Filed: March 15, 2016
`
`
`Filed on behalf of: AbbVie Biotechnology Ltd.
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
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`
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`
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`COHERUS BIOSCIENCES INC.,
`Petitioner,
`
`v.
`
`
`ABBVIE BIOTECHNOLOGY LTD.,
`Patent Owner.
`
`__________________
`
`
`Case IPR2016-00188
`Patent No. 9,017,680
`
`__________________
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`Mylan v. Genentech
`IPR2016-00710
`Merck Ex. 1131, Pg. 1
`
`

`

`TABLE OF CONTENTS
`
`IPR2016-00188
`
`Page(s)
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`FACTUAL STATEMENT .............................................................................. 5
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`State of the Art ...................................................................................... 5
`
`Preliminary D2E7 Clinical Trial Data .................................................10
`
`The ’680 Patent ...................................................................................14
`
`Prosecution of the ’135 Patent ............................................................15
`
`Prosecution of the ’680 Patent ............................................................17
`
`III. LEVEL OF ORDINARY SKILL IN THE ART AND CLAIM
`CONSTRUCTION ........................................................................................18
`
`A.
`
`B.
`
`Level of Ordinary Skill in the Art .......................................................18
`
`Claim Construction..............................................................................18
`
`1.
`
`2.
`
`3.
`
`“A method of reducing signs and symptoms” ..........................18
`
`“once every 13-15 days” ...........................................................20
`
`“40 mg dosage unit form” .........................................................20
`
`IV. THE CHALLENGED CLAIMS WOULD NOT HAVE BEEN
`OBVIOUS OVER VAN DE PUTTE IN VIEW OF KEMPENI ..................20
`
`A. A POSA Would Not Have Been Drawn Toward a
`Subcutaneously-Administered Fixed Dose with MTX .......................21
`
`B. A POSA Would Not Have Been Drawn Toward the 20 mg
`Weekly Dose in van de Putte ..............................................................24
`
`C. A POSA Would Not Have Been Motivated to Stretch the 20 mg
`Weekly van de Putte Dose into a 40 mg Every-Other-Week
`Dose .....................................................................................................29
`
`1.
`
`Petitioner ignores the prior art reports of up-dosing .................29
`
`i
`
`Merck Ex. 1131, Pg. 2
`
`

`

`Case IPR2016-00188
`
`2.
`
`Petitioner’s “dose-stretching” arguments are flawed ...............32
`
`D.
`
`Petitioner Cannot Establish that a POSA Would Have
`Reasonably Expected Success .............................................................36
`
`1.
`
`2.
`
`The known data on D2E7 half-life would not have led to
`a reasonable expectation of success ..........................................36
`
`Petitioner’s analysis of the available half-life data is
`wrong.........................................................................................40
`
`Boehringer and BioMarin Are Inapposite ...........................................43
`
`Secondary Considerations Support the Nonobviousness of the
`Challenged Claims ..............................................................................44
`
`The Petition Is Particularly Deficient with Respect to
`Dependent Claims 3 and 4 ..................................................................47
`
`E.
`
`F.
`
`G.
`
`V.
`
`35 U.S.C. § 325(d) SUPPORTS DENIAL OF THE PETITION ..................48
`
`VI. CONCLUSION ..............................................................................................52
`
`
`
`
`
`ii
`
`Merck Ex. 1131, Pg. 3
`
`

`

`TABLE OF AUTHORITIES
`
`Case IPR2016-00188
`
` Page(s)
`
`Cases
`Avanir Pharms., Inc. v. Actavis S. Atl., LLC,
`36 F. Supp. 3d 475 (D. Del. 2014) ...................................................................... 39
`
`Avanir Pharms. Inc. v. Par Pharm, Inc.,
`612 F. App’x 613 (Fed. Cir. 2015) ..................................................................... 39
`
`BioMarin Pharm. Inc. v. Genzyme Therapeutic Prods. Ltd.,
`IPR2013-00534, Paper 81 (Feb. 23, 2015) ......................................................... 43
`
`Boehringer Ingelheim Int’l GmbH v. Genentech, Inc.,
`IPR2015-00417, Paper 11 (July 14, 2015) ......................................................... 43
`
`Coalition for Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01799, Paper 9 (Mar. 10, 2016) .......................................................... 23
`
`Cont’l Can Co. USA v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 46
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 21, 39
`
`Dr. Reddy’s Labs., Ltd. v. Galderma Labs., Inc.,
`IPR2015-01782, Paper 10 (Feb. 16, 2016) ......................................................... 39
`
`Funai Elec. Co. v. Gold Charm Ltd.,
`IPR2015-01491, Paper 15 (Dec. 28, 2015) ............................................ 48, 49, 52
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 47
`
`Gen. Elec. Co. v. Tas Energy Inc.,
`IPR2014-00163, Paper 11 (May 13, 2014) ......................................................... 40
`
`Integrated Global Concepts, Inc. v. Advanced Messaging Techs., Inc.,
`IPR2014-01027, Paper 16 (Dec. 22, 2014) ............................................ 40, 49, 52
`
`iii
`
`Merck Ex. 1131, Pg. 4
`
`

