IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________________________
`
`FRONTIER THERAPEUTICS, LLC
`
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`
`
`Patent Owner
`
`___________________________________
`
`Inter Partes Review Case No. IPR2016-00649
`Patent Number 8,664,231
`
`
`
`EXPERT DECLARATION OF DR. SEAN NICHOLSON
`
`June 2, 2016
`
`
`
`Page 1
`
`
`
`
`
`
`
`
`Medac Exhibit 2032
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 0001
`
`
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________________________
`
`FRONTIER THERAPEUTICS, LLC
`
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`
`
`Patent Owner
`
`___________________________________
`
`Inter Partes Review Case No. IPR2016-00649
`Patent Number 8,664,231
`
`
`
`EXPERT DECLARATION OF DR. SEAN NICHOLSON
`
`June 2, 2016
`
`
`
`Page 1
`
`
`
`
`
`
`
`
`Medac Exhibit 2032
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 0001
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`
`
`
`
`Table of Contents
`
`Attorney Docket No.
`110670-0010-651
`
`I.
`
`Qualifications .................................................................................................... 3
`
`II. Assignment ....................................................................................................... 4
`
`III. Summary Of Opinions ...................................................................................... 7
`
`IV. Background ....................................................................................................... 9
`
`V. The Development Of A Product Using The Innovation, Like Rasuvo™,
`Presented Companies with A Valuable Economic Opportunity ............................. 11
`
`Potential Sales For A Product Containing The Innovation Are Substantial,
`A.
`And This Was Expected Prior To The Filing Of The ‘231 Patent ....................... 11
`B.
`Patients May Prefer A Product Using The Innovation Versus Pre-Existing
`Forms of Methotrexate .......................................................................................... 20
`C. A Product Containing The Innovation Could Lower Costs For Third-Party
`Payors And Patients By Delaying or Reducing The Use Of Biologic Treatments
`
`24
`
`VI. There Were No Substantial Barriers To Entry In The United States Market
`For A Methotrexate Product Using The Innovation ................................................ 29
`
`VII. Despite The Substantial Economic Opportunity For A Product Using The
`Innovation And The Lack of Substantial Barriers To Entry, Such An Innovation
`Had Not Been Developed Prior To The Filing Of The ‘231 Patent ........................ 36
`
`
`
`
`
`
`
`
`
`Page 2
`
`Page 00002
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`I.
`
`Qualifications
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`1. I am a Professor in the Department of Policy Analysis and Management at
`Cornell University and a research associate at the National Bureau of Economic
`Research. Prior to assuming my current position at Cornell, I served as an
`Assistant Professor in Healthcare Systems at the Wharton School of the
`University of Pennsylvania. I have a Ph.D. in economics from the University of
`Wisconsin-Madison and an A.B. in economics from Dartmouth College. My
`research and teaching specialty is the economics of healthcare. My curriculum
`vitae, including a list of publications, is attached as Appendix A.
`2. In my academic career, I have researched the economics of the healthcare
`industry, with an emphasis on the economic behavior of, and interaction
`between, government and employer-sponsored health plans, hospitals, and
`physicians. I have published articles in leading academic journals regarding my
`field of study. In addition, I have served as a principal investigator on research
`projects sponsored by the Centers for Disease Control and Prevention, the
`Agency for Healthcare Research and Quality, the Robert Wood Johnson
`Foundation, and by leading pharmaceutical companies such as Merck & Co.,
`Inc., Pfizer, Astra Zeneca, and Johnson & Johnson. I have also consulted to
`four biopharmaceutical companies, Cephalon, Inc., Amgen, Merck, and Pfizer,
`and provided executive education for Edwards Lifesciences, Anesthesia
`Business Group, the Hospital Association of New York State (HANYS), the
`West Penn Allegheny Health System, Teva Pharmaceutical Industries, Ltd,
`Aventis, Wyeth, Eisai, and Johnson & Johnson. In addition, I have experience
`working as a management consultant in the hospital industry.
