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 JOHN POSNER, PH.D., MB.BS., FRCP
`
`
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`QUALIFICATIONS ........................................................................................ 1
`
`SUMMARY OF OPINIONS ........................................................................... 6
`
`III. THE CLAIMS AND DISCLOSURE OF THE ’737 AND ’135
`PATENTS ........................................................................................................ 8
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART ...........................................11
`
`V.
`
`CLAIM INTERPRETATION .......................................................................12
`
`VI. STATE OF THE ART ...................................................................................13
`
`A. VDP 1999 Discloses Subcutaneous Fixed Dosing of D2E7 to
`Treat RA (ex. 1003)............................................................................. 13
`
`B.
`
`C.
`
`Kempeni Discloses that Administering 0.5 mg/kg D2E7,
`EOW, is Effective to Treat RA (ex. 1004) .......................................... 14
`
`VDP 2000 Discloses Subcutaneous Fixed Dosing of D2E7 to
`Treat RA Over 6 Months (ex. 1107) ................................................... 22
`
`D.
`
`Rau Teaches EOW Subcutaneous Dosing of D2E7 (ex. 1017) .......... 24
`
`VII. THE PRIOR ART MOTIVATED THE POSA TO ACHIEVE THE 40
`MG D2E7 SUBCUTANEOUS EOW REGIMEN, AND PROVIDED
`A REASONABLE EXPECTATION OF SUCCESS ....................................25
`
`A. A POSA Would Have Been Motivated to Combine VDP 1999
`with Kempeni to Achieve the 40 mg D2E7 Subcutaneous
`EOW Regimen, With a Reasonable Expectation of Success .............. 25
`
`B.
`
`A POSA Would Have Been Motivated to Combine VDP 2000
`With Rau to Achieve the 40 mg D2E7 Subcutaneous EOW
`Regimen, With a Reasonable Expectation of Success ........................ 28
`
`VIII. A POSA WOULD HAVE BEEN MOTIVATED TO PURSUE A
`FIXED, SUBCUTANEOUS EOW REGIMEN ............................................30
`
`A.
`
`POSAs Recognized the Advantages of a Subcutaneous Fixed
`Dose ..................................................................................................... 30
`
`i.
`
`ii.
`
`A POSA Would Have Been Motivated to Choose
`Subcutaneous Fixed Dosing Based on the Disclosures of
`Both VDP 1999 and Kempeni ..................................................32
`
`A POSA Would Have Been Motivated to Choose
`Subcutaneous Fixed Dosing Based on the Disclosures of
`VDP 2000 and Rau ...................................................................33
`
`i
`
`

`

`B.
`
`POSAs Recognized the Advantages of Less Frequent
`Injections ............................................................................................. 33
`
`i.
`
`ii.
`
`A POSA Would Choose EOW Dosing Based on the
`Disclosures of VDP 1999 and Kempeni ...................................34
`
`A POSA Would Choose EOW Dosing Based on the
`Disclosures of VDP 2000 and Rau ...........................................35
`
`IX. THE PRIOR ART DID NOT TEACH AWAY FROM THE 40 MG
`D2E7 SUBCUTANEOUS EOW REGIMEN ...............................................36
`
`A. A POSA Reading VDP 2000 and Rau Would Not Avoid the
`20 mg Weekly Dose ............................................................................ 36
`
`B.
`
`C.
`
`VDP 2000 and Rau Taught the POSA More Than D2E7’s
`Half-Life, Including that D2E7 Could be Administered
`Subcutaneously EOW, and that a 20 mg Weekly Fixed Dose
`Was Effective to Treat RA .................................................................. 39
`
`Concerns about Bioavailability Would Not Deter the POSA
`from Converting Kempeni’s 0.5 mg/kg Regimen from
`Intravenous to Subcutaneous ............................................................... 40
`
`D. Kempeni Discloses “Biweekly” Dosing and Does Not Teach
`Away.................................................................................................... 41
`
`E.
`
`Concerns about Anti-Drug Antibodies Would Not Deter the
`POSA from Pursuing a 40 mg, Subcutaneous, EOW D2E7
`Dosing Regimen .................................................................................. 42
`
`i.
`
`ii.
`
`Concerns about Anti-Drug Antibodies Would Not Deter
`the POSA from Combining VDP 1999 and Kempeni to
`Achieve a 40 mg, Subcutaneous, EOW D2E7 Dosing
`Regimen ....................................................................................43
`
`Concerns about Anti-Drug Antibodies Would Not Deter
`the POSA from Combining VDP 2000 and Rau to
`Achieve a 40 mg, Subcutaneous, EOW D2E7 Dosing
`Regimen ....................................................................................49
`
`X.
`
`CONCLUSIONS ...........................................................................................49
`
`
`
`
`ii
`
`

