Paper No. 9
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`Boehringer Ingelheim International GmbH and
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Petitioner
`
`
`v.
`
`
`Genentech, Inc.
`Patent Owner
`___________________
`
`CASE IPR2015-00417
`Patent 7,976,838
`___________________
`
`
`
`
`GENENTECH’S PATENT OWNER PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`Mylan v. Genentech
`IPR2016-00710
`Merck Ex. 1125, Pg. 1
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................................ 1
`
`II. BACKGROUND ........................................................................................................... 4
`
`A. Prosecution History ................................................................................................. 4
`
`B. FDA Approval Of Rituximab To Treat Rheumatoid Arthritis ........................ 5
`
`III. CLAIM CONSTRUCTION ......................................................................................... 8
`
`A. The Preamble Phrase “a human patient who experiences an
`inadequate response to a TNFα-inhibitor” Is Limiting. .................................... 9
`
`1.
`
`“[A] human patient who experiences an inadequate response to
`a TNFα-inhibitor” Is Limiting Because It Provides The
`Antecedent Basis For “the patient” In The Body Of Each
`Claim. ................................................................................................................ 9
`
`2. The Specification Makes Clear That “a human patient who
`experiences an inadequate response to a TNFα-inhibitor” Is An
`Important Characteristic Of The Claimed Invention. ............................ 11
`
`3. Reliance On “a human patient who experiences an inadequate
`response to a TNFα-inhibitor” To Distinguish Prior Art
`During Prosecution Also Indicates That The Phrase is
`Limiting. ......................................................................................................... 13
`
`4.
`
`“[A] human patient who experiences an inadequate response to
`a TNFα-inhibitor” Is Someone Who Has Actually Experienced
`An Inadequate Response To A TNFα-inhibitor. ..................................... 14
`
`B. “[T]wo intravenous doses of 1000 mg” In Claim 2 Cannot Be
`Construed To Be The Same As “an amount that is effective to
`provide an ACR50 response at week 24, ACR70 response at week
`24, or no erosive progression at weeks 24 and beyond.” ................................ 15
`
`- i -
`
`Merck Ex. 1125, Pg. 2
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`Page
`
`C. The “wherein” Clauses Of Claims 10 And 12-14 Are Limiting. .................... 16
`
`1. The “wherein” Clauses Relate Back To And Clarify The
`“administering” Steps And The Methotrexate Limitations. ................... 17
`
`2. The “wherein” Clauses Do Not State Necessary Results Of
`Other Limitations In The Claims. .............................................................. 17
`
`3. Construing The “wherein” Clauses Of Claims 12-14 As
`Nonlimiting Would Create Absurd Outcomes. ....................................... 19
`
`4. Reliance During Prosecution On Limitations In The Disputed
`“wherein” Clauses To Distinguish References Further Indicates
`That Those Clauses Are Limiting. .............................................................. 20
`
`D. The Phrase “achieving a clinical response selected from the group
`consisting of ACR50 response at week 24, ACR70 response at week
`24, and no erosive progression at weeks 24 and beyond” Is Limiting. ......... 20
`
`1. The “achieving a clinical response” Phrase In The Preambles
`Of Claims 12-14 Is Limiting Because The Bodies of The
`Claims Depend On And Derive Antecedent Basis From The
`Phrase. ............................................................................................................. 20
`
`2. Reliance On The Claimed Responses To Distinguish
`References During Prosecution Further Indicates That The
`Same Phrase In The Preamble Of Claim 11 Is Limiting. ....................... 21
`
`IV. BOEHRINGER FAILS TO DEMONSTRATE ANY REASONABLE
`LIKELIHOOD OF PREVAILING ON ANTICIPATION. ............................. 22
`
`A. Boehringer Erroneously Reads Limitations Out Of The Claims To
`Make Its Anticipation Arguments. ...................................................................... 23
`
`B. Boehringer’s Fallback Position That The Alleged Prior Art
`Inherently Discloses The Limitations Sought To Be Read Out Of
`The Claims Also Fails As A Matter Of Law. .................................................... 23
`
`- ii -
`
`Merck Ex. 1125, Pg. 3
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`Page
`
`V. BOEHRINGER FAILS TO DEMONSTRATE ANY REASONABLE
`LIKELIHOOD OF PREVAILING ON OBVIOUSNESS. ............................... 26
`
`A. Boehringer Never Attempts To Explain How Any Reference Or
`Combination Of References Allegedly Renders Obvious Any Claim
`Of The Patented Invention. ................................................................................. 26
`
`1. Nowhere Does Boehringer Articulate Any Reason To Have
`Modified Or Combined Specific References. ........................................... 29
`
`2. Boehringer Fails To Establish That Any Of Its Modifications
`Or Combinations Were Obvious To Try. ................................................ 33
`
`3. Nowhere Does Boehringer Establish Any Reasonable
`Expectation Of Success In Practicing The Claimed Inventions. .......... 34
`
`4. Boehringer Fails To Address Any Individual Claims And
`Cherry-picks From The References It Cites, Ignoring Their
`Teachings As A Whole, Including Teachings Away. .............................. 36
`
`a) Boehringer Never Explains How Gaps Between Claim 1
`And The Relied-Upon References Allegedly Would Have
`Been Bridged By Modification Or Combination. ............................. 37
`
`(i) Edwards 2002 (Ex. 1003) Alone .................................................. 37
`
`(ii) Edwards 2002 (Ex. 1003) in view of De Vita 2001 (Ex.
