Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS IV LLC
`
`
`
`Jeffrey S. Ward (Reg. No. 32,774)
`MERCHANT & GOULD, P.C.
`10 E. Doty Street
`Suite 600
`Madison, WI 53703-3376
`Telephone: (608) 280-6751
`Facsimile: (612) 332-9081
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`COALITION FOR AFFORDABLE DRUGS IV LLC
`Petitioner
`
`
`By:
`
`
`
`
`
`v.
`
`PHARMACYCLICS, INC.
`Patent Owner
`
`_____________________
`
`Case No. To Be Assigned
`Patent No. 8,754,090
`_____________________
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,754,090
`UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq.
`
`
`
`
`
`
`
`

`

`A.
`
`B.
`
`C.
`
`D.
`
`Real Party-In-Interest ...................................................................................3
`
`Notice of Related Matters ............................................................................4
`
`Designation of Lead and Backup Counsel ...................................................5
`
`Notice of Service Information .....................................................................6
`
`PAYMENT OF FEES ..............................................................................................6
`
`REQUIREMENTS UNDER 37 C.F.R. §42.104 .....................................................6
`
`TABLE OF CONTENTS
`
`I. INTRODUCTION ...........................................................................................................1
`
`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. §42.8 ...............................3
`
`
`
`
`
`
`
`
`
`III.
`
`IV.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`V.
`
`
`
`
`
`
`
`IV.
`
`
`
`
`
`
`
`A.
`
`B.
`
`
`
`
`
`
`
`
`
`
`Grounds for Standing ...................................................................................6
`
`Identification of Challenge and Precise Relief Requested ...........................7
`
`1.
`
`
`
`
`
`
`Specific Art and Statutory Ground on Which the Challenge
`is Based ............................................................................................7
`
`a. Anticipation................................................................................7
`
`b. Obviousness ...............................................................................8
`
`2.
`
`Evidence Relied Upon to Support the Challenge ..........................10
`
`OVERVIEW ..........................................................................................................10
`
`A.
`
`B.
`
`C.
`
`Overview of the ’090 Patent ......................................................................10
`
`Person of Ordinary Skill in the Art ............................................................13
`
`State of the Prior Art ..................................................................................13
`
`CLAIM CONSTRUCTION ...................................................................................20
`
`A.
`
`B.
`
`C.
`
`“Treating” ..................................................................................................20
`
`“About” ......................................................................................................21
`
`“Mantle Cell Lymphoma”..........................................................................22
`
`
`
`i
`
`

`

`
`
`A.
`
`
`
`B.
`
`
`C.
`
`
`An inhibitor of Bruton’s tyrosine kinase (Btk) having the
`Structure .....................................................................................................24
`
`Administering to the individual once per day between about
`420 mg to about 840 mg of an oral dose ....................................................26
`
`D. Wherein the once per day oral dose is about 560 mg ................................27
`
`A method for treating mantle cell lymphoma in an individual
`who has already received at least one prior therapy for
`mantle cell lymphoma ................................................................................23
`
`
`VII. CLAIMS 1 AND 2 ARE ANTICIPATED BY NCT00849645 .............................22
`
`
`
`
`
`
`
`
`
`
`
`
`
`VII. CLAIMS 1 AND 2 ARWE INVALID AS OBVIOUS .........................................28
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`VIII. CONCLUSION ......................................................................................................43
`
`
`A.
`
`B.
`
`
`
`
`
`
`
`
`
`
`
`
`
`C.
`
`D.
`
`E.
`
`A POSA Would Have Been Motivated to Combine the Prior Art ............28
`
`The Prior Art Discloses the Elements of Claims 1 and 2 ..........................30
`
`1.
`
`
`
`2.
`
`
`3.
`
`
`4.
`
`A method for treating mantle cell lymphoma in an
`individual who has already received at least one prior therapy
`for mantle cell lymphoma ..............................................................30
`
`An inhibitor of Bruton’s tyrosine kinase (Btk) having the
`Structure .........................................................................................31
`
`Administering to the individual once per day between about
`420 mg to about 840 mg of an oral dose ........................................33
`
`Wherein the once per day oral dose in about 560 mg ....................35
`
`A POSA Would Have Had Reasonable Expectation of Success ...............36
`
`The Claimed Method Would Have Been Obvious to Try .........................37
`
`No Secondary Considerations Rebut Obviousness ....................................39
`
`ii
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`
`Cases
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`
`575 F.3d 1341 (Fed. Cir. 2009)..............................................................................38
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs.,
`
`246 F3d 1368 (Fed. Cir. 2001)......................................................................... 40-41
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`
`668 F.3d 1340 (Fed. Cir. 2012)..............................................................................35
`
`Cohesive Techs., Inc. v. Waters Corp.,
`
`543 F.3d 1351 (Fed. Cir. 2008)..............................................................................21
`
`Emi Group N. Am. V. Cypress Semiconductor Corp.,
`
`268 F.3d 1342 (Fed. Cir. 2001)..............................................................................42
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`
`737 F.3d 731 (Fed. Cir. 2013).......................................................................... 34-35
`
`Graham v. John Deere Co.,
`
`383 U.S. 1 (1966) ...................................................................................................28
`
`Hoffman La Roche, Inc. v. Apotex Inc.,
`
`748 F.3d 1326 (Fed. Cir. 2014)..............................................................................36
`
`In re Alford,
`
`300 F.2d 929 (C.C.P.A. 1962) ...............................................................................41
`
`In re Baxter Travenol Labs,
`
`952 F.2d 388 (Fed. Cir. 1991).......................................................................... 39-40
`
`In re O’Farrell,
`
`853 F.2d 894 (Fed. Cir. 1988).......................................................................... 36-37
`
`In re Huai-Hung Kao,
`
`639 F.3d 1057 (Fed. Cir. 2011)..............................................................................42
`
`In re Kubin,
`
`561 F.3d 1351 (Fed. Cir. 2009)..............................................................................38
`
`In re Peterson,
`
`315 F.3d 1325 (Fed. Cir. 2003)..............................................................................34
`
`
`iii
`
`

