (Id. at 26:1-27:7.) WO 085 thus provides further
evidence suggesting a direct relationship between structure and function among
thalidomide and its analogs i.e., that structural similarity is reasonably predictive
of functional similarity. (Ex. 1007, 94-96, 140-141.)

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5.

Summary: Claims 2-6 And 10 Are Obvious Over Piper,


Kaplan, Agrawal, And WO 085

Motivation to Combine the References: Given the foregoing (id. at


129-144), the disclosures in Piper, Kaplan, Agrawal, and WO 085 would have
been easily combined by one of ordinary skill in the art before July 1996 because
each of these references teaches the same parent compound (thalidomide) and
various analogs thereof in relation to medical treatments. (Id. at 145-153.)
In particular, each of Piper, Kaplan, and Agrawal discloses the use of
thalidomide and its analogs for treating ENL, and each also teaches that antiinflammation and immunosuppression are important to the efficacy and activity of
thalidomide and its analogs. Additionally, WO 085 discloses that thalidomide and
its analogs inhibit angiogenesis. Further, these references disclose some of the
same analogs of thalidomide e.g., EM 12 is taught by Piper, Kaplan, and WO
085; AH 13 is taught by Piper and Agrawal; and 3- and 4-hydroxythalidomide are
taught by Piper and Agrawal. (Ex. 1007, 145-153.)
Hence, in view of the known activities and structures of thalidomide, EM 12,
and structurally similar amino- and hydroxyl-substituted analogs thereof, one of
ordinary skill in the art would have readily combined the teachings of Piper,
Kaplan, Agrawal, and WO 085 to develop thalidomide analogs having an aminoor hydroxyl-substituted benzo ring, and at least one important functional activity of

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Patent No. 5,635,517
thalidomide (i.e., anti-inflammation or immunosuppression) for use in effectively
treating at least ENL by reducing TNF. (Id.)
Reasonable Expectation of Success: Regarding thalidomide, the prior art
teaches that this parent compound exhibits at least the following activities: TNF
inhibition (as taught by Kaplan), anti-inflammation (as taught by Piper and
Agrawal), immunosuppression (as taught by Piper and Agrawal), and antiangiogenesis (as taught by WO 085). (Id. at 155.) Regarding its well-known
adjacent analog, EM 12, the prior art teaches that this structurally similar
compound likewise exhibits several of the same key activities namely, TNF
inhibition (as taught by Kaplan), anti-inflammation (as taught by Piper), and antiangiogenesis (as taught by WO 085). (Id. at 156.) The prior art likewise teaches
that other compounds that are structurally similar to both thalidomide and EM 12
exhibit some of these same activities as well. For instance, AH 13 was found to
exhibit anti-inflammation (as taught by Piper and Agrawal); AH 14 was found to
exhibit immunosuppression (as taught by Piper); 3- and 4-hydroxythalidomide
were found to exhibit anti-inflammation (as taught by Piper and Agrawal); and 3and 4-hydroxyl-substituted EM 12 were found to exhibit anti-angiogenesis (as
taught by WO 085). (Id. at 157.)
From this, one of ordinary skill in the art would have reasonably expected
other structurally similar analogs of thalidomide and EM 12 to behave like their
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Patent No. 5,635,517
parent compounds. (Id. at 157-164.) Such an expectation would have been
particularly reasonable because it has long been common practice in the art to
research and develop structurally similar versions of a parent compound in order to
identify an analog with improved, or simply separately marketable, properties. (Id.
at 159-162.)
Furthermore, Piper, Kaplan, Agrawal, and WO 085 would readily have led
one of ordinary skill in the art to identify a finite family of structurally similar
analogs that would be reasonably expected to have certain activities in common
with their parent compound, including TNF inhibition. (Id. at 165.) This is, at
least in part, because the prior art suggests that anti-inflammation,
immunosuppression, TNF reduction, and anti-angiogenesis are all among the
global characteristics one would expect to be exhibited by structurally similar
analogs of thalidomide. (Id. at 158.)
The recognition of a finite family of analogs is significant to an obviousness
analysis because it is well-established that [a] prima facie case of obviousness
may be made when chemical compounds have very close structural similarities and
similar utilities. See MPEP 2144.09(I); see also In re Deuel, 51 F.3d 1552, 1558
(Fed. Cir. 1995) (Structural relationships may provide the requisite motivation or
suggestion to modify known compounds to obtain new compounds. For example, a
prior art compound may suggest its homologs because homologs often have similar
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Patent No. 5,635,517
properties and therefore chemists of ordinary skill would ordinarily contemplate
making them to try to obtain compounds with improved properties.); see also See
In re Petering, 301 F.2d 676, 681 (CCPA 1962) (disclosure of a small and
delimited genus is tantamount to disclosing each one of its constituent species).
Additionally, [o]ne of the ways in which a patents subject matter can be proved
obvious is by noting that there existed at the time of invention a known problem
for which there was an obvious solution encompassed by the patents claims.
KSR, 550 U.S. at 419-20. When there is a design need or a market pressure to
solve a problem and there are a finite number of identified, predictable solutions, a
person of ordinary skill has good reason to pursue the known options within his or
her technical grasp. Id. at 421.
Here, the prior art emphasizes EM 12 as a primary analog of interest having
close structural and functional similarity to thalidomide (as taught by Piper,
Kaplan, and WO 085). The prior art also emphasizes amino- and hydroxylsubstituted analogs, and their ability to retain key anti-inflammatory activity (as
taught by Piper and Agrawal), which is likewise exhibited by compounds that are
capable of inhibiting TNF (as suggested by Kaplan). (Ex. 1007, 157-158, 162,
165.) From this, one of ordinary skill would have reasonably expected amino- and
hydroxyl-substituted analogs of both thalidomide and EM 12 to share key activities
in common with the parent compounds, including TNF inhibition. (Id. at 16246

