Filed on behalf of: Sawai USA, Inc. and Sawai Pharmaceutical Co., Ltd.
`By: Brian J. Sodikoff
`Martin S. Masar III
`KATTEN MUCHIN ROSENMAN, LLP
`525 W. Monroe St.
`Chicago, IL 60661
`Tel.: 312-902-5200
`Fax: 312-902-1061
`Email: brian.sodikoff@kattenlaw.com
`Email: martin.masar@kattenlaw.com
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`SAWAI USA, INC. and SAWAI PHARMACEUTICAL CO., LTD.,
`Petitioners,
`
`v.
`
`ASTELLAS PHARMA INC.,
`Patent Owner
`
`Case No. IPR__
`Patent No. 6,346,532
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................ 1
`
`A.
`
`Brief Overview of the Challenged Claims. .......................................... 1
`
`1.
`
`2.
`
`“Compound” claims 1, 3-6, 9, and 15 all include
`mirabegron. ............................................................................... 2
`
`“Composition” claims 11, 12, and 16 all include
`mirabegron formulated with pharmaceutically acceptable
`carriers. ..................................................................................... 4
`
`B.
`
`Brief Overview of the Relevant Technology. ...................................... 4
`
`II.
`
`STATEMENT OF PRECISE RELIEF FOR EACH CLAIM
`CHALLENGED ......................................................................................... 10
`
`III. CLAIM CONSTRUCTION ........................................................................ 11
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART ......................................... 11
`
`V. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ............................................................................... 14
`
`A.
`
`[Ground 1] Claims 1, 3-6, 9, 11, 12, 15, and 16 were Obvious
`Under 35 U.S.C. § 103 Over Merck US197, in view of Blin, in
`Combination with Silverman and/or Thornber. ................................. 14
`
`1.
`
`2.
`
`3.
`
`Under the Proper Legal Framework, the Obviousness
`Analysis Starts with the Most Structurally Similar
`Compound in the Prior Art. ..................................................... 14
`
`Because Mirabegron was Obvious, Each of the
`Challenged Claims are Unpatentable. ..................................... 18
`
`“Compound” Claims 1, 3-6, 9, and 15 were Obvious
`Because a POSA Would Have Been Motivated to Make
`Mirabegron with a Reasonable Expectation of Success. .......... 19
`
`a. Merck US197 Disclosed Mirabegron Sulfonamide
`and its Utility as a β3-Agonist. ...................................... 21
`
`-i-
`
`

`

`b.
`
`A POSA Would Have Been Motivated to Change
`the Sulfonamide into an Amide with a Reasonable
`Expectation of Success in Making Mirabegron and
`It Being a Selective β3-Agonist. ................................... 26
`
`4.
`
`“Composition” Claims 11, 12, and 16 Were Obvious
`Because a POSA Would Have Been Motivated to Make a
`Composition Comprising Mirabegron and a
`Pharmaceutical Carrier with a Reasonable Expectation of
`Success. .................................................................................. 31
`
`5.
`
`Conclusion of Ground 1. ......................................................... 33
`
`B.
`
`[Ground 2] Claims 1, 3-6, 9, 11, 12, 15, and 16 Were Obvious
`Under 35 U.S.C. § 103 Over Merck US197, in view of Blin, in
`Combination with Merck US048 and Silverman and/or
`Thornber. .......................................................................................... 36
`
`1.
`
`“Compound” Claims 1, 3-6, 9, and 15 were Obvious
`Because a POSA Would Have Been Motivated to Make
`Mirabegron with a Reasonable Expectation of Success. .......... 37
`
`a.
`
`b.
`
`A POSA Would Have Selected the Merck US197
`Table 3 Compounds as Lead Compounds. .................... 37
`
`A POSA Would Have Been Motivated to Modify
`the Merck US197 Lead Compounds to Make
`Mirabegron With a Reasonable Expectation of
`Success. ........................................................................ 42
`
`2.
`
`“Composition” Claims 11, 12, and 16 Were Obvious
`Because a POSA Would Have Been Motivated to Make a
`Composition Comprising Mirabegron and a
`Pharmaceutical Carrier with a Reasonable Expectation of
`Success. .................................................................................. 48
`
`3.
`
`Conclusion of Ground 2. ......................................................... 48
`
`C.
`
`Secondary Considerations ................................................................. 52
`
`VI. GROUNDS FOR STANDING ................................................................... 54
`
`VII. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................ 55
`
`-ii-
`
`

