`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`Paper No. 7
`October 12, 2021
`
`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 2021-01024
`
`U.S. Patent No. 7,521,052
`
`_________________________________________________
`
`
`
`
`
`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 ’052 PATENT ......................................................................................... 10
`A. Specification ................................................................................................. 10
`B. Prosecution History ..................................................................................... 13
`C. Claim ............................................................................................................. 15
`D. Level of Ordinary Skill in the Art .............................................................. 16
`IV. CLAIM CONSTRUCTION ............................................................................ 16
`A. “administering an . . . anti-IL-6 receptor antibody . . . and
`methotrexate (MTX)” .................................................................................. 17
`B. “an effective amount of an anti-IL-6 receptor antibody (anti-IL-
`6R antibody)”; “an effective amount of methotrexate (MTX)” .............. 20
`V. ARGUMENT ..................................................................................................... 23
`A. Ground 1: Yoshizaki Does Not Disclose a Combination Treatment
`With Effective Amounts of the Two Drugs. .............................................. 24
`1. Yoshizaki Fails to Disclose Administering MTX and an Anti-
`IL-6R Antibody in the Same Treatment Regimen. ............................. 26
`2. Yoshizaki Fails to Disclose an “effective amount” of MTX. ............... 27
`
`i
`
`

`

`B. Ground 2: Nishimoto Does Not Disclose a Combination Treatment
`of Effective Amounts of the Two Drugs. ................................................... 28
`1. “effective amount” of an anti-IL-6R antibody .................................... 29
`2. “effective amount” of MTX ................................................................... 31
`C. Ground 3: Nishimoto and Weinblatt Do Not Supply a Reasonable
`Expectation of Success. ................................................................................ 32
`D. The Board Should Decline to Institute Under NHK Spring/Fintiv. ........ 39
`VI. CONCLUSION ................................................................................................ 42
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Abbott Labs. v. Baxter Pharm. Prods., Inc.,
`334 F.3d 1274 (Fed. Cir. 2003) .......................................................................... 20
`Apple Inc. v. Fintiv, Inc., IPR2020-00019,
`Paper 11 (PTAB Mar. 20, 2020) ............................................................. 39, 40, 41
`Baran v. Med. Device Tech., Inc., 616 F.3d
`1309 (Fed. Cir. 2010) .......................................................................................... 18
`Braintree Labs., Inc. v. Novel Labs., Inc., 749
`F.3d 1349 (Fed. Cir. 2014) ................................................................................. 21
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder
`Sys., Inc., 725 F.3d 1341 (Fed. Cir. 2013) .......................................................... 30
`Cont. Can Co. USA, Inc. v. Monsanto Co., 948
`F.2d 1264 (Fed. Cir. 1991) ................................................................................. 31
`ERBE Elektromedizin GmbH v. Int’l Trade
`Comm’n, 566 F.3d 1028 (Fed. Cir. 2009) .......................................................... 18
`Institut Pasteur & Universite Pierre Et Marie
`Curie v. Focarino, 738 F.3d 1337 (Fed. Cir. 2013) ..................................... 32, 38
`NHK Spring Co. v. Intri-Plex Techs., Inc.,
`IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018) ............................................... 39
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) ....................... 17, 19, 20, 22
`Sandoz Inc. v. Amgen Inc., 137 S. Ct. 1664 (2017) ................................................. 39
`Sanofi v. Lupin Atlantis Holdings S.A.,
`No. 15-415-RGA, 2016 WL 5842327
`(D. Del. Oct. 3, 2016) ......................................................................................... 20
`Scripps Clinic & Res. Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) .................................................................... 28, 31
`
`iii
`
`

`

`Studiengesellschaft Kohle v. Dart Indus., Inc.,
`726 F.2d 724 (Fed. Cir. 1984) ...................................................................... 28, 31
`Teleflex, Inc. v. Ficosa N. Am. Corp.,
`299 F.3d 1313 (Fed. Cir. 2002) .......................................................................... 27
`Tr. Colum. Univ. v. Symantec Corp.,
`811 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 20
`Statutes
`42 U.S.C. § 262(l) .............................................................................................. 39, 40
`35 U.S.C. § 314(a) ..................................................................................................... 1
`
`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
`United States Patent 7,521,052 claims a method of treating rheumatoid
`
`arthritis (“RA”) with a combination therapy of methotrexate and a humanized
`
`antibody targeting interleukin-6 receptors. One such antibody is tocilizumab, the
`
`active ingredient of Actemra®, a drug discovered by the Patent Owner (Chugai)
`
`and approved by FDA for the treatment of RA and other diseases.
`
`Petitioners contend that two publications by scientists associated with
`
`Chugai, describing early use of experimental antibodies, anticipate the patent’s
`
`single claim. The Petition also challenges the claim as obvious over one of those
`
`publications and a reference disclosing the treatment of RA with methotrexate
`
`combined with a different, novel antibody another company had developed.
`
`Because there is no reasonable likelihood the claim is invalid under either
`
`theory, the Board should deny institution. 35 U.S.C. § 314(a).
`
`II. BACKGROUND
`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
`
`extra-articular manifestations” and thus “has features of a systemic disease that is
`
`capable of involving a variety of major organ systems.” Id.
`
`1
`
`

