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 2021-01024
`Patent 7,521,052
`____________________
`
`
`PATENT OWNER’S RESPONSE
`
`

`

`TABLE OF CONTENTS
`
`IPR2021-01024
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND ............................................................................................. 2
`
`
`
`
`
`Rheumatoid Arthritis ............................................................................. 2
`
`RA Treatments ...................................................................................... 3
`
`1.
`
`2.
`
`3.
`
`NSAIDs, Steroids, and Traditional DMARDs ........................... 4
`
`Biologic DMARDs ..................................................................... 5
`
`Combination Therapies ............................................................... 8
`
`III. THE ’052 PATENT ....................................................................................... 10
`
`IV. CLAIM CONSTRUCTION .......................................................................... 12
`
`
`
`
`
`“administering an . . . anti-IL-6 receptor antibody . . . and
`methotrexate (MTX)” .......................................................................... 12
`
`“an effective amount of an anti-IL-6 receptor antibody (anti-IL-
`6R antibody)”; “an effective amount of methotrexate (MTX)” .......... 15
`
`V. ARGUMENT ................................................................................................. 18
`
` Ground 1: Yoshizaki Does Not Disclose a Combination
`Treatment with Effective Amounts of the Two Drugs ....................... 18
`
`1.
`
`2.
`
`Yoshizaki ................................................................................... 19
`
`Analysis ..................................................................................... 20
`
`
`
`
`
`Ground 2: Nishimoto Does Not Disclose a Combination
`Treatment of Effective Amounts of the Two Drugs ........................... 30
`
`1.
`
`2.
`
`Nishimoto 2002 ......................................................................... 30
`
`Analysis ..................................................................................... 31
`
`Ground 3: Nishimoto 2002 and Weinblatt 2003 Do Not Render
`Claim 1 Obvious .................................................................................. 32
`
`1.
`
`2.
`
`Both Experts Agree That a “Successful” RA
`Combination Therapy Requires Improved Efficacy
`Without Undue Toxicity. .......................................................... 33
`
`There Was No Reasonable Expectation that the Claimed
`Combination Would Demonstrate Increased Efficacy. ............ 35
`
`i
`
`

`

`3.
`
`There Was No Reasonable Expectation That the Claimed
`Combination Would Have Been Safe. ...................................... 45
`
`VI. CONCLUSION .............................................................................................. 51
`
`IPR2021-01024
`
`
`
`
`
`
`
`ii
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`

`

`IPR2021-01024
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Abbott Labs. v. Baxter Pharm. Prods., Inc.,
` 334 F.3d 1274 (Fed. Cir. 2003) ......................................................................... 18
`
`Baran v. Med. Device Tech., Inc.,
` 616 F.3d 1309 (Fed. Cir. 2010) ......................................................................... 15
`
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
` 661 F.3d 629 (Fed. Cir. 2011) ........................................................................... 29
`
`CommScope Tech. LLC v. Dali Wireless Inc.,
`10 F. 4th 1289 (Fed. Cir. 2021) .......................................................................... 28
`
`Eli Lilly and Co. v. Teva Pharms. Int’l, GmbH,
`8 F.3d 1331 (Fed. Cir. 2021) .................................................................. 32, 33, 51
`
`ERBE Elektromedizin GmbH v. Int’l Trade Comm’n,
`566 F.3d 1028 (Fed. Cir. 2009) .......................................................................... 15
`
`In re Montgomery,
` 677 F.3d 1375 (Fed. Cir. 2012) ......................................................................... 29
`
`Liebel-Flarsheim Co. v. Medrad, Inc.,
` 481 F.3d 1371 (Fed. Cir. 2007) ......................................................................... 28
`
`Novartis Pharms. Corp. v. W.-Ward Pharms. Int’l Ltd.,
`923 F.3d 1051 (Fed. Cir. 2019) .......................................................................... 33
`
`Phillips v. AWH Corp.,
` 415 F.3d 1303 (Fed. Cir. 2005) ......................................................................... 12
`
`Sanofi v. Lupin Atlantis Holdings S.A.,
`No. 15-415-RGA, 2016 WL 5842327 (D. Del. Oct. 3, 2016) ............................ 18
`
`Summit 6, LLC v. Samsung Elecs. Co.,
` 802 F.3d 1283 (Fed. Cir. 2015) ......................................................................... 28
`
`Vitronics Corp. v. Conceptronic, Inc.,
` 90 F.3d 1576 (Fed. Cir. 1996) ........................................................................... 12
`
`iii
`
`

