Coalition for Affordable Drugs VI LLCv.Celgene CorporationDownload PDFPatent Trial and Appeal BoardNov 16, 201508690258 (P.T.A.B. Nov. 16, 2015) Copy Citation Trials@uspto.gov Paper 22 Tel: 571-272-7822 Entered: November 16, 2015 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 2 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 IPR2015-01169 Patent 5,635,517 3 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 IPR2015-01169 Patent 5,635,517 4 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 Challenged Claims Piper (Ex. 1002) 1 in view of Kaplan (Ex. 1003) 2 § 103 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). IPR2015-01169 Patent 5,635,517 5 References Statutory Basis Challenged Claims Piper in view of Kaplan, Agrawal (Ex. 1004), 3 and WO ’085 (Ex. 1005) 4 § 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). IPR2015-01169 Patent 5,635,517 6 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. 33–35 (citing Ex. 1007 ¶¶ 116–128). IPR2015-01169 Patent 5,635,517 7 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 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 “[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. IPR2015-01169 Patent 5,635,517 8 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. IPR2015-01169 Patent 5,635,517 9 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 IPR2015-01169 Patent 5,635,517 10 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. IPR2015-01169 Patent 5,635,517 11 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). IPR2015-01169 Patent 5,635,517 12 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 IPR2015-01169 Patent 5,635,517 13 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. IPR2015-01169 Patent 5,635,517 14 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. IPR2015-01169 Patent 5,635,517 15 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. IPR2015-01169 Patent 5,635,517 16 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, IPR2015-01169 Patent 5,635,517 17 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, IPR2015-01169 Patent 5,635,517 18 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 IPR2015-01169 Patent 5,635,517 19 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 IPR2015-01169 Patent 5,635,517 20 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 citations in relation to Ex. 1005 refer to pages numbers in the original document, located at the top of the reference. IPR2015-01169 Patent 5,635,517 21 corresponding to thalidomide analogs having an amino group on the benzene ring, and a single C=O in the 5-carbon ring. In relation to those claims, Petitioner contends that Agrawal teaches a preference for amino-substituted analogs, as well as “a preference for analogs with an amino- or hydroxyl substituted benzo ring.” Pet. 40–41 (citing Ex. 1004, 512, Ex. 1007 ¶¶ 87–89, 139 (similarly discussing and citing Agrawal)). We are not persuaded. As discussed above, Agrawal, like Piper, discloses the testing of many thalidomide analogs and suggests that analogs exhibiting both anti- inflammatory and immunosuppressive activities (i.e., active in both the carrageenan and PFC assays) would be useful to treat ENL. Ex. 1004, 512; see also Pet. 41–42 (referring to that teaching in Agrawal). Both Piper and Agrawal indicate that 4-hydroxythalidomide (AH 20) is active in both assays, 3-hydroxy-thalidomide (AH 22) and 4-amino-thalidomide (AH 13) are active only in the carrageenan assay (not the PFC assay), and 3-amino- thalidomide (AH 14) is inactive in both assays. Thus, at most, both references suggest a preference, in the context of treating ENL, for an analog with a hydroxyl group at a specific location in the benzene ring (4-hydroxy, not 3-hydroxy), and no particular preference for analogs with an amino group on the benzene ring. Petitioner contends that WO ’085 “teaches that each of thalidomide, EM 12, and 3-, 4-, 5-, and 6-hydroxyl-substituted EM 12 inhibit angiogenesis,” and that “EM 12 is a more potent inhibitor of angiogenesis than thalidomide.” Pet. 42. Petitioner then contends that an ordinary artisan “would have readily combined the teachings” of the four cited references “to develop thalidomide analogs having an amino or hydroxyl-substituted benzo IPR2015-01169 Patent 5,635,517 22 ring, and at least one important functional activity of thalidomide (i.e., anti- inflammation or immunosuppression) for use in effectively treating at least ENL by reducing TNFα.” Id. at 43–44 (citing Ex. 1007 ¶¶ 145–153). Petitioner does not point us to anything in Agrawal or WO ’085 that overcomes the deficiencies mentioned above in relation to Petitioner’s assertion that an ordinary artisan would have combined the teachings of Piper and Kaplan to develop thalidomide analogs having an amino group on the benzene ring for use in reducing TNFα levels. As discussed above, teachings in Agrawal and Piper are very similar and, at best, suggest a preference for an analog with a hydroxyl group at a