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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
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`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`SANDOZ INC.,
`Petitioner
`
`v .
`
`PHARMACYCLICS LLC,
`Patent Owner.
`
`U.S. Patent No. 9,795,604 to Byrd et al.
`Issue Date: October 24, 2017
`Title: Methods of Treating and Preventing Graft Versus Host Disease
`
`
`
`Inter Partes Review No.: IPR2019-00865
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,795,604
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................... 2
`
`A.
`
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1). ........................... 2
`
`B.
`
`C.
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2). .................................... 2
`
`Lead and Back-Up Counsel and Service Under 37 C.F.R. §§
`42.8(b)(3) and 42.8(b)(4). ..................................................................... 3
`
`III.
`
`PAYMENT OF FEES UNDER 37 C.F.R. § 42.103 ....................................... 3
`
`IV. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ............................ 4
`
`V.
`
`BACKGROUND TECHNOLOGY AND THE ’604 PATENT ..................... 4
`
`A.
`
`Background Technology. ...................................................................... 4
`
`1.
`
`2.
`
`Ibrutinib. ...................................................................................... 4
`
`Graft Versus Host Disease. ......................................................... 6
`
`a.
`b.
`
`Two Types of GVHD: Acute and Chronic. ...................... 7
`Chronic GVHD ................................................................. 9
`
`B.
`
`The ’604 Patent ...................................................................................10
`
`1.
`
`2.
`
`3.
`
`4.
`
`Lineage of the ’604 Patent. .......................................................10
`
`Summary of Relevant Prosecution History. .............................10
`
`Claims of the ’604 Patent. .........................................................11
`
`Claim Construction. ..................................................................12
`
`a.
`b.
`
`c.
`
`“Therapeutically Effective Amount.” .............................14
`“Thereby Treating the Chronic GVHD in the
`Patient” ...........................................................................15
`Ibrutinib’s Chemical Structure. ......................................17
`
`i
`
`

`

`
`
`VI. THE PERTINENT PRIOR ART ...................................................................18
`
`A.
`
`The ’085 Publication. ..........................................................................19
`
`1.
`
`2.
`
`The ’085 Publication Is a Prior Art Printed Publication. ..........19
`
`The Pertinent Disclosures of the ’085 Publication. ..................20
`
`B.
`
`Shimabukuro-Vornhagen. ...................................................................22
`
`1.
`
`Is a Prior Art Printed
`Shimabukuro-Vornhagen
`Publication. ...............................................................................22
`
`2.
`
`The Pertinent Disclosures of Shimabukuro-Vornhagen. ..........24
`
`C.
`
`Herman. ...............................................................................................26
`
`1.
`
`2.
`
`Herman Is a Prior Art Printed Publication. ...............................26
`
`The Pertinent Disclosures of Herman. ......................................27
`
`D. Uckun. .................................................................................................28
`
`1.
`
`2.
`
`Uckun Is a Prior Art Printed Publication. .................................28
`
`The Pertinent Disclosures of Uckun. ........................................29
`
`VII.
`
`IDENTIFICATION OF CHALLENGES ......................................................30
`
`VIII. THE CLAIMS OF THE ’604 PATENT ARE UNPATENTABLE AND
`THUS THE PETITION HAS A REASONABLE LIKELIHOOD OF
`PREVAILING ...............................................................................................31
`
`A. A Person of Ordinary Skill in the Art. ................................................31
`
`B.
`
`Ground 1: The Challenged Claims Are Anticipated by the ’085
`Publication. ..........................................................................................32
`
`1.
`
`2.
`
`Legal Standard for Anticipation................................................32
`
`The ’085 Publication Anticipated Claim 1 of the ’604
`Patent. ........................................................................................34
`
`a.
`
`“A method of treating chronic graft versus host
`disease (GVHD).” ...........................................................34
`
`ii
`
`

