UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL
`BOARD
`
`______________________________
`
`SANDOZ INC.,
`Petitioner
`
`v.
`
`ABBVIE BIOTECHNOLOGY LTD.,
`Patent Owner
`
`________________________________
`
`U.S. Patent No.: 9,187,559
`Issue Date: Nov. 17, 2015
`Title: Multiple-Variable Dose Regimen for Treating Idiopathic
`Inflammatory Bowel Disease
`__________________________________
`
`DECLARATION OF INGVAR BJARNASON, M.D.,
`M.S.c., F.R.C.Path, F.R.C.P.(Glasg), D.S.c.
`
`

`

`B.
`
`I.
`II.
`
`TABLE OF CONTENTS
`QUALIFICATIONS .....................................................................................1
`THE ’559 PATENT......................................................................................4
`A.
`The Claims of the ’559 Patent.............................................................4
`B.
`The Specification of the ’559 Patent ...................................................7
`C.
`The Priority Date of the ’559 Patent..................................................11
`LEVEL OF ORDINARY SKILL IN THE ART .........................................11
`III.
`IV. CLAIM INTERPRETATION.....................................................................13
`V.
`SUMMARY OF OPINIONS ......................................................................15
`VI.
`THE TEACHINGS OF THE PRIOR ART .................................................17
`A.
`IBD Includes the Closely Related, TNF-α Mediated
`Conditions Crohn’s Disease and UC.................................................17
`Crohn’s Disease and UC Had Long Been Treated With the
`Same Drugs at the Same or Similar Doses ........................................18
`1.
`Steroids.................................................................................. 19
`2.
`Sulphasalazine ....................................................................... 20
`3.
`Azathioprine .......................................................................... 20
`4.
`Cyclosporine.......................................................................... 21
`5.
`Hydroxychloroquine .............................................................. 22
`6.
`Methotrexate.......................................................................... 22
`7.
`Levamisole ............................................................................ 23
`IBD Causes Severe Symptoms and Requires Rapid
`Treatment..........................................................................................24
`Treatment of IBD Requires Both Induction and
`Maintenance Treatment Phases, Using Different Drugs or
`Dosing Regimens..............................................................................25
`1.
`Before TNF-α Inhibitors, the Prior Art Taught the Need
`for Using Different Drugs for Induction and Maintenance
`Therapies ............................................................................... 26
`
`C.
`
`D.
`
`ii
`
`

`

`2.
`
`3.
`
`2.
`
`2.
`
`3.
`
`The Prior Art Taught Using Different Dosing Regimens
`of Infliximab to Induce Remission and to Maintain
`Remission of IBD .................................................................. 28
`The Prior Art Taught The Use of Higher Induction Doses
`to Treat Several Other Disorders............................................ 31
`AbbVie’s Prior Art Taught the Use of a 40 mg EOW
`Adalimumab Dosing Regimen to Treat IBD, and Taught
`That Higher Adalimumab Doses Were Safe and Effective in
`RA ....................................................................................................34
`Disclosure of the 2003 HumiraTM Package Insert (ex.
`1.
`1026) ..................................................................................... 34
`Disclosure of Patent Application Publication WO ’330
`(ex. 1020)............................................................................... 36
`VII. CLAIMS 1-30 OF THE ’559 PATENT ARE OBVIOUS OVER THE
`PRIOR ART ...............................................................................................40
`A.
`A POSA Would Have Been Motivated to Treat IBD with an
`Induction Dose of 160 mg/80 mg, and Would Have Had A
`Reasonable Expectation of Success in So Doing...............................40
`1.
`A POSA would have reasonably used 80 mg eow as the
`basis for an IBD induction regimen........................................ 40
`A POSA would have modified the induction regimen to
`provide rapid relief of IBD symptoms.................................... 43
`A POSA would have combined the known 40 mg
`adalimumab eow maintenance dosing regimen for IBD
`with the induction dose .......................................................... 45
`Claims 1 and 4 of the ’559 Patent Are Obvious Over the
`2003 HumiraTM Package Insert and WO ’330 in View of
`Goodman & Gilman, the 2002 Remicade® Package Insert
`and Hanauer......................................................................................46
`Claims 2, 3, 5 and 6 of the ’559 Patent Are Obvious Over
`the 2003 HumiraTM Package Insert and WO ’330 in View of
`Goodman & Gilman, the 2002 Remicade® Package Insert
`and Hanauer......................................................................................47
`Claims 7, 8, 21, 22, 23 and 30 of the ’559 Patent Are
`Obvious Over the 2003 HumiraTM Package Insert and WO
`
`D.
`
`E.
`
`B.
`
`C.
`
`iii
`
`