`1006) ................................................................................................. 39
`
`(iii) Edwards 2002 (Ex. 1003) in view of Tuscano (Ex.
`1008) ................................................................................................. 41
`
`(iv) Genentech Press Release (Ex. 1004) alone and in view
`of De Vita 2001 (Ex. 1006) or Tuscano (Ex. 1008) .................. 44
`
`(v) Curd PCT Publication (Ex. 1005)................................................ 45
`
`(vi) Curd PCT Publication (Ex. 1005) in view of De Vita
`2001 (Ex. 1006) or Edwards 2001 (Ex. 1022) or
`Tuscano (Ex. 1008) or De Vita 2001 with Edwards
`2001. ................................................................................................. 47
`
`- iii -
`
`Merck Ex. 1125, Pg. 4
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`Page
`
`(vii) De Vita 2001 (Ex. 1006) In Combination with the
`Curd PCT Publication (Ex. 1005) alone and also with
`Edwards 2001 (Ex. 1022) or Tuscano (Ex. 1008). .................... 48
`
`b) Boehringer Likewise Never Explains How The Gaps
`Between Each Of Claims 2-14 And The Relied-Upon
`References Allegedly Would Have Been Bridged By
`Modification Or Combination With Other References. ................. 49
`
`(i) None of Boehringer’s References Teaches “No
`Erosive Progression,” As Required By Claims 10 and
`14. ..................................................................................................... 50
`
`(ii) Boehringer’s References Fail To Teach Achieving At
`Least An ACR50 Or ACR70 Response In TNFα-
`Inadequate Responders, As Required By Claims 2-7
`and 11-13. ........................................................................................ 52
`
`(iii) None Of Boehringer’s References Teaches
`Administering Methylprednisolone And Prednisone,
`As Required By Claim 6. ............................................................... 52
`
`B. Boehringer Fails To Rebut The Record Evidence Of Objective
`Indicia Of Non-Obviousness. ............................................................................. 53
`
`1. The Claimed Inventions Satisfied A Long-Felt But Unsolved
`Need For Treatment Of Rheumatoid Arthritis In Patients Who
`Did Not Respond To Anti-TNFα Therapy. ............................................. 54
`
`2. The Claimed Inventions Produced Unexpected Results. ....................... 57
`
`3. The Claimed Inventions Have Enjoyed Great Commercial
`Success ............................................................................................................ 58
`
`VI. CONCLUSION ............................................................................................................ 59
`
`
`
`- iv -
`
`Merck Ex. 1125, Pg. 5
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`
`Cases
`Allergan, Inc. v. Apotex, Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ................................................................ 24, 25, 26
`
`Amgen Inc. v. F. Hoffman-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) ........................................................................... 35
`
`Apple, Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) ........................................................................... 53
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ............................................................................. 24
`
`Bell Commc’ns Research. v. Vitalink Commc’ns.,
`55 F.3d 615 (Fed. Cir. 1995) ........................................................................ 11, 21
`
`Brinkman Corp. v. Coprecitec S.L.,
`IPR2013-00435, Paper 6 (Oct. 29, 2013) .......................................................... 10
`
`CAE Screenplates Inc. v. Heinrich Fiedler Gmbh & Co. Kg,
`224 F.3d 1308 (Fed. Cir. 2000) ........................................................................... 16
`
`Catalina Mktg. Int’l, Inc. v. Coolsavings.com,
`289 F.3d 801 (Fed. Cir. 2002) ...................................................................... 13, 20
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1341 (Fed. Cir. 2013) ........................................................................... 30
`
`Corning Glass Works v. Sumitomo Electric USA, Inc.,
`868 F.2d 1251 (Fed. Cir. 1989) ........................................................................... 12
