Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`Paper 9
`Entered: February 8, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FUSTIBAL LLC,
`Petitioner,
`
`v.
`
`BAYER HEALTHCARE LLC,
`Patent Owner.
`____________
`
`Case IPR2016-01490
`Patent 8,637,553 B2
`____________
`
`
`Before LORA M. GREEN, RAMA G. ELLURU, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`INTRODUCTION
`
`Fustibal LLC. (“Petitioner”) filed a Petition requesting an inter partes
`review of claims 1–16 of U.S. Patent No. 8,637,553 B2 (Ex. 1001, “the ’553
`Patent”). Paper 1 (“Pet.”). Bayer Healthcare LLC (“Patent Owner”) filed a
`Preliminary Response to the Petition. Paper 6 (“Prelim. Resp.”). We have
`jurisdiction under 35 U.S.C. § 6 and 35 C.F.R. § 42.4(a).
`
`
`
`
`571-272-7822
`
`
`
`
`
`Paper 9
`Entered: February 8, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FUSTIBAL LLC,
`Petitioner,
`
`v.
`
`BAYER HEALTHCARE LLC,
`Patent Owner.
`____________
`
`Case IPR2016-01490
`Patent 8,637,553 B2
`____________
`
`
`Before LORA M. GREEN, RAMA G. ELLURU, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`INTRODUCTION
`
`Fustibal LLC. (“Petitioner”) filed a Petition requesting an inter partes
`review of claims 1–16 of U.S. Patent No. 8,637,553 B2 (Ex. 1001, “the ’553
`Patent”). Paper 1 (“Pet.”). Bayer Healthcare LLC (“Patent Owner”) filed a
`Preliminary Response to the Petition. Paper 6 (“Prelim. Resp.”). We have
`jurisdiction under 35 U.S.C. § 6 and 35 C.F.R. § 42.4(a).
`
`
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`Case IPR2016-01490
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`Institution of an inter partes review is authorized by statute when “the
`information presented in the petition . . . and any response . . . shows that
`there is a reasonable likelihood that the petitioner would prevail with respect
`to at least 1 of the claims challenged in the petition.” 35 U.S.C. § 314; see
`37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition and the
`Preliminary Response, we exercise our discretion under 35 U.S.C. § 325(d)
`to decline Petitioner’s request for institution of an inter partes review based
`on some grounds. In addition, we determine that Petitioner has not shown a
`reasonable likelihood that it would prevail in showing the unpatentability of
`any of the challenged claims. Accordingly, we decline to institute an inter
`partes review of claims 1–16 of the ’530 Patent.
`
`A.
`
`Related Applications and Proceedings
`The ’553 Patent to Boyer et al., issued from Application No.
`10/895,985 (“the ‘985 Application”), filed July 22, 2004, and claims benefit
`of priority to Provisional Applications No. 60/489,102 and 60/540,326 filed
`July 23, 2003 and Feb. 2, 2004, respectively. Ex. 1001, [21], [60]. Patent
`Owner identifies a continuation application of the ’985 Application,
`Application No. 13/669,103, as pending. See Paper 3, 2.
`Patent Owner states that the ’553 Patent has been asserted in the
`following district court proceedings: Bayer HealthCare LLC v. Teva Pharm.
`USA, Inc., No. 1:16-01221-LPS (D. Del.) and Bayer HealthCare LLC v.
`Apotex, Inc., No. 1:16-01222-LPS (D. Del.). Paper 8, 2. According to
`Petitioner, “the development of regorafenib (the claimed compound of the
`’553 Patent)” is at issue in Onyx Pharms. Inc. v. Bayer Corp., Case No. C
`09-2145 (EMC) (N.D. Cal. Oct 17, 2011). Pet. 1–2; see Prelim. Resp. 9–10
`& n.4.
`
`2
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`B.
