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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL
`BOARD
`
`______________________________
`
`SANDOZ INC.,
`Petitioner
`
`v.
`
`ABBVIE BIOTECHNOLOGY LTD.,
`Patent Owner
`
`________________________________
`
`U.S. Patent No.: 8,911,737
`Issue Date: Dec. 16, 2014
`Title: Methods of Administering Anti-TNFα Antibodies
`__________________________________
`
`DECLARATION OF SIMON M. HELFGOTT, M.D., C.M.
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`TABLE OF CONTENTS
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`I.
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`QUALIFICATIONS ........................................................................................ 1
`
`II.
`
`SUMMARY OF OPINIONS ........................................................................... 4
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`III. DISCLOSURE OF THE ’737 and ’135 PATENTS ....................................... 5
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`IV. LEVEL OF ORDINARY SKILL IN THE ART ............................................. 7
`
`V.
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`CLAIM INTERPRETATION ......................................................................... 7
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`VI. A POSA Would Understand from VDP 2000 (ex. 1107) that the 20
`mg D2E7 Dose was Effective in Treating RA ................................................ 9
`
`A. Disclosure of VDP 2000 ....................................................................... 9
`
`B.
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`VDP 2000 Taught a POSA that Weekly Doses of 20, 40 and 80
`mg D2E7 Administered Subcutaneously Are All Effective in
`Treating RA .........................................................................................10
`
`VII. A POSA Would Understand that the 0.5 mg/kg D2E7 Dose
`Administered in Kempeni Reduced the Signs, Symptoms, and/or
`Progression of RA..........................................................................................13
`
`A.
`
`Background .........................................................................................13
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`1.
`2.
`
`Kempeni’s Description of Clinical Trials (ex. 1004) ...............13
`Rau’s Description of DE001, DE003 and DE004 (ex.
`1017) .........................................................................................16
`
`B.
`
`C.
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`AbbVie’s “Up-Dosing” Argument ......................................................21
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`Opinions ..............................................................................................22
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`1.
`
`2.
`3.
`
`“Up-Dosing” in Kempeni Did Not Indicate Lack of
`Treatment with the 0.5 mg/kg Dose .............................................22
`Rau Confirms that 0.5 mg/kg D2E7 Is Effective to Treat RA .....25
`The Efficacy of 0.5 mg/kg D2E7 Is Further Supported by
`Weisman (ex. 1108) ..................................................................28
`
`VIII. CONCLUSIONS ...........................................................................................30
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`DECLARATION OF SIMON M. HELFGOTT
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`I, Simon M. Helfgott, M.D., C.M. declare that:
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`1. My name is Simon M. Helfgott.
`
`2.
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`I am submitting this declaration in support of a petition that Sandoz
`
`Inc. (“Sandoz”), is filing in the U.S. Patent and Trademark Office seeking inter
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`partes review of U.S. Patent No. 8,911,737 (the “’737 patent,” ex. 1001).
`
`I.
`
`QUALIFICATIONS
`
`3.
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`I am a Rheumatologist in the Division of Rheumatology and
`
`Immunology at Brigham and Women’s Hospital, where I have been a faculty
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`member since 1986. Since 2004, I have been our Division’s Director of Education
`
`and Fellowship Training.
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`4.
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`From 1985 to 1986, I was a Research Fellow in the Department of
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`Rheumatology and Immunology at Brigham and Women’s Hospital and Beth
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`Israel Hospital.
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`5.
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` From 1981 to 1985, I was a Medical Research Council of Canada
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`Fellow in Rheumatology and Immunology at Brigham and Women’s Hospital.
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`6.
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`From 1980 to 1981, I was a Clinical Fellow in Rheumatology at
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`McGill University.
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`From 1979 to 1980, I served as the Assistant Chief Resident in
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`7.
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`
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`Medicine at the Montreal General Hospital.
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`8.
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`From 1977 to 1979, I served as an Intern and a Resident in Medicine
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`at the Montreal General Hospital.
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`9. My educational experience is summarized as follows:
`
`a. I received a D.C.S. degree from McGill University in 1972.
`
`b. I received an M.D. degree from McGill University in 1977.
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`c. I received a C.M. degree from McGill University in 1977.
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`d. I am Board Certified in Internal Medicine and Rheumatology by the
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`American Board of Internal Medicine.
