Paper No. ___
`Filed: July 30, 2015
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`COALITION FOR AFFORDABLE DRUGS IV LLC
`
`Petitioner,
`
`
`v.
`
`
`PHARMACYCLICS LLC
`
`Patent Owner
`
`__________________
`
`
`Case IPR2015-01076
`
`Patent No. 8,754,090
`
`__________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE TO
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,754,090
`
`
`

`

`
`
`Table of Contents
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`BACKGROUND ............................................................................................. 5
`
` Overview of the ’090 Patent .................................................................. 7
`A.
`
`
`B.
`
`
`C.
`
`Prosecution History ............................................................................... 8
`
`Person of Ordinary Skill in the Art .....................................................12
`
`III. CLAIM CONSTRUCTION ..........................................................................14
`
`
`A.
`
`“administering to the individual once per day between about
`420 mg to about 840 mg of an oral dose” (claim 1), “wherein
`the once per day oral dose is about 560 mg” (claim 2) .......................15
`
`
`B.
`
`“mantle cell lymphoma” ......................................................................17
`
`IV. THE PETITION’S PROCEDURAL DEFECTS PRECLUDE
`INSTITUTION ON BOTH GROUNDS .......................................................18
`
`
`A.
`
`
`B.
`
`Petitioner Fails To Meet Its Threshold Burden To Prove Its
`Primary Reference, Exhibit 1002, Is A Printed Publication ...............19
`
`Petitioner Did Not Make The Cited April 2009 Press Release
`Prior Art Of Record, Which Warrants Denial Of the Second
`Ground .................................................................................................21
`
`
`C.
`
`Petitioner Fails To Name All Real Parties-in-Interest ........................23
`
`V.
`
`PETITIONER IS NOT REASONABLY LIKELY TO PREVAIL ON
`GROUND 1—ANTICIPATION OVER EXHIBIT 1002 .............................26
`
`
`A.
`
`Petitioner Cannot Legally Establish That Exhibit 1002
`Discloses All Limitations of Claims 1 and 2 ......................................27
`
`1.
`
`“A method for treating mantle cell lymphoma in an
`individual who has already received at least one prior
`therapy for mantle cell lymphoma” ..........................................29
`
`i
`
`

`

`Page
`
`2.
`
`3.
`
`“administering to the individual once per day between
`about 420 mg to about 840 mg” (claim 1) or “wherein the
`once per day oral dose is about 560 mg” (claim 2) ..................32
`
`“administering…an inhibitor of Bruton’s tyrosine kinase
`(Btk) having the structure: ........................................................34
`
`
`B.
`
`The Board Should Deny Institution Under 35 U.S.C. § 325(d)
`Because The Patent Office Already Considered Petitioner’s Art
`And Arguments Regarding Ground 1 .................................................35
`
`VI. PETITIONER IS NOT REASONABLY LIKELY TO PREVAIL ON
`GROUND 2—OBVIOUSNESS BY EXHIBIT 1002 IN VIEW OF
`THE ’582 PUBLICATION (EXHIBIT 1003) AND THE PRESS
`RELEASE (EXHIBIT 1004) .........................................................................38
`
`
`A.
`
`Petitioner’s Obviousness Analysis Fails To Consider The
`Claimed Methods As A Whole And Is Grounded In
`Impermissible Hindsight .....................................................................39
`
`1.
`
`2.
`
`Petitioner Has Not Met Its Burden To Establish A
`Motivation To Combine Or Obviousness To Try .....................40
`
`Petitioner Has Not Established A Reasonable
`Expectation of Success .............................................................44
`
`
`B.
`
`
`C.
`
`The Combination of The Exhibits Do Not Teach or Suggest
`The Dosing Limitations of Claims 1 and 2 .........................................48
`
`Petitioner Improperly Dismisses Secondary Considerations of
`Nonobviousness ...................................................................................49
`
`1.
`
`2.
`
`Petitioner Improperly Dismisses The Evidence of
`Secondary Considerations Pharmacyclics Provided To
`The Patent Office ......................................................................50
`
`Additional Secondary Considerations Are Strong
`Evidence of Nonobviousness ....................................................54
`
`
`D.
`
`The Board Should Deny Institution Under 35 U.S.C. § 325(d)
`Because The Patent Office Already Considered The Art and
`Arguments Regarding Ground 2 .........................................................56
`
`ii
`
`

