`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`COHERUS BIOSCIENCES, INC.,
`Petitioner
`
`v.
`
`HOFFMANN-LAROCHE INC.,
`Patent Owner.
`_______________
`
`Patent No. 8,063,182
`_______________
`
`
`PETITION
`to Institute an Inter Partes Review of U.S. Patent No. 8,063,182
`under 37 C.F.R. § 42.100 et seq.
`
`
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313–1450
`Submitted Electronically via the PTAB E2E
`
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES ................................................................................... vi 
`
`EXHIBIT LIST ...................................................................................................... viii 
`
`I. 
`
`INTRODUCTION ........................................................................................... 1 
`
`II.  MANDATORY NOTICES ............................................................................. 7 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Real Party-in-Interest (37 C.F.R. § 42.8 (b)(1)) .................................... 7 
`
`Related Matters (37 C.F.R. § 42.8 (b)(2)) ............................................. 7 
`
`Lead and Back-up Counsel (37 C.F.R. § 42.8 (b)(3)) ........................... 8 
`
`Service Information (37 C.F.R. § 42.8 (b)(4)) ...................................... 8 
`
`III. 
`
`PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................... 8 
`
`IV.  REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ............................ 9 
`
`A.  Grounds for Standing Under 37 C.F.R. § 42.104(a) ............................. 9 
`
`B. 
`
`Challenge Under 37 C.F.R. § 42.104(b); Relief Requested .................. 9 
`
`V. 
`
`THE ’182 PATENT ......................................................................................... 9 
`
`A. 
`
`B. 
`
`C. 
`
`The ’182 Patent Only Generically Encompasses Fusion
`Proteins Comprising the 75-kDa TNFR, and Does Not
`Specifically Disclose Etanercept ........................................................... 9 
`
`The Claims of the ’182 Patent Cover a Genus of Fusion
`Proteins Comprising Soluble Fragments of the 75-kDa TNFR
`and the hinge-CH2-CH3 Region of Human IgG ................................ 11 
`
`The Priority Date of the ’182 Patent Is No Earlier Than
`August 31, 1990. ................................................................................. 13 
`
`D. 
`
`The Prosecution History of the ’182 Patent ........................................ 14 
`
`ii
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`1. 
`
`2. 
`
`The Board Found the ’182 Patent Nonobvious Based
`Solely on Alleged Evidence of Unexpected Results,
`Which the Examiner Did Not Substantively Address .............. 15 
`
`CFAD’s Prior Petition for IPR Challenging the ’522
`Patent Relied on Different Prior Art than Coherus’
`Petition, and Failed to Substantively Address
`Unexpected Results ................................................................... 16 
`
`VI.  LEVEL OF SKILL IN THE ART ................................................................. 19 
`
`VII.  CLAIM CONSTRUCTION UNDER 37 C.F.R. 42.104(B)(3) ..................... 19 
`
`VIII.  PATENTS AND PRINTED PUBLICATIONS RELIED ON IN
`THIS PETITION ........................................................................................... 20 
`
`A.  U.S. Patent No. 5,395,760 (“Smith”) – May 10, 1990 ........................ 21 
`
`B.  Watson et al., “A Homing Receptor-IgG Chimera as a Probe
`for Adhesive Ligands of Lymph Node High Endothelial
`Venules” (“Watson”) – June 1990 ...................................................... 22 
`
`C. 
`
`Zettlmeissl et al., “Expression and Characterization of Human
`CD4:Immunoglobulin Fusion Proteins” (“Zettlmeissl”) – June
`1990 ..................................................................................................... 24 
`
`D. 
`
`Prior Art Informing the General Knowledge of the POSA ................. 25 
`
`IX.  THE CHALLENGED CLAIMS ARE OBVIOUS OVER THE
`PRIOR ART ................................................................................................... 26 
`
`A.  Ground 1: The Claims of the ’182 Patent Are Obvious Over
`Watson in view of Smith ’760 ............................................................. 27 
`
`1. 
`
`2. 
`
`Applying Watson’s General Method for Efficient
`Expression of Fusion Proteins to the TNFR Sequences
`Taught by Smith Results in a Fusion Protein That Falls
`Within the Scope of Every Claim of the ’182 Patent ............... 28 
`
`The Prior Art Motivated the POSA to Combine Watson
`and Smith .................................................................................. 33 
`
`iii
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`3. 
`
`4. 
`
`The POSA Had a Reasonable Expectation of Success in
`Preparing the Fusion Proteins Claimed in the ’182
`Patent ......................................................................................... 36 
`
`Nothing in the Prior Art “Teaches Away” from
`Preparing the Claimed TNFR:hinge IgG Fusion Proteins ........ 38 
`
`B. 
`
`Ground 2: The Claims of the ’182 Patent Are Obvious Over
`Smith in view of Zettlmeissl and Watson ........................................... 40 
`
`1.  Modifying Smith’s TNFR:IgG Fusion Proteins As
`Taught By Zettlmeissl and Watson Results in the Exact
`Fusion Proteins Recited in the ’182 Patent Claims .................. 40 
`
`2. 
`
`3. 
`
`Zettlmeissl and Watson Motivated the POSA to Modify
`Smith’s Fusion Proteins to Optimize Expression ..................... 43 
`
`The POSA Had a Reasonable Expectation of Success in
`Preparing the Claimed Fusion Proteins .................................... 45 
`
`C. 
`
`The Limitations of Claims 2-36 Are Obvious .................................... 46 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`Specific TNFR Peptide Sequences (Claims 2-3, 11, 13,