`

`
`
`b.
`
`c.
`
`“Administering to a patient having chronic GVHD
`a therapeutically effective amount of” ibrutinib. ............36
`“Thereby treating the chronic GVHD in the
`patient.” ...........................................................................37
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`The ’085 Publication Anticipated Claims 4, 13, and 15. ..........38
`
`The ’085 Publication Anticipated Claims 6, 7, 8, 29, 30,
`31, 44, 45, 46, 51, 52, and 53. ...................................................39
`
`The ’085 Publication Anticipated Claim 9. ..............................41
`
`The ’085 Publication Anticipated Claim 10. ............................42
`
`The ’085 Publication Anticipated Claims 24, 28, 35, 39,
`43, 50, and 55. ...........................................................................43
`
`C.
`
`Ground 2: The Challenged Claims Would Have Been Obvious
`over the ’085 Publication. ...................................................................44
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Legal Standard for Obviousness. ..............................................44
`
`Claim 1 of the ’604 Patent Would Have Been Obvious
`over the ’085 Publication in View of a POSA’s
`Knowledge in the Art. ...............................................................45
`
`a.
`
`b.
`
`A POSA Would Have Been Motivated to Combine
`the Teachings of the ’085 Publication with a
`POSA’s Knowledge in the Art. ......................................45
`Claim 1 Would Have Been Obvious over the ’085
`Publication in View of a POSA’s Knowledge in the
`Art, With a Reasonable Expectation of Success. ...........47
`
`Obviousness of Claims 4, 13, and 15. .......................................49
`
`Obviousness of Claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51,
`52, and 53. .................................................................................50
`
`Obviousness of Claim 9. ...........................................................50
`
`Obviousness of Claim 10. .........................................................51
`
`Obviousness of Claims 24, 28, 35, 39, 43, 50, and 55. ............52
`
`iii
`
`

`

`
`
`8.
`
`Secondary Considerations of Nonobviousness. ........................53
`
`D. Ground 3: The Challenged Claims Would Have Been Obvious
`over the ’085 Publication in View of Shimabukuro-Vornhagen
`and Herman. ........................................................................................54
`
`1.
`
`Claim 1 of the ’604 Patent Would Have Been Obvious
`over the ’085 Publication in View of Shimabukuro-
`Vornhagen and Herman. ...........................................................54
`
`a.
`
`b.
`
`A POSA Would Have Been Motivated to Combine
`the Teachings
`of
`the
`’085 Publication,
`Shimabukuro-Vornhagen, and Herman. .........................54
`Claim 1 Would Have Been Obvious over the
`Combination of References, With a Reasonable
`Expectation of Success. ..................................................57
`
`Obviousness of Claims 4, 13, and 15. .......................................59
`
`Obviousness of Claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51,
`52, and 53. .................................................................................60
`
`Obviousness of Claim 9. ...........................................................60
`
`Obviousness of Claim 10. .........................................................61
`
`Obviousness of Claims 24, 28, 35, 39, 43, 50, and 55. ............61
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`E.
`
`Ground 4: The Challenged Claims Would Have Been Obvious
`over the ’085 Publication in View of Shimabukuro-Vornhagen
`and Uckun. ...........................................................................................62
`
`1.
`
`2.
`
`A POSA Would Have Been Motivated to Combine the
`Teachings of
`the
`’085 Publication, Shimabukuro-
`Vornhagen, and Uckun. ............................................................62
`
`The Challenged Claims Would Have Been Obvious over
`the Combination of References, With a Reasonable
`Expectation of Success. ............................................................65
`
`IX. CONCLUSION ..............................................................................................67
`
`
`
`
`
`iv
`
`

