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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`__________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`__________________________________
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`FUSTIBAL LLC
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`Petitioner
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`v.
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`BAYER HEALTHCARE LLC
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`Patent Owner of
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`U.S. Patent 8,637,553 to Boyer et al.
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`Appl. No. 10/895,985 filed Jul. 22, 2004
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`Issued Jan. 28, 2014
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`________________________________
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`IPR Trial No. Unassigned
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`_______________________________________
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,637,553
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`UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, et seq.
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`TABLE OF CONTENTS
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`I. MANDATORY NOTICES ............................................................................. 1
`
`A.
`
`Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .................................... 1
`
`B.
`
`C.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)) .............................................. 1
`
`Identification of Counsel (37 C.F.R. § 42.8(b)(3)) ............................... 2
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`D.
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`Service Information (37 C.F.R. § 42.8(b)(4)) ....................................... 2
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`II. GROUNDS FOR STANDING AND PROCEDURAL STATEMENT ......... 2
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`III.
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`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
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`PRECISE RELIEF REQUESTED .................................................................. 3
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`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............... 3
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`V.
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............... 4
`
`A.
`
`Summary of the Argument .................................................................... 4
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`B.
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`C.
`
`Level of Ordinary Skill in the Art ......................................................... 6
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`Claim Construction................................................................................ 6
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`D.
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`Printed Publications Relied On ............................................................. 7
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`1.
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`2.
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`3.
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`4.
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`Riedl (Ex. 1002) .......................................................................... 8
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`Park (Ex. 1004) .........................................................................10
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`Aherne (Ex. 1005) .....................................................................12
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`Additional Prior Art Confirming the General Knowledge of a
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`Person of Ordinary Skill in the Art ...........................................12
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`E.
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`Ground 1: Claims 1-16 Are Anticipated by Riedl. .............................13
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`1.
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`2.
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`3.
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`4.
`
`5.
`
`Claim 13 Is Anticipated by Riedl .............................................13
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`Claim 1 Is also Anticipated by Riedl ........................................17
`
`Claims 2-5 and 15 Are also Anticipated by Riedl ....................17
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`Claims 6-9, 14, and 16 Are also Anticipated by Riedl .............17
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`Claims 10, 11, and 12 Are Anticipated by Riedl ......................18
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`F.
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`Ground 2: Claims 1-16 Are Unpatentable as Obvious over Riedl ......19
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`1.
`
`2.
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`3.
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`4.
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`5.
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`Claim 13 Is Obvious over Riedl................................................19
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`Claim 1 Is also Obvious over Riedl ..........................................22
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`Claims 2-5 and 15 Are also Obvious over Riedl ......................22
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`Claims 6-9, 14, and 16 Are also Obvious over Riedl ...............23
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`Claims 10, 11, and 12 Are Obvious over Riedl ........................23
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`G. Ground 3: Claims 1-16 Are Unpatentable as Obvious over Aherne,
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`Park, and Riedl ....................................................................................24
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`1.
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`2.
`
`3.
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`Claim 13 Is Obvious over Aherne, Park, and Riedl .................25
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`Claim 1 Is also Obvious over Aherne, Park, and Riedl ............34
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`Claims 2-5 and 15 Are also Obvious over Aherne, Park, and
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`Riedl ..........................................................................................34
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`4.
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`Claims 6-9, 14, and 16 Are also Obvious over Aherne, Park,
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`and Riedl ...................................................................................35
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`5.
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`Claims 10, 11, and 12 Are Obvious over Aherne, Park, and
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`Riedl ..........................................................................................35
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`H. Ground 4: Claims 1-16 Are Unpatentable as Obvious over Riedl and
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`Park ......................................................................................................37
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`1.
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`2.
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`3.
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`4.
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`5.