`17-19, 26-27, 35) ....................................................................... 46 
`
`An IgG1 Heavy Chain (Claims 4, 11, 13, 16, 20, 24, 26,
`35) ............................................................................................. 47 
`
`The Heavy Chain Sequences Consist Essentially of
`Those Encoded by the pCD4-Hγ1 Vector (Claims 5, 10,
`21, 25) ....................................................................................... 47 
`
`A Pharmaceutical Composition Comprising a
`Pharmaceutically Acceptable Carrier (Claims 6, 12, 29,
`36) ............................................................................................. 48 
`
`The Protein is Purified (Claims 7, 14, 22, 28) .......................... 49 
`
`The Protein is Produced by Mammalian / CHO Cells
`(Claims 8, 15, 23, 26, 32, 33).................................................... 49 
`
`iv
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`7. 
`
`The Protein Consists (Essentially) of the TNFR
`Fragment and the Hinge-CH2-CH3 Region (Claims 9,
`11, 16, 24, 26, 31, 34, 35) ......................................................... 50 
`
`8. 
`
`Independent Claims 13, 18, 26, and 30 Are Obvious ............... 51 
`
`D.  Any Objective Indicia Cannot Overcome the Strong Showing
`of Obviousness .................................................................................... 53 
`
`1. 
`
`2. 
`
`3. 
`
`Increased Binding Affinity for TNF Compared to the
`Soluble Receptor Was Expected, and Motivated the
`POSA to Make the Claimed Fusion Proteins ........................... 54 
`
`Superior Neutralization of TNF Compared to the
`Soluble Receptor Was Expected, and Motivated the
`POSA to Make the Claimed Fusion Proteins ........................... 56 
`
`Differences Between the Claimed Fusion Proteins and
`Antibodies Were Expected, and Patent Owner Has Not
`Demonstrated Any Surprisingly Superior Results .................... 58 
`
`a. 
`
`b. 
`
`c. 
`
`d. 
`
`Lack of CDC Was Expected ........................................... 59 
`
`Patent Owner’s Evidence Regarding ADCC Is
`Unreliable ....................................................................... 61 
`
`Lack of Aggregation Was Not Unexpected ................... 63 
`
`Patent Owner Has Not Compared the Closest
`Prior Art and Has Not Shown that Any
`Unexpected Results are Significant ................................ 64 
`
`X. 
`
`CONCLUSION .............................................................................................. 66 
`
`
`
`
`
`
`
`v
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`TABLE OF AUTHORITIES
`
`Cases 
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ....................................................................... 53, 64
`
`Bruckelmyer v. Ground Heaters, Inc.,
`445 F.3d 1374 (Fed. Cir. 2006) ............................................................................ 23
`
`Constant v. Advanced Micro-Devices, Inc.,
`848 F.2d 1560 (Fed. Cir. 1988) ............................................................................ 14
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ......................................................................................... 19
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ............................................................................ 38
`
`Ex parte NutraSweet Co.,
`19 U.S.P.Q.2d 1586 (BPAI 1991) ........................................................................ 65
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .............................................................................. 58
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................. 26
`
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................ 20
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 26, 39
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................ 43
`
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) ..................................................................... 27, 64
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 ................................................................................................ 38, 63
`
`vi
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`Suffolk Techs., LLC v. AOL Inc.,
`752 F.3d 1358 (Fed. Cir. 2014) ............................................................................ 22
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) ..................................................................... 53, 65
`
`Statutes 
`
`35 U.S.C. § 102 ........................................................................................... 20, 22, 24
`
`35 U.S.C. § 103 ....................................................................................... 9, 20, 25, 26
`
`35 U.S.C. § 112 ........................................................................................................ 19
`
`Rules  
`
`37 C.F.R. § 42.100 ................................................................................................... 19
`
`37 C.F.R. § 42.103 ..................................................................................................... 8
`
`37 C.F.R. § 42.104 .............................................................................................. 9, 19
`
`37 C.F.R. § 42.15 ....................................................................................................... 8
`
`37 C.F.R. § 42.8 .....................................................................................................7, 8
`
`FED. R. EVID. 803 .............................................................................................. 22, 24
`
`FED. R. EVID. 901 .............................................................................................. 22, 24
`
`
`
`
`
`vii
`
`