`

`DECLARATION OF JOHN POSNER
`
`I, John Posner, Ph.D., MB.BS., FRCP declare that:
`
`1. My name is John Posner;
`
`2.
`
`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 pharmaceutical consultant, physician, clinical pharmacologist
`
`and founder of John Posner Consulting, which I founded in 1999. I have worked
`
`with both large and small pharmaceutical and biotech companies on drug
`
`development projects in a wide range of therapeutic areas. Much of my work as a
`
`consultant has been to devise drug development strategies and early development
`
`plans for new molecular entities and to take these drugs forward by designing and
`
`monitoring Phase I and Phase II studies which include evaluation of
`
`pharmacodynamics and pharmacokinetics. I also serve on and chair data
`
`monitoring committees for clinical trials; mostly in the early phases of clinical
`
`development. In the past, I have prepared clinical overviews, summaries and
`
`briefing documents for regulatory submissions in the United States, Europe and
`
`Australia.
`
`1
`
`

`

`4.
`
`Since 2008, I have been a Visiting Professor at King’s College
`
`London, School of Biomedical and Health Sciences, where I teach modules in
`
`Clinical Pharmacology and Drug Development.
`
`5.
`
`Prior to founding John Posner Consulting, I worked from 1996 to
`
`1999 as a Medical Director and subsequently Chief Executive Officer of BIOS
`
`(Consultancy & Contract Research) Ltd.
`
`6.
`
`From 1995 to 1996, I was the International Director of Clinical Study
`
`Units at GlaxoWellcome plc where I was responsible for running a 24-bed Clinical
`
`Pharmacology Unit.
`
`7.
`
`From 1986 to 1995, I was Head of Clinical Pharmacology at the
`
`Wellcome Foundation Ltd. where I devised and executed plans for evaluating the
`
`human pharmacology of numerous novel compounds, mostly small molecules but
`
`also biologics including peptides and monoclonal antibodies. I established and ran
`
`the Wellcome clinical study unit based in King’s College Hospital, London and
`
`was responsible for design and reporting of pharmacokinetics of all clinical trials
`
`conducted by the Medical Division.
`
`8.
`
`From 1982 to 1985, I was a Clinical Pharmacologist for the Wellcome
`
`Foundation Ltd.
`
`9. My educational experience is summarized as follows:
`
`2
`
`

`

` I received a B.S.c. degree in Pharmacology from King’s College,
`
`London, in 1968.
`
` I received a Ph.D. in Pharmacology from King’s College, London, in
`
`1971.
`
` I received a MB.BS. (medical degree) from King’s College Hospital,
`
`London, in 1974.
`
`10. Starting in 1974, I worked as a junior doctor in a number of hospitals
`
`in London and gained my Membership of the Royal College Physicians by
`
`examination in 1976. Starting in 1977, I was a Resident in Internal Medicine at
`
`Ben Gurion University of the Negev, Beer Sheba Israel, obtained Board
`
`Certification in Internal Medicine in Israel in 1981 and subsequently worked as an
`
`Attending Physician.
`
`11.
`
`I am a Fellow of the British Pharmacological Society and served as an
`
`Executive Editor of the British Journal of Clinical Pharmacology for many years.
`
`12.
`
`I am currently a Board member of the Faculty of Pharmaceutical
`
`Medicine of the Royal Colleges of Physicians, UK and am Director of the
`
`Faculty’s Diploma and Certificate in Human Pharmacology. I previously served as
`
`Chairman of the Faculty’s Board of Examiners and continue to serve as an
`
`examiner.
`
`3
`
`

