throbber
Trials@uspto.gov Paper 22
`Tel: 571-272-7822
`Entered: November 16, 2015
`
`
`
`
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`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 IPR2015-01169
`Patent 5,635,517
`______________
`
`
`
`Before TONI R. SCHEINER, JACQUELINE WRIGHT BONILLA, and
`TINA E. HULSE, Administrative Patent Judges.
`
`
`BONILLA, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`

`

`IPR2015-01169
`Patent 5,635,517
`
`
`I.
`
`INTRODUCTION
`
`Coalition For Affordable Drugs VI LLC (“Petitioner” or “CFAD”)
`
`filed a Petition requesting inter partes review of claims 1–10 of U.S. Patent
`
`No. 5,635,517 (Ex. 1001, “the ’517 Patent”). Paper 1 (“Pet.”). Celgene
`
`Corporation (“Patent Owner”) filed a Preliminary Response. Paper 16
`
`(“Prelim. Resp.”). We have jurisdiction under 35 U.S.C. § 314(a), which
`
`provides that an inter partes review may not be instituted “unless . . . there is
`
`a reasonable likelihood that the petitioner would prevail with respect to at
`
`least 1 of the claims challenged in the petition.”
`
`Upon consideration of the Petition and the Preliminary Response, and
`
`for the reasons explained below, we determine that Petitioner has not
`
`established a reasonable likelihood that it would prevail in showing the
`
`unpatentability of any claim challenged in the Petition. Accordingly, we
`
`decline to institute an inter partes review.
`
`A. Related Proceedings
`
`The parties indicate that the ’517 patent is the subject of a district
`
`court proceeding, Celgene Corporation v. Natco Pharma Ltd., C.A. No.
`
`2:10-cv-5197 (D.N.J.) (including consolidated related C.A. No. 2:12-cv-
`
`4571 (D.N.J.)). Pet. 8; Paper 7. On October 27, 2015, the Board instituted
`
`inter partes reviews of challenged claims in two unrelated patents owned by
`
`Patent Owner, challenged by Petitioner, in Case Nos. IPR2015-01092 (Paper
`
`20), IPR2015-01096 (Paper 21), IPR2015-01102 (Paper 21), and IPR2015-
`
`01103 (Paper 22).
`
`B. The ’517 Patent
`
`The ’517 patent is directed to methods of reducing levels of tumor
`
`necrosis factor α (“TNFα”) in a mammal by administering “amino
`
`
`
`2
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`

`

`IPR2015-01169
`Patent 5,635,517
`
`substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and 1,3-
`
`dioxoisoindolines,” i.e., certain thalidomide analogs with an added amino
`
`group (-NH2) in a benzene ring of the chemical structure. Ex. 1001, 1:6–11;
`
`see also Pet. 1, 15–16 (showing chemical structures of thalidomide and
`
`compounds recited in claims 3–10).
`
`The ’517 patent discloses that TNFα is a cytokine released by
`
`mononuclear phagocytes in response to immunostimulators. Ex. 1001,
`
`1:14–16. Excessive or unregulated TNFα production has been implicated in
`
`a number of diseases. Id. at 1:21–3:18. “Decreasing TNFα levels and/or
`
`increasing cAMP levels” may help treat “many inflammatory, infectious,
`
`immunological or malignant diseases.” Id. at 3:59–4:6.
`
`The ’517 patent describes the discovery that certain compounds
`
`“decrease the levels of TNFα and elevate the levels of adenosine 3’,5’-cyclic
`
`monophosphate” (“cAMP”), and that such compounds have the formula:
`
`
`
`Id. at 4:20–33. Thus, the disclosed compounds have an amino group (-NH2)
`
`group attached to a carbon in the left 6-carbon benzene ring portion and, in
`
`some compounds, X is a C=O and Y is a CH2 in the 5-carbon ring portion.
`
`C. Illustrative Claims
`
`The ’517 patent contains ten claims. Independent claims 1 and 10 and
`
`dependent claims 2 and 7 are representative, and are reproduced below.