`

`Petitioner
`Exhibit No.
`1001
`1002
`1003
`
`1004
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`EXHIBIT LIST
`
`Document
`
`U.S. Patent No. 8,163,522, Brockhaus et al.
`Declaration of Dennis R. Burton, Ph.D.
`Watson et al., “A Homing Receptor-IgG Chimera as a Probe for
`Adhesive Ligands of Lymph Node High Endothelial Venules,” J.
`Cell Biology, 110:2221-2229 (June 1990)
`U.S. Patent No. 5,395,760, Smith et al.
`Zettlmeissl et al., “Expression and Characterization of Human
`CD4: Immunoglobulin Fusion Proteins,” DNA and Cell Biology,
`9(5):347-353 (June 1990)
`Applicants’ Appeal Brief for U.S. Patent App. No. 08/444,790
`(filed Feb. 28, 2008)
`Smith et al., “A Receptor for Tumor Necrosis Factor Defines an
`Unusual Family of Cellular and Viral Proteins,” Science,
`248:1019-1023 (May 25, 1990)
`“Preliminary Response Under 37 C.F.R. §42.107 of Patent Owner
`and Real Parties In Interest” filed in Coalition for Affordable
`Drugs V LLC v. Hoffmann-La Roche Inc., IPR2015-01792, Paper
`No. 10 (PTAB Dec. 14, 2015)
`Physicians’ Desk Reference, entry for ENBREL®, pp. 1752-1755
`(56th ed. 2002)
`“Decision Denying Institution of Inter Partes Review” filed in
`Coalition for Affordable Drugs V LLC v. Hoffmann-La Roche Inc.,
`IPR2015-01792, Paper No. 14 (PTAB March 11, 2016)
`European Patent App. No. 90107393.2, Karjalainen et al. (filed
`April 19, 1990)
`Declaration of Joseph B. Tamblyn, with English Translation of
`European Application Ser. No. 90116707.2 (granted as EP
`0417563B1), filed August 31, 1990, attached as Exhibit A, and
`original German-language document, attached as Exhibit B
`
`
`
`viii
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`Declaration of Joseph B. Tamblyn, with English Translation of CH
`Application Ser. No. 1347/90, filed April 20, 1990, attached as
`Exhibit A, and original German-language document attached as
`Exhibit B
`Declaration of Joseph B. Tamblyn, with English Translation of CH
`Application Ser. No. 746/90, filed March 8, 1990, attached as
`Exhibit A, and original German-language document attached as
`Exhibit B
`Declaration of Joseph B. Tamblyn, with English Translation of CH
`Application Ser. No. 3319/89, filed September 12, 1989, attached
`as Exhibit A, and original German-language document attached as
`Exhibit B
`(Not Used)
`(Not Used)
`Dembic et al., “Two Human TNF Receptors Have Similar
`Extracellular, But Distinct Intracellular, Domain Sequences,”
`Cytokine, 2(4):231-237 (July 1990)
`U.S. Patent No. 5,116,964, Capon et al.
`Declaration Under 37 C.F.R. § 1.132 of Dr. Werner Lesslauer for
`U.S. Patent App. No. 08/444,791 (filed Dec. 9, 2004)
`Decision on Appeal for U.S. Patent App. 08/444,790, Ex parte
`Brockhaus, No. 2009-014889 (BPAI Nov. 22, 2010)
`U.S. Pat. No. 5,428,130, Capon et al.
`(Not Used)
`Declaration of Taruna Arora, Ph.D. Under 37 C.F.R. 1.132 for
`U.S. Patent App. No. 08/444,790 (signed Dec. 16, 2010)
`(Not Used)
`“Petition” filed in Coalition for Affordable Drugs V LLC v.
`Hoffmann-La Roche Inc., IPR2015-01792, Paper No. 1 (PTAB
`Aug. 22, 2015)
`U.S. Patent No. 6,004,781, Seed
`Affidavit of Spencer J. Johnson with Appendices 1-4
`
`1013
`
`1014
`
`1015
`
`1016
`1017
`1018
`
`1019
`1020
`
`1021
`
`1022
`1023
`1024
`
`1025
`1026
`
`1027
`1028
`
`ix
`
`