`3. My research projects have included examining how physicians form their
`treatment styles and how those styles change over time, examining how
`
`
`
`
`Page 3
`
`Page 00003
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`managed care insurance plans are able to reduce medical spending and
`premiums, identifying what types of firms are most effective at developing
`drugs, examining why biotechnology and pharmaceutical firms form drug
`development alliances and merge and the impact of those decisions, assessing
`risk in the healthcare industry, and determining the value of new medical
`technologies. I co-edited the Oxford Handbook of the Economics of the
`Biopharmaceutical Industry, which covers many topics, including how firms
`finance research and development, set drug prices, and market pharmaceutical
`products. I have also conducted research and offered expert testimony in
`several cases in the healthcare industry. A list of the matters in which I have
`testified in the last four years is attached as Appendix B.
`
`II. Assignment
`
`4. Frontier Therapeutics, LLC (“Petitioner”) has petitioned for Inter Partes
`Review (“IPR) of United States Patent No. US 8,664,231 B2 (the “‘231
`patent”), which is owned by Medac Gesellschaft für klinische Spezialpräparate
`mbH (collectively with its United States subsidiary Medac Pharma, Inc.,
`“Medac”). The ‘231 patent issued in the United States on March 4, 2014.1 The
`claim at issue in the ‘231 patent relates to a method characterized by the
`subcutaneous administration of “methotrexate…at a concentration of more than
`
`
`1 United States Patent No. US 8,664,231 B2 (Ex. 1001). I am informed and
`
`understand that the priority application of this patent was filed in Germany on July
`
`21, 2006 and in the European Patent Office, as Receiving Office for the Patent
`
`Cooperation Treaty, on July 20, 2007. Id.
`
`
`
`
`Page 4
`
`Page 00004
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`30 mg/ml” for the treatment of inflammatory autoimmune diseases.2 I will refer
`to this claim as the “Innovation” throughout my report. Medac markets a
`methotrexate product, Rasuvo™ (methotrexate) injection (“Rasuvo™”), which
`I understand uses the Innovation.3 Antares Pharma, Inc. (“Antares”) also
`markets a methotrexate product, Otrexup™ (methotrexate) injection
`(“Otrexup™”), which I understand uses the Innovation.
`5. I understand that a key question at issue in this IPR is whether the Innovation
`was obvious. I have been retained by counsel for Medac to evaluate whether
`there were economic reasons why no company had introduced a product like
`Rasuvo™ or Otrexup™, i.e., a product using the Innovation, for the treatment
`of inflammatory autoimmune disease, examples of which include rheumatoid
`arthritis, psoriasis, and polyarticular juvenile idiopathic arthritis (“PJIA”) in the
`United States prior to July 21, 2006, the earliest priority date of the ‘231 patent.
`I refer to this date as the date of the “filing of the ‘231 patent” throughout my
`report. The absence of a product using the Innovation, without an underlying
`economic reason for such an absence, is evidence that the Innovation was not
`obvious.
`6. I evaluate two economic factors that should affect whether a company had the
`economic incentive to introduce a product using the Innovation into the United
`States market:
`a. First, I evaluate whether there was a valuable economic opportunity in
`the market for drugs treating inflammatory autoimmune diseases,
`
`2 Ex. 1001 cl. 8.
`
`3 Ex. 2061 (“About Rasuvo™,” Medac Pharma,
`
`www.rasuvo.com/patients/background).
`
`
`
`
`Page 5
`
`Page 00005
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`example of which include rheumatoid arthritis, PJIA, and psoriasis in the
`United States that could be captured by a product using the Innovation. I
`also evaluate if this was known prior to the filing of the ‘231 patent on
`July 21, 2006.
`b. Next, I evaluate whether there were any substantial entry barriers facing a
`company interested in launching a product in the United States using the
`Innovation before the filing of the ‘231 patent. I also evaluate whether
`such a product existed prior to the filing of the ‘231 patent.
