IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`KOIOS PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FUER KLINISCHE
`SPEZIALPRÄPARATE MBH,
`Patent Owner
`____________
`
`Case No. IPR2016-01370
`Patent Number 8,664,231
`____________
`
`Before JACQUELINE WRIGHT BONILLA, TONI R. SCHEINER,
`and ERICA A. FRANKLIN, Administrative Patent Judges
`
`
`
`PATENT OWNER’S RESPONSE
`UNDER 37 C.F.R. § 42.120
`
`
`
`1
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`Introduction .................................................................................................... 1
`
`II. The Parties and Experts ................................................................................ 4
`A.
`Patent Owner and Its Experts ............................................................ 4
`1.
`Dr. Elena Massarotti ................................................................. 5
`2.
`Dr. Sean Nicholson .................................................................... 5
`3.
`Dr. Thomas Zizic ....................................................................... 5
`4.
`Dr. John Clark ........................................................................... 6
`Petitioner And Its Experts .................................................................. 6
`
`B.
`
`III. The ‘231 Patent and Prosecution History ................................................... 7
`A.
`The ‘231 Patent .................................................................................... 7
`B. Relevant Prosecution History ............................................................. 9
`
`IV. MTX and the Treatment of Inflammatory Autoimmune Diseases......... 10
`
`V. Claim Construction ..................................................................................... 14
`
`VI. Anticipation (Grounds 1 and 4): The Cited Art Does Not
`Anticipate Any Claims ................................................................................ 15
`A. Grint Does Not Disclose The Features Of Claims 1, 2, 4-6,
`11-13, 17, And 22 Or Their Arrangement As In Those
`Claims (Ground 1) ............................................................................. 17
`1.
`Petitioner Failed To Demonstrate That Subcutaneous
`Administration Of Above 30 mg/ml MTX Was
`Conventional Or Convenient and Effective ......................... 22
`Petitioner Failed To Demonstrate That There Is No
`Reasonable Difference In How The Claimed
`Invention Operates Over Grint’s Entire
`Concentration And Dose Ranges ........................................... 25
`
`2.
`
`i
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`B. Wyeth Does Not Disclose The Features Of Claims 1-6, 11-
`13, 17-18, And 22 Or Their Arrangement As In Those
`Claims (Ground 4) ............................................................................. 30
`1. Wyeth’s Focus Is Not On Subcutaneous
`Administration ........................................................................ 31
`2. Wyeth Does Not Teach the Claimed Concentrations
`for Inflammatory Autoimmune Diseases .............................. 32
`
`VII. Obviousness (Grounds 2, 3, and 6): The Cited Art Does Not
`Render Any Claims Obvious ...................................................................... 42
`A. Grint, Arthur, Moitra, and Insulin Admin Do Not Render
`Obvious Claims 7-10, 14-16, or 19-21 (Ground 2) ......................... 45
`B. Grint and Alsufyani Do Not Render Obvious Claim 18
`(Ground 3) .......................................................................................... 47
`C. Wyeth, Brooks, Arthur, and Moitra Do Not Render
`Obvious Claims 1-6, 11-13, 17-18, or 22 (Ground 5) ..................... 47
`
`VIII. Secondary Considerations Demonstrate Nonobviousness ....................... 48
`A.
`Petitioner Ignored Known Evidence of Copying ........................... 49
`B.
`The Methods Of The Challenged Claims Have Received
`Praise .................................................................................................. 50
`C. No One Made The Methods Of The Challenged Claims,
`Despite Strong Incentives ................................................................. 51
`
`IX. Conclusion .................................................................................................... 52
`
`
`
`
`ii
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) .......................................................... 25, 26, 27, 28
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 26
`
`Dennison Mfg. Co. v. Panduit Corp.,
`475 U.S. 809 (1986) ........................................................................................ 3, 42
`
`Graham v. John Deere, Co.
`383 U.S. 1 (1966) ................................................................................................ 48
`
`In re Arkley,
`455 F.2d 586 (C.C.P.A. 1972) ............................................................................ 16
`
`Ineos USA LLC v. Berry Plastics Corp,
`783 F.3d 865 (Fed. Cir. 2015) ............................................................................ 26
`
`Net MoneyIN, Inc. v. Verisign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .................................................................... 17, 22
`
`Synopsis Inc. v. Mentor Graphics Corp.,
`IPR2012-00041, slip op. (PTAB Feb. 22, 2013) ................................................ 18
`
`OTHER AUTHORITIES
`
`37 C.F.R.