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`10. A full description of my background and qualifications can be found
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`in my curriculum vitae (CV), which is attached to this declaration as Appendix A.
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`11.
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`I have been an expert in the relevant field since at least 1986. I have
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`authored articles on anti-TNF-α antibodies. See, e.g., N. Beckwith & S. M.
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`Helfgott, Neurologic and Psychiatric Effects of Biologic Antirheumatic Drugs, in
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`TEXTBOOK OF NEURORHEUMATOLOGY (in press); E. I. Lichtman et al., Emerging
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`Therapies for Systemic Lupus Erythematosus—Focus on Targeting Interferon-
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`Alpha, 143 CLINICAL IMMUNOLOGY 210 (2012); S. Raychaudhuri et al.,
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`Development of Active Tuberculosis Following Initiation of Infliximab Despite
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`Appropriate Prophylaxis, 46 RHEUMATOLOGY (OXFORD) 887 (2007); Alyssa K.
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`Johnsen et al., Comparison of 2 Doses of Etanercept (50 vs 100 mg) in Active
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`
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`Rheumatoid Arthritis: A Randomized Double Blind Study, 33 J. RHEUMATOLOGY
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`659 (2006); H. T. Ang & S. Helfgott, Do the Clinical Responses and
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`Complications Following Etanercept or Infliximab Therapy Predict Similar
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`Outcomes with the Other Tumor Necrosis Factor-Alpha Antagonists in Patients
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`with Rheumatoid Arthritis?, 30 J. RHEUMATOLOGY 2315 (2003).
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`12. Since 2005, I have co-directed the teaching block at Harvard Medical
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`School (HMS-Year I) known as, Immunity In Defense and Disease, that is devoted
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`to the study of autoimmune conditions including rheumatoid arthritis and I
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`regularly instruct HMS Year-IV students on the topic of “The Management of
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`Autoimmune Diseases” as part of their pharmacology elective course.
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`13. By June 8, 2001 (which I have been asked to assume is the earliest
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`priority date for the ’737 patent), I had been treating patients with rheumatoid
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`arthritis (“RA”) for over 20 years.
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`14.
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`In formulating the opinions expressed in this declaration, I have relied
`
`upon my training, knowledge, and experience in the field of rheumatology,
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`including treating patients with RA. I have also considered the ’737 patent and the
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`publications and materials referred to as Exhibits throughout this declaration, and
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`listed in Appendix B.
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`15. Throughout this declaration, I may refer to the treatment of RA as the
`
`
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`“relevant field.”
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`16.
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`I have been retained by Sandoz as an expert in the relevant field to
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`provide my opinions on the subject matter of the ’737 patent.
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`17.
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`I am being compensated for my time at my normal hourly consulting
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`rate. My compensation is not dependent upon and does not affect the substance of
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`my opinions.
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`II.
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`SUMMARY OF OPINIONS
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`18.
`
`I have been asked to address an argument raised by AbbVie during
`
`inter partes reviews (“IPRs”) of U.S. Patent No. 8,889,135 (the “’135 patent”) that
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`a person having ordinary skill in the art (“POSA”) reading a prior art publication
`
`by van de Putte et al. (“VDP 2000”) would not have considered the subcutaneously
`
`administered 20 mg weekly D2E7 dose disclosed in that reference to be efficacious
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`in treating RA by reducing the signs and symptoms of the disease. I have reviewed
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`the efficacy data described in VDP 2000 for a clinical study of weekly,
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`subcutaneous fixed doses of 20, 40, and 80 mg D2E7 to treat RA. As explained
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`below, I disagree with AbbVie’s assertion. To the contrary, it is my opinion that
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`VDP 2000 would have taught a POSA that the weekly dose of 20 mg D2E7 as well
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`as the 40 mg and 80 mg weekly D2E7 doses, were all effective in reducing the
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`signs and symptoms of RA.
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`I have also been asked to address an argument raised by AbbVie
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`19.
