`Tel: 571-272-7822
`Entered: November 16, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________
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`COALITION FOR AFFORDABLE DRUGS VI LLC,
`Petitioner,
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`v.
`
`CELGENE CORPORATION,
`Patent Owner.
`_____________
`
`Case IPR2015-01169
`Patent 5,635,517
`______________
`
`
`
`Before TONI R. SCHEINER, JACQUELINE WRIGHT BONILLA, and
`TINA E. HULSE, Administrative Patent Judges.
`
`
`BONILLA, Administrative Patent Judge.
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`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`IPR2015-01169
`Patent 5,635,517
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`I.
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`INTRODUCTION
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`Coalition For Affordable Drugs VI LLC (“Petitioner” or “CFAD”)
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`filed a Petition requesting inter partes review of claims 1–10 of U.S. Patent
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`No. 5,635,517 (Ex. 1001, “the ’517 Patent”). Paper 1 (“Pet.”). Celgene
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`Corporation (“Patent Owner”) filed a Preliminary Response. Paper 16
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`(“Prelim. Resp.”). We have jurisdiction under 35 U.S.C. § 314(a), which
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`provides that an inter partes review may not be instituted “unless . . . there is
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`a reasonable likelihood that the petitioner would prevail with respect to at
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`least 1 of the claims challenged in the petition.”
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`Upon consideration of the Petition and the Preliminary Response, and
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`for the reasons explained below, we determine that Petitioner has not
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`established a reasonable likelihood that it would prevail in showing the
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`unpatentability of any claim challenged in the Petition. Accordingly, we
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`decline to institute an inter partes review.
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`A. Related Proceedings
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`The parties indicate that the ’517 patent is the subject of a district
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`court proceeding, Celgene Corporation v. Natco Pharma Ltd., C.A. No.
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`2:10-cv-5197 (D.N.J.) (including consolidated related C.A. No. 2:12-cv-
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`4571 (D.N.J.)). Pet. 8; Paper 7. On October 27, 2015, the Board instituted
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`inter partes reviews of challenged claims in two unrelated patents owned by
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`Patent Owner, challenged by Petitioner, in Case Nos. IPR2015-01092 (Paper
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`20), IPR2015-01096 (Paper 21), IPR2015-01102 (Paper 21), and IPR2015-
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`01103 (Paper 22).
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`B. The ’517 Patent
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`The ’517 patent is directed to methods of reducing levels of tumor
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`necrosis factor α (“TNFα”) in a mammal by administering “amino
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`2
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`IPR2015-01169
`Patent 5,635,517
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`substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and 1,3-
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`dioxoisoindolines,” i.e., certain thalidomide analogs with an added amino
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`group (-NH2) in a benzene ring of the chemical structure. Ex. 1001, 1:6–11;
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`see also Pet. 1, 15–16 (showing chemical structures of thalidomide and
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`compounds recited in claims 3–10).
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`The ’517 patent discloses that TNFα is a cytokine released by
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`mononuclear phagocytes in response to immunostimulators. Ex. 1001,
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`1:14–16. Excessive or unregulated TNFα production has been implicated in
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`a number of diseases. Id. at 1:21–3:18. “Decreasing TNFα levels and/or
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`increasing cAMP levels” may help treat “many inflammatory, infectious,
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`immunological or malignant diseases.” Id. at 3:59–4:6.
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`The ’517 patent describes the discovery that certain compounds
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`“decrease the levels of TNFα and elevate the levels of adenosine 3’,5’-cyclic
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`monophosphate” (“cAMP”), and that such compounds have the formula:
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`Id. at 4:20–33. Thus, the disclosed compounds have an amino group (-NH2)
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`group attached to a carbon in the left 6-carbon benzene ring portion and, in
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`some compounds, X is a C=O and Y is a CH2 in the 5-carbon ring portion.
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`C. Illustrative Claims
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`The ’517 patent contains ten claims. Independent claims 1 and 10 and
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`dependent claims 2 and 7 are representative, and are reproduced below.
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`1. The method of reducing undesirable levels of TNFα in a
`mammal which comprises administering thereto an effective
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`3
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`IPR2015-01169
`Patent 5,635,517
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`amount of a compound of the formula:
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`
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`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.