`

`Case IPR2016-00188
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 47
`
`Merial Ltd. v. Virbac,
`IPR2014-01279, Paper 13 (Jan. 22, 2015) .......................................................... 49
`
`Microboards Tech., LLC v. Stratasys Inc.,
`IPR2015-00287, Paper 13 (May 28, 2015) ......................................................... 49
`
`Neil Ziegman, N.P.Z., Inc. v. Stephens,
`IPR2015-01860, Paper 11 (Feb. 24, 2016) ......................................................... 48
`
`Omron Oilfield & Marine, Inc. v. MD/Totco, L.P.,
`IPR2013-00265, Paper 11 (Oct. 31, 2013) ......................................................... 47
`
`Orthopedic Equip. Co. v. United States,
`702 F.2d 1005 (Fed. Cir. 1983) .......................................................................... 21
`
`PPC Broadband, Inc. v. Corning Optical Commc’ns RF, LLC,
`No. 2015-1361, 2016 WL 692368 (Fed. Cir. Feb. 22, 2016) ............................. 45
`
`Tiffany & Co. v. Lazare Kaplan Int’l, Inc.,
`IPR2015-00024, Paper 7 (Apr. 20, 2015) ........................................................... 49
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 27
`
`Federal Statutes
`
`35 U.S.C. § 325(d) ............................................................................................... 1, 48
`
`
`
`
`iv
`
`Merck Ex. 1131, Pg. 5
`
`

`

`
`
`EXHIBIT
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`2008
`2009
`2010
`2011
`2012
`2013
`2014
`2015
`
`PATENT OWNER’S EXHIBIT LIST
`
`IPR2016-00188
`
`DESCRIPTION
`Declaration of Janet Pope Under 37 CFR § 1.132 dated January
`31, 2014, submitted during prosecution of U.S. Application No.
`10/163,657 (U.S. Patent No. 8,889,135) (corresponds to Ex. 1002
`at 1141-1171)
`Declaration of Michael E. Weinblatt, MD, Under 37 CFR § 1.132
`dated February 3, 2014, submitted during prosecution of U.S.
`Application No. 10/163,657 (U.S. Patent No. 8,889,135)
`(corresponds to Ex. 1002 at 1173-1199)
`Declaration of Diane R. Mould Under 37 CFR § 1.132 dated
`January 29, 2014, submitted during prosecution of U.S.
`Application No. 10/163,657 (U.S. Patent No. 8,889,135)
`(corresponds to Ex. 1002 at 1201-1233)
`Declaration of Mr. Medgar Williams Under 37 CFR § 1.132
`dated February 7, 2014, submitted during prosecution of U.S.
`Application No. 10/163,657 (U.S. Patent No. 8,889,135)
`(corresponds to Ex. 1002 at 1240-1251)
`Declaration Under 37 C.F.R. § 1.132 of Harmut Kupper dated
`July 1, 2008, submitted during prosecution of U.S. Application
`No. 10/163,657 (U.S. Patent No. 8,889,135) (“Kupper I Decl.”)
`(corresponds to Ex. 1002 at 600-604)
`Declaration Under 37 C.F.R. § 1.132 by Dr. Harmut Kupper
`dated June 4, 2010, submitted during prosecution of U.S.
`Application No. 10/163,657 (U.S. Patent No. 8,889,135)
`(“Kupper II Decl.”) (corresponds to Ex. 1002 at 808-818)
`Rituximab/RITUXAN® label (Nov. 1997)
`Trastuzumab/HERCEPTIN® label (Sept. 1998)
`Abciximab/REOPRO® label (Nov. 4, 1997)
`Daclizumab/ZENAPAX® label (Dec. 1997)
`Basiliximab/SIMULECT® label (May 1998)
`Palivizumab/SYNAGIS® label (Mar. 2014)
`Gemtuzumab/MYLOTARG® label (Aug. 2005)
`Alemtuzumab/CAMPATH® label (May 2001)
`Adalimumab M10-261 Clinical Study Report R&D/09/173
`(Apr. 9, 2010)
`
`v
`
`Merck Ex. 1131, Pg. 6
`
`