`§ 42.65(a) .............................................................................................................. 2
`§ 42.100(b) .......................................................................................................... 14
`§ 42.120 ................................................................................................................. 1
`
`35 U.S.C.
`§ 314(a) ................................................................................................................. 1
`§ 316(e) ................................................................................................................. 1
`
`iii
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`
`
`EXHIBIT LIST
`
`2002
`
`Exhibit Description
`Kurnick D. et al., “Bioavailability of oral vs. subcutaneous low-dose
`2001
`methotrexate in patients with Crohn’s disease,” Aliment. Pharmacol.
`Ther., 2003, vol. 18:57-63
`Breslin, et al., “Improving Tolerance and Bioavailability of
`Methotrexate by Switching from Oral to Subcutaneous Route of
`Administration,” Rheumatology 388 (2005)
`Balis, et al., “Pharmacokinetics of Subcutaneous Methotrexate,” Journal
`of Clinical Oncology 6(12):1882-1886 (1988)
`Chapter 16: Human: Veterinary Technology Cross Over, Long Acting
`Animal Health Drug Products: Fundamentals and Applications, Baird et
`al., Springer (2013)
`Chapter 3: Drug Administration, Drug Therapy In Nursing, 3rd Ed.,
`Aschenbrenner DS and Venable SJ, Wolters Kluwer Health (2009)
`Antares Pharma Press Release, “Antares Pharma Announces the
`Publication of a Head-to-Head, Randomized, Crossover Study of Oral
`versus Subcutaneous Methotrexate in Patients with Rheumatoid
`Arthritis,” Business Wire (Apr. 17, 2014)
`Consulting Agreement between Medac Pharma, Inc. and Dr. Michael
`Schiff, M.D., executed September 7, 2012
`RA Advisory Council: Overview & Meeting Objectives, October 5,
`2012
`Koios Pharmaceuticals LLC Press Release, “Koios Pharmaceuticals
`Files Challenge to High-Cost Drug’s Patent,” Business Wire (July 20,
`2016)
`Declaration of Brian Gummow in Support Of Patent Owner’s
`Preliminary Response
`Declaration of Terri Shoemaker in Support Of Patent Owner’s
`Preliminary Response
`U.S. Patent 8,480,631
`Andrea T. Borchers et al., “The Use of Methotrexate in
`Rheumatoid Arthritis,” Seminars in Arthritis and Rheumatism,
`Vol. 34, No. 1 (Aug. 2004)
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`2013
`
`iv
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2015
`
`2016
`
`Exhibit Description
`2014
`Jiří Grim et al., “Pharmacokinetics and Pharmacodynamics of
`Methotrexate in Non-Neoplastic Diseases,” Special Populations
`(2003)
`Drugs@FDA: FDA Approved Drug Products (Mexate), available
`at
`http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?f
`useaction=Search.DrugDetails, last visited May 22, 2016
`Schiff, et al., “Head-to-head, randomised, crossover study of oral versus
`subcutaneous methotrexate in patients with rheumatoid arthritis,” Ann
`Rheum Dis 0:1-3 (2014)
`Bingham SJ et al. “Parenteral methotrexate should be given before
`biological therapy,” Rheumatology, 2003, vol. 42: 1009-1010
`Expert Declaration of Elena Massarotti, M.D.
`Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 7th
`Ed, 1985
`2007 CDC Guidelines for Isolation Precautions: Preventing
`Transmission of Infectious Agents in Healthcare Settings
`SICOR Pharmaceuticals ANDA Suitability Petition Methotrexate
`Injection, USP (100mb/mL), dated April 28, 2006
`Brazeau et al. “Current Perspectives on Pain Upon Injection of Drugs,”
`J. Pharm. Sci., 1998, vol. 87(6):667-677
`Reserved
`“Clinical Guidelines, Extravasation,” West Suffolk Hospitals (July
`2011)
`Boyle, D. et al., “Vesicant Extravasation: Myths and Realities”
`Oncology Nursing Forum, Vol. 22, No 1(January 1995)
`Drugs@FDA Summary Table
`Drugs@FDA Search Results for “Methotrexate,” available
`at http:///www.accessdata.fda.gov/scripts/cder/drugsatfda/
`index.cfm
`“Extravasation guidelines 2007, Guidelines Implementation
`Toolkit”
`Pavy S. et al., “Methotrexate therapy for rheumatoid arthritis: clinical
`practice guidelines based on published evidence and expert opinion,”
`Joint Bone Spine, 2006, vol. 73:388-395
`
`2017
`
`2018
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`2024
`
`2025
`
`2026
`2027
`
`2028
`
`2029
`
`
`
`v
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2031
`
`2032
`2033
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`Exhibit Description
`2030
`Declaration of Maria Salgado in Support of Patent Owner’s Preliminary
`Response from IPR2016-00649 dated 6/2/16
`Parshuram, C. et al. “Occurrence and Impact of Unanticipated
`Variation in Intravenous Methotrexate Dosing” Annals of
`Pharmacotherapy, Vol. 40 (May 2006)
`Expert Declaration of Dr. Sean Nicholson
`MTX Information with Strength (MEDAC-NJ 0002040)
`Ashburn, T. et al., “Drug Repositioning: Identifying and Developing
`New Uses for Existing Drugs,” Nature Reviews Drug Discovery, Vol.
`3, No. 8, pp. 673-683 (2004)
`Augustin, M. et al., “Adherence in the Treatment of Psoriasis: A
`Systematic Review,” Dermatology, Vol. 222, pp. 363-374 (2011)
`Van den Bemt, B., et al., “Medication Adherence in Patients With
`Rheumatoid Arthritis: A Critical Appraisal of the Existing Literature,”
`Expert Review of Clinical Immunology, Vol. 8, No. 4, pp. 337-351
`(2012)
`Beyer, V. et al., “Recent Trends in Systemic Psoriasis Treatment
`Costs,” Archives of Dermatology, Vol. 146, No. 1, pp. 46-54 (2010)
`Goutsou, M. et al., “Biologics Utilization for Rheumatoid Arthritis in the
`United States: An Observational Longitudinal Study,” Journal of
`Medical Marketing, Vol. 13, No. 2, pp. 74-81 (2013)
`Gowdie, P., “Review of Disease - Modifying Anti Rheumatic Drugs in
`Paediatric Rheumatic Disease,” 18th Expert Committee on the
`Selection and Use of Essential Medicines (2010)
`Greenapple, R., “Trends in Biologic Therapies for Rheumatoid
`Arthritis: Results from a Survey of Payers and Providers,” American
`Health & Drug Benefits, Vol. 5, No. 2, pp. 83-92 (2012)
`Helmick, C. et al., “Estimates of the Prevalence of Arthritis and Other
`Rheumatic Conditions in the United States,” Arthritis and Rheumatism,
`Vol. 58, No. 1, pp. 15-25 (2008)
`Kalb, R. et al., “Methotrexate and Psoriasis: 2009 National Psoriasis
`Foundation Consensus Conference,” Journal of American Academy of
`Dermatology, Vol. 60, No. 5, pp. 824-837 (2009)
`Kurd, S. et al., “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 (2009)
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`
`
`vi
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`Exhibit Description
`Menter, A. et al., “Guidelines of Care for the Management of Psoriasis
`2044
`and Psoriatic Arthritis: Section 4,” Journal of the American Academy of
`Dermatology, Vol. 61, No. 3, pp. 451-485 (2009)
`Michaud, K. et al., “Direct Medical Costs and Their Predictors in Patients
`with Rheumatoid Arthritis,” Arthritis & Rheumatism, Vol. 48, No. 10,
`pp. 2750-2762 (2003)
`Mount, C. et al., “Rheumatoid Arthritis Market,” Nature Reviews Drug
`Discovery, Vol. 4, pp. 11-12 (2005)
`Paul, S. et al., “How to Improve R&D Productivity: The Pharmaceutical
`Industry’s Grand Challenge,” Nature Reviews Drug Discovery, Vol. 9,
`No. 3, pp. 203-214 (2010)
`Rachakonda, T. et al., “Psoriasis Prevalence Among Adults in the United
`States,” Journal of the American Academy of Dermatology, Vol. 70,
`No. 3, pp. 512-516 (2014)
`Saag, K. et al., “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
`(2008)
`Smith, K., “Systemic Therapy of Psoriasis Using Methotrexate,” Skin
`Therapy Letter, Vol. 6, No. 3, pp. 1-5 (2000)
`Steinwachs, D., “Pharmacy Benefit Plans and Prescription Drug
`Spending,” Journal of the American Medical Association, Vol. 288, No.