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`Claim 13 Is Obvious over Riedl and Park ................................37
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`Claim 1 Is also Obvious over Riedl and Park ...........................44
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`Claims 2-5 and 15 Are also Obvious over Riedl and Park .......44
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`Claims 6-9, 14, and 16 Are also Obvious over Riedl and Park 45
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`Claims 10, 11, and 12 Are Obvious over Riedl and Park .........45
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`I.
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`Ground 5: Claims 1-16 Are Unpatentable as Obvious over Aherne and
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`Park ......................................................................................................46
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`1.
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`1.
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`2.
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`3.
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`Claim 13 Is Obvious over Aherne and Park .............................47
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`Claim 1 Is also Obvious over Aherne and Park ........................55
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`Claims 2-5 and 15 Are also Obvious over Aherne and Park ....55
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`Claims 6-9, 14, and 16 Are also Obvious over Aherne and Park
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` ...................................................................................................56
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`4.
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`Claims 10, 11, and 12 Are Obvious over Aherne and Park ....566
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`VI. TABLE OF ADDITIONAL PRIOR ART ....................................................58
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`VII. CONCLUSION ..............................................................................................59
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`LIST OF EXHIBITS
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`Exhibit No.
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`Description
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`1001
`
`Boyer et al., U.S. Patent No. 8,637,553, titled “Fluoro
`
`Substituted Omega-Carboxyaryl Diphenyl Urea for the
`
`Treatment and Prevention of Diseases and Conditions,” issued
`
`Jan. 28, 2014.
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`1002
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`Riedl et al., WO 00/42012, titled “ω-Carboxyaryl Substituted
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`Diphenyl Ureas as RAF Kinase Inhibitors,” published July 20,
`
`2000.
`
`1003
`
`Answer in Onyx Pharmaceuticals, Inc. v. Bayer Corp. et al.,
`
`No. CV-09 2145 MHP, (N.D.C.A. filed Aug. 12, 2009).
`
`1004
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`Park et al., titled “Metabolism of fluorine-containing drugs,”
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`41 Annu. Rev. Pharmacol. Toxicol., 2001, p. 443-470.
`
`1005
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`Aherne et al., titled “Finding the Needle in the Haystack: Why
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`High-throughput Screening Is Good for your Health”, 4 Breast
`
`Cancer Research 4, (June 10, 2002).
`
`1006
`
`Wakefield (Dr. Basil Wakefield), titled “Fluorinated
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`Pharmaceuticals”, Innovations in Pharm. Tech (Jan. 2000).
`
`1007
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`Seebach, Dieter, titled “Organic Synthesis – Where now?”,
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`Angew. Chem. Int. Ed. Engl. 29 (1990), p. 1320-1367.
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`1008
`
`Declaration of Brian Shoichet, Ph.D.
`
`1009
`
`Dr. Brian Shoichet’s curriculum vitae
`
`1010
`
`Regan et al., titled “Pyrazole Urea-Based Inhibitors of p38
`
`MAP Kinase: From Lead Compound to Clinical Candidate”,
`
`45 J. of Medicinal Chemistry 14 (May 25, 2002), p. 2994-
`
`3008.
`
`1011
`
`Suganuma et al., titled “Mechanisms of Cancer Prevention by
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`Tea Polyphenols Based on Inhibition of TNF-α Expression”,
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`BioFactors 13 (2000), p. 67–72.
`
`1012
`
`First Amended Complaint in Onyx Pharmaceuticals, Inc. v.
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`Bayer Corp. et al., No. CV-09 2145 MHP, (N.D.C.A. filed
`
`June 15, 2009).
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`Pursuant to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Fustibal LLC
`
`(“Petitioner”) petitions for Inter Partes Review (“Petition”) of Claims 1 through 16
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`of U.S. Patent No. 8,637,553 to Boyer et al., titled “Fluoro Substituted Omega-
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`Carboxyaryl Diphenyl Urea for the Treatment and Prevention of Diseases and
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`Conditions” (“the ’553 patent,” Ex. 1001). Concurrently filed herewith is a Power
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`of Attorney pursuant to 37 C.F.R. § 42.10(b). Pursuant to 37 C.F.R. § 42.103,
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`Petitioner authorizes the PTO to charge Deposit Account 05-1323 for the fee set
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`forth in 37 C.F.R. § 42.15(a) and authorizes any additional fees to be charged to
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`the same account.