`

`VII. AT MINIMUM, THE BOARD SHOULD DENY THE
`REDUNDANT GROUND ............................................................................57
`
`VIII. CONCLUSION ..............................................................................................59
`
`Page
`
`
`
`
`
`iii
`
`

`

`
`
`Table of Authorities
`
`Page(s)
`
`Cases
`
`Am. Hosp. Supply Corp. v. Travenol Labs., Inc.,
`745 F.2d 1 (Fed. Cir. 1984) ..................................................................................42
`
`Amneal Pharms., LLC v. Endo Pharms., Inc.,
`Case IPR2014-00360, 2015 WL 4500654 (July 22, 2015) ........................... 48, 49
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ..............................................................................50
`
`Cepheid v. Roche Molecular Sys., Inc.,
`Case IPR2015-00255, Paper No. 8 (June 11, 2015) .............................................27
`
`Cisco Sys., Inc. v. Constellation Tech. L.L.C.,
`IPR2014-00871, 2014 WL 7325813 (Dec. 19, 2014) ..........................................21
`
`Cisco Sys., Inc. v. Constellation Techs. LLC,
`IPR2014-00914, Paper No. 11, 2015 WL 66520 (Jan. 2, 2015) ..........................19
`
`Cisco Systems, Inc. v. Custom Media Techs., LLC,
`IPR2014-01272, 2015 WL 430117 (Jan. 30, 2015) .........................................3, 22
`
`Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc.,
`807 F.2d 955 (Fed. Cir. 1986) ....................................................................... 12, 13
`
`Daicel Corp. v. Celanese Int’l Corp.,
`IPR2014-01515, Paper No. 11, at 17 (Mar. 30, 2015) .........................................41
`
`Dell, Inc. v. Selene Comm’n Techs., LLC,
`IPR2014-01411, Paper No. 23, 2015 WL 834148 (Feb. 26, 2015) ............... 20, 21
`
`EMC Corp. v. Personalweb Techs., LLC,
`IPR2013-00087, 2013 WL 5970178 (June 5, 2013) ............................................58
`
`Ferring B.V. v. Watson Labs, Inc.,
`764 F.3d 1382 (Fed. Cir. 2014) ..................................................................... 16, 55
`
`Hulu, LLC v. Intertainer, Inc.,
`Case IPR2014-01456, Paper No. 8 (Mar. 6, 2015) ...............................................36
`
`iv
`
`

`

`Page(s)
`
`Idle Free Sys., Inc. v. Bergstrom, Inc.,
`IPR2012-00027, Paper No. 26 (June 11, 2013) ....................................................58
`
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................20
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) ..................................................................... 30, 31
`
`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962) ..............................................................................35
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ................................................................. 28, 30, 33
`
`In re Wyer,
` 655 F.2d 221 (C.C.P.A. 1981) .............................................................................19
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ............................................................................54
`
`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol Ltd.,
`IPR2014-00309, 2014 WL 8331340 (Mar. 23, 2015) ..........................................50
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ..............................................................................51
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ....................................................................................... 40, 43
`
`L-3 Commc’n Holdings, Inc. v. Power Survey, LLC,
`IPR2014-00832, Paper No. 9, 2014 WL 6468495 (Nov. 14, 2014) .....................19
`
`Liberty Mutual Insurance Co. v. Progressive Casualty Insurance Co.,
`CBM-2012-00003, 2012 WL 9494791 (Oct. 25, 2012) ................................ 58, 59
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................16
`
`Microboards Tech. v. Stratasys Inc.,
`Case IPR2015-00287, Paper No. 13 (May 28, 2015) ...........................................36
`
`v
`
`