`

`13. A full description of my background and qualifications can be found
`
`in my curriculum vitae (CV), which is attached to this declaration as Appendix A.
`
`14.
`
`I have published more than 60 full papers in peer reviewed journals
`
`and have co-authored chapters and served as an Editor of “The Textbook of
`
`Pharmaceutical Medicine.” See, e.g., THE TEXTBOOK OF PHARMACEUTICAL
`
`Medicine (John P. Griffin et al. eds., 7th ed. 2013); John Posner, Exploratory
`
`Development, in THE TEXTBOOK OF PHARMACEUTICAL MEDICINE (John P. Griffin
`
`et al. eds., 7th ed. 2013) (all previous editions); John Posner & Steve Warrington,
`
`Objectives and Design of Clinical Trials, in THE TEXTBOOK OF PHARMACEUTICAL
`
`MEDICINE (John P. Griffin et al. eds., 7th ed. 2013); Raymond A. Huml & John
`
`Posner, Biosimilars, in THE TEXTBOOK OF PHARMACEUTICAL MEDICINE (John P.
`
`Griffin et al. eds., 7th ed. 2013); John Posner & P. E. Rolan, Clinical
`
`Pharmacokinetics, in THE TEXTBOOK OF PHARMACEUTICAL MEDICINE (J. P. Griffin
`
`et al. eds., 3rd ed. 1998) (all previous editions). I am the author of a regular article
`
`on Clinical Pharmacology for surgeons in training: John Posner, Clinical
`
`Pharmacology: The Basics, 33 SURGERY 104 (2015).
`
`15.
`
`In formulating the opinions expressed in this declaration, I have relied
`
`upon my training, knowledge, and experience in the field of pharmacology,
`
`including the study of the pharmacokinetics of monoclonal antibodies as
`
`therapeutic agents. I have also considered the ’737 patent and the publications and
`
`4
`
`

`

`materials referred to as Exhibits throughout this declaration, and listed in Appendix
`
`B.
`
`16. By June 8, 2001, (which I have been asked to assume is the earliest
`
`priority date for the ’737 patent), I had been designing dosing regimens for clinical
`
`trials for 18 years. As a clinical pharmacologist I conducted a large number of
`
`Phase I/II studies across many therapeutic areas. Most of the work was with small
`
`chemical molecules but I also conducted studies with peptides for pain/analgesia
`
`and sickle cell disease and I was intimately involved in the design and conduct of
`
`the first administration to humans of a monoclonal antibody called Campath, an
`
`anti-CD52 antibody, now known as alemtuzumab. The subjects in that study were
`
`patients with Non-Hodgkin’s Lymphoma.
`
`17. Throughout this declaration, I may refer to the field of pharmacology,
`
`including the study of pharmacokinetics of pharmaceutical formulations containing
`
`antibodies as the “relevant field.”
`
`18.
`
`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. I have reviewed the
`
`’737 patent, and understand that its claims recite methods of treating Crohn’s
`
`disease (“Crohn’s”).
`
`5
`
`

`

`19.
`
`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.
`
`SUMMARY OF OPINIONS
`
`20.
`
`I understand from counsel that the ’737 patent is descended from an
`
`application that issued to AbbVie as U.S. Patent No. 8,889,135 (the “’135 patent,”
`
`ex. 1093). I have reviewed the ’737 patent and the ’135 patent. Both patents share
`
`a common specification. Both patents also claim methods of treatment that
`
`comprise administering subcutaneously a total body dose of 40 mg of a human
`
`anti-Tumor Necrosis Factor alpha (TNF-α) antibody, having amino acid sequences
`
`corresponding to adalimumab (or “D2E7”), once every 13-15 days i.e. every other
`
`week (“eow”) for a time period sufficient to treat a specified condition. The only
`
`difference between claim 1 of the two patents is that the ’135 patent specifies
`
`rheumatoid arthritis (“RA”) as the condition to be treated and the ’737 patent
`
`specifies Crohn’s as the condition to be treated.
`
`21.
`
`I understand from counsel that, in Final Written Decisions dated May
`
`16, 2017 and July 6, 2017, respectively, the Patent Trial and Appeal Board (the
`
`“Board”) found all claims of the ’135 RA method of treatment patent to be invalid
`
`as obvious over two separate prior art combinations: (1) Kempeni (ex. 1004) and
`
`6
`
`