`7. I am being compensated for my time and services at my usual consulting rate of
`$800 per hour. My compensation is not contingent on the content of my
`opinions or on the outcome of this litigation. I was assisted in my research by
`staff at Cornerstone Research who worked under my direction. Appendix C
`contains a list of materials that I have considered in forming my opinions. Each
`of these materials is a type of document that experts in my field would
`reasonably rely upon when forming their opinions. In addition, I have relied
`upon my training and experience as an economist who has studied the
`healthcare industry for over 25 years.
`8. During the course of my analysis I reviewed a variety of materials, including
`public press and academic articles. I also had a discussion with Terri
`Shoemaker, Medac Pharma’s CEO, on November 14, 2014.
`
`9. I hereby declare that all statements made herein of my own knowledge are true
`
`and that all statements made on information and belief are believed to be true;
`
`and further that these statements were made with the knowledge that willful
`
`false statements and the like so made are punishable by fine or imprisonment,
`
`
`
`
`Page 6
`
`Page 00006
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`or both, under 18 U.S.C. 1001. If called to testify as to the truth of the matters
`
`stated herein, I could and would testify competently.
`
`10. My opinions are based on currently available information. I reserve the right to
`provide further analysis later in this proceeding if necessary. Also, to the extent
`that new information or data become available, I may supplement my analyses
`and opinions.
`
`III. Summary Of Opinions
`
`11. There was a valuable economic opportunity to manufacture and sell a product
`using the Innovation in the United States prior to the filing of the ‘231 patent.
`The opportunity existed because: (a) potential sales for a product using the
`Innovation were substantial; (b) there were known issues with oral methotrexate
`and prior forms of injectable methotrexate that could be overcome by a product
`like Rasuvo™, which uses the Innovation; and (c) a product like Rasuvo™
`could lower costs for government and employer-sponsored health plans (“third-
`party payors”) and patients by delaying or reducing treatment with expensive
`biologic drugs (“biologics”).
`12. Not only was there a valuable economic opportunity for a product like
`Rasuvo™, there would have been no substantial barriers to entry in this market
`prior to the filing of the ‘231 patent, assuming Petitioner’s assertions regarding
`
`
`
`
`Page 7
`
`Page 00007
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`the safety of a product using the Innovation are true.4 In other words, any
`company wanting to launch a product using the Innovation in the United States
`would not have faced substantial obstacles to doing so. Methotrexate products
`had been widely used for decades, and the patent on the methotrexate
`compound had expired many years prior. Moreover, (under Petitioner’s
`assertions) there would have been no other potential barriers to entry that were
`substantial, including research and development costs to bring a methotrexate
`product containing the Innovation to market; costs associated with sourcing the
`ingredients of and manufacturing a product containing the Innovation; costs of
`obtaining approval for such a product from the U.S. Food and Drug
`Administration (“FDA”); costs faced by patients in changing treatments; and
`costs to educate physicians and third-party payors on the benefits of such a
`product.
`13. The fact that (a) the economic opportunity was valuable and (b) there were
`(assuming Petitioner’s assertions to be true) no substantial barriers to entry
`indicates that there were no economic reasons discouraging a firm in the United
`States from developing a product that used the Innovation prior to the filing of
`the ‘231 patent. However, no such product existed in the United States prior to
`this date. These facts provide evidence that the Innovation was not obvious.
`
`
`4 I am informed and understand that Petitioner asserts that the subcutaneous
`
`administration of methotrexate at concentrations of more than 30 mg/ml was
`
`known and safe prior to the filing of the ‘231 patent. Petition for Inter Partes
`
`Review of U.S. Patent No. 8,664,231, Frontier Therapeutics, LLC v. Medac
`
`Gesellschaft für klinische Spezialpräparate mbH, 2/22/16 at 20, 36 and 51.
