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.: 8,974,790
`Issue Date: Mar. 10, 2015
`Title: Methods of Administering Anti-TNFα Antibodies
`__________________________________
`
`DECLARATION OF INGVAR BJARNASON, M.D.,
`M.S.c., F.R.C.Path, F.R.C.P.(Glasg), D.S.c.
`
`

`

`I.
`II.
`
`2.
`
`3.
`
`TABLE OF CONTENTS
`QUALIFICATIONS .....................................................................................1
`THE ’790 PATENT......................................................................................4
`A.
`The Claims of the ’790 Patent.............................................................4
`B.
`The Specification of the ’790 Patent ...................................................5
`C.
`The Priority Date of the ’790 Patent....................................................6
`LEVEL OF ORDINARY SKILL IN THE ART ...........................................6
`III.
`IV. CLAIM INTERPRETATION.......................................................................9
`V.
`SUMMARY OF OPINIONS ......................................................................11
`VI.
`STATE OF THE ART ................................................................................12
`A.
`Disclosure of Patent Application Publication WO 97/29131
`(“Salfeld”) (ex. 1006)........................................................................12
`Disclosure of Sandborn (ex. 1005)....................................................15
`1.
`Crohn’s Disease Studies Described by Sandborn................... 16
`a)
`Infliximab Crohn’s Disease Studies ..............................16
`b)
`CDP571 Crohn’s Disease Study....................................20
`RA Studies Described by Sandborn ....................................... 20
`a)
`Infliximab RA Studies ..................................................20
`b)
`CDP571 RA Studies .....................................................23
`UC Studies Described by Sandborn ....................................... 24
`a)
`Infliximab UC Study.....................................................24
`b)
`CDP571 UC Studies .....................................................25
`Summary of Sandborn ........................................................... 25
`4.
`VII. A POSA WOULD HAVE A REASONABLE EXPECTATION OF
`SUCCESS THAT THE RA DOSING REGIMEN OF D2E7
`WOULD ALSO TREAT IBD.....................................................................26
`A.
`The Relationship Between RA and IBD Has Long Been
`Established in the Prior Art...............................................................26
`Crohn’s Disease and UC Were Known to be Closely
`Related Conditions............................................................................29
`
`B.
`
`B.
`
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`C.
`
`D.
`
`E.
`
`A POSA Knew That TNF-α Was Linked to the
`Pathogenesis of RA and IBD ............................................................30
`The Prior Art Taught That TNF-α Inhibitors Could Treat
`RA and IBD with the Same Dosing Regimens..................................33
`The Long History of Treating IBD with RA Drugs at RA
`Doses................................................................................................43
`1.
`Steroids.................................................................................. 45
`2.
`Sulphasalazine ....................................................................... 46
`3.
`NSAIDs ................................................................................. 47
`4.
`Azathioprine .......................................................................... 48
`5.
`Cyclosporine.......................................................................... 50
`6.
`Hydroxychloroquine .............................................................. 51
`7.
`Penicillamine ......................................................................... 52
`8.
`Methotrexate.......................................................................... 53
`9.
`Levamisole ............................................................................ 54
`VIII. THE PRIOR ART DOES NOT TEACH AWAY FROM THE
`CLAIMED DOSING REGIMEN ...............................................................59
`A.
`The Prior Art Taught That the Same Doses of TNF-α
`Inhibitors Would Be Effective in Treating Both RA and
`IBD...................................................................................................59
`The POSA Would Also Have Considered Prior Art Dosing
`of CDP571........................................................................................61
`IX. CLAIMS 1-6 OF THE ’790 PATENT ARE OBVIOUS OVER THE
`PRIOR ART ...............................................................................................62
`A.
`Administering 40 mg D2E7 Subcutaneously EOW to Treat
`RA Was Obvious ..............................................................................62
`Claim 1 of the ’790 Patent Is Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................63
`Claim 2 of the ’790 Patent Is Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................64
`
`B.