`

`EXHIBIT
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`Case IPR2016-00188
`
`DESCRIPTION
`Scheldon Kress, M.D., Clinical Review: Abbott, Biologic
`Licensing Application STN 125057 Adalimumab - for use in the
`treatment of rheumatoid arthritis, CENTER FOR BIOLOGICS
`EVALUATION AND RESEARCH OFFICE OF THERAPEUTICS
`RESEARCH AND REVIEW DIVISION OF CLINICAL TRIAL DESIGN AND
`ANALYSIS IMMUNOLOGY AND INFECTIOUS DISEASES BRANCH
`HFM-582 (Dec. 24, 2002)
`Malcom Rowland & Thomas N. Tozer,, Chapter 3: Intravenous
`Dose, and Chapter 4: Extravascular Dose, in CLINICAL
`PHARMACOKINETICS CONCEPTS AND APPLICATIONS
`(3d ed. 1995)
`Christopher J. H. Porter & Susan A. Charman, Lymphatic
`Transport of Proteins After Subcutaneous Administration, J.
`PHARM. SCI., 89(3):297-310 (2000)
`R. Rau, Erfahrungen mit D2E7, ZETTSCHRIFT FUR
`RHEUMATOLOGIE, 58(Supplement 1):Abstract S51 (1999)
`(original German)
`R. Rau, Experiences with D2E7, J. RHEUMATOL., 58(Supplement
`1):Abstract S51 (1999) (certified English translation)
`L. B. A. van de Putte, et al., Efficacy and safety of adalimumab
`as monotherapy in patients with rheumatoid arthritis for whom
`previous disease modifying antirheumatic drug treatment has
`failed, ANN. RHEUM. DIS., 63(5):508-516 (2004)
`Fabien B. Vincent, et al., Antidrug antibodies (ADAb) to tumor
`necrosis factor (TNF)-specific neutralising agents in chronic
`inflammatory diseases: a real issue, a clinical perspective, ANN.
`RHEUM. DIS., 72:165-178 (2013)
`Pauline A. van Schouwenburg, et al., Immunogenicity of anti-
`TNF biologic therapies for rheumatoid arthritis, NAT. REV.
`RHEUMATOL., 9:164-172 (2013)
`Ravinder N. Maini, et al., Therapeutic Efficacy of Multiple
`Intravenous Infusions of Anti-Tumor Necrosis Factor α
`Monoclonal Antibody Combined with Low-Dose Weekly
`Methotrexate in Rheumatoid Arthritis, ARTHRITIS &
`RHEUMATISM, 41(9):1552-1563 (1998)
`Frederick Wolfe, et al., Consensus Recommendations for the
`Assessment and Treatment of Rheumatoid Arthritis, J.
`RHEUMATOL., 28(6):1423-1430 (2001)
`
`vi
`
`Merck Ex. 1131, Pg. 7
`
`

`

`Case IPR2016-00188
`
`EXHIBIT
`2026
`
`2027
`
`2028
`
`2029
`2030
`
`2031
`
`2032
`2033
`
`DESCRIPTION
`James R. O’Dell, Chapter 10: Combination Disease-Modifying
`Anti-Rheumatic Drug (DMARD) Therapy, in Modern
`Therapeutics in Rheumatic Diseases (George C. Tsokos ed.,
`2002)
`Zhiqiang An, Monoclonal antibodies - a proven and rapidly
`expanding therapeutic modality for human diseases, PROTEIN
`CELL, 1(4):319-330 (2010)
`Peter F. Bross, et al., Approval Summary: Gemtuzumab
`Ozogamicin in Relapsed Acute Myeloid Leukemia, CLINICAL
`CANCER RES., 7:1490-1496 (2001)
`U.S. Application No. 11/443,943, January 29, 2009 Amendment
`and Response to Office Action
`Direct Narrative Statement of Brian C. Reisetter, Ph.D., Novo
`Nordisk A/S et al. v. Caraco Pharm. Labs., Ltd. et al., No. 2:05-
`cv-40188 (E.D. Mich. Aug. 11, 2010) (D.I. 488)
`Luke Timmerman, Abbott’s Humira, the 3rd-in-Class Drug that
`Toppled Lipitor as No. 1, BIOBEAT (Apr. 16, 2012)
`U.S. Patent No. 8,889,135 to Fischkoff et al. (“the ’135 patent”)
`Peter A. Andersen, et al., Weekly Pulse Methotrexate in
`Rheumatoid Arthritis: Clinical and Immunologic Effects in a
`Randomized, Double-Blind Study, ANN. INTERN. MED.,
`103(4):489-496 (1985)
`
`vii
`
`Merck Ex. 1131, Pg. 8
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`