`

`Page(s)
`
`Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013) ............................................................................43
`
`Pall Corp. v. Micron Separations,
`66 F.3d 1211 (Fed. Cir. 1995) ..............................................................................16
`
`Palo Alto Networks, Inc. v. Juniper Networks, Inc.,
`IPR2013-00466, 2014 WL 2528623 (Jan. 28, 2014) ...........................................58
`
`PAR Pharm. Inc. v. TWI Pharms. Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ............................................................................48
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................51
`
`PRISM Pharma Co. v. Choongwae Pharma Corp.,
`Case IPR2015-00315, Paper No. 14 (July 8, 2014) ..............................................36
`
`Reflectix, Inc. v. Promethean Insulation Tech. LLC,
`IPR2015-00047, Paper No. 18, 2015 WL 1927414 (Apr. 24, 2015) ............ 23, 25
`
`RPX Corp. v. VirnetX, Inc.,
`IPR2014-00171, Paper No. 49 (June 5, 2014) ......................................................24
`
`S.S. Steiner, Inc. v. John I. Haas, Inc.,
`IPR2014-01490, Paper No. 7, at 17-18 (Mar. 16, 2015) ......................................43
`
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) ..................................................................... 27, 28
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) ..................................................................... 40, 49
`
`Tempo Lighting, Inc. v. Tivoli, LLC,
`742 F.3d 973 (Fed. Cir. 2014) ..............................................................................14
`
`Tissue Transplant Tech., Ltd. v. Mimedx Grp., Inc.,
`IPR2015-00320, Paper No. 13 at 9-10 (June 29, 2015) .......................................27
`
`Zerto, Inc. v. EMC Corp.,
`IPR2014-01254, 2015 WL 981664 (Mar. 3, 2015) ..............................................25
`
`vi
`
`

`

`Page(s)
`
`Zoll Lifecor Corporation v. Philips Elecs. N. Am. Corp.,
`IPR2013-00607, 2014 WL 1253105 (Mar. 20, 2014) ..........................................24
`
`Statutes
`
`21 U.S.C §356(b)(1).................................................................................................55
`
`21 U.S.C. § 356 ........................................................................................................55
`
`21 U.S.C. § 356(a)(1) ................................................................................................. 6
`
`35 U.S.C. § 311(b) ............................................................................................ 18, 19
`
`35 U.S.C. § 312(a)(2) ...............................................................................................23
`
`35 U.S.C. § 314(a) ...................................................................................................26
`
`35 U.S.C. § 315 ........................................................................................................23
`
`35 U.S.C. § 316(a)(11) .............................................................................................57
`
`Other Authorities
`
`77 FED. REG. 48,756 .................................................................................................23
`
`Rules
`
`37 C.F.R. § 42.1 .......................................................................................................57
`
`37 C.F.R. § 42.100(b) ..............................................................................................14
`
`37 C.F.R. § 42.12 .....................................................................................................26
`
`37 C.F.R. § 42.6(c). ..................................................................................................22
`
`37 C.F.R. § 42.65 .....................................................................................................20
`
`
`
`vii
`
`