`

`STATUTE
`STATUTE
`
`35 US.C. § 103 oes ceeeeeceseessecseeeneescessesseecseesneeseessecsessesessessesseecaessnesseeseesseeensees 33
`35 U.S.C. § 103 ........................................................................................................ 33
`
`
`
`IPR2021-01024
`IPR2021-01024
`
`1V
`iv
`
`

`

`IPR2021-01024
`
`I.
`
`INTRODUCTION
`
`The single claim of U.S. Patent No. 7,521,052 covers treatment of
`
`rheumatoid arthritis (“RA”) through a combined regimen of methotrexate and an
`
`anti-IL-6 receptor antibody. Relying on the unexamined and unrebutted testimony
`
`of Petitioners’ expert, Dr. Thomas Zizic, the Board’s Institution Decision found it
`
`reasonably likely that one of Petitioners’ references, Yoshizaki, disclosed the
`
`claimed regimen before the April 2003 priority date and that two others—
`
`Nishimoto 2002 and Weinblatt 2003—render the claim obvious.
`
`At deposition, however, Dr. Zizic walked back much of the testimony the
`
`Board credited. And on the material points where Dr. Zizic stood by his opinions,
`
`Patent Owner’s distinguished expert, Dr. Gregg Silverman of the NYU Langone
`
`Center, explains at length why Dr. Zizic is wrong. In particular, Dr. Silverman
`
`details: (i) why Yoshizaki, a report of experimental use in the mid-1990s, does not
`
`actually disclose the treatment of a patient with methotrexate and Patent Owner’s
`
`experimental antibody, and (ii) why Nishimoto 2002 and Weinblatt 2003 would not
`
`have provided the POSA with any reasonable expectation the claimed combination
`
`would be successful by the standard both experts agree success should be
`
`measured.
`
`For these reasons, the Board should confirm the challenged claim.
`
`1
`
`

`

`IPR2021-01024
`
`II. BACKGROUND
`
` Rheumatoid Arthritis
`
`Rheumatoid arthritis (“RA”) is a crippling disease that afflicts an estimated
`
`one percent of the adult population worldwide. Ex. 2026 (Kelley’s 2001) at 32. It
`
`is an autoimmune disorder that inflicts severe joint swelling and pain in the hands
`
`and feet of a patient and can worsen into destruction of the bone and cartilage in
`
`the joints, leading to deformities and causing decreased mobility and other serious
`
`handicaps. Because they are immunocompromised, RA patients have an
`
`increased risk of infection and serious heart disease. Ex. 2036 (Declaration of
`
`Gregg J. Silverman, M.D.), ¶ 9 (Silverman Decl.).
`
`Despite years of study, the precise pathogenesis of rheumatoid arthritis still
`
`remains unknown. Unlike with many other diseases, there is not a single
`
`biomarker that informs a doctor whether her patient is suffering from RA.
`
`Clinical diagnosis and measurement of RA activity is based on a complete
`
`evaluation by the physician of factors, including the patient’s demographic
`
`features, counts of involved joints, distribution of tender and swollen joints, and
`
`the absence of other obfuscating diagnoses and other conditions that have some
`
`overlap of clinical features. Id. ¶ 10.
`
`There is no known cure for RA. Instead, “[t]he goal of treatment is to arrest
`
`the disease and achieve remission,” but drug-free remission “occurs infrequently.”
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`2
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`