`

`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.
`
`By the 1990s the DMARD of choice for most physicians was methotrexate
`
`(“MTX”), a small-molecule drug initially developed as a chemotherapy agent and
`
`often toxic, Ex. 2015 (Kremer 1998) at 1; Ex. 2012 (Frei 1975) at 1. The scientific
`
`2
`
`

`

`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 liver
`
`toxicity (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). “Methotrexate 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 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 monotherapies, physicians treating patients with RA also
`
`experimented with combinations of different DMARDs. Some proved more
`
`3
`
`

`

`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 by several physicians that looked at treatments
`
`pairing MTX with other drugs also found mixed results. Ex. 2022 (Verhoeven
`
`1998) at 3. Administering combinations of MTX with other drugs 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 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.
`
`4
`
`

`

`C. Biologic Treatments for RA
`A revolution in the treatment of RA occurred 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 is 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
`
`medical problem only to create other, unpredictable, and potentially more serious
`
`5
`
`

`

`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
`
`studying them in the early 2000s still did not know whether these drugs inhibited
`
`6
`
`

`

`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 tried using these
`
`biologics and others in development in combination 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
`
`that only extensive clinical testing could demonstrate the safety of any therapy
`
`7
`
`

`

`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
`
`find their way to the cells, an antibody that mimicked a soluble receptor produced a
`
`8
`
`

`

`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 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
`
`standalone therapy and also in combination with MTX at specified doses.
`
`9
`
`

`

`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.
`
`Petitioners’ Copying of Actemra®
`E.
`Petitioners have announced plans to develop a “biosimilar” copy of the
`
`Actemra® drug. Ex. 2028 (Fresenius News Release 2021). They began trials
`
`evaluating their tocilizumab in 2017, Ex. 2029 (Clinical Trial NCT03282851), and
`
`have progressed to testing its administration in combination with methotrexate.
`
`Ex. 2030 (Clinical Trial NCT04512001) at 4 (requiring patients in trial to receive
`
`“a stable dose between 10 and 25 mg/week methotrexate”).
`
`III. THE ’052 PATENT
`Specification
`A.
`The ’052 Patent describes data collected during a European phase II clinical
`
`trial (“CHARISMA”) conducted in 2001-03. The inventors are two Chugai
`
`scientists (Osamu Okuda and Noriaki Yoshida) and a researcher at the Kennedy
`
`Institute of Rheumatology (Ravinder Maini) who designed the study to further
`
`explore tocilizumab monotherapy dosages, evaluate whether a combination therapy
`
`comprising tocilizumab and MTX might be safe and effective, and explore which
`
`dosages of tocilizumab and MTX could be safely and effectively combined. See
`
`Ex. 1001 (’052 Patent) at 16:10-18:67. The trial enrolled 359 patients with active
`
`RA who had received MTX for at least six months with an inadequate response or
`
`10
`
`

`

`a disease flare in that period. Id. at 16:27-33, 18:9. The CHARISMA study
`
`divided the volunteers into seven groups. Three groups received dosages of
`
`tocilizumab (MRA) of 2, 4, or 8 mg/kg, respectively, four times total at four-week
`
`intervals. Three other groups received tocilizumab on that same dosing schedule
`
`but administered in combination with 10-25 mg of MTX every week. The last
`
`group received the same weekly dose of MTX plus placebo. Id. at 16:34-42.
`
`
`
`The inventors assessed patient improvement using a scale the American
`
`College of Rheumatology developed that looked to categories of disease activity
`
`such as the number of swollen joints or the patient’s overall pain assessment. Id. at
`
`16:51-67. An ACR 20 score meant that the patient achieved a 20 percent or
`
`greater improvement in at least three categories of disease activity over the course
`
`of the study. And ACR 50 and ACR 70 scores, in turn, required 50 and 70 percent
`
`improvements in three out of five categories. Id. Producing ACR 70 responses in
`
`patients was important. Unlike ACR 20 or ACR 50 responses, an ACR 70
`
`response was deemed a “Major Clinical Response” that indicated “significant
`
`improvement” for the patient. Ex. 1009 (1999 FDA Guidance) at 6-7.
`
`The specification reported the study results in Table 1, copied below:
`
`11
`
`