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`I. MANDATORY NOTICES
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`A. Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
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`Fustibal LLC (“Fustibal”) is the real party-in-interest for Petitioner.
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`B. Related Matters (37 C.F.R. § 42.8(b)(2))
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`Petitioner is not aware of any reexamination certificates or pending
`
`prosecution concerning the ’553 patent. Petitioner is not a party to, or aware of,
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`any prior or pending litigation regarding infringement or invalidity of the ’553
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`patent. However, one case discusses Bayer’s conduct (breach of contract; breach
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`of the implied covenant of good faith and fair dealing; breach of fiduciary duty;
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`and declaratory relief) in the development of regorafenib (the claimed compound
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`of the ʼ553 patent) to avoid payments to a collaborator. That case is Onyx Pharms.
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`Inc. v. Bayer Corp., Case No. C 09-2145 (EMC) (N.D. Cal. Oct 17, 2011) in the
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`United States District Court Northern District of California, San Francisco
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`Division.
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`C.
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`Identification of Counsel (37 C.F.R. § 42.8(b)(3))
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`Lead Counsel
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`Back-up Counsel
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`Jonathan Lindsay
`Anne Elise Herold Li
`(Reg. No. 45,810)
`(Reg. No. 58,131)
`Crowell & Moring LLP
`Crowell & Moring LLP
`590 Madison Avenue, 20th Fl. 3 Park Plaza, 20th Fl.
`New York, NY 10022
`Irvine, CA 92614-8505
`ali@crowell.com
`jlindsay@crowell.com
`Tel: 212-895-4279
`Tel: 949-798-1325
`Fax: 212-223-4134
`Fax: 949-263-8414
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`D.
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`Service Information (37 C.F.R. § 42.8(b)(4))
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`Please direct all correspondence to lead counsel and back-up counsel at the
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`contact information above. Petitioner consents to service by electronic mail at
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`ali@crowell.com and jlindsay@crowell.com.
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`II. GROUNDS FOR STANDING AND PROCEDURAL STATEMENT
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`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’553 patent
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`is available for IPR and that the Petitioner is not barred or estopped from
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`requesting IPR on the grounds identified herein.
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`III.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
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`Petitioner requests inter partes review and cancellation of claims 1 through
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`16 of the ’553 patent on one or more of the grounds under 35 U.S.C. §§ 102 and
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`103 set forth herein. The ’553 patent is to be reviewed under pre-AIA 35 U.S.C.
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`§§ 102 and 103.
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`Petitioner’s detailed statement of the reasons for the relief requested is set
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`forth below in the section titled “Statement of Reasons for Relief Requested.” In
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`accordance with 37 C.F.R. § 42.6(c), copies of the exhibits are filed herewith. In
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`addition, this Petition is accompanied by the Declaration of Brian Shoichet, Ph.D.,
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`Ex. 1008.
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`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
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`A petition for inter partes review must demonstrate “a reasonable likelihood
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`that the petitioner would prevail with respect to at least one of the claims
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`challenged in the petition.” 35 U.S.C. § 314(a). This Petition meets this threshold.
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`As explained below, for each of the grounds of unpatentability proposed, there is a
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`reasonable likelihood that Petitioner will prevail with respect to at least one of the
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`challenged claims.