`

`
`
`PATENT OWNER’S EXHIBIT LIST
`
`Pharmacyclics
`Exhibit No.
`
`DESCRIPTION
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`2008
`
`2009
`
`2010
`
`2011
`
`FDA Press Release, “FDA Approves Imbruvica For Rare Blood
`Cancer” (Nov. 13, 2013), available at
`http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncement
`s/ucm374761.htm
`Howard, O., “Mantle Cell Lymphoma.” Malignant Lymphomas
`Ed. Grossbard, ML London: BC Decker Inc. 2002 135-51)
`Wang, M., et al., Targeting BTK with Ibrutinib in Relapsed or
`Refractory Mantle-Cell Lymphoma, 369 N. Eng. J. Med. 507
`(2013)
`European Medicines Agency, “Assessment Report for Torisel”
`(August 25, 2009), available at
`http://www.ema.europa.eu/docs/en_GB/document_library/EPAR
`_-_Assessment_Report_-
`_Variation/human/000799/WC500039918.pdf
`Ohio State University Medical Center. "Drug shows surprising
`efficacy as treatment for chronic leukemia, mantle cell
`lymphoma." ScienceDaily (June 19, 2013) available at
`www.sciencedaily.com/releases/2013/06/130619195217.htm.
`Johnson & Johnson Press Release, “Ibrutinib Receives Two
`Oncology Breakthrough Therapy Designations from U.S. Food
`and Drug Administration” (Feb. 12, 2013), available at
`http://www.jnj.com/news/all/ibrutinib-receives-two-oncology-
`breakthrough-therapy-designations-from-us-food-and-drug-
`administration
`S. 3187 Prescription Drug User Fee Amendments of 2012
`Office Action, Non-Final Rejection (March 13, 2013), U.S.
`Patent App. No. 13/340,522
`Notice of Allowability (March 31, 2014), U.S. Patent App. No.
`13/340,522
`Chang, B.Y., et al “Egress of CD191CD51 cells into peripheral
`blood following treatment with the Bruton tyrosine kinase
`inhibitor ibrutinib in mantle cell lymphoma patients” Blood,
`122(14): 2412-2424
`Schlette, E., et al, “CD23 Expression in Mantle Cell Lymphoma:
`Clinicopathologic Features of 18 Cases” Am J. Clin. Pathol.
`
`viii
`
`

`

`
`
`Pharmacyclics
`Exhibit No.
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`DESCRIPTION
`
`2003;120:760-766
`Form ADV Brochure of Hayman Capital Management L.P. (Mar.
`30, 2015)
`Form ADV of Hayman Capital Management L.P. (Mar. 30,
`2015)
`Delaware Certificates of Formation for Coalition for Affordable
`Drugs (ADROCA) LLC and Coalition for Affordable Drugs II
`LLC through XV
`Request for Continued Examination and Information Disclosure
`Statement (January 31, 2014), U.S. Patent App. No. 13/340,522
`Argyriou, A.A., et al., “Bortezomib-induced peripheral
`neurotoxicity: an update,” Arch Toxicol (2014) 88:1669–1679
`PRNewswire, “Pharmacyclics Reports Fourth Quarter and Full
`Year 2014 Financial Results and Provides Business Updates”
`(Feb. 18, 2015), available at http://www.prnewswire.com/news-
`releases/pharmacyclics-reports-fourth-quarter-and-full-year-
`2014-financial-results-and-provides-business-updates-
`300038067.html
`Highlights of Prescribing Information: Imbruvica (ibrutinib),
`available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/2031
`47s000lbl.pdf
`
`ix
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Mantle cell lymphoma (“MCL”) is a rare and aggressive subtype of B-cell
`
`non-Hodgkin’s lymphoma (“NHL”), accounting for only approximately 6% of all
`
`NHL cases in the United States. (Ex. 2001.) MCL is “incurable with standard
`
`therapeutic techniques.” (Exs. 1019 at 5, 2002 at 135.) Accordingly, MCL—and
`
`especially relapsed or refractory MCL—is a difficult disease to treat. (Exs. 1019 at
`
`5; 2002 at 135.) The prognosis for patients diagnosed with MCL is poor. (Exs.
`
`2003 at 2; 1019 at 5; 2002 at 135.) Most patients receiving prior art therapies
`
`eventually relapsed and died. (Ex. 2003 at 2.)
`
`In trying to find a long-needed solution for those terminally ill patients,
`
`Patent Owner Pharmacyclics developed a novel, life-prolonging cancer therapy,
`
`Imbruvica® (ibrutinib), a small molecule inhibitor of Bruton’s tyrosine kinase
`
`(“Btk”). Imbruvica®, a first-in-class Btk inhibitor, was only the second drug the
`
`FDA designated as a “breakthrough therapy” that ultimately received approval.
`
`(Ex. 2001.) The FDA awarded that designation to Imbruvica® in early 2013
`
`because it “may offer a substantial improvement over available therapies” for
`
`treating MCL in patients who have received at least one prior therapy. (Ex. 2001.)
`
`The two claims in U.S. Patent No. 8,754,090 (“the ’090 patent”), subject of
`
`the instant petition for inter partes review (“Petition”), relate to novel methods for
`
`treating MCL with ibrutinib in an individual who has already received at least one
`
`1
`
`

