`Filed on behalf of: Astellas Pharma Inc.
`
`Paper No. ___
`Date: February 8, 2018
`
`
`
`
`
`
`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. IPR2018-00079
`Patent No. 6,346,532
`_________________
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. §42.107
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`I. 
`
`Introduction ...................................................................................................... 1 
`
`A.  What Is Mirabegron? ............................................................................. 2 
`
`B. 
`
`The Petition Should Be Denied Institution ........................................... 3 
`
`II. 
`
`Background ...................................................................................................... 6 
`
`III.  Level of Ordinary Skill in the Art ................................................................... 8 
`
`IV.  Law .................................................................................................................. 9 
`
`A. 
`
`B. 
`
`Burden of Proof ..................................................................................... 9 
`
`Board’s Discretion Based on Art Already Considered
`During Prosecution ................................................................................ 9 
`
`C. 
`
`Obviousness ......................................................................................... 10 
`
`V.  Ground 1 – Merck US197 in View of Blin, in Combination
`with Silverman and/or Thornber .................................................................... 14 
`
`A. 
`
`B. 
`
`C. 
`
`This Board Should Exercise Its Discretion Not to
`Institute Ground 1 of This Petition ...................................................... 14 
`
`Petitioners’ “Most Structually Similar Compound”
`Analysis Is Wrong ............................................................................... 17 
`
`Petitioners Are Wrong as a Matter of Law That
`“Mirabegron Sulfonamide” Is Disclosed in Merck US197 ................ 20 
`
`1. 
`
`2. 
`
`3. 
`
`Petitioners’ Hindsight Construction Does Not
`Account for the Overall Teachings in Merck
`US197 ........................................................................................ 23 
`
`Petitioners’ “Preferred Subgenus” Does Not Single
`Out a Definite and Limited Class of Compounds ..................... 27 
`
`Petitioners’ Representations Regarding Blin Do
`Not Narrow the Disclosure in Merck US197 in
`Support of Creating “Mirabegron Sulfonamide” ...................... 32 
`
`
`
`- i -
`
`

`

`D. 
`
`The Substitution of the Sulfonamide for the Amide Is
`Based on Hindsight ............................................................................. 35 
`
`1. 
`
`2. 
`
`3. 
`
`Petitioners Provide No Reasoned Motivation to
`Swap Out a Key Component of Merck US197 ........................ 35 
`
`Petitioners Ignore the Overall Teaching of
`Thornber and Silverman ........................................................... 37 
`
`Thorber and Silverman Disclose Other Possible
`Bioisosteres ............................................................................... 38 
`
`Petitioners Fail to Credibly Articulate What the
`Reasonable Expectation of Success Would Be ................................... 39 
`
`Petitioners Are Wrong with Respect to Their Arguments
`About Binding Omissions at the PTO ................................................. 41 
`
`Petitioners’ Obviousness Arguments for Composition
`Claims Also Fail .................................................................................. 42 
`
`E. 
`
`F. 
`
`G. 
`
`VI.  Ground 2 - Merck US197, in View of Blin, in Combination
`with Merck US048 and Silverman and/or Thornber ..................................... 43 
`
`A. 
`
`Petitioners Do Not Account for the Full Scope and
`Content of the Prior Art ....................................................................... 43 
`
`1. 
`
`2. 
`
`Blin Discloses Other Compounds with Data ............................ 44 
`
`Blin Disclosures Do Not Narrow the Selection As
`Petitioners Describe .................................................................. 44 
`
`4. 
`
`3. 
`
`Petitioners Admit That Other Companies Were
`Working On and Disclosing β3 Compounds ............................. 46 
`Petitioners Fail to Account for the Full Scope of
`the Merck Patent Estate on β3 ................................................... 46 
`Petitioners’ Hindsight Selection of Compounds 90-92 as
`Leads Goes Against the Teachings of Merck US197 ......................... 48 
`
`Structural Modifications on Petitioners’ Lead
`Compounds Are Based on Hindsight .................................................. 51 
`
`B. 
`
`C. 
`
`
`
`- ii -
`
`