`
`B.
`
`C.
`
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`D.
`
`E.
`
`Claim 3 of the ’790 Patent Is Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................65
`Claims 4-6 of the ’790 Patent Are Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................66
`
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`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. 8,974,790 (“the’790 patent,” ex. 1001).
`
`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
`
`from the University of London in 1997, and my F.R.C.Path from the Royal College
`
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`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 UC and Crohn’s disease
`
`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 UC and Crohn’s disease. 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.
`
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`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 UC. I have also considered the ’790 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 available 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.
`
`11.
`
`Throughout this declaration, I may refer to the treatment of UC 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 ’790 patent.
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`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 ’790 PATENT
`A.
`The Claims of the ’790 Patent
`14.
`The ’790 patent has one independent claim – claim 1 – which reads as
`
`follows:
`
`[a] method for treating ulcerative colitis in a human
`subject, comprising administering subcutaneously to a
`human subject having ulcerative colitis a total body dose
`of 40 mg of a human anti-TNFα antibody once every 13-
`15 days for a time period sufficient to treat the ulcerative
`colitis, wherein the anti-TNFα antibody comprises an
`IgG1 heavy chain constant region; a variable light (“VL”)
`chain region comprising a CDR1 having the amino acid
`sequence of SEQ ID NO:7, a CDR2 having the amino
`acid sequence of SEQ ID NO:5, and a CDR3 having the
`amino acid sequence of SEQ ID NO:3; and a variable
`heavy (“VH”) chain region comprising a CDR1 having
`the amino acid sequence of SEQ ID NO:8, a CDR2
`having the amino acid sequence of SEQ ID NO:6and
`[sic] a CDR3 having the amino acid sequence of SEQ ID
`NO:4.
`
`Ex. 1001 at claim 1. I understand that the amino acid sequences specified in the
`
`claims of the ’790 patent correspond to the antibody adalimumab (also known as
`
`D2E7).
`
`15.
`
`The remaining claims of the ’790 patent all depend from claim 1,
`
`meaning that they claim the method of claim 1 plus additional limitations. Claim 2
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`further specifies amino acid sequences for the antibody, which sequences I
`
`understand correspond to the antibody adalimumab. Id. at claim 2. Claim 3
`
`specifies that the human subject has had an unwanted immune response to a
`
`chimeric or humanized anti-TNF-α antibody. Id. at claim 3. Claims 4-6 all specify
`
`that the antibody is administered for a period of at least 24 weeks. Id. at claims 4-
`
`6. Specifically, claim 4 recites the method of claim 3, wherein the antibody is
`
`administered for a period of at least 24 weeks. Id. at claim 4. Claim 5 recites the
`
`method of claim 2, wherein the antibody is administered for a period of at least 24
`
`weeks. Id. at claim 5. Claim 6 recites the method of claim 1 wherein the antibody
`
`is administered for this time period. Id. at claim 6.
`
`B.
`16.
`
`The Specification of the ’790 Patent
`The specification of the ’790 patent states that, “[i]n a preferred
`
`embodiment, the invention provides methods of treating disorders in which the
`
`administration of an anti-TNFα antibody is beneficial, comprising subcutaneously
`
`administering to the subject biweekly an antibody or antibody portion of the
`
`invention such that the disorder is treated.” Id. at 24:27-31. The specification
`
`further states that “[t]here are numerous examples of disorders in which TNFα[]
`
`activity is detrimental” (id. at 25:1-3) and lists more than two dozen such disorders,
`
`including sepsis (id. at 25:6-35), autoimmune diseases (id. at 25:36-67), infectious
`
`diseases (id. at 26:1-26), transplantations (id. at 26:27-54), malignancies (id. at
`
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`26:55-64), pulmonary disorders (id. at 26:65 – 27:12), intestinal disorders (id. at
`
`27:12-25), cardiac disorders (id. at 27:26-33), and “others” (id. at 27:34-62).
