Paper No. 8
`October 12, 2021
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`FRESENIUS KABI USA, LLC and FRESENIUS KABI SWISSBIOSIM GmbH
`Petitioners,
`
`v.
`
`CHUGAI SEIYAKU KABUSHIKI KAISHA,
`Patent Owner.
`
`_________________________________________________
`
`IPR 2021-01025
`
`U.S. Patent No. 10,744,201
`
`_________________________________________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`

`

`
`
`
`TABLE OF CONTENTS
`
`I. INTRODUCTION .............................................................................................. 1
`II. BACKGROUND ................................................................................................. 1
`A. Rheumatoid Arthritis .................................................................................... 1
`B. Disease Modifying Anti-Rheumatic Drugs .................................................. 2
`C. Biologic Treatments for RA .......................................................................... 5
`D. Interleukin-6 ................................................................................................... 8
`E. Petitioners’ Copying of Actemra® .............................................................. 10
`III. THE ’201 PATENT ......................................................................................... 10
`A. The Specification .......................................................................................... 10
`B. Prosecution History ..................................................................................... 13
`C. Claims ........................................................................................................... 16
`IV. THE PETITION .............................................................................................. 17
`V. ARGUMENT ..................................................................................................... 18
`A. The Board Should Decline to Institute Under Section 325(d). ................ 18
`1. Ground 1 Rehashes the Same Art and Arguments the
`Examiner Considered and Properly Declined to Credit. ................... 19
`2. The Examiner Considered and Rejected the Obviousness
`Arguments Petitioners Advance in Ground 2. ..................................... 27
`B. Petitioners Fail to Show a Reasonable Likelihood That Any Claim
`of the ’201 Patent is Invalid. ....................................................................... 34
`1. Nishimoto Does Not Anticipate. ............................................................. 35
`2. The Claims Are Not Obvious. ............................................................... 40
`
`i
`
`

`

`C. The Board Should Decline to Institute Under NHK Spring/Fintiv. ........ 54
`VI. CONCLUSION ................................................................................................ 57
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Advanced Bionics, LLC v. Med-El Elektromedizinische
`Geräte GmbH, IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) ................passim
`Apple Inc. v. Fintiv, Inc., IPR2020-00019,
`Paper 11 (PTAB Mar. 20, 2020) ............................................................. 54, 55, 56
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ........................................passim
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 53
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1341 (Fed. Cir. 2013) .......................................................................... 37
`Cont. Can Co. USA, Inc. v. Monsanto Co., 948 F.2d 1264
`(Fed. Cir. 1991) ................................................................................................... 38
`In re Robertson, 169 F.3d 743 (Fed. Cir. 1999) ...................................................... 39
`In re Soni, 54 F.3d 746 (Fed. Cir. 1995) .................................................................. 51
`Institut Pasteur & Universite Pierre Et Marie Curie
`v. Focarino, 738 F.3d 1337 (Fed. Cir. 2013) ...................................................... 47
`Indivior Inc. v. Rhodes Pharms. L.P., IPR2018-00795,
`Paper 23 (PTAB Oct. 4, 2018) ............................................................................ 26
`King Pharms., Inc. v. Eon Labs., Inc., 616 F.3d 1267
`(Fed. Cir. 2010) ................................................................................................... 40
`Metabolite Labs., Inc. v. Lab. Corp. Am. Holdings,
`370 F.3d 1354 (Fed. Cir. 2004) .......................................................................... 39
`NHK Spring Co. v. Intri-Plex Techs., Inc.,
`IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018) ............................................... 54
`
`iii
`
`

`

`Plant Genetic Sys., N.V. v. Dekalb Gen. Corp.,
`315 F.3d 1335 (Fed. Cir. 2003) .......................................................................... 53
`Sandoz Inc. v. Amgen Inc., 137 S. Ct. 1664 (2017) ........................................... 54, 55
`Scripps Clinic & Res. Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) .......................................................................... 37
`Studiengesellschaft Kohle, m.b.H v. Dart Indus.,
`726 F.2d 724 (Fed. Cir. 1984) ...................................................................... 35, 38
`Statutes
`35 U.S.C. § 314(a) ................................................................................................... 34
`35 U.S.C. § 325(d) ............................................................................................passim
`42 U.S.C. § 262(l) .............................................................................................. 54, 55
`
`
`
`iv
`
`