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`
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`during IPRs of the ’135 patent that a POSA would not have understood a prior art
`
`publication by Kempeni as suggesting that its disclosed 0.5 mg/kg biweekly dose of
`
`D2E7 was effective to treat RA, because Kempeni discloses that some patients on
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`the 0.5 mg/kg D2E7 every other week (“eow”) regimen who did not reach certain
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`clinical goals (as defined by the study protocol) were “up-dos[ed]”—i.e., had their
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`D2E7 doses increased. Coherus Biosciences Inc. v. AbbVie Biotech. Ltd.,
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`IPR2016-00172, Final Written Decision, Paper No. 60, at 28 (hereinafter
`
`“Coherus”). As explained below, it is my opinion that the POSA would have
`
`understood from the prior art disclosures that the 0.5 mg/kg D2E7 eow regimen was
`
`effective to treat—i.e., reduce the signs, symptoms, and/or progression—of RA,
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`and would not have been deterred from using this regimen by the description in
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`Kempeni that doses were increased for certain patients in that treatment group.
`
`III. DISCLOSURE OF THE ’737 and ’135 PATENTS
`
`20.
`
`I understand from counsel that the ’737 patent is descended from an
`
`application that issued to AbbVie as the ’135 patent (ex. 1093). The ’737 and ’135
`
`patents share a common specification. I further understand that both patents claim
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`methods of treatment comprising administering subcutaneously a total body dose
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`of 40 mg of a human anti-Tumor Necrosis Factor-alpha (TNF-α) antibody, having
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`amino acid sequences corresponding to adalimumab (or “D2E7”), once every 13-
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`15 days for a time period sufficient to treat a specified condition.1 See generally
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`
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`exs. 1001, 1093. The only substantive difference between claim 1 of the ’737 and
`
`’135 patents is that the condition specified in the ’135 patent is RA (ex. 1093 at
`
`claim 1) and the condition specified in the ’737 patent is Crohn’s disease. Ex.
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`1001 at claim 1.
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`21.
`
`I understand that in a Final Written Decision dated May 16, 2017 the
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`Patent Trial and Appeal Board (the “Board”) found all claims of the ’135 patent to
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`be invalid as obvious over prior art publications from 1999 by Kempeni (ex. 1004)
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`and van de Putte (“VDP 1999,” ex. 1003). Coherus at 44. I further understand
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`that in another Final Written Decision dated July 6, 2017, the Board found all
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`claims of the ’135 patent to be invalid as obvious over a prior art publication by
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`Rau (ex. 1017) and a later (2000) prior art publication by van de Putte (“VDP
`
`2000,” ex. 1107). Boehringer Ingelheim Int’l. GMBH v. AbbVie Biotech. Ltd., No.
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`IPR2016-00408, Final Written Decision, Paper No. 46, at 44 (July 6, 2017)
`
`(hereinafter “BI408”).
`
`22.
`
`I further understand that Sandoz submits in its present petition that it
`
`would have been obvious to the POSA, in light of the prior art, to use the RA
`
`dosing regimen of the ’135 patent to treat Crohn’s disease, as claimed in the ’737
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`patent.
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`1 Dosing every 13-15 days is also referred to as eow dosing.
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
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`23.
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`I have been informed that a POSA is a hypothetical person who is
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`presumed to have been aware of all relevant art at the time of the invention.
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`24.
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`I further understand that the POSA is a person of ordinary creativity
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`(not an automaton), who understands the scientific principles applicable to the
`
`pertinent art. Said hypothetical person may also have the skill sets of more than
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`one individual.
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`25. Because I have been asked to address issues raised in IPR proceedings
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`involving the ’135 patent, which has claims directed to the treatment of RA, I have
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`analyzed those issues from the perspective of a POSA in the treatment of RA
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`patients.
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`26. Accordingly, the POSA for the issues I am addressing would be a
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`rheumatologist or other physician experienced in treating patients with RA and
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`would have an M.D. and at least three years’ post-residency experience treating
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`patients for RA, including with anti-TNF-α drugs.
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`V. CLAIM INTERPRETATION
`
`27.