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`2. The method according to claim 1 in which X is C=O and Y
`is CH2.
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`7. The method according to claim 1 in which each of X and Y
`is C=O.
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`10. 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.
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`Dependent claims 3–6 depend from claim 2, and claims 8 and 9 depend from
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`claim 7.
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`D. Proposed Grounds of Unpatentability
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`Petitioner advances three grounds of unpatentability under 35 U.S.C.
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`§ 103 in relation to the challenged claims in the ’517 patent (Pet. 11):
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` References
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`Statutory
`Basis
`Piper (Ex. 1002)1 in view of Kaplan (Ex. 1003)2 § 103
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`Challenged
`Claims
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`1, 7–9
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`1 Piper et al., Anti-inflammatory immunosuppressive thalidomide analogs,
`49(4) INT’L J. OF LEPROSY 511–512 (1981) (“Piper”) (Ex. 1002)
`2 Kaplan et al., U.S. Patent No. 5,385,901, filed Oct. 2, 1992, issued Jan. 31,
`1995 (“Kaplan”) (Ex. 1003).
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`4
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` References
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`Piper in view of Kaplan, Agrawal (Ex. 1004),3
`and WO ’085 (Ex. 1005)4
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`Statutory
`Basis
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`Challenged
`Claims
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`§ 103
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`2–6, 10
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`Piper in view of Kaplan, Agrawal, and Keith
`(Ex. 1006)5
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`§ 103
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`2–6, 10
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`In addition, Petitioner supports its challenges in the Petition with the
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`Declaration of Clayton H. Heathcock, Ph.D. (Ex. 1007). Pet. 11.
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`II. ANALYSIS
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`A. Claim construction
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`For inter partes review, claim terms in an unexpired patent are given
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`their broadest reasonable interpretation in light of the patent specification.
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`37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
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`1278–79 (Fed. Cir. 2015). Claim terms are given their ordinary and
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`customary meaning, as would be understood by one of ordinary skill in the
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`art in the context of the entire disclosure. In re Translogic Tech., Inc.,
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`504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definition for a claim
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`term must be set forth in the specification with reasonable clarity,
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`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
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`1994).
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`3 Agrawal et al., Structure activity relationship studies of thalidomide
`analogs as anti-inflammatory and immunosuppressive agents, 49(4) INT’L J.
`OF LEPROSY 512 (1981) (“Agrawal”) (Ex. 1004).
`4 D’Amato et al., WO 94/20085, published Sept. 15, 1994 (“WO ‘085”)
`(Ex. 1005).
`5 Keith & Walters, NATIONAL TOXICOLOGY PROGRAM’S CHEMICAL
`SOLUBILITY COMPENDIUM (Lewis Publishers, Inc. 1992) (“Keith”) (Ex.
`1006).
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`5
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`Petitioner presents chemical names and structures for the different
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`compounds recited in claims 3–6 and 8–10 of the ’517 patent. Pet. 13–16.
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`Patent Owner does not dispute those names and structures. Prelim. Resp. 4–
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`5. We are persuaded that the chemical names and structures provided in the
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`Petition (Pet. 15–16) in relation to those compounds correspond to the
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`ordinary and customary meaning of the recited terms as understood by one
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`of ordinary skill in the art, consistent with disclosures in the specification.
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`Notably, all compounds recited in the challenged claims contain an
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`amino group (-NH2) on the benzene ring of the compound. Id.; Ex. 1001,
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`claims 1–10. We determine that other claim terms need not be construed
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`explicitly for purposes of this Decision.
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`B. Asserted ground of obviousness of claims 1 and 7–9 over Piper
`(Ex. 1002) and Kaplan (Ex. 1003)
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`Petitioner contends that claims 1 and 7–9 of the ’517 patent would
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`have been obvious over Piper and Kaplan. Pet. 24–36. Petitioner contends
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`that “one of ordinary skill in the art would have readily combined the
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`teachings of Piper and Kaplan to develop thalidomide analogs having one or
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`both of [anti-inflammatory and immunosuppressive] functional activities for
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`use in effectively treating at least [erythema nodosum leprosum] by reducing
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`TNFα.” Pet. 32–33 (citing Ex. 1007 ¶¶ 112–115). Petitioner also contends
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`that one would have reasonably expected “Piper’s amino-thalidomide
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`analogs AH 14 and AH 13 to successfully exhibit the same activity as their
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`common parent compound (thalidomide) because AH 14 and AH 13 have
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`high structural similarity to the parent and also exhibit at least one key
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`activity of the parent (i.e., anti-inflammation or immunosuppression).” Pet.