`

`
`
`King Pharms., Inc. v. Econ Labs., Inc.,
`
`616 F.3d 1267 (Fed. Cir. 2010)..............................................................................41
`
`MEHL/Biophile Int’l Corp. v. Milgraum,
`
`192 F.3d 1362 (Fed. Cir. 1999)..............................................................................42
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`
`395 F.3d 1364 (Fed. Cir. 2005).................................................................. 21-22, 28
`
`Ortho-McNeil Pharm. Inc. v. Caraco Pharm Labs., Ltd.,
`
`476 F.3d 1321 (Fed. Cir. 2007)..............................................................................21
`
`Pall Corp. v. Micron Separations, Inc.,
`
`66 F.3d 1211 (Fed. Cir. 1995)................................................................................21
`
`Pfizer, Inc. v. Apotex, Inc.,
`
`480 F.3d 1348 (Fed. Cir. 2007)..................................................................37, 40, 43
`
`
`
`
`
`iv
`
`

`

`I.
`
`INTRODUCTION
`
`Coalition for Affordable Drugs IV LLC (“Petitioner”) respectfully
`
`requests an Inter Partes review (“IPR”) for Claims 1-2 of U.S. Patent No.
`
`8,754,090 (“the ’090 Patent”) (Ex. 1001) in accordance with 35 U.S.C. §§ 311-
`
`319 and 37 C.F.R. § 42.100 et seq. The ’090 Patent is assigned to
`
`Pharmacyclics, Inc. (“the Patent Owner” or “the applicant”).
`
`The ’090 Patent has two claims directed to a method for treating mantle
`
`cell lymphoma (“MCL”) in a patient using a prior art pharmaceutical compound
`
`now known as ibrutinib, where that patient has already received at least one
`
`prior therapy to treat MCL. Claims 1 and 2 are anticipated by a prior art
`
`document describing a phase 1 clinical trial entitled Study of the Safety and
`
`Tolerability of PIC-32765 in Patients with Recurrent B Cell Lymphoma
`
`(February 23, 2009), https://clinicaltrials.gov/archive/NCT00849654/
`
`2009_02_23 (“NCT00849654”) (Ex. 1002) sponsored by the Patent Owner
`
`itself. That clinical trial document describes the use of a compound having the
`
`designation PCI-32765 in a dose escalation study. A person of ordinary skill in
`
`the art (“POSA”) would have understood that only two compounds could
`
`potentially be PCI-32765 – ibrutinib or a racemic mixture containing ibrutinib.
`
`Further, the clinical trial document discloses the patients to be treated and the
`
`doses to be used. Given that the compound designated as PCI-32765 can be
`
`1
`
`