`

`1. 
`
`2. 
`
`3. 
`
`The Substitution of the Sulfonamide for the Amide
`Is Based on Hindsight ............................................................... 53 
`
`Petitioners’ Argument Regarding Bioisosteres
`Contradicts Their Argument for Adding a
`Methylene Spacer ...................................................................... 53 
`
`Petitioners’ Arguments Regarding Side Chain Are
`Based on Hindsight ................................................................... 55 
`
`Petitioners Fail to Credibly Articulate What the
`Reasonable Expectation of Success Would Be ................................... 57 
`
`Petitioners Are Wrong with Respect to Their Arguments
`About Binding Omissions at the PTO ................................................. 58 
`
`Petitioners’ Obviousness Arguments for Composition
`Claims Also Fail .................................................................................. 58 
`
`D. 
`
`E. 
`
`F. 
`
`VII.  Conclusion ..................................................................................................... 58 
`
`
`
`
`
`
`- iii -
`
`

`

`Cases 
`
`TABLE OF AUTHORITIES
`
`Atofina v. Great Lakes Chem. Corp.,
` 441 F.3d 991 (Fed. Cir. 2006) ............................................................... 22, 23
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
` 619 F.3d 1346 (Fed. Cir. 2010) ....................................................... 12, 13, 36
`
`Diamond Rubber Co. v. Consol. Rubber Tire Co.,
` 220 U.S. 428 (1911) ................................................................................ 4, 12
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
` 533 F.3d 1353 (Fed. Cir. 2008) ............................................................. 11, 12
`
`Ex Parte Jimenez Mayorga,
` No. 2010-012157 (B.P.A.I. Sept. 30, 2011) ................................................. 19
`
`In re Baird,
` 16 F.3d 380 (Fed. Cir. 1994) ..................................................... 20, 22, 25, 26
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig.,
` 676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 10
`
`In re Dillon,
` 919 F.2d 688 (Fed. Cir. 1990) ................................................... 12, 18, 19, 20
`
`In re Jones,
` 958 F.2d 347 (Fed. Cir. 1992) ...................................................................... 22
`
`In re Kahn,
` 441 F.3d 977 (Fed. Cir. 2006) ........................................................................ 9
`
`In re Magnum Oil Tools Int’l, Ltd.,
` 829 F.3d 1364 (Fed. Cir. 2016) .................................................................... 20
`
`In re McLamore,
` 54 C.C.P.A. 1544 (1967) .............................................................................. 22
`
`KSR Int’l Co. v. Teleflex Inc.,
` 550 U.S. 398 (2006) ................................................................................ 9, 19
`
`
`
`- iv -
`
`

`

`Otsuka Pharm. Co. v. Sandoz, Inc.,
` 678 F.3d 1280 (Fed. Cir. 2012) ........................................... 10, 11, 12, 20, 44
`
`Pfizer Inc. v. Mylan Pharms. Inc.,
` 71 F. Supp. 3d 458, (D. Del. 2014) .............................................................. 21
`
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
` 555 Fed. App’x 961 (Fed. Cir. 2014) ........................................................... 44
`
`Pfizer, Inc. v. Apotex, Inc.,
` 480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 19
`
`Takeda Chem. Indus. v. Alphapharm Pty., Ltd.,
` 492 F.3d 1350 (Fed. Cir. 2007) ....................................................... 11, 12, 20
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
` 231 F.3d 1339 (Fed. Cir. 2000) ............................................................. 13, 41
`
`P.T.A.B. Cases 
`Apotex Inc. v. Merck Sharp & Dohme Corp.,
`IPR2015-00419, Paper 18 (P.T.A.B. Oct. 27, 2015) .............................. 18, 20
`
`Apotex Inc. v. Merck Sharp & Dohme Corp.,
` IPR2015-00419, Paper 14 (P.T.A.B. June 25, 2015) ................................... 17
`
`Coalition for Affordable Drugs VII LLC v. Pozen Inc.,
` IPR2015-01344, Paper 22 (P.T.A.B. Dec. 17, 2015) ..................................... 9
`
`Complex Innovations, LLC v. Amgen Inc.,
`IPR2016-00085, Paper 10 (P.T.A.B. April 13, 2016) ................................... 43
`
`Cultec, Inc. v. Stormtech LLC,
`IPR2017-00777, Paper 7 (P.T.A.B. Aug. 22, 2017) ................................. 9, 16
`
`Hospira, Inc. v. Genentech, Inc.,
` IPR2017-00739, Paper 16 (P.T.A.B. July 27, 2017) ............................... 9, 10
`
`Incyte Corp. v. Concert Pharms., Inc.,
`IPR2017-01256, Paper 9 (P.T.A.B. Oct. 19, 2017) ................................ 11, 17
`
`Mylan Labs. Ltd. v. Aventis Pharma S.A.,
` IPR2016-00627, Paper 10 (P.T.A.B. Aug. 23, 2016) ................................... 13
`
`
`
`- v -
`
`