`

`VIII. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ......... 56
`
`IX. CONCLUSION .......................................................................................... 56
`
`X. APPENDIX – LIST OF EXHIBITS .............................................................. 1
`
`
`
`-iii-
`
`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Albrecht,
`514 F.2d 1385 (C.C.P.A. 1975) ........................................................................ 14
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .......................................................................... 54
`
`Ex parte Cao,
`No. 2010-00408 (B.P.A.I. Sept. 21, 2011) ....................................................... 17
`
`In re Cuozzo Speed Techs., LLC,
`778 F.3d 1271 (Fed. Cir. 2015) ........................................................................ 11
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ........................................................................ 36
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) (en banc) ................................................... passim
`
`Ex parte Dong,
`No. 2011-010047 (P.T.A.B. Jan. 28, 2013) ...................................................... 18
`
`EWP Corp. v. Reliance Universal Inc.,
`755 F.2d 898 (Fed. Cir. 1985) .......................................................................... 15
`
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) ........................................................................ 17
`
`Ex parte Gaul,
`No. 2011-008222 (B.P.A.I. Jan. 5, 2012) ......................................................... 18
`
`In re Grabiak,
`769 F.2d 729 (Fed. Cir. 1985) .......................................................................... 18
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ............................................................................................. 16
`
`In re Grasselli,
`713 F.2d 731 (Fed. Cir. 1983) .......................................................................... 53
`
`-iv-
`
`

`

`In re Hoch,
`428 F.2d 1341 (C.C.P.A. 1970) ........................................................................ 14
`
`In re Huston,
`308 F.3d 1267 (Fed. Cir. 2002) ........................................................................ 18
`
`Ex parte Jimenez Mayorga,
`No. 2010-012157 (B.P.A.I. Sept. 30, 2011) ..................................................... 18
`
`KSR Int’l v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................. 15-17, 36
`
`In re Lamberti,
`545 F.2d 747 (C.C.P.A. 1976).......................................................................... 17
`
`Mast Foos, & Co. v. Stover Mfg. Co.,
`177 U.S. 485 (1900) ......................................................................................... 16
`
`In re McLaughlin,
`443 F.2d 1392 (C.C.P.A. 1971) ........................................................................ 15
`
`In re Merck,
`800 F.2d 1091 (Fed. Cir. 1986) ........................................................................ 54
`
`In re Muchmore,
`433 F.2d 824 (C.C.P.A. 1970).......................................................... 3, 19, 34, 49
`
`Otsuka Pharm. Co. Ltd. v. Sandoz Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ........................................................................ 36
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ........................................................................ 18
`
`In re Stemniski,
`444 F.2d 581 (C.C.P.A. 1971).......................................................................... 14
`
`In re Wilder,
`563 F.2d 457 (C.C.P.A. 1977).......................................................................... 14
`
`In re Wood,
`582 F.2d 638 (C.C.P.A. 1978).......................................................................... 14
`
`
`
`-v-
`
`

`

`I.
`
`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Sawai USA, Inc. and
`
`Sawai Pharmaceutical Co., Ltd. (“Petitioners”) hereby request review of certain
`
`claims of United States Patent No. 6,346,532 to Maruyama et al. (“the
`
`’532 patent,” Ex. 1001) that issued on February 12, 2002, had an ex parte
`
`reexamination certificate issued on February 24, 2015, and is currently assigned to
`
`Astellas Pharma Inc. (“Patent Owner”). This Petition demonstrates, by a
`
`preponderance of the evidence, that there is a reasonable likelihood that Claims 1,
`
`3-6, 9, 11-12, 15, and 16 of the ’532 patent are obvious in light of the prior art.1
`
`Thus, an IPR should be instituted and these claims should be found unpatentable
`
`and ultimately canceled.
`
`A. Brief Overview of the Challenged Claims.
`The ’532 patent discloses a large genus of compounds that are referred to as
`
`“amide derivatives” and have the general formula:
`
`
`
`
`1 All references to claim numbers are to those existing after the ex parte
`reexamination.
`
`
`
`-1-
`
`