`

`E.
`
`F.
`
`’330 in View of Goodman & Gilman, the 2002 Remicade®
`Package Insert and Hanauer..............................................................48
`Claims 9, 10, 11, 12, 15, 17, 18, 20, 24, 26, 27, 29 of the
`’559 Patent Are Obvious Over the 2003 HumiraTM Package
`Insert and WO ’330 in View of Goodman & Gilman, the
`2002 Remicade® Package Insert and Hanauer...................................49
`Claims 13, 14, 16, 19, 25 and 28 of the ’559 Patent Do Not
`Require the POSA to Perform Any Additional Steps
`Beyond the Obvious Methods Recited in the Claims from
`Which They Depend .........................................................................50
`
`iv
`
`

`

`DECLARATION OF INGVAR BJARNASON
`
`I, Ingvar Bjarnason, M.D., M.S.c., F.R.C.Path, F.R.C.P.(Glasg), D.S.c., declare
`
`that:
`
`1.
`
`2.
`
`My name is Ingvar Bjarnason.
`
`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
`
`partes review (“IPR”) of U.S. Patent No. 9,187,559 (“the ’559 patent,” ex. 10011).
`
`I.
`
`QUALIFICATIONS
`3.
`I am a practicing gastroenterologist, Professor of Digestive Diseases
`
`and Lead for Research in gastroenterology at King’s College Hospital, London.
`
`4.
`
`I am accredited in Gastroenterology, Internal Medicine, and Chemical
`
`Pathology.
`
`5.
`
`I graduated in medicine “Candidati Medicinae et Chirurgiae” from
`
`University of Iceland in 1977, and received my M.S.c. in Biochemistry from
`
`Chelsea College, University of London in 1983. In 1986, I received the degree of
`
`“Summos in Medicina Honores et Medicinae Doctorem” (Ph.D. equivalent) from
`
`the University of Iceland, and was the youngest Icelander to be awarded the degree
`
`by 16 years. I went on to earn my D.S.c. (Doctor of Science) degree in Medicine
`
`1 Pincites in my Declaration to exhibits marked with an asterisk (*) refer to
`stamped-on page numbers. All other pincites in my Declaration are to original
`page numbers.
`
`1
`
`

`

`from the University of London in 1997, and my F.R.C.Path from the Royal College
`
`of Pathologist, London, as well as my F.R.C.P. from the Royal College of
`
`Physicians and Surgeons, Glasgow, both in 1999.
`
`6.
`
`I have been a practicing gastroenterologist for over 35 years.
`
`Throughout that time I have treated thousands of patients suffering from
`
`inflammatory bowel disease (“IBD”), an umbrella term for diseases involving
`
`chronic inflammation of the digestive tract, including ulcerative colitis (“UC”) and
`
`Crohn’s disease. Since their approval in the late 1990s to early 2000s, I have
`
`regularly prescribed and administered anti-TNF-α drugs to IBD patients.
`
`Throughout my professional career I have had close clinical and academic
`
`collaborations with rheumatologists, especially during the years 1983 to 2005. I
`
`have seen thousands of patients with the various arthropathies with and without
`
`IBD.
`
`7.
`
`I am the author of over 200 peer reviewed publications, including
`
`dozens of papers focusing on IBD, including Crohn’s disease and UC. I presently
`
`serve on the editorial boards of the professional journals Inflammopharmacology,
`
`and the Scandinavian Journal of Gastroenterology. From 2006 to 2015, I served
`
`on the Advisory Board of Nature Clinical Practice Gastroenterology &
`
`Hepatology. From 2002 to 2006, I served on the editorial board of the professional
`
`journal GUT.
`
`2
`
`