`

`1029
`
`1030
`
`1031
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`Declaration of Lynne Weaver with copy of Watson et al. “A
`Homing Receptor-IgG Chimera as a Probe for Adhesive Ligands
`of Lymph Node Endothelial Venules,” J. Cell Biology., 110:2221-
`2229 (June 1990) stamped by Lipscomb Library on June 14, 1990
`attached as Exhibit A
`Declaration of Carmen Debord with copy of Zettlmeissl et al.,
`“Expression and Characterization of Human CD4:
`Immunoglobulin Fusion Proteins,” DNA and Cell Biology,
`9(5):347-353 (June 1990), stamped by the Library of Congress on
`July 10, 1990, attached as Exhibit A
`U.S. Patent No. 8,063,182, Brockhaus, et al.
`Capon et al., “Designing CD4 immunoadhesins for AIDS
`therapy,” Nature, 337:525-531 (Feb. 9, 1989)
`Byrn et al., “Biological properties of a CD4 immunoadhesin,”
`Nature, 344:667–670 (Apr. 12, 1990)
`Brennan et al., “Inhibitory Effect of TNFα Antibodies on Synovial
`Cell Interleukin-1 Production in Rheumatoid Arthritis,” The
`Lancet, 334:244-247 (July 29, 1989).
`Traunecker et al., “Highly efficient neutralization of HIV with
`recombinant CD4-immunoglobulin molecules,” Nature, 339:68-70
`(May 4, 1989)
`Smith and Baglioni, “The Active Form of Tumor Necrosis Factor
`is a Trimer,” J. Biol. Chem., 262(15):6951-6954 (May 25, 1987)
`Smith and Baglioni, “Multimeric Structure of the Tumor Necrosis
`Factor Receptor of HeLa Cells,” J. Biol. Chem., 264(25): 14646-
`14652 (Sept. 5, 1989)
`Karush, “Multivalent Binding and Functional Affinity,”
`Contemporary Topics in Molecular Immunology, 217-228 (1976)
`Greenbury et al., “The Reaction with Red Cells of 7S Rabbit
`Antibody, its Sub-units and their Recombinants,” Immunology,
`8:420-431 (1965)
`
`x
`
`

