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.: 8,911,737
`Issue Date: Dec. 16, 2014
`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.
`
`B.
`
`2.
`
`TABLE OF CONTENTS
`QUALIFICATIONS .....................................................................................1
`THE ’737 PATENT......................................................................................4
`A.
`The Claims of the ’737 Patent.............................................................4
`B.
`The Specification of the ’737 Patent ...................................................5
`C.
`The Priority Date of the ’737 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
`Summary of Sandborn ........................................................... 24
`3.
`VII. A POSA WOULD HAVE A REASONABLE EXPECTATION OF
`SUCCESS THAT THE RA DOSING REGIMEN OF D2E7
`WOULD ALSO TREAT IBD.....................................................................25
`A.
`The Relationship Between RA and IBD Has Long Been
`Established in the Prior Art...............................................................25
`A POSA Knew That TNF-α Was Linked to the
`Pathogenesis of RA and IBD ............................................................27
`The Prior Art Taught that TNF-α Inhibitors Could Treat RA
`and IBD With the Same Dosing Regimens .......................................29
`The Long History of Treating IBD with RA Drugs at RA
`Doses................................................................................................36
`
`B.
`
`C.
`
`D.
`
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`Steroids.................................................................................. 38
`1.
`Sulphasalazine ....................................................................... 39
`2.
`NSAIDs ................................................................................. 40
`3.
`Azathioprine .......................................................................... 41
`4.
`Cyclosporine.......................................................................... 42
`5.
`Hydroxychloroquine .............................................................. 43
`6.
`Penicillamine ......................................................................... 44
`7.
`Methotrexate.......................................................................... 45
`8.
`Levamisole ............................................................................ 46
`9.
`VIII. THE PRIOR ART DOES NOT TEACH AWAY FROM THE
`CLAIMED DOSING REGIMEN ...............................................................50
`A.
`The Prior Art Taught That the Same Doses of TNF-α
`Inhibitors Would Be Effective in Treating Both RA and
`Crohn’s.............................................................................................50
`The POSA Would Also Have Considered Prior Art Dosing
`of CDP571........................................................................................52
`IX. CLAIMS 1-6 OF THE ’737 PATENT ARE OBVIOUS OVER THE
`PRIOR ART ...............................................................................................54
`A.
`Administering 40 mg D2E7 Subcutaneously EOW to Treat
`RA Was Obvious ..............................................................................54
`Claim 1 of the ’737 Patent Is Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................54
`Claim 2 of the ’737 Patent Is Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................56
`Claim 3 of the ’737 Patent Is Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................56
`Claims 4-6 of the ’737 Patent Are Obvious Over Salfeld
`Combined with the Prior Art Rendering the RA Dosing
`Regimen Obvious, in View of Sandborn...........................................57
`
`B.
`
`B.
`
`C.
`
`D.
`
`E.
`
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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. 8,911,737 (“the’737 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 Crohn’s disease. I have also considered the ’737
`
`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 Crohn’s
`
`disease 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 ’737 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 ’737 PATENT
`A.
`The Claims of the ’737 Patent
`14.
`The ’737 patent has one independent claim – claim 1 – which reads as
`
`follows:
`
`[a] method for treating Crohn’s disease in a human subject,
`comprising administering subcutaneously to a human subject having
`Crohn’s disease 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
`Crohn’s disease, 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:6 and 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 ’737 patent correspond to the antibody adalimumab (also known as
`
`D2E7).
`
`15.
`
`The remaining claims of the ’737 patent all depend from claim 1,
`
`meaning that they claim the method of claim 1 plus additional limitations. Claim 2
`
`further specifies amino acid sequences for the antibody, which sequences I
`
`understand correspond to the antibody adalimumab. Id. at claim 2. Claim 3
`
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`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.
`
`B.
`
`16.
`
`The Specification of the ’737 Patent
`
`The specification of the ’737 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
`
`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).
