Bass IPR Celgene

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

[email protected]

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

iii

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



iv

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



v

5. Summary: Claims 2-6 And 10 Are Obvious Over Piper, Kaplan, Agrawal, And WO 085 ............................................................................43

E. 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

VII. CONCLUSION ...........................................................................................59



vi

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



vii

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



1

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-



2

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

1 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.)



3

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 anti-

inflammatory 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)



4

and its adjacent analogs AH 13 and AH 14 all exhibit clinically relevant anti-

inflammatory 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 amino-

substituted 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



5

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



6

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.



7

(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



8

(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. 10-

5197 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 Back-Up Counsel

Jeffrey D. Blake, Esq.

Reg. No. 53,214

Merchant & Gould PC

191 Peachtree Street N.E., Suite 4300

Atlanta, GA 30303



[email protected]

Dianna G. El Hioum, Esq.

Reg. No. 52,949

Merchant & Gould PC

767 Third Avenue, 23rd Floor

New York, NY 10017



[email protected]

Ryan James Fletcher, Ph.D., Esq.

(Pro Hac Vice)

Merchant & Gould PC

1801 California Street, Suite 3300

Denver, CO 80202




9


[email protected]

Brent E. Routman, Esq.

(Pro Hac Vice)

Merchant & Gould PC

3200 IDS Center

80 South Eighth Street

Minneapolis, MN 55402



[email protected]

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 [email protected].

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)



10

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.



11

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 Claim Nos. Proposed Statutory Rejections

1 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 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. 3 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.



12

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.



13

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 # Recited Chemical Compound Name

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






14

8 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline


10 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):



15

(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 # Claimed Compound










16




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.



17

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 non-

adversarial 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 epoxy-

thalidomide 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.



18

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 hydroxyl-

thalidomide 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



19

(Compound 1) with that of a dioxo amino-thalidomide analog (Compound 2),

and concluded that both compounds inhibit TNF but that the dioxo amino-

thalidomide 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 amino-

thalidomide analogs, including Stirlings Compound 2). See PTAB IPR2012-

00006 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



20

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.)



21

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, 78-

86.) In fact, the 517 Patent expressly admits this by stating 1,3-dioxo-2-(2,6-

dioxopiperidin-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



22

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, 406-

07 (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



23

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.



24

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:



25

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 1,3-

dioxo-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 1,3-

dioxo-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 anti-



26

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 3-

aminothalidomide 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.



27

(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 3-

aminothalidomide except that the amino group on the benzo ring is in the 4-

position, 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



28

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

Another thalidomide analog tested by Piper is EM 12, which was well-

known 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 anti-

inflammatory 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



29

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.)



30

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:



31

(Id. at 5:31-39). It is noted that the depicted structure of 3-phthalimidino-2,6-

dioxo 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



32

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



33

compound (thalidomide) and various analogs thereof in relation to treating the

same condition (ENL). (Id. at 112-115.) Both references also teach the well-

known 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., anti-

inflammation 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 5-

or 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:



34

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



35

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.

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.

Claims 1 and 7-9 Ground 1: Disclosures in Piper and Kaplan

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:

in which in said

compound one of X and

Y is C=O and the other of

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 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

with sheep erythrocytes (a mouse model of

immunosuppression). (Ex. 1002 at 511.) Piper also



36

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

to claim 1 in which each

of X and Y is C=O.

Piper discloses AH 14 and AH 13, which each has

the formula of claim 1 in which each of X and Y is

C=O. (Ex. 1002 at 511.)


to claim 7 in which said

compound is 1,3-dioxo-2-

(2,6-dioxopiperidin-3-yl)-

4-aminoisoindoline.

Piper discloses AH 14, which is 1,3-dioxo-2-(2,6-

dioxopiperidin-3-yl)-4-aminoisoindoline. (Ex. 1002 at

511.)


to claim 7 in which said

compound is 1,3-dioxo-2-

(2,6-dioxopiperidin-3-yl)-

5-aminoisoindoline.

Piper discloses AH 13, which is 1,3-dioxo-2-(2,6-

dioxopiperidin-3-yl)-5-aminoisoindoline. (Ex. 1002 at

511.)



37

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:






38







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)-5-

aminoisoindoline, 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-3-

yl)-7-aminoisoindoline. Hence, claim 10 encompasses any one of the four

compounds recited in claims 3-6.



39

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 3-

hydroxythalidomide) 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



40

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 hydroxyl-

substituted 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-



41

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, 87-

89, 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



42

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.)



43

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 anti-

inflammation 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 amino-

or hydroxyl-substituted benzo ring, and at least one important functional activity of



44

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 anti-

angiogenesis (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 anti-

angiogenesis (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 3-

and 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



45

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



46

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 hydroxyl-

substituted 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 162-



47

163.) Such a group of analogs only includes 13 compounds, 9 of which are in the

prior art, as summarized below:

Compound5 Prior Art

1 3-amino-substituted THAL (AH 14) Piper

2 4-amino-substituted THAL (AH 13) Piper, Agrawal

3 3-hydroxyl-substituted THAL Piper, Agrawal

4 4-hydroxyl-substituted THAL Piper, Agrawal

5 EM 12 Piper, Kaplan, WO 085

6 3-hydroxyl-substituted EM 12 WO 085

7 4- hydroxyl -substituted EM 12 WO 085 8 5-hydroxyl-substituted EM 12 WO 085 9 6- hydroxyl -substituted EM 12 WO 085 10 3-amino-substituted EM 12 --

11 4-amino-substituted EM 12 --



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 5-

substituted thalidomide, respectively, to the extent that each molecule is racemic.

(Ex. 1007, 163.)



48

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 amino-

substituted 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,



49

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 Ground 2: Disclosures in Piper, Kaplan, Agrawal

and WO 085

2. The method according to

claim 1 in which X is C=O

and Y is CH2.

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 4-

aminothalidomide (AH 13) was anti-inflammatory

when screened using carrageenan-induced rat paw

edema (a rat model of inflammation), 3-amino-

thalidomide (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



50

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).)



51

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 hydroxyl-substituted analog of EM 12:

(Ex. 1005 at 17:5.)


claim 2 in which said

compound is 1-oxo-2-(2,6-

dioxopiperidin-3-yl)-5-

aminoisoindoline.

See claim 2 disclosures.




dioxopiperidin-3 -yl)-4-

aminoisoindoline.






aminoisoindoline.






aminoisoindoline.


10. A compound selected

from the group consisting of




52

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

The prior a

Documents

Bass IPR Celgene