`
`Eaton Corp. v. Rockwell Int’l Corp.,
`323 F.3d 1332 (Fed. Cir. 2003) .................................................................... 10, 21
`
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
`676 F. Supp. 2d 352 (D.N.J. 2009) ..................................................................... 25
`
`Eli Lilly & Co. v. Teva Pharms. USA, Inc.,
`No. IP 02-0512-C-B/S, 2004 WL 1724632 (S.D. Ind. July 29, 2004) .......... 25
`
`Ex Parte Behzad,
`Appeal 2011-007124, 2014 WL 1311619 (P.T.A.B. Mar. 28, 2014) ............. 19
`
`- v -
`
`Merck Ex. 1125, Pg. 6
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`
`Ex Parte Berzofsky
`Appeal No. 2010-011270, 2011 WL 891756 .................................................... 18
`
`Ex Parte Lutz,
`Appeal 2010-007127, 2013 WL 1309969 (P.T.A.B. Mar. 14, 2013) ............. 10
`
`Ex Parte May,
`Appeal No. 1999-0941, 1999 WL 33224337 (B.P.A.I. Jan. 1, 2009) ............ 25
`
`Ex Parte Peltz,
`Appeal 2012-011729, 2015 WL 430562 (P.T.A.B. Jan. 13, 2015) .......... 25, 26
`
`Funai Elec. Co. v. Daewoo Elecs. Corp.,
`616 F.3d 1357 (Fed. Cir. 2010) ........................................................................... 19
`
`Google, Inc. v. EveryMD.com LLC,
`IPR2014-00347, Paper 9 (May 22, 2014) .......................................................... 28
`
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) .................................................................... 17, 18
`
`Hoffman-La Roche Inc. v. Apotex, Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ........................................................................... 35
`
`In re Bond,
`910 F.2d 831 (Fed. Cir. 1990) ............................................................................... 9
`
`In re Skvorecz,
`580 F.3d 1262 (Fed. Cir. 2009) ........................................................................... 22
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ........................................................................... 36
`
`Integraph Hardware Techs. Co. v. Toshiba Corp.,
`508 F. Supp. 2d 752 (N.D. Cal. 2007) ............................................................... 18
`
`Lone Star Distrib., Inc. v. Thermolife Int’l, LLC,
`IPR2014-01201, Paper 12 (Feb. 2, 2015) .......................................................... 25
`
`Martek Biosciences Corp. v. Nutrinova, Inc.,
`579 F.3d 1363 (Fed. Cir. 2009) ........................................................................... 14
`
`Medichem, SA v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ........................................................................... 32
`
`- vi -
`
`Merck Ex. 1125, Pg. 7
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`
`Naughty Dog, Inc. v. McRO, Inc.,
`IPR2014-00197, Paper 11 (May 28, 2014) ........................................................ 28
`
`Norman Int’l, Inc., v. Hunter Douglas, Inc.,
`IPR2014-01173, Paper 7 (Feb. 10, 2015) .......................................................... 36
`
`NTP, Inc. v. Research In Motion, Ltd.,
`418 F.3d 1282 (Fed. Cir. 2005) ...................................................................... 9, 10
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .................................................................... 33, 34
`
`Phigenix, Inc. v. Genentech, Inc.,
`IPR2014-00842, Paper 10 (Dec. 9, 2014).......................................................... 10
`
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) ........................................................................... 21
`
`Poly-Am., LP v. GSI Lining Tech., Inc.,
`383 F.3d 1303 (Fed. Cir. 2004) ........................................................................... 12
`
`Power Integrations, Inc. v. Fairchild Semiconductor Int’l, Inc.,
`711 F.3d 1348 (Fed. Cir. 2013) ........................................................................... 54
`
`Rotable Techs., LLC v. Motorola Mobility LLC,
`567 F. App’x 941 (Fed. Cir. 2014) ............................................................... 12, 13
`
`Rowe v. Dror,
`112 F.3d 473 (Fed. Cir. 1997) ............................................................................. 21
`
`Smith & Nephew, Inc. v. Bonutti Skeletal Innovations, LLC,