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`33–35 (citing Ex. 1007 ¶¶ 116–128).
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`6
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`1. Piper (Ex. 1002)
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`Piper discloses that thalidomide is effective in controlling erythema
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`nodosum leprosum (“ENL”) reactions in lepromatous leprosy. Ex. 1002,
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`511, 1st col. Piper states that ENL has two clinically relevant cites of action:
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`(1) an anti-inflammatory cite of action, detectable in a “carrageenan” assay
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`in rats, and (2) an immunosuppressive site of action, detectable in a plaque
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`forming cells (“PFC”) assay in mice. Using those two assays, Piper
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`screened “[a]pproximately 50 thalidomide analogs.” Id. at 511, 2nd col.
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`Discussing over 40 different analogs in particular, Piper states that it
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`screened “[t]hirteen α-substituted glutarimides with changes in the 6
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`membered phthalimide moiety.” Id. In this context, in addition to other
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`compounds, Piper discusses “[f]our compounds involv[ing] electron
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`donating substitutions (amino- or hydroxyl-) on the 6 membered phthalimide
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`system.” Id. Regarding those four compounds, Piper states that “three are
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`active in carrageenan (4-hydroxythalidomide or AH 20, 3-
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`hydroxythalidomide or AH 22, and 4-aminothalidomide or AH 13),” and
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`“[o]ne, AH 20, is active in PFC and one, 3-aminothalidomide or AH 14,
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`enhances PFC.” Id. Thus, according to Piper, AH 22 (3-hydroxy) and AH
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`13 (4-amino) are “active” in the carrageenan assay, i.e., exhibit anti-
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`inflammatory activity, AH 20 (4-hydroxy) is “active” in both assays, and
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`AH 14 (3-amino) “enhances PFC.” Id.
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`Piper also discusses “[t]wo compounds represent[ing] changes in the 5
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`membered ring system of the phthalimide moiety and two involv[ing] major
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`alterations of the phthalimide system.” Id. Two out of those four
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`compounds, “EM 12 and glutethimide, are active in carrageenan.” Id.
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`7
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`Although a number of disclosed compounds are active in only one or
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`neither assay, Piper states, in addition to AH 20, that a “pyridine N-oxide-
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`substituted phthalimide, AH 3, has activity in both systems.” Id. Piper also
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`teaches that D,L-thalidomide and D-thalidomide are active in both assays,
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`although L-thalidomide is only active in the PFC assay. Id. at 512, 1st col.;
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`see also Prelim. Resp. 23 (contending that D-thalidomide, AH 3, and AH 20
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`were active in both assays, but “[f]or the remaining compounds, some were
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`active in one but not both assays, while some were inactive in both.”). Piper
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`does not mention TNFα. Ex. 1002, 511–12.
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`2. Kaplan (Ex. 1003)
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`Kaplan discloses methods for treating toxic concentrations of TNFα
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`using thalidomide and certain analogs of thalidomide, such as “preferred
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`compounds” encompassed by formula II:
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`Ex. 1003, 4: 4–26. Kaplan teaches that “[e]specially preferred compounds”
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`are compounds A–H, which include compounds C, D, G, and H depicted
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`below.
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`8
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`Id. at 4:26–5:39. The parties do not dispute that compound H corresponds to
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`EM 12 in Piper. Pet. 30; Prelim. Resp. 30.
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`Figures 1–4 in Kaplan show results of assays testing the effect of
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`thalidomide and/or a TNFα inhibitor pentoxyfylline (“PTN”) on induced
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`TNFα production, protein synthesis by human peripheral blood monocytes,
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`levels of different cytokines, and inhibition of reverse transcriptase
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`production. Ex. 1003, 8:29–10:48. Figures 5–7 show results in assays
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`measuring the inhibition of reverse transcriptase (“RT”) production, for
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`example in cells stimulated with TNFα, comparing the effect of thalidomide
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`and PTN with compounds C, D, G, and H. Id. at 10:49–60.