`
`
`
`
`Page 8
`
`Page 00008
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`IV. Background
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`14. Petitioner has petitioned for IPR of Medac’s ‘231 patent. Claim 1 at issue in
`the ‘231 patent relates to the subcutaneous administration of methotrexate
`solution “at a concentration of more than 30 mg/ml,” for treatment of
`inflammatory autoimmune diseases, i.e., the Innovation.5 I understand that the
`‘231 patent also discusses the delivery mechanism of this concentrated solution
`to potential patients, including “wherein the medicament is contained in an
`injection device for a single application.”6
`15. Otrexup™, which contains methotrexate for subcutaneous administration using
`an autoinjector,7 was filed in December 2012 and approved by the FDA in
`October 20138. It is indicated for the treatment of rheumatoid arthritis,
`
`
`5 Ex. 1001 (United States Patent No. US 8,664,231 B2) claim 1.
`
`6 Ex. 1001 (United States Patent No. US 8,664,231 B2) claim 8 .
`
`7 Ex. 2074 at 4, 5, 20 (“Highlights of Prescribing Information: OXTREXUP™,”
`
`Drugs@FDA, 11/14,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204824s003lbl.pdf).
`
`8 Ex. 2068 at 1, 4 (“FDA Approval Letter: Otrexup™,” Drugs@FDA, 10/13/13,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204824Orig1s000Appro
`
`v.pdf, ).
`
`
`
`
`Page 9
`
`Page 00009
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`psoriasis, and PJIA.9 Otrexup™ is sold in four dosage forms: 10 mg/0.4 ml (25
`mg/ml), 15 mg/0.4 ml (37.5 mg/ml), 20 mg/0.4 ml (50 mg/ml), and 25 mg/0.4
`ml (62.5 mg/ml).10 I understand that Otrexup™ is licensed under the ’231
`patent and that these last three dosages use the Innovation.
`16. Medac sells a methotrexate product called Rasuvo™, which uses the
`Innovation.11 It is dispensed via an autoinjector and is approved for the
`treatment of rheumatoid arthritis, psoriasis, and PJIA.12 Rasuvo™ was
`
`
`9 Ex. 2068 at 4 (“FDA Approval Letter: Otrexup™,” Drugs@FDA, 10/13/13,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204824Orig1s000Appro
`
`v.pdf, ).
`
`10 Ex. 2068 at 4 (“FDA Approval Letter: Otrexup™,” Drugs@FDA, 10/13/13,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204824Orig1s000Appro
`
`v.pdf, ).
`
`11 Ex. 2075 at 1, 4, and 5 (“Highlights of Prescribing Information: RASUVO™,”
`
`Drugs@FDA, 7/14,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205776s000lbl.pdf, p.
`
`5).
`
`12 Ex. 2069 at 1, 4 (“FDA Approval Letter: Rasuvo™,” Drugs@FDA, 7/10/14,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/205776Orig1s000lt
`
`r.pdf, ).
`
`
`
`
`Page 10
`
`Page 00010
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`approved by the FDA in July 2014.13 Rasuvo™ is sold in ten dosage forms, in
`increments of 2.5 mg, ranging from 7.5 mg/0.15 ml to 30 mg/0.6 ml.14 All ten
`dosage forms have the same concentration, 50 mg/ml, and therefore, I
`understand that all of them use the Innovation.
`
`V. The Development Of A Product Using The Innovation, Like
`Rasuvo™, Presented Companies with A Valuable Economic
`Opportunity
`
`17. A product using the Innovation (like Rasuvo™) represented a valuable
`economic opportunity to companies because it could serve a large and growing
`market; it could provide unique benefits that were not available with existing
`forms of methotrexate; and it could provide cost-savings to third-party payors
`and patients by delaying or reducing the use of expensive alternate forms of
`treatment, such as biologics, for inflammatory autoimmune diseases.
`
`A.