`

`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`Mohler et al., “Soluble Tumor Necrosis Factor (TNF) Receptors
`Are Effective Therapeutic Agents in Lethal Endotoxemia and
`Function Simultaneously as Both TNF Carriers and TNF
`Antagonists,” J. Immunology, 151(3):1548-1561 (Aug. 1, 1993)
`Blank et al., “Antibody Affinity and Valence in Viral
`Neutralization,” J. Immunology, 108(3):665-673 (Mar. 1972)
`Schneider et al., “Genetically engineered immunoglobulins reveal
`structural features controlling segmental flexibility,” Proc. Natl.
`Acad. Sci. USA, 85:2509-2513 (Apr. 1988)
`Oi et al., “Correlation between segmental flexibility and effector
`function of antibodies,” Nature, 307:136-140 (Jan. 12, 1984)
`Gregory et al., “The Solution Conformations of the Subclasses if
`Human IgG Deduced from Sedimentation and Small Angle X-ray
`Scattering Studies,” Molecular Immunology, 24(8):821-829 (1987)
`Lachmann and Hughes-Jones, “Initiation of Complement
`Activation,” Springer Seminars in Immunopathology 7:143-162
`(1984)
`Kohno et al., “Adalimumab and Infliximab Bind to Fc-Receptor
`and C1q and Generate Immunoprecipitation: A Different
`Mechanism From Etanercept,” Amgen Inc., 1495 (2005)
`Khare et al., “Mechanisms of Cell Death Induced by Tumor
`Necrosis Factor Antagonists,” Amgen Inc. (2005)
`Mitoma et al., “Mechanisms for Cytotoxic Effects of Anti-Tumor
`Necrosis Factor Agents on Transmembrane Tumor Necrosis Factor
`α-Expressing Cells,” Arthritis & Rheumatism, 58(5):1248-1257
`(May 2008).
`FDA Drug Safety Communication: Drug labels for the Tumor
`Necrosis Factor-alpha (TNFα) blockers no include warnings about
`infection with Legionelle and Listeria bacteria (Sept. 7, 2011)
`Ellison et al., “The nucleotide sequence of a human
`immunoglobulin Cγ1 gene,” NAR, 10(13):4071-4079 (1982).
`Jayapal et al., “Recombinant Protein Therapeutics from CHO Cells
`- 20 Years and Counting,” Chemical Engineering Progress
`103(10):40-47 (2007)
`
`xi
`
`

`

`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`1062
`
`1063
`
`1064
`
`1065
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`Klinman et al. “The Role of Antibody Bivalence in the
`Neutralization of Bacteriophage,” 99(6):1128-1133 (1967)
`Loumaye et al., “Binding Affinity and Biological Activity of
`Gonadotropin-Releasing Hormone Agonists in Isolated Pituitary
`Cells,” Endocrinology, 111(3):730-736 (1982)
`Gliemann and Gammeltoft, “The Biological Activity and the
`Binding Affinity of Modified Insulins Determined on Isolated Rat
`Fat Cells,” Diabetologia, 10:105-113 (1974)
`Parekh et al., “Development and validation of an antibody-
`dependent cell-mediated cytotoxicity-reporter gene assay,” Landes
`Biosci., 4(3):310-318 (2012)
`Beutler and Cerami, “Tumor Necrosis, Cachexia, Shock, and
`Inflammation: A Common Mediator,” Ann. Rev. Biochem.
`57:505-18 (1988)
`Arend and Dayer, “Cytokines and Cytokine Inhibitors or
`Antagonists in Rheumatoid Arthritis,” Arthritis & Rheumatism,
`33(3):305-315 (March 1990)
`Engelmann et al., “Two Tumor Necrosis Factor-binding Proteins
`Purified from Human Urine,” J. Bio. Chem., 265(3):1531-1536
`(January 1990)
`Amgen, “Press Release: Enbrel® (etanercept) Patent Issued,”
`(Nov. 22, 2011)
`Applicants’ Reply Appeal Brief for U.S. Patent App. No.
`08/444,790 (filed May 26, 2009)
`Amendment for U.S. Patent App. 08/444,790 (filed Dec. 16, 2010)
`Notice of Allowance of U.S. Patent App. No. 08/444,790 (filed
`Aug. 31, 2011)
`Supplemental Amendment In Response to Office Action of U.S.
`Patent App. No. 08/444,790 (filed Nov. 14, 2006)
`Third Declaration of Dr. Werner Lesslauer Under 37 C.F.R. §
`1.132 for U.S. Patent App. No. 08/444,790 (filed Nov. 14, 2006)
`Application for U.S. Patent Application No. 07/580,013 (filed
`Sept. 10, 1990)
`
`
`
`xii
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`I.
`
`INTRODUCTION
`
`Coherus BioSciences, Inc. (“Coherus”) petitions for inter partes review
`
`(“IPR”) of claims 1-36 of U.S. Patent No. 8,063,182 (“the ’182 patent,” Ex. 1031),
`
`assigned to Hoffmann-LaRoche Inc. (“Patent Owner”). This petition and the
`
`accompanying declaration of Dennis R. Burton, Ph.D. (Ex. 1002) demonstrate that
`
`each of the claims is unpatentable as obvious over (1) Watson (Ex. 1003) in view
`
`of U.S. Patent No. 5,395,760 (“Smith,” Ex. 1004), and (2) Smith in view of
`
`Zettlmeissl (Ex. 1005) and Watson.
`
`The ’182 patent claims “fusion proteins” that combine: (1) a soluble
`
`fragment of the 75 kilodalton human tissue necrosis factor receptor (“TNFR”);
`
`with (2) the hinge-CH2-CH3 region of the heavy chain of a human IgG antibody.
`
`Ex. 1002 ¶40. The resulting fusion protein replaces the variable region of an IgG
`
`antibody’s heavy chain with the 75-kDa TNFR, and eliminates the unnecessary
`
`light chain and CH1 domain:
`
`
`
`1
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`
`
`Id. ¶¶36, 40 (figures adapted from Ex. 1006, 12-13).1
`
`The Patent Owner was not the first to isolate and sequence the 75-kDa
`
`TNFR, nor was it the first to develop a fusion protein combining a soluble
`
`fragment of a receptor protein with the hinge-CH2-CH3 region of a human IgG
`
`heavy chain (“receptor:hinge IgG”). Multiple prior art publications recognized the
`
`promising therapeutic potential of such fusion proteins, and reported their
`
`advantageous properties such as specific binding to the receptor’s target ligand,
`
`bivalent display of the receptor, increased neutralization, ease of production and
`
`purification, and long serum half-life. Id. ¶¶63-90, 126-127; Ex. 1003, 2224-25;
`
`Ex. 1005, 350-51.
`
`
`1 All citations refer to the Exhibits’ native page numbers, except that IPR Page
`numbers are used for Exhibits 1012-1015, 1020, 1059, and 1062.
`
`2
`
`