`

`8.
`
`I am a previous member of the American Gastroenterology
`
`Association, the British Society of Gastroenterology, and the European Society of
`
`Comparative Gastroenterology.
`
`9.
`
`A copy of my Curriculum Vitae and a list of my publications is
`
`attached as Appendix A.
`
`10.
`
`In formulating the opinions expressed in this declaration, I have relied
`
`upon my training, knowledge, and experience in the field of gastroenterology,
`
`including treating patients with IBD. I have also considered the ’559 patent and
`
`the publications and materials referred to as Exhibits throughout this declaration,
`
`and listed in Appendix B. In my declaration, I cite to articles and abstracts that
`
`were published in medical journals. Over the course of my career, I have
`
`subscribed to many such journals and/or have accessed them in libraries or from
`
`online databases. In my experience, journal issues are known to physicians as
`
`sources of information on the treatment of IBD, and are readily accessible to the
`
`public (either through the mail to subscribers, including libraries, or online when
`
`published over the internet), as of approximately the date printed on the face of the
`
`reference, if not slightly earlier. Additionally, certain of the references cited in my
`
`declaration are package inserts (or “labels”) for commercially marketed
`
`prescription drugs. Based on my experience throughout my career as a practicing
`
`physician, including in 2003, doctors review the labels for the drugs they prescribe.
`
`3
`
`

`

`Physicians know (and would have known in 2003) that labels for the drugs they
`
`prescribe are available for their review, and physicians in fact do review them.
`
`Drug labels are available from a variety of sources, including the FDA website, the
`
`manufacturers’ website, the Physicians’ Desk Reference (“PDR”) and in print form
`
`accompanying the commercial drug product. Physicians could and did access such
`
`labels from these sources, as I have done personally many times.
`
`11.
`
`Throughout this declaration, I may refer to the treatment of IBD as the
`
`“relevant field.”
`
`12.
`
`I have been retained by Sandoz as an expert in the relevant field to
`
`provide my opinions on the subject matter of the ’559 patent.
`
`13.
`
`I am being compensated for my time at my normal hourly consulting
`
`rate. My compensation is not dependent upon and does not affect the substance of
`
`my opinions.
`
`II.
`
`THE ’559 PATENT
`
`A.
`14.
`
`The Claims of the ’559 Patent
`The ’559 patent recites methods of treating idiopathic IBD, and has
`
`two independent claims – claims 1 and 4.
`
`15. Claim 1 reads as follows:
`
`[a] multiple-variable dose method for treating idiopathic
`inflammatory bowel disease in a human subject in need
`thereof, comprising subcutaneously administering to the
`human subject:
`
`4
`
`

`

`a first dose of 160 mg of adalimumab administered to
`the human subject within a day; and
`a second dose of 80 mg of adalimumab administered
`to the human subject within a day, wherein the
`second dose is administered two weeks following
`administration of the first dose.
`
`Ex. 1001 at claim 1.
`
`16. Claims 2, 3, 9, 10, 13 and 15-23 depend, directly or indirectly, from
`
`claim 1, meaning that they claim the method of claim 1 plus additional limitations.
`
`17. Claim 2 depends from claim 1 and specifies that the method further
`
`comprises administering to the subject a subsequent subcutaneous injection of 40
`
`mg of adalimumab two weeks following administration of the second dose. Claim
`
`3 depends from claim 2 and further specifies that additional subsequent
`
`subcutaneous injections of 40 mg of adalimumab are administered two weeks
`
`apart, i.e., every other week (“eow”).
`
`18. Claims 9, 15 and 18 depend, respectively, from claims 1, 2 and 3, and
`
`specify that the human subject has Crohn’s disease.
`
`19. Claims 10, 17 and 20 depend, respectively, from claims 1, 2 and 3,
`
`and specify that the human subject has UC.
`
`5
`
`