`
`The ’553 Patent and Relevant Background
`The ’553 Patent is generally directed to “[a] compound of Formula I
`(reproduced below): salts thereof, prodrugs thereof, metabolites thereof,
`[and] pharmaceutical compositions containing such a compound.” Ex. 1001,
`Abstract.
`
`
`Formula 1 depicts the compound regorafenib, to which the ’553 Patent is
`directed. The Specification describes compounds of Formula I as “potent
`inhibitor[s of] raf kinase, VEGFR kinase, p38 kinase, and PDGFR kinase,
`which are all molecular targets of interest for the treatment and prevention of
`osteoporosis, inflammatory disorders, hyper-proliferative disorders, and
`angiogenesis disorders, including cancer.” Id. at 9:10–17.
`
`The compound of Formula I (regorafenib), is the active ingredient in
`the anti-cancer drug STIVARGA®, marketed by Bayer HealthCare
`Pharmaceuticals Inc. for the treatment of certain types of colorectal cancer.
`See Pet. 4, Prelim. Resp. 1, 5; Ex. 2001,1 1, 11. Patent Owner points out
`that the discovery of regorafenib was preceded by the kinase inhibitor
`sorafenib, which has the following structure.
`
`
`1 STIVARGA® prescribing information dated June 2016.
`
`3
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`The above structure depicts the structure of sorafenib. Sorafenib is the
`active ingredient in the drug product NEXAVAR®, indicated for the
`treatment of certain renal, hepatocellular, and thyroid cancers. Prelim. Resp.
`5; Ex. 20042, 1, 16; see Pet. 5.
`
`C.
`
`Challenged Claims
`Representative claim 13 recites:
`13. A compound of Formula (I)
`
`
`The remaining claims relate to salts, stereoisomers, and metabolites of the
`above compound.
`
`D.
`
`The Asserted Prior art and Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 4):
`
`Ground Reference(s)
`1
`Riedl3
`2
`Riedl
`
`Basis
`§ 102
`§ 103
`
`Claims
`1–16
`1–16
`
`
`2 NEXAVAR® prescribing information revised November 2013.
`3 Riedl et al., WO 00/42012 A1, published July 20, 2000.
`
`4
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`Ground Reference(s)
`3
`Riedl, Ahern,4 and Park5
`
`4
`
`5
`
`Riedl and Park
`
`Aherne and Park
`
`Basis
`§ 103
`
`§ 103
`
`§ 103
`
`Claims
`1–16
`
`1–16
`
`1–16
`
`
`Petitioner also relies on the Declaration of Brian Shoichet, Ph.D. (“Shoichet
`Declaration”). Ex. 1008. As an initial matter, Patent Owner contends that
`Dr. Shoichet’s Declaration should be accorded no weight because it fails to
`either state that it is made under penalty of perjury pursuant to 28 U.S.C.
`§ 1764 or contain the affirmation prescribed in 37 C.F.R. § 1.68. Prelim.
`Resp. 19–20, 33. Although we agree with Patent Owner that the Shoichet
`Declaration is facially defective, at this stage of the proceeding, we decline
`to give the Declaration “no weight” on that basis.
`
`E.
`
`Prosecution History Leading to the Issuance of the ’553 Patent
`Applicants disclosed Riedl in an Information Disclosure Statement
`dated March 18, 2008. Ex. 2005, 193. In allowing the then-pending claims,
`the Examiner’s Reasons for Allowance provided that:
`After a thorough search, the closest prior art, WO 00/42012 to
`Riedl, et al. was found to teach similar phenyl-urea derivatives
`as kinase inhibitors. However, the WO document fails to teach
`or render obvious the instant claimed compounds according to
`Formula (I), and does not fairly suggest their salts or
`pharmaceutical compositions.
`
`
`4 Aherne et al., Finding the needle in the haystack: why high-throughput
`screening is good for your health, 4(4) BREAST CANCER RES. 148–154,
`© 2002 BioMed Central Ltd.
`5 Park et al., Metabolism of Fluorine-Containing Drugs, 41 ANN. REV.