`

`
`
`only one of two things (both of which have ibrutinib), the disclosure in the
`
`clinical trial document describes every element of the methods of claims 1 and
`
`2. Those claims are therefore invalid as anticipated.
`
`Even if claims 1 and 2 are not anticipated by the clinical trial document
`
`(which they are), those claims would have been obvious to a POSA at the time
`
`of the ’090 Patent over the clinical trial document in view of two other Patent
`
`Owner documents, a published patent application (Ex. 1003) and a press release
`
`announcing (Ex. 1004), that disclose information concerning ibrutinib. A
`
`POSA would have been motivated to combine the disclosure of the clinical trial
`
`document with the published application and the press release to result in a
`
`method of using ibrutinib in the claimed doses to treat relapsed or refractory
`
`MCL. This combination discloses every element of claims 1 and 2, thus a
`
`POSA would have a reasonable expectation of its success.
`
`Indeed, the examiner of the application that resulted in the ’090 Patent
`
`recognized the obviousness of the claims during prosecution. The examiner
`
`repeatedly rejected the applicant’s proposed claims, causing the applicant to
`
`cancel all but two of them. The applicant ultimately persuaded the examiner to
`
`allow the claims by arguing that “ibrutinib demonstrates substantial
`
`improvement over existing therapies,” which were “not taught or suggested by
`
`the cited art.” (Ex. 1013 at 5.) These alleged “unexpected results,” however,
`
`2
`
`

`

`
`
`should have been given no patentable weight because they were not made in
`
`comparison to the closest prior art (ibrutinib) and were merely the inherent
`
`result of an obvious method of treatment with ibrutinib.
`
`
`
`For the reasons explained herein, Petitioner is likely to prevail on showing
`
`the invalidity of the challenged claims. Petitioner requests that the Board institute
`
`an IPR and cancel claims 1 and 2 of the ’090 Patent.
`
`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8
`A. Real Party-In-Interest
`
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Coalition For
`
`Affordable Drugs IV LLC (“CFAD”), Hayman Credes Master Fund, L.P.
`
`(“Credes”), Hayman Orange Fund SPC – Portfolio A (“HOF”), Hayman
`
`Sunnyvale Fund LP (“HSF”), Hayman Capital Master Fund, L.P. (“HCMF”),
`
`Hayman Capital Management, L.P. (“HCM”), Hayman Offshore Management,
`
`Inc. (“HOM”), Hayman Investments, L.L.C. (“HI”), nXn Partners, LLC
`
`(“nXnP”), IP Navigation Group, LLC (“IPNav”), J. Kyle Bass, and Erich
`
`Spangenberg are the real parties in interest (collectively, “RPI”). The RPI
`
`hereby certify the following information: CFAD is a wholly owned subsidiary
`
`of Credes. Credes is a limited partnership. HOF is a segregated portfolio
`
`company. HSF is a limited partnership. HCMF is a limited partnership. HCM
`
`is the general partner and investment manager of Credes, HSF and HCMF.
`
`3
`
`

`

`
`
`HCM is the investment manager of HOF. HOM is the administrative general
`
`partner of Credes and HCMF. HI is the general partner of HCM. J. Kyle Bass is
`
`the sole member of HI and sole shareholder of HOM. CFAD, Credes, HOF,
`
`HSF, and HCMF act, directly or indirectly, through HCM as the general partner
`
`and/or investment manager of Credes, HOF, HSF, and HCMF. nXnP is a paid
`
`consultant to HCM. Erich Spangenberg is 98.5% member of nXnP. IPNav is a
`
`paid consultant to nXnP. Erich Spangenberg is the 98.5% member of IPNav.
`
`Other than HCM with J. Kyle Bass in his capacity as the Chief Investment
`
`Officer of HCM and nXnP with Erich Spangenberg in his capacity as the
`
`Manager of nXnP, no other person (including any investor, limited partner, or
`
`member or any other person in any of CFAD, Credes, HOF, HSF, HCMF,
`
`HCM, HOM, HI, nXnP, or IPNav) has authority to direct or control (i) the
`
`timing of, filing of, content of, or any decisions or other activities relating to this
`
`Petition or (ii) any timing, future filings, content of, or any decisions or other
`
`activities relating to the future proceedings related to this Petition. All of the
`
`costs associated with this Petition will be borne by HCM, CFAD, Credes, HOF,
`
`HSF and/or HCMF.
`
`B. Notice of Related Matters
`
`
`
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is not aware of any judicial or
`
`administrative matters that could affect, or be affected by, a decision in this
`
`4
`
`