`

`20. Claims 13, 16 and 19 depend, respectively, from claims 9, 15, and 18,
`
`and specify that the human subject achieves a Crohn’s Disease Activity Index
`
`(CDAI) 2 score of <150.
`
`21. Claims 21, 22 and 23 depend from claims 1, 2 and 3, respectively, and
`
`specify that each subcutaneous injection is administered using a pre-filled syringe.
`
`22. Claim 4, the other independent claim of the ’559 patent, reads as
`
`follows:
`
`[a] multiple-variable dose method for treating idiopathic
`inflammatory bowel disease in a human subject in need
`thereof, comprising subcutaneously administering to the
`human subject:
`a first dose of 160 mg of adalimumab administered as
`a set of four injections of 40 mg of adalimumab
`administered to the human subject within a day; and
`a second dose of 80 mg of adalimumab administered
`as a set of two injections of 40 mg of adalimumab
`administered to the human subject within a day,
`wherein the second dose is administered two weeks
`following administration of the first dose.
`
`Ex. 1001 at claim 4. Accordingly, the only difference between claim 1 and claim 4
`
`is that claim 4 specifies the number of injections by which the first and second
`
`doses of adalimumab are administered.
`
`2 The CDAI has been one of the most common scoring systems used to measure
`Crohn’s disease activity in clinical research since well before the assumed priority
`date of the ’559 patent. See, e.g., ex. 1016 at 2020 (“In clinical research . . . .
`[c]omposite scoring systems, most commonly the Crohn’s Disease Activity Index
`(CDAI []), are used in an attempt to integrate the many possible features of the
`disease.”).
`
`6
`
`

`

`23. Claims 5-8, 11, 12, 14 and 24-30 all depend, directly or indirectly,
`
`from claim 4.
`
`24. Claim 5 depends from claim 4 and specifies that the method further
`
`comprises administering to the subject a subsequent subcutaneous injection of 40
`
`mg of adalimumab two weeks following administration of the second dose. Claim
`
`6 depends from claim 5 and further specifies that additional subsequent
`
`subcutaneous injections of 40 mg of adalimumab are administered two weeks
`
`apart, i.e., eow.
`
`25. Claims 7, 8 and 30 depend, respectively, from claims 4, 5 and 6, and
`
`specify that each subcutaneous injection is administered using a pre-filled syringe.
`
`26. Claims 11, 24 and 27 depend, respectively, from claims 4, 5 and 6,
`
`and specify that the human subject has Crohn’s disease.
`
`27. Claims 12, 26 and 29 depend, respectively, from claims 4, 5 and 6,
`
`and specify that the human subject has UC.
`
`28. Claims 14, 25 and 28 depend, respectively, from claims 11, 24 and 27,
`
`and specify that the human subject achieves a CDAI score of <150.
`
`B.
`29.
`
`The Specification of the ’559 Patent
`The specification of the ’559 explains that the goal of the “multiple-
`
`variable dose” method claimed in the patent is to “induc[e] remission” of IBD
`
`(Crohn’s disease) by administering “at least one induction dose of a TNFα
`
`7
`
`

`

`inhibitor.” Ex. 1001 at 2:52-59. The specification defines the term “[m]ultiple-
`
`variable dose regimen” as follows:
`
`“[m]ultiple-variable dose regimen” or “multiple-variable
`dose therapy” describe a treatment schedule which is
`based on administering different amounts of TNFα
`inhibitor at various time points throughout the course of
`treatment. In one embodiment, the invention describes a
`multiple-variable dose method of treatment comprising
`an induction phase and a treatment phase, wherein a
`TNFα inhibitor is administered at a higher dose during
`the induction phase than the treatment phase.
`Id. at 11:40-48.
`
`30.
`
`The specification further states that the induction or loading dose “is
`
`larger in comparison to the maintenance or treatment dose.” Id. at 11:62-65. “The
`
`induction dose is often used to bring the drug in the body to a steady state amount,
`
`and may be used [] to achieve maintenance drug levels quickly.” Id. at 11:66-12:1.
`
`The specification of the ’559 patent discloses “a 160 mg dose followed by an 80
`
`mg dose” as one example of an “induction phase treatment[].” Id. at 63:53-58.
`
`31.
`
`In contrast to the induction dose, the “treatment dose” or
`
`“maintenance dose” “is the amount of TNFα [inhibitor] taken by a subject to
`
`maintain or continue a desired therapeutic effect.” Id. at 12:16-20. “A treatment
`
`dose is administered subsequent to the induction dose.” Id. at 12:18-19.
`
`32.
`
`The ’559 patent discloses two clinical studies with various dosing
`
`regimens of adalimumab to treat Crohn’s disease. Id. at 73:41-76:20. These
`
`8
`
`