`

`IPR2021-01024
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`Ex. 1010 (2002 Guidelines) at 14. Consequently, rheumatologists treating RA
`
`patients look to control or limit the extent of their patients’ joint damage; relieve
`
`their often-excruciating pain; prevent loss of function; and do all of this while
`
`closely monitoring the toxicities inflicted by the most common drugs used to treat
`
`the disease. Ex. 2036 (Silverman Decl.), ¶ 11.
`
`Treatment goals are measured by the improvement of these conditions. The
`
`most common measurement tool is a scale developed by the American College of
`
`Rheumatology (“ACR”) that measures improvement in seven aspects of disease
`
`activity. An ACR20 score, for example suggests that “the number of swelling
`
`joints and the number of pain joints are improved by 20% or more and
`
`improvement by 20% or more is observed in three out of the five remaining
`
`items[.].” Ex. 1001 (’052 Patent) at 16:54-57.
`
` RA Treatments
`
`As of the priority date, rheumatologists used four different types of drugs to
`
`treat RA patients:
`
`-- Non-steroidal anti-inflammatory drugs (“NSAIDs”) to relieve RA
`
`pain and reduce inflammation, swelling, and fever;
`
`-- Steroids to reduce the inflammation levels that make RA joints
`
`swollen, stiff, and painful;
`
`3
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`

`

`IPR2021-01024
`
`-- Traditional “disease-modifying antirheumatic drugs” (“DMARDs”),
`
`typically synthetic, small-molecule medicines that had been available to
`
`doctors for one purpose or another for some time; and
`
`-- Biologic DMARDs, a new class of large-molecule, protein-based
`
`medicines produced through recombinant technologies.
`
`The big difference between NSAIDs and steroids on the one hand, and the two
`
`types of DMARDs on the other, is that latter could slow disease progression while
`
`the former could not. Ex. 2036 (Silverman Decl.), ¶ 12.
`
`1.
`
`NSAIDs, Steroids, and Traditional DMARDs
`
`As of April 2003, the most common NSAIDs administered to RA patients
`
`were ibuprofen and naproxen. Clinicians would prescribe only one NSAID,
`
`switching one for another if the patient was unresponsive. When physicians
`
`included steroids in the treatment regimen, the most common were prednisone or
`
`solumedrol. Ex. 2036 (Silverman Decl.), ¶ 13.
`
`The treatment regimen for a “majority of patients with newly diagnosed RA”
`
`also included “DMARD therapy within 3 months of diagnosis.” Ex. 1010 (2002
`
`Guidelines) at 2. The list of traditional DMARDs in use at the time was large and
`
`included hydroxychloroquine, sulfasalazine, methotrexate, leflunomide,
`
`azathioprine, D-penicillamine, gold (oral and intramuscular), minocycline,
`
`cyclosporine, and staphylococcal protein A immunoadsorption. Id. at 4; Ex. 2036
`
`4
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`

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`IPR2021-01024
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`(Silverman Decl.), ¶¶ 14-15. Though DMARDs could slow or stall the progression
`
`of RA, eventually “adverse events emerge or [the] drugs become ineffective,” so
`
`switching drugs was common. It was estimated that “50-60% of patients treated
`
`with a DMARD require[d] a subsequent course with another drug.” Ex. 2001
`
`(Aleatha 2002) at 3.
`
`Among the traditional DMARDs, MTX—a drug initially developed as a
`
`chemotherapy agent —was widely prescribed even though very little was known
`
`about how MTX worked to alleviate RA symptoms, and why so many RA patients
`
`did not respond to it. Ex. 2036 (Silverman Decl.), ¶ 16; Ex. 2012 (Frei 1975) at 1;
`
`Ex. 2014 (Kremer 1994) at 1; Ex. 2015 (Kremer 1998) at 1-3. MTX was well-
`
`known to cause increased toxicity (particularly liver toxicity) with escalating
`
`dosages and contribute to additive toxicity in combination with other hepatoxic or
`
`immunosuppressive drugs. Ex. 2036 (Silverman Decl.), ¶¶ 16-17 (citing Ex. 2015
`
`(Kremer 1998); Ex. 1020 (2000 PDR – Methotrexate); Ex. 2021 (Rheumatrex
`
`Label 2003); Ex. 2006 (Conaghan 1995); Ex. 2016 (Kremer 2002)). MTX had
`
`even been associated with deaths “in the treatment of . . . Rheumatoid Arthritis.”
`
`Ex. 1020 (2000 PDR – Methotrexate) at 3.
`
`2.
`
`Biologic DMARDs
`
`In the 1990s researchers looking to develop new therapies employed
`
`emergent recombinant protein technology to develop monoclonal antibodies and
`
`5
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`