`14, pp. 1773-1774 (2002)
`DiMasi, J. et al., “R&D Costs and Returns to New Drug Development:
`A Review of the Evidence,” in P. Danzon, and S. Nicholson (eds), The
`Oxford Handbook of The Economics of the Biopharmaceutical Industry,
`Oxford University Press, pp. 21-46 (2012)
`Eisenberg, R., “Patents and Regulatory Exclusivity,” in P. Danzon, and
`S. Nicholson (eds), The Oxford Handbook of The Economics of the
`Biopharmaceutical Industry, Oxford University Press, pp. 167-198
`(2012)
`Malani, A. et al., “The Regulations of Medical Products,” in P. Danzon,
`and S. Nicholson (eds), The Oxford Handbook of the Economics of the
`Biopharmaceutical Industry, Oxford University Press, pp. 100-142
`(2012)
`Stoller, G. et al., “Use of Plasma Pharmacokinetics to Predict
`
`2050
`
`2051
`
`2052
`
`2053
`
`2054
`
`2055
`
`
`
`vii
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2056
`
`2057
`
`2058
`2059
`
`Exhibit Description
`and Prevent Methotrexate Toxicity,” New England Journal of
`Medicine (Sept. 1977)
`“October 2006 ASP Pricing File - Updated 12/19/07,” Centers for
`Medicare and Medicaid Services,
`http://www.cms.gov/apps/ama/license.asp?file=/McrPartBDrugAvgSalesP
`rice/downloads/oct06asphcpcs.zip
`“October 2014 ASP Pricing File 09/12/14,” Centers for Medicare and
`Medicaid Services,
`http://www.cms.gov/apps/ama/license.asp?file=/McrPartBDrugAvgSalesPri
`ce/downloads/2014-October-ASP-Pricing-File.zip
`Declaration of Brian Gummow in Support of Patent Owner’s Response
`“Antares Pharma Announces Availability of Otrexup™ (Methotrexate)
`Injection for Subcutaneous Use to Treat Rheumatoid Arthritis (RA) and
`psoriasis in adults, and polyarticular idiopathic arthritis (pJIA) in
`Children,” Antares Pharma Press Release, dated Jan. 15, 2014
`“Supply of a Cancer Drug May Run Out Within Weeks,” New York
`Times, dated Feb. 10, 2012
`“About Rasuvo™,” Medac Pharma,
`http://www.rasuvo.com/patients/background
`“Antares Pharma’s (ATRS) CEO Paul Wotton on Q1 2014 Results -
`Earnings Call Transcript,” Seeking Alpha, May 9, 2014,
`http://seekingalpha.com/article/2206743-antarespharmas-atrs-ceo-paul-
`wotton-on-q1-2014-results-earnings-call-transcript?part=single
`“Antares: Thoughts on the Upcoming Otrexup™ Launch,” Seeking Alpha,
`Nov, 8, 2013, http://seekingalpha.com/article/1822102-antares-thoughts-
`on-the-upcoming-otrexuplaunch
`“Antares; My View of How Otrexup™ and Medac's New Product
`Rasuvo™ May Compete (ATRS, Buy, $2.54),” SmithOnStocks, July
`12, 2014, http.//smithonstocks.com/antares-my-view-of-how-otrexup-and-
`medacs-new-productrasuvo-may-compete-atrs-buy-2-54/
`“Arthritis Today Drug Guide,” Arthritis Foundation,
`http://www.arthritistoday.org/arthritis-treatment/medications/drug-
`guide/search-byclass.php?drugclass=DMARDs
`
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`
`
`viii
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2067
`
`2068
`
`2069
`
`2070
`
`2071
`
`2072
`
`Exhibit Description
`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,
`Sept. 26, 2011,
`http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016454/
`“Drug Guide: DMARDs,” Arthritis Foundation,