`

`Id. at Col. 2:31-50. These compounds are phenylethanolamine derivatives
`
`(highlighted in red) connected to a variety of amide substituents (highlighted in
`
`blue) with an alkylphenyl spacer (not highlighted). The ‘532 patent specifically
`
`describes 113 actual examples with specific structures, but the claimed genus
`
`encompasses at least hundreds of thousands of compounds with different structural
`
`components. Ex. 1001 at Cols. 16:5-28:67; Ex. 1002 at ¶¶37-39.2
`
`The ‘532 patent does not contain any reference to human clinical trials. The
`
`specification describes testing in two rodent models for diabetes (Ex. 1001 at Col.
`
`11:1-55) and in vitro studies for β3-receptor selectivity (id. at Col. 11:56-12:11),
`
`but fails to provide any actual data for any of the hundreds of thousands of
`
`compounds disclosed or claimed.
`
`1.
`
`“Compound” claims 1, 3-6, 9, and 15 all
`mirabegron.
`
`include
`
`Independent Claims 1, 5, and 6, and dependent Claims 3, 4, 9, and 15 claim
`
`various sized groups of pharmaceutical compounds, each of which includes
`
`mirabegron as a species. Independent Claim 1 defines a broad genus of
`
`compounds with the following structure:
`
`
`2 Petitioners submit the declaration of Dr. Robert M. Williams, Ph.D., who is a
`University Distinguished Professor of Chemistry at Colorado State University and
`an expert in medicinal chemistry in support of this petition. Dr. Williams’ relevant
`experience and expertise can be found in his declaration (Ex. 1002 at ¶¶1-33) and
`his CV (Ex. 1003).
`
`
`
`-2-
`
`

`

`
`Ex. 1001, Reexam. at Col. 1:25-35. Dependent Claims 3, 4, 9, and 15 define
`
`various subgenera of Claim 1. Ex. 1001 at Col. 46:15-17; Ex. 1001, Reexam. at
`
`Col. 2:1-23, 2:51-52; Ex. 1002 at ¶¶39-44.
`
`
`
`Independent Claim 5 is directed specifically to mirabegron and states “[a]
`
`compound of formula (Ia):
`
`
`or a salt thereof.” The compound of Claim 5 is also known as (R)-2-(2-
`
`aminothiazol-4-yl)-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide.
`
` Ex.
`
`1002 at ¶42.
`
`
`
`Independent Claim 6 defines a nine-member genus (excluding salts), one of
`
`which is mirabegron. Ex. 1001 at Col. 45:30-46:5; Ex. 1002 at ¶43. Mirabegron is
`
`also within the scope of Claims 1, 3, 4, 9, and 15. Ex. 1002 at ¶43.
`
`
`
`These claims are unpatentable for obviousness because mirabegron, a
`
`species of them all, is obvious. See In re Muchmore, 433 F.2d 824, 824-25
`
`
`
`-3-
`
`

