Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS IV LLC By: 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

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.

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TABLE OF CONTENTS

I. INTRODUCTION ...........................................................................................................1 II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. 42.8 ...............................3 A. Real Party-In-Interest ...................................................................................3 B. Notice of Related Matters ............................................................................4 C. Designation of Lead and Backup Counsel ...................................................5 D. Notice of Service Information .....................................................................6 III. PAYMENT OF FEES ..............................................................................................6 IV. REQUIREMENTS UNDER 37 C.F.R. 42.104 .....................................................6 A. Grounds for Standing ...................................................................................6 B. 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 V. OVERVIEW ..........................................................................................................10 A. Overview of the 090 Patent ......................................................................10 B. Person of Ordinary Skill in the Art ............................................................13 C. State of the Prior Art ..................................................................................13 IV. CLAIM CONSTRUCTION ...................................................................................20 A. Treating ..................................................................................................20 B. About ......................................................................................................21 C. Mantle Cell Lymphoma..........................................................................22

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

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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 OFarrell, 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

iv

King Pharms., Inc. v. Econ Labs., Inc., 616 F.3d 1267 (Fed. Cir. 2010)..............................................................................41 MEHL/Biophile Intl 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

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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

2

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 applicants 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,

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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.

4

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

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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

A Power of Attorney is being filed concurrently herewith in accordance with

37 C.F.R. 42.10(b).

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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

7

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)

8

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 Patents 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-Hodgkins 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 Patents 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 Brutons

Tyrosine Kinase, 2 ChemMedChem 58 (2007) (Pan) (Ex. 1005), Lee Honigberg

9

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. Natl 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., Brutons 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).

10

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 Brutons 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-Hodgkins 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

11

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

12

claims. (Ex. 1001 at col. 149:2-28.)

On December 23, 2012 the examiner, in a telephonic interview, requested a

Restriction Election to which the Applicant responded with an election of a

method for treating relapsed or refractory non-Hodgkins lymphoma using a

specific species of Btk inhibitor that was to be designated later. (Ex. 1015.) This

was formalized in the Requirement for Restriction/Election filed on January 3,

2013. (Ex. 1016.)

On February 4, 2013, Applicant elected the species of Btk inhibitor as

and the type of lymphoma as mantle cell lymphoma (MCL).

(Ex. 1017.)

During prosecution, the Examiner issued a Final Rejection on November 1,

2013, in which all claims were rejected under 35 U.S.C. 103 as obvious over

several prior art references not involved in this Petition. (Ex. 1018.) Notably,

however, the Examiner indicated that a POSA would have identified PCI-32765 as

the claimed structure from any of various sources disclosing the structure. (Id.)

The Examiner stated that the citation of the additional sources disclosing the

13

structure was not an introduction of a new reference, [but] only used to add to the

rebuttal by the Examiner to show that the structure of PCI-32765 is known prior to

the filing of the instant application. (Id.)

In response, the applicants did not argue that the claimed structure was not

shown in the prior art. Instead, the applicants relied upon alleged unexpected

results as a basis to overcome the outstanding obviousness rejection, citing the

remarkable clinical results achieved with ibrutinib for the FDA to approve the

drug for use. (Ex. 1019 at 5.) B. Person of Ordinary Skill in the Art

A POSA at the time of the alleged invention of the 090 Patent would have

been a medical doctor specializing in hematology and having several years of

experience treating patients with B-cell NHL, including MCL. (Ex. 1021 at 49-

50.) A POSA may also have been a medical doctor or researcher with a Ph.D in

biochemistry or related field having several years of experience researching

treatments for B-cell NHLs. (Id.)

C. State of the Prior Art

MCL is a hematologic cancer. (Ex. 1021 at 37.) It was and is generally

regarded as an aggressive, incurable disease with the median survival of affected

patients being 3-4 years. (Ex. 1009 at 1489) MCL is known to represent 3-10%

of all NHLs. (Id. at 1488.)