`
`1. The method of reducing undesirable levels of TNFα in a
`mammal which comprises administering thereto an effective
`
`
`
`3
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`

`

`IPR2015-01169
`Patent 5,635,517
`
`
`amount of a compound of the formula:
`
`
`
`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.
`
`2. The method according to claim 1 in which X is C=O and Y
`is CH2.
`
`7. The method according to claim 1 in which each of X and Y
`is C=O.
`
`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.
`
`Dependent claims 3–6 depend from claim 2, and claims 8 and 9 depend from
`
`claim 7.
`
`D. Proposed Grounds of Unpatentability
`
`Petitioner advances three grounds of unpatentability under 35 U.S.C.
`
`§ 103 in relation to the challenged claims in the ’517 patent (Pet. 11):
`
` References
`
`Statutory
`Basis
`Piper (Ex. 1002)1 in view of Kaplan (Ex. 1003)2 § 103
`
`Challenged
`Claims
`
`1, 7–9
`
`
`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).
`
`
`
`4
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`

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`IPR2015-01169
`Patent 5,635,517
`
` References
`
`Piper in view of Kaplan, Agrawal (Ex. 1004),3
`and WO ’085 (Ex. 1005)4
`
`Statutory
`Basis
`
`Challenged
`Claims
`
`§ 103
`
`2–6, 10
`
`Piper in view of Kaplan, Agrawal, and Keith
`(Ex. 1006)5
`
`§ 103
`
`2–6, 10
`
`
`In addition, Petitioner supports its challenges in the Petition with the
`
`Declaration of Clayton H. Heathcock, Ph.D. (Ex. 1007). Pet. 11.
`
`II. ANALYSIS
`
`A. Claim construction
`
`For inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable interpretation in light of the patent specification.
`
`37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
`
`1278–79 (Fed. Cir. 2015). Claim terms are given their ordinary and
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`art in the context of the entire disclosure. In re Translogic Tech., Inc.,
`
`504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definition for a claim
`
`term must be set forth in the specification with reasonable clarity,
`
`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994).
`
`
`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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`IPR2015-01169
`Patent 5,635,517
`
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`Petitioner presents chemical names and structures for the different
`
`compounds recited in claims 3–6 and 8–10 of the ’517 patent. Pet. 13–16.
`
`Patent Owner does not dispute those names and structures. Prelim. Resp. 4–
`
`5. We are persuaded that the chemical names and structures provided in the
`
`Petition (Pet. 15–16) in relation to those compounds correspond to the
`
`ordinary and customary meaning of the recited terms as understood by one
`
`of ordinary skill in the art, consistent with disclosures in the specification.
`
`Notably, all compounds recited in the challenged claims contain an
`
`amino group (-NH2) on the benzene ring of the compound. Id.; Ex. 1001,
`
`claims 1–10. We determine that other claim terms need not be construed
`
`explicitly for purposes of this Decision.
`
`B. Asserted ground of obviousness of claims 1 and 7–9 over Piper
`(Ex. 1002) and Kaplan (Ex. 1003)
`
`Petitioner contends that claims 1 and 7–9 of the ’517 patent would
`
`have been obvious over Piper and Kaplan. Pet. 24–36. Petitioner contends
`
`that “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 [anti-inflammatory and immunosuppressive] functional activities for
`
`use in effectively treating at least [erythema nodosum leprosum] by reducing
`
`TNFα.” Pet. 32–33 (citing Ex. 1007 ¶¶ 112–115). Petitioner also contends
`
`that one would have reasonably expected “Piper’s 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).” Pet.
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`33–35 (citing Ex. 1007 ¶¶ 116–128).
`
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`6
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`IPR2015-01169
`Patent 5,635,517
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`1. Piper (Ex. 1002)
`
`Piper discloses that thalidomide is effective in controlling erythema
`
`nodosum leprosum (“ENL”) reactions in lepromatous leprosy. Ex. 1002,
`
`511, 1st col. Piper states that ENL has two clinically relevant cites of action:
`
`(1) an anti-inflammatory cite of action, detectable in a “carrageenan” assay
`
`in rats, and (2) an immunosuppressive site of action, detectable in a plaque
`
`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.