`

`proceeding.
`
`C. Designation of Lead and Backup Counsel
`
`
`
`Lead Counsel:
`Jeffrey S. Ward
`Registration No. 32,774
`MERCHANT & GOULD, P.C.
`10 E. Doty Street
`Suite 600
`Madison, WI 53703-3376
`Telephone: (608) 280-6751
`Facsimile: (612) 332-9081
`jward@merchantgould.com
`
`Backup Counsel:
`Jeffrey D. Blake, Esq.
`Registration No. 58,884
`MERCHANT & GOULD, P.C.
`191 Peachtree Street N.E.
`Suite 4300
`Atlanta, GA 30303
`Telephone: (404) 954-5040
`Facsimile: (404) 954-5099
`jblake@merchantgould.com
`
`Brent E. Routman
`(Pro Hac Vice)
`MERCHANT & GOULD, P.C.
`3200 IDS Center
`80 South 8th Street
`Minneapolis, MN 55402-2215
`Telephone: (612) 332-5300
`Facsimile: (612) 332-9081
`broutman@merchantgould.com
`
`Shane A. Brunner
`(Pro Hac Vice)
`MERCHANT & GOULD, P.C.
`10 E. Doty Street
`Suite 600
`Madison, WI 53703-3376
`Telephone: (608) 280-6753
`Facsimile: (612) 332-9081
`sbrunner@merchantgould.com
`
` Power of Attorney is being filed concurrently herewith in accordance with
`
` A
`
`37 C.F.R. § 42.10(b).
`
`
`
`5
`
`

`

`D. Notice of Service Information
`
`Papers concerning this matter should be served by Express Mail, hand-
`
`delivery, or electronic mail at the following addresses:
`
`
`
`Mailing Address: Jeffrey S. Ward, Esq.
`
`
`
`MERCHANT & GOULD P.C.
`
`
`
`10 E. Doty Street, Suite 600
`
`
`
`Madison, WI 53703-3376
`
`Electronic Mail:
`
`jward@merchantgould.com and
`ImbruvicaIPR@merchantgouild.com
`Main Telephone: (608) 280-6751
`Main Facsimile:
`(612) 332-9081
`
`
`
`
`
`
`
`
`
`
`III. PAYMENT OF FEES
`Payment of $23,000.00 for the fees set forth in 37 C.V.R. § 42.15(a)(1-4) for
`
`this Petition for Inter Partes Review accompanies this request by way of credit
`
`card payment. The undersigned further authorizes payment for any additional fees
`
`that might be due in connection with this Petition to be charged to Deposit Account
`
`No. 13-2725.
`
`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104
`A. Grounds for Standing
`
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ’090
`
`Patent is available for Inter Partes review in accordance with 37 C.F.R. §
`
`42.102(a)(2), and that the Petitioner is not barred or estopped from requesting Inter
`
`Partes review challenging the claims of the ’090 Patent on the grounds identified
`
`in this Petition. None of Petitioner, any real party in interest, or any privy of
`
`6
`
`

`

`
`
`Petitioner has received a final written decision under 35 U.S.C. § 318(a) with
`
`respect to any claim of the ’090 Patent on any ground that was raised or could have
`
`been raised by Petitioner, any real party in interest, or any privy of Petitioner in
`
`any inter partes review, post grant review, or covered business method patent
`
`review.
`
`Further, Petitioner certifies that: (1) Petitioner has not filed a civil action
`
`challenging the validity of a claim of the ’090 Patent; (2) none of the Petitioner,
`
`any real party-in-interest, or any privy of the Petitioner was served with a
`
`complaint alleging infringement of the ’090 Patent; (3) the estoppel provisions of
`
`35 U.S.C. § 315(e)(1) do not prohibit this inter partes review; and (4) the ’090
`
`Patent is not a patent described in section 3(n)(1) of the Leahy-Smith America
`
`Invents Act and so is available for this inter partes review, per 37 C.F.R. § 42.102
`
`(a)(2).
`
`B.
`
`Identification of Challenge and Precise Relief Requested
`
`Pursuant to 37 C.F.R. § 42.104(b), Petitioner challenges Claims 1-2 of the
`
`’090 Patent and seeks a ruling that those claims are unpatentable under 35 U.S.C.
`
`§102(b) and 35 U.S.C. §103(a).
`
`1. Specific Art and Statutory Grounds on Which the Challenge is
`Based
`a. Ground 1: Claims 1 And 2 Are Anticipated Under 35
`U.S.C. § 102(b)
`
`
`
`7
`
`