`

`van de Putte 1999 (ex. 1003) (“VDP 1999”)1; and (2) van de Putte 2000 (ex. 1107)
`
`(“VDP 2000”) and Rau (ex. 1017)2. Coherus Biosciences Inc. v. AbbVie Biotech.
`
`Ltd., No. IPR2016-00172, Final Written Decision, Paper 60, at 44 (May 16, 2017)
`
`(hereinafter “Coherus”); Boehringer Ingelheim Int’l. GMBH v. AbbVie Biotech.
`
`Ltd., No. IPR2016-00409, Final Written Decision, Paper 46, at 44 (July 6, 2017)
`
`(hereinafter “BI409”); Boehringer Ingelheim Int’l. GMBH v. AbbVie Biotech. Ltd.,
`
`No. IPR2016-00408, Final Written Decision, Paper No. 46, at 44 (July 6, 2017)
`
`(hereinafter “BI408”). I understand that Sandoz submits in its petition for IPR of
`
`the ’737 patent, that it would have been obvious to a person having ordinary skill
`
`in the art (“POSA”) to use the RA dosing regimen of the ’135 patent to treat
`
`Crohn’s.
`
`22.
`
`I have reviewed the publications of the two prior art combinations (1)
`
`VDP 1999 and Kempeni and (2) VDP 2000 and Rau, and, consistent with the
`
`Board’s findings, it is my opinion that both of those prior art combinations
`
`separately render obvious the claimed dosing RA regimen of the ’135 patent.
`
`Specifically, it is my opinion that:
`
`
`1 I understand that VDP 1999 and Kempeni are prior art to the ’135 and ’737
`patents because they were published more than one year before the earliest
`assumed priority date for those patents of June 8, 2001.
`
` 2
`
` I understand that VDP 2000 and Rau were published less than one year before
`the earliest assumed priority date of June 8, 2001, but that AbbVie did not
`challenge the prior art status of these references in the IPR proceedings.
`
`7
`
`

`

` A POSA would be motivated to combine the disclosures of
`either the (1) VDP 1999 and Kempeni combination or (2) VDP
`2000 and Rau combination to arrive at a subcutaneous, 40 mg
`D2E7 eow dosing regimen to treat RA.
`
` A POSA would have a reasonable expectation of success in
`treating RA with a subcutaneous, 40 mg D2E7 eow dosing
`regimen, based on either the (1) VDP 1999 and Kempeni
`combination or (2) VDP 2000 and Rau combination.
`
` A POSA would not have been deterred from using a
`subcutaneous, 40 mg D2E7 eow dosing regimen to treat RA
`based on concerns about bioavailability.
`
` A POSA would not have been deterred from using a
`subcutaneous, 40 mg D2E7 eow dosing regimen to treat RA
`based on concerns about anti-drug antibodies (“ADAs”).
`
`III. THE CLAIMS AND DISCLOSURE OF THE ’737 AND ’135
`PATENTS
`
`
`23. The ’737 patent claims a method for treating Crohn’s in a human
`
`subject that comprises administering subcutaneously a total body dose of 40 mg of
`
`a TNF-α antibody (having a variable light chain region, a variable heavy chain
`
`region, and complementarity determining regions (“CDR”) that, respectively, have
`
`specific amino acid sequences) once every 13-15 days (also referred to as every
`
`other week or “eow”) for a time period sufficient to treat Crohn’s. Ex. 1001 at
`
`claim 1.
`
`24. The ’737 patent has 1 independent claim, claim 1. I understand that
`
`Sandoz is seeking IPR of claims 1-6.
`
`25. Claim 1 reads as follows:
`
`8
`
`

