`
`Filed: October 28, 2016
`
`
`Filed on behalf of: AbbVie Biotechnology Ltd.
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`
`
`
`
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH and
`BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`
`ABBVIE BIOTECHNOLOGY LTD.,
`Patent Owner.
`
`__________________
`
`
`Case IPR2016-00409
`Patent No. 8,889,135 B2
`
`__________________
`
`
`
`PATENT OWNER’S RESPONSE
`
`

`

`TABLE OF CONTENTS
`
`Case IPR2016-00409
`
`Page(s)
`
`I.
`
`II.
`
`
`INTRODUCTION ........................................................................................... 1
`
`FACTUAL STATEMENT .............................................................................. 5
`
`A.
`
`The Prior Art ......................................................................................... 5
`
`1.
`
`2.
`
`3.
`
`4.
`
`Kempeni 1999 ............................................................................. 8
`
`van de Putte 1999 ......................................................................11
`
`Rau 1998 ...................................................................................13
`
`Schattenkirchner 1998 ..............................................................14
`
`B.
`
`The PK Data in Kempeni ....................................................................15
`
`The ’135 Patent ...................................................................................16
`C.
`D. HUMIRA® ...........................................................................................16
`INSTITUTION DECISION ..........................................................................17
`
`III.
`
`IV. GROUND 1: THE CHALLENGED CLAIMS WOULD NOT HAVE
`BEEN OBVIOUS FROM VAN DE PUTTE AND KEMPENI ...................19
`
`A.
`
`The Clinical And PK Data in Kempeni 1999 Would Not Have
`Motivated A POSA To Practice The Claimed Invention ....................21
`
`1.
`
`The available clinical data taught away from the claimed
`invention ....................................................................................21
`
`a.
`
`b.
`
`c.
`
`The 0.5mg/kg doses in the prior art taught away ...........22
`
`The “biweekly” dose described in Kempeni taught
`away ................................................................................30
`
`The data in van de Putte taught away .............................32
`
`2.
`
`The available PK data taught away from the claimed
`invention ....................................................................................34
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`

`

`Case IPR2016-00409
`
`a.
`
`b.
`
`c.
`
`The Cmin values of an every-other-week dose
`would have been lower than those of a weekly
`dose .................................................................................34
`
`The difference in Cmin values between a weekly
`20mg dose and an every-other-week 40mg dose
`would have been significant ...........................................37
`
`The lower Cmin of an every-other-week regimen
`would have raised concerns about anti-drug
`antibodies ........................................................................41
`
`3.
`
`4.
`
`5.
`
`Half-life does not provide sufficient information to
`design a dosing regimen ............................................................45
`
`Doubling both the dose and interval between doses can
`abolish efficacy irrespective of “linear pharmacokinetics” ......49
`
`Patent Owner has never “admitted” equivalence between
`a 20 mg weekly dose and a 40 mg biweekly dose ....................51
`
`B.
`
`The Claimed Invention Is Not Invalid Under An “Obvious To
`Try” Theory Or The Result Of “Routine Optimization” ....................52
`
`C. Objective Indicia Support the Non-Obviousness of the Claims .........57
`
`1.
`
`2.
`
`3.