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Patent No. 5,635,517
163.) Such a group of analogs only includes 13 compounds, 9 of which are in the
prior art, as summarized below:

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

Compound5
3-amino-substituted THAL (AH 14)
4-amino-substituted THAL (AH 13)
3-hydroxyl-substituted THAL
4-hydroxyl-substituted THAL
EM 12
3-hydroxyl-substituted EM 12
4- hydroxyl -substituted EM 12
5-hydroxyl-substituted EM 12
6- hydroxyl -substituted EM 12
3-amino-substituted EM 12
4-amino-substituted EM 12
5-amino-substituted EM 12
6-amino-substituted EM 12

Prior Art
Piper
Piper, Agrawal
Piper, Agrawal
Piper, Agrawal
Piper, Kaplan, WO 085
WO 085
WO 085
WO 085
WO 085
-----

Given the foregoing, it would have been a matter of obvious and routine
experimentation for one of ordinary skill in the art to make the four remaining
analogs of EM 12 (covered by claims 2-6 and 10) with a reasonable expectation
that such analogs would likewise exhibit some of the same key activities of their
parent compound (EM 12). (Id. at 164-165.) In fact, amino-substituted EM 12
analogs would have been especially expected to exhibit TNF inhibition in view of
the prior art teachings that connect anti-inflammation with TNF inhibition i.e.,
Pipers teaching that EM 12 is anti-inflammatory, Kaplans teaching that EM 12
5

It should be noted that 3- and 4-substituted thalidomide is the same as 6- and 5substituted thalidomide, respectively, to the extent that each molecule is racemic.
(Ex. 1007, 163.)
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Patent No. 5,635,517
reduces TNF as do other anti-inflammatory compounds, and Agrawals teaching
that amino-substituted analogs retain the anti-inflammatory activity of the parent.
(Id.) Moreover, the teaching in WO 085 that hydroxyl-substituted EM 12 shares
another functional property (anti-angiogenesis) with both EM 12 and thalidomide,
further supports the conclusion that structurally similar analogs of thalidomide and
EM 12 are expected to exhibit similar activity. (Id.)
All four amino-substituted EM 12 analogs would also have been easy to
make by common methods of organic synthesis. (Id. at 130, 164.) Moreover,
one of ordinary skill in the art would have been particularly interested in making
these four analogs because they would have higher polarity than the parent
compound, and thus provide further benefits. (Id. at 187.) Specifically, it has long
been known in the art that increased polarity corresponds to increased water
solubility, which renders compounds easier to formulate and more bioavailable
after administration. (Id. at 188.)
In summary, the foregoing factors would have led one of ordinary skill in
the art to reasonably expect administration of effective amounts of aminosubstituted EM 12 (including all of the compounds recited in claims 2-6 and 10 of
the 517 Patent) to reduce TNF in mammals. (Id. at 137-153.) Further, one of
ordinary skill would have had good reason to pursue these few known options, all
of which would have been well within his or her technical grasp. (Id. at 137-144,
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Patent No. 5,635,517
154-166.) The combination of Piper, Kaplan, Agrawal, and WO 085 thus
discloses all of the limitations of claims 2-6 and 10. The following claim chart
shows the limitations of these claims, and the disclosure of each in the prior art.
Claim
2. The method according to
claim 1 in which X is C=O
and Y is CH2.