`

`
`
`Exhibit
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`LISTING OF EXHIBITS
`
`Description
`Aletaha, D. & Smolen, J.S., The rheumatoid arthritis patient in
`the clinic: comparing more than 1300 consecutive DMARD
`courses, RHEUMATOL., 41:1367-74 (2002).
`
`Bulpitt, K., Biologic Therapies in Rheumatoid Arthritis, CURR.
`RHEUMATOL. REP., 1:157-63 (1999).
`
`Calabrese, L.H., Molecular differences in anitcytokine
`therapies, CLIN. EXPER. RHEUMATOL., 21:241-48 (2003).
`
`Carmichael, S.J., et al., Combination therapy with methotrexate
`and hydroxychloroquine for rheumatoid arthritis increases
`exposure to methotrexate, J. RHEUMATOL., 29(10):2077-83
`(2002).
`
`Combe, B., et al., EULAR recommendations for the
`management of early arthritis: report of a task force of the
`European Standing Committee for International Clinical
`Studies Including Therapeutics (ESCISIT), ANN. RHEUMATOL.
`DIS., 66:34-45 (2007).
`
`Conaghan, P.G. & Brooks, P., Disease-modifying antirheumatic
`drugs, including methotrexate, gold, antimalarials, and D-
`penicillamine, CURR. OP. RHEUMATOL., 7:167-73 (1995).
`
`Cutolo, M., et al., Anti-inflammatory mechanisms of
`methotrexate in rheumatoid arthritis, ANN. RHEUMATOL. DIS.,
`60:729-35 (2001).
`
`Deon, D., et al., Cross-talk between IL-1 and IL-6 signaling
`pathways in rheumatoid arthritis synovial fibroblasts, J.
`IMMUNOL., 167(9):5395-5403 (2001).
`
`European Medicines Agency, ICH Topic E 5 (R1) Ethnic
`Factors in the Acceptability of Foreign Clinical Data, Sept.
`1998, https://www.ema.europa.eu/en/documents/scientific-
`
`v
`
`

`

`Exhibit
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`Description
`guideline/ich-e-5-r1-ethnic-factors-acceptability-foreign-
`clinical-data-step-5_en.pdf.
`
`Felson, D.T., et al., The efficacy and toxicity of combination
`therapy in rheumatoid arthritis, ARTHRITIS RHEUMATOL.,
`37(10):1487-91 (1994).
`
`Fleischmann, R.M., Examining the efficacy of biologic therapy:
`are there real differences?, J. RHEUMATOL., Suppl. 65:27-32
`(2002).
`
`Frei, E., et al., Seminars in Medicine of the Beth Israel
`Hospital, Boston: New Approaches to Cancer Chemotherapy
`with Methotrexate, NEW ENG. J. MED., 292(16):846-51 (1975).
`
`Keyston, E.C., Abandoned therapies and unpublished trials in
`rheumatoid arthritis, CURR. OP. RHEUMATOL., 15:253-58
`(2003).
`
`Kremer, J.M., The mechanism of action of methotrexate in
`rheumatoid arthritis: the search continues, J. RHEUMATOL.,
`21:1-5 (1994).
`
`Kremer, J.M., Methotrexate and Emerging Therapies,
`RHEUMATOL. DIS. CLIN. N. AM., 24(3):651-58 (1998).
`
`Kremer, J.M., Not yet time to change the guidelines for
`monitoring methotrexate liver toxicity: they have served us
`well, J. RHEUMATOL., 29(8):1590-92 (2002).
`
`Elliott, M.J. & Maini, R.N., Anti-cytokine therapy in
`rheumatoid arthritis, BAILLIERES CLIN. RHEUMATOL., 9(4):633-
`52 (1995).
`
`Moreland, L.W., Initial experience combining methotrexate
`with biologic agents for treating rheumatoid arthritis, J.
`RHEUMATOL., Suppl. 44:78-83 (1996).
`
`
`vi
`
`