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`Figure 5 indicates that compound G presents the highest percent of
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`RT inhibition, and compound D presents the second highest. Id. at Fig. 5.
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`Figures 6 and 7 present more variable results in relation to compounds C, D,
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`G, and H, as compared to thalidomide, but in all three figures, compound G
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`presents the highest percentage inhibition activity. Id. at Figs. 5–7.
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`In its background section, Kaplan teaches that “thalidomide has long
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`been employed for the treatment of erythema nodosum leprosum (ENL),”
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`among other diseases. Id. at 2:42–55. Additionally, Kaplan discloses that
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`TNFα is “one of several cytokines released mainly by mononuclear
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`phagocytes together with several other cytokines in response to stimuli to the
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`immune system.” Id. at 2:56–59; see also id. at 3:41–49 (stating that TNFα,
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`IL-1, IL-6, IL-8, GM-CSF “are necessary for a proper immune response”
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`and “produced by mononuclear phagocytes,” and “[s]till other cytokines are
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`produced by the T-cells”). In addition to being associated with the
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`destruction of tumor cells, and present “in response to immunostimulators
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`such as bacterial and viral infections,” TNFα “is markedly elevated in ENL.”
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`Id. at 2:60–3:2.
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`Kaplan teaches that toxicity associated with TNFα is observed in
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`conditions such as cachexia, septic shock, and infections with retroviruses
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`(e.g., HIV). Id. at 3:3–40. Kaplan further discloses that “antiinflammatory
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`and immunosuppressive steroids such as prednisolone and dexamethasone
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`have been employed to treat the debilitating effects of TNFα,” but those
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`“agents also block the production of other cytokines so that the patients
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`become susceptible to life threatening infections.” Id. at 3:50–55.
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`3. Analysis
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`We agree with Petitioner that Piper discloses, among other
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`thalidomide analogs, the three compounds known as 3-aminothalidomide
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`(AH 14), 4-aminothalidomide (AH 13), and EM-12, which have the
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`following chemical structures.
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`10
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`Pet. 3, 27–28. Petitioner persuades us that the composition recited in claim
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`8 corresponds to AH 14, and, therefore, compositions recited in method
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`claims 1, 7, and 8 encompass AH 14. Pet. 29. Petitioner also persuades us
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`that the composition recited in claim 9 corresponds to AH 13, and, therefore,
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`compositions recited in method claims 1, 7, and 9 encompass AH 14. Id.
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`As noted above, both Piper and Kaplan teach that thalidomide is
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`effective to treat ENL reactions in leprosy. Piper teaches that ENL involves
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`two cites of action, i.e., anti-inflammatory activity (measured by the
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`carrageenan assay) and immunosuppressive activity (measured by the PFC
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`assay). Piper teaches that most of the 50 screened analogs are active in only
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`one or neither assay. Piper teaches that thalidomide itself, as well as two
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`analogs, AH 3 and AH 20, are active in both assays. None of those three
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`compounds contains an amino group on the benzene ring, as required by
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`each of the challenged claims. See Prelim. Resp. 23 (presenting chemical
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`structures).
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`Petitioner refers us to two compounds in Piper (of the 50 screened) as
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`analogs having an amino group on the benzene ring, AH 13 and AH 14. Pet.
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`26–28. Petitioner and Patent Owner agree that AH 13 is active in only one
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`assay, the carrageenan (anti-inflammatory) assay. Pet. 26; Prelim. Resp. 29.
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`Petitioner asserts that AH 14 is only active in the other assay, the PFC
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`(immunosuppressive) assay, but Patent Owner contends that AH 14 actually
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`is active in neither assay. Pet. 26; Prelim. Resp. 13, 28–29. Evidence cited
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`by Patent Owner persuades us that AH 14 is inactive in both assays—that
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`the statement in Piper that AH 14 “enhances PFC” means that AH 14 is
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`immunostimulatory, not immunosuppressive. Id. at 28–29 (citing Ex. 1002,
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`511; Ex. 2029, 69–70).