`

`Mylan Labs. Ltd. v. Aventis Pharma S.A.,
` IPR2016-00627, Paper 12 (P.T.A.B. Jan. 26, 2017) .................................... 12
`
`Mylan Pharms. Inc. v. Nissan Chem. Indus., Ltd.,
`IPR2015-01069, Paper 24 (P.T.A.B. Oct. 20, 2015) ..................................... 17
`
`Sawai USA, Inc. and Sawai Pharm. Co., Ltd. v. Nissan Chem. Indus., Ltd.,
`IPR2015-01647, Paper 9 (P.T.A.B. Feb. 4, 2016) ................................. 17, 18
`
`Torrent Pharms. Ltd. v. Merck Frosst Canada & Co.,
`IPR2014-00559, Paper 10 (P.T.A.B. Jan. 7, 2015) ....................................... 18
`
`Torrent Pharms. Ltd. v. Merck Frosst Canada & Co.,
`IPR2014-00559, Paper 8 (P.T.A.B. Oct. 1, 2014) ........................................ 17
`
`Statutes 
`
`35 U.S.C. § 103(a) .................................................................................................... 10
`
`35 U.S.C. § 307 .......................................................................................................... 8
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314(a) ..................................................................................................1, 9
`
`35 U.S.C. § 316(e) ...................................................................................................... 1
`
`35 U.S.C. § 325(d) .............................................................................................. 9, 14
`
`Regulations 
`
`37 C.F.R. § 42.104(b)(4) ........................................................................................... 9
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.108(c) ................................................................................................ 9
`
`37 C.F.R. 1.610(b)(2) ............................................................................................... 42
`
`37 C.F.R. 1.610(b)(5) ............................................................................................... 42
`
`MPEP 2811 .............................................................................................................. 41
`
`MPEP 2811.01 ......................................................................................................... 42
`
`
`
`- vi -
`
`

`

`
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`
`
`EXHIBITS
`
`Myrbetriq® (mirabegron) Product Label, extended release tablets,
`revised: July 2017
`(“Exh. 2001” or “Myrbetriq® label”)
`Orange Book: Approved Drug Products with Therapeutic
`Equivalent Evaluations, FDA, available at:
`https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
`(“search by active ingredient” for “mirabegron”)
`(“Exh. 2002”)
`Myrbetriq: Mechanism of Action, available at:
`https://www.myrbetriqhcp.com/mechanism-of-action/
`(“Exh. 2003”)
`Myrbetriq: What is Myrbetriq?, available at:
`https://www.myrbetriq.com/side-effects/
`(“Exh. 2004”)
`WO 97/16189, titled “Combination Therapy For The Treatment
`Of Diabetes and Obesity” (“Exh. 2005”)
`File History of US Patent Application 08/233,166 (“Exh. 2006”)
`
`
`
`- vii -
`
`