`

`Case IPR2016-00188
`
`I.
`
`INTRODUCTION
`Coherus BioSciences Inc. (“Petitioner”) seeks inter partes review of U.S.
`
`Patent No. 9,017,680 (“the ’680 patent”), contending that claims 1-4 are rendered
`
`obvious by the van de Putte abstract in view of Kempeni. The claims of the ’680
`
`patent cover the FDA-approved method of using D2E7 (the active ingredient in
`
`HUMIRA®) in combination with methotrexate (“MTX”) to reduce signs and
`
`symptoms in patients with moderately to severely active rheumatoid arthritis
`
`(“RA”). The Board should deny the Petition because it fails to demonstrate a
`
`reasonable likelihood that Petitioner will prevail on its single ground.
`
`At the outset, the Board should deny the Petition pursuant to 35 U.S.C.
`
`§ 325(d) because Petitioner merely rehashes the same arguments thoroughly
`
`considered by the Examiner of this patent during prosecution of the parent case.
`
`The exact same combination of references that forms the basis for Petitioner’s sole
`
`obviousness ground was considered by the Examiner. The issues raised by
`
`Petitioner and its declarants correspond directly to the issues that were raised
`
`during prosecution by the Examiner and overcome by Patent Owner. Because
`
`Petitioner has failed to present any persuasive new evidence that was not before the
`
`Examiner, the Petition is cumulative, and the Board should decline to institute trial.
`
`As summarized here and discussed in more detail in sections that follow,
`
`Petitioner fails to meet its burden for several reasons.
`
`1
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`Merck Ex. 1131, Pg. 9
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`

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`Case IPR2016-00188
`
`First, Petitioner’s arguments are based on a hindsight evaluation of the art
`
`that picks and chooses portions of references while ignoring the art as a whole.
`
`The van de Putte and Kempeni references taken together describe early clinical
`
`studies involving D2E7 having different routes of administration, dosing
`
`schedules, and dosing amounts. Most of those studies utilized body-weight dosing,
`
`consistent with recognized concerns that a fixed-dose regimen would not safely
`
`and effectively treat patients of different weights. Although the claims are directed
`
`to use of D2E7 in combination with MTX, most of those studies, including the
`
`study reported in van de Putte, excluded use of MTX. This is largely ignored by
`
`Petitioner and its declarants. Petitioner’s selection of the fixed-dose regimens
`
`described in van de Putte as the basis of its obviousness attack is pure hindsight.
`
`And even as to van de Putte, Petitioner’s focus on the 20 mg dose is driven by
`
`hindsight given that the 20 mg dose was inferior to the other doses disclosed by
`
`van de Putte.
`
`Second, Petitioner’s argument that a POSA would have been motivated to
`
`“stretch” a weekly dose based on patient convenience ignores critical efficacy and
`
`safety issues. Under-dosing a monoclonal antibody such as D2E7 presented
`
`serious concerns due to the increased risk of forming anti-drug antibodies, which
`
`significantly decrease efficacy and increase side effects. The prior art, including
`
`Kempeni, showed that patients receiving a weight-based dose supposedly
`
`2
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`Merck Ex. 1131, Pg. 10
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`