`IPR2013-00605, Paper 9 (Feb. 26, 2014) ............................................. 13, 21, 22
`
`Tasco, Inc. v. Pagnani,
`IPR2013-00103, Paper 6 (May 23, 2013) ................................................... 27, 28
`
`Tempo Lighting, Inc. v. Tivoli, LLC,
`742 F.3d 973 (Fed. Cir. 2014) ............................................................................. 20
`
`Texas Instruments v. ITC,
`988 F.2d 1165 (Fed. Cir. 1993) .................................................................... 17, 18
`
`TRW Auto. U.S. LLC, v. Magna Elecs., Inc.,
`IPR2014-00293, Paper 21 (Aug. 28, 2014) ....................................................... 28
`
`- vii -
`
`Merck Ex. 1125, Pg. 8
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .................................................................... 29, 30
`Statutes
`
`35 U.S.C. § 102 .................................................................................................................. 25
`
`35 U.S.C. § 103 .................................................................................................................. 25
`
`35 U.S.C. § 312 .................................................................................................................. 27
`
`37 C.F.R. § 42.104 ............................................................................................................ 27
`
`37 C.F.R. § 42.22 .............................................................................................................. 27
`
`MPEP § 2143(I)(E) .......................................................................................................... 33
`
`
`
`- viii -
`
`Merck Ex. 1125, Pg. 9
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`
`I.
`
`INTRODUCTION
`
`Rheumatoid arthritis (“RA”) is a debilitating autoimmune disorder with no
`
`known cure and a dreadful prognosis. RA patients suffer a chronic course of disease
`
`that, even with therapy, often results in painful joint destruction, deformity, disability,
`
`and even premature death. Ex. 1001 at 4:3-7.
`
`RA therapy has been “traditionally characterized by escalation.” Ex. 1028 at
`
`309. “The first step is non-steroidal anti-inflammatory drugs (NSAIDs), and then if
`
`necessary a sequence of progressively toxic second-line drugs (disease-modifying
`
`antirheumatic drugs [DMARDs]) is introduced.” Id.
`
`In the 1990s, targeted therapies called TNFα-inhibitors kindled new hope for
`
`RA patients. But for many patients, that hope proved fleeting. According to
`
`Petitioner, physicians quickly recognized that “[a]pproximately 40% of patients do not
`
`respond to TNFα-inhibitors.” Pet. 36. Because “TNF-inhibitors were generally given
`
`after the patient had failed at least 2-3 conventional RA therapies, . . . patients who
`
`were eligible for treatment with TNF-inhibitors [in the first place] had already
`
`demonstrated that their disease was particularly hard to treat and drug-refractory.” Ex.
`
`1016 at ¶ 6. Patients needed an effective alternative treatment.
`
`For years, RA patients who responded inadequately to TNFα-inhibitors had no
`
`other meaningful choices. Genentech, Inc. sought to change that—and succeeded.
`
`Genentech believed that rituximab (Rituxan®), a treatment initially developed and
`
`FDA approved for treating certain types of blood cancers, could be taken at a
`
`- 1 -
`
`Merck Ex. 1125, Pg. 10
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`different dose and dosing schedule to treat RA patients. And Genentech was correct.
`
`
`
`The results of clinical testing were remarkable. Nearly one third of RA patients
`
`demonstrated clinical improvement in a matter of months. For certain patients,
`
`rituximab actually halted erosive progression of RA. The FDA approved rituximab for
`
`the treatment of patients with moderate to severe RA who had experienced an
`
`inadequate response to a TNFα-inhibitor.
`
`Genentech ultimately obtained U.S. Patent 7,976,838 (the ’838 patent) for this
`
`novel treatment. Boehringer Ingelheim International GmbH and Boehringer
`
`Ingelheim Pharmaceuticals, Inc. (together “Boehringer”) now request inter partes
`
`review of the patent. Because they have failed to demonstrate a reasonable likelihood
`
`of prevailing with respect to any claim, their request should be denied.