`
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`17. Among the “intestinal disorders” listed in the specification of the ’737
`
`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 specification further notes that “[c]himeric
`
`murine anti-hTNFα antibodies have undergone clinical testing for treatment of
`
`Crohn’s disease.” Id. at 27:18-20. The examples of the ’737 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 ’737 Patent
`
`For purposes of this declaration, I have been asked to assume that the
`
`priority date of the ’737 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 ’737
`
`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 ’737 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 Crohn’s disease 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 Crohn’s disease with anti-TNFα antibodies in
`general.
`
`Ex. 1010 at 6-7. These considerations, as described by the patent examiner,
`
`suggest that the skills of both a pharmacologist designing a dosing regimen and a
`
`physician treating Crohn’s disease would be relevant.
`
`21. Based on my review of the ’737 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 ’737 patent would have the skill sets of a team comprising a pharmacologist
`
`having experience with monoclonal antibody drugs, a gastroenterologist or other
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`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 ’737 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 ’737 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 ’737 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
`
`described below, it is my opinion that a POSA would have found the methods of
`
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`treatment claimed in the ’737 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 ’737 patent recite methods for treating Crohn’s
`
`disease in a human subject comprising administering a human anti-TNF-α antibody
`
`“for a time period sufficient to treat Crohn’s disease.” Ex. 1001 at claim 1. I
`
`understand that Sandoz submits that “for a time period sufficient to treat Crohn’s
`
`disease” means “for a time period sufficient to reduce the signs and/or symptoms
`
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`of Crohn’s disease.” 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 ’737 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 (May 17, 2016). I understand that this construction was confirmed by the
`
`Board in its Final Written Decisions. See, e.g., No. IPR2016-00172, Final Written
`
`Decision, Paper No. 60, at 9 (May 16, 2017). In inflammatory arthritis, including
`
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`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 Crohn’s disease, 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 Crohn’s disease.
`
`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 ’737 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.,
`
`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
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`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 Crohn’s disease, and
`
`that the POSA would have had a reasonable expectation of success that the dosing
`
`regimen would, in fact, treat Crohn’s disease by reducing its signs and symptoms.
`
`VI.
`
`STATE OF THE ART
`
`A.
`
`30.
`
`Disclosure of Patent Application Publication WO 97/29131
`(“Salfeld”) (ex. 1006)
`The Salfeld patent application (WO 97/29131) published on August
`
`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.
`
`31.
`
`Salfeld shares portions of its specification with the ’737 patent and,
`
`like the ’737 patent, discloses that TNF-α “has been implicated in activating tissue
`
`inflammation and causing joint destruction in rheumatoid arthritis.” Id. at 38:35 –
`
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`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
`
`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
`
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`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
`
`immune reaction, the human anti-chimeric antibody (HACA) reaction, especially
`
`when administered for prolonged period[s], e.g., for chronic indications, such as
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`rheumatoid arthritis.” Id. at 4:8-13. 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 Crohn’s disease, by subcutaneously
`
`administering D2E7 to a human subject, for a time period sufficient to treat
`
`Crohn’s disease. In other words, Salfeld discloses every element of claim 1 of the
`
`’737 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.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. 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 TABLE 2. Patient response in studies of anti-TNFa agents for Crohn's disease
`
`
`Reference Reference
`
`Response Response
`
`
`
`Treatment Treatment
`
`
`
`Duration Duration
`
`
`
`I I
`
`
`Infl iximab Infl iximab
`
`Active Active
`
`
`
`Active Active
`
`
`
`Active Active
`
`
`
`Active Active
`
`
`
`12 weeks 12 weeks
`
`
`
`— —
`
`
`
`8 weeks 8 weeks
`
`
`
`4 weeks 4 weeks
`
`
`
`4 weeks 4 weeks
`
`Fistulae Fistulae
`
`
`
`18 weeks 18 weeks
`
`
`
`Placebo Placebo
`
`
`
`1 mg/kg 1 mg/kg
`
`
`
`5 mg/kg 5 mg/kg
`
`
`
`10 mg/kg 10 mg/kg
`
`
`
`20 mg/kg 20 mg/kg
`
`
`
`Indication Indication
`
`
`
`R. R.