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`Petitioner agrees that Kaplan does not disclose thalidomide analogs
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`having an amino group on the benzene ring, but points to EM 12, also
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`disclosed in Piper, called compound H in Kaplan. Pet. 30; Ex. 1002, 511,
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`2nd col.; Ex. 1003, 5:30–39. EM 12 contains no amino group on the
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`benzene ring, but contains one C=O on the 5-carbon ring. Pet. 28, 30–31.
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`Petitioner contends that Kaplan teaches a method of inhibiting TNFα
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`production by administering EM 12, citing claim 1 in Kaplan (Ex. 1003),
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`which recites a compound encompassing EM 12. Pet. 30. Petitioner also
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`contends that Kaplan indicates that EM 12 is one of eight “[e]specially
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`preferred” analogs disclosed in the reference. Id. at 31; Ex. 1003, 4:27–5:39.
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`Independent claim 1 and dependent claims 7–9 of the ’517 patent
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`recite methods of reducing TNFα levels in a mammal by administering
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`certain thalidomide analogs having an amino group on the benzene ring. As
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`Patent Owner points out, Piper does not mention TNFα. Prelim. Resp. 19;
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`Ex. 1002, 511–12. Consequently, Petitioner necessarily combines certain
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`teachings in Piper (disclosing AH 13 and AH 14, each having an amino
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`group on the benzene ring) with those in Kaplan (disclosing methods of
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`inhibiting TNFα using different thalidomide analogs). As such, Petitioner’s
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`contentions regarding reasons to combine relevant teachings from the two
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`references, as well as assertions regarding a reasonable expectation of
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`success in performing recited methods, are critical to our analysis. Pet. 32–
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`35.
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`a) Alleged Reasons to Combine Piper and Kaplan
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`Petitioner contends that disclosures in Piper and Kaplan “would have
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`been easily combined by one of ordinary skill” because “each one teaches
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`the same parent compound (thalidomide) and various analogs thereof in
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`12
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`relation to treating the same condition (ENL).” Pet. 32–33 (citing Ex. 1007,
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`¶¶ 112–115). We are not persuaded, however, that Piper sufficiently teaches
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`or suggests that AH 13, AH 14, or EM 12 would be useful to treat ENL.
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`Piper discloses that ENL involves two mechanisms of action, and, therefore,
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`suggests that compounds exhibiting both activities (as measured in the two
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`assays) might be useful to treat ENL. Such compounds include D, L- and D-
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`thalidomide (expressly disclosed in Piper as useful to treat ENL), AH 3, and
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`AH 20. We are not persuaded that Piper teaches or suggests sufficiently that
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`any other disclosed compounds active in only one or neither assay, such as
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`AH 13, AH 14, or EM 12, would have been effective in treating ENL.
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`In addition, Patent Owner persuades us that Kaplan does not teach
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`treating ENL with any compound other than thalidomide itself. Prelim.
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`Resp. 16–17. Kaplan does not describe using any of the disclosed analogs,
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`e.g., any of compounds A–H, such as EM 12, to treat ENL. Rather, at most,
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`in its background section, Kaplan states that “thalidomide has long been
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`employed for the treatment” of ENL, as well as other diseases, and that
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`TNFα “is markedly elevated in ENL.” Ex. 1003, 2:42–55, 3:1–2.
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`Petitioner contends that Kaplan teaches using EM 12 to reduce TNFα
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`levels, and both Piper and Kaplan “teach the well-known analog EM 12, and
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`that anti-inflammatory and immunosuppressive properties are important to
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`the efficacy and activity of thalidomide and its analogs.” Pet. 30–33 (citing
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`Ex. 1007 ¶¶ 90–120). Thus, according to Petitioner, “one of ordinary skill in
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`the art would have readily combined the teachings of Piper and Kaplan to
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`develop thalidomide analogs having one or both of these important
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`functional activities for use in effectively treating at least ENL by reducing
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`TNFα.” Id.