`
`I have reviewed the Final Written Decisions invalidating the ’135
`
`patent, in which the Board construed the claim phrase “for a time period sufficient
`
`to treat the rheumatoid arthritis” to mean “for a time period sufficient to reduce the
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`signs, symptoms, and/or progression of RA.” BI408 at 11; Coherus at 9. I agree
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`with this definition because it is consistent with how I use the term “treat” in
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`connection with treating my RA patients, for whom the goal of treatment is to
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`reduce the signs, symptoms, and/or progression of disease. I have further reviewed
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`the specification of the ’135 patent and find that this definition is consistent with
`
`the disclosure of the specification, which states:
`
`the invention provides methods of treating disorders in
`which TNFα activity is detrimental. These methods
`include inhibiting human TNFα activity by subcutaneous,
`biweekly administration of an anti-TNFα antibody such
`that the disorder is treated. . . . [A] disorder in which α
`[sic] activity is detrimental is a disorder in which
`inhibition of TNFα activity is expected to alleviate the
`symptoms and/or progression of the disorder.
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`Ex. 1093 at 3:39-43, 24:58-60. For purposes of this declaration, I will accordingly
`
`define the phrase “for a time period sufficient to treat the rheumatoid arthritis” to
`
`mean “for a time period sufficient to reduce the signs, symptoms, and/or
`
`progression of RA.” I additionally note that the claims of the ’135 patent do not
`
`require any specific level of therapeutic effect. Rather, it is my opinion that any
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`reduction of the signs, symptoms, and/or progression of RA would constitute
`
`“treating” RA as is required by the claims.
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`VI. A POSA Would Understand from VDP 2000 that the 20 mg D2E7 Dose
`was Effective in Treating RA (ex. 1107)
`
`
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`A. Disclosure of VDP 2000
`
`28. VDP 2000 (a 2000 abstract by van de Putte et al.) reports a phase II,
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`randomized, placebo-controlled study assessing the efficacy of D2E7 in treating
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`RA. Ex. 1107 at 2.2 In VDP 2000, patients were subcutaneously administered
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`weekly doses of either placebo, or 20 mg, 40 mg or 80 mg D2E7 for three months.
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`Id. After three months, patients in the placebo group were switched to still-blinded
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`40 mg D2E7 administered weekly, and the D2E7-treated patients continued
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`treatment as randomized. Id. VDP 2000 reported clinical responses after 3 and 6
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`months of treatment. Id. Response or improvement for each dosing group was
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`measured using American College of Rheumatology (“ACR”) 20, Tender Joint
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`Count (“TJC”), Swollen Joint Count (“SJC”), and C-Reactive Protein (“CRP”)
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`levels. Id.
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`29. The full results of VDP 2000 are shown below:
`
`
`
`% Response or Improvement
`
`Treatment
`
`Plac/40 mg 20 mg
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`40 mg
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`80 mg
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`3/6
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`3/6
`
`3/6
`
`3/6
`
`Treatment
`period
`[months]
`
`
`2 I understand the AbbVie did not challenge the prior art status of VDP 2000
`during IPR No. 2016-00408.
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`ACR 20
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`10/59
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`49/56
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`57/64
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`56/63
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`TJC [Median] 5/55
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`57/69
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`61/63
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`55/63
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`SJC [Median]
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`16/56
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`42/54
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`59/68
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`61/62
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`CRP [Median] 1/67
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`54/59
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`67/58
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`64/66
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`Id.
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`30. VDP 2000 additionally reported that all doses of D2E7 administered
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`in the study (20, 40 and 80 mg) reduced the signs and symptoms of RA: “[f]or all
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`efficacy parameters studied, all doses of D2E7 were statistically significantly
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`superior to placebo (p < 0.001). 20, 40 and 80 mg/week were statistically equally
`
`efficacious when given [subcutaneously] in patients with active RA.” Id. “The
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`treatment benefit was stable for all parameters over time.” Id. VDP 2000
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`additionally reported that, “[t]he type and incidence of adverse events was similar
`
`between the three dose groups of D2E7 and placebo.” Id.
`
`B. VDP 2000 Taught a POSA that Weekly Doses of 20, 40 and 80 mg
`D2E7 Administered Subcutaneously Are All Effective in Treating
`RA
`
`31. As described above, VDP 2000 discloses data on the clinical
`
`responses achieved after 3 and 6 months, respectively, of treatment with weekly,
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`subcutaneously administered doses of 20, 40 and 80 mg D2E7. The 3 month data
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`also provide a comparison against clinical responses achieved among a treatment
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`group receiving placebo. As shown and reported by VDP 2000, all doses of D2E7
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`
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`were statistically significantly superior to placebo at 3 months. Id.