`

`(C.C.P.A. 1970) (“Since we agree with the board’s conclusion of obviousness as to
`
`these narrow claims, the broader claims must likewise be obvious.”).
`
`2.
`
`“Composition” claims 11, 12, and 16 all include mirabegron
`formulated with pharmaceutically acceptable carriers.
`
`Dependent Claims 11, 12, and 16 are directed
`
`to pharmaceutical
`
`compositions that include compounds (as defined in one of the “compound”
`
`claims), along with a pharmaceutically acceptable carrier.
`
` Compositions
`
`containing mirabegron with a pharmaceutically acceptable carrier is a species of
`
`each of these claims. These claims are unpatentable because it would be obvious
`
`to formulate mirabegron along with a pharmaceutically acceptable carrier because
`
`a POSA would have reasonably expected it to be a β3-adrenergic receptor agonist.
`
`Brief Overview of the Relevant Technology.
`
`B.
`The ’532 patent claims priority to a Japanese Application filed on October
`
`17, 1997. Id. at 1. By October 1997, adrenergic receptors (ARs) had been
`
`researched for around fifty years. In the late 1940s, two major types of ARs were
`
`designated alpha (α) and beta (β) to distinguish major differences elicited in
`
`various organ systems by adrenergic agents. See, e.g., Ex. 1004 at 529. Initially,
`
`α-ARs were generally associated with contraction of smooth muscle in various
`
`organs. See, e.g., id. The β-AR was generally associated with inhibitory
`
`responses, except in the heart. See, e.g., id.
`
`
`
`-4-
`
`

`

`In the late 1960s, studies demonstrated that there were two β-AR subtypes.
`
`See, e.g., Ex. 1004 at 529; Ex. 1005 at 2821; Ex. 1006 at 1094; Ex. 1008, at Col.
`
`1:14-15; see also Ex. 1001 at Col. 1:45-50. The receptor mediating responses in
`
`the heart and lipolysis was designated β1, while the receptor mediating
`
`vasodepressor activity and bronchodilation was labelled β2. See, e.g., Ex. 1004 at
`
`529; Ex. 1008 at Col. 1:15-18; see also Ex. 1001 at Col. 1:45-50.
`
`In the 1980s, a third subtype, β3-AR, was hypothesized and then confirmed.
`
`See, e.g., Ex. 1004 at 530; Ex. 1005 at 2821; Ex. 1006 at 1094; Ex. 1008 at Col.
`
`1:21-24; Ex. 1025 at 168-69. As the ’532 Patent admits, “it has been known …
`
`that stimulation of β3-receptor shows an anti-obesity and an anti-hyperglycemia
`
`action (such as decrease in triglyceride, decrease in cholesterol and increase in
`
`HDL-cholesterol).” Ex. 1001 at Col. 1:45-54; see also Ex. 1004 at 544 (stating
`
`there was a “need for selective antagonists and labelled ligands which have
`
`sufficiently high affinity for the β3-adrenoreceptor.”). In fact, the POSA would
`
`have been motivated to look for new β3-AR agonists because “[t]here [we]re strong
`
`indications that β3-adrenoreceptor agonists of appropriate selectivity, efficacy and
`
`pharmacodynamics in man could prove clinically useful in the treatment of obesity
`
`in association with dieting, and for correcting raised blood sugar in diabetics.” Id.
`
`Additional motivation to search for new β3-AR agonists and a suggested method to
`
`do so was disclosed in Blin. See Ex. 1006 at 1097.
`
`
`
`-5-
`
`

`

`At that time, the structure-activity relationship of agonists (and antagonists)
`
`of the β3-adrenoreceptor was also being researched and summarized. See, e.g., Ex.
`
`1006 at 1102; see also Ex. 1007 at PTO_00001116 (Astellas admitting Blin
`
`“discusses the structural-activity features responsible for the β3 potency and
`
`selectivity of ligands.”). In fact, Blin identified a “minimal pharmacophore”
`
`necessary for selective β3-AR activity that included (i) an aromatic group, which
`
`could stabilize aryl-aryl interactions, (ii) a beta-hydroxyl or an ether function,
`
`which could establish a hydrogen bond, and (iii) a protonated amine, which should
`
`create an ionic bridge with a negatively charged carboxyl function inside the
`
`pocket site:
`
`
`
`See Ex. 1006 at 1101-02, Figure 7; see also Ex. 1007 at PTO_00001116 (Astellas
`
`admitting “Blin teaches that potent β3-agonists may have the following minimal
`
`pharmacophore”); PTO_00001474 (Examiner stating Blin taught that “[p]otent β3
`
`adrenergic receptor agonists may have one of the following [two] minimal
`
`pharmacophores ….”); Ex. 1002 at ¶¶94. Blin also suggested that “β3 efficiency is
`
`determined by the long and bulky amine substituent moiety of the ligands, which
`
`may interact with helices positioned on the opposite side, relative to those
`
`
`
`-6-
`
`