`http://www.arthritistoday.org/arthritis-treatment/medications/types-of-
`drugs/disease-modifying-drugs/drug-guide-dmards.php
`“FDA Approval Letter: Otrexup™,” Drugs@FDA, Oct. 11, 2013,
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204824Orig2s
`000Approv.pdf
`“FDA Approval Letter: Rasuvo™,” Drugs@FDA, July 10, 2014,
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205776Orig1s
`000Approv.pdf
`“FDA OKs a New Methotrexate Injection Device,” Arthritis
`Foundation, Aug. 15, 2014, http://www.arthritistoday.org/news/new-
`methotrexate-autoinjector-349.php
`"FDA Summary Review: Otrexup™," Drugs@FDA, Oct. 15,
`2013, http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/
`204824Orig1s000Admincorres.pdf
`“Frequently Asked Questions on Prescription Drug User Fees
`(PDUFA),” U.S. Food and Drug Administration,
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusines
`sAssistance/ucm069943.htm
`“Guidance for Industry: Applications Covered by Section
`505(b)(2),”U.S. Food and Drug Administration, Oct. 1999,
`http://www.fda.gov/downloads/Drugs/.../Guidances/ucm079345.pdf
`“Highlights of Prescribing Information: OXTREXUP™,”
`Drugs@FDA, Nov. 2014, http://www.accessdata.fda.gov/
`drugsatfda_docs/label/2014/204824s003lbl.pdf
`“Highlights of Prescribing Information: RASUVO™,”
`Drugs@FDA, July 2014, https://www.accessdata.fda.gov/
`drugsatfda_docs/label/2014/205776s000lbl.pdf
`
`2073
`
`2074
`
`2075
`
`
`
`ix
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2077
`
`2078
`
`2079
`
`Exhibit Description
`2076
`“How Medicare Prescription Drug Plans and Medicare Advantage
`Plans with Prescription Drug Coverage (MA-PDs) Use Pharmacies,
`Formularies, & Common Coverage Rules,” Department of Health &
`Human Services, October 2015,
`https://www.medicare.gov/Publications/Pubs/pdf/11136.pdf
`“Jefferies Boosts PT on Antares Pharma (ATRS) 20% into
`OTREXUP™ PDUFA; Maintains Buy,” StreetInsiden.com, Oct. 8,
`2013, http://www.streetinsider.com/Analyst+Comments/
`Jefferies+Boosts+PT+on+Antares+Pharma+%28ATRS%29+20%25+int
`o+OTREXUP+PDUFA%3B+Maintains+Buy/8758127.html
`“Juvenile Idiopathic Arthritis (JIA),” NYU Langone Medical Center
`Division of Pediatric Rheumatology,
`http://pediatrics.med.nyu.edu/rheumatology/patient-care/juvenile-
`idiopathic-arthritis-jia
`“Memorandum Report: Comparison of First-Quarter 2012 Average Sales
`Prices and Average Manufacturer Prices: Impact on Medicare
`Reimbursement for Third Quarter 2012, OEI-03-12-00730,”
`Department of Health and Human Services, Dec. 12, 2012,
`https://oig.hhs.gov/oei/reports/oei-03-12-00730.pdf
`“Methotrexate Fact Sheet,” American College of Rheumatology,
`May 2012, https://www.rheumatology.org/practice/clinical/patients/
`medications/methotrexate.pdf
`“Prescription Drug Trends,” Kaiser Family Foundation, Fact Sheet
`#3057-30, Oct. 2004,
`http://www.cigna.com/pdf/Prescription-Drug-Trends-Oct2004.pdf
`“Psoriasis Treatments with Next Generation Vitamin D Analogs,”
`Wisconsin Alumni Research Foundation, http://www.warf.org/for-
`industry/vitamin-d/psoriasis/psoriasis.cmsx
`“Questions and Answers about Juvenile Arthritis,” National
`Institute of Arthritis and Musculoskeletal and Skin Diseases, Aug.