Ground 2: Disclosures in Piper, Kaplan, Agrawal


and WO 085
Piper discloses two clinically relevant sites
[modes] of action [of thalidomide] in ENL one
anti-inflammatory, the other immunosuppressive.
(Ex. 1002 at 511.) Piper also discloses that 4aminothalidomide (AH 13) was anti-inflammatory
when screened using carrageenan-induced rat paw
edema (a rat model of inflammation), 3-aminothalidomide (AH 14) was immune-suppressive
activity when screened using splenic antibody or
plaque forming cells (PFC) in mice four days after
i.v. immunization with sheep erythrocytes (a mouse
model of immunosuppression), and EM 12 was
anti-inflammatory in the carrageenan model. (Ex.
1002 at 511.) The structures of AH 14, AH 13, and
EM 12 are:

Kaplan discloses, It has now been discovered that


the debilitating effects of toxic concentrations of
TNF-, whether acute or chronic, can be controlled
in humans by treating a human patient in need of
such treatment with an anti-debilitating amount of a
compound within the scope of the above
description. (Ex. 1003 at 3:58-63.) Kaplan also
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Patent No. 5,635,517
discloses preferred compounds include those
represented by formula II

wherein X is CH2 or C=O; [R] is H, CH2CH3,


C6H5, CH2C6H5, CH2CH=CH2, or
(Ex. 1003 at 3:66-4:22.) Kaplan also discloses
[e]specially preferred compounds including

(Ex. 1003 at 4:26-5:39.)


Kaplan also discloses, The studies described
hereinafter will be recognized by those skilled in
the art as establishing that the compounds of this
invention selectively inhibit the production of
human TNF- without substantially affecting the
production of other proteins or of total serum
protein. (Ex. 1003 at 6:12-17.)
Agrawal discloses a structure-activity relationship
study . . . in an effort to develop an analog of
thalidomide which may be effectively employed in
the clinical management of erythema nodosum
leprosum (ENL) occurring in lepromatous
leprosy. (Ex. 1004 at 512, left col.) Agrawal also
discloses analysis of thalidomide analogs
containing NO2, COOH, NH2, or OH groups. The
agents containing the electron donating groups
such as 3 or 4-hydroxy and 4-aminothalidomide
retained the anticarrageenan activity, whereas the
analogs with electron withdrawing groups such as
4-nitro or 4-carboxy were not active in this assay
system. (Ex. 1004 at 512, right col., part b).)
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Patent No. 5,635,517
Agrawal concludes, The results suggest that
modifications in the parent thalidomide molecule
can be made which retain the anti-inflammatory
and immunosuppressive activity, but yet may be
expected to alter the neurotoxic and teratogenic
properties. (Ex. 1004 at 512, right col.)
WO 085 discloses a method for preventing
unwanted angiogenesis by administration of
compounds such as thalidomide and related
compounds. (Ex. 1005 at 1:20-25.) In particular,
WO 085 discloses the following hydroxylsubstituted analog of EM 12:

3. The method according to


claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3-yl)-5aminoisoindoline.
4. The method according to
claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3 -yl)-4aminoisoindoline.
5. The method according to
claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3 -yl)-6aminoisoindoline.
6. The method according to
claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3 -yl)-7aminoisoindoline.
10. A compound selected
from the group consisting of

(Ex. 1005 at 17:5.)


See claim 2 disclosures.

See claim 2 disclosures.

See claim 2 disclosures.

See claim 2 disclosures.

See claim 2 disclosures.

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1-oxo-2-(2,6dioxopiperidin-3-yl)-5aminoisoindoline, 1-oxo-2(2,6-dioxopiperidin-3-yl)-4aminoisoindoline, 1-oxo-2(2,6-dioxopiperidin-3-yl)-6aminoisoindoline, and 1oxo-2-(2,6-dioxopiperidin3-yl)-7-aminoisoindoline.
E.