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`We agree with Petitioner that both Piper and Kaplan disclose EM 12
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`and at least Piper suggests that both “anti-inflammatory and immuno-
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`suppressive properties are important to the efficacy and activity of
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`thalidomide and its analogs.” Id. As discussed above, however, we are not
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`persuaded that Piper discloses sufficiently that EM 12, which exhibits only
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`anti-inflammatory activity in Piper, would have been useful to treat ENL.
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`Moreover, while Kaplan suggests that EM 12 may be useful to reduce TNFα
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`levels, Kaplan, alone or in combination with Piper, does not suggest
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`sufficiently that a thalidomide analog containing an amino group on the
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`benzene ring (in contrast to compounds, including EM 12, disclosed in
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`Kaplan) would be useful to reduce TNFα levels.
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`Piper, which discusses ENL, does not mention TNFα, nor does it
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`establish a relationship between results from the two assays regarding ENL’s
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`two sites of action (carrageenan and/or PFC) and TNFα levels. Prelim.
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`Resp. 19–20. Kaplan, at most, states that thalidomide is useful to treat ENL
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`and reduce TNFα levels, and that TNFα levels are “markedly elevated in
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`ENL.” Ex. 1003, 2:42–45, 3:1–2. Nonetheless, and even if Kaplan also
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`suggests that EM 12 may reduce TNFα levels, the reference does not suggest
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`sufficiently that by doing so, EM 12 would be useful to treat ENL. In
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`addition, while Piper discloses EM 12 (among many analogs), and may
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`indicate that this analog is active in the carrageenan assay (i.e., has at least
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`some anti-inflammatory activity), we agree with Patent Owner that neither
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`Piper nor Kaplan (which is silent on the two Piper assays) establishes
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`sufficiently that anti-inflammatory activity alone by any analog (such as AH
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`13) necessarily corresponds to an ability to reduce TNFα levels.
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`14
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`Additional information cited by Patent Owner further persuades us
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`that Petitioner does not establish sufficiently that a link exists between
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`treating ENL and reducing TNFα levels. For example, Patent Owner
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`provides information indicating that EM 12, which Kaplan suggests may
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`reduce TNFα, only “has marginal activity in the carrageenan assay with
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`activity at the highest dose tested but no activity in lower doses, and it lacks
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`activity in the PFC assay.” Prelim. Resp. 43–44 (citing Ex. 2028, 673, 1st
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`col.; Ex. 2029, 70). Such evidence runs counter to the notion that an
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`ordinary artisan would have understood that one could treat ENL by using
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`any thalidomide analog (such as EM 12) that reduces TNFα, as Petitioner
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`suggests. Pet. 33.
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`Furthermore, as noted by Patent Owner and stated in Kaplan, immune
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`responses involve a number of different biological molecules, including
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`cytokines such as IL-1, IL-6, IL-8, GM-CSF, as well as other cytokines
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`produced by T-cells, in addition to TNFα. As Patent Owner notes, “some
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`anti-inflammatory agents, such as nonsteroidal anti-inflammatory drugs
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`(NSAIDs), actually increase TNFα production in rheumatoid synovia and
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`whole blood.” Prelim. Resp. 22 (citing Ex. 2020, Abstract). Information
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`before us, therefore, fails to establish sufficiently a correlation between anti-
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`inflammatory activity (as measured in the carrageenan assay in Piper) with a
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`reduction in TNFα levels in particular, even assuming the references indicate
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`that EM 12 does both things.
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`Lastly, as noted by Patent Owner, data in Kaplan suggests that
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`compound G works better than EM 12 to inhibit TNFα, indicating that
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`Kaplan does not favor using EM 12 in particular. Ex. 1003, Figures 5–7;
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`Prelim. Resp. 33–34.
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`Thus, at most, Piper and Kaplan together indicate that thalidomide is
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`useful to both treat ENL and reduce TNFα levels, and EM 12 (and other
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`analogs lacking the amino group on the benzene ring) may reduce TNFα,
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`even if EM 12 exhibits activity in only one out of two relevant sites of action
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`for ENL. Petitioner does not establish sufficiently that an ordinary artisan
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`reading those two references would have had reason to pick AH 13 or AH
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`14 (out of over 40 analogs discussed in Piper) in particular for use in a
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`method to reduce TNFα levels (disclosed in Kaplan in relation to different
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`analogs).