`

`Case IPR2016-00188
`
`equivalent to the claimed 40 mg dose had to be “up-dosed” to higher doses due to
`
`inadequate clinical response. A POSA would have been concerned about under-
`
`dosing and would have considered a 20 mg weekly dose too low to serve as the
`
`starting point for stretching the dose to an every-other-week interval.
`
`Third, Petitioner’s conclusory assertions about half-life, which serve as the
`
`touchstone for its arguments regarding motivation and reasonable expectation of
`
`success, lack scientific merit. The crux of Petitioner’s theory is the assumption
`
`that serum half-life alone can meaningfully inform the choice of a dosing interval.
`
`But the evidence shows that for therapeutic monoclonal antibodies, half-life is not
`
`a reliable predictor of dosing interval. Determining an appropriate dosing interval
`
`requires patient-specific data on
`
`therapeutic
`
`response and drug serum
`
`concentrations. Dr. Baughman, Petitioner’s pharmacokineticist, admits that this
`
`information was important and also acknowledges it was unknown for D2E7 as of
`
`the effective filing date of the ’680 patent. Moreover, Petitioner’s half-life
`
`argument is premised on the scientifically incorrect assumption that the full dose of
`
`a subcutaneously administered antibody would reach the patient’s blood stream.
`
`Fourth, objective
`
`evidence
`
`supports
`
`the patentability of
`
`the
`
`claims. Evidence that HUMIRA®’s commercial success is attributable to the
`
`features of the claimed dosing regimen was submitted during prosecution of the
`
`parent patent to the ’680 patent. The Examiner agreed that the evidence
`
`3
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`Merck Ex. 1131, Pg. 11
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`

`

`Case IPR2016-00188
`
`established a nexus between the commercial success and the features of the
`
`claimed dosing regimen in the parent patent. Both that patent and the ’680 patent
`
`are directed to an approved method of administering HUMIRA® for treating
`
`RA. Petitioner’s attempt to attribute HUMIRA®’s commercial success to other
`
`factors is insufficient to overcome the Examiner’s conclusion that Patent Owner’s
`
`showing was “convincing and considered to be commensurate in scope” with the
`
`claimed invention.
`
`Fifth, the expert declarations submitted by Petitioner do not address or fail
`
`to dispute the scientific facts relevant to obviousness but rely instead on conclusory
`
`opinions and irrelevant contentions. Moreover, outside of the context of this
`
`proceeding, each of Petitioner’s declarants has made statements consistent with
`
`Patent Owner’s positions. For example, while Dr. Baughman argues in this
`
`proceeding that it would have been routine to develop the claimed dosing regimen,
`
`a document submitted in support of one of her own patent applications takes the
`
`exact opposite position: “The determination of the dosing schedule of a drug,
`
`such as a therapeutic antibody, . . . is very complex going far beyond routine
`
`optimization.”
`
` Ex. 2029 (Jan. 29, 2009 Response in U.S. Application
`
`No. 11/443,943), 7 (emphasis added).
`
`In short, Petitioner’s arguments are duplicative of issues considered
`
`thoroughly by the Examiner during prosecution and are wholly without merit. The
`
`4
`
`Merck Ex. 1131, Pg. 12
`
`

`

`Case IPR2016-00188
`
`Board should therefore refuse to institute trial because the Petition is cumulative or
`
`deny the Petition on its merits.1
`
`II.
`
`FACTUAL STATEMENT
`State of the Art
`A.
`Therapeutic Monoclonal Antibodies. In June 2001 when the priority
`
`application for the ’680 patent was filed, there was limited experience with the use
`
`of antibodies as therapeutic agents. Only ten antibodies were approved for clinical
`
`use in the United States. Ex. 2027 (An), Table 1 (reporting monoclonal antibodies
`
`approved for clinical use); see also labeling information for those antibodies,
`
`including Ex. 2014, 13; Ex. 2008, 2; Ex. 1012, 1; Ex. 2009, 17; Ex. 2007, 2;
`
`Ex. 2011, 7; Ex. 2012, 1; Ex. 2010, 2; and Ex. 2028 (Bross), 2. None was
`
`approved for subcutaneous administration as recited in the ’680 patent. Id.
`
`Indeed, HUMIRA® was the first FDA-approved antibody labeled for subcutaneous
`
`administration. Id.; see also Ex. 1034, 1.
`
`
`1 Petitioner presents essentially the same arguments that it previously made in
`
`IPR2016-00172 challenging related U.S. Patent No. 8,889,135 (“the ’135 patent”).
`
`A review of the two petitions, and the three declarations supporting each of the
`
`petitions, reveals their substantial similarity. Compare, e.g., Pet. 32-38 with
`
`IPR2016-00172 Pet. 31-37.
`
`5
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`Merck Ex. 1131, Pg. 13
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`