`
`There was a long-felt but unmet need for new RA
`therapies ....................................................................................57
`
`Despite low predicted trough levels, the claimed
`invention is unexpectedly effective ..........................................58
`
`The claimed invention was a commercial success as a
`result of its efficacious and safe dosing regimen ......................60
`
`V. GROUND 2: THE CHALLENGED CLAIMS WOULD NOT HAVE
`BEEN OBVIOUS OVER RAU 1998 IN VIEW OF
`SCHATTENKIRCHNER 1998 AND VAN DE PUTTE..............................62
`
`VI. THE CLAIMS REQUIRE A THERAPEUTICALLY MEANINGFUL
`LEVEL OF EFFICACY ................................................................................64
`
`VII. CONCLUSION ..............................................................................................66
`
`ii
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`

`

`
`
`TABLE OF AUTHORITIES
`
`Case IPR2016-00409
`
` Page(s)
`
`Federal Cases
`Avanir Pharms., Inc. v. Actavis S. Atl., LLC,
`36 F. Supp. 3d 475 (D. Del. 2014) ...................................................................... 46
`
`Avanir Pharms. Inc. v. Par Pharm. Inc.,
`612 F. App’x 613 (Fed. Cir. 2015) ..................................................................... 46
`
`BioMarin Pharm. Inc. v. Genzyme Therapeutic Products Ltd.,
`IPR2013-00534, Paper 81 (Feb. 23, 2015) ......................................................... 56
`
`Coherus Biosciences Inc. v. AbbVie Biotechnology Ltd.,
`IPR2016-00172, Paper 9 (May 17, 2016) ........................................................... 17
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 46
`
`Demaco Corp. v. F. Von Langsdorff Licensing, Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .......................................................................... 61
`
`Dr. Reddy’s Labs., Ltd. v. Galderma Labs., Inc.,
`IPR2015-01782, Paper 10 (Feb. 16, 2016) ......................................................... 46
`
`Endo Pharms, Inc. v. Depomed, Inc.,
`IPR2014-00652, Paper 68 (Sept. 16, 2015) ........................................................ 28
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 28
`
`Hoffman-La Roche, Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .......................................................................... 53
`
`Innopharma Licensing, Inc. v. Senju Pharm. Co.,
`IPR2015-00903, Paper 82 (July 28, 2016) ......................................................... 61
`
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................. 4, 53, 55
`
`iii
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`

`

`Case IPR2016-00409
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .............................................................. 20, 53, 57
`
`In re Magnum Oil Tools, Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) ............................................................................ 4
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .......................................................................... 28
`
`Merck & Co., v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 61
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 55
`
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) .......................................................................... 19
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .................................................................... 20, 53
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 60
`
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 18
`
`Federal Statutes
`
`35 U.S.C. § 103 ........................................................................................................ 17
`
`
`
`iv
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`

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`Case IPR2016-00409
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`I.
`
`INTRODUCTION
`The Board instituted inter partes review of claims 1-5 of U.S. Patent No.
`
`8,889,135 (“the ’135 patent”) to determine whether they would have been obvious
`
`based on (1) the combination of van de Putte 1999 (Ex. 1008) and Kempeni 1999
`
`(Ex. 1011) and (2) the combination of van de Putte 1999 (Ex. 1008), Rau 1998
`
`(Ex. 1006), and Schattenkirchner 1998 (Ex. 1007). In its decision, the Board
`
`indicated that, on the record before it, the selection of the claimed dosing regimen
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`would “have been no more than a routine optimization” of the dosing regimens
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`disclosed in the prior art. Paper 9, 19. The full record now before the Board
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`proves otherwise.1
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`A person of ordinary skill in the art (“POSA”) would not have been
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`motivated to “optimize” the dosing regimens in the prior art to arrive at the
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`claimed dosing regimen. Nor would a POSA have expected that the claimed
`
`
`1 With this response, Patent Owner submits the declarations of Allan Gibofsky, an
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`expert rheumatologist, Alexander Vinks, an expert in pharmacokinetics, Jeffrey
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`Sailstad, an expert in anti-drug antibodies, Bryan Harvey, a former FDA official
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`who addresses the non-routine nature of biologic clinical trials, and Jerry
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`Hausman, an economics expert who discusses the commercial success of the
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`claimed invention. See Exs. 2071-2075.
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`1
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`Case IPR2016-00409
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`dosing regimen would work. To the contrary, the clinical and pharmacokinetic
`
`(“PK”) data in the prior art taught away from the claimed invention because a
`
`POSA would have believed that the claimed dosing regimen would result in drug
`
`concentration levels that were too low to treat rheumatoid arthritis (“RA”).
`
`Ground 1 of the Petition relies on the same prior art as the Petitions filed by
`
`Coherus Biosciences, Inc. (“Coherus”; see IPR2016-00172, IPR2016-00188,
`
`IPR2016-00199). The nominally different art of Ground 2 discusses the identical
`
`clinical trials as the art at issue in Ground 1. Petitioner relies on the same
`
`arguments as Coherus, at best repackaging them with different emphases. But
`
`Petitioner’s repackaged arguments have no more merit than those made by
`
`Coherus and should be rejected for the same reasons.