`

`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`
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`
`
`
` PAGE(S)
`
`Amneal Pharms., LLC v. Supernus Pharms., Inc.,
`IPR2013-00368, Paper 8 (P.T.A.B. Dec. 17, 2013) ........................................... 55
`
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) .......................................................................... 23
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ...................................................................passim
`
`Chi Mei Innolux Corp. v. Semiconductor Energy Lab. Co.,
`IPR2013-00028, Paper 14 (P.T.A.B. Mar. 21, 2014) ................................... 29, 30
`
`ClassCo, Inc. v. Apple, Inc.,
`838 F.3d 1214 (Fed. Cir. 2016) .......................................................................... 14
`
`Connell v. Sears, Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .......................................................................... 51
`
`Edmund Optics, Inc. v. Semrock, Inc.,
`IPR 2014-00599 ............................................................................................ 34, 35
`
`Edwards Lifesciences LLC v. Cook Inc.,
`582 F.3d 1322 (Fed. Cir. 2009) .......................................................................... 18
`
`Endo Pharm. Inc. v. Watson Labs., Inc., No. 13-CV-192,
`2014 U.S. Dist. LEXIS 84804, 2014 WL 2859349 (E.D. Tex. June
`23, 2014) ............................................................................................................. 15
`
`Ericsson Inc. v. Intellectual Ventures I LLC,
`2015 WL 2409306 (P.T.A.B. May 18, 2015) ..................................................... 24
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 54
`
`Google Inc. v. Jongerius Panoramic Techs, LLC,
`IPR2014-00191, Paper 70 (P.T.A.B. Aug. 12, 2014) ......................................... 34
`
`v
`
`

`

`
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) .......................................................................... 34
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) .................................................................... 36, 42
`
`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962) .....................................................................passim
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) ...................................................................passim
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 46, 47
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .......................................................................... 47
`
`Minton v. Nat’l Ass’n of Securities Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) .................................................................... 15, 41
`
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 55
`
`Novo Nordisk Pharms., Inc. v. Bio–Tech. Gen. Corp.,
`424 F.3d 1347 (Fed. Cir. 2005) .......................................................................... 34
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2008) .......................................................................... 55
`
`Pharmacyclics LLC v. Fresenius Kabi USA, LLC,
`1:18-cv-00192-CFC (D. Del) ................................................................................ 2
`
`Pharmacyclics LLC v. Zydus Worldwide DMCC,
`Civ. No. 1:18-cv-00275-CFC (D. Del.) ................................................................ 2
`
`Prometheus Labs. Inc. v. Roxane Labs., Inc.,
`No. 2013 U.S. Dist. LEXIS 135284, 2013 WL 5333033 (D.N.J.
`Sep. 23, 2013) ..................................................................................................... 41
`
`Provepharm Inc. v. Wista Laboratories Ltd.,
`2018 WL 3326805 (P.T.A.B. July 6, 2018) ..................................... 23, 24, 27, 29
`
`vi
`
`

`

`
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) .................................................................... 34, 36
`
`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) ........................................................ 51, 52, 53, 54
`
`Sharp Corp. v. Surpass Tech Innovation LLC,
`IPR2015-00021, Paper 10 (P.T.A.B. Mar. 18, 2015) ......................................... 29
`
`Spezialpräparate mbH,
`IPR2016-01370, Paper 13 (P.T.A.B. Feb. 8, 2017) .....................................passim
`
`Texas Instruments Inc. v. ITC,
`988 F.2d 1165 (Fed. Cir. 1993) .......................................................................... 15
`
`Thorner v. Sony Computer Ent. Am. LLC,
`669 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 16
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) ...................................................................passim
`
`STATUTES
`
`35 U.S.C. § 102 .................................................................................................passim
`
`35 U.S.C. § 103 .................................................................................................passim
`
`35 U.S.C. § 112 .................................................................................................. 11, 14
`
`35 U.S.C. § 282(b) ................................................................................................... 12
`
`35 U.S.C. § 315(e) ..................................................................................................... 2
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.6 ......................................................................................................... 4
`
`37 C.F.R. § 42.8 ..................................................................................................... 2, 3
`
`37 C.F.R. § 42.100 ................................................................................................... 13
`
`37 C.F.R. § 42.103 ..................................................................................................... 3
`
`37 C.F.R. § 42.104 ..................................................................................................... 4
`
`vii
`
`