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`Case IPR2016-00188
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`Rheumatoid Arthritis. RA is a life-long, progressive inflammatory disease
`
`of the joints and surrounding tissue. Left untreated, the persistent inflammation
`
`causes joint pain, bone destruction, deformity, and potentially life-threatening
`
`complications. See Ex. 2001 (Pope Decl.) ¶ 49.2 There is no cure; patients require
`
`long-term, usually life-long, treatment.
`
`In the 1990s, RA was treated with an assortment of non-steroidal anti-
`
`inflammatory drugs, corticosteroids, and so-called disease modifying anti-
`
`rheumatic drugs (“DMARDs”). Ex. 1003 (Kempeni), 1. One DMARD in
`
`particular, a known chemotherapy agent capable of suppressing the immune
`
`response called MTX (Ex. 2033 (Andersen), 3), became the drug of choice in the
`
`treatment of RA, demonstrating improved efficacy compared to other DMARDs
`
`for at least some patients. Ex. 2026, 15, 19. While MTX and other DMARDs
`
`offered an improvement over existing therapies, they were only “moderately
`
`successful” in alleviating the discomforts of swollen, painful joints and typically
`
`
`2 The Pope (Ex. 2001), Weinblatt (Ex. 2002), Mould (Ex. 2003), Williams
`
`(Ex. 2004), and Kupper (Exs. 2005, 2006) Declarations were submitted during
`
`prosecution of the ’135 patent and can be found in Petitioner’s Ex. 1002. For ease
`
`of reference they have been separated out as discrete exhibits.
`
`6
`
`Merck Ex. 1131, Pg. 14
`
`

`

`failed to halt the aggressive course of the disease long-term. Ex. 1003 (Kempeni),
`
`Case IPR2016-00188
`
`1.
`
`Anti-TNFα Biologics. In a 1999 “Guidance for Industry,” the FDA
`
`reviewed the state of existing RA therapies and remarked that there was an
`
`“ongoing search for more effective therapeutics that have a positive impact on the
`
`natural history of the disease . . . .” Ex. 1016, 4. The search for new treatments
`
`focused on inhibiting tumor necrosis factor alpha (“TNFα”). Ex. 1015 (Updated
`
`Consensus Statement), 1-2.
`
`TNFα is an important protein in the immune system. However, as of June
`
`2001, it was known to be implicated in different autoimmune diseases, including
`
`RA. Ex. 1001 (’680 patent), 25:37-43. Biologic agents designed to block TNFα
`
`activity, including antibodies and TNFα receptor fusion proteins, were a new class
`
`of drugs with promise for treating RA. Ex. 1003 (Kempeni), 1; Ex. 2003 (Mould
`
`Decl.) ¶ 17.
`
`These drugs presented unique safety and efficacy issues. Ex. 1003
`
`(Kempeni), 1; see also Ex. 1016 (FDA Guidance), 17. By targeting TNFα, anti-
`
`TNFα biologics suppress the patient’s immune system, creating an associated risk
`
`of infection. Ex. 2001 (Pope Decl.) ¶ 55; Ex. 2003 (Mould Decl.) ¶¶ 52-53.
`
`Further, because they are foreign proteins, biologics stimulate the patient’s
`
`immune system to generate antibodies against the drugs themselves (anti-drug
`
`7
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`Merck Ex. 1131, Pg. 15
`
`