14

At the time the application for the 090 Patent was filed, persons skilled in

the art were looking for more effective ways to treat hematologic cancers,

including B-cell NHLs such as MCL. (Ex. 1021 at 34-38.) One company

exploring such treatments was the Patent Owners. (Id. at 39.) Notably, the

Patent Owner was prolific in publishing its drug development work in the area,

much of which would later turn out to be prior art to the 090 Patent. (See, e.g.,

Exs. 1002-1003.) The Patent Owner published patent applications, press releases,

articles, abstracts, and clinical study recruitment documents detailing its

development of a compound called PCI-32765. (See, e.g., Exs. 1002-1004 and

1006.) PCI-32765 was being developed for the treatment of relapsed or refractory

B-cell NHL, i.e. B-cell NHL that had not been successfully eliminated by prior

treatment therapies. (See, e.g., Ex. 1002.)

Also at this time, researchers in the field were interested in new and

improved treatments for patients who failed first-line therapy for B-cell NHLs,

including MCL. (Ex. 1021 at 87.) Thus, a POSA would have been interested in

finding a therapy for treating MCL patients who had failed first-line therapy. (Id.)

Such a POSA would have closely followed the Patent Owners many publications

regarding its development of PCI-32765 for the treatment of the B-cell NHLs. (Id.

at 42.) The following documents are generally presented in a chronological order.

15

The Blood 2007 Abstract - In 2007, Lee Honigberg, a researcher at the

Patent Owners company and one of the inventors of the 090 Patent, presented

studies regarding PCI-32765 at the American Society of Hematology (ASH)

Annual Meeting, which is a prestigious conference in the field of hematology.

This conference would have been well-known to a POSA. (Ex. 1021 at 40-42.)

Honigbergs abstract of the studies was also published in Blood, the leading

journal in the field hematology. (Ex. 1006; Ex. 1021 at 40.) The abstract is titled

Targeting Btk in Lymphoma: PCI-32765 Inhibits Tumor Growth in Mouse

Lymphoma Models and a Fluorescent Analog of PCI-32765 Is an Active-Site

Probe That Enables Assessment of Btk Inhibition In Vivo (Blood 2007). (Ex.

1006.)

Blood 2007 discloses that there is increasing evidence indicating that B-cell

receptor (BCR) signaling is required for survival of non-Hodgkins lymphoma

(NHL) cells. (Id. at 1592.) Blood 2007 continues that there have been few

highly selective small molecule inhibitors of Btk, but the Patent Owner had

developed a series of covalent Btk inhibitors that target Cys-481 in Btk. (Id.)

Blood 2007 further discloses that PCI-32765 is a Cys-481 targeting Btk inhibitor

that has been optimized for potency, selectivity and pharmacokinetics. (Id.)

Blood 2007 also states that [i]n order to further characterize the selectivity and in

16

vivo potency of PCI-32765, we have developed PCI-33380, an active-site probe

consisting of a covalent Btk inhibitor linked to the fluorophore Bodipy-FL. (Id.).

In other words, Blood 2007 shows that PCI-33380 is an analog of PCI-

32765 linked to the fluorophore Bodipy-FL. (Ex. 1021 at 96.) Blood 2007 also

reports that Btk inhibition by PCI-32765 induces apoptotic cell death and inhibits

the growth of a variety of tumor cell lines derived from patients with different low-

grade (cell line DHL-4) and high-grade (cell lines DHL-6, WSU-DLCL2, OCI-

Ly10, DOHH2) B-cell lymphomas in vitro and in vivo. (Ex. 1006.) Further, a

POSA would have understood that the Patent Owner had developed PCI-32765

(and its analog PCI-33380) that showed significant promise as a treatment of B-

cell NHL, and that the compound would be evaluated in clinical trials. (Ex. 1021

at 42.) This would have led a POSA to look closely at the Patent Owners

development of PCI-32765 as a treatment for B-cell NHL.

Pan, Nature 2010 and MacPartlin Three additional prior art articles

(Pan, Nature 2010 and MacPartlin) combine with Blood 2007 to specifically

identify the chemical structure of PCI-32765. (Ex. 1021 at 46-48.) Pan

discloses certain selective irreversible inhibitors of Btk, including a compound

referred to as Compound 4. (Ex. 1005 at 59.) Compound 4 is drawn as a non-

stereospecific enantiomer in Scheme 1 and Table 3. Further in Table 3,

Compounds 13 and 14 in Pan are distinguished from Compound 4 as specific

17

stereo isomers. Compound 13 is the R enantiomer of Compound 4 and is now

known as ibrutinib. (Id.) Notably, Nature 2010 states that PCI-32765 is

compound 13 in ref. 25, and ref. 25 is cited as Pan. (Ex. 1023 at 91-92.)