`

`Exhibit
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`Description
`Okuda, O., Anti-IL-6 receptor antibody MRA, Chugai Pharm.
`Co., Ltd., Project Promotion Dep’t (Jan. 21, 2003) (A301).
`
`Okuda, O., Anti-IL-6 receptor antibody MRA, Chugai Pharm.
`Co., Ltd., Project Promotion Dep’t (Jan. 21, 2003) (A302).
`
`Rheumatrex®, Methotrexate Sodium Tablets, Oct. 2003,
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/08
`085slr052,scm055_rheumatrex_lbl.pdf.
`
`Verhoeven, A.C., et al., Combination therapy in rheumatoid
`arthritis: updated systematic review, BRIT. J. RHEUMATOL.,
`37:612-19 (1998).
`
`Weinblatt, M.E., et al., A trial of etanercept, a recombinant
`tumor necrosis factor receptor:fc fusion protein, in patients
`with rheumatoid arthritis receiving methotrexate, NEW ENG. J.
`MED., 340:253-59 (1999).
`
`Williams, H.J., et al., Comparison of auranofin, methotrexate,
`and the combination of both in the treatment of rheumatoid
`arthritis, ARTHRITIS RHEUMATOL., 35(3):259-69 (1992).
`
`Xing, Z., et al., IL-6 is an antiinflammatory cytokine required
`for controlling local or systemic acute inflammatory responses,
`J. CLIN. INVEST., 311-20 (1998).
`
`1 Shaun Ruddy et al., KELLEY’S TEXTBOOK OF RHEUMATOLOGY
`Chs. 20, 62, 64, & 65 (6th ed. 2001).
`
`Uchida, K., Acceptability of Foreign Clinical Trial Data in
`Japan, DRUG INF. J., 22:103-08 (1988).
`
`Fresenius Kabi’s tocilizumab biosimilar candidate MSB11456
`shows positive results in two clinical trials, Fresenius Kabi,
`Sept. 7, 2021, https://www.fresenius-kabi.com/news/fresenius-
`kabi-tocilizumab-shows-positive-results-in-two-clinical-trials.
`
`
`vii
`
`

`

`Description
`Pharmacokinetics/Pharmacodynamics (PK/PD) Equivalence
`Study of MSB11456 (NCT03282851), ClinicalTrials.gov,
`https://clinicaltrials.gov/ct2/show/NCT03282851 (last updated
`Feb. 12, 2020).
`
`MSB11456 in Participants with Moderately to Severely Active
`Rheumatoid Arthritis (NCT04512001), ClinicalTrials.gov,
`https://clinicaltrials.gov/ct2/show/NCT04512001 (last updated
`Mar. 11, 2021).
`
`
`2021.09.27 Email from K. DeJong to T. Fletcher.
`
`Exhibit
`
`2029
`
`2030
`
`
`2031
`
`
`
`
`viii
`
`

`

`I.
`
`INTRODUCTION
`This is the paradigm case for denying institution under 35 U.S.C. § 325(d).
`
`All of the art Petitioners cite was before the Examiner during prosecution. All of
`
`Petitioners’ arguments were, in substance, the bases for rejections the Examiner
`
`eventually withdrew.
`
`Even if the Petition’s arguments were new, they would not justify institution
`
`because there is no reasonable likelihood any of the challenged claims are invalid.
`
`To the contrary, the Examiner was plainly correct in finding them neither obvious
`
`nor anticipated. For either of these reasons, the Petition should be denied.
`
`II. BACKGROUND
`United States Patent 10,744,201 claims the coadministration of tocilizumab
`
`and methotrexate, in specified dosages and with a specified effect, to treat
`
`rheumatoid arthritis (“RA”). Tocilizumab is a recombinant humanized antibody
`
`that targets interleukin-6 (“IL-6”) receptors and is the active ingredient of
`
`Actemra®, a drug the Patent Owner (Chugai) developed and that FDA has
`
`approved for treating RA and other diseases.
`
`The ’201 Patent claims priority to an application filed on April 28, 2003.
`
`A. Rheumatoid Arthritis
`RA is a chronic, inflammatory disease afflicting about 1 percent of the
`
`population worldwide. See Ex. 2026 (Kelley’s 2001) at 32. Although principally
`
`characterized by swelling and discomfort in the joints, RA “can exhibit a variety of
`
`1
`
`