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`V.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`STATEMENT OF REASONS FOR THE RELIEF REQUESTED
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`The challenged claims of the ’553 patent are generally directed to
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`pharmaceutical compounds to treat diseases mediated by raf, VEGFR, PDGFR,
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`p38 and flt-3, and, in particular, to regorafenib (the claimed compound) and
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`compositions containing regorafenib. Claims 1-16 of the ’553 patent are
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`unpatentable based on the following grounds:
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`Ground 1: Claims 1-16 are Anticipated by Riedl;
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`Ground 2: Claims 1-16 are Unpatentable as Obvious Over Riedl;
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`Ground 3: Claims 1-16 are Unpatentable as Obvious Over Aherne, Park,
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`and Riedl;
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`Ground 4: Claims 1-16 are Unpatentable as Obvious Over Riedl and Park;
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`Ground 5: Claims 1-16 are Unpatentable as Obvious Over Aherne and
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`Park.
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`A.
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`Summary of the Argument
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`The structure of the claimed compound, regorafenib, is identical to that of its
`
`predecessor compound sorafenib (BAY 43-9006) but for the substitution of a
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`single fluorine atom. See Figures 1(a) and 1(b) below.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`Figure 1(a). Claimed Compound, Regorafenib (Claim 1 of the ’553 patent)
`
`
`
`CH3
`
`N H
`
`O
`
`N
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`CF3
`
`O
`
`O
`
`N
`
`H
`
`N
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`H
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`F
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`Cl
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`
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`Figure 1(b). Predecessor Compound, Sorafenib (BAY 43-9006)
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`Petitioner submits that claims of the ’553 patent are invalid as anticipated by
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`prior art that discloses regorafenib that reads on independent claims 1, 5, 9, 10, 11,
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`12 and 13.
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`Petitioner further submits that the subject matter of all of the claims of
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`the ’553 patent would have been arrived at by following the teachings and
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`suggestions of the prior art which would have motivated a person ordinarily skilled
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`in the art to develop regorafenib by choosing sorafenib as a starting compound and
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`increasing functionality of that compound by substituting a single fluorine atom in
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`place of a single hydrogen atom at the claimed fluorine position on the central
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`benzene ring. In the present case, a person of ordinary skill in the art would have
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`had more than a reasonable expectation that such a substitution would have
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`improved the safety and efficacy of the drug.
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`B.
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`Level of Ordinary Skill in the Art
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`A person of ordinary skill in the art (abbreviated as “POSA”) is presumed to
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`be aware of pertinent art, thinks along conventional wisdom in the art, and is a
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`person of ordinary creativity. With respect to the ’553 patent, a POSA would have
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`had knowledge of the scientific literature concerning pharmaceutical compositions.
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`A POSA typically would have a PhD, MD, MS, or another degree relating to
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`pharmaceutical chemistry (e.g. biology, chemistry, medicinal chemistry, medicine,
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`pharmacology, or a closely related discipline), and such a POSA would have
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`substantial familiarity, training, or experience with pharmaceutical compositions.
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`C. Claim Construction
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`In accordance with 37 C.F.R. § 42.100(b), each of the claims is presumed to
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`take on its ordinary and customary meaning based on the broadest reasonable
`
`interpretation of the claim language. Petitioner does not believe that the Applicant
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`attributed any special meanings to the claim terms in the ’553 patent when the
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`broadest reasonable interpretation standard is applied, except for the following
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`terms:
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`• “pharmaceutically acceptable salt” appearing in claims 1-4, 9 and 10,
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`has been defined as “a relatively non-toxic, inorganic or organic acid
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`addition salt of a compound of the present invention.” (See Ex. 1001,
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`col. 9, ll. 56-62).
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`• “physiologically acceptable carrier” appears in claims 6-9, 14 and 16,
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`and at page 10 of the specification. However, the specification only
`
`defines the term “pharmaceutically acceptable carrier” (Ex. 1001, col.
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`20, ll. 46-51). Therefore, the term “physiologically acceptable
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`carrier” has been interpreted as its ordinary and customary meaning
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`(i.e. a carrier that is relatively non-toxic for human
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`ingestion/administration).
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`Petitioner’s position regarding the scope of the claims should not be taken as
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`an assertion regarding the appropriate claim scope in other adjudicative forums
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`where a different claim interpretation standard may apply.
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`D.