`
`Discussing over 40 different analogs in particular, Piper states that it
`
`screened “[t]hirteen α-substituted glutarimides with changes in the 6
`
`membered phthalimide moiety.” Id. In this context, in addition to other
`
`compounds, Piper discusses “[f]our compounds involv[ing] electron
`
`donating substitutions (amino- or hydroxyl-) on the 6 membered phthalimide
`
`system.” Id. Regarding those four compounds, Piper states that “three are
`
`active in carrageenan (4-hydroxythalidomide or AH 20, 3-
`
`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,
`
`enhances PFC.” Id. Thus, according to Piper, AH 22 (3-hydroxy) and AH
`
`13 (4-amino) are “active” in the carrageenan assay, i.e., exhibit anti-
`
`inflammatory activity, AH 20 (4-hydroxy) is “active” in both assays, and
`
`AH 14 (3-amino) “enhances PFC.” Id.
`
`Piper also discusses “[t]wo compounds represent[ing] changes in the 5
`
`membered ring system of the phthalimide moiety and two involv[ing] major
`
`alterations of the phthalimide system.” Id. Two out of those four
`
`compounds, “EM 12 and glutethimide, are active in carrageenan.” Id.
`
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`7
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`IPR2015-01169
`Patent 5,635,517
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`
`Although a number of disclosed compounds are active in only one or
`
`neither assay, Piper states, in addition to AH 20, that a “pyridine N-oxide-
`
`substituted phthalimide, AH 3, has activity in both systems.” Id. Piper also
`
`teaches that D,L-thalidomide and D-thalidomide are active in both assays,
`
`although L-thalidomide is only active in the PFC assay. Id. at 512, 1st col.;
`
`see also Prelim. Resp. 23 (contending that D-thalidomide, AH 3, and AH 20
`
`were active in both assays, but “[f]or the remaining compounds, some were
`
`active in one but not both assays, while some were inactive in both.”). Piper
`
`does not mention TNFα. Ex. 1002, 511–12.
`
`2. Kaplan (Ex. 1003)
`
`Kaplan discloses methods for treating toxic concentrations of TNFα
`
`using thalidomide and certain analogs of thalidomide, such as “preferred
`
`compounds” encompassed by formula II:
`
`Ex. 1003, 4: 4–26. Kaplan teaches that “[e]specially preferred compounds”
`
`are compounds A–H, which include compounds C, D, G, and H depicted
`
`
`
`below.
`
`
`
`8
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`

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`IPR2015-01169
`Patent 5,635,517
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`
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`Id. at 4:26–5:39. The parties do not dispute that compound H corresponds to
`
`EM 12 in Piper. Pet. 30; Prelim. Resp. 30.
`
`Figures 1–4 in Kaplan show results of assays testing the effect of
`
`thalidomide and/or a TNFα inhibitor pentoxyfylline (“PTN”) on induced
`
`TNFα production, protein synthesis by human peripheral blood monocytes,
`
`levels of different cytokines, and inhibition of reverse transcriptase
`
`production. Ex. 1003, 8:29–10:48. Figures 5–7 show results in assays
`
`measuring the inhibition of reverse transcriptase (“RT”) production, for
`
`example in cells stimulated with TNFα, comparing the effect of thalidomide
`
`and PTN with compounds C, D, G, and H. Id. at 10:49–60.
`
`Figure 5 indicates that compound G presents the highest percent of
`
`RT inhibition, and compound D presents the second highest. Id. at Fig. 5.
`
`Figures 6 and 7 present more variable results in relation to compounds C, D,
`
`G, and H, as compared to thalidomide, but in all three figures, compound G
`
`presents the highest percentage inhibition activity. Id. at Figs. 5–7.