`

`implicated more specifically in ligand binding.” Ex. 1006 at 1099, id. at 1103
`
`(“extended conformations [of the long alkylamine chains], which could be adopted
`
`in the less encumbered β3 site, may induce agonistic effects.”); Ex. 1002 at ¶¶94.
`
`It was also recognized that “[t]he stereochemistry of the phenethanolamine
`
`has a crucial influence on the potency and selectivity …” and the prior art taught
`
`methods to produce the desired R-configuration at the chiral carbon in the minimal
`
`pharmacophore:
`
`R
`
`
`
`HN
`
`OH
`
`See, e.g., Ex. 1005 at 2821; Ex. 1008 at Col. 15:13-31, Compound Ic; Col. 55,
`
`Claim 3; Ex. 1002 at ¶95.
`
`By October 1997, it was common for a research team to create a series of
`
`structurally similar compounds and to conduct testing on them, such as running
`
`them through assays.3 See generally Exs. 1008-1014; see also Ex. 1002 at ¶96. It
`
`was also common for a pharmaceutical research team to be able to hypothesize the
`
`3 Notably, the specific assay used by the ’532 patent Applicants to test for β3-
`selectivity was disclosed in the prior art. For example, Merck US197 taught that
`“[r]ecently, assays have been developed which more accurately predict the effects
`that can be expected in humans [, which] utilize cloned human β3 receptors which
`have been expressed in Chinese hamster ovary cells ….” Ex. 1008 at Col. 1:59-
`64. “The agonist and antagonist effects of the various compounds on the cultivated
`cells provides an indication of the antiobesity and antidiabetic effects of the
`compounds in humans.” Id. at Col. 1:64-67; Ex. 1002 at ¶96, n.5.
`-7-
`
`
`
`

`

`structure of compounds and
`
`to have a reasonable expectation of
`
`their
`
`pharmaceutical utility based on their similarity to other compounds. Id.; see also
`
`Ex. 1015 at PTO_00000823 (Examiner stating, “it is obvious to a chemist skilled
`
`in the art to select any species of the genus that will have reasonably similar
`
`properties and equal or better pharmaceutical use.”); Ex. 1002 at ¶96. By October
`
`1997, as admitted by Astellas, the prior art taught that compounds “that are said to
`
`be selective β3-adrenergic receptor agonists having very little β1 and β2 adrenergic
`
`receptor activity” would be “expected to be useful in the treatment of Type II
`
`diabetes.” Ex. 1007 at PTO_00001117 (discussing Ex. 1012); see also Ex. 1002 at
`
`¶96.
`
`The ‘532 patent specifically identifies the compounds disclosed in WO
`
`95/29159 (“Merck WO159,” Ex. 1013)4 as known desirable examples of selective
`
`β3-agonists. Id. at Col. 1:67-2:5. Merck WO159 (and its equivalent, Merck
`
`US197) taught and disclosed phenylethanolamine derivatives that were “selective
`
`β3 adrenergic receptor agonists with very little β1 and β2 adrenergic receptor
`
`activity” that had “potent activity in the treatment of Type II diabetes and obesity.”
`
`Ex. 1008 at Abstract. A preferred sub-genus of Merck US197 had the following
`
`structure:
`
`
`4 This patent application shares a specification with the patent that eventually
`issued as U.S. Patent 5,541,197 (Ex. 1008), which is referred to herein as “Merck
`US197.”
`
`
`
`-8-
`
`