`

`ART CITED IN THE FILE HISTORY OF U.S. PAT. NO. 6,346,532
`
` U.S. Pat. No. 5,541,197 (Fisher et al.)
`
` U.S. Pat. No. 5,553,475 (Hayashi et al.)
`
` U.S. Pat. No. 5,614,544 (Sohda et al.)
`
` DE 3,743,265 (Schromm, Kurt et al.)
`
` JP 10,218,861 (M. Tetsuo et al.)
`
` Konosu T. et al. “Triazol Antifungal”, Chem. Pharm. Bull., 39/10, 2581-9
`
`(1991)
`
` U.S. Pat. No. 6,048,884 (Maruyama et al.)
`
` U.S. Pat. No. 6,177,454 (Maruyama et al.)
`
` U.S. Pat. No. 5,223,614 (Schromm et al.)
`
` WO 95/29159 (Fisher et al.)
`
` Blin et al., “Structural and Conformational Features Determining Selective
`
`Signal Transduction in the β3-Adrenergic Receptor,” Molecular
`
`Pharmacology, 44:1094-1104 (1993)
`
` WO 94/18161 (Fisher et al.)
`
` Thornber, C.W., “Isosterism and Molecular Modification in Drug Design,”
`
`Chem. Soc. Rev. 18:563-580 (1979)
`
`
`
`
`
`- viii -
`
`

`

`
`
`
`I.
`
`Case IPR2018-00079
`U.S. Patent No. 6,346,532
`
`Introduction
`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Patent Owner Astellas
`
`Pharma, Inc. (“Astellas” or “Patent Owner”) submits this Preliminary Response to
`
`Sawai USA, Inc. and Sawai Pharmaceutical Co., Ltd.’s (“Sawai” or “Petitioners”)
`
`Petition for Inter Partes Review (“IPR”) of U.S. Patent No. 6,346,532 (“the ’532
`
`patent”).
`
`For this IPR trial to be instituted, Petitioners must establish that there is a
`
`reasonable likelihood of prevailing on the issue of unpatentability with respect to
`
`any of the claims they challenge. 35 U.S.C. § 314(a). The burden rests on
`
`Petitioners to prove unpatentability. 35 U.S.C. § 316(e). Petitioners here,
`
`however, fall short of showing any likelihood of prevailing.
`
` Petitioners assert that claims 1, 3-6, 9, 11-12, 15, and 16 of the ’532 patent
`
`– a patent that claims novel β3-adrenoceptor agonist compounds and compositions
`
`thereof – are unpatentable due to the purported obviousness of the specific
`
`compound mirabegron. (Petition at 1, 3, 4). Mirabegron is a successful drug for
`
`treating bladder conditions that Petitioners seek permission to market under their
`
`Abbreviated New Drug Application (“ANDA”).
`
`The Petition asserts two grounds of invalidity. As Petitioners’ asserted
`
`grounds stand or fall on the obviousness of the mirabegron compound, this Patent
`
`
`
`- 1 -
`
`

`

`Case IPR2018-00079
`
`U.S. Patent No. 6,346,532
`
`Owner’s Preliminary Response will focus on the deficiencies of this Petition and
`
`why it should not be instituted, with reference to mirabegron.
`
`A. What Is Mirabegron?
`Mirabegron, (R)-2-(2-aminothiazol-4-yl)-4’-[2-(2-hydroxy-2-
`
`phenylethyl)amino]ethyl]acetanilide, is a singular, specific compound with (i) a
`
`unique combination of structural elements that distinguish it from all of the prior
`
`art, and most notably from the prior art cited by Petitioners, and (ii) unique
`
`qualities as a medicine that underscore its use as a first-in-class treatment for
`
`certain bladder conditions.
`
`Structurally, mirabegron is:
`
`
`
`Distinctive features of that structure include:
`
`A – a phenyl group that is unsubstituted;
`
`B – a carbonyl group;
`
`C – a methylene group or “spacer”;
`
`D – a thiazole group connected at its 4-position to the methylene group;
`
`
`
`- 2 -
`
`