`PHARMACOL. TOXICOL, 443–70, © 2001 Annual Reviews.
`
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`Ex. 2005, 352–353.
`Applicants repeatedly requested continued examination under
`37 C.F.R. § 1.114 to permit the submission of additional art (see id. at 396,
`568; Ex. 2006, 854) and the amendment of the claims (Ex, 2006, 695–702).
`Following each such submission, the Examiner issued a Notice of
`Allowability repeating the above-quoted Reasons for Allowance (Ex. 2005,
`397, 569; Ex. 2006, 855), including with respect to claims 1–16 as issued
`(Ex. 2006, 913).
`
`
`
`ANALYSIS
`
`A.
`
`Person of Ordinary Skill in the Art.
`Petitioner contends that a person of ordinary skill in the art “typically
`would have a PhD, MD, MS, or another degree relating to pharmaceutical
`chemistry (e.g. biology, chemistry, medicinal chemistry, medicine,
`pharmacology, or a closely related discipline), and . . . would have
`substantial familiarity, training, or experience with pharmaceutical
`compositions.” Pet. 6. Patent Owner has not challenged Petitioner’s
`proposed interpretation of a skilled artisan. We adopt Petitioner’s proposed
`interpretation for purposes of this opinion. See Prelim. Resp. 6 & n.1; see
`also Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the level
`of ordinary skill in the art may be evident from the prior art).
`
`B.
`
`Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`
`6
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`Under that standard, we presume that a claim term carries its “ordinary and
`customary meaning,” which “is the meaning the term would have to a person
`of ordinary skill in the art in question” at the time of the invention. In re
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); see also
`Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under
`a broadest reasonable interpretation, words of the claim must be given their
`plain meaning, unless such meaning is inconsistent with the specification
`and prosecution history.”). 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).
`Petitioner (correctly) contends that the ’553 Patent expressly defines
`the claim term “pharmaceutically acceptable salt” as “‘a relatively non-toxic,
`inorganic or organic acid addition salt of a compound of the present
`invention.’” Pet. 7 (quoting Ex. 1001, 9:56–62). Patent Owner does not
`presently object to this definition. Based on the specification’s express
`disclosure, we agree that the cited definition applies. See Prelim. Resp. 6 &
`n.2. The parties agree that all other terms should be accorded their ordinary
`and customary meaning. Id.; Pet. 6–7.
`Our reviewing court counsels that only those terms that are in
`controversy need be construed, and only to the extent necessary to resolve
`the controversy. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`795, 803 (Fed. Cir. 1999). Accordingly, for purposes of this decision, we
`determine that no further construction is necessary.
`
`C.
`
` Ground 1: Anticipation by Riedl (Ex. 1002)
`Petitioner asserts that claims 1–16 are anticipated by Riedl. Pet. 13–
`19. Patent Owner disagrees. Prelim. Resp. 7–21.
`
`7
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`Overview of Riedl
`i.
`Riedl teaches that “[t]he p21ras oncogene is a major contributor to the
`development and progression of human solid cancers and is mutated in 30%
`of all human cancers.” Ex. 1002, 1:19–20.6 In these cancer cells, mutated
`ras protein “delivers constitutive growth signals to downstream effectors
`such as the enzyme raf kinase.” Id. at 1:21–28. Normal growth of such cells
`can be restored by inhibiting the raf kinase signaling pathway. Id. at 1:30–
`2:7. Studies have shown that interfering with the raf kinase signaling
`pathway in ras-transformed cells (i.e., by deactivating raf kinase or by
`expression of dominant negative mutants of MEK (the substrate of raf
`kinase)) can restore normal growth. Id.
`Accordingly, Riedl discloses a class of compounds of the general
`Formula 1, purported to be “inhibitors of the enzyme raf kinase . . . useful
`. . . in the treatment of tumors and/or cancerous cell growth mediated by raf
`kinase.” Id. at 2:10–20. Riedl presents no enzymatic or biological data for
`any individual compound.