`

`O
`
`S
`
`HN
`
`OH
`
`A
`
`
`See, e.g., Ex. 1008 at Col. 4:25-345 (“[p]referred compounds of the instant
`
`R
`
`O
`
`NH
`
`invention are realized when in the above structural Formula (I): R2 and R3 are
`
`hydrogen …; X is –CH2-; n is 0 …, m is 1; … and R4, R5, and R6 are hydrogen.”);
`
`Col. 15:13-31 (preferred stereoisomers); Ex. 1002 at ¶97. Even further, Merck
`
`US197 disclosed preferences for A and R that would include the following
`
`compound:
`
`
`
`See id.; id. at Cols. 3:15-18; 2:41; 2:46; 3:52-53; 4:30; 15:13-31, 6:33-7:1; 15:64-
`
`16:5. This compound differs from mirabegron by the carbonyl group in
`
`mirabegron being replaced with a sulfonyl group (shown in red), which was a
`
`common biosisosteric replacement known to the POSA. Ex. 1002 at ¶¶97, 115-
`
`120, 142-156; Ex. 1007, PTO_00001475 (Examiner stating that Thornber taught
`
`that a carbonyl group may be replaced with the bioisosteric sulfone group).
`
`
`5 R in the above structure is used as a shorthand for “(CH2)r-R7.”
`
`
`
`-9-
`
`

`

`II.
`
`STATEMENT OF PRECISE RELIEF FOR EACH CLAIM
`CHALLENGED
`
`Petitioner requests review of Claims 1, 3-6, 9, 11, 12, 15 and 16 of the ʼ532
`
`patent under 35 U.S.C. § 311 and AIA § 6. Petitioner contends each of these
`
`Claims should be canceled as unpatentable under 35 U.S.C. § 103 (2012) as
`
`follows:
`
`Ground
`
`Claims
`
`1, 3-6, 9, 11, 12,
`15, and 16
`
`1, 3-6, 9, 11, 12,
`15, and 16
`
`Description
`Obvious under § 103 over Merck US197 in view of
`Blin,
`in combination with Silverman
`(and/or
`Thornber), in view of a POSA’s general knowledge
`and skill
`Obvious under §103 over Merck US197 in view of
`Blin, in combination with Merck US048, in further
`combination with Silverman (and/or Thornber), in
`view of a POSA’s general knowledge and skill
`
`1
`
`2
`
`
`
`As described above, the earliest possible priority date for the ʼ532 patent
`
`claims is October 17, 1997. Merck US197 (Ex. 1008) issued on July 30, 1996,
`
`Blin (Ex. 1006) was published in 1993, Silverman (Ex. 1016) was published in
`
`1992, and Thornber (Ex. 1017) was published in January 1979. Thus, each
`
`reference for Ground 1 is available as prior art against the challenged claims under
`
`35 U.S.C. § 102(b) (2012).
`
`As for Ground 2, Merck US048 (Ex. 1010) issued on January 4, 2000, but
`
`claims priority to a provisional application filed on January 28, 1997, and thus
`
`qualifies as prior art under, at least, 35 U.S.C. § 102(e).
`
`
`
`-10-
`
`

`

`III. CLAIM CONSTRUCTION
`A claim subject to inter partes review receives the broadest reasonable
`
`construction or interpretation in light of the specification of the patent in which it
`
`appears, because among other reasons, the patent owner has an opportunity to
`
`amend the claims. See 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC,
`
`778 F.3d 1271, 1279-82 (Fed. Cir. 2015).
`
`The claims of the ‘532 patent generally use conventional terminology. Ex.
`
`1002 at ¶84. The patent disclosure offers specific definitions (see, e.g., Ex. 1001 at
`
`Cols. 3:4-4:7), but these definitions are also conventional. Ex. 1002 at ¶84. None
`
`of the challenged claims are limited to treating a certain disease state. Therefore,
`
`they are broad and cover any pharmacological utility.
`
`Petitioners reserve the right to propose alternative constructions to any that
`
`the Patent Owner may raise during this IPR.
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`As of October 1997, a hypothetical person having ordinary skill in the art
`
`(“POSA”) would have some combination of the following skills and experience:
`
`designing target compounds towards drug discovery; designing and preparing
`
`formulations of drugs
`
`that exhibit agonistic and/or antagonistic activity;
`
`understanding the biological aspects of drug development; and understanding work
`
`
`
`-11-
`
`