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`First, like Coherus, Petitioner relies on weight-based dosing regimens in the
`
`prior art to supply both the motivation to modify the 20mg weekly dosing regimen
`
`of van de Putte 1999 and a reasonable expectation of success. The prior art,
`
`however, showed that the weight-based dose of 0.5mg/kg that Petitioner alleges is
`
`equivalent to the claimed 40mg dose (obtained by multiplying 0.5mg/kg by an
`
`average patient weight of 80kg) was insufficient to treat RA. In the primary study
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`relied on by Petitioner, every single patient receiving the 0.5mg/kg dose was
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`switched to a higher dose by 12 weeks after the trial began (or withdrew from the
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`study altogether) because the 0.5mg/kg dose did not work. These clinical results
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`2
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`

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`Case IPR2016-00409
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`would have indicated to a POSA that the claimed methods of treatment would have
`
`been insufficient. Consequently, a POSA would not have been motivated to try the
`
`claimed dosing regimens and would not have expected them to succeed.
`
`Second, also like Coherus, Petitioner bases its obviousness theory on a
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`comparison between the drug concentrations resulting from the weekly doses
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`disclosed in van de Putte 1999 and the claimed 40mg every-other-week dose. But
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`Petitioner’s oversimplification of the amount of D2E7 antibody in the body after
`
`two weeks is incorrect and ignores the multiple, complex PK parameters involved
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`in predicting drug concentration at steady state. In particular, as Petitioner’s PK
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`expert conceded, a POSA would have expected the minimum drug concentration
`
`between each dose (“Cmin”) to be less in the claimed dosing regimen than the
`
`minimum drug concentration in the dosing regimens disclosed in van de Putte
`
`1999. Ex. 2069, 126:1-10 (acknowledging that a lower Cmin was a “logical
`
`expectation”). Lower troughs of drug concentration would have raised both
`
`efficacy and safety issues.
`
`A POSA would have been particularly concerned about under-dosing
`
`patients with D2E7 because of the fear that too little drug in the blood would
`
`increase the risk of anti-drug antibodies (“ADAs”). In addition to presenting safety
`
`concerns, ADAs were known to decrease the efficacy of biologic drugs by
`
`increasing the speed at which they are removed from the body or by interfering
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`3
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`Case IPR2016-00409
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`with the ability to bind to their targets. Once an immune response to an anti-TNFα
`
`biologic is generated, any loss of efficacy is typically permanent and the patient
`
`may no longer respond to the drug at all.
`
`In short, because the prior art taught away, the claimed invention could not
`
`have resulted from “routine optimization.” The clinical and PK evidence available
`
`to a POSA would have suggested that a fixed 40mg every-other-week dose would
`
`not be an effective dose across the patient population. A POSA seeking to develop
`
`a safe and effective dosing regimen for D2E7 from among the numerous dosing
`
`options that were possible would therefore not have been led to the claimed
`
`invention or found it “obvious to try.” See KSR Int'l Co. v. Teleflex Inc., 550 U.S.
`
`398, 421 (2007). And a POSA who nonetheless tried the claimed invention would
`
`not reasonably have expected it to work. Petitioner has thus failed to carry its
`
`burden of proving that the challenged claims are unpatentable. In re Magnum Oil
`
`Tools, Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016) (“[T]he Board must base its
`
`decision on arguments that were advanced by a party, and to which the opposing
`
`party was given a chance to respond.”).
`
`Further, the objective evidence confirms the patentability of the claims.
`
`Although available clinical and PK data suggested the claimed dosing regimen
`
`would have been insufficient to treat RA, the claimed dosing regimen has
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`unexpectedly been one of the most effective treatments for RA since its
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`4
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`Case IPR2016-00409
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`introduction in 2003, achieving substantial commercial success and satisfying a
`
`long-felt need for new RA therapies. These achievements are directly attributable
`
`to the claimed invention.
`
`II.
`
`FACTUAL STATEMENT
`A. The Prior Art
`In June 2001, biologic agents designed to block TNFα activity were a new
`
`class of drugs that had shown promise for treating RA. Ex. 1011, 3; Ex. 2071 ¶16;
`
`Ex. 2075 ¶52. At that time, there were two FDA-approved anti-TNFα biologics:
`
`ENBREL® (a TNFα receptor fusion protein) and REMICADE® (a chimeric
`
`monoclonal antibody containing both murine and human sequences). Ex. 2071
`
`¶¶31-33, 74; Ex. 2075 ¶53.