`

`
`
`
`
`Claims 1-2 of the ’090 Patent are unpatentable because they are anticipated
`
`under 35 U.S.C. § 102(b) by NCT00849654 (Ex. 1002). NCT00849654 has a
`
`publication date more than one year before the ’090 Patent’s earliest possible
`
`effective filing date of June 3, 2010, and thus NCT00849654 is available as prior
`
`art under 35 U.S.C. § 102(b).
`
`b. Ground 2: Claims 1 And 2 Are Obvious Under 35
`U.S.C. § 103(a)
`
`
`
`Claims 1-2 of the ‘090 Patent are unpatentable because they are obvious
`
`under 35 U.S.C. § 103(a) over NCT00849654 (Ex. 1002) in view of the combined
`
`teachings of U.S. Patent Application Publication No. 2008/0139582 (filed Dec. 26,
`
`2007) (“the ’582 Publication”) (Ex. 1003), and Press Release, Pharamacyclics,
`
`Pharmacyclics Initiates Phase I Clinical Trial of Novel Oral Btk Inhibitor for
`
`Refractory B-Cell Non-Hodgkin’s Lymphoma (April 13, 2009) (“the 2009 Press
`
`Release”) (Ex. 1004).
`
`
`
`Each of these publications has a publication date more than one year before
`
`the ’090 Patent’s earliest effective filing date of June 3, 2010. On this basis, they
`
`are each available as prior art under 35 U.S.C. § 102(b).
`
`
`
`Additional references cited herein to establish the state-of-the-art, the reason
`
`to combine the prior art, and the reasonable expectation of success include
`
`Zhengying Pan, et al., Discovery of Selective Irreversible Inhibitors for Bruton’s
`
`Tyrosine Kinase, 2 ChemMedChem 58 (2007) (“Pan”) (Ex. 1005), Lee Honigberg
`
`8
`
`

`

`
`
`et al., Targeting Btk in Lymphoma: PCI-32765 Inhibits Tumor Growth in Mouse
`
`Lymphoma Models and a Fluorescent Analog of PCI-32675 Is an Active-Site
`
`Probe That Enables Assessment of Btk Inhibition In Vivo, Blood (ASH Annual
`
`Meeting Abstracts), November 2007, at 1592 (“Blood 2007”) (Ex. 1006),
`
`Christophe Le Tourneau et al., Dose Escalation Methods in Phase I Cancer
`
`Clinical Trials, 101 J. Nat’l Cancer Inst. 708 (2009) (Ex. 1007), Jonathan
`
`McConathy, Ph.D., & Michael J. Owens, Ph.D., Stereochemistry in Drug Action,
`
`5 Primary Care Companion J Clinical Psychiatry 70 (2003) (Ex. 1008), Stefano A.
`
`Pileri & Brunangelo Falini, Mantle Cell Lymphoma, 94 Haematologica 1488
`
`(2009) (Ex. 1009), Agency For Toxic Substances and Disease Registry, Public
`
`Health Assessment Guidance Manual, (2005) (“the 2005 Manual”) (Ex. 1010), M.
`
`MacPartlin et al., Bruton’s Tyrosine Kinase is not essential for Bcl-Abr-mediated
`
`transformation of lymphoid or myeloid cells, Leukemia (2008) 22, 1354-60
`
`(“MacPartlin,” Ex. 1011), PubMed Open Chemistry Database for PCI-32765
`
`Racemate, first published on June 26, 2007 (“PubMed 2007,” Ex. 1012), the 2008
`
`WHO classifications of lymphomas (“WHO,” Ex. 1013), and R. Eric Davis, et al.,
`
`Chronic Active B-Cell-Receptor Signalling in Diffuse Large B-Cell Lymphoma,
`
`Nature, Vol. 463, Letters, 88-92 (January 7, 2010) (“Nature 2010, Ex. 1023).
`
`9
`
`