`

`A method for treating Crohn’s disease in a human
`1.
`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.
`
`Id.
`
`26. Claims 2-6 of the ’737 patent depend, directly or indirectly, from
`
`claim 1. Id. at claims 2-6. Dependent claim 2 narrows the variable light chain
`
`region and variable heavy chain region of claim 1 to specific amino acid
`
`sequences. Id. at claim 2. Dependent claim 3 narrows claim 1 to human subjects
`
`who have had an unwanted immune response to a chimeric or humanized anti-
`
`TNF-α antibody. Id. at claim 3. Dependent claims 4, 5 and 6 depend from claims
`
`3, 2 and 1, respectively, and require that the anti-TNF-α antibody is administered
`
`for a period of at least 24 weeks. Id. at claims 4-6.
`
`9
`
`

`

`27.
`
`I understand that D2E73, which encompasses adalimumab, described
`
`in the specification of the ’737 patent, corresponds to the antibody amino acid
`
`sequences of claims 1-6.
`
`28. Claim 1 of the ’135 patent is identical to claim 1 of the ’737 patent
`
`except that the condition “rheumatoid arthritis” (“RA”) is substituted for the
`
`condition “Crohn’s disease.” Ex. 1093 at claim 1.
`
`29. The specifications of the ’737 and ’135 patents are the same. The
`
`common specification 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.” Ex. 1001 at 24:27-31.4 The specification provides examples of such
`
`disorders, including autoimmune diseases (id. at 25:36-67) and intestinal disorders.
`
`Id. at 27:13-25 (stating that “[i]ntestinal [d]isorders” includes “idiopathic
`
`inflammatory bowel disease, which includes two syndromes, Crohn’s disease and
`
`ulcerative colitis”).
`
`
`3 For the purposes of this Declaration only, I have been asked to refer to the
`claimed antibody as “D2E7.” I understand that this should not prejudice Sandoz’s
`ability to challenge the meaning, scope, and indefiniteness of the term in other
`proceedings.
`
` For ease of reference, I have cited to the ’737 specification.
`
` 4
`
`10
`
`

`

`30. The common specification provides examples of the use of D2E7 to
`
`treat RA, but does not include any examples where Crohn’s is being treated.
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`
`31.
`
`I have been informed that a POSA is a hypothetical person who is
`
`presumed to have been aware of all relevant art at the time of the invention. I
`
`further understand that the POSA is a person of ordinary creativity (not an
`
`automaton), who understands the scientific principles applicable to the pertinent
`
`art, and may also have the skill sets of a team of individuals.
`
`32. Based on my review of the ’737 patent, including its claims, the prior
`
`art, and my experience and knowledge in the field, it is my opinion that the
`
`claimed methods involve the determination of appropriate dosing regimens for
`
`drugs, including antibody drugs, in the treatment of Crohn’s. Accordingly, a
`
`POSA with respect to the ’737 patent would have the skill sets of a team,
`
`comprising a gastroenterologist or other physician experienced in treating patients
`
`with Crohn’s and a pharmacologist having experience with antibody drugs.
`
`Additionally, since the ’737 patent takes its claimed dosing regimen directly from
`
`the RA dosing regimen of the ’135 patent, the POSA team would include a
`
`rheumatologist or other physician experienced in treating patients with RA.
`
`11
`
`

