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
`
`___________________________________
`
`Case No. IPR2016-00649
`Patent Number 8,664,231
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`Page 1 of 79
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`KOIOS Exhibit 1009
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`

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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
`110670-0010-651
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`Introduction ...................................................................................................... 1
`A.
`The PO And Its Experts ........................................................................ 1 
`B.
`The Petitioner And Its Experts .............................................................. 2 
`C.
`The Board Should Exercise Its Discretion And Not Institute
`Trial ....................................................................................................... 3 
`The Petition And PO’s Preliminary Response ...................................... 4 
`D.
`The Petition Is Defective Because It Fails To Name All Real
`Parties-In-Interest .......................................................................................... 11 
`Petitioner’s Experts Are Not Credible And Their Opinions Lack
`Foundation: The Board Should Afford Their Opinions No Weight ............. 14 
`A.
`Dr. Gershwin’s Opinions Should Be Accorded No Weight ............... 15 
`B. Mr. Gammon’s Opinions Should Be Accorded No Weight ............... 16 
`Dr. Gershwin’s And Mr. Gammon’s Assertion About FDA And
`C.
`Mexate Misses The Point: It Is What The Skilled Artisan
`Would Understand From Mexate, Not Its FDA Approval .................. 18 
`IV. Authentication: Petitioner Has Ignored Its Threshold Duty To Qualify
`The Non-Patent Documents On Which It Relies As Prior Art, Printed
`Publications .................................................................................................... 19 
`Overview Of ‘231 .......................................................................................... 20 
`V.
`VI. MTX And The Treatment Of Inflammatory Autoimmune Diseases
`With MTX ..................................................................................................... 20 
`VII. The Disclosure Of Claimed Method Of ‘231 ................................................ 24 
`VIII. Claim Construction ........................................................................................ 26 
`IX. Anticipation (Ground 1) – A Failure of Proof: Petitioner Has Not Met
`Its Reasonable Likelihood Burden Of Establishing That Grint
`Anticipates Claims 1, 2, 4, 5, 6, 11, 12, 13, 17, and 22 ................................. 27 
`Petitioner Failed To Demonstrate That Grint Discloses The
`A.
`Features Of Claims 1, 2, 4, 5, 6, 11, 12, 13, 17, And 20 And
`Their Arrangement Identically As In Those Claims ........................... 29 
`Petitioner Failed To Demonstrate That Subcutaneous
`Administration of Above 30mg/ml MTX Was Conventional At
`The Relevant Date ............................................................................... 32 
`
`B.
`
`- i -
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`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0010-651
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`X.
`
`C.
`
`B.
`
`C.
`
`Petitioner Failed To Demonstrate That There Is No Reasonable
`Difference In How The Claimed Invention Operates Over
`Grint’s Concentration Range .............................................................. 34 
`Obviousness (Grounds 2-5)—Failures of Proof: Petitioner Has Not
`Met Its Reasonable Likelihood Burden Of Establishing That The
`Challenged Claims Would Have Been Obvious In July 2006 ...................... 36 
`A.
`Obviousness (Ground 2)—A Failure of Proof: Petitioner Has
`Not Met Its Burden Of Establishing A Reasonable Likelihood
`of Prevailing on Its Argument That Grint Renders Claims 7-10,
`14-16, And 19-21 Obvious In View Of Insulin Admin ....................... 39 
`Obviousness (Ground 3)—A Failure of Proof: Petitioner Has
`Not Met Its Burden Of Establishing A Reasonable Likelihood
`That Grint Renders Claim 18 Obvious In View Of Alsufyani ............ 40 
`Obviousness (Ground 4)—A Failure of Proof: Petitioner Has
`Not Met Its Burden Of Establishing A Reasonable Likelihood
`That Mexate Or Hospira Renders Claims 1-5, 11, 12, 13, 17,
`And 22 Obvious In View Of Brooks ................................................... 41 
`(a)
`Petitioner Failed To Address The Correlation
`Between Dose And Vial Selection ................................. 45 
`Petitioner Failed To Establish Why The Skilled
`Artisan Would Make A Wasteful Choice ....................... 47 
`Petitioner Failed To Address The Full Range Of
`Concentrations Disclosed By Mexate Or Why The
`Skilled Artisan Would Be Motivated To Use High
`Concentration MTX For Subcutaneous Or
`Intramuscular Injection Based On The Disclosure
`Of Mexate ....................................................................... 49 
`Petitioner Failed To Establish That The Skilled
`Artisan Would Use Hospira For The Treatment Of
`Psoriasis In the Method of The Challenged Claims ....... 52 
`The Petitioner Failed To Establish Why The
`Skilled Artisan Would Make A Wasteful Choice .......... 55 
`The Petitioner Failed To Address Why The Skilled
`Artisan Would Be Motivated To Use High
`Concentration Methotrexate To Treat Psoriasis
`Based On The Disclosure Of Hospira ............................ 57 
`
`(b)
`
`(c)
`
`(a)
`
`(b)
`
`(c)
`
`- ii -
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
`110670-0010-651
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`D.