Ground 3: Claims 2-6 And 10 (1-Oxo Analogs) Are Obvious


Over Piper, Kaplan, Agrawal, And Keith

The prior art references cited herein when combined disclose all of the
limitations of claims 2-6 and 10 because one of ordinary skill in the art could have
readily started with EM 12 as the lead compound and then made simple structural
modifications that would have been expected to maintain and improve the
properties of the compounds. One of ordinary skill in the art would have
recognized this and thus combined these prior art disclosures with a reasonable
expectation of success in arriving at the claimed subject matter. (Ex. 1007, 167189.)
1.

Piper And Kaplan Point To EM 12 As The Lead Compound

In 1981, Piper disclosed EM 12 among approximately 50 thalidomide


analogs that were tested to assess their anti-inflammatory and immunosuppressive
activities in rat and mouse models, respectively. (Ex. 1002 at 511.) As discussed
above, these animal models were chosen to represent the two clinically relevant

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Patent No. 5,635,517
modes of action of thalidomide in ENL. (Id.) According to Pipers study, EM 12
was found to retain the anti-inflammatory activity of its parent compound
(thalidomide). (Id.) Piper also discloses that thalidomide analogs having an aminosubstituted benzo ring (namely, AH 13 and AH 14 discussed above) have antiinflammatory or immunosuppressive activity. (Ex. 1002 at 511.)
In 1995, Kaplan disclosed that thalidomide and certain thalidomide analogs,
including EM 12, effectively reduce TNF in humans. (Ex. 1003 at 3:58-63; claim
1.) As discussed above, Kaplan identifies EM 12 as one of eight [e]specially
preferred compounds. (Ex. 1003 at 4:26-5:39.) Kaplans claim 1 also includes
EM 12 among the limited number of thalidomide analogs encompassed by the
general formula recited in this claim. See In re Petering, 301 at 681 (disclosure of a
small and delimited genus is tantamount to disclosing each one of its constituent
species). Notably, none of Kaplans seven other [e]specially preferred
thalidomide analogs are covered by the formula of claim 1 in Kaplan. (Ex. 1007,
92.) Hence, one of ordinary skill would have readily identified EM 12 as Kaplans
most preferred compound. (Id. at 92, 173.)
Given the foregoing, Piper and Kaplan point to EM 12 as the lead
compound among thalidomide analogs capable of effectively reducing TNF in
mammals. (Id. at 170-174.)

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Patent No. 5,635,517
2.

Agrawal Provides Motivation To Aminate EM 12

Agrawal discloses a study of thalidomide analogs that revealed a preference


for amino-substituted analogs. Specifically, as discussed above, Agrawal found
that analogs containing the electron donating groups such as 3 or 4-hydroxy and
4-aminothalidomide retained the anticarrageenan activity [which is indicative of
anti-inflammatory activity], whereas the analogs with electron withdrawing groups
such as 4-nitro or 4-carboxy were not active in this assay system. (Ex. 1004 at
512, right col., part b; Ex. 1007, 172.)
In considering which changes to make to the structure of the lead compound,
EM 12, one of ordinary skill in the art would have been motivated to make the
simple change of adding an amino group to the benzo ring of EM 12 based on
Agrawals teaching that such a modification is expected to beneficially retain the
anti-inflammatory activity of the parent compound. (Ex. 1007, 175-176.)
Further, since Piper had already shown that EM 12 retains the antiinflammatory activity of thalidomide, and that the amino-substituted thalidomide
analog AH 13 likewise retains the anti-inflammatory activity of thalidomide (as
confirmed by Agrawal), one of ordinary skill would have readily concluded that
amino-substituted EM 12 (i.e., EM 12 with an amino group attached at any one of
the open positions on the benzo ring) would be anti-inflammatory as well. (Id. at
174-176.) Given the close structural relationship among thalidomide, EM 12, and

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Patent No. 5,635,517
amino-substituted EM 12, one of ordinary skill would then have reasonably
expected such amino-substituted EM 12 analogs to likewise exhibit a similar
ability to reduce TNF in mammals, as demonstrated in Kaplan with respect to
thalidomide and EM 12. (Id. at 176.)
3.