`

`
`
`M.P.E.P. § 2111.01(IV)(A) ...................................................................................... 16
`
`M.P.E.P. § 2111.01(IV)(A) ...................................................................................... 16M.P.E.P. § 2111.01(IV)(A) ...................................................................................... 16
`
`M.P.E.P. § 2154.01 ...................................................................................... 20, 21, 22
`
`M.P.E.P. § 2154.01 ...................................................................................... 20, 21, 22M.P.E.P. § 2154.01 ...................................................................................... 20, 21, 22
`
`
`
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`
`viii
`
`ViiiViii
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`

`

`
`
`TABLE OF EXHIBITS
`
`1004
`
`1005
`
`1007
`
`Exhibit
`Ex #
`1001 U.S. Patent No. 9,795,604 B2 (“the ’604 Patent”)
`1002 U.S. Patent Pub. No. 2015/0140085 A1 (“the ’085 Publication ”)
`Shimabukuro-Vornhagen et al., “The role of B cells in the pathogenesis
`1003
`of graft-versus-host disease,” BLOOD, Volume 114, No. 24, pp. 4919–
`4927, December 3, 2009 (“Shimabukuro-Vornhagen”)
`Herman et al., “Bruton tyrosine kinase represents a promising therapeutic
`target for treatment of chronic lymphocytic leukemia and is effectively
`targeted by PCI-32765,” BLOOD, Volume 117, No. 23, pp. 6287–6296,
`June 9, 2011 (“Herman”)
`Uckun et al., “Bruton’s tyrosine kinase as a molecular target in treatment
`of leukemias and lymphomas as well as inflammatory disorders and
`autoimmunity,” EXPERT OPINION ON THERAPEUTIC PATENTS, Volume 20,
`No. 11, pp. 1457–1470, November 2010 (“Uckun”)
`1006 Declaration of James L. M. Ferrara M.D., D.Sc.
`Goldstein et al., “Induction of Costimulatory Molecules B7-1 and B7-2 in
`Murine B Cells: the CBA/N Mouse Reveals a Role for Bruton’s Tyrosine
`Kinase in CD4- Mediated B7 Induction,” MOLECULAR IMMUNOLOGY,
`Volume 33, No. 6, pp. 541–551, 1996 (“Goldstein”)
`1008 Declaration of Sylvia D. Hall-Ellis, Ph.D.
`July 22, 2016 Amendment and Response in Appl. No. 14/523,650
`1009
`Barak et al., “Cytokine Dysregulation in Chronic Graft Versus Host
`Disease,” LEUKEMIA AND LYMPHOMA, Volume 17, pp. 169–173, 1995
`(“Barak”)
`PCT No. PCT/US2013/047958
`Cetkovic-Cvrlje, “Dual targeting of Bruton’s tyrosine kinase and Janus
`kinase 3 with rationally designed inhibitors prevents graft-versus-host
`disease (GVHD) in a murine allogeneic bone marrow transplantation
`model,” BRITISH JOURNAL OF HAEMATOLOGY, Volume 126, pp. 821–827,
`2004
`1013 U.S. Patent No. 7,514,444 B2
`Provisional Patent Application No. 61/666,562 and filing receipt
`1014
`Honigberg et al., “The Bruton tyrosine kinase inhibitor PCI-32765 blocks
`B-cell activation and is efficacious in models of autoimmune disease and
`B-cell malignancy,” PROCEEDINGS OF THE NATIONAL ACADEMY OF
`SCIENCES OF THE USA, Volume 107, No. 29, pp. 13075–13080, July 20,
`2010
`
`1010
`
`1011
`
`1012
`
`1015
`
`ix
`
`