`

`
`
`
`Case IPR2018-00079
`U.S. Patent No. 6,346,532
`E – an amino group at the 2-position of the thiazole.
`
`As Petitioners concede by relying solely on arguments of obviousness,
`
`nothing in the prior art discloses that unique structure.
`
`Mirabegron’s unique properties include, at least, its selective binding to and
`
`activation of the β3 receptor in human tissue, which enable its use to treat
`
`overactive bladder while avoiding the undesired side effects that can result from
`
`activation of β1 and β2 receptors.
`
`To succeed in their Petition, Petitioners bear the burden of showing that, (1)
`
`starting from something disclosed in the prior art, (2) a person of ordinary skill in
`
`the art (“POSA”) would have been guided to obvious choices concerning the
`
`modifications required to reach that unique structure, and (3) would have made
`
`those modifications with a reasonable expectation of achieving mirabegron’s
`
`unique properties. Petitioners’ arguments fail at each of those three critical
`
`elements.
`
`The Petition Should Be Denied Institution
`
`B.
`The Petition is remarkable in several aspects.
`
`First, Petitioners’ Ground 1 relies entirely on references that were either
`
`considered or are substantially the same as those considered in the original
`
`prosecution, supplemental examination, and/or ex parte reexamination of the ’532
`
`patent. Petitioners fail to describe how these references are being considered in a
`
`
`
`- 3 -
`
`

`

`Case IPR2018-00079
`
`U.S. Patent No. 6,346,532
`
`new light and fail to provide a compelling reason why this Board should
`
`readjudicate the same prior art as was already presented and considered by the
`
`Examiners.
`
`Second, Petitioners assert in Ground 1 that the more than 100 years of U.S.
`
`jurisprudence admonishing the use of hindsight knowledge in determining
`
`patentability is wrong. See, Diamond Rubber Co. v. Consol. Rubber Tire Co., 220
`
`U.S. 428 (1911). When the invention at issue is a new chemical compound, an
`
`obviousness attack requires establishing both the relevant starting point a POSA
`
`would have chosen (the “Lead Compound”) as well as why it would have been
`
`obvious to make the specific modifications of that starting point required to obtain
`
`the claimed compound. Neither of those essential requirements can be satisfied by
`
`relying on hindsight. Petitioners’ argument that a challenger is allowed simply to
`
`take the claimed invention as its reference point and then scour the prior art to find
`
`the closest prior art structure as the starting point necessarily depends entirely on
`
`hindsight. Because this approach is wrong as a matter of law, and is the essential
`
`basis for all of Petitioners’ Ground 1 arguments, institution based on Ground 1
`
`should be summarily denied.
`
`Third, even if Petitioners were correct that a challenger is permitted to use
`
`hindsight to select and rely on the closest structural prior art compound as the
`
`starting point for an obviousness argument, it would have to be a compound that is
`
`
`
`- 4 -
`
`

`

`Case IPR2018-00079
`
`U.S. Patent No. 6,346,532
`
`actually disclosed in the prior art. All of Petitioners’ arguments are based on the
`
`flawed premise that a compound it labels “mirabegron sulfonamide”1 is, in fact,
`
`found in the prior art. But that is pure fiction. Neither that structure, nor the
`
`“mirabegron sulfonamide” name, exist in the prior art – they are nowhere disclosed
`
`in U.S. Patent No. 5,541,197 (“Merck US197,” Exh. 1008) or in any other cited
`
`prior art reference – but the structure is instead only created by Petitioners cobbling
`
`together selected portions of the Merck US197 patent in a manner that disregards
`
`the teaching of the disclosure itself and the “mirabegron sulfonamide” name is
`
`derived directly from the Patent Owner’s naming of the mirabegron compound
`
`claimed by the ’532 patent. Each portion of this fictionalized “prior art”
`
`compound is selected with hindsight knowledge of what would be required to
`
`arrive at the mirabegron structure. In fact, the express substituent preferences
`
`recited in Merck US197 actually teach away from the creation of Petitioners’
`
`“mirabegron sulfonamide.”
`
`Fourth, to the extent Petitioners attempt in Ground 2 to satisfy their burden
`
`of identifying the lead compound a POSA would have chosen for modification,
`
`they select three remote examples out of more than 200 compounds specifically
`
`disclosed in the Merck US197 patent as their requisite starting point. That
`
`
`1 Because Petitioners concede that mirabegron was not known in the prior art, the
`very selection of that name underscores that the argument is entirely based on
`hindsight.
`
`
`
`- 5 -
`
`