`
`17. Among the “intestinal disorders” listed in the specification of the ’790
`
`patent as being treatable with the antibodies of the invention is “idiopathic
`
`inflammatory bowel disease, which includes two syndromes, Crohn’s disease and
`
`ulcerative colitis.” Id. at 27:21-25. The examples of the ’790 patent, however, all
`
`describe the use of D2E7 to treat rheumatoid arthritis (“RA”) – the patent includes
`
`no example where D2E7 is used to treat Crohn’s disease or UC.
`
`C.
`
`18.
`
`The Priority Date of the ’790 Patent
`
`For purposes of this declaration, I have been asked to assume that the
`
`priority date of the ’790 patent is June 8, 2001.
`
`III. LEVEL OF ORDINARY SKILL IN THE ART
`19.
`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 June 8, 2001 assumed priority date of the ’790
`
`patent.1 I also understand that the POSA is a person of ordinary creativity (not an
`
`1 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.
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`automaton), who understands the scientific principles applicable to the pertinent
`
`art. Said hypothetical person may also have the skill sets of more than one
`
`individual.
`
`20. During prosecution of the application that led to the ’790 patent, the
`
`examiner described the characteristics of a POSA as follows:
`
`[i]n contemplating the specific dosage regimen that
`should be used to treat a patient having ulcerative colitis
`with the claimed anti-TNFα antibody one of ordinary
`skill in the art would have to consider a number of factors
`including the biophysical properties of the anti-TNFα
`antibody to be administered; the route of administration,
`e.g., intravenous vs. subcutaneous; the dosage form, e.g.,
`dosing as a function of patient body weight vs. dosing
`with a predetermined quantity of active compound in the
`form of physically discrete units; and the frequency of
`dosage, e.g., weekly vs. biweekly.
`
`Moreover, one of ordinary skill in the art would have
`looked to experiences treating ulcerative colitis with anti-
`TNFα antibodies in general.
`
`Ex. 1010 at 6. These considerations, as described by the patent examiner, suggest
`
`that the skills of both a pharmacologist designing a dosing regimen and a physician
`
`treating UC would be relevant.
`
`21. Based on my review of the ’790 patent, relevant portions of the
`
`prosecution history, 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 ’790 patent would have the skill sets of a team comprising a pharmacologist
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`having experience with monoclonal antibody drugs, a gastroenterologist or other
`
`physician treating patients for IBD (including Crohn’s disease and UC) and,
`
`because the IBD dosing regimens are borrowed directly from the dosing regimen
`
`for RA, a rheumatologist or other physician treating RA.
`
`22.
`
`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.
`
`23.
`
`I understand that Dr. John Posner, a pharmacologist, is submitting a
`
`declaration regarding the pharmacology aspects of the ’790 patent, and is of the
`
`opinion that the pharmacologist on the POSA team would have 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.
`
`24.
`
`I also understand that Dr. Simon Helfgott, a rheumatologist, is
`
`submitting a declaration regarding the rheumatology aspects of the ’790 patent,
`
`and is of the opinion that the rheumatologist on the team would have an M.D. and
`
`at least three years’ post-residency experience treating patients for RA, including
`
`with anti-TNF-α drugs.
`
`25.
`
`I have considered the ’790 patent from the perspective of a POSA as
`
`of June 8, 2001, in light of the state of the art in the relevant field at the time. As
`
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`described below, it is my opinion that a POSA would have found the methods of
`
`treatment claimed in the ’790 patent to be obvious in view of the state of the art
`
`and the disclosures in the prior art.
`
`IV. CLAIM INTERPRETATION
`26.
`Patients with IBD (including Crohn’s disease and UC) suffer from
`
`chronic inflammation of the bowel. Ex. 1027 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.