`
`Every reference Boehringer relies on was fully considered by the Patent Office
`
`during examination, except for an abstract that the Office previously considered in the
`
`form of a full-length article. The Patent Office determined that none of these
`
`references renders the claims unpatentable. Boehringer has failed to identify any
`
`teachings in the references that support a contrary conclusion.
`
`Because it cannot carry its burden, Boehringer instead attempts—in the guise
`
`of claim construction—to read out of the claims various limitations that it finds
`
`problematic. This includes one of the defining characteristics of the claimed methods:
`
`treating “a human patient who experiences an inadequate response to a TNFα-
`
`inhibitor.” Boehringer argues that this description of the patient should be ignored
`
`- 2 -
`
`Merck Ex. 1125, Pg. 11
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`because it appears in the preambles of claims. Yet the patent specification makes clear
`
`
`
`that this targeted patient is a key characteristic of the inventions. Indeed, the
`
`description of the targeted patient in each preamble provides the antecedent basis for
`
`references to “the patient” in the bodies of the claims. Boehringer’s attempt to read
`
`this key limitation (and others) out of the claims is contrary to law.
`
`Although Boehringer asserts that the claims are anticipated, it does not even try
`
`to show that all of the claim elements and their limitations are expressly disclosed in a
`
`single prior art reference. Rather, Boehringer’s anticipation position depends on its
`
`effort to read limitations out of the claims. Because that effort fails, so too does
`
`Boehringer’s anticipation argument. Boehringer’s fallback position—that the alleged
`
`prior art inherently discloses these limitations—also fails. There is no evidence that
`
`the limitations were necessarily present in prior art. Boehringer tries to rely on
`
`probabilities to establish inherent anticipation, even though the Federal Circuit has
`
`repeatedly held that probabilities are never sufficient to establish an inherent
`
`disclosure. Limitations must be necessarily present, not probably present.
`
`As for its obviousness challenge, Boehringer never even tries to explain how
`
`any reference or combination of references allegedly renders obvious any claim of the
`
`patented invention. Boehringer never identifies differences between any claim and any
`
`reference, much less explains how the differences allegedly would have been bridged
`
`by modification or combination with other references. Nor does Boehringer articulate
`
`any reason for a skilled artisan to have modified or combined specific references, any
`
`- 3 -
`
`Merck Ex. 1125, Pg. 12
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`basis for concluding that its modifications or combinations would have been obvious
`
`
`
`to try, or any reasonable expectation of success in practicing the claimed inventions.
`
`Instead, Boehringer simply addresses claim limitations piecemeal, lists references and
`
`combinations in a table without explanation, and improperly tries to lay the burden on
`
`the Board to divine some theory of obviousness. The Board repeatedly has declined
`
`to institute trial under such circumstances.
`
`Boehringer also fails to rebut the objective indicia of non-obviousness,
`
`including evidence of record that the claimed inventions satisfied a long-felt but
`
`unsolved need for treatment of RA in patients who did not respond to anti-TNFα
`
`therapy. And Boehringer fails to rebut the evidence of unexpected results, including
`
`no erosive progression of RA in more than half of such patients.
`
`Boehringer’s petition for inter partes review falls far short of demonstrating a
`
`reasonable likelihood of prevailing with respect to any claim of the ’838 patent. The
`
`Board should therefore decline to institute trial.
`
`II. BACKGROUND
`A. Prosecution History
`The prosecution of the ’838 patent began with a provisional application filed
`
`on April 9, 2003. Ex. 1001. Boehringer acknowledges that the claims of ’838 patent
`
`are entitled to at least that priority date. Pet. 5-6.
`
`Every reference that Boehringer identifies in its “Prior Art and Proposed
`
`Combinations” (Pet. 55-57) was cited during prosecution of the ’838 patent and
`
`- 4 -
`
`Merck Ex. 1125, Pg. 13
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`considered by the Patent Office, with one exception: Instead of the clinical study
`
`
`
`abstract that Boehringer refers to as “De Vita 2001” (Ex. 1006), a full-length article
`
`reporting on the very same study was cited and considered. Ex. 1001 (identifying in
`
`the “References Cited” De Vita et al., “Efficacy of Selective B Cell Blockade in the
`
`Treatment of Rheumatoid Arthritis,” Arthritis and Rheumatism 46(8): 2029-2033
`
`(Aug. 2002)).