`

`
`
`1016
`
`Advani et al., “Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765)
`Has Significant Activity in Patients With Relapsed/Refractory B-Cell
`Malignancies,” JOURNAL OF CLINICAL ONCOLOGY, Volume 31, No. 1, pp.
`88–94, January 1, 2013
`Dolgin, “Precision therapies take aim at non-Hodgkin’s lymphoma”
`NATURE, Volume 563, S46–S47, November 14, 2018
`1018 U.S. Patent No. 8,476,284 B2
`1019 U.S. Patent No. 8,497,277 B2
`1020 Orange Book Listing for Ibrutinib 420 mg Capsules
`1021 April 22, 2016 Office Action in Appl. No. 14/523,650
`Auphan et al., “Immunosuppression by Glucocorticoids: Inhibition of NF-
`κB Activity Through Induction of IκB Synthesis,” SCIENCE, Volume 270,
`pp. 286–290, October 13, 1995
`
`1017
`
`1022
`
`x
`
`

`

`Petition for Inter Partes Review
` of U.S. Patent No. 9,795,604
`
`
`
`Sandoz Inc. (“Petitioner”) petitions for inter partes review (“IPR”), seeking
`
`cancellation of Claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39, 43–46, 50–53, and 55
`
`(the “Challenged Claims”) of U.S. Patent No. 9,795,604 B2 (“the ’604 Patent”)
`
`(EX1001) owned by Pharmacyclics LLC (“Patent Owner”).
`
`I.
`
`INTRODUCTION
`
`The ’604 Patent is directed to methods of treating chronic graft versus host
`
`disease (“GVHD”)—a condition that patients can develop after receiving a stem cell
`
`transplant—by administering a drug called ibrutinib. Ibrutinib was developed and
`
`publicly disclosed nearly a decade before the filing of the ’604 Patent in 2013.
`
`Despite the volume of patent and non-patent literature related to ibrutinib that existed
`
`in 2013, during prosecution, none of the references the Examiner cited or discussed
`
`related to ibrutinib. Additionally, none of the references the Examiner cited or
`
`discussed related to GVHD. Unlike the art addressed during prosecution, all of the
`
`art that is the subject of this Petition relates to ibrutinib and/or GVHD, including
`
`chronic GVHD.
`
`Indeed, the art cited in this Petition discloses administering ibrutinib to treat
`
`GVHD, thus anticipating the Challenged Claims of the ’604 Patent. The art also
`
`discloses the cellular mechanisms involved in GVHD, and chronic GVHD
`
`specifically. It further teaches the known mechanisms of action of ibrutinib, which
`
`work on the very mechanisms the art teaches as being critical to the etiology of
`
`
`
`

`

`Petition for Inter Partes Review
` of U.S. Patent No. 9,795,604
`
`
`chronic GVHD. It also teaches that drugs whose cellular function is similar to
`
`ibrutinib were known to treat GVHD, including chronic GVHD. Thus, in addition
`
`to anticipating the Challenged Claims of the ’604 Patent, the art cited in this Petition
`
`renders those Claims obvious. Accordingly, the Board should find the Challenged
`
`Claims of the ’604 Patent anticipated and/or obvious, and therefore unpatentable.
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1).
`
`Sandoz Inc. and Lek Pharmaceuticals D.D.1 are the real parties-in-interest.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2).
`
`To Petitioner’s knowledge, the ’604 Patent is the subject of Pharmacyclics
`
`LLC v. Zydus Worldwide DMCC, Civ. No. 1:18-cv-00275-CFC (D. Del.), which has
`
`been consolidated with Pharmacyclics LLC v. Fresenius Kabi USA, LLC, 1:18-cv-
`
`00192-CFC (D. Del). The ’604 Patent has not been the subject of any previous
`
`petition for IPR. U.S. Patent Application No. 15/586,058, filed May 3, 2017, is
`
`related to the ’604 Patent.
`
`
`1 Lek Pharmaceuticals D.D. is identified as a real party-in-interest solely for
`
`purposes of this Petition and for purposes of any estoppel under 35 U.S.C. 315(e),
`
`and not for any other purpose.
`
`2
`
`