`2013, http://www.niams.nih.gov/Health Info/Juv Arthritis/#1
`“Rheumatoid Arthritis Signs and Symptoms,” Johns Hopkins
`Arthritis Center, http://www.hopkinsarthritis.org/arthritis-
`info/rheumatoid-arthritis/ra-symptoms/
`“State and County QuickFacts,” United States Census
`Bureau, http://quickfacts.census.gov/qfd/states/00000.html
`FDA Orange Book Data File Patent.txt
`
`2080
`
`2081
`
`2082
`
`2083
`
`2084
`
`2085
`
`2086
`
`
`
`x
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`2091
`
`2092
`2093
`2094
`2095
`
`2096
`
`Exhibit Description
`2087
`FDA Orange Book Data File Products.txt
`2088
`FDA Orange Book Data File Exclusivity.txt
`2089
`Compilation of Drug Labels
`2090
`Curtis, Jeffrey R. et al., “Use of Oral and Subcutaneous
`Methotrexate in Rheumatoid Arthritis Patients in the United
`States,” 66 Arthritis Care & Research 1604 (2014)
`Striesow, Frank et al., “Preferences, satisfaction and usability of
`subcutaneously administered methotrexate for rheumatoid arthritis
`or psoriatic arthritis: results of a postmarketing surveillance study
`with a high-concentration formulation,” 4 Therapeutic Advances
`in Musculoskeletal Disease 3 (2012)
`Expert Declaration of Dr. Thomas M. Zizic
`Expert Declaration of Dr. John Clark
`Reserved
`N.R. Gaze, “Tissue Necrosis Cause by Commonly Used
`Intravenous Infusions,” Lancet 417 (Aug. 19, 1978)
`Robert J. Ignoffo et al., “Therapy of Local Toxicities Cause by
`Extravasation of Cancer Chemotherapeutic Drugs,” 7 Cancer
`Treatment Reviews 17 (1980)
`R.T. Dorr, “Antidotes to Vesicant Chemotherapy Extravasations,”
`4 Blood Reviews 41 (1990)
`L. Schulmeister, “Extravasation Management: Clinical Update”
`Seminars in Oncology Nursing, Vol. 27, No. 1 (Feb. 2011)
`“Methotrexate 100 mg/ml Injection” product by Hospira UK Ltd.,
`Date of First Authorization 13 March 1987, Date of Revision of
`the Text 22 November 2005
`
`2097
`
`2098
`
`2099
`
`
`
`xi
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`Pursuant to § 42.120, 1 Patent Owner medac Gesellschaft für Klinische
`
`Spezialpräparate mbH (“Medac”) responds to the Petition for Inter Partes Review
`
`(“IPR”) of U.S. Patent No. 8,664,231 (“the ‘231 patent”) (“Petition,” Pap. 1). As
`
`detailed below, because Petitioner has failed to make the required showing of
`
`anticipation or obviousness on any instituted grounds, Medac respectfully requests
`
`a final written decision confirming the patentability of all challenged claims of the
`
`‘231 patent.
`
`I.
`
`Introduction
`
`The Board, under the “reasonable likelihood” standard, instituted this IPR on
`
`five of Petitioner’s six grounds, all of which are based on two primary references:
`
`Grint and Wyeth. § 314(a). None of the asserted grounds renders the challenged
`
`claims invalid by the stricter preponderance of the evidence standard applied at
`
`trial. § 316(e).
`
`Petitioner’s arguments about the state of the art of injecting methotrexate
`
`(“MTX”) subcutaneously to treat rheumatoid arthritis, and about the asserted
`
`references, obscure a critical and basic fact: no one used MTX at concentrations
`
`
`1 Section cites are to 35 U.S.C. or 37 C.F.R. as context indicates, and all
`
`emphasis/annotations/color added and internal quotations/citations omitted unless
`
`noted.
`
`1
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`above 25 mg/mL for this purpose before July 2006. See, e.g., Ex. 2018 ¶¶ 17, 25,
`
`26, 33, 42; Ex. 2092 ¶¶ 17; Ex. 1034 ¶ 123. At a minimum, concentrations of 50
`
`mg/mL were available but never used for this treatment and route of administration.
`
`See, e.g., Ex. 2018 ¶¶ 21, 52; Ex. 2092 ¶¶ 17, 35; Ex. 2093 ¶ 25. Indeed, even that
`
`50 mg/ml concentration was never used, without further dilution, for any treatment.