`
`Potential Sales For A Product Using The Innovation Are Substantial,
`And This Was Expected Prior To The Filing Of The ‘231 Patent
`
`
`18. As described above, Rasuvo™ is indicated for the treatment of rheumatoid
`arthritis and psoriasis in adults, and PJIA in children. As will be described in
`
`13 Ex. 2069 at 8 (“FDA Approval Letter: Rasuvo™,” Drugs@FDA, 7/10/14,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/205776Orig1s000lt
`
`r.pdf,).
`
`14 Ex. 2069 at 4 (“FDA Approval Letter: Rasuvo™,” Drugs@FDA, 7/10/14,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/205776Orig1s000lt
`
`r.pdf, ).
`
`
`
`
`Page 11
`
`Page 00011
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`this section, these conditions affect a substantial number of patients in the
`United States, and in the mid-2000s, the market for these conditions was
`expected to grow. Moreover, the available treatment options of using
`methotrexate and expensive biologic drugs meant that there was a substantial
`market opportunity in the United States for a drug like Rasuvo™ that could
`delay or reduce the use of biologics.15
`
`19. The three conditions that Rasuvo™ is indicated to treat affect a large number of
`people in the United States in the mid-2000s. Specifically, rheumatoid arthritis
`affected an estimated 1.3 million adults in the United States in 2005.16 An
`estimated 294,000 children had a rheumatic condition in the period 2001–
`2004,17 and currently, more than 300,000 children in the United States are
`estimated to have juvenile idiopathic arthritis.18 Psoriasis affected an estimated
`
`
`15 Ex. 2012 (Bingham SJ et al. “Parenteral methotrexate should be given before
`
`biological therapy,” Rheumatology, 2003, vol. 42: 1009-1010).
`
`16 Ex. 2041 at 4 (Helmick, C. et al. (2008), “Estimates of the Prevalence of
`
`Arthritis and Other Rheumatic Conditions in the United States,” Arthritis and
`
`Rheumatism, Vol. 58, No. 1, pp. 15–25).
`
`17 Ex. 2041 at 5 (Helmick, C. et al. (2008), “Estimates of the Prevalence of
`
`Arthritis and Other Rheumatic Conditions in the United States,” Arthritis and
`
`Rheumatism, Vol. 58, No. 1, pp. 15–25).
`
`18 Juvenile idiopathic arthritis may be categorized into several subtypes, of which
`
`PJIA is one. Ex. 2078 at 1 (“Juvenile Idiopathic Arthritis (JIA),” NYU Langone
`
`
`
`
`Page 12
`
`Page 00012
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`5 million adults in the United States in 2003-2004,19 and 7.4 million adults in
`the United States in 2013.20
`
`20. Rheumatoid arthritis, psoriasis, and PJIA in children are often treated with
`either methotrexate21 or with biologic drugs. Methotrexate represents a “first-
`
`
`Medical Center Division of Pediatric Rheumatology,
`
`http://pediatrics.med.nyu.edu/rheumatology/patient-care/juvenile-idiopathic-
`
`arthritis-jia).
`
`19 Ex. 2043 at 1 (Kurd, S. et al. (2009), “The Prevalence of Previously Diagnosed
`
`and Undiagnosed Psoriasis in US Adults,” Journal of the American Academy of
`
`Dermatology, Vol. 60, Issue 2, pp. 218–224).
`
`20 Ex. 2048 at 1 (Rachakonda, T. et al. (2014), “Psoriasis Prevalence Among
`
`Adults in the United States,” Journal of the American Academy of Dermatology,
`
`Vol. 70, No. 3, pp. 512–516).
`
`21 Methotrexate is a Disease-Modifying Antirheumatic Drug (DMARD).