`
`Obviousness (Ground 5)—A Failure of Proof: Petitioner Has
`Failed To Meet Its Burden Of Establishing A Reasonable
`Likelihood That Mexate Or Hospira Renders Claims 7-10, 14-
`16, And 19-21 Obvious In View Of Brooks And Insulin Admin ........ 60 
`XI. Obviousness An Incomplete Analysis: Secondary Considerations ............... 61 
`XII. Conclusion ..................................................................................................... 62 
`
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`
`
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`
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`Attorney Docket No.
`110670-0010-651
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`
`TABLE OF AUTHORITIES
`
`
`CASES
`Atofina v. Great Lakes Chemical Corp.,
`441 F. 3d 991 (Fed. Cir. 2006) ........................................................................... 34
`
`Page(s)
`
`Clearvalue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 34
`
`Dennison Mfg. Co. v. Panduit Corp.,
`475 U.S. 809 (1986) .....................................................................................passim
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 61
`
`In re Arkley,
`455 F.2d 586 (CCPA 1972) ................................................................................ 28
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 52
`
`In re Suitco Surface, Inc.,
`603 F.3d 1255 (Fed. Cir. 2010) .......................................................................... 26
`
`Ineos USA LLC v. Berry Plastics Corp,
`783 F.3d 865 (Fed. Cir. 2015) ............................................................................ 34
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 43
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 61
`
`Net MoneyIN, Inc. v. Verisign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .................................................................... 29, 32
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 26
`
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`KOIOS Exhibit 1009
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`
`
`
`Attorney Docket No.
`110670-0010-651
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`
`Square, Inc. v. Unwired Planet, LLC,
`CBM2014-00156, Paper 11 at 17-20 (Dec. 24, 2014)........................................ 20
`
`Synopsis Inc. v. Mentor Graphics Corp.,
`IPR2012-00041, Pap. 16 at 12-13 (Feb. 22, 2013) ............................................. 29
`
`Taylor v. Sturgell,
`553 U.S. 880 (2008). ........................................................................................... 12
`
`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 61
`
`STATUTES
`
`21 U.S.C. § 355(j)((4)(G) ........................................................................................ 18
`
`35 U.S.C. §312(a) .................................................................................................... 14
`
`35 U.S.C. §312(a)(2) ................................................................................................ 11
`
`35 U.S.C. §314 ..................................................................................................... 5, 11
`
`35 U.S.C. § 315(e) ............................................................................................. 12, 14
`
`35 U.S.C.§ 325(d) ...................................................................................................... 3
`
`OTHER AUTHORITIES
`
`21 C.F.R. § 314.127(a)(7) ........................................................................................ 18
`
`37 C.F.R. § 42.8(b)(1) .............................................................................................. 14
`
`37 C.F.R. § 42.24 ....................................................................................................... 1
`
`37 C.F.R. §42.106 .................................................................................................... 12
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.107 and .............................................................................................. 2
`
`37 C.F.R. § 42.108(c) ................................................................................................. 5
`
`77 Fed. Reg. 48,759 (Aug. 14, 2012) ................................................................ 12, 13
`
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`Page 6 of 79
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`KOIOS Exhibit 1009
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`
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`Attorney Docket No.