`The compounds of Formula 1 have the general structure A-D-B,
`where
`D is NH-C(O)-NH-,
`A is a substituted moiety of up to 40 carbon atoms of the formula:
`–-L-(M-L1)q , where L is a 5 or 6 membered cyclic structure
`bound directly to D, L1 comprises a substituted cyclic moiety
`having at least 5 members, M is a bridging group having at least
`one atom, q is an integer of from 1-3; and each cyclic structure
`of L and L1 contains 0-4 members of the group consisting of
`nitrogen, oxygen and sulfur, and
`
`
`6 We refer, herein, to the original pagination of the cited references rather
`than to that supplied by the parties.
`
`8
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`B is a substituted or unsubstituted, up to tricyclic aryl or
`heteroaryl moiety of up to 30 carbon atoms with at least one 6-
`member cyclic structure bound directly to D containing 0-4
`members of the group consisting of nitrogen, oxygen and sulfur.
`Id. at 2:22–3:8; see also id at 3:9–5:31 (further defining elements A and B).
`Riedl further discloses the use of halogen moieties in at least portions
`of Formula I element B. See id. at 3:6–4:25. “Suitable halogen groups
`include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a
`group replaced by a halogen atom) being possible where an alkyl group is
`substituted by halogen, mixed substitution of halogen atom types also being
`possible on a given moiety.” Id. at 6:5–8.
`Riedl discloses numerous examples with the scope of Formula 1
`including the formula for sorafenib:7
`
`
`(see id. at 41:21–42:1). The above structure depicts the structure of
`sorafenib. At page 8 of the Petition, Petitioner numbers the central ring of
`sorafenib, which we adopt for convenience as shown below:
`
`.
`
`
`
`7 For context, we note that “D” in the Formula 1 A-D-B structure is
`
`.
`
`9
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`See Ex. 1008 ¶ 50. The above structure depicts the structure of sorafenib
`with the carbons of the central ring numbered. Riedl also discloses the
`compound:
`
`
`Id. at 43:1–4. The above structure is similar to sorafenib, but for a single
`substitution of methyl (“Me”) for hydrogen at position 3 of the central ring.
`Elsewhere in the reference, Riedl presents the synthesis and structure of 103
`“Exemplified Compounds” (id. at 53:15–88:5), including two compounds
`similar to sorafenib but for substitutions in the central ring of chlorine at
`position 3’ (id. at 63:5–8, 81 (entry 49)), or chlorine at position 2’ (id. at
`63:21–26, 82 (entry 52)). See Ex. 1008 ¶ 51.
`Relying on its expert, Dr. Shoichet, Petitioner contends that single
`halogen substitutions at position 3’ or 2’ of sorafenib provides the same
`molecule as single substitutions at position 3 or 2, respectively, such that
`Riedl inherently discloses single substitutions of chlorine at both the 3 and 2
`positions of sorafenib. Pet. 15 (citing Ex. 1008 ¶¶ 51–54). Although Dr.
`Shoichet’s explanation of this equivalency relies on exhibits not of record
`(see Ex. 1008 ¶¶ 52–53 (discussing Exhibits 1013 and 1014)), Patent Owner
`does not expressly deny the contention. See e.g. Prelim. Resp. 19 (arguing
`instead that “Dr. Shoichet’s Declaration is not evidence and therefore is not
`properly before the Board at this time”). For purposes of this opinion only,
`we accept that Riedl discloses sorafenib, and examples structurally similar to
`sorafenib, with single substitutions of methyl at position 3, chlorine at
`position 3, and chlorine at position 2.
`
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`Analysis of Ground 1 Under 35 U.S.C. § 325(d)
`ii.
`Institution of inter partes review is discretionary. See 35 U.S.C.