specific location in the benzene ring (4-hydroxy, not 3-hydroxy), without sufficiently indicating a preference for analogs with an amino group on the benzene ring. In addition, Kaplan, the only cited reference to discuss methods of reducing TNFα, does not discuss, much less indicate a preference for, thalidomide analogs with an amino group on the benzene ring. In relation to WO ’085, Petitioner does not explain or reasonably support that inhibiting angiogenesis correlates to reducing TNFα. Even assuming Petitioner had established such a correlation, however, all four references in combination potentially would have suggested a preference for EM 12 or EM 12 containing a 4-hydroxyl group in the benzene ring. For the reasons discussed above, however, we are not persuaded that any of the four references, either alone or in combination, sufficiently suggests using a thalidomide analog containing an amino group on the benzene ring, whether to treat ENL, reduce TNFα, or inhibit angiogenesis. IPR2015-01169 Patent 5,635,517 23 Petitioner’s discussion of WO ’085 does not persuade us “that structural similarity is reasonably predictive of functional similarity.” Pet. 42 (citing Ex. 1007 ¶¶ 94–96, 140–141). We likewise are not persuaded by Petitioner’s assertions regarding a reasonable expectation of success, which again rely on contentions that an ordinary artisan “would have reasonably expected other structurally similar analogs of thalidomide and EM 12 to behave like their parent compounds.” Id. at 44–45 (citing Ex. 1007 ¶¶ 155– 165). As discussed above, information of record, such as Piper and Agrawal, indicates that one of ordinary skill would have known that even small chemical differences in thalidomide analogs impacted biological activity. For example, Piper and Agrawal indicate that the absence or presence, as well as the specific location, of a hydroxyl or amino group on the benzene ring impacts whether that analog exhibits anti-inflammatory and/or immunosuppressive activity (as tested in carrageenan and PFC assays). In addition, as Petitioner concedes, neither Kaplan (the only reference discussing TNFα) nor WO ’085 discloses the use of a thalidomide analog containing an amino group on the benzene ring. Pet. 47. As Petitioner also recognizes, no cited reference discloses the use of an EM 12 analog containing an amino group on the benzene ring. Id. For the reasons discussed above, we are not persuaded that any cited reference, either alone or in combination, reasonably suggests substituting a hydroxyl group with an amino group on the benzene ring to produce a thalidomide analog useful in reducing TNFα levels. IPR2015-01169 Patent 5,635,517 24 4. Analysis—Claim 10 We likewise are not persuaded that an ordinary artisan would have had sufficient reason to prepare any of the four compounds recited in claim 10. All four compounds in claim 10 comprise an amino group on the benzene ring (like AH 13 and AH 14) and a single C=O in the 5-carbon ring (like EM 12). Petitioner has not established sufficiently, with reasonable underpinnings, why one would have produced such compounds for any reason, for example to produce analogs that inhibit angiogenesis (discussed in WO ’085). As Petitioner notes, none of the cited references disclose EM 12 (or other analog having a single C=O in the 5-carbon ring) modified to have an amino group on the benzene ring. Pet. 47. While WO ’085 teaches a compound having a hydroxyl group on the benzene ring (like AH 20) and a single C=O on the 5-carbon ring (like EM 12), Petitioner does not explain sufficiently why one would substitute the hydroxyl group in that analog with an amino group. For example, we are not persuaded that Petitioner contends or reasonably establishes a link between inhibiting angiogenesis (disclosed in WO ’085), treating ENL (or anti-inflammatory and/or immuno-suppressive activities) (disclosed in Piper and Agrawal), and/or reducing TNFα (disclosed in Kaplan). Petitioner’s general arguments regarding the “known activities and structures of thalidomide, EM 12, and structurally similar amino- and hydroxyl-substituted analogs thereof” do not establish that link, nor reasonably provide a reason to make the specific hydroxyl to amino substitution needed here. Piper and Agrawal disclose that AH 20 (4-hydroxythalidomide), but not AH 22 (3-hydroxylthalidomide), exhibits both anti-inflammatory and IPR2015-01169 Patent 5,635,517 25 immunosuppressive activities (both sites of action for ENL). Ex. 1002, 511, 2nd col. Kaplan discloses EM 12 (Ex. 1003, 5:30–39), and WO ’085 discloses EM 12 with a hydroxyl group on any of carbons 1, 2, 3, 4, 5 and 6 of the benzene ring (Ex. 1005, 17). Thus, at most, even if we assume a link exists between treating ENL, reducing TNFα, and/or inhibiting angiogenesis, the four references would have led an ordinary artisan to make a specific version from a genus disclosed in WO ’085, i.e., a species of EM 20 modified to include a hydroxyl group