`110670-0010-651
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`Actavis v. Research Corp. Techs.,
`No. IPR2014-01126, Pap. 21 at 10-13 (Jan. 9, 2015) ......................................... 20
`
`Cardiocom, LLC v. Robert Bosch Healthcare Systems, Inc.,
`IPR2013-00439, Pap. 26 at 15-16 (January 16, 2014) ....................................... 52
`
`Cisco Sys. v. Constellation Techs.,
`No. IPR2014-01085, Pap. 11 at 7–9 (Jan. 9, 2015) ............................................ 19
`
`Kinetic Techs., Inc. v. Skyworks Solutions, Inc.,
`IPR2014-00529, Pap. 8 at 15-16 (Sept. 23, 2014) .............................................. 52
`
`Lupin Ltd. v. Vertex Pharmaceuticals Inc.,
`IPR2015-00405, Pap. 13 at 8 (Jul. 9, 2015)........................................................ 62
`
`Merial Ltd. v. Virbac,
`IPR2014-01279, Pap. 13 at 26-27 (P.T.A.B. Jan. 22, 2015) .............................. 62
`
`Zoll Lifecor Corp. v. Philips Electronics North America. et al.,
`IPR2013-00606, Pap. 13, p. 12 (March 20, 2014) ........................................ 11, 14
`
`
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`EXHIBITS
`
`Attorney Docket No.
`110670-0010-651
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`
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`2001
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`2002
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`2003
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`2004
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`2006
`2007
`2008
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`2012
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`2013
`2014
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`2015
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`January 8, 2016 Letter from Jason Greer to Terri Shoemaker re
`Rasuvo™ and Orange Book-Listed U.S. Patent No. 8,664,231
`WA Secretary of State Registration Detail for Frontier Therapeutics,
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`WA Secretary of State Registration Detail for Jason Paul Greer
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`State of Washington Business Licensing Service entry for Jason Paul
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`2016
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`Expert Declaration of Dr. Sean Nicholson
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`KOIOS Exhibit 1009
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`Attorney Docket No.
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`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
`
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`KOIOS Exhibit 1009
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`

`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`
`2071
`
`2072
`
`2073
`
`2074
`
`2075
`
`2076
`
`2077
`
`2078
`
`"FDA Summary Review: Otrexup™," Drugs@FDA, Oct. 15,
`2013,
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204824Orig1s
`000Admincorres.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/2014/204824s003l
`bl.pdf
`
`“Highlights of Prescribing Information: RASUVO™,”
`Drugs@FDA, July 2014,
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205776s00
`0lbl.pdf
`“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+into+OTREXUP+PDU
`FA%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
`
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`KOIOS Exhibit 1009
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`

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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`2079
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`2080
`
`2081
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`2082
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`2083
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`2084
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`2085
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`2086
`2087
`2088
`2089
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`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`“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/meth
`otrexate.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
`FDA Orange Book Data File Products.txt
`FDA Orange Book Data File Exclusivity.txt
`Compilation of Drug Labels
`
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`KOIOS Exhibit 1009
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`

`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0010-651
`
`Pursuant to 37 C.F.R. § 42.107, Patent Owner medac Gesellschaft für
`
`
`
`
`Klinische Spezialpräparate mbH (hereinafter “Medac” or “PO”) submits this
`
`Preliminary Response to the above-captioned Petition for Inter Partes Review
`
`(“IPR”) of U.S. Patent 8,664,231 (“’231”) (“Pet.,” Paper 1).
`
`I.
`
`Introduction
`A. The PO And Its Experts
`PO is a privately-held German pharmaceutical company with over 1,000
`
`employees worldwide. It has developed over sixty specialized therapeutics,
`
`including methotrexate (“MTX”) for the treatment of inflammatory autoimmune
`
`diseases. PO launched its first MTX product in the early 1980s. Today, it markets
`
`METOJECT® (RASUVO® in the US) under ‘231. Its US subsidiary, Medac
`
`Pharma, launched RASUVO® in the US in late 2014.
`
`PO’s experts are recognized experts in the field of ‘231 and the economic
`
`issues that underly the development of drugs.
`
`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. Ex.2018 ¶1.