`
`27. Claims 1-6 of the ’790 patent recite methods for treating UC in a
`
`human subject comprising administering a human anti-TNF-α antibody “for a time
`
`period sufficient to treat the ulcerative colitis.” Ex. 1001 at claim 1. I understand
`
`that Sandoz submits that “for a time period sufficient to treat the ulcerative colitis”
`
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`means “for a time period sufficient to reduce the signs and/or symptoms of
`
`ulcerative colitis.” 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. I have additionally reviewed the ’790 patent, and find
`
`that Sandoz’s proposed definition is consistent with the disclosure of the patent,
`
`which provides:
`
`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
`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.
`
`Ex. 1001 at 3:42-47, 24:60-63.
`
`28.
`
`I understand that in its decision to institute previous IPRs on
`
`AbbVie’s patent relating to the D2E7 dosing regimen for RA (U.S. Patent No.
`
`8,889,135, “the ’135 patent,” ex. 1093), the Patent Trial and Appeal Board (the
`
`“Board”) construed “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.” See, e.g., Coherus BioSciences Inc. v. AbbVie Biotech. Ltd.,
`
`Case No. IPR2016-00172, Decision Institution of Inter Partes Review, Paper No.
`
`9, at 10 (P.T.A.B. May 17, 2016). I understand that this construction was
`
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`confirmed by the Board in its Final Written Decision. See, e.g., Coherus
`
`BioSciences Inc. v. AbbVie Biotech. Ltd., No. IPR2016-00172, Final Written
`
`Decision, Paper No. 60, at 9 (P.T.A.B. May 16, 2017). In inflammatory arthritis,
`
`including RA, disease progression centers on pathologic changes in the synovium
`
`of the joints. See generally ex. 1029 at 833-60. These changes in the joints are
`
`visible in x-ray images, and have allowed clinicians to develop a standardized
`
`measure for stages of disease progression. Id. at 598, 833-60. In UC, there is no
`
`analogous, standardized measure of disease progression. Accordingly, while it was
`
`entirely appropriate for the Board to include “progression” in its claim construction
`
`for the RA dosing patent, “progression” is not included as an element of Sandoz’s
`
`proposed claim construction for UC.
`
`V.
`
`SUMMARY OF OPINIONS
`
`29.
`
`I understand that in its Final Written Decisions for the ’135 IPR, the
`
`Board found that the prior art renders obvious the same method of treatment as is
`
`claimed in the ’790 patent, when that method is used to treat RA. In other words,
`
`the Board invalidated as obvious AbbVie’s claims in the ’135 patent to a dosing
`
`regimen of subcutaneously administered 40 mg of adalimumab every other week
`
`(“eow”) to treat RA. See, e.g., Boehringer Ingelheim Int’l GMBH v. AbbVie
`
`Biotech. Ltd., No. IPR2016-00408, Final Written Decision, Paper No. 46, at 43-44
`
`(P.T.A.B. July 6, 2017); Boehringer Ingelheim Int’l GmbH v. AbbVie Biotech. Ltd.,
`
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`Case No. IPR2016-00409, Final Written Decision, Paper No. 46, at 45-48
`
`(P.T.A.B. July 6, 2017); Coherus BioSciences Inc., Case No. IPR2016-00172,
`
`Final Written Decision, Paper No. 60, at 44 (P.T.A.B. May 16, 2017). I further
`
`understand that Sandoz’s experts, Dr. Posner and Dr. Helfgott have provided
`
`opinions reaching the same conclusion as the Board. Given that this adalimumab
`
`dosing regimen is obvious to treat RA, it is my opinion – for the reasons discussed
`
`herein – that the POSA would have been motivated based on the disclosures of the
`
`prior art to use this same adalimumab dosing regimen to treat UC, and that the
`
`POSA would have had a reasonable expectation of success that the dosing regimen
`
`would, in fact, treat UC by reducing its signs and symptoms.
`
`VI.
`
`STATE OF THE ART
`A.
`Disclosure of Patent Application Publication WO 97/29131
`(“Salfeld”) (ex. 1006)
`The Salfeld patent application (WO 97/29131) published on August
`
`30.