at the same location in the benzene ring as AH 20. For the same reasons discussed above, Petitioner’s assertion that “known activities and structures of thalidomide, EM 12, and structurally similar amino- and hydroxyl-substituted analogs” would have provided a reason to prepare a thalidomide analog having an amino group on the benzene ring is not supported reasonably by information before us. Pet. 43. Furthermore, we are not persuaded that the compounds of claim 10 correspond to only a “few known options” of possible relevant thalidomide analogs, as Petitioner contends. Pet. 48. As noted by Patent Owner, the cited references disclose a large number of possible thalidomide analogs. See Prelim. Resp. 42 n.15 (“WO ’085 alone discloses billions of thalidomide analogs,” “Kaplan discloses over one hundred,” “Piper discloses ‘approximately 50 thalidomide analogs,’” and “Agrawal discloses various modifications suggesting hundreds of additional analogs”) (citations omitted). Of those many possible thalidomide analogs, the cited references suggest that a subset of analogs—analogs lacking an amino group on the benzene ring—may be useful to treat ENL, reduce TNFα, or inhibit angiogenesis. Information before us does not establish adequately that one of ordinary skill in the art would have had reason to modify one specific IPR2015-01169 Patent 5,635,517 26 analog disclosed in WO ’085 (out of many) to prepare the specific “four amino-substituted EM 12 analogs” recited in claim 10. Pet. 48. 5. Conclusion For the reasons discussed above, Petitioner has not established a reasonable likelihood of prevailing on the ground that claims 2–6 and 10 of the ’517 patent would have been obvious over Piper in view of Kaplan, Agrawal, and WO ’085. D. Asserted ground of obviousness of claims 2–6 and 10 over Piper, Kaplan, Agrawal, and Keith (Ex.1006) Petitioner contends that claims 2–6 and 10 of the ’517 patent would have been obvious over Piper, Kaplan, Agrawal, and Keith. Pet. 52–59. In relation to Piper, Kaplan, and Agrawal, Petitioner asserts similar contentions to those discussed above. Id. at 52–55. In this ground, Petitioner additionally relies on Keith, which, as Petitioner notes, discloses “solubility information for a variety of chemical compounds, including thalidomide and EM 12.” Pet. 55 (citing Ex. 1006 at 190, 397). Petitioner does not explain adequately how Keith overcomes the deficiencies mentioned above in relation to Petitioner’s assertion that an ordinary artisan would have combined the teachings of Piper, Kaplan, and Agrawal—deficiencies equally applicable to the assertion in this ground—to practice the methods of claims 2–6, or prepare the specific compounds recited in claim 10. At most, Petitioner argues, based on Keith, that an ordinary artisan would have known that thalidomide and EM 12 “are practically insoluble in water.” Pet. 55 (citing Ex. 1007 ¶ 178). Petitioner also contends, citing conclusory statements by Dr. Heathcock in support, that “increasing the IPR2015-01169 Patent 5,635,517 27 solubility of a drug can significantly enhance its bioavailability,” and that an ordinary artisan “would have generally known that the addition of an electron donating substituent (e.g., an amino or hydroxyl group) to the benzo ring of EM 12 would likely increase its solubility.” Id. (citing Ex. 1007 ¶¶ 178, 187). Thus, according to Petitioner, “one would have been driven to aminate EM 12 in order to improve its poor solubility.” Id. at 55–56 (citing Ex. 1007 ¶¶ 178, 187–188). For all the reasons discussed above, information before us does not suggest or point adequately to modifying EM 12 or another relevant compound to contain an amino group on the benzene ring. Keith does not overcome that deficiency by merely disclosing the solubility of EM 12 and thalidomide. Even assuming one would have had reason to prepare a more soluble thalidomide analog, Patent Owner persuades us that an ordinary artisan would have faced “a potentially limitless list of modifications,” without sufficient guidance pointing to the addition of an amino group on the benzene ring in particular. Prelim. Resp. 54–55. For the reasons discussed above, Petitioner has not established a reasonable likelihood of prevailing on the ground that claims 2–6 and 10 of the ’517 patent would have been obvious over Piper in view of Kaplan, Agrawal, and Keith. III. CONCLUSION For the foregoing reasons, the information presented in the Petition and accompanying evidence does not establish a reasonable likelihood that Petitioner would prevail in showing the unpatentability of claims 1–10 of the ’517 patent. IPR2015-01169 Patent 5,635,517 28 IV. ORDER It is ORDERED that the Petition is denied and no trial is instituted. For PETITIONER: Jeffrey Blake jblake@merchantgould.com Dianna El Hioum delhioum@merchantgould.com For PATENT OWNER: Francis Cerrito nickcerrito@quinnemanuel.com Anthony Insogna aminsogna@jonesday.com Copy with citationCopy as parenthetical citation