`

`presented or published by others in the field, such as the exemplary references
`
`discussed below, representing the state of the art.
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`Typically, a POSA in the relevant field in October 1997 would have had a
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`Master’s or Ph.D. degree in organic, medicinal, or pharmaceutical chemistry, or a
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`related discipline; a minimum of three years of training or experience in the
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`pertinent field; and an appreciation for the factors relating to the drug-development
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`process. Alternatively, a POSA might have less education but considerably more
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`professional experience.
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`Also, a POSA would have knowledge of drugs for treating diabetes and/or
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`obesity, including other β3-adrenergic agonist compounds and/or β-adrenergic
`
`agonist compounds that have utility in treating other diseases. A POSA would also
`
`have had an understanding of pharmaceutical formulation science (as a concept
`
`and in practice) or would be part of a team with such knowledge. It would be
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`common for a POSA to create or hypothesize a number of chemically similar
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`compounds during drug development, with the ability to have a reasonable
`
`expectation as to their pharmacological activity based on structural similarity to
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`other known active compounds.
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`The lack of specific guidance in the specification of the ’532 patent confirms
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`a high level of skill in the art. For example, the patent includes only limited
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`description of the various pharmaceutical compositions that it claims. There are no
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`
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`validated or tested dosages for those compositions and no examples describing any
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`actual compositions produced by the inventors. Rather than providing specific
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`guidance regarding dosages for the claimed compositions, the patent invites the
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`POSA to turn to the knowledge and resources readily available to him/her when
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`selecting and formulating pharmaceutical dosage forms. For instance, Applicants
`
`admitted “[a] pharmaceutical composition containing one or more of the
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`compound [sic] of the present invention or the salt thereof as an effective
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`ingredient is prepared using common pharmaceutically acceptable vehicles.” Ex.
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`1001 at Col. 12:12-15. Also, rather than providing specific guidance for the
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`compositions, the patent provides broad dosage ranges and administration methods
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`(id. at Col 12: 20-29). This provides essentially no guidance for selecting actual
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`dosages or treatment regimens. Ex. 1002 at ¶82.
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`Hence, the ’532 patent relies on a high level of skill in the art to be able to
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`practice the invention. Thus, the level of ordinary skill in the art as of October 17,
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`1997 was high.
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`

`

`EXPLANATION
`V. DETAILED
`UNPATENTABILITY
`A.
`
`OF
`
`GROUNDS
`
`FOR
`
`[Ground 1] Claims 1, 3-6, 9, 11, 12, 15, and 16 were Obvious
`Under 35 U.S.C. § 103 Over Merck US197, in view of Blin, in
`Combination with Silverman and/or Thornber.
`1.
`
`Under the Proper Legal Framework, the Obviousness Analysis
`Starts with the Most Structurally Similar Compound in the Prior
`Art.
`
`In Dillon, the Federal Circuit held that
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`structural similarity between claimed and prior art subject matter,
`proved by combining references or otherwise, where the prior art
`gives reason or motivation to make the claimed compositions, creates
`a prima facie case of obviousness, and ... the burden (and opportunity)
`then falls on an applicant to rebut that prima facie case.
`
`919 F.2d 688, 692 (Fed. Cir. 1990). Under this approach, a prior art compound
`
`qualified as a starting point for a prima facie case if it was structurally similar to
`
`the claimed compound and the prior art disclosed any utility regarding the prior art
`
`compound. Id. at 697; see also In re Stemniski, 444 F.2d 581, 586 (C.C.P.A.
`
`1971). There was no requirement that the prior art compound have the same utility
`
`as the claimed compound or that the prior art compound have more beneficial
`
`properties than other prior art compounds. See, e.g., In re Hoch, 428 F.2d 1341
`
`(C.C.P.A. 1970); In re Albrecht, 514 F.2d 1385 (C.C.P.A. 1975); In re Wilder, 563
`
`F.2d 457 (C.C.P.A. 1977); In re Wood, 582 F.2d 638 (C.C.P.A. 1978).6 Rather, a
`
`
`6 In some cases, the Federal Circuit has applied a strict “lead compound analysis”
`(LCA) to determine whether a prior art compound qualifies as a starting point to
`-14-
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`