Keith Provides Further Motivation To Aminate EM 12

Keith is a book published in 1992 that provides solubility information for a


variety of chemical compounds, including thalidomide and EM 12. According to
Keith, the water solubilities of EM 12 and thalidomide are each described as:
Water: <1 mg/mL @ 22C. (Ex. 1006 at 190, 397.) One of ordinary skill in the
art would thus readily conclude that both of these compounds are practically
insoluble in water. (Ex. 1007, 178.)
Solubility has long been a critical factor to those of ordinary skill in the art
because increasing the solubility of a drug can significantly enhance its
bioavailability. (Id.) Additionally, it is well-known that a compound that is easier
to dissolve in water is much easier to formulate into a variety of dosage forms. (Id.)
Thus, solubility is a key consideration when formulating pharmaceuticals and
administering them to mammals. (Id.) One of ordinary skill in the art would have
generally known that the addition of an electron donating substituent (e.g., an
amino or hydroxyl group) to the benzo ring of EM 12 would likely increase its
solubility. (Id. at 187.) Therefore, one of ordinary skill would have been driven to
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Patent No. 5,635,517
aminate EM 12 in order to improve its poor solubility. (Id. at 178, 187-188.)
4.

Summary: Claims 2-6 And 10 Are Obvious Over Piper,


Kaplan, Agrawal, And Keith

Motivation to Combine the References: Given the foregoing, the


disclosures in Piper, Kaplan, and Agrawal would have been easily combined by
one of ordinary skill in the art before July 1996, because each of these references
teaches the same parent compound (thalidomide) and various analogs thereof in
relation to treating the same condition (ENL), and that anti-inflammation is
important to the efficacy and activity of thalidomide and its analogs. (Id. at 180184.) Also, Piper, Kaplan, and Keith all disclose important properties of EM 12
(i.e., anti-inflammatory activity, as taught by Piper; TNF inhibition, as taught by
Kaplan; and near insolubility, as taught by Keith). (Id.at 183.) Hence, one of
ordinary skill working in this field would have readily combined the teachings of
Piper, Kaplan, Agrawal, and Keith to develop amino-substituted EM 12 analogs
for use in effectively treating at least ENL by reducing TNF. (Id. at 168, 180184.)
Reasonable Expectation of Success: By July 1996, one of ordinary skill in
the art would have known that EM 12 is a lead compound from which to develop
other thalidomide analogs that would have the same or improved properties. (Id. at
170-171, 173.) One of ordinary skill would also have known from Keith that

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Petition For Inter Partes Review


Patent No. 5,635,517
EM 12 is practically insoluble in water. (Id. at 178.) Further, Agrawal suggests
that amino-substituted thalidomide analogs advantageously retain a clinically
relevant activity (anti-inflammation) of thalidomide. (Id. at 176, 187.) From
this, it would have been obvious for one of ordinary skill in the art to add an amino
group to the benzo ring of EM 12 with a reasonable expectation that such an
addition would yield an EM 12 analog that exhibits both the anti-inflammatory
activity and TNF inhibition of its parent (EM 12). (Id. at 176, 188.) Moreover,
one of ordinary skill in the art would have known that adding an amino group to
the benzo ring of EM 12 would increase the solubility of the compound, and thus
achieve a significant improvement, making the drug easier to formulate and more
bioavailable upon administration. (Id. at 178, 187-188.)
In summary, the foregoing factors would have led one of ordinary skill in
the art to reasonably expect administration of an effective amount of aminosubstituted EM 12 (including each of the compounds recited in claims 2-6 and 10
of the 517 Patent) to reduce TNF in mammals. (Id. at 170-179, 185-189.) The
combination of Piper, Kaplan, Agrawal, and Keith thus discloses all the limitations
of claims 2-6 and 10. The following claim chart shows the limitations of these
claims, and the disclosure of each in the prior art.

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Petition For Inter Partes Review


Patent No. 5,635,517
Claim
2. The method according to
claim 1 in which X is C=O
and Y is CH2.