`

`
`
`2. Evidence Relied Upon to Support the Challenge
`Petitioner relies upon the publications cited herein in support of Grounds 1
`
`and 2. Petitioner also relies upon the Declaration of Djordje Atanackovic, M.D.
`
`(Ex.1021), and the documents cited therein. Attached are an Exhibit List and
`
`copies of the references per 37 C.F.R. § 42.63(e) and 37 C.F.R. § 42.6 (c).
`
`V. OVERVIEW
`A. Overview of the ’090 Patent
`
`
`
`The ’090 Patent is entitled “Use of Inhibitors of Bruton’s Tyrosine Kinase
`
`(BTK).” (Ex. 1001.) The ’090 Patent issued on June 17, 2014. It is a continuation
`
`of U.S. Application Ser. No. 13/153,317, filed Jun. 3, 2011, which claims the
`
`benefit of priority from several U.S. provisional applications, the earliest of which
`
`were filed on June 3, 2010.
`
`
`
`The ’090 Patent describes methods for treating hematological malignancies
`
`with Btk inhibitors. (Id. at col. 1:53-58; see also Ex. 1021 at ¶¶30-33.) The
`
`hematological malignancies identified in the specification of ’090 Patent include
`
`several B-cell non-Hodgkin’s Lymphomas (“NHLs”), including MCL. (Id. at col.
`
`2:57-60.)
`
`
`
`The ’090 Patent has 2 claims. Claim 1 recites:
`
`A method for treating mantle cell lymphoma in an
`
`individual who has already received at least one prior
`
`10
`
`