`

`studies are described in Examples 1 and 2. Id. The ’559 patent does not disclose
`
`any UC clinical trials.
`
`33.
`
`The study described in Example 1 was a multiple-variable dose study
`
`of adalimumab for treating Crohn’s disease. Id. at 73:43-75:21. Subjects were
`
`randomized equally to one of four groups (three treatment groups and one placebo
`
`group). Patients received a “loading dose” at week 0 and a “treatment dose” at
`
`week 2. Id. at 74:1-8. Specifically, “[p]atients received one of the following
`
`multiple variable dose treatment regimens at Week 0 (baseline) and Week 2 (Week
`
`0/Week 2): 160 mg/80 mg D2E7; 80 mg/40 mg D2E7; 40 mg/20 mg D2E7; or
`
`placebo/placebo.” Id. at 74:4-7. All doses were administered subcutaneously. Id.
`
`at 74:7-8. Table 1 discloses the percentage of patients achieving clinical remission
`
`(defined as a CDAI of < 150) at week 4 of treatment:
`
`TABLE 1
`
`D2E7 induces clinical remission in treatment gimps at Week 4
`
`Plaoebo. (cid:9)
`
`40120 nig (cid:9)
`
`80/40 ling (cid:9)
`
`160180 mg
`
`CDAI g 150 (cid:9)
`
`12% (cid:9)
`
`18% (cid:9)
`
`24% (cid:9)
`
`36510*
`
`(`cicooks p = 0.0101 )
`(Flaccho n = 74; 20 mg.] = 74; 40 (cid:9)
`
`n = 75; 80 .rog = 7{)
`
`As is shown in Table 1, 36% of patients achieved remission from the 160/80 mg
`
`dose of adalimumab. Id. at tbl. 1.
`
`34.
`
`The patent specification states, with respect to Example 1:
`
`9
`
`

`

`[i]n sum, multiple, variable doses of D2E7 significantly
`increased the frequency of remission of disease in
`Crohn’s disease subjects. In combination, 30% of
`subjects receiving D2E7 doses of 80/40 mg and 160/80
`mg achieved remission in comparison to only 12% of
`placebo subjects.
`
`Id. at 75:9-14.
`
`35.
`
`Example 2 assessed administration of 80 mg of adalimumab
`
`subcutaneously at week 0 and 40 mg at week 2 to Crohn’s disease patients who
`
`could not continue to be successfully treated with infliximab, due to lack of
`
`sustained response or drug intolerance. Id. at 75:30-40. The study concluded that
`
`this dosing regimen “was well tolerated and was clinically beneficial” in patients
`
`“who had previously received and responded to infliximab, but who no longer had
`
`a sustained response to or could not tolerate infliximab.” Id. at 76:16-20.
`
`36.
`
`The specification also describes the association between rheumatoid
`
`arthritis (“RA”) and IBD and that both conditions are mediated by TNF-α. These
`
`facts were well known in the prior art, as is acknowledged by the explanation in
`
`the specification that TNF-α “has been implicated in playing a role in the
`
`pathophysiology of a variety of autoimmune diseases . . . [and] has been implicated
`
`in activating tissue inflammation and causing joint destruction in rheumatoid
`
`arthritis.” Id. at 24:13-17 (citations omitted). The ’559 patent’s specification
`
`further explains that TNF-α “has been implicated in the pathophysiology of
`
`inflammatory bowel disorders including Crohn’s disease (see e.g., Tracy et al.
`
`10
`
`

`

`(1986) Science 234:470; Sun et al. (1988) J. Clin. Invest. 81:1328; MacDonald et
`
`al. (1990) Clin. Exp. Immunol. 81:301).” Id. at 28:50-55. Therefore, “TNFα
`
`inhibitors, including human antibodies, and antibody portions such as D2E7, may
`
`be used in a multiple-variable dose method to treat autoimmune diseases, . . .
`
`includ[ing] rheumatoid arthritis” (id. at 24:37-41) and “Crohn’s disease.” Id. at
`
`25:14-17.
`
`C.
`37.
`
`The Priority Date of the ’559 Patent
`For purposes of this declaration, I have been asked to assume that the
`
`priority date of the ’559 patent is April 9, 2004.
`
`III. LEVEL OF ORDINARY SKILL IN THE ART
`38.
`I have been informed that a person having ordinary skill in the art
`
`(“POSA”) is a hypothetical person who is presumed to have been aware of all
`
`relevant art at the time of the invention. For purposes of this Declaration, I have
`
`been asked to assess the state of the art, including based on any references I rely on
`
`herein, as of one year before the April 9, 2004 assumed priority date of the ’559
`
`patent.3 I also understand that the POSA is a person of ordinary creativity (not an
`
`automaton), who understands the scientific principles applicable to the pertinent
`
`3 I understand from counsel that references published more than one year before
`the effective filing date of a U.S. patent are considered prior art without regard to
`the actual date of invention of the claimed subject matter.
`
`11
`
`