`

`extra-articular manifestations” and thus “has features of a systemic disease that is
`
`capable of involving a variety of major organ systems.” Id.
`
`As of the priority date (2003), scientists had been studying the causes of RA
`
`for decades, id., but “[d]espite intensive work, only modest progress ha[d] been
`
`achieved in determining the cause of RA.” Id. While detailed studies in the 1990s
`
`resulted in “clues” as to the source of the disease, “the plain truth is that [scientists]
`
`still simply [did] not know what causes RA” by the early 2000s. Id.; see also Ex.
`
`2014 (Kremer 1994) at 1. The disease is instead characterized by a collection of
`
`symptoms. Ex. 2026 (Kelley’s 2001) at 83-84.
`
`B. Disease Modifying Anti-Rheumatic Drugs
`This poor understanding of RA drove extensive experimentation with
`
`potential treatments, with physicians evaluating dozens of putative “disease-
`
`modifying antirheumatic drugs” (“DMARDs”)—including antimalarials, various
`
`forms of gold, azathioprine, sulfasalazine, methotrexate, cyclosporin A, and
`
`penicillamine, Ex. 2001 (Aletaha 2002) at 3. A silver bullet eluded discovery.
`
`“[T]rue remission or cure is still rare.” Id. at 7. DMARDs could stall the
`
`progression of RA but eventually “adverse events emerge or [the] drugs become
`
`ineffective,” so “50-60% of patients treated with a DMARD require[] a subsequent
`
`course with another drug.” Id.
`
`2
`
`

`

`By the 1990s the DMARD of choice for most physicians was methotrexate
`
`(“MTX”), a toxic small-molecule drug initially developed as a chemotherapy
`
`agent, Ex. 2015 (Kremer 1998) at 1; Ex. 2012 (Frei 1975) at 1. The scientific
`
`community was unsure, however, exactly how or why MTX worked to alleviate
`
`RA symptoms; why it was ineffective in many patients afflicted with RA; and why
`
`its efficacy generally waned with continued use. See Ex. 2014 (Kremer 1994) at 1;
`
`Ex. 2015 (Kremer 1998) at 2-3. Despite considerable study only “[t]antalizing and
`
`sometimes contradictory clues about how MTX might work in RA ha[d] emerged.”
`
`Ex. 2014 (Kremer 1994) at 1; see also Ex. 2015 (Kremer 1998) at 3; Ex. 1020
`
`(2000 PDR – Methotrexate) at 4.
`
`What physicians did know was that MTX (not surprisingly, for a cancer
`
`treatment) was “associated with the potential for serious toxicity,” especially in the
`
`liver (hepatotoxicity). Ex. 2015 (Kremer 1998) at 3; see also Ex. 1020 (2000 PDR
`
`– Methotrexate) at 3 (noting potential for “hepatotoxicity” with prolonged use of
`
`MTX). Its label warned that “[m]ethotrexate has the potential for serious toxicity,”
`
`Ex. 2021 (Rheumatrex Label 2003) at 8, and indeed had been associated with
`
`deaths “in the treatment of . . . Rheumatoid Arthritis,” Ex. 1020 (2000 PDR –
`
`Methotrexate) at 3; see also Ex. 2006 (Conaghan 1995) at 3 (noting “serious
`
`complications of methotrexate therapy, especially hepatic and pulmonary
`
`3
`
`

`

`toxicity”). Patients prescribed MTX had to undergo regular blood tests “to assess
`
`the very real potential for liver damage.” Ex. 2016 (Kremer 2002) at 3.
`
`Besides DMARD monotherapies, physicians treating patients with RA also
`
`experimented with combinations of the drugs. Some combinations proved more
`
`efficacious than administration of each DMARD alone, but other combinations
`
`produced only greater toxicity with no incremental relief. Many physicians viewed
`
`such combinations with skepticism and caution. A 1994 publication of the
`
`American College of Rheumatology concluded, based on five separate clinical
`
`trials, that “[c]ombination therapy, as it ha[d] been used in [those] clinical trials,
`
`does not offer a substantial improvement in efficacy, but does have higher toxicity
`
`than single drug therapy.” Ex. 2010 (Felson 1994) at 1; see also Ex. 2006
`
`(Conaghan 1995) at 1 (noting that “combination DMARD treatments have been
`
`disappointing” and “reports of clinically useful combinations are rare”).
`
`This applied in particular to combination therapies utilizing MTX. Ex. 2010
`
`(Felson 1994) at 3. A 1998 article that looked at treatments pairing MTX with
`
`other drugs found mixed results. Ex. 2022 (Verhoeven 1998) at 3. Administering
`
`combinations that included MTX required “extra vigilance,” as “patients receiving
`
`the combination . . . may be at increased risk of MTX induced toxicities.” See Ex.
`
`2004 (Carmichael 2002) at 6; Ex. 1020 (2000 PDR – Methotrexate) at 3.
`
`Physicians were advised to “await the results of [clinical] trials of one new agent at
`
`4
`
`