`

`Case IPR2016-00188
`
`antibodies). Ex. 2001 (Pope Decl.) ¶ 46; Ex. 2002 (Weinblatt Decl.) ¶¶ 36-37;
`
`Ex. 2003 (Mould Decl.) ¶ 57. Anti-drug antibodies were known to cause infusion-
`
`or injection-site reactions as well as more serious effects such as anaphylaxis.
`
`Ex. 2001 (Pope Decl.) ¶ 46; Ex. 2002 (Weinblatt Decl.) ¶ 36. The FDA
`
`characterized the formation of anti-drug antibodies as a “particular concern with
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`biological agents . . . .” Ex. 1016, 14.
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`Anti-drug antibodies can also lessen efficacy. Once a patient has generated
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`anti-drug antibodies, a drug that once alleviated symptoms may no longer be
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`suitable for future use. Ex. 2003 (Mould Decl.) ¶ 55. This concern was expressly
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`recognized by the FDA in its 1999 Guidance on developing biologics for the
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`treatment of RA. Ex. 1016, 14 (noting that anti-drug antibodies may “result[] in
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`changes in therapeutic benefit over time”). There, the FDA advised that RA
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`clinical trials should be “of at least six months’ duration,” in part because
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`“products with the potential to elicit antibody formation should be assessed for
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`durability, since antibodies may block effectiveness.” Id. at 5.
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`These safety and efficacy concerns were explicitly recognized for the only
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`two TNFα inhibitors approved by the FDA as of 2001, REMICADE® and
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`ENBREL®. REMICADE® is a chimeric monoclonal antibody (containing both
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`murine and human amino acid sequences) administered as a series of intravenous
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`infusions at a dose based on a patient’s body weight. Ex. 1012 (REMICADE®
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`Case IPR2016-00188
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`label), 1, 12. Despite the ability of health-care providers to tailor the dose
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`administered, the REMICADE® label contained a black-box warning disclosing the
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`risk of serious infection, “including sepsis and fatal infections,” that could result
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`from blocking TNFα. Id. at 6; see also Ex. 2001 (Pope Decl.) ¶ 55; Ex. 2003
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`(Mould Decl.) ¶ 52. And it also warned of the formation of anti-drug antibodies,
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`explaining that “[p]atients who were antibody-positive were more likely to
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`experience an infusion reaction” and “development of a lupus-like syndrome.”
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`Ex. 1012, 7; see also Ex. 2001 (Pope Decl.) ¶ 55; Ex. 2002 (Weinblatt Decl.) ¶ 37;
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`Ex. 2003 (Mould Decl.) ¶ 57. ENBREL®, a TNFα receptor fusion protein, was
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`administered at a dose of 25 mg given twice weekly via subcutaneous injection.
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`Ex. 1011 (ENBREL® label), 1, 5. Anti-drug antibodies were detected in 16% of
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`RA patients receiving ENBREL®, and
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`its
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`label warned
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`that “long-term
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`immunogenicity of ENBREL is unknown.” Id. at 3.
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`Importantly, the risk of developing anti-drug antibodies was known to
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`correlate with lower concentrations of drug in the blood. Ex. 2003 (Mould Decl.)
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`¶ 55. For example, clinical data with REMICADE® showed that “the rate of [anti-
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`drug antibody] responses was inversely proportional to the dosage; thus, [anti-drug
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`antibody] formation occurred in 53%, 21%, and 7% of the patients who were
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`receiving repeated treatment with [REMICADE®] at 1, 3, and 10 mg/kg,
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`respectively.” Ex. 2024 (Maini), 12 (emphasis added); see also Ex. 1012
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`Case IPR2016-00188
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`(REMICADE® label), 7; Ex. 2001 (Pope Decl.) ¶ 46; Ex. 2002 (Weinblatt Decl.)
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`¶ 37; Ex. 2003 (Mould Decl.) ¶ 57. This inverse relationship occurs because lower
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`doses of monoclonal antibodies have lower minimum serum levels (trough levels
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`or concentrations) between doses. Ex. 2003 (Mould Decl.) ¶ 73. This mimics the
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`natural intermittent exposure of the immune system to foreign antigens,
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`contributing to the production of antibodies against the antigens. Id. at ¶ 55.
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`Lengthening the dosing interval of a drug was known to cause lower trough
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`concentrations and an increased risk of developing anti-drug antibodies. Id. at
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`¶ 60.
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`In short, treatment with anti-TNFα antibodies raised safety and efficacy
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`concerns related to both over-dosing and under-dosing. Over-dosing exposed
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`patients to the risk of serious infections as reflected in REMICADE®’s black-box
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`label warning. Under-dosing carried the risk of developing anti-drug antibodies,
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`causing the drug to become less effective or even unsuitable for further use, as well
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`as raising the possibility of causing anaphylaxis, a serious, life-threatening allergic
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`reaction. It was against this backdrop that the clinical trials for D2E7 began.
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`Preliminary D2E7 Clinical Trial Data
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`B.
`Prior to June 2001, the art contained preliminary data from five D2E7
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`clinical trials designed and conducted by Patent Owner. Limited information about
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`these trials was published in abbreviated form in review articles and conference