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`prior art reference must be considered for everything it teaches and is not limited to
`
`the particular invention it is describing and attempting to protect. See EWP Corp.
`
`v. Reliance Universal Inc., 755 F.2d 898, 907 (Fed. Cir. 1985).
`
`In KSR Int’l v. Teleflex Inc., the Supreme Court confirmed that obviousness
`
`determinations require an expansive, flexible, and functional approach. See 550
`
`U.S. 398, 415, 419 (2007). When there is a design need or market pressure to
`
`solve a problem and there are a finite number of identified, predictable solutions, a
`
`POSA has a good reason to pursue the options known in the art. Id. If this leads to
`
`the anticipated success, it is likely the product not of innovation but of ordinary
`
`skill and common sense. Id. at 421. Obviousness is “necessarily a reconstruction
`
`based upon hindsight reasoning,” but so long as it is based on the knowledge and
`
`content of the art rather than on the patent disclosure, that is permissible. In re
`
`McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971).
`
`Under KSR and Dillon, the chosen prior art compound can be any compound
`
`that has utility, and the motivation to modify it could be to make another
`
`compound with similar utility. Obviousness does not require a POSA to have the
`
`motivation of the inventors, but instead can have any motivation. A compound
`
`with a known utility can motivate a POSA to make another compound with the
`
`same utility.
`
`prove obviousness. However, this is contrary to its own earlier en banc decision in
`Dillon and Supreme Court precedent.
`
`
`
`-15-
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`

`

`Strict application of the LCA effectively restricts the knowledge of the
`
`POSA in contravention to the Patent Act, as well as Supreme Court precedent and
`
`Dillon. The POSA is presumed to be aware of all of the art that has come before
`
`the alleged invention. See, e.g., Mast Foos, & Co. v. Stover Mfg. Co., 177 U.S.
`
`485, 493 (1900) (“Having all these various devices before him, and whatever the
`
`facts may have been, he is chargeable with a knowledge of all preexisting devices
`
`….”). Thus, the effect of a compound being disclosed in the prior art is to
`
`anticipate and hence to render unpatentable any later attempt to claim that
`
`compound. The disclosed compound also makes unpatentable any compounds that
`
`are obvious variants. See Graham, 383 U.S. at 14 (“An invention which has been
`
`made, and which is new in the sense that the same thing has not been made before,
`
`may still not be patentable if the difference between the new thing and what was
`
`known before is not considered sufficiently great to warrant a patent.”).
`
`By imposing a strict threshold “lead compound” requirement in some cases,
`
`the Federal Circuit has improperly constricted the concept of obviousness. For
`
`example, it was common and ordinary course for a POSA to make multiple
`
`alterations to various prior art compounds. In such situations, a new chemical
`
`compound may be obvious (or at least obvious to try) even if it is not created
`
`through alteration of the most promising compound(s) in a specific prior art field.
`
`See KSR, 550 U.S. at 421 (“When there is a design need or market pressure to
`
`
`
`-16-
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`

`

`solve a problem and there are a finite number of identified, predictable solutions, a
`
`[POSA] has good reason to pursue the known options within his or her technical
`
`grasp.”). The LCA departs from Section 103 because it fails to allow for the fact
`
`that variants of compounds disclosed in the prior art may be obvious, rather than
`
`being limited to just variants of the most promising compounds. See, e.g., In re
`
`Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) (obviousness does not require that
`
`the claimed invention be the “preferred, or the most desirable” choice.); In re
`
`Lamberti, 545 F.2d 747, 750 (C.C.P.A. 1976) (“all disclosures of the prior art,
`
`including unpreferred embodiments, must be considered.”).
`
`Every compound that is disclosed in the prior art belongs to the public. The
`
`public is also entitled to be able to make obvious modifications of those prior art
`
`compounds. Requiring the skilled artisan to be motivated in the first instance to
`
`select the most promising prior art compound is not grounded in Section 103 or
`
`Supreme Court precedent. See KSR, 127 S. Ct. at 1741. As such, the LCA should
`
`not be required in the proper analysis of the obviousness of compound claims like
`
`those in the ’532 P