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`b) Alleged Reasonable Expectation of Success
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`Petitioner also contends that an ordinary artisan would have
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`reasonably expected Piper’s AH 14 and AH 13 to exhibit the same activity
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`as thalidomide because AH 14 and AH 13 have high structural similarity to
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`that parent compound and exhibit “at least one key activity of the parent
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`(i.e., anti-inflammation or immunosuppression).” Pet. 33. In support,
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`Petitioner refers to EM 12 and its activities (as shown in Piper and Kaplan),
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`and cites Dr. Heathcock’s Declaration for the proposition that “those of
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`ordinary skill may expect compounds of high structural similarity that have
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`an important functional activity in common to have other activities in
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`common as well.” Pet. 34 (citing Ex. 1007, ¶¶ 118, 119). We note that
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`other than referring to Piper and Kaplan generally, the cited paragraphs in
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`Dr. Heathcock’s Declaration cite no evidence in support of that proposition.
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`Ex. 1007, ¶¶ 118, 119.
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`Other information of record before us, by contrast, indicates that even
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`the smallest of chemical differences in thalidomide analogs impacts
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`biological activity. Teachings in Piper alone indicate that different analogs,
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`even those differing only by the addition and/or location of a single
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`“electron donating” group on the benzene ring, exhibit different activities.
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`Piper discusses “[t]hirteen α-substituted glutarimides with changes in the 6
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`membered phthalimide moiety.” Ex. 1002, 511, 2nd col. Of those, many
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`are active in one or the other assay (carrageenan or PFC) or neither assay.
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`Among those thirteen, Piper also discusses “[f]our compounds involv[ing]
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`electron donating substitutions (amino- or hydroxyl-) on the 6 membered
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`phthalimide system.” Id. Among those four compounds, and even among
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`the two compounds containing an amino group on the 6-carbon benzene ring
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`(AH 13 and AH 14), Piper found differing results in the two assays. For
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`example, Piper states that AH 13 is active in the carrageenan assay but not
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`the PFC assay, while AH 14 “enhances PFC” and is inactive in the
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`carrageenan assay. Id.; see also Prelim. Resp. 29 (noting differing assay
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`results for thalidomide and different analogs, including those with a
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`hydroxyl group on the benzene ring, AH 22 and AH 20).
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`Thus, Patent Owner persuades us, consistent with binding case law,
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`that “even minor structural modifications to a chemical compound can have
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`significant and highly unpredictable effects on functionality,” as evidenced
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`by Piper and other references of record here. Prelim. Resp. 26–27 (citing
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`relevant Federal Circuit and other case law) (citations omitted). We are not
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`persuaded by Petitioner’s contention that “those of ordinary skill may expect
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`compounds of high structural similarity that have an important functional
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`activity in common to have other activities in common as well.” Pet. 34.
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`When arguing a reasonable expectation of success, Petitioner also
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`contends that “by disclosing steroids [prednisolone and dexamethasone] that
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`exhibit anti-inflammation, immunosuppression, and TNFα inhibition,
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`Kaplan identifies another direct relationship—i.e., between compounds that
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`are anti-inflammatory or immunosuppressive and compounds that block
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`TNFα.” Pet. 34–35 (citing Ex. 1007 ¶ 120 (citing Ex. 1003, 3:50–55)).
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`Petitioner does not contend, however, that either steroid is a thalidomide
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`analog. In addition, Kaplan teaches that those steroids exhibit both anti-
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`inflammatory and immunosuppressive activities, similarly to thalidomide,
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`but unlike EM 12 (as disclosed in Piper). In any event, Kaplan’s discussion
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`about steroids unrelated in structure does not indicate sufficiently that one
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`would have expected entirely different compounds (e.g., AH 13 or AH 14)
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`to reduce TNFα levels.
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`4. Conclusion
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`For the reasons discussed above, Petitioner has not established a
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`reasonable likelihood of prevailing on the ground that claims 1 and 7–9 of
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`the ’517 patent would have been obvious over Piper in view of Kaplan.