`
`In its background section, Kaplan teaches that “thalidomide has long
`
`been employed for the treatment of erythema nodosum leprosum (ENL),”
`
`among other diseases. Id. at 2:42–55. Additionally, Kaplan discloses that
`
`
`
`9
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`IPR2015-01169
`Patent 5,635,517
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`TNFα is “one of several cytokines released mainly by mononuclear
`
`phagocytes together with several other cytokines in response to stimuli to the
`
`immune system.” Id. at 2:56–59; see also id. at 3:41–49 (stating that TNFα,
`
`IL-1, IL-6, IL-8, GM-CSF “are necessary for a proper immune response”
`
`and “produced by mononuclear phagocytes,” and “[s]till other cytokines are
`
`produced by the T-cells”). In addition to being associated with the
`
`destruction of tumor cells, and present “in response to immunostimulators
`
`such as bacterial and viral infections,” TNFα “is markedly elevated in ENL.”
`
`Id. at 2:60–3:2.
`
`Kaplan teaches that toxicity associated with TNFα is observed in
`
`conditions such as cachexia, septic shock, and infections with retroviruses
`
`(e.g., HIV). Id. at 3:3–40. Kaplan further discloses that “antiinflammatory
`
`and immunosuppressive steroids such as prednisolone and dexamethasone
`
`have been employed to treat the debilitating effects of TNFα,” but those
`
`“agents also block the production of other cytokines so that the patients
`
`become susceptible to life threatening infections.” Id. at 3:50–55.
`
`3. Analysis
`
`We agree with Petitioner that Piper discloses, among other
`
`thalidomide analogs, the three compounds known as 3-aminothalidomide
`
`(AH 14), 4-aminothalidomide (AH 13), and EM-12, which have the
`
`following chemical structures.
`
`
`
`10
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`IPR2015-01169
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`Pet. 3, 27–28. Petitioner persuades us that the composition recited in claim
`
`8 corresponds to AH 14, and, therefore, compositions recited in method
`
`claims 1, 7, and 8 encompass AH 14. Pet. 29. Petitioner also persuades us
`
`that the composition recited in claim 9 corresponds to AH 13, and, therefore,
`
`compositions recited in method claims 1, 7, and 9 encompass AH 14. Id.
`
`As noted above, both Piper and Kaplan teach that thalidomide is
`
`effective to treat ENL reactions in leprosy. Piper teaches that ENL involves
`
`two cites of action, i.e., anti-inflammatory activity (measured by the
`
`carrageenan assay) and immunosuppressive activity (measured by the PFC
`
`assay). Piper teaches that most of the 50 screened analogs are active in only
`
`one or neither assay. Piper teaches that thalidomide itself, as well as two
`
`analogs, AH 3 and AH 20, are active in both assays. None of those three
`
`compounds contains an amino group on the benzene ring, as required by
`
`each of the challenged claims. See Prelim. Resp. 23 (presenting chemical
`
`structures).
`
`Petitioner refers us to two compounds in Piper (of the 50 screened) as
`
`analogs having an amino group on the benzene ring, AH 13 and AH 14. Pet.
`
`26–28. Petitioner and Patent Owner agree that AH 13 is active in only one
`
`assay, the carrageenan (anti-inflammatory) assay. Pet. 26; Prelim. Resp. 29.
`
`Petitioner asserts that AH 14 is only active in the other assay, the PFC
`
`(immunosuppressive) assay, but Patent Owner contends that AH 14 actually
`
`is active in neither assay. Pet. 26; Prelim. Resp. 13, 28–29. Evidence cited
`
`by Patent Owner persuades us that AH 14 is inactive in both assays—that
`
`the statement in Piper that AH 14 “enhances PFC” means that AH 14 is
`
`immunostimulatory, not immunosuppressive. Id. at 28–29 (citing Ex. 1002,
`
`511; Ex. 2029, 69–70).