`

`
`
`C. Lead and Back-Up Counsel and Service Under 37 C.F.R. §§
`42.8(b)(3) and 42.8(b)(4).
`
`Petition for Inter Partes Review
` of U.S. Patent No. 9,795,604
`
`
`Lead Counsel
`
`
`
`Kirk T. Bradley
`Reg. No. 46,571
`ALSTON & BIRD LLP
`101 South Tryon Street, Suite 4000
`Charlotte, NC 28280
`704-444-1000 (Telephone)
`704-444-1730 (Facsimile)
`kirk.bradley@alston.com
`
`
`
`Back-Up Counsel
`
`
`Siraj M. Abhyankar
`Reg. No. 62,022
`ALSTON & BIRD LLP
`1201 W Peachtree Street NE #4900
`Atlanta, GA 30309
`404-881-7687 (Telephone)
`404-253-8887 (Facsimile)
`shri.abhyankar@alston.com
`
`Christopher L. McArdle
`(pro hac vice application to be filed)
`ALSTON & BIRD LLP
`90 Park Avenue, Suite 1200
`New York, NY 10016
`212-210-9400 (Telephone)
`212-922-3843 (Facsimile)
`chris.mcardle@alston.com
`
`
`Petitioner consents to email service at the addresses identified above. Filed
`
`herewith are a Power of Attorney and an Exhibit List pursuant to § 42.10(b) and §
`
`42.63(e).
`
`III. PAYMENT OF FEES UNDER 37 C.F.R. § 42.103
`
`The required fee is paid through Deposit Acct. No. 160605, and the Office is
`
`authorized to charge any fee deficiencies and credit overpayments to that account
`
`(Customer ID No. 00826).
`
`3
`
`