`

`Case IPR2018-00079
`
`U.S. Patent No. 6,346,532
`
`selection is not based on any special significance given to those examples by
`
`Merck or by disclosed pharmacological data, but rather on another use of hindsight
`
`to ferret out the closest examples Petitioners could find to mirabegron. And, even
`
`then, Petitioners can only arrive at mirabegron by postulating a series of
`
`modifications that again are similarly hindsight-driven, rest on incorrect assertions
`
`of bioisosterism, and are contrary to the preferences expressed in the Merck US197
`
`disclosure. Petitioners also cite, but ignore in their analysis, references that
`
`disclose other potential leads, including at least one reference that contains
`
`compounds with activity data, and give no reasoned explanation for why a POSA
`
`would ignore those compounds and instead choose the three remote examples in
`
`Merck US197.
`
`Fifth, Petitioners fail to articulate either the standard for or the basis for any
`
`reasonable expectation of success a POSA would have in making the proposed
`
`modifications.
`
`For at least these reasons, Petitioners have not demonstrated a reasonable
`
`likelihood of showing that any challenged claim is unpatentable. Accordingly,
`
`Patent Owner requests that the Board deny institution of the IPR against the ’532
`
`patent.
`
`II. Background
`The ’532 patent, titled Amide Derivatives or Salts Thereof, is directed to
`
`
`
`- 6 -
`
`

`

`Case IPR2018-00079
`
`U.S. Patent No. 6,346,532
`
`phenethanol amide derivative compounds, compositions thereof, and methods of
`
`using them. (Exh. 1001 at 23-30). The compounds are disclosed as being selective
`
`β3 receptor agonists.2 The ’532 patent specifically claims the compound
`
`mirabegron, the active pharmaceutical ingredient in Astellas’s marketed
`
`pharmaceutical product Myrbetriq®:
`
`
`
`(Exh. 2002 at 1; see, e.g., Exh. 1001 at 30, col. 2 l. 30). While the compounds and
`
`compositions of the ’532 patent are generally disclosed as, at least, anti-obesity,
`
`anti-hyperlipemia, and anti-diabetic agents (see Exh. 1001 at 2, col. 2 ll. 31-41), it
`
`was later discovered that mirabegron exhibited utility for other indications as well.
`
`Mirabegron received FDA marketing approval on June 28, 2012. (Exh.
`
`2002 at 1). It is approved for the treatment of overactive bladder (OAB) with
`
`symptoms of urge urinary incontinence, urgency, and urinary frequency. (Exh.
`
`2001 at 1). Not only is it a first-in-class treatment for OAB, but it is also the only
`
`β3 receptor agonist approved for use for any indication by the FDA. (Exh. 2003 at
`
`1; Exh. 2004 at 3).
`
`2 β3 receptor agonists are also referred to as, for example, β3 adrenoceptor agonists,
`β3 agonists, β3 adrenergic agonists, beta-3 agonists, beta-3 receptor agonists, and/or
`beta-3 adrenergic agonists.
`
`
`
`- 7 -
`
`