`
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`11
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`Petitioner agrees that Kaplan does not disclose thalidomide analogs
`
`having an amino group on the benzene ring, but points to EM 12, also
`
`disclosed in Piper, called compound H in Kaplan. Pet. 30; Ex. 1002, 511,
`
`2nd col.; Ex. 1003, 5:30–39. EM 12 contains no amino group on the
`
`benzene ring, but contains one C=O on the 5-carbon ring. Pet. 28, 30–31.
`
`Petitioner contends that Kaplan teaches a method of inhibiting TNFα
`
`production by administering EM 12, citing claim 1 in Kaplan (Ex. 1003),
`
`which recites a compound encompassing EM 12. Pet. 30. Petitioner also
`
`contends that Kaplan indicates that EM 12 is one of eight “[e]specially
`
`preferred” analogs disclosed in the reference. Id. at 31; Ex. 1003, 4:27–5:39.
`
`Independent claim 1 and dependent claims 7–9 of the ’517 patent
`
`recite methods of reducing TNFα levels in a mammal by administering
`
`certain thalidomide analogs having an amino group on the benzene ring. As
`
`Patent Owner points out, Piper does not mention TNFα. Prelim. Resp. 19;
`
`Ex. 1002, 511–12. Consequently, Petitioner necessarily combines certain
`
`teachings in Piper (disclosing AH 13 and AH 14, each having an amino
`
`group on the benzene ring) with those in Kaplan (disclosing methods of
`
`inhibiting TNFα using different thalidomide analogs). As such, Petitioner’s
`
`contentions regarding reasons to combine relevant teachings from the two
`
`references, as well as assertions regarding a reasonable expectation of
`
`success in performing recited methods, are critical to our analysis. Pet. 32–
`
`35.
`
`a) Alleged Reasons to Combine Piper and Kaplan
`
`Petitioner contends that disclosures in Piper and Kaplan “would have
`
`been easily combined by one of ordinary skill” because “each one teaches
`
`the same parent compound (thalidomide) and various analogs thereof in
`
`
`
`12
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`IPR2015-01169
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`relation to treating the same condition (ENL).” Pet. 32–33 (citing Ex. 1007,
`
`¶¶ 112–115). We are not persuaded, however, that Piper sufficiently teaches
`
`or suggests that AH 13, AH 14, or EM 12 would be useful to treat ENL.
`
`Piper discloses that ENL involves two mechanisms of action, and, therefore,
`
`suggests that compounds exhibiting both activities (as measured in the two
`
`assays) might be useful to treat ENL. Such compounds include D, L- and D-
`
`thalidomide (expressly disclosed in Piper as useful to treat ENL), AH 3, and
`
`AH 20. We are not persuaded that Piper teaches or suggests sufficiently that
`
`any other disclosed compounds active in only one or neither assay, such as
`
`AH 13, AH 14, or EM 12, would have been effective in treating ENL.
`
`In addition, Patent Owner persuades us that Kaplan does not teach
`
`treating ENL with any compound other than thalidomide itself. Prelim.
`
`Resp. 16–17. Kaplan does not describe using any of the disclosed analogs,
`
`e.g., any of compounds A–H, such as EM 12, to treat ENL. Rather, at most,
`
`in its background section, Kaplan states that “thalidomide has long been
`
`employed for the treatment” of ENL, as well as other diseases, and that
`
`TNFα “is markedly elevated in ENL.” Ex. 1003, 2:42–55, 3:1–2.
`
`Petitioner contends that Kaplan teaches using EM 12 to reduce TNFα
`
`levels, and both Piper and Kaplan “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.” Pet. 30–33 (citing
`
`Ex. 1007 ¶¶ 90–120). Thus, according to Petitioner, “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
`
`TNFα.” Id.
`
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`13
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`We agree with Petitioner that both Piper and Kaplan disclose EM 12
`
`and at least Piper suggests that both “anti-inflammatory and immuno-
`
`suppressive properties are important to the efficacy and activity of
`
`thalidomide and its analogs.” Id. As discussed above, however, we are not
`
`persuaded that Piper discloses sufficiently that EM 12, which exhibits only
`
`anti-inflammatory activity in Piper, would have been useful to treat ENL.