`

`Petition for Inter Partes Review
` of U.S. Patent No. 9,795,604
`
`
`IV. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104
`
`Petitioner certifies that the ’604 Patent is available for IPR and that Petitioner
`
`is not barred or estopped from requesting an IPR challenging the claims of the ’604
`
`Patent on the grounds identified herein. Petitioner requests IPR and cancellation of
`
`the Challenged Claims as unpatentable for the reasons set forth below. Pursuant to
`
`37 C.F.R. § 42.6(d), copies of the references are filed herewith.
`
`V. BACKGROUND TECHNOLOGY AND THE ’604 PATENT
`
`A. Background Technology.
`
`1.
`
`Ibrutinib.
`
`By the time the ’604 Patent was filed in 2013, the drug molecule “ibrutinib”
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`had been extensively studied and analyzed, and there was a wide body of literature
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`disclosing ibrutinib, its uses, and its mechanisms of action. (EX1006 at ¶¶ 15–23
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`(declaration of Petitioner’s technical expert, James L. Ferrara M.D.).)
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`Celera Genomics developed ibrutinib in 2005 while studying Bruton’s
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`tyrosine kinase (“BTK”) function. (EX1017 at S46.) In 2006, Pharmacyclics—the
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`Patent Owner in this proceeding—bought the rights to ibrutinib. (Id.) After
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`purchasing the rights to ibrutinib (also known as “PCI-32765”), Pharmacyclics
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`began filing patent applications covering both the ibrutinib compound and its uses
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`in treating various B-cell diseases. For instance, in 2006 Pharmacyclics filed for and
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`obtained U.S. Patent No. 7,514,444 (“the ’444 Patent”) which discloses and claims
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`the chemical structure for ibrutinib as follows:
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`(EX1012 at 36:30–50 & claim 8; EX1006 at ¶ 18.) Pharmacyclics also filed
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`continuations of the ’444 Patent directed to, for example, using ibrutinib to treat B-
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`cell-related diseases such as B-cell lymphomas, chronic lymphocytic leukemia
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`(“CLL”), Waldenström’s macroglobulinemia
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`(“WM”), and non-Hodgkin
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`lymphomas. (EX1018 at claim 11; EX1019 at claims 8, 9, & 18; EX1006 at ¶ 19;
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`EX1020 (Orange Book listing for ibrutinib).)
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`By 2010, ibrutinib was known to treat arthritis and lupus-related kidney
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`disease (in mice) as well as B-cell non-Hodgkin lymphoma (in dogs). (EX1006 at
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`¶ 20; EX1015 at 13075.) Phase I studies in humans were conducted that same year.
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`(EX1006 at ¶ 21; EX1016 at 89, 93.) By 2013 (before the ’604 Patent was filed),
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`third-party patent filings disclosed administering ibrutinib to treat GVHD. (EX1006
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`at ¶¶ 55, 58; EX1002 at ¶ [0098].)
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`Before the ’604 Patent was filed in October 2013, ibrutinib’s mechanisms of
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`action relevant to treating GVHD were likewise known. For instance, both B cells
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`and T cells were known to be implicated in GVHD. (EX1006 at ¶ 23.) In a first
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`mechanism of action, ibrutinib was known to irreversibly bind to BTK in B cells,
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`thus blocking B cells from activating T cells. (EX1006 at ¶ 23; EX1003 at 4920–21;
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`EX1007 at 541.) In a second mechanism of action, ibrutinib was known to inhibit
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`the production of certain inflammatory cytokines—proteins created by certain cells,
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`including T cells—known to play an important role in chronic GVHD. (EX1006 at
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`¶ 23; EX1004 at 6291.)
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`2. Graft Versus Host Disease.
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`GVHD is a complication that can arise from a hematopoietic stem cell
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`transplant. (EX1006 at ¶ 24.) Hematopoietic stem cell transplantation, commonly
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`known as bone marrow transplantation, is a well-known, potentially curative
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`treatment for a number of hematologic diseases. (Id. at ¶ 26; EX1003 at 4919.) Such
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`transplantation is used to treat approximately a dozen diseases, including acute
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`myeloid leukemia, chronic myeloid leukemia, CLL, Hodgkin and Non-Hodgkin
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`lymphoma, and aplastic anemia. (EX1006 at ¶ 26.) Typically, a patient will be
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`administered medication via chemotherapy that kills the cells in the patient’s bone
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`marrow. (Id. at ¶ 27; EX1003 at 4919.) The goal is to eliminate the cells in the bone
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`marrow, thereby eliminating the underlying disease. (EX1006 at ¶ 27.)
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`After the bone marrow has been ablated, the patient (the “host”) will receive
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`transplanted bone marrow (the “graft”) from a donor containing stem cells and white
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`blood cells (which contain B cells and T cells). (Id. at ¶ 25.) In successful
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`transplantations, the transplanted stem cells and white blood cells regenerate and
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`function normally, without recurrence of
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`the disease
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`that prompted
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`the
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`transplantation. (Id. at ¶ 27.) Sometimes, though, a patient will develop GVHD,
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`where the donated bone marrow or peripheral blood stem cells view the patient’s
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`body as foreign, causing the donated cells to attack the body. (Id. at ¶¶ 25, 28.)
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`GVHD is thus an immune-mediated disease resulting from an interaction between