Thus, Nature 2010 identifies the structure of PCI-32765 as R enantiomer called

Compound 13 in Pan.

Further, MacPartlin states that Compound 4 from Pan is known as PCI-

31523. (Ex. 1011 at 1354.) MacPartlin further discloses compound PCI-33380 is

the Bodipy-FL conjugate of the pure R enantiomer of PCI-31523, citing to Blood

2007. (Id. at 1355.) As established above, Blood 2007 shows that PCI-33380 is an

analog of PCI-32765 linked to the fluorophore Bodipy-FL.

A POSA would have understood from the combination of Pan, Nature 2008,

MacPartlin and Blood 2007 that PCI-32765 (used in clinical trial NCT00849654,

Ex. 1002) is the R-enantiomer of PCI-31253 (i.e., the R-enantiomer ofCompound

4 in Pan, which itself is Compound 13 in Pan). (Ex. 1021 at 48.) The R-

enantiomer of Compound 4 in Pan is now known as ibrutinib. Thus, the

combination of Blood 2007, Pan and MacPartlin discloses the structure of PCI-

32765 in the prior art.

The 582 Publication - At around the same time, the Patent Owner was

attempting to patent certain pharmaceutical compounds that inhibit Btk. (Ex. 1021

at 39.) A patent application covering these compounds was eventually published

18

as the 582 Publication on June 12, 2008. (Ex. 1003.) The 582 Publication

teaches compounds for a medicament for the inhibition of Brutons tyrosine

kinase (Btk) activity that can be orally administered to a human for the

treatment of cancer, including mantle cell lymphoma. (Id. at [0029]-[0030],

[0041].) The 582 Publication further teaches a dose range of 1-1500 mg per

day. (Id. at [0399].)

Example 2 of the 582 Publication discloses the Btk inhibitory activity of

twelve compounds in two in vitro assays. (Id. at Table 2.) The test data provided

in Table 2 of Example 2 of the 582 Publication discloses that Compound 13 has

the most potent Btk inhibitory activity in the acellular kinase assay. (Ex. 1003 at

[00458].) Compound 13 (now called ibrutinib) is the R-enantiomer of Compound

4. (Ex. 1021 at 47-48, 72, 76.) The 582 Publication further discloses that,

based on these test results, the R-configuration was determined as the slightly

preferred absolute stereochemistry configuration by two sets of enantiomers (11 vs.

12 and 13 vs. 14). (Ex. 1003 at [461] (emphasis added).)

The 582 Publication identifies PCI-32765 as Compound 4 of Example 2.

(Id.) Another reference in the PubChem Open Chemistry Database also identifies

PCI-32765 as Compound 4 in the 582 Publication. (Ex. 1012, entry for PCI-

32765 Racemate.) However, this is contradicted by the above-discussed

combination of Blood 2007, Pan and MacPartlin, which discloses PCI-32765 as the

19

R-enantiomer of Compound 4 in the 582 Publication (i.e., Compound 13 in the

582 Publication). As such, a POSA would understand that PCI-32765 was

disclosed by the prior art to be one of two structures: (1) ibrutinib (Compound 13

of Pan established by the combination of Blood 2007, Pan and MacPartlin) or (2) a

racemic mixture that contains ibrutinib (disclosed as Compound 4 of the 582

Publication). (Ex. 1021 at 46-48.)

The Clinical Trial Document (NCT00849654) - Subsequent to the above

references the Patent Owner published a notice of clinical trial NCT00849654 on

February 2, 2009. (Ex. 1002; see also Ex. 1021 at 44.) (NCT00849654). It

provides the details of a Phase I clinical study with PCI-32765, including

information about how PCI-32765 would be tested in patients with recurrent B-cell

Non-Hodgkins lymphoma according to the WHO definition that have failed 1 previous treatment for lymphoma. (Id.) NCT00849654 also discloses that PCI-

32765 would be orally administered once per day at six different doses, including

doses of 8.3 mg/kg/day, 12.5 mg/kg/day and 17.5 mg/kg/day. (Id.) The Patent

Owner anticipated recruiting 36 patients for the study. (Id.) As will be discussed

below, this reference anticipates claims 1 and 2 of the 090 patent.