`

`a time when used with MTX” before administering combination therapies that
`
`might add only toxicity to patients who were suffering plenty already. Ex. 2015
`
`(Kremer 1998) at 3.
`
`C. Biologic Treatments for RA
`A revolution in the treatment of RA began in the late 1990s and early 2000s
`
`with the development of biologics that targeted cytokines associated with joint
`
`inflammation. Cytokines, “small proteins that are major effectors of the immune
`
`response,” Ex. 2002 (Bulpitt 1999) at 1-2, appear in elevated amounts in the joints
`
`of patients with RA, Ex. 2026 (Kelley’s 2001) at 5-6. Since some cytokines were
`
`known to be “proinflammatory,” scientists theorized that targeting them could help
`
`patients suffering from crippling inflammation. See, e.g., id. at 5-6, 23-24.
`
`But interfering with the biological process of cytokines was risky business.
`
`“Cytokines frequently have [] multiple biologic functions with overlapping
`
`effects.” Id. at 21. Thus, the “same cytokine may have different effects under
`
`different situations,” and “different cytokines can elicit the same biologic
`
`response.” Ex. 2002 (Bulpitt 1999) at 2. Those in the art understood that “[t]he
`
`result of cytokine manipulation is far from predictable.” Id. A single cytokine can
`
`affect organs throughout the body, not just the joints, so “[p]otentially all organ
`
`systems could be affected in different ways by the same agent” developed to
`
`neutralize it. Id. Targeting or interfering with cytokines might resolve one
`
`5
`
`

`

`medical problem only to create other, unpredictable, and potentially more serious
`
`ones. Id. Researchers “fail[ed] in developing most of these agents.” Ex. 2013
`
`(Keystone 2003) at 5.
`
`In 1998, FDA approved the first biologic treatment for RA, a fusion protein
`
`called etanercept. This molecule targets tumor necrosis-factor alpha (“TNF-α”), a
`
`proinflammatory cytokine often found in inflamed areas of the body, and whose
`
`inhibition scientists had theorized for years would reduce the joint inflammation
`
`RA patients suffered. Ex. 2026 (Kelley’s 2001) at 5-6; see also Ex. 2003
`
`(Calabrese 2003) at 2; Ex. 2017 (Elliott 1995) at 3. By 2002, FDA approved two
`
`other recombinant molecules targeting TNF-α: infliximab, a chimeric antibody,
`
`and adalimumab, a fully human antibody. Ex. 2003 (Calabrese 2003) at 3. All
`
`three molecules work essentially the same way: binding to TNF-α and preventing it
`
`from interacting with TNF-α receptors on the cell. See id.
`
`In 2001, FDA also approved another biologic RA treatment, anakinra, that
`
`targeted a different proinflammatory cytokine called interleukin-1 (“IL-1”). Ex.
`
`2026 (Kelley’s 2001) at 23. Anakinra is a recombinant human IL-1 receptor
`
`antagonist that inhibits IL-1 from activating the receptor. Ex. 2003 (Calabrese
`
`2003) at 3.
`
`Although extensive clinical testing established their safety and efficacy, the
`
`therapeutic pathways of these biologics were poorly understood. Scientists
`
`6
`
`