`

`
`
`
`Case IPR2018-00079
`U.S. Patent No. 6,346,532
`The ’532 patent issued on February 12, 2002 with 14 original claims. (Exh.
`
`1001 at 1, 23-24). Patent Owner requested supplemental examination of all 14
`
`claims of the ’532 on November 21, 2013. (Exh. 1007 at 1-2, 27). On January 31,
`
`2014 the Patent and Trademark Office (“PTO”) issued a Supplemental
`
`Examination Certificate and ex parte reexamination was ordered for items of
`
`information raising a Substantial New Question of Patentability with respect to
`
`claims 1-5, 7-11, 13 and 14. (Id. at 379-82, 384). Claims 1-5, 7-11, 13 and 14 of
`
`the ’532 patent, under application/control number 96/000,045, underwent ex parte
`
`reexam. (Id. at 384). After all rejections were overcome by Astellas, an Ex Parte
`
`Reexamination Certificate under 35 U.S.C. § 307 was issued on February 24, 2015.
`
`(Id. at 486-87). Claims 1, 3-5, and 11 were found patentable as amended, claims 9,
`
`10, 13 and 14, all dependent on amended claims, were determined patentable, and
`
`new claims 15-17 were determined to be patentable. Claims 2, 7 and 8 were
`
`cancelled and claims 6 and 12 did not undergo reexam. (Id. at 487).
`
`III. Level of Ordinary Skill in the Art
`Patent Owner does not necessarily agree with Petitioners’ assertions
`
`regarding a POSA. (Petition at 11-12). Nonetheless, the analysis and outcome for
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`an institution decision should not be affected by Petitioners’ definition of a POSA.
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`Given the deficiencies in the Petition, institution should be denied under any
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`reasonable definition of a POSA.
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`IV. Law
`A. Burden of Proof
`Petitioners bear the burden of establishing a reasonable likelihood of
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`Case IPR2018-00079
`U.S. Patent No. 6,346,532
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`unpatentability. 35 U.S.C. § 314(a); 37 C.F.R. § 42.108(c); Coalition for
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`Affordable Drugs VII LLC v. Pozen Inc., IPR2015-01344, Paper 22 at 24 (P.T.A.B.
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`Dec. 17, 2015). To meet this burden, Petitioners must specify where each element
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`of the claim is found in the prior art relied upon. 37 C.F.R. § 42.104(b)(4).
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`Further, “rejections on obviousness grounds cannot be sustained by mere
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`conclusory statements; instead, there must be some articulated reasoning with
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`some rational underpinning to support the legal conclusion of obviousness.” KSR
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`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2006) (quoting In re Kahn, 441 F.3d
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`977, 988 (Fed. Cir. 2006)).
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`B.
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`Board’s Discretion Based on Art Already Considered During
`Prosecution
`The institution of an IPR is discretionary. 35 U.S.C. § 314(a). This Board
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`has specific discretion under 35 U.S.C. § 325(d) not to institute an IPR because
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`“the same or substantially the same prior art” were presented to the Office during
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`prosecution. Cultec, Inc. v. Stormtech LLC, IPR2017-00777, Paper No. 7 at 1
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`(P.T.A.B. Aug. 22, 2017) (designated as “Informative” on October 24, 2017); see
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`also Hospira, Inc. v. Genentech, Inc., IPR2017-00739, Paper 16 at 1 (P.T.A.B. July
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`27, 2017) (designated as “Informative” on October 24, 2017).
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`Case IPR2018-00079
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`The decision to institute on art that has already been considered should be
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`balanced with other competing interests including conserving the resources of the
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`Office and granting patent owners quiet and harassment-free enjoyment of their
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`patent rights. See Hospira, Inc., IPR2017-00739, Paper 16 at 18.
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`C. Obviousness
`A patent claim is invalid as obvious under 35 U.S.C. § 103(a) if the
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`“differences between the claimed subject matter and the prior art are such that the
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`subject matter as a whole would have been obvious at the time the invention was
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`made to a person having ordinary skill in the art.” Otsuka Pharm. Co. v. Sandoz,
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`Inc., 678 F.3d 1280, 1290 (Fed. Cir. 2012) (citations omitted). Obviousness claims
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`inspired by hindsight should be rejected. In re Cyclobenzaprine Hydrochloride
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`Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1070-71 (Fed. Cir. 2012).
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`“Evidence of obviousness . . . is insufficient unless it indicates that the possible
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`options skilled artisans would have encountered were ‘finite,’ ‘small,’ or ‘easily
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`traversed,’ and that skilled artisans would have had a reason to select the route that
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`produced the claimed invention.” Id. at 1072 (citations omitted).
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`In the case of a new chemical compound, a two part inquiry is ordinarily
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`used to evaluate obviousness over the prior art. First, “the court determines
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`whether a chemist of ordinary skill would have selected the asserted prior art