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`IPR2021-01024
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`other biologic agents to treat RA. These prospective biologic treatments targeted
`
`various cytokines associated with joint inflammation, including tumor necrosis
`
`factor alpha (“TNFα”), interleukin-1 (“IL-1”), and interleukin-6 (“IL-6”). Ex.
`
`2002 (Bulpitt 1999) at 1-2. But biologic therapy in RA was a nascent and
`
`unpredictable field at this time, and the RA landscape was dotted with various
`
`biologics that initially had been pursued with enthusiasm but eventually failed. Ex.
`
`2013 (Keystone 2003) at 15:253-258; Ex. 2036 (Silverman Decl.), ¶ 18. As one
`
`article from the period explained: “The result of cytokine manipulation is far from
`
`predictable.” Ex. 2002 (Bulpitt 1999) at 2.
`
`Because these cytokines were known to be “proinflammatory,” scientists
`
`theorized that targeting them could help patients suffering from crippling
`
`inflammation. Etanercept, a fusion protein that targeted TNFα, in 1998 became the
`
`first biologic to receive FDA approval to treat RA. Ex. 2026 (Kelley’s 2001) at 5-
`
`6. FDA subsequently approved two monoclonal antibodies targeting the same
`
`cytokine: the chimeric antibody infliximab in 1999 and the fully human antibody
`
`adalimumab in 2002. Ex. 1013 (2001 PDR – Remicade); Ex. 1033 (2002 Humira
`
`FDA Label) at 7, 14, 16. Around the same time FDA approved anakinra, a
`
`biologic that targeted a different proinflammatory cytokine called interleukin-1
`
`(“IL-1”). Ex 2026 (Kelley’s 2001) at 23; Ex. 2036 (Silverman Decl.), ¶ 18.
`
`6
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`

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`IPR2021-01024
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`Development of a biologic targeting IL-6 proceeded more slowly and in the
`
`face of skepticism that it would be as successful. Unlike TNFα, IL-6 was
`
`understood to have both “pro- and anti-inflammatory activity,” meaning that
`
`therapies targeting this cytokine possibly could aggravate RA symptoms rather
`
`than mitigate them. Ex. 2026 (Kelley’s 2001) at 5-6, 25. Antibodies targeting IL-6
`
`directly might actually extend that cytokine’s activity. Id. at 25. This meant that
`
`inhibiting IL-6 directly, for example, the same way infliximab and adalimumab
`
`target TNFα, could in theory actually worsen the patient’s RA symptoms. See id.
`
`A number of experts had concluded 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. 2036 (Silverman Decl.), ¶ 32; Ex. 2017 (Elliott 1995) at 15. And
`
`when early development of tocilizumab commenced, those in the field were
`
`skeptical that a drug employing an IL-6 blockade could successfully treat RA
`
`given its broad mechanism of action and other biological differences from TNFα
`
`inhibitors. Ex. 2036 (Silverman Decl.), ¶¶ 20, 31-33.
`
`Nevertheless, Chugai persisted in developing the antibody later known as
`
`tocilizumab, a humanized antibody that did not bind directly to IL-6 but instead to
`
`the receptor to which IL-6 would otherwise bind to trigger its biological function.
`
`After years of testing, Actemra®, Chugai’s product comprising tocilizumab,
`
`7
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`

`

`IPR2021-01024
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`received FDA approval in 2010 and has become an important tool for clinicians
`
`treating patients with RA. Ex. 2036 (Silverman Decl.), ¶ 33.
`
`3.
`
`Combination Therapies
`
`Starting in the mid-1990s, clinicians began to administer treatment regimens
`
`that included two (and on occasion) three DMARDs with increasing frequency. A
`
`Mayo Institute publication in 2000 estimated that about half of RA patients being
`
`treated by rheumatologists were prescribed DMARD combinations. Ex. 1007
`
`(Matteson 2000) at 4. The other half typically received DMARD monotherapy.
`
`See Ex. 2037 (Zizic Tr.) at 73:14-18; Ex. 2036 (Silverman Decl.), ¶ 21.
`
`DMARDs that worked as monotherapies, however, did not always work in
`
`combination, and researchers who studied the practice published reports expressing
`
`skepticism. Ex. 2036 (Silverman Decl.), ¶¶ 22-25. In the mid-1990s, “reports of
`
`clinically useful combinations [of individually proven DMARDs] are rare,” Ex.
`
`2006 (Conaghan 1995) at 1, including combinations where MTX was one of the
`
`DMARDs. A study combining azathioprine and MTX “was no more effective than
`
`either of the agents alone.” Ex. 2039 (Willkens 1995) at 7. A study combining
`
`MTX and auranofin “did not demonstrate any advantage in efficacy over single-
`
`drug treatment within the time frame of th[e] study.” Ex. 2024 (Williams 1992) at
`
`1. And studies combining sulfasalazine and methotrexate showed “no significant
`
`differences in efficacy,” while also demonstrating “a trend suggesting a more toxic
`
`8
`
`