`
`32. That all three D2E7 doses of VDP 2000 were effective to treat RA
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`would be readily apparent to a POSA reviewing the ACR 20 responses reported in
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`that reference. The ACR is a composite index used to measure disease severity in
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`RA patients, by taking into account a number of signs and symptoms of the
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`disease. A POSA would understand that an “ACR-20” response indicates that a
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`patient has achieved 20% improvement in tender joint count and swollen joint
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`count, as well as 20% improvement in each of at least 3 of the following criteria:
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`erythrocyte sedimentation rate (“ESR”); “global estimation of disease activity by
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`the physician and by the patient”; “pain by the Visual Analog Scale”; and
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`“functional impairment.” Ex. 1017 at 6. Accordingly, if a patient has achieved
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`ACR 20, a POSA would understand that 5 of the signs and/or symptoms of her RA
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`have been reduced by at least 20%.
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`33. VDP 2000 reported that 49% of patients receiving the 20 mg weekly
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`dose of D2E7 achieved ACR 20 by 3 months. Ex. 1107 at 2. At 6 months, 56% of
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`the patients in this dosing group had reached ACR 20. Id. In contrast, after 3
`
`months only 10% of patients in the placebo group achieved ACR 20. Id.3
`
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`3 As reported by VDP 2000, placebo patients were switched to 40 mg weekly
`D2E7 after 3 months. Ex. 1107 at 2.
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`Therefore, at 3 months, 39% more patients in the 20 mg D2E7-treated group
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`achieved ACR 20 as compared with the placebo group.
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`34. A POSA would understand that a 39% increase over placebo of
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`patients reaching ACR 20 indicated that the 20 mg weekly dose of D2E7 was
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`clinically efficacious. Similarly, each of the parameters of the ACR20, including
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`the TJC, SJC and C-RP noted similarly raised percentages of patients in the 20 mg
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`weekly dosed group with improvement, suggesting that this dose provided a
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`durable and measurable clinical and laboratory response. This conclusion would
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`be entirely consistent with conclusions the FDA reached in evaluating a clinical
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`trial that resulted in the approval of the TNF-α inhibitor Remicade® (infliximab)
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`for RA, in which the percent of patients achieving ACR 20 response was compared
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`at 30 weeks between dosing groups receiving either 3 mg/kg or 10 mg/kg Remicade®,
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`or placebo, at various dosing intervals. Ex. 1111 at 20, tbl. 3.8. At 30 weeks, 50%
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`to 58% of patients in the Remicade®-treated groups achieved ACR 20. Id. In
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`contrast, 20.5% of patients in the placebo group achieved this response. Id. In
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`other words, 30-38% more patients in the Remicade®-treated groups achieved
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`ACR 20 as compared with placebo. Based on this data, the FDA concluded that
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`“[a]ll of the dosing regimens evaluated in the pivotal trial, T22, showed benefit as
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`adjunctive therapy to MTX in the treatment of patients with rheumatoid arthritis.”
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`Ex. 1111 at 26. On November 10, 1999, the FDA approved Remicade® for the
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`
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`treatment of RA at a dose of 3 mg/kg. Ex. 1112; Ex. 1051 at 1087.
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`35. Accordingly, a POSA would recognize, based on the data reported by
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`VDP 2000, that the 20 mg weekly D2E7 dose was clinically effective, and
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`sufficient to treat RA. Additionally, as I note above the claimed dosing regimen of
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`the ’135 patent does not require a specific level of efficacy in treating RA, rather, it
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`requires only that the dose be administered for a time period sufficient to treat –
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`i.e., reduce the signs, symptoms and/or progression of – RA. All doses reported in
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`VDP 2000 clearly met this standard, as reported at both 3 and 6 months.
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`VII. A POSA Would Understand that the 0.5 mg/kg D2E7 Dose Administered
`in Kempeni Reduced the Signs, Symptoms, and/or Progression of RA
`
`A. Background
`
`1. Kempeni’s Description of Clinical Trials (ex. 1004)
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`36. Kempeni, a 1999 review paper that I understand was published by
`
`AbbVie researchers, describes multiple clinical trials of D2E7 to treat RA. Ex.
`
`1004.4 The first three of these trials are most relevant for purposes of this
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`declaration.
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`4 I understand that Kempeni is prior art because it was published more than one
`year before the earliest priority date for the ’135 and ’737 patents, June 8, 2001.