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`IPR2016-00649
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`
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`Attorney Docket No.
`110670-0010-651
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`
`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.
`
`The Petitioner And Its Experts
`
`B.
`The Petitioner is a reverse patent troll looking for a payoff. It first
`
`threatened to file an IPR. Ex.2001 at 1-2. When that did not result in the payoff
`
`for which it hoped, it filed this IPR. It is almost an identical copy of the IPR that
`
`Antares filed in 2014 (IPR2014-01091) (“Antares IPR”). In that IPR the Board
`
`instituted trial on some grounds (Ex.1033), at a time when PO was not permitted to
`
`file testimony in its Preliminary Response. PO has now provided what the Board
`
`on the previous record found missing. Id. 10, 20-12. The Antares IPR settled
`
`before PO’s §41.120 Response and supporting testimony was filed.
`
`As described in more detail below (II, infra, pp. 11-14), Petitioner is a
`
`limited liability company established about two months before it filed this IPR. Its
`
`place of business is the residence of a Mr. Jason Greer (“Greer”) in Edmonds,
`
`Washington. The LLC appears not to be the only real party in interest. Further,
`
`neither Greer nor any of his companies has apparently ever brought a drug to the
`
`market or licensed a third party to do so.
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`IPR2016-00649
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`
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`Attorney Docket No.
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`
`Petitioner’s experts are anything but in the technical field of ‘231.
`
`Dr. Gershwin
`
`1.
`Dr. Gershwin has conducted no primary research on the use of MTX in the
`
`treatment of inflammatory autoimmune diseases. The only articles on which he is
`
`listed as an author in that field are review articles. Ex.2008. To the extent that Dr.
`
`Gershwin has treated inflammatory autoimmune diseases with MTX, his
`
`declaration is silent on the concentrations he used. Ex.1012 ¶20 Finally, Dr.
`
`Gershwin’s declaration is virtually identical to Dr. Weinblatt’s declaration from the
`
`Antares IPR (Ex.2006). Yet, Dr. Gershwin does not even include Dr. Weinblatt’s
`
`declaration among the documents that he reviewed. Ex.1012 ¶23.
`
`2. Mr. Gammon
`Mr. Gammon is a drug compounder. Ex.1013 ¶6. He has never treated a
`
`patient, much less treated an inflammatory autoimmune disease with MTX. While
`
`he says that he has compounded MTX, he does not say to what concentration or for
`
`what indication or mode of administration. Id. He filed substantially the same
`
`declaration that he filed in the prior Antares IPR.
`
`C. The Board Should Exercise Its Discretion And Not Institute Trial
`Under the facts of this IPR, the Board should exercise its discretion and not
`
`institute trial. 35 U.S.C.§ 325(d).
`
`Antares and PO settled the previous IPR before PO’s Response was filed.
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`IPR2016-00649
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
`110670-0010-651
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`Petitioner is trying to take advantage of that settlement by filing an IPR and expert
`
`
`
`
`declarations that are substantially the same, in the context of the grounds on which
`
`the Board instituted trial, as those that Antares filed. The Board should not
`
`countenance this behavior by a reverse patent troll, who is looking for no more
`
`than a quick payoff. Any other result would subject PO, and others similarly
`
`situated, to copycat IPRs, all in the name of “give me some money to go away.”
`
`That is neither fair nor just. It would also not foster the purpose of IPRs. Most
`
`importantly, it would make “settlement” after institution of trial illusory. Such
`
`settlement would just be the road map for a money-making scheme of a copycat
`
`reverse patent troll.
`
`D. The Petition And PO’s Preliminary Response
`On its face, the Petitioner fails to provide the Board with the basic evidence
`
`required to institute trial. If the Board nonetheless institutes trial, PO will address
`
`in detail in its §42.120 Response the numerous substantive errors and shortcomings
`
`that underlie each of Petitioner’s arguments and the purported evidence on which it
`
`relies.
`
`In this paper, PO addresses only the meaning of certain of the challenged
`
`claim terms and the single relevant issue: Petitioner’s failure of proof (a reasonable
`
`likelihood that at least one of the challenged claims is unpatentable). Indeed,
`
`Petitioner has failed to