`

`IPR2021-01024
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`profile of th[e] combination.” Ex. 2040 (Haagsma 1997) at 1; Ex. 2041
`
`(Dougados 1999) at 5. As one review article concluded: “Combination therapy, as
`
`it has been used in recent clinical trials, does not offer substantial improvement in
`
`efficacy, but does have higher toxicity than single drug therapy.” Ex. 2010 (Felson
`
`1994) at 1.
`
`Once biologic DMARDs started showing safety and efficacy in the latter
`
`half of the 1990s, researchers began testing whether efficacy could be improved
`
`and safety maintained by administering them in combination with MTX. These
`
`efforts met with uneven success. Ex. 2036 (Silverman Decl.), ¶¶ 26-27. Trials
`
`combining MTX with the new TNFα inhibitors—infliximab, etanercept, and
`
`adalimumab—were successful in that patients receiving them generally fared better
`
`than on MTX alone without significantly elevated toxicity. Ex. 1008 (Weinblatt
`
`2003) at 1; Ex. 1015 (Maini 1998) at 1; Ex. 2023 (Weinblatt 1999) at 1. In fact,
`
`infliximab was determined to require co-administration of MTX, an
`
`immunosuppressant, to block a dangerous immune reaction to infliximab itself.
`
`Ex. 1015 (Maini 1998) at 2.
`
`But as with combinations of traditional DMARDs, combinations involving
`
`other biologic DMARDs did not always work. Ex. 2036 (Silverman Decl.), ¶¶ 28-
`
`30. Researchers focusing on an anti-CD5 immunoconjugate and an anti-CD4
`
`antibody to remove targeted immune cells as potential RA therapies tested each of
`
`9
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`