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`In the first trial described by Kempeni (“DE001”5), 120 patients were
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`37.
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`
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`treated with single doses of D2E7 ranging from 0.5 to 10 mg/kg, administered by
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`intravenous (“i.v.”) injection. Ex. 1004 at I71. Kempeni reported that
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`[p]atients were followed up for at least four weeks to
`determine the pharmacokinetics of D2E7, as well as to
`evaluate the safety and clinical efficacy of the compound
`in terms of onset, duration and magnitude of response.
`Positive response was defined [, per the study protocol,]
`as a decrease of at least 1.2 . . . in the [Disease Activity
`Score, or “DAS”].
`
`Id.
`
`38. As reported by Kempeni, “[t]he data from this first therapeutic trial . .
`
`. were very encouraging.” Id. “The therapeutic effects [of D2E7] became evident
`
`within 24 hours to one week after D2E7 administration and reached the maximum
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`effect after 1–2 weeks, with dose response reaching a plateau at 1 mg/kg D2E7.” Id.
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`Kempeni further reported that “[s]ingle doses of D2E7 were well tolerated and the
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`dose increment scheme was followed as planned reaching the maximum dose of 10
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`mg/kg without any evidence of clinically relevant or dose related adverse effects.”
`
`Id. In terms of pharmacokinetics, “[t]he estimated mean terminal half life was 11.6
`
`to 13.7 days.” Id.
`
`
`5 Kempeni does not use the internal AbbVie reference numbers (e.g., “DEXXX”)
`for the clinical trials it describes. I use those numbers herein merely for ease of
`reference. The AbbVie internal reference numbers are identified in an article by
`Rau (ex. 1017).
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`39. The second trial described by Kempeni (“DE003”) was an open label
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`
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`extension study following DE001. Id. Patients from DE001 “in whom the effect
`
`of D2E7 had declined below response status by week 4” entered the DE003
`
`extension study. Id. Patients from DE001 “who maintained a response at week 4
`
`were continued without retreatment until their response status was lost. Thereafter,
`
`these patients could also continue in the extension study.” Id.
`
`40. As reported by Kempeni, patients who participated in the DE003
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`“extension study received a second blinded dose identical to their first dose.”6 Id.
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`Starting “[f]rom the third dose onwards, all patients were given active drug”—in
`
`other words, placebo patients were switched to a dose of D2E7 corresponding to
`
`their respective treatment group. Id. “D2E7 was administered every two weeks
`
`until responses could be rated as ‘good’, defined as an absolute DAS of < 2.4.” Id.
`
`So that the researchers could measure the duration of the “good” response,
`
`“patients were retreated only upon disease flare up.” Id. Kempeni additionally
`
`reported that “[t]o keep as many patients as possible in the study for the long term
`
`evaluation of safety, patients who did not respond well after 0.5 or 1 mg/kg received
`
`higher doses of up to a maximum of 3 mg/kg.” Id. Kempeni reported the results of
`
`DE003 as follows:
`
`
`6 The second dose was “given after a minimum period of four weeks and only
`after loss of initial . . . response status.” Ex. 1004 at I71.
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`[t]he response in the DAS over time demonstrated
`sustained
`therapeutic effects and some continuing
`improvement after multiple
`infusions of D2E7.
`Response rates of more than 80% have been achieved
`with a mean dosing interval of 2.5 weeks. After six
`months, 86% of patients continued to receive treatment
`with D2E7
`indicating
`that
`long
`term
`intravenous
`treatment with D2E7 in the dose range from 0.5 to 10
`mg/kg was well tolerated.
`
`
`
`Id.
`
`41. The third trial reported by Kempeni (“DE004”) assessed “[t]he safety
`
`and efficacy of weekly subcutaneous administration of 0.5 mg/kg D2E7 . . . in 24
`
`patients with active RA . . . .” Id. Patients were treated with the weekly 0.5 mg/kg
`
`dose of D2E7 for 3 months. Id. at I71-72. “The dose of D2E7 was increased to 1
`
`mg/kg subcutaneously weekly for non-responders or [patients] losing their responder
`
`status.” Id. at I72. Kempeni reported that “[t]he investigators concluded that
`
`D2E7 given subcutaneously was safe and as effective as when administered
`
`intravenously demonstrating that subcutaneous self administration is a promising
`
`approach for D2E7.” Id.