`
`14, 1997, and is titled “Human Antibodies that Bind Human TNFα.” Ex. 1006.
`
`The claims of the Salfeld application are directed to, among other things, “[a]n
`
`isolated human antibody” with amino acid sequences corresponding to D2E7 (id.
`
`at claim 15), and “[a] pharmaceutical composition comprising the antibody” D2E7.
`
`Id. at claim 45. Salfeld further discloses “[t]he most preferred recombinant
`
`antibody of the invention, termed D2E7” and the amino acid sequences of that
`
`antibody. Id. at 5:19-24.
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`31.
`
`Salfeld shares portions of its specification with the ’790 patent and,
`
`like the ’790 patent, discloses that TNF-α “has been implicated in activating tissue
`
`inflammation and causing joint destruction in rheumatoid arthritis.” Id. at 38:35 –
`
`39:1. Salfeld further states, “[c]himeric and humanized murine anti-hTNFα
`
`antibodies have undergone clinical testing for treatment of rheumatoid arthritis.”
`
`Id. at 39:9-10. Salfeld teaches that “[t]he human antibodies, and antibody portions
`
`of the invention can be used to treat autoimmune diseases, in particular those
`
`associated with inflammation, including rheumatoid arthritis . . . .” Id. at 39:13-15.
`
`32.
`
`Similarly, with respect to intestinal disorders, Salfeld discloses that
`
`TNF “has been implicated in the pathophysiology of inflammatory bowel
`
`disorders,” and that “[c]himeric murine anti-hTNFα antibodies have undergone
`
`clinical testing for treatment of Crohn’s disease.” Id. at 41:15-20. Salfeld
`
`additionally teaches that “[t]he human antibodies, and antibody portions, of the
`
`invention, also can be used to treat intestinal disorders, such as idiopathic
`
`inflammatory bowel disease, which includes two syndromes, Crohn’s disease and
`
`ulcerative colitis.” Id. at 41:20-23.
`
`33.
`
`Salfeld teaches that “[t]he pharmaceutical compositions of the
`
`invention may include a ‘therapeutically effective amount’ or a ‘prophylactically
`
`effective amount’ of an antibody or antibody portion of the invention.” Id. at 35:3-
`
`5. “A ‘therapeutically effective amount’ refers to an amount effective, at dosages
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`and for periods of time necessary, to achieve the desired therapeutic result.” Id. at
`
`35:5-7. “A ‘prophylactically effective amount’ refers to an amount effective, at
`
`dosages and for periods of time necessary, to achieve the desired prophylactic
`
`result.” Id. at 35:12-14.
`
`34.
`
`In its discussion of dosage regimens for pharmaceutical compositions
`
`comprising the antibodies of the invention, Salfeld states that “[d]osage regimens
`
`may be adjusted to provide the optimum desired response (e.g., a therapeutic or
`
`prophylactic response).” Id. at 35:17-18. The specification further discloses that a
`
`dosing “range for a therapeutically or prophylactically effective amount” of D2E7
`
`is “0.1-20 mg/kg, more preferably 1-10 mg/kg.” Id. at 35:31-33. Notably, Salfeld does
`
`not teach that this dosing range is specific to any of the individual diseases or
`
`conditions disclosed. Rather, the dosing range is given generically, for all
`
`disclosed diseases and conditions. See id.
`
`35.
`
`Salfeld additionally teaches methods for administering pharmaceutical
`
`compositions comprising D2E7, stating that “[t]ypical preferred compositions are
`
`in the form of injectable or infusible solutions,” (id. at 30:2-3) and that
`
`“intramuscular or subcutaneous injection” are “preferred” modes of administration.
`
`Id. at 30:7-8.
`
`36.