`§ 314(a); 37 C.F.R. § 42.108. Our discretion on whether to institute is
`guided, in part, by 35 U.S.C. § 325(d), which states that “the Director may
`take into account whether, and reject the petition or request because, the
`same or substantially the same prior art or arguments previously were
`presented to the Office.” Patent Owner requests that the Board exercise its
`discretion to deny institution with respect to Ground 1 because Riedl was
`expressly considered by the Examiner during the prosecution of the ’553
`Patent. Prelim. Resp. 7–8. As noted in section I(E), above, in allowing
`claims 1–16 of the ’533 Patent, the Examiner expressly referred to Riedl as
`the closest prior art, yet found that it “fails to teach . . . the instant claimed
`compounds.” Ex. 2006, 913; see also Ex. 2005, 397, 569; Ex. 2006, 855
`(same, with respect to similar claims).
`Petitioner fails to mention that Riedl was cited during prosecution, let
`alone that the Examiner repeatedly highlighted Riedl as the closest prior art
`in the Examiner’s Reasons for Allowance. Despite this omission, Petitioner
`implicitly asks us to second-guess the Examiner by instituting trial on the
`basis that Riedl anticipates claims 1–16. This we decline to do.
`Pursuant to 35 U.S.C. § 325(d), we decline to institute trial with
`respect to Ground 1 because the Examiner repeatedly considered Riedl
`during prosecution, determined that Riedl was the closet prior art to the
`invention claimed, and expressly allowed the challenged claims over the
`Riedl reference. In the alternative, we further decline to institute trial with
`respect to Ground 1 on the merits, as discussed below.
`
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`Analysis of Ground 1 on the Merits
`iii.
`“It is well established that the disclosure of a genus in the prior art is
`not necessarily a disclosure of every species that is a member of that genus.”
`Atofina v. Great Lakes Chem. Corp., 441 F.3d 991, 999 (Fed. Cir. 2006).
`Rather, “whether a generic disclosure necessarily anticipates everything
`within the genus . . . depends on the factual aspects of the specific disclosure
`and the particular products at issue.” Sanofi–Synthelabo v. Apotex, Inc., 550
`F.3d 1075, 1083 (Fed. Cir. 2008). Of “critical importance” in conducting
`this analysis is “how one of ordinary skill in the art would understand the
`relative size of a genus or species in a particular technology.” OSRAM
`Sylvania, Inc. v. Am. Induction Techs., Inc., 701 F.3d 698, 706 (Fed. Cir.
`2012). On the one hand, “when the class of compounds that falls within the
`genus is so limited that a person of ordinary skill in the art can ‘at once
`envisage each member of this limited class,’ . . . a reference describing the
`genus anticipates every species within the genus.” In re Gleave, 560 F.3d
`1331, 1338 (Fed. Cir. 2009) (quoting Eli Lilly & Co. v. Zenith Goldline
`Pharm., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006)) (emphasis added).
`Conversely, where “the number of compounds actually disclosed by [the
`asserted prior art] numbers in the millions (including all proposed alternative
`substituents),” the prior art genus cannot anticipate a later species claim. Eli
`Lilly, 471 F.3d at 1376.
`In addition to the raw number of disclosed compounds, a person of
`ordinary skill in the art would understand to look at any expressed “pattern
`of preferences” in the prior art, such as preferred embodiments, in assessing
`the scope of the generic disclosure. Sanofi-Synthelabo v. Apotex, Inc., 470
`F.3d 1368, 1377 (Fed. Cir. 2006). Therefore, to anticipate a later-claimed
`species, a pattern of preferences or other related teaching or suggestion must
`
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`lead to a genus small enough that a person of ordinary skill in the art would
`at once envisage the claimed species, e.g., “‘a small recognizable class with
`common properties.’” Sanofi-Synthelabo, 550 F.3d at 1083 (citing In re
`Ruschig, 343 F.2d 965, 974 (CCPA 1965)).