`

`art. Said hypothetical person may also have the skill sets of more than one
`
`individual.
`
`39. Based on my review of the ’559 patent and the prior art, and on my
`
`experience and knowledge in the field, it is my opinion that the hypothetical POSA
`
`pertaining to the subject matter of the ’559 patent would have the skill sets of a
`
`team comprising a pharmacologist having experience with TNF-α inhibitors and a
`
`gastroenterologist or other physician treating patients for IBD (including Crohn’s
`
`disease and UC).
`
`40.
`
`The gastroenterologist on the POSA team would have an M.D. and at
`
`least three years’ post-residency experience treating patients having IBD, including
`
`Crohn’s disease and UC, including with anti-TNF-α drugs.
`
`41.
`
`I understand that Dr. John Posner, a clinical pharmacologist, is
`
`submitting a declaration regarding the pharmacology aspects of the ’559 patent,
`
`and is of the opinion that the pharmacologist on the POSA team would have had a
`
`Ph.D. in pharmacology, pharmacokinetics, or a related field, and at least three
`
`years of experience working on the pharmacokinetics and/or pharmacodynamics of
`
`biologic drugs.
`
`42.
`
`I have considered the ’559 patent from the perspective of a POSA as
`
`of April 9, 2004, in light of the state of the art in the relevant field at the time. As
`
`described below, it is my opinion that a POSA would have found the methods of
`
`12
`
`

`

`treatment claimed in the ’559 patent to be obvious in view of the state of the art
`
`and the disclosures in the prior art.
`
`IV. CLAIM INTERPRETATION
`Patients with idiopathic4 IBD (including Crohn’s disease and UC)
`43.
`
`suffer from chronic inflammation of the bowel. Ex. 1036 at 1713, 1746-47. The
`
`most common signs and symptoms of this bowel inflammation are pain and
`
`diarrhea, but fever, weight loss, and intestinal bleeding can also occur. Id. at 1713-
`
`14, 1742-43, 1753. In severe cases, perianal fissures, fistulas and/or abscesses may
`
`also be present. Id. at 1714, 1753-54. The goal in treating IBD is to reduce
`
`inflammation of the bowel, thereby reducing these signs and symptoms. Id. at
`
`1725, 1753-54. Remission of IBD can be induced by appropriate treatment, but
`
`relapse is always a possibility – the disease can never truly be cured. Id. at 1727,
`
`1753-54 (discussing strategies for prevention of relapse). Accordingly, when
`
`gastroenterologists speak of “treating” IBD (including Crohn’s disease and UC)
`
`they are referring to measures that will reduce the signs and symptoms of the
`
`disease.
`
`44. Claims 1-30 of the ’559 patent recite multiple-variable dose methods
`
`for treating idiopathic IBD in a human subject comprising administering a human
`
`TNF-α antibody. Ex. 1001. I understand that Sandoz submits that, to the extent
`
`4 The adjective “idiopathic” means that the initial cause of the disease is unknown.
`Both Crohn’s disease and UC are considered to be idiopathic forms of IBD.
`
`13
`
`

`

`the word “treating” is construed, this term means “reducing the signs and/or
`
`symptoms of” IBD, without requiring any specific level of efficacy. I agree with
`
`this definition, as it is consistent with how gastroenterologists, including myself,
`
`regularly use the word “treating” as it relates to IBD patients, for whom the goals
`
`of treatment are reducing the signs and/or symptoms of the disease by inducing
`
`remission and/or maintaining symptom remission. I additionally note that, where
`
`certain dependent claims (claims 13, 14, 16, 19, 25 and 28) require specific levels
`
`of efficacy as measured by achievement of CDAI score, those claims expressly so
`
`state. I have also reviewed the ’559 patent, and find that Sandoz’s proposed
`
`definition is consistent with the disclosure of the patent, which provides:
`
`[t]his invention provides a multiple-variable dose method
`of treating a TNFα-related disorder in which the
`administration of a TNFα inhibitor is beneficial. . . . As
`used herein, the term “a disorder in which TNFα activity
`is detrimental” is intended to include diseases and other
`disorders in which the presence of TNFα in a subject
`suffering from the disorder has been shown to be or is
`suspected of being either responsible for the
`pathophysiology of the disorder or a factor that
`contributes to a worsening of the disorder. Accordingly, a
`disorder in which TNFα activity is detrimental is a
`disorder in which inhibition of TNFα activity is expected
`to alleviate the symptoms and/or progression of the
`disorder.
`
`Id. at 13:40-42, 23:27-36.
`
`14
`
`