`
`D2E7 (HUMIRA®) is also a monoclonal antibody but was developed solely
`
`from human genetic material. Ex. 2071 ¶40; Ex. 2075 ¶76. It was the first fully-
`
`human antibody to be approved by the FDA and the first antibody of any kind
`
`approved by FDA for subcutaneous administration. Ex. 2071 ¶40; Ex. 2072 ¶11;
`
`Ex. 2075 ¶58; Ex. 2027, 10-12. Notably, the use of monoclonal antibodies as
`
`therapeutic agents was in its infancy in 2001. Only 11 such antibodies had been
`
`approved, most for acute rather than chronic conditions. Ex. 2072 ¶11.
`
`The prior art pertaining to D2E7 contained preliminary data from four Phase
`
`I clinical trials and one Phase II trial. See Ex. 2071 ¶¶43-51; Ex. 2075 ¶77, 91.
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`5
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`Case IPR2016-00409
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`Limited information about these early trials was published in abbreviated form in
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`review articles and conference abstracts, including van de Putte 1999 (Ex. 1008),
`
`Kempeni 1999 (Ex. 1011), Rau 1998 (Ex. 1006), and Schattenkirchner 1998 (Ex.
`
`1007).2 Collectively, the D2E7 prior art discussed a variety of dosing strategies
`
`involving different routes of administration, dosing schedules, dosing amounts, and
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`response rates. Ex. 2071 ¶16; Ex. 2070, 50:7-52:6; 53:9-53:22; Ex. 2075 ¶78, 85,
`
`88, 92.
`
`The different trials were denominated by number, e.g., DE001, and
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`individual trials are discussed in several references. A summary of the D2E7 trials
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`relied on by Petitioner involving weight-based doses (every trial except the DE007
`
`trial) is shown in the table below.
`
`
`2 As explained in a publication co-authored by Petitioner’s declarant Dr. Weisman,
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`abstracts are “Category D evidence” (the lowest form) because “they are not
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`complete and may change by the time the data are published, or may not be
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`published as full papers at all.” Ex. 2038, 7; see also Ex. 2070, 284:12-285:1;
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`286:18-287:19.
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`6
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`Case IPR2016-00409
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`Weight-based D2E7 Study
`(Reference)
`
`Doses (mg/kg) Route
`
`Dose Frequency
`
`Up-dosing
`
`DE001
`(Kempeni 1999,
`Rau 2000)
`
`0.5, 1, 3, 5,
`and 10
`
`IV
`
`Single
`
`N/A
`
`DE003
`(Kempeni 1999,
`Rau 1998, Rau 2000)
`
`Based on efficacy;
`0.5
`1, 3, 5,
`mean interval
`,IV
`and 10
`of 2.5 weeks
`
`DE004
`(Kempeni 1999,
`Schattenkirchner 1998,
`Rau 2000)
`
`DE010
`(Kempeni 1999,
`Rau 2000)
`
`0.5 and 1
`
`SC
`
`Weekly
`
`1 (with MTX)
`
`IV, SC
`
`Single*
`
`YES
`
`YES
`
`
`
`The clinical trials that led to the claimed invention did not constitute the
`
`* Open-label study continued but data not available in prior art
`
`
`
`exercise of “routine optimization” of a dosing regimen. Developing a clinical trial
`
`for an investigational new drug is a complex and unpredictable endeavor. Ex.
`
`2072 ¶¶7-9, 13-18. Clinical trials of a biologic product—particularly an
`
`investigational new drug that has not yet been approved for human use—require an
`
`enormous investment of resources and face a high risk of failure. Id. ¶¶8, 15-20.
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`Notably, biologics routinely fail to advance towards approval at even the later
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`phases of clinical trials for any number of reasons, including the failure of a drug’s
`
`dosing regimen. Id. ¶¶9, 18-20. Indeed, poor dose selection was the leading
`
`reason for delay and denial of FDA approval based on a review of NDAs
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`submitted between 2000 and 2012. Id. ¶18; Ex. 2080, 4, 6.