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`Printed Publications Relied On
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`Petitioner relies on the following patents and publications:
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`1.
`
`Riedl (Ex. 1002)
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`WO 00/42012, titled “ω-Carboxyaryl Substituted Diphenyl Ureas as RAF
`
`Kinase Inhibitors” (“Riedl,” Ex. 1002) published on July 20, 2000. Riedl is prior
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`art to the ’553 patent under 35 U.S.C. § 102(b). Riedl discloses a family of
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`compounds for treating RAF mediated diseases, such as cancer, including the
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`sorafenib compound. See Figure 2 (below), the structure of sorafenib.
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`
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`Ex. 1002 at p. 42 (numbers added on the central benzene ring for clarity of
`
`discussion).
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`Riedl also teaches single modifications of the sorafenib compound on the
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`middle ring. See Figure 3 (below).
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`Ex. 1002 at p. 43 (numbers added for clarity on the central benzene ring). In this
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`example, a methyl group was substituted at position 3. In another example, a
`
`chlorine is substituted on sorafenib middle ring at position 3’. Ex. 1002 at p. 63,
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`line 5 (entry 49); see also p. 80-81, Table 4 (entry 49). It is noted that a chlorine
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`substitution at position 3’ on sorafenib middle ring makes the same compound as a
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`chlorine substitution at position 3 on sorafenib middle ring. See also Ex. 1008 at
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`¶51-54. Riedl also discloses an example with a chlorine substituted at position 2’.
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`Ex. 1002 at p. 63, lines 22-26 (entry 52); see also p. 80-82, Table 4 (entry 52). It is
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`noted that a chlorine substitution at position 2’ on sorafenib middle ring makes the
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`same compound as a chlorine substitution at position 2 on sorafenib middle ring.
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`See also Ex. 1008 at ¶51-54.
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`Riedl further discloses that halogens are good candidates to be substituted.
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`Ex. 1002, at p. 4. “Suitable halogen groups include F, Cl, Br, and/or I, from one to
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`per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being
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`possible where an alkyl group is substituted by a halogen, mixed substitution of
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`halogen atom types also being possible on a given moiety.” Ex. 1002, p. 6, lines 5-
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`8.
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`Critically, the assignee of the ’553 patent admits that Riedl broadly discloses
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`sorafenib with a fluorine substitution at position 3 (which is regorafenib, the
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`claimed compound in the ’553 patent). Ex. 1003, p. 15, lines 13-241. This
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`admission was made in the Onyx case (discussed supra in Section I.B.). The
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`complaint in that case alleged that Riedl disclosed “sorafenib and its halogenated
`
`brethren.” Ex. 1012 (Complaint). In response to that assertion, the patent
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`assignee “further admit[s] that certain generic claims of [Riedl] could be read to
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`cover a variety of compound structures including the structure of sorafenib and
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`regorafenib.” Ex. 1003, Answer, p. 15, lines 22-24. Despite this admission, the
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`patent assignee denied that “the regorafenib molecule was disclosed in [Riedl].” Id.
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`at p. 15, lines 26-27.
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`2.
`
`Park (Ex. 1004)
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`“Metabolism of Fluorine-Containing Drugs,” by Park et al. (“Park,” Ex.
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`1004) was published in the Annual Review of Pharmacology and Toxicology in
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`2001. Park is prior art to the ’553 patent under 35 U.S.C. § 102(b).
`
`
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`1 In Exhibit 1003, the German Bayer Entities are referring to the January 13, 1999
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`patent application and the issued patent U.S. Pat. No. 7,351,834 of Riedl et al. It is
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`noted that Exhibit 1002 (WO 00/42012 to “Riedl”) cited in Ground 1 is the PCT
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`application that U.S. Pat. No. 7,351,834 claims priority to, where the disclosure
`
`and claims are substantially the same.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`Park discloses that fluorine substitution on a drug molecule “can be used
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`constructively by medicinal chemists to improve both the safety and the efficacy of
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`the drug.” Ex. 1004 at 443. Park also discloses a flow diagram to illustrate the
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`benefits of substituting a fluorine (relating to physicochemical properties,
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`pharmacokinetic properties, pharmacological consequences), which is reproduced
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`below. Ex. 1004 at 444. Park also discloses that fluorine substitution “can be used
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`to alter the rate of drug metabolism and thereby produce a drug with a longer
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`duration of action. Such an approach has already been used successfully for several
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`classes of drugs”. Id at 464.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`3.