`

`V.
`
`SUMMARY OF OPINIONS
`45.
`For the reasons described herein, it is my opinion that it would have
`
`been obvious to the POSA to use a higher initial induction dosing regimen of
`
`adalimumab, such as the claimed dosing regimen of 160 mg adalimumab followed
`
`two weeks later by 80 mg, to treat IBD (which includes Crohn’s disease and UC)
`
`because the prior art taught that:
`
` Treating IBD requires first inducing remission of the disease and then
`maintaining remission;
`
` Different drugs and/or dosing regimens are used to induce remission of
`IBD, than are used to maintain remission of IBD;
`
` The FDA had approved a regimen for inducing remission of Crohn’s
`disease using the TNF-α inhibitor infliximab that administered more drug
`in a shorter period of time compared to the approved maintenance
`regimen;
`
` The prior art taught the use of higher induction doses (as compared to
`maintenance doses) to treat other disorders;
`
` Adalimumab administered at 40 mg eow was an appropriate dosing
`regimen to maintain remission of IBD;
`
` Adalimumab could safely be administered at higher doses, for example in
`a dosing regimen of 80 mg eow; and
`
` Patients with IBD need treatments that provide rapid therapeutic benefits
`because IBD is a severe, sometimes life-threatening, disease.
`
`46. As explained in detail herein, given all of these prior art teachings, a
`
`POSA would have been motivated to design a method for the treatment of IBD
`
`with adalimumab comprising a higher initial dosing regimen to induce IBD
`
`15
`
`

`

`remission, as compared with the obvious 40 mg adalimumab eow IBD
`
`maintenance regimen. A POSA would have reasonably expected that a dosing
`
`regimen using higher doses of adalimumab than were used in the disclosed 40 mg
`
`eow IBD maintenance regimen would be useful to induce IBD remission. To
`
`determine which adalimumab induction regimen to use to induce remission of
`
`IBD, a POSA would look to the limited number of adalimumab dosing regimens
`
`which had been proven to safely and effectively treat other TNF-α related disorders
`
`using doses higher than the 40 mg eow IBD maintenance regimen -- e.g., 80 mg
`
`adalimumab eow. Additionally, because IBD can cause severe, life-threatening
`
`symptoms, it is my opinion that a POSA would have been motivated to bring drug
`
`levels in the patient’s body up to levels associated with the higher, induction
`
`dosing regimen as rapidly as possible. I understand that Sandoz’s expert, Dr.
`
`Posner, explains that the use of a 160 mg loading dose of adalimumab at the
`
`beginning of the induction regimen can achieve this result, with respect to an 80
`
`mg eow induction dosing regimen. Accordingly, it is my opinion that a POSA
`
`would have been motivated to combine the teachings of the prior art to arrive at the
`
`adalimumab induction dosing regimen claimed in the ’559 patent, and would have
`
`had a reasonable expectation of success in so doing.
`
`47. As also described herein, it is my opinion that it would have been
`
`obvious to the POSA to follow the claimed adalimumab induction dosing regimen
`
`16
`
`