`

`
`
`prior therapy for MCL. Notwithstanding Petitioner, hedge fund subsidiary the
`
`Coalition for Affordable Drugs IV, LLC’s (“Petitioner” or “Coalition”) motivation
`
`in filing the Petition1, the Petition itself contains three fundamental procedural
`
`flaws that warrant denial. First, both of Petitioner’s patentability challenges
`
`primarily rely on a copy of a webpage that Petitioner fails to prove is a printed
`
`publication. Petitioner’s only support for its conclusion that Exhibit 1002 was
`
`published is a conclusory statement from its expert, Dr. Djorde Atanackovic, who
`
`does not profess to have personal knowledge or evidence regarding that exhibit’s
`
`publication. (Pet. at 19.) Reliance on its expert’s unsupported statement alone is
`
`insufficient to meet the Petitioner’s burden. Because Petitioner failed to provide
`
`any evidence that its primary reference for both grounds qualifies as a “printed
`
`publication”, the Board should deny the Petition as a whole.
`
`Second, Petitioner did not provide the proper Exhibit 1004, one of the two
`
`secondary references Petitioner relies upon for its second ground. Petitioner
`
`identifies that exhibit as an April 2009 press release, but Exhibit 1004 is a
`
`December 2009 press release. Because Petitioner did not make the April 2009
`
`press release of record, it cannot provide a basis upon which an inter partes review
`
`
`1 Pharmacyclics is filing a motion for sanctions concurrently with this Petition, as
`
`the Board authorized on July 28, 2015. (Paper No. 15.)
`
`2
`
`

`

`
`
`may be instituted and the Board should deny the second ground in its entirety.
`
`Cisco Systems, Inc. v. Custom Media Techs., LLC, IPR2014-01272, 2015 WL
`
`430117, at *14 (Jan. 30, 2015).
`
`Third, the Petitioner fails to identify all real parties-in-interest. Although
`
`Petitioner identified several entities in its Petition, available information shows that
`
`the Petitioner omitted several real parties-in-interest. Because naming real parties-
`
`in-interest is a statutory requirement that cannot be waived, Petitioner’s failure to
`
`do so provides a separate basis to deny the Petition.
`
`Petitioner’s analysis of the merits is likewise defective. Even if Petitioner
`
`were to apply the correct legal standards and claim constructions—which it did
`
`not—Petitioner cannot show it is reasonably likely to prevail on either ground.
`
`With respect to anticipation, Petitioner cannot legally show that Exhibit 1002—a
`
`summary of a phase I clinical trial proposal—discloses at least three limitations of
`
`independent claim 1 and dependent claim 2: (1) “treating mantle cell lymphoma in
`
`an individual who has already received at least one prior therapy for mantle cell
`
`lymphoma” (claims 1 and 2); (2) “administering to the individual once per day
`
`between about 420 mg to about 840 mg” (claim 1) or “wherein the once per day
`
`oral dose is about 560 mg” (claim 2); and (3) administering the claimed chemical
`
`structure to the individual. To argue those limitations are disclosed, Petitioner
`
`applies an incorrect inherent anticipation standard. Applying the correct standard
`
`3
`
`