`
`2.
`
`Rau’s Description of DE001, DE003 and DE004 (ex. 1017)
`
`42. The DE001, DE003 and DE004 studies reported by Kempeni were
`
`also described in a June 2000 publication by Rau. Ex. 1017.7
`
`
`7 I understand the AbbVie did not challenge the prior art status of Rau during IPR
`No. 2016-00408.
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`43. With respect to study DE001, Rau, like Kempeni, disclosed that
`
`
`
`patients were given a single i.v. injection of placebo or 0.5 mg/kg, 1 mg/kg, 3 mg/kg, 5
`
`mg/kg or 10 mg/kg D2E7. Id. at 5. Rau reported that for patients given D2E7 “there
`
`was, starting already after 24 hours, a distinct improvement [in swollen joint
`
`count], which amounted to about 40% after one week.” Id. at 6. Rau further
`
`reported, “[t]his improvement persisted at the higher dose for four weeks; after the
`
`lower doses (0.5 or 1 mg per kg of body weight), the number of swollen joints
`
`gradually increased again.” Id. In contrast to the patients given D2E7, patients in
`
`the placebo group experienced “no improvement”—rather “a slight worsening was
`
`observed.” Id. Rau illustrated the swollen joint count data for all doses in the
`
`following figure (“Rau Figure 2”):
`
`Figure 2: DE001 Mean Value of the Number of Swollen Joints.
`
`120
`120
`
`
`
`100 100
`
`BO
`BO
`
`
`
`60 60
`
`40
`40
`
`
`
`20 20
`
`
`
`CI (cid:9)CI (cid:9)
`
`
`
`-3 (cid:9)-3 (cid:9)
`
`
`
`0 (cid:9)0 (cid:9)
`
`Placebo
`Placebo
`
`05 auk.; 05 auk.;
`
`- -
`
`— 1-0 rn&Fkg — 1-0 rn&Fkg
`
`— 3-0 ITS451 — 3-0 ITS451
`— 5.0 rrow1v2
`— 5.0 rrow1v2
`-
`-
`10.0 mg/kg
`10.0 mg/kg
`
`
`
`weeks weeks
`
`
`
`1 (cid:9)1 (cid:9)
`
`
`2 (cid:9)2 (cid:9)
`
`3 (cid:9)3 (cid:9)
`
`4 4
`
`Abb. 2 Mittelwerte der Zahl der geschwollenen Gelenke. Der Abb. 2 Mittelwerte der Zahl der geschwollenen Gelenke. Der
`
`Wert bei Therapiebeginn wurde als 100% gewertet_ Wert bei Therapiebeginn wurde als 100% gewertet_
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`Ex. 1019 at 85.8 The Y-axis of Rau Figure 2 quantifies the mean value of
`
`
`
`the number of swollen joints. Ex. 1017 at 6. The number of swollen joints was
`
`converted to a percentage, with 100% representing the number at the start of
`
`treatment. Id. The X-axis shows the study week. Id. Either placebo or a single
`
`dose of D2E7 at 0.5 mg/kg, 1 mg/kg, 3 mg/kg, 5 mg/kg or 10 mg/kg was administered to
`
`patients at week 0. Id. at 5. Rau Figure 2 shows that, for all D2E7 dosing
`
`groups—including the 0.5 mg/kg group—the number of swollen joints decreased
`
`after a single dose of D2E7 given at week 0. Id. at 6. Further, for all D2E7 dosing
`
`groups, this decrease in the number of swollen joints was maintained until week 2
`
`(2 weeks after the drug was administered). Id.
`
`44. Rau additionally reported that, in DE001, “[o]bservation of an ACR-
`
`20 [American College of Rheumatology] response was determined, at any point in
`
`time, with about 42% of patients” in the 0.5 mg/kg dosing group and 65% of patients
`
`in the 1 mg/kg dosing group achieving an ACR 20 response. Id. The criteria for
`
`achieving ACR 20 was discussed supra ¶ 32.
`
`45. With respect to study DE003, Rau, like Kempeni, reported that
`
`patients who entered the open label extension study were given a second injection
`
`no sooner than 4 weeks after the initial injection that was provided in study DE001.