`IPR2021-01024
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`them in combination with MTX, and both studies showed no significant benefit
`
`compared to MTX monotherapy. Ex. 2018 (Moreland 1996) at 3. They concluded
`
`that the combination “raises the concern of increasing the risk of serious adverse
`
`events including opportunistic infections or the development of malignancies.” Id.
`
`at 4. Another study testing the combination of infliximab and leflunomide found
`
`that while the regimen showed “a substantial improvement in RA disease activity,”
`
`there was such a “high frequency of adverse events” that more than half the
`
`patients enrolled had to drop out. Ex. 2066 (Kiely 2002) at 1 (adverse events “were
`
`common and in some cases severe”).
`
`III. THE ’052 PATENT
`
`The ’052 Patent contains a single claim:
`
`A method for treating rheumatoid arthritis, comprising
`
`administering an effective amount of an anti-IL-6
`
`receptor antibody (anti-IL-6R antibody) and an effective
`
`amount of methotrexate (MTX) to a patient in need
`
`thereof, wherein the anti-IL-6R antibody is a humanized
`
`PM-1 antibody.
`
`Ex. 1001 (’052 Patent) at 22:31-35. The specification supporting it describes data
`
`collected during a phase II clinical trial (CHARISMA) that the inventors designed
`
`to further explore tocilizumab monotherapy dosages, evaluate the effectiveness and
`
`safety of a tocilizumab and MTX combination, and determine the safe and
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`10
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`IPR2021-01024
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`effective dosages of MTX and tocilizumab when combined. Ex. 1001 (’052
`
`Patent) at 16:10-18:67.
`
`The trial divided 359 patients into seven groups, receiving various dosages
`
`MRA (2, 4, or 8 mg/kg four times total at four-week intervals), various dosages of
`
`MRA with 10-25 mg of MTX, or a placebo with MTX. Id. at 16:34-42. The
`
`inventors assessed patient improvement using the ACR scale. The results were as
`
`follows:
`
`
`
`Id. at 17:1-14. The trial “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 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. In terms of dosing, the study
`
`11
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`IPR2021-01024
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`showed that for patients hoping to achieve a “Major Clinical Response” (ACR70),
`
`combination therapy of 8 mg/kg of MRA combined with 10-25 mg/week MTX led
`
`to dramatic improvement. Id. at 17:15-27.
`
`
`
`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.
`
`IV. CLAIM CONSTRUCTION
`
`Claim terms “are generally given their ordinary and customary meaning” as
`
`understood by the person of ordinary skill in the art (“POSA”).1 Phillips v. AWH
`
`Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005) (en banc) (quoting Vitronics Corp.
`
`v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996)). Petitioners and Patent
`
`Owner disagree on the construction of two terms.2
`
`
`
`“administering an . . . anti-IL-6 receptor antibody . . . and
`methotrexate (MTX)”
`
`
`
`1 Patent Owner does not dispute the definition of the POSA offered by Petitioners.
`
`See Ex. 2036 (Silverman Decl.), at ¶¶ 46-52.
`
`2 As the Board acknowledged in its Institution Decision, Patent Owners do not
`
`contest Petitioners’ proposed construction of the phrase “[a] method for treating
`
`rheumatoid arthritis . . . in a patient.” Decision at 6.
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`12
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`IPR2021-01024
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`The Board’s Institution Decision rejected Petitioners’ proposed construction
`
`of this limitation to cover administering both drugs to a patient regardless of
`
`whether they were part of the same treatment regimen. Decision at 9. This is
`
`plainly correct for all the reasons the Board stated. It remains unclear, however,
`
`whether Petitioners intend to press their alternative construction. At his deposition,
`
`Dr. Zizic insisted that Board erred on this point and that claim 1 covers any
`
`treatment of a patient with both MTX and an anti-IL-6 receptor antibody,
`
`regardless of how much time passed between:
`
`Q. And how much time can pass between the administration of
`
`the one and administration of the other?
`
`A. Well, the patent wasn’t clear. It didn’t state it here. But
`
`even on the file history, it was just stated, as I recollect, that
`
`the administration could be simultaneously or with the time
`
`interval. There was no time interval specified in that
`
`dependent claim.
`
`Q. So it could be any amount of time, in your opinion?
`
`A. Well, according to the patent. . . .
`
`Q. So if someone got methotrexate on day one as a
`
`monotherapy and then got tocilizumab 500 days later as a
`
`monotherapy, that would be within the claim, in your
`
`opinion?
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`IPR2021-01024
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`A. It would be within the claim because it wasn’t specified
`
`within the de[pendent] claims of the original patent
`
`submission.
`
`Q. What if a patient were prescribed methotrexate and then it
`
`was found to be either ineffective or toxic and was
`
`discontinued, and a year later, the doctor prescribes
`
`tocilizumab, is that within the claim? . . .
`
`THE WITNESS: Again, I mean, I can see what you’re trying
`