`
`Aherne (Ex. 1005)
`
`“Finding the Needle in the Haystack: Why High-throughput Screening Is
`
`Good for your Health,” by Aherne et al. (“Aherne,” Ex. 1005) was published in
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`Breast Cancer Research on June 10, 2002. Aherne is prior art to the ’553 patent
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`under 35 U.S.C. § 102(b).
`
`Aherne discloses a high throughput screening method for compounds used
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`in treatment of cancers. Ex. 1005 at 148, 150-51. In particular, Aherne discloses
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`using a high-throughput screening method in combination with the Lipinski Rule
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`of 5 (features of most successful drugs) when assessing drug candidates. Id. at 151.
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`Aherne further discloses several compounds that have been successfully tested this
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`way, including the sorafenib compound (referred to as BAY 43-9006). Id. at 152.
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`Aherne discloses that it is desirable to optimize drug candidates. Ex. 1005 at 149-
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`151.
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`4.
`
`Additional Prior Art Confirming the General Knowledge of
`a Person of Ordinary Skill in the Art
`
`In addition to the prior art discussed above, Dr. Shoichet addresses
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`additional prior art confirming the general knowledge of a person of ordinary skill
`
`in July 2003. See infra at Section VI for a table summarizing the disclosure of
`
`these additional printed publications. A person of ordinary skill in the art would
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`have understood that the addition of a fluorine atom to a pharmaceutical active to
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`improve its pharmacological properties was common in the field. See, e.g., Ex.
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`1006 (Wakefield) (“According to a recent book, by 1990 around 220 fluorinated
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`drugs were on the market, representing 8 percent of launched synthetic drugs, and
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`at the time of its publication around 1,500 were under development . ..”); Ex. 1007
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`(Seebach); Ex. 1008 (Shoichet Dec) at ¶30-33. Additionally, a person of ordinary
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`skill in the art would have also understood that introduction of a fluorine improves
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`pharmacological properties such as increasing stability and lipophilicity. Ex. 1006
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`(Wakefield) at 74. Ex. 1008 (Shoichet Dec) at ¶30 and 73.
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`E. Ground 1: Claims 1-16 Are Anticipated by Riedl.
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`1.
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`Claim 13 Is Anticipated by Riedl
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`Claim 13 of the ’553 patent recites the chemical compound regorafenib.
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`Riedl discloses sorafenib. It also discloses three different examples of
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`sorafenib with a single substitution on the middle benzene ring. For example,
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`Riedl discloses methylated sorafenib (which is regorafenib with a methyl group
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`instead of a fluorine), where a methyl group is substituted on sorafenib middle ring
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`at position 3.
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`
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`Ex. 1002 at p. 43 (numbers added for clarity on the central benzene ring). In this
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`example, a methyl group was substituted at position 3. In another example, a
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`chlorine is substituted on sorafenib middle ring at position 3’. Ex. 1002 at p. 63,
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`line 5 (entry 49); see also p. 80-81, Table 4 (entry 49). It is noted that a chlorine
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`substitution at position 3’ on the sorafenib middle ring makes the same compound
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`as a chlorine substitution at position 3 on the sorafenib middle ring. See also Ex.
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`1008 at ¶51-54. Riedl also discloses an example with a chlorine substituted at
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`position 2’. Ex. 1002 at p. 63, line 5 (entry 52); see also p. 80-82, Table 4 (entry
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`52). It is noted that a chlorine substitution at position 2’ on the sorafenib middle
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`ring makes the same compound as a chlorine substitution at position 2 on the
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`sorafenib middle ring. See also Ex. 1008 at ¶51-54.