`

`33. The pharmacologist would have a Ph.D. in pharmacology,
`
`pharmacokinetics, or a related field and at least three years of experience working
`
`on the pharmacokinetics/pharmacodynamics of biologic drugs.
`
`34.
`
`I also understand that Dr. Ingvar Bjarnason, a gastroenterologist, is
`
`submitting a declaration regarding the Crohn’s treatment aspects of the ’737
`
`patent, and is of the opinion that the gastroenterologist on the POSA team would
`
`have an M.D. and at least three years’ post-residency experience treating patients
`
`having Crohn’s disease.
`
`35.
`
`I also understand that Dr. Simon Helfgott, a rheumatologist, is
`
`submitting a declaration regarding certain aspects of the treatment of RA that were
`
`at issue in a prior petition for IPR of the ’135 patent and is of the opinion that the
`
`physician on the POSA team would have an M.D. and at least three years’ post-
`
`residency experience in treating patients having RA.
`
`V. CLAIM INTERPRETATION
`
`36.
`
`I have reviewed the Final Written Decisions of the Board in the
`
`Coherus and BI IPRs, which found the claims of the ’135 patent invalid as obvious
`
`over the prior art. In those decisions, the Board construed the claim phrase “for a
`
`time period sufficient to treat the rheumatoid arthritis” to mean “for a time period
`
`sufficient to reduce the signs, symptoms, and/or progression of RA.” Coherus at 9;
`
`BI408 at 11; BI409 at 11. I understand that Dr. Helfgott agrees with that
`
`12
`
`

`

`definition, and is of the opinion that it is consistent with how the term “treat” is
`
`used in reference to RA patients. I will accordingly use the Board’s definition of
`
`that phrase for purposes of this declaration.
`
`VI. STATE OF THE ART
`
`A. VDP 1999 Discloses Subcutaneous Fixed Dosing of D2E7 to Treat
`RA (ex. 1003)
`
`37. VDP 1999 (a 1999 publication by van de Putte et al., titled “Efficacy
`
`of the Fully Human Anti-TNF Antibody D2E7 in Rheumatoid Arthritis”) reports
`
`the findings of a randomized, double-blinded Phase II dose finding study in 283
`
`patients. Ex. 1003 at 3. Patients in the study received either placebo or D2E7 at
`
`20 mg, 40 mg, or 80 mg, administered as weekly fixed-dose subcutaneous
`
`injections, for three months. Id.
`
`38. Clinical responses, measured at 3 months, are summarized in the table
`
`below:
`
`
`
`IMP IMP
`
`
`'• of pis achieving ACR '• of pis achieving ACR
`
`Median % improvement Median % improvement
`
`Median % improvement Median % improvement
`
`Medinci % improvement Medinci % improvement
`
`
`20 rc'.pon'r 20 rc'.pon'r
`
`in TJC in TJC
`
`in SW; in SW;
`
`in CRP in CRP
`
`
`
`Placehrt Placehrt
`
`
`(n=70) (n=70)
`
`lit lit
`
`
`
`/6 /6
`
`
`
`D2E7 D2E7
`
`
`20 mg 20 mg
`
`(n=71) (n=71)
`
`
`57 57
`
`.0! .0!
`
`55 55
`
`
`
`D2E7 D2E7
`
`
`40 mg 40 mg
`
`(n=70) (n=70)
`
`57 57
`
`61 61
`
`59 59
`
`67 67
`
`
`
`02E7 02E7
`
`
`80 rng 80 rng
`
`(n=72) (n=72)
`
`56 56
`
`55 55
`
`61 61
`
`65 65
`
`
`
`
`Id.
`
`39. As can be seen from the above summary, responses for all D2E7
`
`treatment groups were superior to the responses seen in the placebo group. Id.
`
`13
`
`