`
`DMARDs slow the inflammation of joints caused by rheumatoid arthritis and
`
`PJIA. Methotrexate is one of the most widely used DMARDs. Other DMARDs
`
`prescribed to treat rheumatoid arthritis include: apremilast, azathioprine,
`
`cyclophosphamide, hydroxychloroquine sulfate, leflunomide, mycophenolate
`
`mofetil, sulfasalazine, and tofacitinib. Other DMARDs prescribed to treat juvenile
`
`idiopathic arthritis include: azathioprine, cyclosporine, hydroxychloroquine,
`
`
`
`
`Page 13
`
`Page 00013
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`line” treatment for rheumatoid arthritis and PJIA, i.e., doctors commonly
`choose methotrexate as the first course of treatment after diagnosis.22 The
`American College of Rheumatology
`recommends
`the “initiation of
`methotrexate or leflunomide monotherapy for patients with all disease durations
`
`
`leflunomide, and sulfasalazine. Ex. 2067 (“Drug Guide: DMARDs,” Arthritis
`
`Foundation, http://www.arthritistoday.org/arthritis-treatment/medications/types-of-
`
`drugs/disease-modifying-drugs/drug-guide-dmards.php); Ex. 2065 (“Arthritis
`
`Today Drug Guide,” Arthritis Foundation, http://www.arthritistoday.org/arthritis-
`
`treatment/medications/drug-guide/search-by-class.php?drugclass=DMARDs); Ex.
`
`2039 at 13 (Gowdie, P. (2010), “Review of Disease-Modifying Anti Rheumatic
`
`Drugs in Paediatric Rheumatic Disease,” 18th Expert Committee on the Selection
`
`and Use of Essential Medicines).
`
`22 Ex. 1014 at 2 (“Methotrexate as the anchor drug’ for the treatment of early
`
`rheumatoid arthritis,” Clinical and Experimental Rheumatology, 2003, S-179 to S-
`
`185 at S-180); Ex. 2066 (“DMARDs for Juvenile Idiopathic Arthritis: A Review
`
`of the Research for Parents and Caregivers,” John M. Eisenberg Center for
`
`Clinical Decisions and Communications Science, Baylor College of Medicine,
`
`9/26/11, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016454/).
`
`
`
`
`Page 14
`
`Page 00014
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`and for all degrees of disease activity….”23 Methotrexate is also taken in
`combination with other drugs in certain situations.24 For psoriasis, methotrexate
`is considered to be “second-line” treatment, used when a patient has moderate
`to severe psoriasis but is unresponsive to or unable to take topical medications
`or ultraviolet light therapy. Methotrexate is the most widely prescribed
`systemic (non-topical) therapy for psoriasis.25
`
`23 Ex. 2049 at 7 (Saag, K. et al. (2008), “American College of Rheumatology 2008
`
`Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying
`
`Antirheumatic Drugs in Rheumatoid Arthritis,” Arthritis & Rheumatism (Arthritis
`
`Care & Research), Vol. 59, No. 6, pp. 762–784).
`
`24 Ex. 2049 at 7 (Saag, K. et al. (2008), “American College of Rheumatology 2008
`
`Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying
`
`Antirheumatic Drugs in Rheumatoid Arthritis,” Arthritis & Rheumatism (Arthritis
`
`Care & Research), Vol. 59, No. 6, pp. 762–784); Ex. 2066 (“DMARDs for
`
`Juvenile Idiopathic Arthritis: A Review of the Research for Parents and
`
`Caregivers,” John M. Eisenberg Center for Clinical Decisions and
`
`Communications Science, Baylor College of Medicine, 9/26/11,
`
`http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016454/).
`
`25 Ex. 2044 at 2 (Menter, A. et al. (2009), “Guidelines of Care for the Management
`
`of Psoriasis and Psoriatic Arthritis: Section 4,” Journal of the American Academy
`
`of Dermatology, Vol. 61, No. 3, pp. 451–485).