`In the present case, Petitioner argues Riedl discloses just such a
`sufficiently small genus, comprising “sorafenib . . . [and] three different
`examples of sorafenib with a single substitution on the middle benzene
`ring,” specifically, methyl at position 3, chlorine at position 2/2’, and
`chlorine at position 3/3’. Pet. 13–14, 16. Focusing on the two chlorinated
`compounds, Petitioner further reasons that,
`Riedl discloses both possible distinct positions for a single
`halogen substitution on the middle ring of sorafenib. There are
`only four suitable halogen groups specifically disclosed by
`Riedl: F, Cl, Br, or I. Thus, there are eight individual chemical
`compounds possible when substituting a halogen (of one of the
`suitable halogen groups disclosed by Riedl) at one of these
`positions. These eight possible compounds are disclosed and
`would be readily apparent to one of skill in the art who was
`looking to modify sorafenib. Therefore, Riedl expressly
`discloses the regorafenib compound, rendering claim 13
`anticipated.
`Id. at 16 (citing Ex. 1008 ¶¶ 49–54) (emphasis added).8
`
`Patent Owner responds that Riedl does not expressly disclose
`regorafenib, the compound depicted in claim 13, but instead discloses a
`broad genus (Formula I) encompassing that compound. Prelim. Resp. 9.
`While the present record does not provide a precise estimate of the scope of
`this genus, Patent Owner suggests, not implausibly, that “Formula I
`
`
`8 Petitioner provides similar arguments with respect to claims 1–12, 14, and
`16. Id. at 17–19.
`
`13
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`encompasses well in excess of a billion compounds.” Pet. 11–12.
`Irrespective of the actual number, we agree with Patent Owner that
`Formula I encompasses a vast number of species.
`Where a reference does not “clearly and unequivocally disclose the
`claimed compound,” to be anticipatory reference under 35 U.S.C. § 102, it
`must, nevertheless, “direct those skilled in the art to the compound without
`any need for picking, choosing, and combining various disclosures not
`directly related to each other by the teachings of the cited reference.” In re
`Arkley, 455 F.2d 586, 587 (CCPA 1972). For the reasons set forth at pages
`9–16 of the Preliminarily Response, we agree with Patent Owner that the
`genus relied on by Petitioner, having “‘eight individual chemical compounds
`possible when substituting a halogen”—F, Cl, Br, or I—at position 2/2’ or
`3/3’ of the central ring of sorafenib, does not exist in Riedl, and only results
`from Petitioner’s improper picking and choosing disparate aspects of the
`disclosure. See Prelim. Resp. 13–15 (quoting Pet. 16).
`Most particularly, Petitioner has not sufficiently established that Riedl
`discloses a genus comprising either (1) sorafenib with single substitutions on
`the middle benzene ring comprising chlorine at positions 2/2’ and 3/3’ (and,
`optionally, methyl at position 3), or (2) a derivative genus comprising eight
`singly-halogenated compounds corresponding to sorafenib substituted with
`F, Cl, Br, or I at position 2/2’ or 3/3’ of the central ring.9 Accordingly,
`Petitioner fails to demonstrate why one of ordinary skill in the art would
`
`
`9 Petitioner does not argue that Riedl’s 103 “Exemplified Compounds,”
`discussed at pages 53–75 and depicted in the Tables at pages 76–88 of the
`reference, define a genus. See Prelim. Resp. 13.
`
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`read Riedl as disclosing a genus sufficiently small as to anticipate the
`species set forth in claim 13. See Gleave, 560 F.3d at 1337–38.
`We also agree with Patent Owner that Petitioner’s reasoning is legally
`insufficient to establish anticipation insofar as it requires that the genus of
`“eight possible compounds . . . would be readily apparent to one of skill in
`the art who was looking to modify sorafenib.” See Prelim. Resp. 17–19
`(referencing Pet. 16) (emphasis added). As aptly pointed out by Patent
`Owner, any desire to modify sorafenib relates to obviousness, not
`anticipation. Id. at 17–18; see Callaway Golf Co. v. Acushnet Co., 576 F.3d
`1331, 1347 (Fed. Cir. 2009) (noting that “motivation to combine is not an
`issue” in an “anticipation argument”).