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`compounds as lead compounds, or starting points, for further development efforts”
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`U.S. Patent No. 6,346,532
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`and second, the court analyzes “whether the prior art would have supplied one of
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`ordinary skill in the art with a reason or motivation to modify a lead compound to
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`make the claimed compound with a reasonable expectation of success.” Otsuka,
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`678 F.3d at 1291, 1292 (citations omitted); Incyte Corp. v. Concert Pharms., Inc.,
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`IPR2017-01256, Paper 9 at 14, 17 (P.T.A.B. Oct. 19, 2017) (denying institution in
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`part because the Petitioner “[had] not made a sufficient showing that a person of
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`ordinary skill in the art would have chosen ruxolitinib as a lead compound or that
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`there was reason to [modify] ruxolitinib”). This analysis is often referred to as a
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`“Lead Compound Analysis” or “LCA.”
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`The LCA starts with a reasoned identification of a lead compound. Eisai
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`Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008). A lead
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`compound is “a compound in the prior art that would be most promising to modify
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`in order to improve upon its . . . activity and obtain a compound with better
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`activity.” Takeda Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357
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`(Fed. Cir. 2007). It is often thought of as “a natural choice for further development
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`efforts.” Otsuka, 678 F.3d at 1291 (citations omitted).
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`Selection of a lead compound “is guided by evidence of the compound’s
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`pertinent properties” which may include activity, potency, adverse effects, and
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`“other relevant characteristics in evidence.” Id. at 1292 (citations omitted).
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`Absent such evidence, “mere structural similarity between a prior art compound
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`and the claimed compound” is not enough to establish a motivation to select a
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`compound as a lead. Id. (citing Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d
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`1346, 1354 (Fed. Cir. 2010) and In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990)
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`(en banc)). The LCA is a direct and ineluctable application of the longstanding
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`principle that obviousness cannot be based on hindsight and ex post reasoning.
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`See, Diamond Rubber Co., 220 U.S. at 434-35; Otsuka, 678 F.3d at 1292; Daiichi,
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`619 F.3d, at 1354 (“[T]he attribution of a compound as a lead compound after the
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`fact must avoid hindsight bias; it must look at the state of the art at the time the
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`invention was made to find a motivation to select and then modify a lead
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`compound to arrive at the claimed invention.”); see also Mylan Labs. Ltd. v.
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`Aventis Pharma S.A., IPR2016-00627, Paper 12 at 3-6 (P.T.A.B. Jan. 26, 2017).
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`The second part of the inquiry, assessing the reason or motivation to modify
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`a lead compound, requires “a showing that the prior art would have suggested
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`making the specific molecular modifications necessary to achieve the claimed
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`invention” with a reasonable expectation of success. Takeda, 492 F.3d at 1356,
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`1357, 1361 (citations and internal quotation marks omitted). In assessing the
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`motivation to modify, disclosures within the art may teach away from modifying
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`certain areas of the molecule or substituents, especially where the component being
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`modified is seen as important or essential to the advantageous properties of the
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`molecule. See, e.g., Eisai, 533 F.3d at 1358, 1359 (“The record, however, shows
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`U.S. Patent No. 6,346,532
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`no discernible reason for a skilled artisan to begin with lansoprazole only to drop
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`the very feature, the fluorinated substituent, that gave this advantageous
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`property.”); Daiichi, 619 F.3d at 1356 (“[A] person of ordinary skill in the art
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`would not select the ’902 patent compounds as leads only to disregard one of their
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`distinguishing characteristics, specifically their increased lipophilicity at the 4-
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`position.” (citations and internal quotation marks omitted)).
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`In this second part of the inquiry, there must also be support showing that
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`there would be a reasonable expectation of success in arriving at the claimed
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`invention. In other words, one skilled in the art must be motivated to modify th