`
`Moreover, while Kaplan suggests that EM 12 may be useful to reduce TNFα
`
`levels, Kaplan, alone or in combination with Piper, does not suggest
`
`sufficiently that a thalidomide analog containing an amino group on the
`
`benzene ring (in contrast to compounds, including EM 12, disclosed in
`
`Kaplan) would be useful to reduce TNFα levels.
`
`Piper, which discusses ENL, does not mention TNFα, nor does it
`
`establish a relationship between results from the two assays regarding ENL’s
`
`two sites of action (carrageenan and/or PFC) and TNFα levels. Prelim.
`
`Resp. 19–20. Kaplan, at most, states that thalidomide is useful to treat ENL
`
`and reduce TNFα levels, and that TNFα levels are “markedly elevated in
`
`ENL.” Ex. 1003, 2:42–45, 3:1–2. Nonetheless, and even if Kaplan also
`
`suggests that EM 12 may reduce TNFα levels, the reference does not suggest
`
`sufficiently that by doing so, EM 12 would be useful to treat ENL. In
`
`addition, while Piper discloses EM 12 (among many analogs), and may
`
`indicate that this analog is active in the carrageenan assay (i.e., has at least
`
`some anti-inflammatory activity), we agree with Patent Owner that neither
`
`Piper nor Kaplan (which is silent on the two Piper assays) establishes
`
`sufficiently that anti-inflammatory activity alone by any analog (such as AH
`
`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
`
`that Petitioner does not establish sufficiently that a link exists between
`
`treating ENL and reducing TNFα levels. For example, Patent Owner
`
`provides information indicating that EM 12, which Kaplan suggests may
`
`reduce TNFα, only “has marginal activity in the carrageenan assay with
`
`activity at the highest dose tested but no activity in lower doses, and it lacks
`
`activity in the PFC assay.” Prelim. Resp. 43–44 (citing Ex. 2028, 673, 1st
`
`col.; Ex. 2029, 70). Such evidence runs counter to the notion that an
`
`ordinary artisan would have understood that one could treat ENL by using
`
`any thalidomide analog (such as EM 12) that reduces TNFα, as Petitioner
`
`suggests. Pet. 33.
`
`Furthermore, as noted by Patent Owner and stated in Kaplan, immune
`
`responses involve a number of different biological molecules, including
`
`cytokines such as IL-1, IL-6, IL-8, GM-CSF, as well as other cytokines
`
`produced by T-cells, in addition to TNFα. As Patent Owner notes, “some
`
`anti-inflammatory agents, such as nonsteroidal anti-inflammatory drugs
`
`(NSAIDs), actually increase TNFα production in rheumatoid synovia and
`
`whole blood.” Prelim. Resp. 22 (citing Ex. 2020, Abstract). Information
`
`before us, therefore, fails to establish sufficiently a correlation between anti-
`
`inflammatory activity (as measured in the carrageenan assay in Piper) with a
`
`reduction in TNFα levels in particular, even assuming the references indicate
`
`that EM 12 does both things.
`
`Lastly, as noted by Patent Owner, data in Kaplan suggests that
`
`compound G works better than EM 12 to inhibit TNFα, indicating that
`
`Kaplan does not favor using EM 12 in particular. Ex. 1003, Figures 5–7;
`
`Prelim. Resp. 33–34.
`
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`IPR2015-01169
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`
`Thus, at most, Piper and Kaplan together indicate that thalidomide is
`
`useful to both treat ENL and reduce TNFα levels, and EM 12 (and other
`
`analogs lacking the amino group on the benzene ring) may reduce TNFα,
`
`even if EM 12 exhibits activity in only one out of two relevant sites of action
`
`for ENL. Petitioner does not establish sufficiently that an ordinary artisan
`
`reading those two references would have had reason to pick AH 13 or AH
`
`14 (out of over 40 analogs discussed in Piper) in particular for use in a
`
`method to reduce TNFα levels (disclosed in Kaplan in relation to different
`
`analogs).