`

`
`
`These results revealed that MRA and MTX interacted unpredictably when
`
`administered as a combination therapy. More patients receiving MTX alone
`
`achieved ACR 70 responses than did patients who received MTX combined with
`
`2 mg/kg or 4 mg/kg MRA. The results were dramatically different with patients
`
`who received MTX in combination with the higher MRA dosage level (8 mg/kg).
`
`More than twice as many patients in that cohort achieved ACR 70 responses than
`
`the patients treated only with MTX. The table below summarizes this stark and
`
`unexpected disparity:
`
`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
`
`

`

`For those patients hoping to achieve a “Major Clinical Response,” a combination
`
`therapy of 2 and 4 mg/kg MRA with MTX was no better (and perhaps worse) than
`
`receiving MTX alone, while combining 8 mg/kg of MRA with 10-25 mg MTX led
`
`to dramatic improvement. See id. at 17:15-27.
`
`Besides showing efficacy, the trial results “confirmed” the “safety of MRA
`
`. . . in both MRA monotherapy and for MRA combined with methotrexate.” Id. at
`
`18:61-67. The results showed that administering the combination therapy did not
`
`produce frequent adverse reactions, nor did MRA often cause the immunogenic
`
`response other biologics routinely triggered. Id. at 18:19-33, 54-59.
`
`Prosecution History
`B.
`The ’052 Patent issued from an application filed on April 28, 2004, and
`
`claims priority to an application filed in Great Britain on April 28, 2003. In
`
`response to a restriction requirement, Patent Owner sought claims for the treatment
`
`of IL-6-related diseases by administration of an IL-6 antagonist and an
`
`immunosuppressant. Ex. 1003 (’052 File History) at 252-60.
`
`The Examiner issued a non-final rejection of all pending claims under
`
`§§ 112, 102, and 103. Id. at 262-75. She found that the specification did not
`
`enable treating all IL-6 related diseases with an IL-6 antagonist and an
`
`13
`
`

`

`immunosuppressant; id. at 266-691; rejected the claims as anticipated by several
`
`references disclosing treatment with IL-6 antagonists with immunosuppressants;
`
`id. at 270-73; and found that a prior art reference (“Choy”) disclosing
`
`administration of an IL-6 antagonist in combination with prednisolone rendered it
`
`obvious to administer the IL-6 antagonist with an immunosuppressant like MTX.
`
`Id. at 273-75; Ex. 1027 (Choy 2002).
`
`
`
`Patent Owner responded by narrowing the claims to an IL-6 antagonist that
`
`inhibits binding of IL-6 with the IL-6 receptor and the IL-6 related disease to RA.
`
`Ex. 1003 (’052 File History) at 326-27. Patent Owner argued that such
`
`amendments were sufficient to overcome the § 112 and anticipation rejections. Id.
`
`at 330-32. Patent Owner also argued that Choy did not motivate the POSA to
`
`replace prednisolone with an immunosuppressant like MTX, nor provide the POSA
`
`with a reasonable expectation of success in doing so. Id. 332.
`
`
`
`The Examiner then issued a final rejection of all pending claims under
`
`§§112 and 103. On the former, she reasoned that the narrowed claims still
`
`
`1 The Examiner also issued a 112 rejection that the specification did not enable
`
`reproduction of the IL-6 antibody recited in the claims. Id. at 264-65. Patent
`
`Owner responded to this rejection by depositing a hybridoma cell line producing
`
`the IL-6 antibody. Id. at 330, 335-36.
`
`
`
`14
`
`

`

`required “undue experimentation to determine which anti-IL-6 receptor antibody”
`
`could be administered in the claimed method. Id. at 344. As to obviousness, the
`
`Examiner again reasoned that Choy “suggest[ed] the combined administration of
`
`the immunosuppressant with the anti-IL-6 receptor antibody.” Id. at 351.2
`
`
`
`Patent Owner then cancelled all pending, non-withdrawn claims except for
`
`one and amended that single claim to require administration of a humanized PM-1
`
`antibody (a type of IL-6R antibody) in combination with MTX, each in “effective”
`
`amounts. Id. at 363. Patent Owner argued that as narrowed the claim was
`
`sufficiently enabled. On obviousness, Patent Owner argued that Choy did not give
`
`the POSA “reason to use an anti-IL-6 receptor antibody and methotrexate in
`
`combination.” Id. at 366. Instead, because it prohibited the use of
`
`immunosuppressants like MTX beginning four wee