`
`See, e.g., Ex. 2093 ¶¶ 23-24. Despite ample incentive to develop the claimed
`
`treatment, and the absence of barriers to market entry, no one developed such a
`
`treatment before Medac applied for the ‘231 patent. Ex. 2032 ¶ 41.
`
`Neither Grint nor Wyeth teaches the specific medical application of
`
`challenged claims. Ex. 2018 ¶¶ 21, 25, 41-45, 52, 57-59, 62; Ex. 2092 ¶¶ 32, 35.
`
`At best they relate only to uses for other diseases, different routes of administration
`
`(such as intramuscular and intravenous), and disparate concentration ranges. See,
`
`e.g., Ex. 2018 ¶¶ 21-23, 27, 50-55; Ex. 2092 ¶¶ 31, 36-37. Petitioner improperly
`
`stretches Grint and Wyeth to reach the challenged claims, based on expert opinions
`
`having no factual support. See § 42.65(a) (“Expert testimony that does not disclose
`
`the underlying facts or data on which the opinion is based is entitled to little or no
`
`weight.”).
`
`Moreover, objective indicia of nonobviousness demonstrate that the
`
`challenged claims were nonobvious. Other companies (including Petitioner) have
`
`attempted to copy Medac’s products that embody the challenged claims and in so
`
`
`
`2
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`doing accelerate regulatory approval of their “copy” products. There has also been
`
`industry praise for the novel therapies of the challenged claims: subcutaneous
`
`MTX in the higher, claimed concentrations. Finally, despite ample incentives, no
`
`one else developed the methods of the challenged claims before the filing date of
`
`the ’231 Patent. Ex. 2032 ¶¶ 11-13.
`
`Indeed, what Petitioner has done is to start with the challenged claims and to
`
`try to piece the claimed method together using a retrospective, unsupported
`
`combination of bits and pieces from the documents on which it relies. The
`
`Supreme Court has specifically forbidden such approach. See Dennison Mfg. Co. v.
`
`Panduit Corp., 475 U.S. 809, 810 (1986). Not only does Petitioner rely on
`
`impermissible hindsight, it also ignores what the POSITA at the relevant time did
`
`when treating inflammatory autoimmune diseases with MTX and how they would
`
`have understood the cited documents. From the 1950s until Medac’s invention, no
`
`art taught or suggested (let alone practiced) subcutaneous injection of MTX
`
`solutions having a concentration of more than 30 mg/ml to treat inflammatory
`
`autoimmune diseases. See, e.g., Ex. 2018 ¶¶ 17, 21, 25, 26, 33, 42; Ex. 2092 ¶¶ 17,
`
`28; Ex. 1034 ¶ 123.
`
`Even taking the assertions of Petitioner and its experts at face value, the best
`
`that can be said is two pieces were in the art: (1) MTX solutions having a
`
`concentration of more than 30 mg/ml, and (2) MTX being used to treat
`
`
`
`3
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`inflammatory autoimmune diseases. Yet, in the more than 50 years since MTX was
`
`discovered and then used to treat psoriasis and rheumatoid arthritis, no one had
`
`treated those diseases subcutaneously with MTX having a concentration of more
`
`than 30 mg/ml. See, e.g., Ex. 2018 ¶ 21; Ex. 2092 ¶ 17; Ex. 1034 ¶ 123. And,
`
`Petitioner has not pointed to a single document that says to the contrary. Indeed,
`
`Dr. Miller does not say that he compounded MTX for such treatment, and Dr.
`
`Schiff explicitly said he had not administered such treatment prior to 2006. Ex.
`
`1033; Ex. 1034, ¶ 123. Dr. Massarotti and Dr. Zizic say the same. Ex. 2018, ¶ 17,
`
`21, 25, 26, 33, 42; Ex. 2092, ¶ 17, 28. What better evidence of invention? What
`
`better evidence that Petitioner has not met its preponderance of the evidence
`
`burden than these uncontroverted facts?
`
`Altogether, this evidence shows that the challenged claims are not invalid,
`
`and that Petitioner has failed to meet its preponderance burden to prove otherwise.
`
`II. The Parties and Experts
`A.