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`Case IPR2016-00188
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`abstracts, including the van de Putte (Ex. 1004) and Kempeni (Ex. 1003)
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`references. See also Exs. 1005 (Rau #907); 1009 (Rau #1978); 1017 (van de Putte
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`1998); 1018 (Rau 1998); 1019 (Schattenkirchner); 1023 (Weisman 2000); 1024
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`(van de Putte 2000). Taken as a whole, the prior art showed a variety of possible
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`dosing strategies for D2E7 involving different routes of administration, different
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`dosing schedules, different dosing amounts, and different response rates.
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`Moreover, as explained below, these prior art studies consistently report “up-
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`dosing” from weight-based doses Petitioner alleges are equivalent to the claimed
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`40 mg fixed dose due to inadequate clinical responses.
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`Kempeni discusses several early D2E7 trials, including the DE001/DE003,
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`DE004, and DE010 studies. Ex. 1003. In the DE001 study, patients received a
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`single intravenous dose of D2E7 in an amount based on body weight, with doses
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`ranging from 0.5 mg/kg (0.5 mg of drug per 1 kg of body weight) up to 10 mg/kg.
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`Id. at 2; see also Ex. 1017 (van de Putte 1998); Ex. 1018 (Rau 1998); Ex. 2006
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`(Kupper II Decl.) ¶ 12. Patients in this study were not administered MTX. Ex.
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`1003 (Kempeni), Table 2. The estimated terminal half-life of D2E7 in serum
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`following intravenous administration of a single dose was reported as ranging from
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`11.6 to 13.7 days. Id. at 2.
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`The DE003 study was an open-label continuation of the DE001 study. Id. at
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`2; Ex. 2006 (Kupper II Decl.) ¶ 13. D2E7 was administered intravenously based
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`Case IPR2016-00188
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`on body weight, with some patients dosed once every other week. Ex. 1003
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`(Kempeni), 2. No efficacy data were reported, but Kempeni explains that “patients
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`[in DE003] who did not respond well after 0.5 or 1 mg/kg received higher
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`doses . . . .” Id. (emphasis added); Ex. 2006 (Kupper II Decl.) ¶ 13.
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`Petitioner equates the 0.5 mg/kg intravenous dose disclosed in Kempeni with
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`the claimed subcutaneous 40 mg dose (Petitioner multiplies the 0.5 mg/kg dose by
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`an assumed 80 kg patient). Pet. 28 (Table). As explained during prosecution and
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`as addressed in § IV.C.1 below, it is improper to (1) transform a weight-based dose
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`into a fixed dose without knowledge of the actual distribution of patient weights
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`and (2) convert an intravenous dose to a subcutaneous dose. See Ex. 2003 (Mould
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`Decl.) ¶¶ 34, 40; Ex. 2002 (Weinblatt Decl.) ¶ 31. But even accepting Petitioner’s
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`faulty assumption that weight-based dosing could be equated to fixed dosing in this
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`manner, the only logical conclusion a POSA would have drawn from Kempeni
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`with respect to an every-other-week 40 mg fixed dose is that this dose provided
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`insufficient efficacy across the patient population.
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`The DE004 and DE010 trials reported in Kempeni evaluated subcutaneous
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`administration. The DE004 trial included weekly, subcutaneous administration of
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`a weight-based dose of 0.5 mg/kg of D2E7 without MTX. Ex. 1003 (Kempeni), 2-
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`3; see also Ex. 1019 (Schattenkirchner), 2; Ex. 2006 (Kupper II Decl.) ¶ 17.
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`Case IPR2016-00188
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`Again, “non-responders or those losing their responder status” were up-dosed to 1
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`mg/kg weekly. Ex. 1003 (Kempeni), 3; Ex. 2006 (Kupper II Decl.) ¶ 17.
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`The DE010 trial compared head-to-head a 1 mg/kg dose administered
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`subcutaneously to a 1 mg/kg dose administered intravenously, both with MTX.
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`Ex. 1003 (Kempeni), 3; Ex. 2006 (Kupper II Decl.) ¶ 20. Although “preliminary
`
`data” had suggested
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`that multiple subcutaneous doses produced D2E7
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`concentrations in plasma comparable to intravenous administration, intravenously
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`administered D2E7 showed better efficacy than subcutaneously administered
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`D2E7 for every reported metric. Ex. 1003 (Kempeni), 3; Ex. 2006 (Kupper II
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`Decl.) ¶ 20; Ex. 1005 (Rau #907), 3; Ex. 2003 (Mould Decl.) ¶ 32.
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`Preliminary data from the first phase II trial of D2E7 were reported by van
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`de Putte in the form of a conference abstract. Ex. 1004. This trial, called DE007,
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`featured a three-month placebo-controlled study in which patients received a fixed
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`dose of 20, 40, or 80 mg of D2E7 administered subcutaneously on a weekly
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`schedule. Id. The patients were not administered MTX. The data reported for the
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`40 and 80 mg doses are on their face superior to the 20 mg dose, but van de Putte
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`reported that all doses “were statistically significantly superior to placebo
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`(p < 0.001).” Id. Another prior art report of the DE007 trial reported results
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`exclusively for the 40 mg and 80 mg doses. Ex. 2019 (“Rau S51” original