`

`
`
`reveals that none of those elements are disclosed, as the Patent Office has already
`
`correctly recognized. For at least those reasons and those described below,
`
`Petitioner is not reasonably likely to prevail on its first ground—anticipation—and
`
`the Board should deny institution on that ground.
`
`With respect to obviousness based on Exhibit 1002 in view of Exhibits 1003
`
`and 1004, Petitioner is equally unlikely to prevail. Notwithstanding the procedural
`
`defects mentioned above, Petitioner’s obviousness analysis is grounded in
`
`impermissible hindsight. To conclude the claims are obvious, Petitioner simply
`
`pieces together portions of different references on an element-by-element basis, i.e.
`
`not considering the claims as a whole, providing little reasoning on why a POSA
`
`would have been motivated to combine the references or why there allegedly
`
`would be a reasonable expectation of success in practicing the claimed method.
`
`Moreover, Petitioner cannot show that any of the cited references alone or in
`
`combination teach or suggest any material dosing limitations of the claims.
`
`Petitioner fails to adequately consider secondary considerations, including
`
`unexpected results. Imbruvica® was only the second drug with FDA breakthrough
`
`therapy designation to receive FDA approval and demonstrated over double the
`
`response rate over the prior art treatments. Finally, the Patent Office already
`
`considered all three references during prosecution and correctly issued the claims.
`
`4
`
`

`

`
`
`For at least those reasons, the Petitioner is not likely to prevail on its second
`
`ground—obviousness—and the Board should deny institution on that ground.
`
`For at least all the reasons described herein, the Board should exercise its
`
`discretion to deny institution in its entirety.
`
`II. BACKGROUND
`
`Prior
`
`to FDA approval for Imbruvica®, doctors
`
`typically
`
`treated
`
`hematological malignancies,
`
`including relapsed or refractory MCL, with
`
`combination chemotherapy or intensive chemotherapy plus immunotherapy
`
`followed by stem-cell transplantation. (Ex. 2002; Ex. 2003 at 2.) Those therapies
`
`offered varying degrees of success, depending largely on the therapy, the type of
`
`malignancy, and whether that malignancy was relapsed or refractory. In addition,
`
`those therapies caused varying degrees of side effects, requiring hospitalization in
`
`some instances.
`
`With respect to MCL, traditional chemotherapies plus rituximab, a
`
`monoclonal antibody, such as “R-CHOP”2 were the standard of care for that and all
`
`NHLs at the time of the ’090 patent inventions. (Ex. 2004 at 3.) Aside from
`
`
`2 R-CHOP refers to the combination of the following drugs: rituximab,
`
`cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and
`
`prednisone. (Ex. 2004 at 3.)
`
`5
`
`

`

`
`
`traditional chemotherapies, the FDA had only approved one other therapy for
`
`relapsed or refractory MCL—bortezomib, a proteasome inhibitor—which the FDA
`
`approved for intravenous use at the end of 2006. (Ex. 2001.) Clinical studies
`
`showed that treatment of relapsed or refractory MCL with bortezomib resulted in a
`
`30% initial response rate. (Ex. 2005.) Between December 2006 and the ’090
`
`patent inventions, no new therapies for relapsed or refractory MCL were available
`
`in the United States. Given the poor prognosis of MCL patients treated with prior
`
`art therapies including bortezomib, persons of ordinary skill in the art (“POSAs”)
`
`around the time of the inventions of the ’090 patent spent a long time searching to
`
`improve upon the standard of care.3 (Ex. 2003 at 2.)
`
`During prosecution of the ’090 patent, the FDA granted “breakthrough
`
`therapy” designation for ibrutinib for patients with relapsed or refractory MCL
`
`who have received at least one prior therapy. (Exs. 2001, 2006.) The FDA
`
`designates a drug as a “breakthrough therapy” when “preliminary clinical evidence
`
`indicates that the drug may demonstrate substantial improvement over existing
`
`therapies on 1 or more clinically significant endpoints, such as substantial
`
`treatment effects observed early in clinical development.” (21 U.S.C. § 356(a)(1);
`
`
`3 Even Petitioner and its expert admit that “few if any promising treatments
`
`existed” for MCL at the time of the invention. (Pet. at 28-29; Ex. 1021 ¶¶58, 87.)
`
`6
`
`