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`7
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`Case IPR2016-00409
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`1. Kempeni 1999
`Kempeni discloses several early “weight-based” D2E7 prior art trials. Ex.
`
`1011, 4-5; Ex. 2075 ¶77; Ex. 2071 ¶¶43-48. The first Phase I study (DE001)
`
`examined 120 total patients, divided into 5 groups, who received placebo or a
`
`single intravenous dose of D2E7 based on weight (0.5 to 10mg/kg). Ex. 1011, 4;
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`Ex. 2075 ¶¶79, 83-84; Ex. 2070, 55:13-56:2.
`
`The DE001 study was followed by an open-label extension (DE003) in
`
`which patients continued to receive intravenous injections based on their body-
`
`weight. Ex. 1011, 4; Ex. 2075 ¶85. Specifically, patients received a first dose
`
`identical to the dose received in the DE001 study (0.5, 1, 3, 5 or 10mg/kg) a
`
`minimum of four weeks after the DE001 dose, and only after losing response
`
`status. Ex. 1011, 4; Ex. 1006, 5. Thereafter, patients received D2E7 every 2
`
`weeks “until responses could be rated as ‘good’, defined as an absolute DAS
`
`[Disease Activity Score] of < 2.4.” Ex. 1011, 4. They were then re-treated on a
`
`schedule having a minimum of two week intervals, but only upon disease flare-up.
`
`Ex. 2040, 5; Ex. 1011, 4; Ex. 1006, 5; Ex. 2070, 58:20-59:21; 117:24-118:10. The
`
`mean dosing interval across all doses was 2.5 weeks. Ex. 1011, 4; Ex. 1006, 5; Ex.
`
`2070, 128:17-20; Ex. 2075 ¶87. Kempeni 1999 does not disclose the mean dosing
`
`interval for the 0.5 mg/kg dose or any other specific dose. Ex. 2070, 129:12-
`
`130:25.
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`8
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`Case IPR2016-00409
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`In the second Phase I study (DE004), just 24 patients received weekly
`
`subcutaneous weight-based doses of either placebo or 0.5mg/kg D2E7 for three
`
`months. Ex. 1011, 4-5; Ex. 2075 ¶¶88-89. The third Phase I study reported in
`
`Kempeni (DE010) involved a head-to-head comparison of a single, 1mg/kg
`
`weight-based dose of D2E7 administered either subcutaneously or intravenously in
`
`combination with methotrexate (MTX). Ex. 1011, 5; Ex. 2075 ¶90.
`
`Kempeni reports substantial variability in the effects of D2E7 on patients
`
`(called pharmacodynamic (“PD”) responses) following single administration. Ex.
`
`2075 ¶83. Specifically, in the three highest dose groups of the DE001 trial (the 3,
`
`5, and 10mg/kg groups), “40-70% of patients achieved DAS and ACR20 response
`
`status at 24 hours to 29 days” post-treatment, indicating significant patient-to-
`
`patient variability both with respect to whether the drug would work and how long
`
`it would take.3 Ex. 1011, 4.
`
`
`3 DAS (Disease Activity Score) and ACR20 (American College of Rheumatology)
`
`are composite criteria used to measure the effectiveness of RA treatments. Ex.
`
`1011, 3-4; Ex. 2071 ¶42; Ex. 2092, 1; Ex. 2075 ¶¶80-82. ACR20 requires a 20%
`
`or greater improvement in certain outcomes, while another more robust measure
`
`called ACR50 requires a 50% or greater improvement. Ex. 2071 ¶41.
`
`9
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`Case IPR2016-00409
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`In both of the multi-dose trials reported in Kempeni (DE003 and DE004),
`
`patients who received a weight-based dose of 0.5mg/kg had to be “up-dosed” to
`
`maintain their responder status. Ex. 1011, 4-5; Ex. 2070, 77:16-82:7; Ex. 2075
`
`¶¶86, 88. In the DE003 trial, all of the patients receiving the 0.5mg/kg dose were
`
`up-dosed to higher doses (or withdrew from the study altogether) by week 12. Ex.