`

`
`
`therapy for mantle cell lymphoma comprising
`
`administering to the individual once per day between
`
`about 420 mg to about 840 mg of an oral dose of an
`
`inhibitor of Bruton's tyrosine kinase (Btk) having the
`
`structure:
`
`”
`
`(Id. at col. 149:1-25.) Claim 2 depends from claim 1 and recites: “The method of
`
`claim 1, wherein the once per day oral dose is about 560 mg.” (Id. at col. 149:26-
`
`27.)
`
`
`
`The originally-filed claims of the application that resulted in the ’090 Patent
`
`were directed to treating a hematological malignancy” by “administering … an
`
`irreversible Btk inhibitor.” (Ex. 1014.) The original claims did not address
`
`“treating mantle cell lymphoma” or “an individual who has already received at
`
`least one prior therapy for mantle cell lymphoma,” as is now reflected in the
`
`11
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`claims. (Ex. 1001 at col. 149:2-28.)
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`On December 23, 2012 the examiner, in a telephonic interview, requested a
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`Restriction Election to which the Applicant responded with an election of “a
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`method for treating relapsed or refractory non-Hodgkin’s lymphoma” using a
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`specific species of Btk inhibitor that was to be designated later. (Ex. 1015.) This
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`was formalized in the Requirement for Restriction/Election filed on January 3,
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`2013. (Ex. 1016.)
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`On February 4, 2013, Applicant elected the species of Btk inhibitor as
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` and the type of lymphoma as “mantle cell lymphoma (MCL).”
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`(Ex. 1017.)
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`During prosecution, the Examiner issued a Final Rejection on November 1,
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`2013, in which all claims were rejected under 35 U.S.C. § 103 as obvious over
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`several prior art references not involved in this Petition. (Ex. 1018.) Notably,
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`however, the Examiner indicated that a POSA would have identified PCI-32765 as
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`the claimed structure from any of various sources disclosing the structure. (Id.)
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`The Examiner stated that the citation of the additional sources disclosing the
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`structure was “not an introduction of a new reference, [but] only used to add to the
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`rebuttal by the Examiner to show that the structure of PCI-32765 is known prior to
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`the filing of the instant application.” (Id.)
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`In response, the applicants did not argue that the claimed structure was not
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`shown in the prior art. Instead, the applicants relied upon alleged unexpected
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`results as a basis to overcome the outstanding obviousness rejection, citing the
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`“remarkable clinical results achieved” with “ibrutinib” for the FDA to approve the
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`drug for use. (Ex. 1019 at 5.)  
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`B. Person of Ordinary Skill in the Art
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`A POSA at the time of the alleged invention of the ’090 Patent would have
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`been a medical doctor specializing in hematology and having several years of
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`experience treating patients with B-cell NHL, including MCL. (Ex. 1021 at ¶¶49-
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`50.) A POSA may also have been a medical doctor or researcher with a Ph.D in
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`biochemistry or related field having several years of experience researching
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`treatments for B-cell NHLs. (Id.)
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`C. State of the Prior Art
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`MCL is a hematologic cancer. (Ex. 1021 at ¶37.) It was and is “generally
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`regarded as an aggressive, incurable disease with the median survival of affected
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`patients being 3-4 years.” (Ex. 1009 at 1489) MCL is known to represent 3-10%
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`of all NHLs. (Id. at 1488.)
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`At the time the application for the ’090 Patent was filed, persons skilled in
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`the art were looking for more effective ways to treat hematologic cancers,
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`including B-cell NHLs such as MCL. (Ex. 1021 at ¶¶34-38.) One company
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`exploring such treatments was the Patent Owner’s. (Id. at ¶39.) Notably, the
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`Patent Owner was prolific in publishing its drug development work in the area,
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`much of which would later turn out to be prior art to the ’090 Patent. (See, e.g.,
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`Exs. 1002-1003.) The Patent Owner published patent applications, press releases,
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`articles, abstracts, and clinical study recruitment documents detailing its
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`development of a compound called PCI-32765. (See, e.g., Exs. 1002-1004 and
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`1006.) PCI-32765 was being developed for the treatment of relapsed or refractory
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`B-cell NHL, i.e. B-cell NHL that had not been successfully eliminated by prior
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`treatment therapies. (See, e.g., Ex. 1002.)
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`Also at this time, researchers in the field were interested in new and
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`improved treatments for patients who failed “first-line therapy” for B-cell NHLs,
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`including MCL. (Ex. 1021 at ¶87.) Thus, a POSA would have been interested in
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`finding a therapy for treating MCL patients who had failed first-line therapy. (Id.)
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`Such a POSA would have closely followed the Patent Owner’s many publications
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`regarding its development of PCI-32765 for the treatment of the B-cell NHLs. (Id.
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`at ¶42.) The following documents are generally presented in a chronological order.
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`The Blood 2007 Abstract - In 2007, Lee Honigberg, a researcher at the
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`Patent Owner’s company and one of the inventors of the ’090 Patent, presented
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`studies regarding PCI-32765 at the American Society of Hematology (“ASH”)
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`Annual Meeting, which is a prestigious conference in the field of hematology.
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`This conference would have been well-known to a POSA. (Ex. 1021 at ¶¶40-42.)
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`Honigberg’s abstract of the studies was also published in Blood, the leading
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`journal in the field hematology. (Ex. 1006; Ex. 1021 at ¶40.) The abstract is titled