`

`The authors concluded that “[f]or all efficacy parameters studied, all doses of
`
`D2E7 were statistically significantly superior to placebo (p < 0.001).” Id.
`
`Moreover, “20, 40 and 80 mg/week were nearly equally efficacious when given
`
`[subcutaneously] in patients with active RA.” Id.
`
`40. A POSA reading VDP 1999 would therefore recognize that it
`
`disclosed administering subcutaneously, to a human subject having RA, a weekly
`
`total body dose of 20, 40 or 80 mg D2E7, for a time period sufficient to treat RA.
`
`In other words, VDP 1999 disclosed every element of the ’135 patent’s claimed
`
`RA dosing regimen except for eow frequency of dosing.
`
`B. Kempeni Discloses that Administering 0.5 mg/kg D2E7, EOW, is
`Effective to Treat RA (ex. 1004)
`
`41. Kempeni (a 1999 publication by Kempeni, titled “Preliminary Results
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`of Early Clinical Trials with the Fully Human Anti-TNFα Monoclonal Antibody
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`D2E7”) describes the results of several clinical trials in which D2E7 was
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`administered, using various doses and dosing regimens, to treat RA. Ex. 1004.
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`For the reasons stated below, it is my opinion that Kempeni teaches that
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`administering D2E7 at a dose of 0.5 mg/kg on an eow schedule is effective to treat
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`RA.
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`14
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`42.
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`In the first trial described by Kempeni – which I understand AbbVie
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`(formerly Abbott) referred to as study DE0015 – a total of 120 patients with RA
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`were treated with a single intravenous injection of D2E7. Id. at I71. Cohorts of 24
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`patients (18 treated with D2E7 and 6 treated with placebo) received escalating
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`intravenous doses ranging from 0.5 to 10 mg/kg. Id. For purposes of this study, a
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`“[p]ositive response was defined as a decrease of at least 1.2 (compared with
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`baseline) [in a patient’s Disease Activity Score (“DAS”)]”.6 Id. Patients in study
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`DE001 “were followed up for at least four weeks to determine the
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`pharmacokinetics of D2E7, as well as to evaluate the safety and clinical efficacy of
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`the compound in terms of onset, duration and magnitude of response.” Id.
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`43. Kempeni reported that “[t]he data from this first therapeutic trial . . .
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`were very encouraging.” Id. “The therapeutic effects [of D2E7] became evident
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`within 24 hours to one week after D2E7 administration and reached the maximum
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`effect after 1–2 weeks, with dose response reaching plateau at 1 mg/kg D2E7.” Id.
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`“The estimated mean terminal half life was 11.6 to 13.7 days.” Id.
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`5 See, e.g., ex. 1017 at 6 (describing this study and identifying it as DE001).
`Kempeni does not use these “DE” study numbers, but I include them here as an
`easy way to identify the various trials.
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` 6
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` The “DAS,” as its name suggests, is an index for quantifying disease activity in
`RA that combines measurements representing several aspects of the disease. Ex.
`1100 at 39.
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`15
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`44. Kempeni next described an open label extension study for patients
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`from DE001 “in whom the effect of D2E7 had declined below response status by
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`week 4.” Id. I understand that AbbVie referred to this extension study as
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`“DE003.”7 Patients from DE001 who maintained a clinical response at 4 weeks
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`“were continued without retreatment until their response status was lost” but were
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`thereafter eligible to continue in the extension study. Id.
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`45. Kempeni reported that patients in DE003 received a second blinded
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`dose of either placebo or D2E7, identical to their first dose. Id. Thereafter,
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`starting at dose 3, patients who had received placebo were switched to active drug
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`at a dose corresponding to their assigned treatment group. Id. Kempeni reported
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`that “D2E7 was administered every two weeks until responses could be rated as
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`‘good’, defined as an absolute DAS of < 2.4.” Id. Once patients achieved this
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`“good” response, they were retreated only upon disease flare up, so that the
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`duration of the good response could be measured. Id. “To keep as many patients
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`as possible in the study for the long term evaluation of safety, patients who did not
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`respond well after 0.5 or 1 mg/kg received higher doses of up to a maximum of 3
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`mg/kg.” Id.
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`46. Kempeni reported the results of DE003, stating “[t]he response in the
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`DAS over time demonstrated sustained therapeutic effects and some continuing
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`7 See, e.g., ex. 1017 at 6, which also describes this extension study, and identifies
`it as DE003.
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`16
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`improvement after multiple infusions of D2E7.” Id. Kempeni additionally
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`reported that “[r]esponse rates of more than 80% have been achieved with a mean