`

`Conventional recombinant DNA techniques and host cell expression
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`methods made it a routine matter for a person of ordinary skill in the art (“POSA”)
`
`to create fusion proteins, or to replace one receptor with another in such a fusion.
`
`Ex. 1002 ¶¶30, 91, 103-104. The ’182 patent simply claims an obvious
`
`combination of the known 75-kDa TNFR with optimized fusion proteins taught in
`
`the prior art, as summarized in the following table:
`
`
`
`
`Smith (Ex. 1004), May 1990
`
`Watson (Ex. 1003), June 1990
`
`
`
`
`
`Zettlmeissl (Ex. 1005), June 1990
`
`
`
`
`’182 patent, no earlier than 8/31/1990
`
`
`
`The Patent Owner also was not the first to suggest incorporating the 75-kDa
`
`TNFR into a fusion protein. Smith and co-workers at Immunex Corporation
`
`3
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`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`published and patented the complete sequence of the 75-kDa TNFR in May
`
`1990—beating the Patent Owner in the race to do so. Ex. 1004; Ex. 1007. Smith
`
`identified the soluble, extracellular sequence of the 75-kDa TNFR, and described
`
`its therapeutic administration “for suppressing TNF-dependent inflammatory
`
`responses in humans.” Ex. 1004, 16:60-66, 4:12-21. Smith suggested making
`
`TNFR:IgG fusion proteins because their bivalent display of the TNFR could result
`
`in “enhanced binding affinity for TNF ligand.” Id. at 10:53-66; Ex. 1002 ¶¶57-58,
`
`139.2
`
`After Smith was filed—but before the effective priority date of the ʼ182
`
`patent—several research groups conducted extensive studies to optimize the
`
`location at which the receptor protein is linked to the IgG antibody fragment. This
`
`work culminated in publications by Watson and Zettlmeissl, which independently
`
`reported that receptor:IgG hinge fusion proteins are most “efficiently synthesized”
`
`when the light chain and CH1 domain are deleted, so that the receptor is attached
`
`directly to the hinge-CH2-CH3 region of an IgG antibody’s heavy chain. Ex.
`
`
`2 Patent Owner’s licensee, Amgen, asserts that the ’182 patent covers its product
`Enbrel® (etanercept). Ex. 1059, 1. Etanercept is a fusion protein developed by
`Immunex Corporation that combines the extracellular portion of the 75-kDa TNFR
`with the hinge-CH2-CH3 region of a human IgG1 heavy chain. Id.; Ex. 1008, at 1-
`2, n.1. Immunex’s Smith patent (Ex. 1004) covered etanercept until its expiration
`in 2012. Ex. 1009, 1755.
`
`4
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`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`1003, 2224; Ex. 1005, 347 (reporting the “best expression” was observed for heavy
`
`chain fusion proteins lacking the CH1 domain); Ex. 1002 ¶¶158-167.
`
`Watson and Zettlmeissl used different receptors in their fusion proteins, but
`
`both reported optimal results by employing the identical portion of the IgG heavy
`
`chain as claimed in the ’182 patent. Id. ¶¶77-80, 84-86, 132. Watson also taught
`
`that, based on success using different types of receptor proteins, the methods it
`
`reports could be “of general applicability” for making receptor:hinge IgG fusions.
`
`Ex. 1003, 2228; Ex. 1002 ¶¶83, 141.
`
`It was obvious to apply Watson’s general method for preparing
`
`receptor:hinge IgG fusion proteins—which Watson taught could be used as
`
`“therapeutic reagents against inflammatory diseases”—to prepare a fusion protein
`
`incorporating the anti-inflammatory soluble TNFR taught by Smith. Ex. 1003,
`
`2228; Ex. 1002 ¶¶153-154. In the alternative, it was obvious to modify Smith’s
`
`TNFR:IgG fusion proteins by deleting the light chain and CH1 region of the heavy
`
`chain, because Zettlmeissl and Watson taught that doing so results in optimum
`
`expression of the fusion protein. Ex. 1002 ¶¶145-161. Regardless of the approach
`
`chosen, the prior art taught that the expected result is a fusion protein having a long
`
`half-life that binds to and scavenges TNF to reduce inflammation, with increased
`
`binding affinity for TNF compared to the monomeric receptor. Id. ¶¶127-132; Ex.
`
`1004, 3:3-6, 10:61-66; Ex. 1005, 350-51.
`
`5
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`