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`Targeting Btk in Lymphoma: PCI-32765 Inhibits Tumor Growth in Mouse
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`Lymphoma Models and a Fluorescent Analog of PCI-32765 Is an Active-Site
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`Probe That Enables Assessment of Btk Inhibition In Vivo (“Blood 2007”). (Ex.
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`1006.)
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`Blood 2007 discloses that there “is increasing evidence indicating that B-cell
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`receptor (BCR) signaling is required for survival of non-Hodgkin’s lymphoma
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`(NHL) cells.” (Id. at 1592.) Blood 2007 continues that “there have been few
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`highly selective small molecule inhibitors of Btk,” but the Patent Owner had
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`“developed a series of covalent Btk inhibitors that target Cys-481 in Btk.” (Id.)
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`Blood 2007 further discloses that “PCI-32765 is a Cys-481 targeting Btk inhibitor
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`that has been optimized for potency, selectivity and pharmacokinetics.” (Id.)
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`Blood 2007 also states that “[i]n order to further characterize the selectivity and in
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`vivo potency of PCI-32765, we have developed PCI-33380, an active-site probe
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`consisting of a covalent Btk inhibitor linked to the fluorophore Bodipy-FL.” (Id.).
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`In other words, Blood 2007 shows that PCI-33380 is an analog of PCI-
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`32765 linked to the fluorophore Bodipy-FL. (Ex. 1021 at ¶96.) Blood 2007 also
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`reports that Btk inhibition by PCI-32765 induces apoptotic cell death and inhibits
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`the growth of a variety of tumor cell lines derived from patients with different low-
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`grade (cell line DHL-4) and high-grade (cell lines DHL-6, WSU-DLCL2, OCI-
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`Ly10, DOHH2) B-cell lymphomas in vitro and in vivo. (Ex. 1006.) Further, a
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`POSA would have understood that the Patent Owner had developed PCI-32765
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`(and its analog PCI-33380) that showed significant promise as a treatment of B-
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`cell NHL, and that the compound would be evaluated in clinical trials. (Ex. 1021
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`at ¶42.) This would have led a POSA to look closely at the Patent Owner’s
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`development of PCI-32765 as a treatment for B-cell NHL.
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`Pan, Nature 2010 and MacPartlin – Three additional prior art articles
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`(Pan, Nature 2010 and MacPartlin) combine with Blood 2007 to specifically
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`identify the chemical structure of PCI-32765. (Ex. 1021 at ¶¶ 46-48.) Pan
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`discloses certain selective irreversible inhibitors of Btk, including a compound
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`referred to as Compound 4. (Ex. 1005 at 59.) Compound 4 is drawn as a non-
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`stereospecific enantiomer in Scheme 1 and Table 3. Further in Table 3,
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`Compounds 13 and 14 in Pan are distinguished from Compound 4 as specific
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`stereo isomers. Compound 13 is the R enantiomer of Compound 4 and is now
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`known as ibrutinib. (Id.) Notably, Nature 2010 states that PCI-32765 is
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`“compound 13 in ref. 25,” and “ref. 25” is cited as Pan. (Ex. 1023 at 91-92.)
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`Thus, Nature 2010 identifies the structure of PCI-32765 as R enantiomer called
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`Compound 13 in Pan.
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`Further, MacPartlin states that Compound 4 from Pan is known as PCI-
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`31523. (Ex. 1011 at 1354.) MacPartlin further discloses compound PCI-33380 is
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`the “Bodipy-FL conjugate of the pure R enantiomer of PCI-31523,” citing to Blood
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`2007. (Id. at 1355.) As established above, Blood 2007 shows that PCI-33380 is an
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`analog of PCI-32765 linked to the fluorophore Bodipy-FL.
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`A POSA would have understood from the combination of Pan, Nature 2008,
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`MacPartlin and Blood 2007 that PCI-32765 (used in clinical trial NCT00849654,
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`Ex. 1002) is the R-enantiomer of PCI-31253 (i.e., the R-enantiomer of Compound
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`4 in Pan, which itself is Compound 13 in Pan). (Ex. 1021 at ¶48.) The R-
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`enantiomer of Compound 4 in Pan is now known as ibrutinib. Thus, the
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`combination of Blood 2007, Pan and MacPartlin discloses the structure of PCI-
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`32765 in the prior art.
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`The ’582 Publication - At around the same time, the Patent Owner was
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`attempting to patent certain pharmaceutical compounds that inhibit Btk. (Ex. 1021
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`at ¶39.) A patent application covering these compounds was eventually published
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`as the ’582 Publication on June 12, 2008. (Ex. 1003.) The ’582 Publication
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`teaches compounds for a “medicament for the inhibition of Bruton’s tyrosine
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`kinase (Btk) activity” that can be “orally administered” to a “human” for the
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`treatment of cancer, including “mantle cell lymphoma.” (Id. at [0029]-[0030],
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`[0041].) The ’582 Publication further teaches a dose range of “1-1500 mg per
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`day.” (Id. at [0399].)
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`Example 2 of the ’582 Publication discloses the Btk inhibitory activity of
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`twelve compounds in two in vitro assays. (Id. at Table 2.) The test data provided
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`in Table 2 of Example 2 of the ’582 Publication discloses that Compound 13 has
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`the most potent Btk inhibitory activity in the acellular kinase assay. (Ex. 1003 at
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`[00458].) Compound 13 (now called ibrutinib) is the R-enantiomer of Compound
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`4. (Ex. 1021 at ¶¶47-48, 72, 76.) The ’582 Publication further discloses that,
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`based on these test results, the “R-configuration was determined as the slightly
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`preferred absolute stereochemistry configuration by two sets of enantiomers (11 vs.
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`12 and 13 vs. 14)