`
`2158, Figs. 4 and 5. This need to up-dose indicated that a 0.5mg/kg dose is
`
`insufficient for treating RA across the patient population. See Ex. 2071 ¶¶17, 45-
`
`46, 61, 63-65, 94; Ex. 2075 ¶¶155-156. Petitioner equates this dose with the
`
`claimed 40mg dose (by assuming an average patient weight of 80kg). Pet. 44; Ex.
`
`2069, 129:16-23; Ex. 2070, 61:16-19. Applying Petitioner’s premise, the claimed
`
`40mg dosing regimen also would have been understood to be insufficient.
`
`Moreover, the 0.5mg/kg dose in the DE003 trial was administered
`
`intravenously. Ex. 1011, 4; Ex. 2071 ¶45; Ex. 2070, 55:20-56:8. Compared to
`
`intravenous dosing, subcutaneous administration (administration under the skin)
`
`decreases the bioavailability of the administered drug, because less drug reaches
`
`the bloodstream. Accordingly, subcutaneous dosing of 40mg would have been
`
`understood to result in lower concentrations of drug than those resulting from
`
`intravenous administration of a 0.5mg/kg dose to an 80kg patient. Ex. 2075 ¶¶32-
`
`35, 71, 126-127; see also Ex. 2017, 29; Ex. 2091, 19-20.
`
`10
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`Case IPR2016-00409
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`The 0.5mg/kg dosing regimen of DE004 would also have delivered more
`
`drug than the claimed 40mg every-other-week regimen. The dosing interval for
`
`DE004 was weekly (Ex. 1011, 4); thus, twice as much drug would have been
`
`delivered to an 80kg patient. The evidence of the need to up-dose patients
`
`receiving either a 0.5mg/kg dose weekly (DE004) or 0.5mg/kg intravenously
`
`(DE003) indicates that a subcutaneously administered every-other-week 40mg
`
`dose would be insufficient.
`
`van de Putte 1999
`
`2.
`van de Putte 1999 is a conference abstract that reports preliminary data from
`
`the first D2E7 Phase II trial. Ex. 1008, 7; Ex. 2071 ¶49; Ex. 2075 ¶91. This trial,
`
`called DE007, featured a three-month placebo-controlled study in which patients
`
`received a fixed dose of 20, 40, or 80mg D2E7 administered subcutaneously on a
`
`weekly schedule. Ex. 1008, 7; Ex. 2075 ¶92; Ex. 2069, 83:20-22. DE007 was the
`
`first fixed dose trial; all of the previous trials used weight-based dosing. Ex. 2071
`
`¶43.
`
`The DE007 study was not powered to provide statistically meaningful
`
`comparisons between doses, but only to determine the statistical significance of
`
`each of the doses compared to placebo. Ex. 2071 ¶79; Ex. 2069, 84:5-12. While
`
`the authors concluded that “20, 40 and 80 mg/week were nearly equally
`
`efficacious,” this statement was based on a comparison of each group to placebo,
`
`11
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`

`Case IPR2016-00409
`
`not to each other. Ex. 1008, 7. As discussed in §IV.A.1 infra, the data showed
`
`that while each dose was statistically superior to placebo, the 40 and 80mg doses
`
`were numerically superior to the 20mg dose. Ex. 2071 ¶¶18, 50-51; Ex. 2075 ¶93.
`
`After 3 months, patients receiving placebo were switched to a 40mg weekly
`
`dose. Ex. 2086, 2; Ex. 2075 ¶94. Those patients showed greater improvement in
`
`ACR20, SJC, and CRP after just 3 months of 40mg weekly dosing compared to
`
`patients who received 20mg weekly for 6 months.4 Ex. 2086, 2; Ex. 2071 ¶81.
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`The difference between 20mg and the higher weekly doses becomes even
`
`more evident at 12 months. For example, the ACR50 for the 20mg weekly group
`
`remains essentially the same between 3 and 12 months (24% vs. 25%), whereas the
`
`40mg weekly dose experiences a 59% improvement (27% vs. 43%). Ex. 2090, 5;
`
`Ex. 2071 ¶82. Further, the percent response for patients receiving 40 and 80mg
`
`weekly doses was numerically superior for every clinical measure compared to
`
`20mg weekly. Ex. 2090, 5; Ex. 2071 ¶82.