`

`
`
`Ex. 2007 at 94.) That designation is not often granted and allows expedited
`
`development and review time at the FDA. Preliminary clinical evidence showed
`
`that treating relapsed or refractory MCL with ibrutinib resulted in a 68% response
`
`rate, over two times the response rate of the prior art compounds, earning ibrutinib
`
`that designation. (Ex. 2001, Ex. 2003 at 2.) Moreover, ibrutinib’s oral
`
`administration helped reduce some of the troublesome side effects resulting from
`
`the previous standard of care. Ultimately, the FDA approved Imbruvica® therapy
`
`for MCL in patients who received at least one prior therapy in November 2013.
`
`(Ex. 2001.) Imbruvica® was only the second Breakthrough Therapy that received
`
`FDA approval. (Id.)
`
`
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` Overview of the ’090 Patent A.
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`The ’090 patent, titled “Use of Inhibitors of Bruton’s Tyrosine Kinase
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`(BTK),” issued on June 17, 2014. The ’090 patent discloses methods for treating a
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`hematological malignancy
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`in an
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`individual comprising administering an
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`irreversible Btk inhibitor. (Ex. 1001 at Abstract, col. 1:53-60.) Btk is a key
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`regulator of B-cell development, activation, signaling, and survival and plays a role
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`in a number of hematopoietic cell signaling pathways. (Id. at col. 1:34-49.) In
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`part, the ’090 patent application was based on the unexpected discovery that Btk
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`inhibitors induce mobilization or lymphocytosis of lymphoid cells in hematological
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`malignancies. (Id. at col. 10:62-67.) That mobilization increases the lymphoid
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`cell’s exposure to additional cancer treatment regimens, among other things. (Id.)
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`The ’090 patent issued with two method claims directed to treating MCL in
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`an individual who has already received at least one prior therapy for MCL with
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`ibrutinib. Independent claim 1 recites:
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`1.
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`A method for treating mantle cell lymphoma in an individual
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`who has already received at least one prior therapy for mantle cell
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`lymphoma comprising administering to the individual once per day
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`between about 420 mg to about 840 mg of an oral dose of an inhibitor
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`of Bruton’s tyrosine kinase (Btk) having the structure:
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`(Ex. 1001 at col. 149:1-25.) Claim 2 depends from claim 1 and recites:
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`2.
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`The method of claim 1, wherein the once per day oral dose is
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`about 560 mg.
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`(Id. at col. 149:27-28.)
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`B.
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`Prosecution History
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`The ’090 patent issued from U.S. Application No. 13/340,522 (“the ’522
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`application”) filed on December 29, 2011, which was a continuation of Application
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`No. 13/153,317 filed on June 3, 2011. The ’522 application claimed priority to six
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`provisional applications, the earliest of which was filed on June 3, 2010.
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`In response to an initial restriction/election requirement, the applicant
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`elected claims directed to methods of treating a refractory hematological
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`malignancy (including relapsed or refractory NHL) and elected a single species of
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`Btk inhibitor (ibrutinib), a species of lymphoma (MCL), and a second cancer
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`treatment agent (rituximab). (Ex. 1017.) In the first Office Action following the
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`election, the Examiner rejected all pending claims on various grounds including 35
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`U.S.C. § 103. In connection with that rejection, the Examiner cited a December
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`2009 press release concerning Phase I clinical trial results—the same press release
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`Petitioner erroneously included as Exhibit 1004 to the Petition. (Ex. 2008.) The
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`Examiner also cited two additional references relating to Pharmacyclics’s work
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`with ibrutinib: pending patent Application No. 13/153,291 and Pollyea, Poster
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`Abstracts, 51st ASH Annual Meeting and Exposition (Dec. 3, 2009) (“Pollyea”).
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`(Id.) On November 1, 2013, the Examiner issued a final office action rejecting all