`
`The Office rejected claims based on several of the cited references, including
`
`the full-length De Vita article and a clinical protocol for the study reported in the
`
`“Tuscano” abstract (Ex. 1008). Genentech distinguished these references and also
`
`presented compelling evidence of long-felt unmet need and unexpected results. E.g.,
`
`Ex. 1036 at 11-12. The Office agreed that the cited references neither anticipated nor
`
`rendered obvious the claimed inventions. Ex. 2001 at 2.1
`
`B. FDA Approval Of Rituximab To Treat Rheumatoid Arthritis
`Rituximab is an antibody that binds to a cell-surface antigen called CD20.
`
`Ex. 1001 at 2:32-34. Genentech first obtained FDA approval for rituximab in 1997
`
`
`1 Boehringer asserts that “the European Patent Office revoked the foreign
`
`counterpart of the ’838 patent because it lacked novelty,” Pet. 10 n.4, but fails to
`
`mention that the Technical Board of Appeal later overturned the EPO’s decision on
`
`novelty, finding that the subject matter was “novel and fulfils the requirements of
`
`Article 54 EPC.” Ex. 1018 at 27.
`
`- 5 -
`
`Merck Ex. 1125, Pg. 14
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`for treatment of relapsed or refractory, low-grade or follicular non-Hodgkin’s
`
`
`
`lymphomas. Ex. 1012. Genentech
`
`later worked with collaborators to study
`
`administration of two 1000-mg doses of rituximab—a different dosing regimen than
`
`that approved for treatment of the non-Hodgkin’s lymphomas—in patients with
`
`active moderate to severe RA who had a prior inadequate response to at least one
`
`TNF inhibitor. Genentech’s pivotal Phase III clinical trial was called “REFLEX.”
`
`To assess patient responses, the REFLEX investigators used a scale developed
`
`by the American College of Rheumatology to assign an “ACR” score to measure
`
`improvements. Ex. 2002 at 733-34. The score is expressed as a percentage, which
`
`refers to [a] the percent fewer tender joints, [b] the percent fewer swollen joints, and
`
`[c] the percent improvement in at least three of the following five additional areas:
`
`(i) the patient’s overall (global) assessment of his or her own RA, (ii) the physician’s
`
`global assessment of the patient’s RA; (iii) the patient’s assessment of his or her own
`
`pain; (iv) the patient’s assessment of his or her own physical functioning; and (v) the
`
`results of an erythrocyte sedimentation rate test or a C-reactive protein blood test
`
`(both of which measure inflammation). Id. To score ACR70, for example, a patient
`
`must have at least 70% fewer tender joints, at least 70% fewer swollen joints, and at
`
`least 70% improvement in at least three of areas (i)-(v) above.
`
`The limitations of the ACR scoring system are well known—particularly in
`
`open-label studies, where both the doctor and the patient know that active drug is
`
`being administered to the patient. “Of the 7 outcome measures [for the ACR scale],
`
`- 6 -
`
`Merck Ex. 1125, Pg. 15
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`3 are at least to some extent subjective on the part of the physician (tender joint
`
`
`
`count, swollen joint count, and Physician’s global assessment of disease activity), and
`
`3 are subjective on the part of the patient (patient’s assessment of pain, patient’s
`
`global assessment of disease activity, and patient’s assessment of physical function).”
`
`Ex. 2003 at ¶ 9. Because of this subjectivity, “observer bias inevitably occurs due to
`
`the desire by both the patient and physician to see improvement in the disease
`
`outcomes due to treatment.” Id.
`
`Double-blind studies, where neither the doctors nor the patients know who is
`
`receiving the studied therapy, are preferred because they eliminate observer bias based
`
`on knowledge of the treatment. But even double-blind studies remain vulnerable to
`
`the “placebo effect”—when a patient who is administered an inactive substance
`
`nevertheless perceives, or actually experiences, some level of improvement. Placebo
`
`effects are especially problematic in RA studies because, as one leading RA expert
`
`explains: “it has been clearly demonstrated that ACR20 responses are seen in a
`
`sizeable proportion of patients given ‘placebo’ (inactive substance) treatment in the
`
`setting of a controlled trial (where other patients are receiving an active drug).” Ex.