`

`studying them in the early 2000s still did not know whether these drugs inhibited
`
`cytokines systemically or only within the joints, nor had they determined the
`
`“precise events following cytokine inhibition that lead to therapeutic response.”
`
`Id. at 1.
`
`Besides their use as RA monotherapies, clinicians also experimented with
`
`combining these biologics and others in development with other DMARDs
`
`including MTX. With infliximab, for example, concerns that patients receiving
`
`this chimeric (i.e., half-human, half-mouse) antibody would suffer an
`
`immunogenic response prompted clinicians to experiment using it with MTX, a
`
`known immunosuppressant. Ex. 1015 (Maini 1998) at 2. Some of these clinical
`
`trials demonstrated advantages to combining the therapies, particularly the
`
`biologics targeting TNF-α—infliximab, etanercept, and adalimumab. Ex. 1008
`
`(Weinblatt 2003) at 1; Ex. 1015 (Maini 1998) at 1; Ex. 2023 (Weinblatt 1999) at 1.
`
`But combining MTX with other biologics was not uniformly successful. A
`
`clinical trial combining a “monoclonal anti-CD4 antibody” with MTX did not
`
`show any improvement over administration of MTX alone. Ex. 2022 (Verhoeven
`
`1998) at 2-4. Fully aware that all of the targeted cytokines affected myriad other
`
`processes in the body, clinicians remained “concern[ed over] increasing the risk of
`
`serious adverse events,” particularly given the toxicity risks associated with MTX
`
`when used as a monotherapy. Ex. 2018 (Moreland 1996) at 4. They understood
`
`7
`
`

`

`that only extensive clinical testing could demonstrate the safety of any therapy
`
`combining an anti-cytokine biologic with MTX. Id. FDA warned researchers on
`
`the same point. Ex. 1009 (FDA Guidance) at 17-18.
`
`Interleukin-6
`D.
`Interleukin-6 (“IL-6”), another cytokine found in elevated levels in the joints
`
`of RA sufferers, also attracted the interest of researchers, Ex. 2026 (Kelley’s 2001)
`
`at 25, although certain different properties distinguishing it from TNF-α and IL-1
`
`complicated development of biologics targeting it.
`
`For example, while TNF-α and IL-1 were known to be “major
`
`proinflammatory cytokines,” IL-6 was understood to have both “pro- and anti-
`
`inflammatory activity.” Ex. 2026 (Kelley’s 2001) at 5-6, 25; Ex. 2025 (Xing 1998)
`
`at 1 (finding that IL-6 plays a “crucial anti-inflammatory role”); Ex. 2008 (Deon
`
`2001) at 1 (discussing difference between “proinflammatory cytokines” like TNF-
`
`α and IL-1, and IL-6 which has “clear-cut anti-inflammatory effects”); Ex. 2017
`
`(Elliott 1995) at 14-16 (discussing differences between IL-6 and TNF-α). It was
`
`therefore unclear whether inhibiting IL-6 would aggravate or mitigate the
`
`inflammation RA patients experienced. See Ex. 2017 (Elliott 1995) at 15.
`
`Scientists also discovered that antibodies that targeted IL-6 directly could
`
`actually increase that cytokine’s activity. Ex. 2026 (Kelley’s 2001) at 25. Because
`
`IL-6 binds not only to receptors on the cell but also to soluble receptors that then
`
`8
`
`

`

`find their way to the cells, an antibody that mimicked a soluble receptor produced a
`
`cytokine-receptor complex and “prolong[ed] its activity in the circulation.” Id.
`
`Attempting to inhibit IL-6 directly, the same way etanercept, infliximab, and
`
`adalimumab target TNF-α, could actually worsen the patient’s RA symptoms. See
`
`id. Based on this and other potential problems, many experts had concluded by the
`
`turn of the century that inhibiting IL-6 had “fallen by the wayside” as a potential
`
`method for treating RA. Ex. 2003 (Calabrese 2003) at 6; see also Ex. 2017 (Elliott
`
`1995) at 15 (unlike TNF- α, “[t]he case for IL-6 as a target molecule in RA is
`
`rather more equivocal”).
`
`Despite this skepticism, scientists working at and with Chugai continued to
`
`investigate whether inhibiting IL-6 in some fashion could yield therapeutic
`
`benefits. They developed “MRA” (later known as tocilizumab), a humanized
`
`antibody PM-1 that bound, not directly to IL-6, but instead to the receptors to
`
`which IL-6 would otherwise bind to trigger its biological function. Chugai
`
`conducted clinical trials in order to demonstrate the safety and efficacy of
`
`tocilizumab as an RA treatment, in particular two trials in Japan evaluating MRA
`
`monotherapy and a European trial evaluating MRA in combination with MTX.
`
`Ex. 2020 (Okuda) at 14-27; Ex. 1006 (Nishimoto) at 4-5.
`
`Actemra®, Chugai’s product comprising tocilizumab, received approvals in
`
`Europe and the United States in 2009 and 2010, respectively, to treat RA as a
`
`9
`
`