`
`
`
`
`Page 15
`
`Page 00015
`
`
`
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`21. Biologic drugs can also be used to treat all three indications, sometimes in
`combination with methotrexate. For rheumatoid arthritis and PJIA, this usually
`occurs only when non-biologic drugs have been ineffective.26 For psoriasis,
`both methotrexate and biologics are second-line treatments.27
`
`Attorney Docket No.
`110670-0010-651
`
`22. Prior to the filing of the ‘231 patent, industry observers expected that the
`rheumatoid arthritis market (including the market for methotrexate, other
`DMARDs and biologics) would grow significantly over time. An article
`published in Nature Reviews Drug Discovery in 2005 discussed how the global
`
`
`26 Ex. 2049 at 9-10 (Saag, K. et al. (2008), “American College of Rheumatology
`
`2008 Recommendations for the Use of Nonbiologic and Biologic Disease-
`
`Modifying Antirheumatic Drugs in Rheumatoid Arthritis,” Arthritis & Rheumatism
`
`(Arthritis Care & Research), Vol. 59, No. 6, pp. 762–784); Ex. 2083 (“Questions
`
`and Answers about Juvenile Arthritis,” National Institute of Arthritis and
`
`Musculoskeletal and Skin Diseases, 8/13,
`
`http://www.niams.nih.gov/Health_Info/Juv_Arthritis/#1); Ex. 2038 at 4 (Goutsou,
`
`M. et al. (2013), “Biologics Utilization for Rheumatoid Arthritis in the United
`
`States: An Observational Longitudinal Study,” Journal of Medical Marketing,
`
`Vol. 13, No. 2, pp. 74–81).
`
`27 Ex. 2044 (Menter, A. et al. (2009), “Guidelines of Care for the Management of
`
`Psoriasis and Psoriatic Arthritis: Section 4,” Journal of the American Academy of
`
`Dermatology, Vol. 61, No. 3, pp. 451–485).
`
`
`
`
`Page 16
`
`Page 00016
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`market for rheumatoid arthritis was projected to be more competitive over time,
`with “tremendous potential for growth” and expected compounded annual
`growth rates of 24.4% over the period from 2003 to 2008.28 Similar to the
`rheumatoid arthritis market, the market for psoriasis was expected to grow
`considerably in the period 2005–2015. A report by Datamonitor published in
`2006 projected that sales of psoriasis drugs would exceed $2.3 billion in the
`U.S. alone by 2015, compared to global sales of $1.95 billion in 2005.29
`
`23. Actual growth in these markets has been in line with these projections. Total
`prescriptions of methotrexate for rheumatoid arthritis and PJIA have been
`increasing and totaled 5.4 million in 2013, compared to 4.3 million in 2007
`(Exhibit 1).30 Dollar sales of methotrexate for the rheumatoid arthritis and PJIA
`
`28 Ex. 2046 (Mount, C. et al. (2005), “Rheumatoid Arthritis Market,” Nature
`
`Reviews Drug Discovery, Vol. 4).
`
`29 Ex. 2082 at 2 (“Psoriasis Treatments with Next Generation Vitamin D Analogs,”
`
`Wisconsin Alumni Research Foundation, http://www.warf.org/for-
`
`industry/vitamin-d/psoriasis/psoriasis.cmsx).
`
`30 Exhibits 1–8 are constructed using a dataset provided by Medac. The set of
`
`biologic drugs used in the analysis is also derived from the same data. I
`
`understand from Medac that for these drugs, data from primary care physicians
`
`(including rheumatologists) and nurses generally correspond to prescriptions/sales
`
`of rheumatoid arthritis; data from dermatologists generally correspond to
`
`prescriptions/sales of psoriasis; and data from the pediatricians generally
`
`
`
`
`Page 17
`
`Page 00017
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`indications have also been increasing. In 2013, dollar sales totaled $560.4
`million, up from $461.8 million in 2007 (Exhibit 2). Prescriptions of
`methotrexate (oral and injectable) for psoriasis in the United States rose from
`approximately 179,000 in 2007 to approximately 288,000 in 2013 (Exhibit 3).