`
`Salfeld also discloses that because prior art “chimeric and humanized
`
`antibodies still retain some murine sequences, they still may elicit an unwanted
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`immune reaction, the human anti-chimeric antibody (HACA) reaction, especially
`
`when administered for prolonged period[s], e.g., for chronic indications, such as
`
`rheumatoid arthritis.” Id. at 4:8-13 (citation omitted). Salfeld teaches that the
`
`“entirely human” anti-TNF-α antibodies of the invention “should not elicit [this
`
`unwanted immune] reaction, even if used for prolonged periods.” Id. at 4:14-17.
`
`37. Given all of the above disclosures, it is my opinion that a POSA
`
`would recognize that Salfeld discloses treating UC, by subcutaneously
`
`administering D2E7 to a human subject, for a time period sufficient to treat UC. In
`
`other words, Salfeld discloses every element of claim 1 of the ’790 patent except
`
`for the specific dosing regimen of a total body dose of 40 mg every 13-15 days
`
`(i.e., eow).
`
`Disclosure of Sandborn (ex. 1005)
`B.
`38. A 1999 clinical review published by Sandborn and Hanauer describes
`
`clinical trials of anti-TNF-α agents to treat RA and Crohn’s disease, and confirms
`
`that the same dose of infliximab effective in treating RA was also effective in
`
`treating Crohn’s disease and UC.2 See generally ex. 1005.
`
`2 Sandborn also described RA trials for the TNF-α inhibitor etanercept (a human
`fusion protein now marketed as Enbrel®) but reported that there had not yet been
`published clinical trials for etanercept for Crohn’s disease or UC. Ex. 1005 at 127,
`129.
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`Crohn’s Disease Studies Described by Sandborn
`1.
`Several of the studies reported in Sandborn evaluated infliximab or
`
`39.
`
`CDP5713 for the treatment of Crohn’s disease at a number of doses and dosing
`
`intervals. Sandborn summarizes the studies of these agents for Crohn’s disease in
`
`the table below (“Sandborn Table 2”):
`
`TABLE 2. Patient response in studies of anti-TNFa agents for Crohn's disease
`
`Reference
`Response
`
`Treatment
`
`Duration
`
`I
`
`Infl iximab
`Active
`
`Active
`
`Active
`
`Active
`
`Fistulae
`
`Remission
`
`Derx
`(Ref. 55)
`Van Dullemen
`(Ref. 56)
`McCabe
`(Ref. 57)
`Targan
`(Ref 27)
`Present
`(Ref. 58)
`Rutgeerts
`(Ref. 60)
`Van Dullemen Metastatic
`(Ref. 59)
`
`Stack
`(Ref. 28)
`
`CDP57 I
`Active
`
`Placebo
`
`1 mg/kg
`
`5 mg/kg
`
`10 mg/kg
`
`20 mg/kg
`
`Indication
`
`12 weeks
`
`—
`
`8 weeks
`
`4 weeks
`
`4 weeks
`
`18 weeks
`
`44 weeks
`
`26 weeks
`
`8 weeks
`
`—
`—
`—
`4/24
`17%
`8/31
`26%
`13/37
`35%
`—
`—
`
`5/10
`50%
`
`R.
`
`—
`
`—
`
`—
`1/24
`4%
`4/31
`13%
`8/37
`21%
`
`—
`
`0110
`0%
`
`—
`
`—
`
`—
`2/5
`40%
`
`2/5
`40%
`
`—
`
`—
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`—
`3/5
`60%
`13/27
`48%
`17/31
`55%
`—
`
`1/1
`100%
`8/8
`100%
`4/5
`80%
`14/28
`50%
`18/32
`56%
`24/36
`66%
`1/1
`100%
`
`1/1
`100%
`8/8
`100%
`1(5
`20%
`7/28
`25%
`12/32
`38%
`18/36
`51%
`1/1
`100%
`
`6/20
`30%
`
`—
`
`—
`
`—
`—
`4/5
`80%
`22/27
`82%
`21/31
`67%
`—
`—
`
`—
`
`11/20
`55%
`
`—
`
`2/2
`100%
`4/5
`80%
`18/28
`64%
`
`—
`
`1/1
`100%
`
`—
`
`—
`—
`1/2
`50%
`2/5
`40%
`7/28
`25%
`—
`
`—
`
`0/1
`0%
`
`—
`
`1: Indicates improvement as defined by a decrease in the Crohn's disease activity index score X70 points compared with the baseline measurement
`for patients with active Crohn's disease or Crohn's disease in remission, or closure of 50% Crohn's disease fistulae or metastatic perinea] wounds:
`R, remission as defined by a Crohn's disease activity index score <150 points for patients with active Crohn's disease or Crohn's disease in remission.