`to say but that isn’t what the patent history of this claim is. It
`
`doesn’t specify. It doesn’t preclude that situation from being
`
`within that. It just says within a time interval, is my
`
`recollection. And I think I’m right.
`
`Ex. 2037 (Zizic Tr.) at 166:18-168:8.
`
`
`As Patent Owner showed in its Preliminary Response, and as the Board
`
`recognized, the construction Dr. Zizic applies cannot be correct. The ’052 Patent
`
`arises from a trial assessing the “potential efficacy of repeated intravenous doses of
`
`MRA, both as monotherapy and in combination with methotrexate.” Ex. 1001
`
`(’052 Patent) at 16:15-23. The specification makes it clear that even those patients
`
`in the “MRA alone” cohorts received MTX before the study began. Id. at 16:15-
`
`24, 17:15-26. They had to—the clinical trial protocol required that all study
`
`participants had been treated with MTX for at least six months prior to enrollment.
`
`Id. at 16:26-33. Only the patients who continued to receive MTX during the
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`14
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`IPR2021-01024
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`course of the study, in the same treatment regimen as MRA, fell within the “MTX-
`
`combined groups.” Id. Since the “specification [] draw[s] a direct contrast
`
`between” monotherapy and combination therapy, a construction where the
`
`monotherapy cohorts comprise a null set cannot be correct. Baran v. Med. Device
`
`Tech., Inc., 616 F.3d 1309, 1315-16 (Fed. Cir. 2010); see also ERBE
`
`Elektromedizin GmbH v. Int’l Trade Comm’n, 566 F.3d 1028, 1034 (Fed. Cir.
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`2009) (generally improper to “construe claim language to be inconsistent with the
`
`clear language of the specification”). Accordingly, the Board should construe this
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`claim to require that the anti-IL-6 receptor antibody and MTX be administered as
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`part of the same treatment regimen.
`
`
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`“an effective amount of an anti-IL-6 receptor antibody (anti-IL-
`6R antibody)”; “an effective amount of methotrexate (MTX)”
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`With respect to the other term, the Board preliminarily credited Dr. Zizic’s
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`declaration testimony and construed “effective amount” to mean the effective
`
`monotherapy amount of each drug.
`
`Petitioners provide expert testimony that a POSA would
`
`have understood the plain meaning of the term to include
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`amounts known to be effective in treating RA, regardless
`
`of whether it has such an effect any one particular patient
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`to whom the therapy is administered. Pet. 18–20 (citing
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`Ex. 1003 ¶¶ 128, 131). Based on the current record, we
`
`find that unrebutted testimony persuasive.
`
`15
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`IPR2021-01024
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`See Decision at 12; see also id. at 11 (“claim does not recite or refer to any
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`required combined effectiveness amount”) (emphasis in original).
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`The Board should revisit this question based on the different record before it,
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`in particular Dr. Silverman’s declaration and Dr. Zizic’s deposition testimony.
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`According to both experts, the POSA would not consider the dose of a drug used in
`
`combination with another to be “effective” unless it was expected to produce
`
`results with an acceptable level of toxicity, something that cannot be assessed until
`
`the two drugs are combined as the claim requires. Ex. 2036 (Silverman Decl.),
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`¶¶ 54-56; Ex. 2037 (Zizic Tr.) at 144:14-145:6.
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`Claim 1 requires that the claimed combination is “effective” for “treating
`
`RA” in “a patient in need thereof.” Ex. 1001 (’052 Patent) at 22:31-35. As Dr.
`
`Silverman explains, the POSA would have understood this claim to require the
`
`administration, to a patient suffering from RA, amounts of MRA and MTX that in
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`combination would be expected to reduce the patient’s symptoms, inhibit disease
`
`progression, or both, with acceptable toxicity. Ex. 2036 (Silverman Decl.), ¶ 54.
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`In his deposition, Dr. Zizic agreed that a successful RA treatment must take
`
`toxicity into account:
`
`Q. So in your opinion, what makes an RA treatment successful?
`
`A. You mean, what outcome . . . do I measure success
`
`by[?] . . . [W]ell, reduction of pain and symptoms and
`
`prevention of damage to the joints as an overall goal doing
`
`16
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`IPR2021-01024
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`both of those, preventing long-term damage and disability
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`and also to make them more functional and better quality of