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`Riedl further discloses that halogens are good candidates to be substituted.
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`Ex. 1002, at p. 4. “Suitable halogen groups include F, Cl, Br, and/or I, from one to
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`per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being
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`possible where an alkyl group is substituted by a halogen, mixed substitution of
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`halogen atom types also being possible on a given moiety.” Ex. 1002 at p. 6, lines
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`5-8.
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`The Federal Circuit has held that the question of anticipation depends on
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`whether the claimed combination would be immediately apparent from the prior art
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`disclosure to one of skill in the art. Abbvie Inc. v. Mathilda & Terence Kennedy
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`Inst. of Rheumatology Trust, 764 F.3d 1366, 1379 (Fed. Cir. 2014). In some cases,
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`patents only broadly disclose a genus. See Atofina v. Great Lakes Chem. Corp.,
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`441 F.3d 991, 999 (Fed. Cir. 2006) (“It is well established that the disclosure of a
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`genus in the prior art is not necessarily a disclosure of every species that is a
`
`member of that genus.”). However, when the genus disclosed is small, it will
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`anticipate the species, as a person of ordinary skill in the art can “at once envisage
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`each member of this limited class” when the class of compounds that falls within
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`the genus is so limited. .In re Gleave, 560 F.3d 1331, 1337-38 (Fed. Cir. 2009)
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`(internal citations omitted); In re Petering, 301 F.2d 676 (C.C.P.A. 1962). Further,
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`the “anticipation analysis asks solely whether the prior art reference discloses and
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`enables the claimed invention, and not how the prior art characterizes that
`
`disclosure or whether alternatives are also disclosed.” Perricone, M.D., v. Medicis
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`Pharmaceutical Corp., 432 F.3d 1368, 1376 (Fed. Cir. 2005) (holding that a
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`specific disclosure of a component that was listed as one of fourteen alternatives in
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`the prior art was not merely part of a disclosed genus).
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`In this case, Riedl discloses the structure of sorafenib. Riedl also discloses a
`
`single halogen substitution at positions 3 or 3’ and 2 or 2’ (with examples of a
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`chlorine substitution at either of these positions in sorafenib). As discussed above,
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`a single substitution at position 3 in sorafenib makes the same compound as a
`
`single substitution of the same substituent at position 3’ in sorafenib. Also, a
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`single substitution at position 2 in sorafenib makes the same compound as a single
`
`substitution of the same substituent at position 2’ in sorafenib. Thus, there are two
`
`possible distinct positions (positions 3/ 3’ and 2/ 2’) 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 are disclosed and would
`
`be readily apparent to one of skill in the art who was looking to modify sorafenib.
`
`See also Ex. 1008, ¶49-54. Therefore, Riedl expressly discloses the regorafenib
`
`compound, rendering claim 13 anticipated.
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`2.
`
`Claim 1 Is also Anticipated by Riedl
`
`Because Claim 1 encompasses Claim 13, it is also anticipated by Riedl.
`
`3.
`
`Claims 2-5 and 15 Are also Anticipated by Riedl
`
`Claims 2-5 and 15 are also anticipated by Riedl. These claims are directed to
`
`pharmaceutically acceptable salts of regorafenib, among others. Riedl discloses
`
`that the “present invention is also directed to pharmaceutically acceptable salts of
`
`formula I.” Ex. 1002, p. 6, line 11. Because these claims encompass regorafenib
`
`plus pharmaceutically acceptable salts, they are anticipated by Riedl.
`
`4.