`

`This strong case of obviousness is not overcome by the purported evidence
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`of unexpected results relied on by Patent Owner during prior proceedings. Dr.
`
`Burton, a renowned expert in antibody engineering, thoroughly rebuts Patent
`
`Owner’s claims. First, the fusion proteins’ apparent enhanced affinity for TNF,
`
`and the associated increase in neutralization potency, as compared to the soluble
`
`TNFR were entirely expected—indeed, these were express reasons identified in the
`
`prior art for making receptor:IgG fusions. Ex. 1002 ¶¶168-192. Second, Patent
`
`Owner’s claims of a surprising reduction in alleged “pro-inflammatory” functions
`
`(complement-dependent cytotoxicity (“CDC”), antibody-dependent cell-mediated
`
`cytotoxicity (“ADCC”), and aggregation) compared to monoclonal antibodies are
`
`unsupported by the prior art and/or based on unreliable data. Id. ¶¶193-218.
`
`Third, the Patent Owner has not compared the claimed fusion proteins to the
`
`closest prior art, and its comparisons to FDA-approved monoclonal antibody
`
`treatments demonstrate no practical benefit that could support a finding of
`
`nonobviousness. Id. ¶¶193-194, 221-223.
`
`This petition establishes that each and every feature recited by claims 1-36
`
`of the ’182 patent was disclosed by the prior art, and that claims 1-36 are
`
`unpatentable as obvious. Therefore, there is at least a “reasonable likelihood that
`
`the petitioners would prevail with respect to at least 1 of the claims challenged,” 35
`
`6
`
`