`
`1016 at ¶ 17. “Among such ‘placebo’-treated patients, 20-30% may show an ACR20
`
`response, which is believed to be due to the placebo effect or to the naturally
`
`occurring fluctuations of the disease.” Id.; see also Ex. 2004 at 1935 (showing in Fig. 2
`
`that about 20% of placebo patients exhibited an ACR20 response); Ex. 2005 at 2546
`
`(showing in Fig. 2 that about 30% of placebo patients scored at ACR20 or higher
`
`- 7 -
`
`Merck Ex. 1125, Pg. 16
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`starting at month 3); Ex. 2006 at 1062 (reporting in the Abstract that 22% of placebo
`
`
`
`patients achieved ACR20 scores and 8% achieved ACR50 scores).
`
`To reduce observer bias and distinguish placebo effects, REFLEX was
`
`conducted as a double-blind, placebo-controlled study. The results of the study
`
`showed marked improvement in TNFα inadequate responders who received two 1000
`
`mg doses of rituximab plus methotrexate. Indeed, more than half of such patients
`
`achieved ACR20 scores (versus 18% for placebo plus methotrexate), 27% achieved
`
`ACR50 scores (versus 5% for placebo plus methotrexate), and 12% achieved ACR70
`
`scores (versus 1% for placebo plus methotrexate) at 24 weeks. Ex. 2007 at 2793.
`
`Based on these remarkable results in this particularly hard-to-treat patient population,
`
`the FDA approved rituximab in combination with methotrexate for treatment of
`
`“patients with moderately- to severely- active rheumatoid arthritis who have had an
`
`inadequate response to one or more TNF antagonist therapies.” Ex. 2011 at 18.
`
`Importantly, an extension to the REFLEX study also showed that rituximab
`
`prevented erosive progression in 60% of patients evaluated—even after two years;
`
`that 87% of patients who had no erosive progression in the first year also had no
`
`erosive progression in the second year; and that patients treated with a different dose
`
`of rituximab did not achieve the same outcome. Ex. 2008 at 27-28.
`
`III. CLAIM CONSTRUCTION
`The Board gives a patent claim its “broadest reasonable interpretation
`
`consistent with the specification.” In re Bond, 910 F.2d 831, 833 (Fed. Cir. 1990).
`
`- 8 -
`
`Merck Ex. 1125, Pg. 17
`
`

`

`Case IPR2015-00417 (Patent 7,976,838)
`Patent Owner Preliminary Response
`Boehringer’s claim construction positions are unreasonable because, among other
`
`
`
`things, they expressly read out nearly half the words—or more—of each claim. In
`
`fact, Boehringer invites the Board to eviscerate entire claims through what it calls
`
`“construction.” Indeed, under its proposals, multiple dependent claims would be
`
`reduced to nothing more than: “The method of claim [#].”
`
`A. The Preamble Phrase “a human patient who experiences an
`inadequate response to a TNFα-inhibitor” Is Limiting.
`
`A preamble is limiting if it “recites essential structure or steps, or if it is
`
`necessary to give life, meaning, and vitality to the claim.” NTP, Inc. v. Research In
`
`Motion, Ltd., 418 F.3d 1282, 1305 (Fed. Cir. 2005). The preamble phrase, “a human
`
`patient who experiences an inadequate response to a TNFα-inhibitor,” does both. The
`
`target patient is the object of the claimed steps and provides the antecedent basis for
`
`references to “the patient” in the body of each claim. Moreover, the specification
`
`makes clear that this target patient is a critical characteristic of the claimed inventions.
`
`And Genentech relied on the description of the target patient to distinguish prior art
`
`during prosecution. The description of the target patient in the preambles is limiting.
`
`1. “[A] human patient who experiences an inadequate response to a
`TNFα-inhibitor” Is Limiting Because It Provides The Antecedent
`Basis For “the patient” In The Body Of Each Claim.
`
`Language in a claim preamble is limiting “[w]hen limitations in the body of the
`
`claim rely upon and derive antecedent basis from the preamble.” Eaton Corp. v.
`
`Rockwell Int’l Corp., 323 F.3d 1332, 1339 (Fed. Cir. 2003); NTP, 418 F.3d at 1306
`
`- 9 -
`
`Merck Ex. 1125, Pg. 18
`
`

`

`Case IPR2015-00