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`life.
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`Q. Okay. And at an acceptable level of toxicity?
`
`A. Oh, of course.
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`Ex. 2037 (Zizic Tr.) at 144:14-145:6.
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`Based on this common ground, the POSA would have understood “effective
`
`amount” to mean, not the effective monotherapy amount of each drug, but the
`
`amount that was expected to be effective when used together. As Dr. Silverman
`
`explains: “a treating physician would understand that dosages of two drugs that
`
`are safe and efficacious alone could have significant side effects when used in
`
`combination and, in fact, be toxic in combination.” Ex. 2036 (Silverman Decl.),
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`¶ 55.
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`This understanding of the claim’s plain language comports with the
`
`specification’s discussion of the inventors’ work. In particular, they describe how,
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`in the CHARISMA trial, “effectiveness of MRA” was assessed not just for “MRA
`
`monotherapy” but also “for MRA combined with methotrexate,” and furthermore
`
`that “safety and tolerability” were a critical part of their assessment. They
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`concluded that “safety of MRA was confirmed in both MRA monotherapy and for
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`MRA combined with methotrexate.” Ex. 1001 (’052 Patent) at 18:65-67.
`
`17
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`IPR2021-01024
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`“[T]he term ‘effective amount’ has a customary usage.” Abbott Labs. v.
`
`Baxter Pharm. Prods., Inc., 334 F.3d 1274, 1277-78 (Fed. Cir. 2003). It is “the
`
`amount that is effective to accomplish the purpose of the claim.” Sanofi v. Lupin
`
`Atlantis Holdings S.A., No. 15-415-RGA, 2016 WL 5842327, at *4 (D. Del. Oct. 3,
`
`2016); see also Abbott Labs., 334 F.3d at 1277-78. As the testimony of both sides’
`
`experts confirms, the POSA would not understand an “effective” dose to be one
`
`that treated RA but subjected the patient to toxicity a treating physician would not
`
`tolerate. For this reason the Board should withdraw its tentative construction and
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`enter the one Patent Owner has proposed: “effective amount[s]” of each drug are
`
`those that relieve RA symptoms without undue toxicity when administered in the
`
`same treatment regimen.
`
`V. ARGUMENT
`
` Ground 1: Yoshizaki Does Not Disclose a Combination Treatment
`with Effective Amounts of the Two Drugs
`
`The Board’s Institution Decision tentatively determined that Yoshizaki, a
`
`1998 reference reporting on the treatment of RA patients in Japan, anticipates
`
`claim 1. The Board said it found no “ambiguity that the patient described by
`
`Yoshizaki received MTX along with rhPM-1,” and credited Dr. Zizic’s “currently
`
`unrebutted expert testimony” that this patient received what the POSA would
`
`consider “effective amounts” of the two drugs. Decision at 19, 21.
`
`18
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`IPR2021-01024
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`For the reasons detailed below, including Dr. Silverman’s testimony and Dr.
`
`Zizic’s concessions at his deposition about what constitutes “conventional
`
`treatment,” the Board should revisit this question and reject Ground 1. Ex. 2036
`
`(Silverman Decl.), ¶¶ 58, 61.
`
`1.
`
`Yoshizaki
`
`Yoshizaki discloses the use of “rhPM-1” to treat RA patients in Japan from
`
`1995-1997. Ex. 1005 (Yoshizaki 1998); Ex. 2036 (Silverman Decl.), ¶ 59. RhPM-
`
`1 is an early designation for the humanized antibody later renamed tocilizumab.
`
`The researchers who conducted the study observed that “conventional
`
`therapy with non-steroid anti-inflammatory drugs (NSAIDs) and disease-
`
`modifying antirheumatic drugs (DMARDs) combined with methotrexate (MTX)
`
`and/or steroids is still unsatisfactory,” so that “new therapeutic strategies need to
`
`be defined,” Ex. 1005 (Yoshizaki 1998) at 6. Yoshizaki proposed a therapeutic
`
`approach to “interfere with the IL-6 signal transduction pathway” by “blocking
`
`[the] IL-6 signal with [an] anti-IL-6R antibody.” Id. at 6-7.
`
`The patients included in the study were patients with “severe RA who were
`
`resistant to any conventional therapy.” Id. at 10. They suffered chronic RA
`
`symptoms—including “continuous arthralgia with or without joint deformity,
`
`swollen joints and morning stiffness, combined with systemic or general fatigue,
`
`19
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`

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`IPR2021-01024
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`low appetite, loss of weight and subfever”—“despite treatment with NSAIDs,
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`DMARDs, MTX, and maintenance doses of steroids.” Id.
`
`As the Board recognized, Petitioners’ anticipation argument relies entirely
`
`on two sentences in Figure 8, where the authors describe the treatment received by
`
`one of the patients:
`
`A 67-year-old woman with severe RA given NSAIDs,
`
`DMARDs, MTX and 15 mg predomizolone [sic]3
`
`received 50 mg rhPM-1 twice a week or once a week
`
`combined with the conventional treatment. The clinical
`
`and laboratory abnormalities i