`

`U.S.C. § 314(a), and Coherus respectfully requests that its Petition for IPR be
`
`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`granted.
`
`II. MANDATORY NOTICES
`
`A. Real Party-in-Interest (37 C.F.R. § 42.8 (b)(1))
`Coherus BioSciences, Inc. is the real party-in-interest.
`
`B. Related Matters (37 C.F.R. § 42.8 (b)(2))
`The ’182 patent is the subject of the following judicial or administrative
`
`matters, which may affect, or be affected by, a decision in this proceeding:
`
`The ’182 patent is involved in the pending litigation Immunex Corp. v.
`
`Sandoz Inc., No. 16-cv-01118 (D.N.J. Feb. 26, 2016). Additionally, the ’182
`
`patent was involved in a litigation that is no longer pending: Sandoz Inc. v. Amgen
`
`Inc., 773 F.3d 1274 (Fed. Cir. 2014).
`
`Petitioner has filed a Petition for inter partes review of a patent sharing a
`
`common ancestor and with related subject matter—U.S. Patent No. 8,163,522 (“the
`
`’522 patent,” Ex. 1001) (Case IPR2017-01916, filed August 4, 2017). The Board
`
`previously issued a Written Decision denying a Petition for inter partes review of
`
`the ’522 patent filed by Coalition for Affordable Drugs V LLC (IPR No. 2015-
`
`01792) (Ex. 1010).
`
`In addition to the ’522 patent identified above, Coherus identifies the
`
`following U.S. patent applications and patents that claim the benefit of priority of
`
`7
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`the filing of the ’182 patent or from which the ’182 patent claims priority: U.S.
`
`Patent No. 5,610,279; U.S. Application Nos. 07/580,013 (now abandoned); and
`
`10/715,609 (now abandoned).
`
`C. Lead and Back-up Counsel (37 C.F.R. § 42.8 (b)(3))
`Coherus provides the following designation of counsel:
`
`
`
`
`Email:
`Postal:
`
`Hand Del.:
`Telephone:
`Facsimile:
`
`
`Lead Counsel
`Joseph A. Hynds (Reg. No.
`34,627)
`jhynds@rfem.com
`ROTHWELL, FIGG, ERNST &
`MANBECK, P.C.
`607 14th Street, N.W., Suite 800
`Washington, DC 20005
`Same as Postal
`202-783-6040
`202-783-6031
`
`Back-Up Counsel
`Seth E. Cockrum, Ph.D. (Reg. No.
`70,873)
`scockrum@rfem.com
`ROTHWELL, FIGG, ERNST &
`MANBECK, P.C.
`607 14th Street, N.W., Suite 800
`Washington, DC 20005
`Same as Postal
`202-783-6040
`202-783-6031
`
`Service Information (37 C.F.R. § 42.8 (b)(4))
`
`D.
`Please address all correspondence and service to counsel at the address
`
`provided in Section II.C. Coherus consents to electronic service at the email
`
`addresses above, in addition to litigationparalegals@rfem.com.
`
`III.
`
`PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`Coherus authorizes the Patent and Trademark Office to charge Deposit
`
`Account 02-2135 for the fee set in 37 C.F.R. § 42.15 (a) for this petition, and
`
`further authorizes any additional fees to be charged to this Deposit Account.
`
`8
`
`

`

`Petition for IPR of U.S. Patent No. 8,063,182
`
`
`IV.
`
`REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104
`
`Grounds for Standing Under 37 C.F.R. § 42.104(a)
`
`A.
`Coherus certifies that the ’182 patent is available for IPR and that Coherus is
`
`not barred or estopped from requesting an IPR. Coherus is a biopharmaceutical
`
`company that is developing for U.S. regulatory approval and commercial
`
`introduction an etanercept product for the treatment of disorders such as
`
`rheumatoid arthritis.
`
`B. Challenge Under 37 C.F.R. § 42.104(b); Relief Requested
`Coherus requests IPR and cancellation of all claims of the ’182 patent as
`
`unpatentable on the grounds listed below. The ’182 patent is to be reviewed under
`
`pre-AIA law.
`
`Ground
`No.
`
`Claims
`Challenged
`
`1
`
`2
`
`1-36
`
`1-36
`
`
`V.
`
`THE ’182 PATENT
`
`Statutory Grounds for Unpatentability
`
`Obvious under 35 U.S.C. § 103 in view of Watson
`(Ex. 1003) in combination with Smith (Ex. 1004).
`Obvious under 35 U.S.C. § 103 in view of Smith in
`combination with Zettlmeissl (Ex. 1005) and Watson.
`
`A. The ’182 Patent Only Generically Encompasses Fusion
`Proteins Comprising the 75-kDa TNFR, and Does Not
`Specifically Disclose Etanercept
`
`The ’182 patent is entitled “Human TNF Receptor Fusion Protein,” and
`
`issued on November 22, 20