`
`b) Alleged Reasonable Expectation of Success
`
`Petitioner also contends that an ordinary artisan would have
`
`reasonably expected Piper’s AH 14 and AH 13 to exhibit the same activity
`
`as thalidomide because AH 14 and AH 13 have high structural similarity to
`
`that parent compound and exhibit “at least one key activity of the parent
`
`(i.e., anti-inflammation or immunosuppression).” Pet. 33. In support,
`
`Petitioner refers to EM 12 and its activities (as shown in Piper and Kaplan),
`
`and cites Dr. Heathcock’s Declaration for the proposition that “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.” Pet. 34 (citing Ex. 1007, ¶¶ 118, 119). We note that
`
`other than referring to Piper and Kaplan generally, the cited paragraphs in
`
`Dr. Heathcock’s Declaration cite no evidence in support of that proposition.
`
`Ex. 1007, ¶¶ 118, 119.
`
`Other information of record before us, by contrast, indicates that even
`
`the smallest of chemical differences in thalidomide analogs impacts
`
`biological activity. Teachings in Piper alone indicate that different analogs,
`
`
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`IPR2015-01169
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`even those differing only by the addition and/or location of a single
`
`“electron donating” group on the benzene ring, exhibit different activities.
`
`Piper discusses “[t]hirteen α-substituted glutarimides with changes in the 6
`
`membered phthalimide moiety.” Ex. 1002, 511, 2nd col. Of those, many
`
`are active in one or the other assay (carrageenan or PFC) or neither assay.
`
`Among those thirteen, Piper also discusses “[f]our compounds involv[ing]
`
`electron donating substitutions (amino- or hydroxyl-) on the 6 membered
`
`phthalimide system.” Id. Among those four compounds, and even among
`
`the two compounds containing an amino group on the 6-carbon benzene ring
`
`(AH 13 and AH 14), Piper found differing results in the two assays. For
`
`example, Piper states that AH 13 is active in the carrageenan assay but not
`
`the PFC assay, while AH 14 “enhances PFC” and is inactive in the
`
`carrageenan assay. Id.; see also Prelim. Resp. 29 (noting differing assay
`
`results for thalidomide and different analogs, including those with a
`
`hydroxyl group on the benzene ring, AH 22 and AH 20).
`
`Thus, Patent Owner persuades us, consistent with binding case law,
`
`that “even minor structural modifications to a chemical compound can have
`
`significant and highly unpredictable effects on functionality,” as evidenced
`
`by Piper and other references of record here. Prelim. Resp. 26–27 (citing
`
`relevant Federal Circuit and other case law) (citations omitted). We are not
`
`persuaded by Petitioner’s contention that “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.” Pet. 34.
`
`When arguing a reasonable expectation of success, Petitioner also
`
`contends that “by disclosing steroids [prednisolone and dexamethasone] that
`
`exhibit anti-inflammation, immunosuppression, and TNFα inhibition,
`
`
`
`17
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`IPR2015-01169
`Patent 5,635,517
`
`Kaplan identifies another direct relationship—i.e., between compounds that
`
`are anti-inflammatory or immunosuppressive and compounds that block
`
`TNFα.” Pet. 34–35 (citing Ex. 1007 ¶ 120 (citing Ex. 1003, 3:50–55)).
`
`Petitioner does not contend, however, that either steroid is a thalidomide
`
`analog. In addition, Kaplan teaches that those steroids exhibit both anti-
`
`inflammatory and immunosuppressive activities, similarly to thalidomide,
`
`but unlike EM 12 (as disclosed in Piper). In any event, Kaplan’s discussion
`
`about steroids unrelated in structure does not indicate sufficiently that one
`
`would have expected entirely different compounds (e.g., AH 13 or AH 14)
`
`to reduce TNFα levels.
`
`4. Conclusion
`
`For the reasons discussed above, Petitioner has not established a
`
`reasonable likelihood of prevailing on the ground that claims 1 and 7–9 of
`
`the ’517 patent would have been obvious over Piper in view of Kaplan.