`
`Claims 6-9, 14, and 16 Are also Anticipated by Riedl
`
`Claims 6-9, 14, and 16 are also anticipated by Riedl. These claims are
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`directed to physiologically acceptable carriers of regorafenib, among others. Riedl
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`discloses the use of a pharmaceutical composition of regorafenib and a
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`physiologically acceptable carrier. Ex. 1002, p. 108. Furthermore, Riedl
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`specifically teaches that the carrier is “non-toxic” (Ex. 1002, p. 10, lines 10-14),
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`and that it is intended for human ingestion or administration (Ex. 1002, p. 2, lines
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`10-13 and 22-28; p. 10, lines 10-13). Because these claims encompass regorafenib
`
`plus physiologically acceptable carriers, they are anticipated by Riedl.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`5.
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`Claims 10, 11, and 12 Are Anticipated by Riedl
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`Claims 10-12 of the ‘553 patent all recite substantially similar elements
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`directed to a compound which is a metabolite of the compound of Formula (I).
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`A compound which is a metabolite of a compound of Formula (I) is a
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`derivative of a compound of Formula (I). Claim 10 specifies the substitution sites
`
`as any nitrogen atom of Formula (I) for modification to form such derivative
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`compounds: “the two urea nitrogen atoms, or the pyridine nitrogen atom, or the
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`methylamide functionality, or any combination of the above.” For those specified
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`substitution sites, claim 11 lists possible chemical substitutions (a-g). Claim 12
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`lists three derivative compounds of the compound of Formula (I): the first
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`compound is a compound of Formula (I) where “the amide functionality is de-
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`methylated” (11c); the second compound is a compound of Formula (I) where “the
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`pyridine nitrogen atom is oxidized” (11b); and the third compound is a compound
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`of Formula (I) where “the pyridine nitrogen atom is oxidized and the amide
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`functionality is de-methylated” (11d).
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`Claims 10, 11, and 12 are directed to metabolites that include regorafenib
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`that has been de-methylated. Riedl discloses regorafenib as discussed above with
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`respect to claims 1, 3, and 13. Riedl also discloses that the methyl amide (NH-
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`CH3) functionality attached to the “L1” ring of Formula (I) can be replaced by a
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`substituent such as an NH2 group. Ex. 1002 at p. 3, lines 9-10 and 18-19. Thus,
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`Riedl also discloses regorafenib that has been de-methylated. In addition, Riedl
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`discloses sorafenib that has been de-methylated in entry 43 of Table 4 in Riedl.
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`Ex. 1002 at p. 62 and 80-81. Therefore, claims 10, 11, and 12 are anticipated by
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`Riedl.
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`F. Ground 2: Claims 1-16 Are Unpatentable as Obvious over Riedl
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`Petitioner submits that Claims 1-16 are unpatentable as anticipated over
`
`Riedl. If, for the sake of argument, the Board finds that Riedl fails to anticipate
`
`Claims 1-16 of the ’553 Patent, then such claims would have been obvious over
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`Riedl for the reasons set forth below.
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`
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`For a single reference to be obvious in the chemical field, there must
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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.”
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`Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301 (Fed. Cir.
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`2007) (quoting Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d
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`1350, 1356 (Fed. Cir.2007)).
`
`1.
`
`Claim 13 Is Obvious over Riedl
`
`Claim 13 of the ’553 patent recites the chemical compound regorafenib.
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`Petition for Inter Partes Review of U.S. Patent No. 8,637,553
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`
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`Riedl discloses sorafenib. Riedl also discloses three different examples of
`
`sorafenib with a single substitution on the middle benzene ring. For example,
`
`Riedl discloses methylated sorafenib (which is regorafenib with a methyl group
`
`instead of a fluorine), where a methyl group is substituted on sorafenib middle ring
`
`at position 3.
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`
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`In another example, a chlorine is substituted on sorafenib at position 3’. Ex. 1002
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`at p. 63, line 5 (entry 49); see also p. 80-81, Table 4 (entry 49). A chlorine
`
`substitution at position 3’ on the sorafenib middle ring makes the same compound
`
`as a chlorine substitution at position 3 on sorafenib middle ring. See also Ex. 1008
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`at ¶61. Riedl also discloses an example with chlorine substituted
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