`or closure of 100% of Crohn's disease fistulae or metastatic perinea] wounds.
`
`Id. at 126.
`
`Infliximab Crohn’s Disease Studies
`a)
`40. As is seen from the above table, several of the studies described in
`
`Sandborn demonstrated that infliximab doses of 5 mg/kg and 10 mg/kg were effective
`
`in treating Crohn’s disease, and that, in the placebo-controlled studies described,
`
`3 CDP571 is a humanized monoclonal antibody.
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`significantly more patients on those doses of infliximab achieved improvement
`
`and/or remission as compared to the placebo groups.
`
`41.
`
`Sandborn disclosed that infliximab was first used as a therapy for
`
`Crohn’s disease in a 14-year-old female patient who was treated with 10 mg/kg
`
`infliximab at weeks 0 and 2 (“Derx (Ref. 55)” in Sandborn Table 2 above). Id. at
`
`125. “The patient experienced clinical and endoscopic remission lasting 3
`
`months.” Id.
`
`42.
`
`Sandborn reported that “[t]his initial case report was followed by a
`
`pilot study in 10 patients with medically refractory [Crohn’s disease]” (“Van
`
`Dullemen (Ref. 56)” in Sandborn Table 2). Id. The patients were each given a
`
`single infusion of infliximab, with eight patients receiving a 10 mg/kg dose, and two
`
`patients receiving a 20 mg/kg dose. Id. After receiving their single doses of
`
`infliximab, all 10 patients in this pilot study “experienced clinical and endoscopic
`
`improvement, and 9 of 10 patients experienced clinical remission lasting 8 weeks.”
`
`Id. Sandborn further reported that “[c]linical improvement was accompanied by
`
`impressive endoscopic and histologic healing.” Id.
`
`43.
`
`Sandborn next reported the first dose-response study of infliximab to
`
`treat Crohn’s disease (“McCabe (Ref. 57)” in Sandborn Table 2). Id. Twenty
`
`patients with medically refractory Crohn’s disease were randomized to therapy
`
`with a single dose of infliximab at 1 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg. Id. Clinical
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`improvement, which was defined as a decrease of at least 70 points in the Crohn’s
`
`Disease Activity Index (“CDAI”) score compared to baseline, occurred in 40% of
`
`patients receiving the 1 mg/kg dose, 80% at 5 mg/kg, 80% at 10 mg/kg, and 80% at 20
`
`mg/kg. Id.
`
`44.
`
`Sandborn also reported a subsequent Phase IIb/III trial, designed as a
`
`placebo-controlled dose-ranging study (“Targan (Ref. 27)” in Sandborn Table 2),
`
`in which 108 patients were randomized to receive a single infusion of either
`
`placebo or infliximab at 5 mg/kg, 10 mg/kg, or 20 mg/kg. Id. at 125-26. At 4 weeks,
`
`clinical remission (defined as a CDAI score <150 points) occurred in 4% of the
`
`placebo group, 48% of the 5 mg/kg, 25% of the 10 mg/kg group, and 25% of the 20
`
`mg/kg group. Id. at 126. Sandborn reported, “[t]hese results confirmed that a single
`
`infusion of infliximab was effective for moderately to severely active [Crohn’s
`
`disease] refrac