`

`with the known adalimumab maintenance regimen for IBD ‒ 40 mg adalimumab
`
`administered subcutaneously eow ‒ to maintain remission of IBD. That exact IBD
`
`maintenance dosing regimen was disclosed in a prior art patent publication (WO
`
`02/100,3305) to treat IBD, and was also approved by the FDA to treat RA (ex.
`
`1026).
`
`VI. THE TEACHINGS OF THE PRIOR ART
`
`A.
`
`48.
`
`IBD Includes the Closely Related, TNF-α Mediated Conditions
`Crohn’s Disease and UC
`The umbrella term “IBD” encompasses Crohn’s disease and UC,
`
`which are closely related conditions. Ex. 1037 at 294 (“The term (chronic)
`
`inflammatory bowel disease (IBD) encompasses Crohn’s disease and ulcerative
`
`colitis, which share common epidemiological, genetic, and clinical features and
`
`may represent two poles of a continuous disease spectrum.”) (citation omitted).
`
`Both conditions involve chronic inflammation of the bowel and present with
`
`similar symptoms (e.g., chronic diarrhea and abdominal discomfort). Ex. 1036 at
`
`1708, 1713, 1740, 1742, 1746-47. The primary clinical difference between the
`
`conditions is the precise location of the intestinal inflammation: while UC affects
`
`only the inner lining of the colon and rectum, the inflammation associated with
`
`Crohn’s disease can appear anywhere in the digestive tract. Ex. 1036 at 1710,
`
`1740.
`
`5 Referred to herein as “WO ’330” (ex. 1020).
`
`17
`
`

`

`B.
`
`Crohn’s Disease and UC Had Long Been Treated With the Same
`Drugs at the Same or Similar Doses
`49. As acknowledged in the ’559 patent, TNF-α-mediated inflammation
`
`had long been implicated in Crohn’s disease and UC, much as it had been
`
`implicated in RA. Ex. 1001 at 24:13-17, 28:51-56. Perhaps unsurprisingly,
`
`therefore, it was also well known in the prior art that Crohn’s disease and UC
`
`shared common treatments.
`
`50.
`
`Table 1 below summarizes the long history in the prior art of treating
`
`Crohn’s disease and UC with the same drugs, at the same or similar doses. The
`
`references summarized in the table are described in more detail below.
`
`Drug
`
`Prednisolone
`(infra at ¶ 51)
`Prednisone (id.)
`Sulphasalazine
`(id. at ¶ 52)
`
`Azathioprine
`(id. at ¶ 53)
`
`Cyclosporine
`(id. at ¶ 54)
`
`Table 1 – Drugs Used to Treat Crohn’s Disease
`and UC At the Same or Similar Dose
`IBD dosing regimen
`
`CD
`UC
`25-40 mg/day
`20 mg/day
`10-60 mg (median 20 mg) daily
`1 g/15 kg (= 5 g for a 75 kg
`Up to 6 g/day
`person)
`
`1.5 – 2.5 mg/kg/day
`
`1.5 – 4 mg/kg/day
`
`8.5 mg/kg/day orally for 5-6 weeks or 4
`mg/kg/day intravenously for at least 10
`days
`
`4 mg/kg/day intravenously for up to 14
`days, if improvement, then oral dose
`was administered as 6 to 8 mg/kg/day
`
`18
`
`5-7.5 mg/kg/day orally
`
`

`

`4 mg/kg/day intravenously comparable
`with 12-16 mg/kg/day orally
`
`400 mg/day
`
`400 mg/day
`
`25 mg/week for 12 weeks, tapered
`down to 7.5 mg/week
`150 mg twice a week for the first
`two weeks, then once a week
`thereafter
`Steroids
`1.
`Steroids have long been used in Crohn’s disease and UC and are still a
`
`same
`50 mg 8-hourly ( = 150
`mg/day) for 3 consecutive
`days every 2 weeks
`
`Hydroxy-
`chloroquine
`(id. at ¶ 55)
`Methotrexate
`(id. at ¶ 56)
`Levamisole
`(id. at ¶ 57)
`
`51.
`
`mainstay for gastroenterologists treating IBD. The prior art showed that it was
`
`routine for steroids to be used at the same doses for both UC and CD. See, e.g., ex.
`
`1038 at 1709 (comparing “[c]ombined corticosteroid therapy consist[ing] of oral
`
`prednisolone 5 mg. four times a day and a nightly rectal drip of 100 mg. of
`
`hydrocortisone succinate sodium in solution” and sulphasalazine to treat UC); ex.
`
`1039 at 843 (Crohn’s disease patients “treated with prednisolone received 40 mg
`
`daily for two weeks, 30 mg for two weeks, and 25 mg for two weeks”), ex. 1040 at
`
`172 (administering 60 mg/day prednisone tapered to a maintenance dose of 5 mg/day in
`
`combination with mycophenolate mofetil to patients with Crohn’s and UC and
`
`noting that the r