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`the lymphocytes (which are composed primarily of B cells and T cells) in the donor
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`bone marrow and cells in the recipient’s body. (Id. at ¶ 36.)
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`a.
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`Two Types of GVHD: Acute and Chronic.
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`It has been well known for decades that there are only two types of GVHD:
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`acute and chronic. (EX1006 at ¶ 29.) Some practitioners have distinguished acute
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`and chronic based on the time of onset, with acute GVHD occurring in the first 100
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`days after transplantation and chronic GVHD occurring after day 100. (EX1006 at
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`¶ 29; EX1003 at 4919.) Other practitioners have distinguished acute and chronic
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`based on the clinical characteristics of disease presentation. (EX1006 at ¶ 29;
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`EX1003 at 4919.)
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`Chronic GVHD may develop from acute GVHD or may occur after resolution
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`of acute GVHD. (EX1006 at ¶ 31; EX1003 at 4922.) Prior development of acute
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`GVHD is the primary risk factor for the development of chronic GVHD, although it
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`is possible to develop chronic GVHD without first having developed acute GVHD.
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`(EX1006 at ¶ 31.)
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`Before 2013, it was known that drug treatments for acute GVHD are also
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`given for chronic GVHD, and vice versa. (Id. at ¶ 32.) For example, glucocorticoids
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`(a type of steroid) were known to be “[t]he mainstay first-line therapy” for patients
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`with acute GVHD (EX1003 at 4921–22) and likewise were “the standard regimen
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`as primary treatment for chronic GVHD” (id. at 4922). (EX1006 at ¶ 32.) Similarly,
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`a number of other drugs, such as rituximab, statins, and extracorporeal photopheresis
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`(“ECP”), were reported to be useful in treating both acute and chronic GVHD.
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`(EX1003 at 4919, 4924; EX1006 at ¶ 32.) While steroids have been the primary
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`treatment, they are often ineffective. (EX1006 at ¶ 33.) Some patients become
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`“steroid-dependent,” meaning their GVHD gets worse when treatment with steroids
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`is discontinued. (Id. at ¶ 34.) And some patients may have “steroid-refractory” or
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`“steroid-resistant” GVHD, for which steroids do not work. (Id.) In both cases where
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`steroids were ineffective, it was known to turn to alternative drugs such as ibrutinib.
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`(Id. at ¶¶ 33, 35.)
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`b.
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`Chronic GVHD
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`By 2013, it was known that T cells are the main effector cells mediating
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`chronic GVHD pathogenesis. (EX1006 at ¶ 36; EX1003 at 4919.) It was also known
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`that B cells play an important role in chronic GVHD, because B cells present
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`antigens that bind to and activate T cells, which then attack healthy patient cells.
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`(EX1006 at ¶ 37; EX1003 at 4919, 4920–21.)
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`Based on that mechanism of action, it was known that drugs that prevent B
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`cells from activating T cells can treat chronic GVHD. (EX1006 at ¶¶ 37–39; EX1007
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`at 541.) For example, studies from 2004 demonstrated that inhibiting BTK in B cells
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`(which prevents T-cell activation) prevented severe GVHD in mice. (EX1005 at
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`1461; EX1006 at ¶ 39; EX1012 at 821.) Likewise, human clinical trials reported in
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`2009 confirmed that rituximab—a drug that depletes a patient’s B cells (thus
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`preventing B cells from activating T cells)—also treats chronic GVHD. (EX1003 at
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`4922–23; EX1006 at ¶ 39.)
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`Additionally, because T cells were known to mediate chronic GVHD, other
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`treatment strategies (known prior to October 2013) focused on directly inhibiting T-
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`cell function. (EX1006 at ¶ 36; EX1003 at 4919.) Certain inflammatory cytokines
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`produced by T cells, including IL-6 and TNF-α, were known to be produced in an
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`abnormal fashion in patients with chronic GVHD. (EX1006 at ¶ 36; EX1010 at 169.)
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`Indeed, one of the key mechanisms of action of glucocorticoids (used for treating
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`GVHD) is switching off activated inflammatory genes that encode for inflammatory
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`cytokines such as IL-6 and TNF-α. (EX1006 at ¶ 36.) It was known that ibrutinib
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`likewise inhibits production of IL-6 and TNF-α, and thus can serve to treat chronic
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`GVHD. (Id. at ¶ 23.)
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`B.
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`The ’604 Patent
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`1.
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`Lineage of the ’604 Patent.
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`The ’604 Patent issued on October 24, 2017 from Application No. 14/523,650,
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`which was filed on October 24, 2014, and claims priority to a series of four
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`provisional applications—61/895,981; 61/910,945; 61/973,173; 61/973,176—filed
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`on October 25, 2013; December 2, 2013; Ma