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`dosing interval of 2.5 weeks. After six months, 86% of patients continued to
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`receive treatment with D2E7 indicating that long term intravenous treatment with
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`D2E7 in the dose range from 0.5 to 10 mg/kg was well tolerated.” Id.
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`47. A POSA reading Kempeni would understand that the disclosed results
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`of DE003 – that “D2E7 in the dose range from 0.5 to 10 mg/kg was well tolerated”
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`over a six-month period – indicated that at least some of the patients studied
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`remained on the 0.5 mg/kg eow dosing regimen for the full six months. Id. The
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`POSA would further understand that, under the DE003 study protocol as disclosed
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`by Kempeni, patients would not have been kept in the 0.5 mg/kg eow dosing group
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`over the long term unless they maintained a “good” response on that 0.5 mg/kg
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`eow regimen. Rather, if a patient on the 0.5 mg/kg eow regimen lost a “good”
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`response at any point during the DE003 study, his or her dose would have been
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`increased. Id. (“To keep as many patients as possible in the study for the long
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`term evaluation of safety, patients who did not respond well after 0.5 or 1 mg/kg
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`received higher doses of up to a maximum of 3 mg/kg.”8). Accordingly, based on
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`Kempeni’s disclosure that the 0.5 mg/kg dose was well tolerated long term, the
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`POSA would understand that at least some patients in the 0.5 mg/kg D2E7 eow
`
`
`8 I understand that Dr. Helfgott is addressing AbbVie’s position that these
`increased doses taught away from using a 0.5 mg/kg dose of D2E7 to treat RA.
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`group maintained a “good” response, as defined by the study protocol, through 6
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`months.
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`48. Consistent with Kempeni’s disclosure on DE003, which would lead
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`the POSA to conclude that at least some patients in the 0.5 mg/kg eow dosing
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`group maintained a good response long-term, a 1999 publication of Rau et al.
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`(“Rau 1999”) reports that “[p]atients were treated with . . . D2E7 doses from 0.5 to
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`10 mg/kg for one year mostly at biweekly intervals (study DE001/003).” Ex. 1109
`
`at 6. Rau 1999’s reported results are additionally consistent with the conclusion
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`that the treatment regimen used in the DE003 study was effective. Rau 1999
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`describes evaluation of X-rays of hands, wrists and feet taken at baseline, 6 and 12
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`months in 66 patients and in a subgroup of 22 patients who had X-rays preceding
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`study entry. Id. Rau found that “[d]uring the treatment with D2E7 no evidence for
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`radiographic progression was observed in contrast to the preceding time period
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`with DMARD treatment where a deterioration was obvious.” Id. The authors
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`concluded that the data suggest D2E7 “slows disease progression in RA.” Id.
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`49. The next trial reported by Kempeni (“DE004”)9 evaluated the safety
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`and efficacy of D2E7, administered in weekly subcutaneous doses of 0.5 mg/kg, to
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`24 patients with active RA. Id. This was a double blind, placebo-controlled study
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`in which patients were randomized to D2E7 or placebo for the first 3 months. Id.
`
`
`9 See, e.g., ex. 1017 at 7, which also describes this extension study, and identifies it
`as DE004.
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`at I71-72. Thereafter all responding patients were treated with D2E7 in an open
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`label extension. Id. at I72. Patients who did not respond, or who lost their
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`responder status, had their D2E7 dose increased to 1 mg/kg. Id. A preliminary
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`report of this study was published as an Abstract by Schattenkirchner et al. in
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`1998. Ex. 1110 at 5. Kempeni reported that, “[b]ased on preliminary data, plasma
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`concentrations of D2E7 after multiple subcutaneous doses were comparable to
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`those achieved with intravenous administration.” Id. In terms of efficacy, “[u]p to
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`78% of patients achieved a DAS/ACR 20 response after three months of treatment
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`with subcutaneous D2E7.” Id. Thus, as reported by Kempeni, “[t]he investigators
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`concluded that D2E7 given subcutaneously was safe and as effective as when
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`administered intravenously demonstrating that subcutaneous self administration is
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`a promising approach for D2E7 delivery.” Id.
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`50.
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`In a third randomized, placebo-controlled trial described by Kempeni,
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`D2E7 1 mg/kg was administered as a single subcutaneous or intravenous injection,
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`to RA patients receiving a stable dose of the DMARD methotrexate but whose
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`symptoms were not sufficiently controlled. Id. “An ACR 20 response was seen