`
`C. Asserted ground of obviousness of claims 2–6 and 10 over Piper,
`Kaplan, Agrawal (Ex. 1004), and WO ’085 (Ex.1005)
`
`Petitioner contends that claims 2–6 and 10 of the ’517 patent would
`
`have been obvious over Piper, Kaplan, Agrawal, and WO ’085. Pet. 37–52.
`
`In relation to Piper and Kaplan, Petitioner raises similar contentions to those
`
`discussed above. Id. at 39–40. Petitioner additionally relies on Agrawal
`
`(published alongside Piper), which discusses carrageenan and PFC assay
`
`results using thalidomide analogs, and WO ’085, which discloses methods of
`
`inhibiting angiogenesis using thalidomide and thalidomide analogs. Id. at
`
`40–42. Petitioner again contends that an ordinary artisan would have had
`
`reason to combine teachings in those references to reach the recited methods
`
`
`
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`IPR2015-01169
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`
`and compounds, and one would have had a reasonable expectation of
`
`success in doing so. Id. at 43–49.
`
`1. Agrawal (Ex. 1004)
`
`Like Piper, Agrawal describes a study in an effort to develop
`
`thalidomide analogs that are effective in controlling ENL—again using the
`
`carrageenan (anti-inflammatory) and PFC (immunosuppressive) assays.
`
`Agrawal discusses many different analogs, including “analogs containing
`
`NO2, COOH, NH2, or OH groups.” Ex. 1004, 512, 2nd col. In this context,
`
`Agrawal states that “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.” Id. Agrawal goes on to
`
`state, however, that “the biological activity in the PFC assay did not
`
`correlate with electronic properties since not only the 4-nitro and 4-carboxy
`
`analogs but also the 4-hydroxythalidomide was active in this system.” Id.
`
`Thus, consistent with teachings in Piper, Agrawal indicates that 4-
`
`hydroxythalidomide (AH 20) is active in both assays, and 3-hydroxy-
`
`thalidomide (AH 22) and 4-aminothalidomide (AH 13) are active only in the
`
`carrageenan assay. While it does not discuss 3-aminothalidomide (AH 14)
`
`per se, teachings in Agrawal also are consistent with the fact that AH 14 is
`
`inactive in both assays, as indicated in Piper.
`
`Agrawal also states that study 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.” Id. (emphasis added). Like
`
`Piper, therefore, Agrawal suggests that thalidomide analogs that exhibit both
`
`
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`IPR2015-01169
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`
`anti-inflammatory and immunosuppressive activities (i.e., active in both
`
`assays) would be useful to treat EML.
`
`2. WO ’085 (Ex. 1005)
`
`WO ’085 discloses methods for preventing unwanted angiogenesis by
`
`administering thalidomide and “related compounds.” Ex. 1005, 1:20–25.6
`
`As noted in WO ’085, angiogenesis is the generation of new blood vessels
`
`into a tissue or organ. Id. at 1:28–29.
`
`WO ’085 discloses that “[s]pecific preferred compounds . . . of the
`
`present invention include thalidomide, its precursors, metabolites and
`
`analogs,” and that “[p]articular analogs include EM-12, N-phthaloyl-DL-
`
`glutamic acid (PGA) or N-phthaloyl-DL-glutamine anhydride.” Id. at 14:8–
`
`12. WO ’085 discloses using “epoxides of thalidomide, EM-12 and EM-
`
`138” (id. at 16:1–15) and that the epoxides can be hydrolyzed to form six
`
`compounds, including the two compounds reproduced below.
`
`
`
`Id. at 16:20–17:9. WO ’085 further teaches that “the hydroxyl group can be
`
`on carbons 1, 2, 3, 4, 5 and 6 of the benzene ring.” Id. at 17:10–11.
`
`3. Analysis—Claims 2–6
`
`Claims 2–6 of the ’517 patent depend from claim 1, and recite
`
`methods of reducing TNFα in a mammal by administering compositions
`
`
`6 Page

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