`Total dollar sales of methotrexate for psoriasis were $24.4 million in 2013,
`compared to $17.2 million in 2007 (Exhibit 4).
`
`24. The size of the biologics market for these three indications is also large and
`growing. For instance, Exhibit 5 shows that total prescriptions of biologics for
`rheumatoid arthritis and PJIA rose from 2 million in 2007 to 3.3 million in
`2013. Dollar sales rose even more dramatically. Exhibit 6 shows that dollar
`sales of these drugs rose from $3.8 billion in 2007 to $10.7 billion in 2013 for
`these two indications.31 A study in the Journal of Medical Marketing also
`found that the use of biologics rose from 18.7% to 26.3% of all rheumatoid
`
`
`correspond to prescriptions/sales of PJIA. Restricting the analysis for each
`
`indication to only drugs that are currently approved to treat the relevant indication
`
`does not change my conclusions. MEDAC-NJ 0002040. Conversation with Mary
`
`Theresa (Terri) Shoemaker (CEO, Medac Pharma), 11/14/14.
`
`31 These figures include sales of Actemra®, Cimzia®, Enbrel®, Humira®,
`
`Kineret®, Orencia®, Remicade®, Rituxan®, Simponi®, and Stelara®.
`
`
`
`
`Page 18
`
`Page 00018
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`arthritis cases in the United States between 2005 and 2010.32 Prescriptions for
`biologics in the treatment of psoriasis rose from approximately 469,000 in 2007
`to 538,000 in 2013 (Exhibit 7), and dollar sales rose from $1.1 billion to $1.8
`billion over the same time period (Exhibit 8).
`
`25. The market opportunity for a drug using the Innovation like RasuvoTM arises
`from the large size of the market, as reflected by the substantial sales of
`methotrexate and biologic drugs, as well as from the ability of the Innovation to
`delay or reduce the use of high-cost biologics. Exhibit 9 shows that the average
`sales price (price net of any discounts or rebates from the company) per month
`of rheumatoid arthritis treatment with methotrexate was between $1 and $25 in
`2014. In contrast, the average sales price per month for biologic treatment of
`rheumatoid arthritis was approximately between $1,100 and $13,400. For
`psoriasis, despite both methotrexate and biologics being second-line
`treatments,33 many third-party payors require doctors to try methotrexate prior
`
`
`32 Ex. 2038 at 4 (Goutsou, M. et al. (2013), “Biologics Utilization for Rheumatoid
`
`Arthritis in the United States: An Observational Longitudinal Study,” Journal of
`
`Medical Marketing, Vol. 13, No. 2, pp. 74–81).
`
`33 Ex. 2044 at 2 (Menter, A. et al. (2009), “Guidelines of Care for the Management
`
`of Psoriasis and Psoriatic Arthritis: Section 4,” Journal of the American Academy
`
`of Dermatology, Vol. 61, No. 3, pp. 451–485).
`
`
`
`
`Page 19
`
`Page 00019
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`to using a biologic due to the high cost of biologic treatments.34 For example, a
`2010 study estimated that the total annual per-patient costs for systemic
`psoriasis therapy using methotrexate was slightly over $1,000, whereas biologic
`treatment for psoriasis cost between $18,000 and $28,000.35 As such, any drug
`that could delay or reduce the use of biologic treatment for rheumatoid arthritis,
`PJIA, and psoriasis would be presented with a substantial market opportunity in
`the United States. I explain why a drug like Rasuvo™ could delay the use of
`biologics from a therapeutic perspective in Section V.B. and how a drug like
`Rasuvo™ could lower costs for third-party payors and patients by delating the
`use of biologic treatments in Section V.C.
`
`
`
`B.
`
`Patients May Prefer A Product Using The Innovation Versus Pre-
`Existing Forms of Methotrexate
`
`
`26. As described above, methotrexate is widely used to
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