`
`
`8 All figures reproduced from Rau have been copied from the German language
`version of that reference (ex. 1019), which was available to me in higher resolution
`than the English language version.
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`Id. at 5. Patients received subsequent injections when disease activity increased,
`
`
`
`with a minimum interval of two weeks between injections. Id. In reporting the
`
`results of study DE003, Rau provided the following figure (“Rau Figure 4”)
`
`showing relative improvements in the DAS among dosing groups. Id. at 6. For
`
`ease of visibility, the line showing DAS in the 0.5 mg/kg dosing group has been
`
`colored green.
`
`Figure 4: Mean DAS During Studies DE001 and DE003
`
`
`
`134 134
`
`
`
`so so
`
`won
`won
`
`, Midi ORM
`, Midi ORM
`
`1 lig* 3041mie 1 lig* 3041mie
`•
`.
`•
`.
`
`-3 0 1 2 3 4 6 (cid:9)-3 0 1 2 3 4 6 (cid:9)
`
`43
`43
`
`r
`r
`
`10 12 14 is xl 24tieska 10 12 14 is xl 24tieska
`Abb. 4 Mittelwerte des DAS wahrend der Studie. Ausgangswert
`Abb. 4 Mittelwerte des DAS wahrend der Studie. Ausgangswert
`mr 100%.
`mr 100%.
`
`
`
`Ex. 1019 at 85. The Y-axis of Rau Figure 4 quantifies the DAS score, with 100%
`
`representing the DAS score that patients had just before their first dose of D2E7 or
`
`placebo (the single dose given at week 0 of DE001). Ex. 1017 at 6. The X-axis
`
`shows the study week. Id. The graph shows the transition between study DE001
`
`and study DE003 at week 4, as described by Kempeni and Rau. Ex. 1017 at 5-6;
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`Ex. 1004 at I71. Although the legend for the graph does not identify the placebo or
`
`
`
`0.5 mg/kg groups, both Kempeni and Rau disclosed including those two groups in
`
`the DE001 and DE003 studies. Id. A POSA, however, would be able to determine
`
`which line represents placebo and which represents 0.5 mg/kg. First, because both
`
`papers disclose that at week 6 (after receiving a first injection of placebo at week 0
`
`and a second injection of placebo at week 4) all placebo patients were switched to
`
`active drug (ex. 1017 at 5; ex. 1004 at I71), it is possible to identify the placebo
`
`data as the line that ends at week 6. Second, it is possible to identify the green line
`
`as illustrating the data for the 0.5 mg/kg dosing group based on Rau’s disclosure that
`
`the 0.5 mg/kg dosing group had the lowest relative percentage of ACR 20 responses
`
`(42% of patients) among the D2E7 dosing groups, and that, for each dosing group,
`
`“the DAS . . . was marginally lower” than the ACR 20 response. Ex. 1017 at 6. In
`
`other words, the relative DAS reduction for each dosing group corresponded to the
`
`ACR 20 response for that group. Id. Since ACR 20 response was relatively lower
`
`for the 0.5 mg/kg dosing group than for the other D2E7 dosing groups, the reduction
`
`in DAS was also less in that group as compared to the other D2E7 dosing groups.9
`
`See id. It is important to note, however, that Rau Figure 2 shows that all D2E7
`
`dosing groups—including the 0.5 mg/kg dosing group— saw significant reduction in
`
`
`9 I understand that AbbVie has acknowledged that the line I have colored green
`presents data for the 0.5 mg/kg dosing group. Ex. 1101 at 25.
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`their mean DAS as compared with the placebo dosing group. Id. Moreover, Rau
`
`
`
`Figure 4 shows that the 0.5 mg/kg dosing group maintained their reduction in DAS
`
`through week 12, while on the eow dosing regimen of DE003. Id.
`
`46. Rau additionally described DE004, and reported:
`
`[i]n a further phase 1 study (DE004), 24 patients with
`long-term (10.1 years) “therapy-resistant” (3.4 DMARDs
`[disease modifying antirheumatic drugs]) chronic
`polyarthritis were given 0.5-1 mg per kg of D2E7,
`subcutaneously, weekly over 12 weeks; this led in 78%
`of patients to a “moderate response” in the DAS, which
`was not reached in any placebo patient. D2E7 is
`therefore also effective subcutaneously.
`
`Ex.