`
`
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`2/5 2/5
`
`40% 40%
`
`
`— —
`
`2/5 2/5
`
`40% 40%
`
`
`
`— —
`
`
`
`— —
`
`
`2/2 2/2
`
`100% 100%
`
`4/5 4/5
`
`80% 80%
`
`18/28 18/28
`
`64% 64%
`
`
`— —
`
`— —
`
`1/2 1/2
`
`50% 50%
`
`2/5 2/5
`
`40% 40%
`
`7/28 7/28
`
`25% 25%
`
`— —
`
`
`Derx Derx
`
`(Ref. 55) (Ref. 55)
`
`Van Dullemen Van Dullemen
`
`(Ref. 56) (Ref. 56)
`
`McCabe McCabe
`
`(Ref. 57) (Ref. 57)
`
`Targan Targan
`
`(Ref 27) (Ref 27)
`
`Present Present
`
`(Ref. 58) (Ref. 58)
`
`Rutgeerts Rutgeerts
`
`(Ref. 60) (Ref. 60)
`
`Van Dullemen Metastatic Van Dullemen Metastatic
`
`(Ref. 59) (Ref. 59)
`
`
`Stack Stack
`
`(Ref. 28) (Ref. 28)
`
`
`CDP57 I CDP57 I
`
`Active Active
`
`
`
`
`
`Remission Remission
`
`
`— —
`
`— —
`
`— —
`
`4/24 4/24
`
`17% 17%
`
`8/31 8/31
`
`26% 26%
`
`13/37 13/37
`
`35% 35%
`
`— —
`
`— —
`
`
`5/10 5/10
`
`50% 50%
`
`
`— —
`
`1/24 1/24
`
`4% 4%
`
`4/31 4/31
`
`13% 13%
`
`8/37 8/37
`
`21% 21%
`
`
`
`— —
`
`
`0110 0110
`
`0% 0%
`
`
`
`44 weeks 44 weeks
`
`
`
`26 weeks 26 weeks
`
`
`
`8 weeks 8 weeks
`
`
`— —
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`
`— —
`
`
`— —
`
`— —
`
`3/5 3/5
`
`60% 60%
`
`13/27 13/27
`
`48% 48%
`
`17/31 17/31
`
`55% 55%
`
`— —
`
`
`1/1 1/1
`
`100% 100%
`
`8/8 8/8
`
`100% 100%
`
`4/5 4/5
`
`80% 80%
`
`14/28 14/28
`
`50% 50%
`
`18/32 18/32
`
`56% 56%
`
`24/36 24/36
`
`66% 66%
`
`1/1 1/1
`
`100% 100%
`
`
`1/1 1/1
`
`100% 100%
`
`8/8 8/8
`
`100% 100%
`
`1(5 1(5
`
`20% 20%
`
`7/28 7/28
`
`25% 25%
`
`12/32 12/32
`
`38% 38%
`
`18/36 18/36
`
`51% 51%
`
`1/1 1/1
`
`100% 100%
`
`
`6/20 6/20
`
`30% 30%
`
`
`
`— —
`
`
`
`— —
`
`
`— —
`
`— —
`
`4/5 4/5
`
`80% 80%
`
`22/27 22/27
`
`82% 82%
`
`21/31 21/31
`
`67% 67%
`
`— —
`
`— —
`
`
`
`— —
`
`
`11/20 11/20
`
`55% 55%
`
`
`
`— —
`
`
`1/1 1/1
`
`100% 100%
`
`
`
`— —
`
`
`
`— —
`
`
`0/1 0/1
`
`0% 0%
`
`
`
`— —
`
`
`1: Indicates improvement as defined by a decrease in the Crohn's disease activity index score X70 points compared with the baseline measurement 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: 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. 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. or closure of 100% of Crohn's disease fistulae or metastatic perinea] wounds.
`
`Id. at 126.
`
`a)
`
`Infliximab Crohn’s Disease Studies
`
`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 that was never approved by the
`FDA.
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`64135614
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`16
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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 experience