`For the above reasons, Petitioner has not established a reasonable
`likelihood that claims 1–16 are anticipated by Riedl.
`
`D. Ground 2: Obviousness in view of Riedl (Ex. 1002)
`Petitioner asserts that claims 1–16 are rendered obvious in view of
`Riedl. Pet. 22–59. Patent Owner disagrees. Prelim. Resp. 21–36.
`
`Analysis of Ground 2 Under 35 U.S.C. § 325(d)
`i.
`Patent Owner requests that the Board exercise its discretion to deny
`institution with respect to Ground 2 because Riedl was expressly considered
`by the Examiner during the prosecution of the ’533 Patent. Prelim. Resp.
`36. As noted in section I(E), above, in allowing claims 1–16 of the ’533
`Patent, the Examiner expressly stated that although Riedl was the closest
`prior art, it “fails to . . . render obvious the instant claimed compounds . . .
`and does not fairly suggest their salts or pharmaceutical compositions.”
`Ex. 2006, 913; see also Ex. 2005, 397, 569; Ex. 2006, 855 (same, with
`respect to similar claims).
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`Petitioner fails to mention that Riedl was cited during prosecution, let
`alone that the Examiner repeatedly highlighted Riedl as the closest prior art
`in the Examiner’s Reasons for Allowance. Despite this omission, Petitioner
`implicitly asks us to second-guess the Examiner by instituting trial on the
`basis that Riedl anticipates claims 1–16. As with Ground I, pursuant to
`35 U.S.C. § 325(d), we decline to institute trial with respect to Ground 2. In
`the alternative, we further decline to institute trial with respect to Ground 2
`on the merits, as discussed below.
`
`Analysis of Ground 2 on the Merits
`ii.
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The underlying analysis must include “articulated reasoning with
`some rational underpinning to support the legal conclusion of obviousness.”
`In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006).
`As in the case before us, the determination of whether a claimed
`compound would have been obvious over particular prior art compounds
`typically follows a two prong inquiry. Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280, 1291–93 (Fed. Cir. 2012). First, we determine “whether a
`chemist of ordinary skill would have selected the asserted prior art
`compounds as lead compounds, or starting points, for further development
`efforts.” Id. at 1291. Second, we analyze whether there was a reason to
`modify a lead compound to make the claimed compound with a reasonable
`expectation of success. Id. at 1292; see Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
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`533 F.3d 1353, 1359 (Fed. Cir. 2008) (stating that even “post-KSR, a prima
`facie case of obviousness for a chemical compound still, in general, begins
`with the reasoned identification of a lead compound”).
`Petitioner argues that claim 13 is obvious over Riedl because
`Riedl discloses the structure of sorafenib . . . [and] “single
`halogen substitution [with chlorine] at position 3/3’ and 2/2’. . .
`. Thus, there are two possible distinct positions at which a
`halogen can be substituted on the middle ring of sorafenib. As
`such, Riedl discloses both possible distinct positions for a single
`halogen substitution on the middle ring of sorafenib. There are
`only four suitable halogen groups specifically disclosed by
`Riedl: F, Cl, Br, or I. Thus, there are eight individual chemical
`compounds possible when substituting a halogen (of one of the
`suitable halogen groups disclosed by Riedl) at one of these
`positions. These eight possible compounds would be readily
`apparent to one of skill in the art who was looking to modify
`sorafenib. Therefore, Riedl expressly discloses the regorafenib
`compound, rendering claim 13 obvious over Riedl.
`Id. at 21–22 (citing Ex. 1008 ¶¶ 61–63).10
`As an initial matter, the above argument fails because, as discussed in
`section I(C)(iii), above, Riedl does not “expressly disclose[] the rografenib
`compound,” as Petitioner contends. We further agree with Patent Owner’s
`observation “that the Petition nowhere engages in a ‘lead compound’
`analysis” and, at least with respect to Ground 2, “merely assumes—without
`explanation—that the POSA would select sorafenib for modification.”
