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INTRODUCTION.........................................................................................1
II.
A.
B.
C.
Lead And Back-Up Counsel Under 37 C.F.R. 42.8(b)(3) & 42.10(a) ......8
D.
III.
IV.
A.
B.
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3.
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5.
V.
A.
B.
C.
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E.
F.
VI.
A.
B.
C.
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2.
3.
Summary: Claims 1 And 7-9 Are Obvious Aver Piper And Kaplan ......32
D.
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3.
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VII.
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INTRODUCTION
The 517 Patent is directed to a method of reducing TNF in mammals by
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)
3
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 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
8
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.
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)
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.
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.
10
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.
11
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.
12
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.
Claims 3-6 and 8-10 recite the following chemical compound names:
Claim #
3
4
5
6
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
(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):
14
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
15
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.
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.
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.
16
(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.
17
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
19
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
22
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 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.
23
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:
24
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.
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
27
Piper: 3-aminothalidomide
(AH 14)
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:
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30
31
Summary: Claims 1 and 7-9 are obvious over Piper and Kaplan
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33
36
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:
37
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:
38
39
40
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.)
42
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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.)
47
51
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.
52
53
54
56
57
58
CONCLUSION
For at least the reasons given above, claims 1-10 of the 517 Patent are
Respectfully submitted,
Date: May 7, 2015
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