`

`standalone therapy and also in combination with MTX at specified doses.
`
`Regulators subsequently approved Actemra® to treat Giant Cell Arthritis, Juvenile
`
`Idiopathic Arthritis, CAR T Cell-Induced Cytokine Release Syndrome, and
`
`Systemic Sclerosis-Associated Interstitial Lung Disease.
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`Petitioners’ Copying of Actemra®
`E.
`Petitioners have announced plans to develop a “biosimilar” copy of the
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`Actemra® drug. Ex. 2028 (Fresenius News Release 2021). They began trials
`
`evaluating their tocilizumab in 2017, Ex. 2029 (Clinical Trial NCT03282851), and
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`have progressed to testing its administration in combination with methotrexate.
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`Ex. 2030 (Clinical Trial NCT04512001) at 4 (requiring patients in trial to receive
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`“a stable dose between 10 and 25 mg/week methotrexate”).
`
`III. THE ’201 PATENT
`A. The Specification
`The ’201 Patent describes data collected during the European phase II
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`clinical trial (“CHARISMA”) conducted in 2001-03 and referenced, briefly, in
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`Okuda (Ex. 2020) and Nishimoto (Ex. 1006). The inventors are two Chugai
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`scientists (Osamu Okuda and Noriaki Yoshida) and a researcher at the Kennedy
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`Institute of Rheumatology (Ravinder Maini) who designed the study to further
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`explore tocilizumab monotherapy dosages, evaluate whether a combination therapy
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`comprising tocilizumab and MTX might be safe and effective, and explore which
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`dosages of tocilizumab and MTX could be safely and effectively combined. See
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`10
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`

`

`Ex. 1001 (’201 Patent) at 16:38-19:24. The trial enrolled 359 patients with active
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`RA who had received MTX for at least six months with an inadequate response or
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`a disease flare in that period. Id. at 16:54-60, 18:30. The CHARISMA study
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`divided the volunteers into seven groups. Three groups received dosages of
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`tocilizumab (MRA) of 2, 4, or 8 mg/kg, respectively, four times total at four-week
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`intervals. Three other groups received tocilizumab on that same dosing schedule
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`but administered in combination with weekly doses of 10-25 mg of MTX. The
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`seventh group received the same weekly dose of MTX plus placebo. Id. at 16:63-
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`17:10.
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`
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`The inventors assessed patient improvement using a scale the American
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`College of Rheumatology developed that looked to categories of disease activity
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`such as the number of swollen joints or the patient’s overall pain assessment. Id. at
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`17:11-26. An ACR 20 score meant that the patient achieved a 20 percent or
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`greater improvement in at least three categories of disease activity over the course
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`of the study. And ACR 50 and ACR 70 scores, in turn, required 50 and 70 percent
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`improvements in three out of five categories. Id. Producing ACR 70 responses in
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`patients would be an important achievement. Unlike ACR 20 or ACR 50
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`responses, an ACR 70 response was deemed a “Major Clinical Response” that
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`indicated “significant improvement” for the patient. Ex. 1009 (1999 FDA
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`Guidance) at 6-7.
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`11
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`

`

`The specification reported the study results in Table 1, copied below:
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`
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`These results revealed that MRA and MTX interacted unpredictably when
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`administered as a combination therapy. More patients receiving MTX alone
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`achieved “Major Clinical Responses” (i.e., ACR 70 scores) than did patients who
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`received MTX in combination with 2 mg/kg or 4 mg/kg MRA. The results were
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`dramatically different with patients who received MTX in combination with the
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`higher MRA dosage level (8 mg/kg). More than twice as many patients in that
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`cohort achieved ACR 70 responses than the patients treated only with MTX. The
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`table below summarizes this stark and unexpected disparity:
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`Treatment
`MTX
`MTX + 2 mg/kg MRA
`MTX + 4 mg/kg MRA
`MTX + 8 mg/kg MRA
`
`
`
`ACR 70
`16.3%
`14.0%
`12.2%
`36.7%
`
`12
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`