`
`
`
`
`
`
`
`
`4 SJC refers to Swollen Joint Count. CRP refers to C reactive protein, a biomarker
`
`of inflammation. Ex. 2071 ¶¶41, 49.
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`Case IPR2016-00409
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`
`
`
`20mg
`3 mos./12 mos.
`49/46
`24/25
`52/51
`39/52
`53/55
`
`Percent Response or Improvement
`40mg
`3 mos./12 mos.
`59/60
`27/43
`57/60
`56/65
`61/64
`
`80mg
`3 mos./12 mos.
`56/56
`19/31
`53/60
`54/59
`64/60
`
`ACR20
`ACR50
`TJC (median)
`SJC (median)
`CRP (median)
`
`Other contemporaneous reports of the DE007 study do not even mention the
`
`efficacy of 20mg weekly dosing, indicating that the 40mg weekly regimen was
`
`preferred among the three regimens. Ex. 2020, 4; Ex. 2071 ¶83. Moreover, in the
`
`full-length, peer-reviewed article reporting the data, the authors state that “40 mg
`
`was associated with better results than the other doses.” Ex. 2041, 9 (emphasis
`
`added); Ex. 2071 ¶84; Ex. 2075 ¶95.
`
`Rau 1998
`
`3.
`Rau 1998 is an abstract that reports data from the DE003 study also
`
`discussed in Kempeni. Rau 1998 does not add any material information to the
`
`prior art not also available from Kempeni. Ex. 2071 ¶73; Ex. 2075 ¶85.
`
`As indicated above, DE003 was an open-label continuation of the DE001
`
`study involving intravenously dosed amounts based on body weight. Ex. 1006, 5.
`
`Patients who did not respond well after 0.5 or 1mg/kg received higher doses. Ex.
`
`1011, 4; Ex. 2070, 78:10-80:1. Six patients dropped out of the DE003 study due to
`
`lack of efficacy. Ex. 1006, 5; Ex. 2070, 124:12-25.
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`Case IPR2016-00409
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`Based on Petitioner’s conversion of a 0.5mg/kg weight-based dose to a
`
`40mg fixed dose, the logical conclusion a POSA would have drawn from the
`
`DE003 study, and in particular the up-dosing in that study, is that 40mg of D2E7
`
`administered subcutaneously every-other-week would have been insufficient
`
`across the patient population for reasons noted in §II.A.1, above. See also
`
`§IV.A.1, infra.
`
`Schattenkirchner 1998
`
`4.
`Like Rau 1998, Schattenkirchner 1998 is also an abstract that reports on data
`
`from a study (DE004) discussed in Kempeni. Schattenkirchner 1998 does not add
`
`any material information to the prior art not also available from Kempeni. Ex. 2071
`
`¶73; Ex. 2075 ¶¶88-89.
`
`The DE004 trial included weekly, subcutaneous administration of a weight-
`
`based dose of 0.5mg/kg. Ex. 1011, 4-5; see also Ex. 1007, 5. “[N]on-responders
`
`or those losing their responder status” were up-dosed to 1mg/kg weekly. Ex. 1011,
`
`5; Ex. 1007, 5; see Ex. 2070, 75:6-77:10; 80:2-82:7. Thus, as with the DE003
`
`study (in which up-dosing was also reported), the logical conclusion a POSA
`
`would have drawn from the DE004 study is that the claimed every-other-week
`
`dosing regimen would have been insufficient across the patient population.
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`Case IPR2016-00409
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`The PK Data in Kempeni
`
`B.
`Kempeni reports three PK parameters: (1) mean total serum clearance, (2)
`
`steady-state volume of distribution, and (3) an “estimated mean terminal half life”
`
`of 11.6 to 13.7 days. Ex. 1011, 4; Ex. 2075 ¶79. These three metrics are reported
`
`as ranges in Kempeni, which does not report any patient-specific PK information.
`
`Clearance refers to the rate at which a drug is eliminated from the body and
`
`is typically expressed as mL/min. Ex. 2075 ¶31. Volume of distribution refers to
`
`the theoretical volume over which the drug is distributed. It is typically expressed
`
`as L/kg, where kg is the weight of the patient. Id.