`Patent Owner and Its Experts
`Medac is a privately-held German pharmaceutical company with over 1,000
`
`employees worldwide. It has developed over sixty specialized therapeutics,
`
`including MTX for the treatment of inflammatory autoimmune diseases. Medac
`
`launched its first MTX product in the early 1980s. Today, it markets
`
`METOJECT® (RASUVOTM in the U.S.) under the ‘231 patent. Its U.S. subsidiary,
`
`
`
`4
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`Medac Pharma, launched RASUVOTM in the U.S. in late 2014.
`
`Medac’s experts are recognized experts in the field of the ‘231 patent and
`
`the economic issues underlying drug development.
`
`Dr. Elena Massarotti
`
`1.
`Dr. Elena Massarotti has been a practicing rheumatologist for over 25 years.
`
`During the relevant time (2002-2007), Dr. Massarotti was the Clinical Director of
`
`Rheumatology at Tufts Medical Center (Boston). Ex. 2018 ¶ 4. She routinely
`
`treated patients suffering from inflammatory autoimmune disease with MTX using
`
`oral, intramuscular, and subcutaneous administration. Id. ¶ 1.
`
`Dr. Sean Nicholson
`
`2.
`Dr. Sean Nicholson is a healthcare economist. For the last 20 years, he has
`
`been assessing, inter alia, how and why pharmaceutical companies develop drugs,
`
`taking into account market opportunities as well as barriers to development and
`
`market entry. Ex. 2032 ¶ 3.
`
`Dr. Thomas Zizic
`
`3.
`Dr. Thomas Zizic is a rheumatology physician who has treated arthritis since
`
`the 1970s and has published extensively on such treatments. Ex. 2092 ¶ 1. He is a
`
`Professor of Medicine at The Johns Hopkins University, a founding fellow of the
`
`American College of Rheumatology, and has treated thousands of patients with
`
`rheumatoid arthritis and used MTX extensively, subcutaneously, intramuscularly,
`
`
`
`5
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`and orally. Id.
`
`Dr. John Clark
`
`4.
`Dr. John Clark is the Director of Pharmacy Services at the University of
`
`Michigan Hospitals and Health Centers. Ex. 2093 ¶ 1. He previously held
`
`positions at The Johns Hopkins University, University of Wisconsin, and
`
`University of Toledo. Id. ¶ 3. He has prepared MTX for dozens of patients for the
`
`treatment of cancer and other diseases. Id. ¶ 1.
`
`Petitioner And Its Experts
`
`B.
`Koios has apparently never brought a drug to the market or licensed a third
`
`party to do so. Instead, Koios has threatened to copy Medac’s MTX products and
`
`to piggyback on Medac’s success to compete with it in the U.S. market. Ex. 2009.
`
`Petitioner’s experts are Dr. Michael Schiff and Dr. Donald Miller. Dr.
`
`Schiff is a rheumatologist, but as discussed below, despite opining that the
`
`challenged claims would have been obvious, his own actions say otherwise. He
`
`has never increased the concentration of MTX above 30 mg/ml when treating
`
`patients with inflammatory autoimmune diseases. Ex. 1034 ¶ 123. Rather, he has
`
`acknowledged that he used multiple injections at a lower concentration instead of
`
`increasing the MTX concentration for a single injection. Id. Dr. Miller is a
`
`pharmacist. Like Dr. Schiff, his actions are contrary to his opinions. He has never
`
`compounded MTX in the claimed concentrations. Ex. 1033 ¶¶ 10-11. Indeed,
`
`
`
`6
`
`

`

`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0009-651
`
`neither expert attests to having used or compounded the MTX concentrations of
`
`the challenged claims for the subcutaneous treatment of inflammatory autoimmune
`
`diseases.
`
`III. The ‘231 Patent and Prosecution History
`A. The ‘231 Patent
`The ‘231 patent, “Concentrated Methotrexate Solutions,” issued March 4,
`
`2014 and is assigned to Medac. Ex. 1001. The challenged claims are entitled to
`
`priority to German application (DE) 10 2006 033 837, filed July 21, 2006.2 See
`
`Petition at 2. The ‘231 patent has a single independent claim:
`
`1. A method for the treatment of inflammatory autoimmune diseases
`in a patient in need thereof, comprising subcutaneously administering
`to said patient a medicament comprising methotrexate
`in a
`
`
`2 A related European patent, EP 2046332, is currently involved