`Prelim. Resp. 22–23.
`A lead compound comprises “a natural choice for further development
`efforts” (Altana Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999, 1008
`
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`10 Petitioner provides similar arguments with respect to claims 1–12, 14, and
`16. Id. at 22–25.
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`(Fed. Cir. 2009)), i.e., a prior art compound “that would be most promising
`to modify in order to improve upon its . . . activity and obtain a compound
`with better activity” (Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350, 1357 (Fed. Cir. 2007)). “In determining whether a chemist
`would have selected a prior art compound as a lead, the analysis is guided by
`evidence of the compound’s pertinent properties.” Otsuka Pharm., 678 F.3d
`at 1292. “Absent a reason or motivation based on such prior art evidence,
`mere structural similarity between a prior art compound and the claimed
`compound does not inform the lead compound selection.” Id.
`In setting forth Ground 2, Petitioner invokes a person of ordinary skill
`in the art “who was looking to modify sorafenib.” Prelim. Resp. 22. Neither
`Petitioner nor Petitioner’s expert address why a skilled artisan reading Riedl
`would select that compound for further development. Given that Riedl does
`not highlight any of the vast number of disclosed compounds as having
`particularly beneficial properties or present any enzymatic or biological data,
`we also do not discern from this reference why a person of ordinary skill in
`the art would have selected sorafenib as “a natural choice for further
`development efforts.”
`In addition, as discussed in the context of Grounds 3 and 4 below,
`Petitioner has not sufficiently established that a person of ordinary skill
`would have had a reason to modify a sorafenib to make the claimed
`compound with a reasonable expectation of success.
`For each of the above reasons, Petitioner has not established a
`reasonable likelihood that claims 1–16 are rendered obvious by Riedl.
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`E. Grounds 3 and 4: Obviousness in view of Riedl (Ex. 1002) and Park
`(Ex.1004), and Further in View of Aherne (Ex. 1005)
`Petitioner asserts that claims 1–16 are rendered obvious by the
`combination of Riedl and Park (Ground 4) and further in view of Aherne
`(Ground 3). Pet. 37–52, 25–37, respectively. Patent Owner disagrees.
`Prelim. Resp. 22–36. Because Petitioner’s arguments substantially overlap,
`we consider them together, focusing in particular on Ground 3.
`
`Overview of Park
`i.
`Park discloses the potential benefits of adding one or more fluorine
`atoms to “alter the chemical properties, disposition, and biological activity
`of drugs.” Ex. 1004, 443; see, e.g., id. at 445–446, 456 (exemplars with
`multiple fluorine atoms). In particular, Park teaches that “inclusion of a
`fluorine atom in a drug molecule can influence both the disposition of the
`drug and the interaction of the drug with its pharmacological target,” with
`potential benefits on lipophilicity, pKa, tissue distribution, metabolism,
`pharmacodynamics, and toxicity. Id. at 443 (referencing Fig. 1).
`In summarizing the potential benefits of fluorination, Park states:
`A large number of therapeutic agents contain strategically
`placed fluorine atoms. The introduction of fluorine into a
`molecule can alter both the rate and route of drug metabolism in
`a manner dependent on the site of fluorination in relation to the
`sites of metabolic attack. Fluorine substitution can also influence
`the tissue distribution of a drug, and fluorinated drugs have the
`distinct advantage that their in vivo tissue pharmacokinetics can
`be monitored noninvasively by 19F-labeled magnetic resonance
`spectroscopy. Substitution of fluorine for hydrogen at the site of
`oxidative attack can block metabolism, or deflect metabolism
`along an alternative route of metabolism. However, oxidative
`defluorination can occur in both aromatic and aliphatic systems,
`and therefore formal metabolic studies are always required when
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`using fluorine substitution to determine the role of a particular
`biotransformation in a physiological or toxicological process.
`In terms of drug design, fluorine substitution can be used to
`alter the rate of drug metabolism and thereby produce a drug with
`a longer duration of action. Such an approach has a
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