Ground 3: Disclosures in Piper, Kaplan,


Agrawal and Keith
Piper discloses two clinically relevant sites
[modes] of action [of thalidomide] in ENL one
anti-inflammatory, the other immunosuppressive.
(Ex. 1002 at 511.) Piper also discloses that EM 12
was anti-inflammatory in the carrageenan model.
(Ex. 1002 at 511.) The structure of EM 12 is:

Kaplan discloses, It has now been discovered that


the debilitating effects of toxic concentrations of
TNF-, whether acute or chronic, can be
controlled in humans by treating a human patient
in need of such treatment with an anti-debilitating
amount of a compound within the scope of the
above description. (Ex. 1003 at 3:58-63.) Kaplan
also
discloses [e]specially preferred compounds
including the following (which is EM 12):

(Ex. 1003 at 4:26-5:39.) Kaplans claim 1 formula


encompasses EM 12 as well.
Agrawal discloses analysis of thalidomide analogs
containing NO2, COOH, NH2, or OH groups. The
agents containing the electron donating groups
such as 3 or 4-hydroxy and 4-aminothalidomide
retained the anticarrageenan activity, whereas the
analogs with electron withdrawing groups such as
4-nitro or 4-carboxy were not active in this assay
system. (Ex. 1004 at 512, right col., part b).)

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Petition For Inter Partes Review


Patent No. 5,635,517

3. The method according to


claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3-yl)-5aminoisoindoline.
4. The method according to
claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3 -yl)-4aminoisoindoline.
5. The method according to
claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3 -yl)-6aminoisoindoline.
6. The method according to
claim 2 in which said
compound is 1-oxo-2-(2,6dioxopiperidin-3 -yl)-7aminoisoindoline.
10. A compound selected
from the group consisting of
1-oxo-2-(2,6-dioxopiperidin3-yl)-5-aminoisoindoline, 1oxo-2-(2,6-dioxopiperidin-3yl)-4-aminoisoindoline, 1oxo-2-(2,6-dioxopiperidin-3yl)-6-aminoisoindoline, and
1-oxo-2-(2,6-dioxopiperidin3-yl)-7-aminoisoindoline.
VII.

Keith discloses the following solubility data for


each of EM 12 and thalidomide: Water: <1
mg/mL @ 22C. (Ex. 1006 at 190, 397.)
See claim 2 disclosures.

See claim 2 disclosures.

See claim 2 disclosures.

See claim 2 disclosures.

See claim 2 disclosures.

CONCLUSION
For at least the reasons given above, claims 1-10 of the 517 Patent are

unpatentable as obvious over the references cited herein. Accordingly, Petitioner


59

Petition For Inter Partes Review


Patent No. 5,635,517
respectfully requests IPR and cancellation of claims 1-10 of the 517 Patent.
Respectfully submitted,
MERCHANT & GOULD, P.C.

Respectfully submitted,
Date: May 7, 2015

By: /s/ Jeffrey D. Blake


Jeffrey D. Blake, Reg. No. 58,884
Dianna G. El Hioum, Reg. No. 52,949
Ryan James Fletcher, Ph.D. (Pro Hac Vice)
Brent E. Routman (Pro Hac Vice)
Merchant & Gould P.C.
191 Peachtree Street N.E., Suite 4300
Atlanta, GA 30303
Main Telephone: (404) 954-5100
Main Facsimile: (404) 954-5099
Counsel for Petitioner

60

Petition For Inter Partes Review


Patent No. 5,635,517
CERTIFICATE OF SERVICE ON PATENT OWNER
Pursuant to 37 C.F.R. 42.6(e), the undersigned certifies that on May 7,
2015, a complete and entire copy of this Petition for Inter Partes Review of U.S.
Patent No. 5,635,517, an accompanying Power of Attorney, Exhibit list, and all
supporting Exhibits were provided via UPS, postage prepaid, to the Patent Owner
by serving the correspondence address of record for the 517 Patent.
Attorney of Record
Jones Day for Celgene Corporation
222 E. 41st Street
New York, NY 10017
Respectfully submitted,
MERCHANT & GOULD P.C.
By: /s/ Jeffrey D. Blake
Jeffrey D. Blake, Reg. No. 58,884
Dianna G. El Hioum, Reg. No. 52,949
Ryan James Fletcher, Ph.D. (Pro Hac Vice)
Brent E. Routman (Pro Hac Vice)
Merchant & Gould P.C.
191 Peachtree Street N.E., Suite 4300
Atlanta, GA 30303
Main Telephone: (404) 954-5100
Main Facsimile: (404) 954-5099

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