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`claims, including claim 131,4 under 35 U.S.C. § 103(a) as unpatentable over U.S.
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`4 Claim 131 was ultimately amended and issued as Claim 1.
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`Patent Publication No. 2008/0076921 (“the ’921 Publication”)5 in view of the
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`December 2009 press release and Pollyea for the same reasons previously
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`described in the May 2013 office action. (Ex. 1018.)
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`Following a phone interview, the applicant cancelled all pending claims
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`except for claim 131, amended claim 131 to the same text which ultimately issued
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`as claim 1, and added claim 150, which ultimately issued as dependent claim 2.
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`(Ex. 1019.) In its remarks, the applicant addressed the 35 U.S.C. § 103 rejections
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`over the ’921 Publication in view of, inter alia, the 2009 press release and Pollyea.
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`In addition to the arguments raised previously—i.e., that none of the references
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`alone or in combination taught or suggested a method for treating MCL in an
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`individual who has already received at least one prior therapy for MCL comprising
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`ibrutinib at the claimed dosages—applicant provided data to support a showing of
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`unexpected results of the claimed treatment over the prior art treatments for
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`relapsed or refractory MCL. (Id.) Applicant provided evidence that, unlike the
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`prior treatments for relapsed or refractory MCL which had a 30% response rate,
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`treatment with ibrutinib resulted in a 68% overall response rate in the phase II
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`5 The ’921 Publication is in the same family as Exhibit 1003, U.S. Publication No.
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`2008/0139582 (“the ’582 Publication”), and significantly shares a specification.
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`clinical trial. (Id. at 5.) The applicant also provided evidence that the FDA
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`recently granted ibrutinib the rare “[b]reakthrough status designation.” (Id.)
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`On January 27, 2014, the Examiner issued a Notice of Allowability. (Ex.
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`1020.) In that notice, the Examiner explained that the ’921 Publication, the
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`December 2009 press release, and Pollyea were the closest prior art of record. (Id.)
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`Although the Examiner found that the ’921 Publication disclosed a genus of
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`compounds useful in treating “B-cell proliferative disorder” and that ibrutinib was
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`one of those compounds, the Examiner found it did not explicitly teach or suggest
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`a method of treating MCL comprising administering the claimed dosage of
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`ibrutinib. (Id.) With respect to the December 2009 press release (Exhibit 1004),
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`the Examiner noted that it discloses “a multicenter dose escalation phase I trial of
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`orally administered Bruton’s tyrosine kinase (Btk) inhibitor PCI-32765 in patients
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`with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL) or chronic
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`leukemia (CLL)” but expressly found that that disclosure did not teach or suggest
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`“the use of ibrutinib in treating mantle cell lymphoma, the dosage amounts claimed
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`in a patient who has already received at least one prior art therapy for mantle cell
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`lymphoma.” (Id. at 3-4.) Thereafter, the applicant filed additional supplemental
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`information disclosure statements, citing, among other things, additional references
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`relating to Pharmacyclics’s own work developing ibrutinib as a treatment for
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`lymphomas, including Exhibit 1002, and sought a request for continued
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`examination. The Examiner then issued a second Notice of Allowance, stating that
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`the “reasons for allowance are the same as stated in the office action dated
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`1/27/2014.” (Ex. 2009.) The ’090 patent eventually issued in June 2014.
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`C.
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`Person of Ordinary Skill in the Art
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`Petitioner’s Definition
`A POSA at the time of the alleged
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`Patent Owner’s Definition
`A POSA at the time of the inventions of
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`invention of the ’090 Patent would have
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`the ’090 patent wou