`
`Terminal half-life, a calculated value, refers to the time taken for the
`
`concentration of the drug in the blood to fall by 50% during the elimination phase
`
`of a PK profile (the period when the rate of drug elimination due to excretion
`
`and/or metabolism predominates). Id. ¶30. Terminal half-life provides no
`
`information about the “absorption” phase (the period when the drug moves from
`
`the site of administration to the blood) or “distribution” phase (the period in which
`
`the drug is distributed to other areas in the body). Id. ¶¶26-27, 33, 37; see also Ex.
`
`2017, 14-20. Thus, in the case of a subcutaneously administered drug, the terminal
`
`half-life does not reflect how long the drug is in the body, nor does it provide any
`
`information about how long the drug is at the site of action. Ex. 2075 ¶111.
`
`Importantly, half-life also does not itself reveal any information about the
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`Case IPR2016-00409
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`concentration of drug in the blood, the PK parameter of primary importance for
`
`designing a dosing regimen. Id. ¶¶37, 110, 112; Ex. 2091, 41.
`
`Neither Kempeni nor any other prior art reference reports key exposure
`
`metrics, such as Cmin, Cmax, or AUC, for D2E7. Ex. 2075 ¶132; Ex. 2069, 92:18-
`
`93:20. Cmax and Cmin respectively refer to the peaks and troughs of a curve that
`
`graphs exposure to a drug over time. Ex. 2075 ¶¶36, 40. AUC is the total area
`
`under a PK curve and reflects overall exposure to a drug. Id. ¶36.
`
`C. The ’135 Patent
`The ’135 patent claims priority to an application filed June 8, 2001.
`
`Ex. 1001, (60). It contains five claims directed to methods of treating RA in a
`
`human involving administering an anti-TNFα antibody having the six CDRs and
`
`heavy chain constant region of D2E7. Id., 45:11-46:30. The claims cover the first-
`
`approved dosing regimen for HUMIRA®.
`
` Each of the claims requires
`
`administering a total body dose of 40mg subcutaneously once every 13-15 days for
`
`a period of time sufficient to treat RA. Id.
`
`D. HUMIRA®
`HUMIRA® was first approved for the treatment of RA at the end of
`
`December 2002. Ex. 2071 ¶40; Ex. 2134, 1; Ex. 2135, 14. As the Panel
`
`recognized, it is uncontroverted that HUMIRA® has been a commercial success in
`
`the treatment of RA. See Paper 9, 19-20.
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`Case IPR2016-00409
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`The success of HUMIRA® is largely attributable to its safety and efficacy,
`
`which is inextricably bound up with the invention of a safe and efficacious dosing
`
`regimen. Ex. 2073 ¶14-15. HUMIRA® also satisfied the need for an anti-TNFα
`
`therapy that could be safely self-administered at home, that did not require weight-
`
`based calculations of dose amount, and that maximized patient comfort and
`
`convenience by limiting the number of injections. Ex. 2071 ¶¶102-103. Each of
`
`these features results from the claimed invention as a whole.
`
`III.
`
`INSTITUTION DECISION
`The Board instituted inter partes review of claims 1-5 of the ’135 patent
`
`based on the combination of Kempeni 1999 and van de Putte 1999 (Ground 1) and
`
`the combination of Rau 1998, Schattenkirchner 1998, and van de Putte 1999
`
`(Ground 2) under 35 U.S.C. §103. Paper 9, 22-23.
`
`The Board did not expressly define the level of skill of a POSA. See Paper
`
`9, 9 n.5. In IPR2016-00172, however, the Board defined a POSA for the ’135
`
`patent as a person possessing the skill sets of both a physician treating RA patients
`
`and a pharmacokineticist with experience in monoclonal antibodies. Coherus
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`Case IPR2016-00409
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`Biosciences Inc. v. AbbVie Biotechnology Ltd., IPR2016-00172, Paper 9, 5-6 n.3
`
`(May 17, 2016). The Board should adopt the same definition here.5
`
`The Board declined to construe the phrase “for a time period sufficient to
`
`treat the rheumatoid arthritis” but noted that the claim term “does not require a
`
`particular level of efficacy.” Paper 9, 7. The