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`C. Asserted ground of obviousness of claims 2–6 and 10 over Piper,
`Kaplan, Agrawal (Ex. 1004), and WO ’085 (Ex.1005)
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`Petitioner contends that claims 2–6 and 10 of the ’517 patent would
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`have been obvious over Piper, Kaplan, Agrawal, and WO ’085. Pet. 37–52.
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`In relation to Piper and Kaplan, Petitioner raises similar contentions to those
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`discussed above. Id. at 39–40. Petitioner additionally relies on Agrawal
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`(published alongside Piper), which discusses carrageenan and PFC assay
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`results using thalidomide analogs, and WO ’085, which discloses methods of
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`inhibiting angiogenesis using thalidomide and thalidomide analogs. Id. at
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`40–42. Petitioner again contends that an ordinary artisan would have had
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`reason to combine teachings in those references to reach the recited methods
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`and compounds, and one would have had a reasonable expectation of
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`success in doing so. Id. at 43–49.
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`1. Agrawal (Ex. 1004)
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`Like Piper, Agrawal describes a study in an effort to develop
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`thalidomide analogs that are effective in controlling ENL—again using the
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`carrageenan (anti-inflammatory) and PFC (immunosuppressive) assays.
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`Agrawal discusses many different analogs, including “analogs containing
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`NO2, COOH, NH2, or OH groups.” Ex. 1004, 512, 2nd col. In this context,
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`Agrawal states that “agents containing the electron donating groups such as
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`3 or 4-hydroxy and 4-aminothalidomide retained the anticarrageenan
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`activity, whereas the analogs with electron withdrawing groups such as 4-
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`nitro or 4-carboxy were not active in this assay.” Id. Agrawal goes on to
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`state, however, that “the biological activity in the PFC assay did not
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`correlate with electronic properties since not only the 4-nitro and 4-carboxy
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`analogs but also the 4-hydroxythalidomide was active in this system.” Id.
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`Thus, consistent with teachings in Piper, Agrawal indicates that 4-
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`hydroxythalidomide (AH 20) is active in both assays, and 3-hydroxy-
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`thalidomide (AH 22) and 4-aminothalidomide (AH 13) are active only in the
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`carrageenan assay. While it does not discuss 3-aminothalidomide (AH 14)
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`per se, teachings in Agrawal also are consistent with the fact that AH 14 is
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`inactive in both assays, as indicated in Piper.
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`Agrawal also states that study results “suggest that modifications in
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`the parent thalidomide molecule can be made which retain the anti-
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`inflammatory and immunosuppressive activity, but yet may be expected to
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`alter the neurotoxic and teratogenic properties.” Id. (emphasis added). Like
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`Piper, therefore, Agrawal suggests that thalidomide analogs that exhibit both
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`anti-inflammatory and immunosuppressive activities (i.e., active in both
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`assays) would be useful to treat EML.
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`2. WO ’085 (Ex. 1005)
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`WO ’085 discloses methods for preventing unwanted angiogenesis by
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`administering thalidomide and “related compounds.” Ex. 1005, 1:20–25.6
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`As noted in WO ’085, angiogenesis is the generation of new blood vessels
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`into a tissue or organ. Id. at 1:28–29.
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`WO ’085 discloses that “[s]pecific preferred compounds . . . of the
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`present invention include thalidomide, its precursors, metabolites and
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`analogs,” and that “[p]articular analogs include EM-12, N-phthaloyl-DL-
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`glutamic acid (PGA) or N-phthaloyl-DL-glutamine anhydride.” Id. at 14:8–
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`12. WO ’085 discloses using “epoxides of thalidomide, EM-12 and EM-
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`138” (id. at 16:1–15) and that the epoxides can be hydrolyzed to form six
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`compounds, including the two compounds reproduced below.
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`Id. at 16:20–17:9. WO ’085 further teaches that “the hydroxyl group can be
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`on carbons 1, 2, 3, 4, 5 and 6 of the benzene ring.” Id. at 17:10–11.
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`3. Analysis—Claims 2–6
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`Claims 2–6 of the ’517 patent depend from claim 1, and recite
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`methods of reducing TNFα in a mammal by administering compositions
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