`

`For those patients hoping to achieve a “Major Clinical Response,” a combination
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`therapy of 2 and 4 mg/kg MRA with MTX was no better (and perhaps worse) than
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`receiving MTX alone, while combining 8 mg/kg of MRA with 10-25 mg MTX led
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`to dramatic improvement. See id. at 17:30-52.
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`Besides showing efficacy, the trial results “confirmed” the “safety of MRA
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`. . . in both MRA monotherapy and for MRA combined with methotrexate.” Id. at
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`19:18-24. The results showed that administering the combination therapy did not
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`produce frequent adverse reactions, nor did MRA often cause the immunogenic
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`response other biologics routinely triggered. Id. at 18:42-57, 19:11-17.
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`Prosecution History
`B.
`The ’201 Patent issued from an application Patent Owner filed March 13,
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`2018, and claims priority to an application filed in Great Britain on April 28,
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`2003.1 After a preliminary amendment and a restriction requirement, Patent
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`Owner sought claims directed to methods for treating RA comprising
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`administration of MRA at certain dosages in combination with MTX. Ex. 1004
`
`(File History) at 131.
`
`
`1 U.S. Application No. 15/919,429, claiming priority to, inter alia, Great Britain
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`Application No. 0309619.5, filed on April 28, 2003.
`
`13
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`

`

`In a non-final rejection of those claims, Ex. 1004 (File History) at 141, the
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`Examiner found them obvious over, inter alia, the combination of “Okuda (2003)
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`in view of Maini et al (1998).” Id. at 156-58. Okuda is a 2003 presentation from
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`one of the Chugai inventors that referenced the ongoing CHARISMA trial but
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`without disclosing the structure of the trial or any of the dosing details. Ex. 2020
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`(Okuda) at 27. Maini 1998, a publication from another of the inventors, disclosed
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`results from a Kennedy Institute trial from the late 1990s treating RA patients with
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`a combination of MTX and infliximab, an anti-TNF-α antibody. Ex. 1015 (Maini
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`1998) at 1.2
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`Following the rejection, Patent Owner met with the Examiner to discuss
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`these references, Ex. 1004 (File History) at 181, and thereafter amended the claims
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`to narrow the dosages of both MRA and MTX and recite that the claimed treatment
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`results in an improved likelihood of achieving an ACR 70 response. Id. at 764. In
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`its remarks, Patent Owner pointed out that Okuda was “silent with respect to
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`dosage of MTX administered, and the time of MTX administration,” and also that
`
`
`2 While not relevant to the issues in this IPR, the Examiner also issued rejections
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`on enablement and indefiniteness grounds, Ex. 1004 (File History) at 142-52,
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`which the Patent Owner resolved by providing a declaration and clarifying the
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`indefiniteness issues in subsequent claim amendments, id. at 763-69.
`
`14
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`

`

`the biologic molecule (infliximab) that was tested in Maini targeted a “different
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`cellular pathway” than MRA. Id. at 770-71. Maini’s discussion of infliximab
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`usage therefore would not provide guidance about dosage and timing for
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`administering MTX in combination with MRA as recited by the claims. Id. at 771.
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`Patent Owner also argued that an ACR 70 response is a “very high clinical bar”,
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`that combining MTX with 8 mg/kg MRA (but not 2 mg/kg or 4 mg/kg MRA)
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`dramatically and unexpectedly improved the likelihood of achieving an ACR 70
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`response compared to MTX alone, and that the data disclosed in the application
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`showed synergistic results with 8 mg/kg MRA combined with MTX. Id. at 769-
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`70.
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`This persuaded the Examiner to allow all pending claims. Id. at 2088. She
`
`reasoned that none of the “prior art of record describe[d] or suggest[ed]” the
`
`claimed methods of coadministering 8