The 2009 Press Release - The Patent Owner further disclosed in its 2009

Press Release that it had begun treating patients in a Phase I dose-escalation study

to evaluate the safety and tolerability of PCI-32765, an orally available, selective

20

inhibitor of Brutons tyrosine kinase, or Btk, as a potential treatment for patients

with relapsed or refractory B-cell non-Hodgkins lymphoma (NHL). (Ex. 1004 at

1; see also Ex. 1021 at 43.) The Patent Owner further reported in its 2009 Press

Release that Preliminary results from the Phase I trial show good patient

tolerability under conditions of Btk-drug occupancy with potent bioactivity in

targeted cell populations derived from the B-Cell lymphoma patients. (Id.)

VI. CLAIM CONSTRUCTION The terms of claims 1-2 are to be given their broadest reasonable

interpretation, as understood by one of ordinary skill in the art. See 37 C.F.R.

42.100 (b).

A. Treating

Claim 1 uses the term treating. According to the 090 patent treating

includes, alleviating, abating or ameliorating a disease or condition, or symptoms

thereof; managing a disease or condition, or symptoms thereof; preventing

additional symptoms; ameliorating or preventing the underlying metabolic causes

of symptoms; inhibiting the disease or condition, e.g., arresting the development of

the disease or condition; relieving the disease or condition; causing regression of

the disease or condition, relieving a condition caused by the disease or condition;

or stopping the symptoms of the disease or condition. The terms treat, treating

or treatment, include, but are not limited to, prophylactic and/or therapeutic

21

treatments. (Ex. 1001 at 27:26-37.) A POSA would understand that ameliorating

or preventing the underlying metabolic causes of symptoms includes inhibiting

Btk in a patient. (Id.; Ex. 1021 at 52.)

B. About

Claims 1 and 2 use the term about in the context of the dose to be

administered. Claim 1 states that the dose is about 420 mg to about 820 mg (id.

at col. 149:5), and claim 2 provides a dose of about 560 mg. (Id. at col. 149:28.)

The United States Court of Appeals for the Federal Circuit has held that the

claim term about does not have universal meaning in patent claims. Cohesive

Techs., Inc. v. Waters Corp., 543 F.3d 1351, 1368 (Fed. Cir. 2008)(citing Pall

Corp. v. Micron Separations, Inc., 66 F.3d 1211, 1217 (Fed. Cir. 1995)). Rather,

the term about avoids a strict numerical boundary to the specified parameter. Id.

Its range must be interpreted in its technological and stylistic context, which is

provided in the patent specification, the prosecution history, and other claims.

Ortho-McNeil Pharm. Inc. v. Caraco Pharm Labs., Ltd., 476 F.3d 1321, 1326

(Fed. Cir. 2007)(noting that [i]t is appropriate to consider the effects of varying

that parameter or that [e]xtrinsic evidence of meaning and usage in the art may

be helpful in determining the criticality of the parameter . . . .).

Here, about should have its ordinary meaning of approximately. Merck

& Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364, 1369-70 (Fed. Cir. 2005)

22

(reversing district courts construction of about as exactly because about had

its ordinary meaning of approximately). A POSA would understand about in

this context to encompass doses that are not materially different from the express

dose. This would include a 10% variance from the express dose because such a

difference has no material effect on patient treatment and the 090 patent makes no

distinction between doses of even greater difference in terms of efficacy,

tolerability or anything else. (Ex. 1021 at 54, 65, 84.)

C. Mantle Cell Lymphoma

Claim 1 uses the term mantle cell lymphoma. The 090 patent defines

mantle cell lymphoma as a subtype of B-cell lymphoma. (Ex. 1001 at col. 36:4-

5; see also Ex. 1013 at 524 (identifying MCL as one of 38 subtypes of B-cell

lymphoma).)

VII. GROUND 1: CLAIMS 1 AND 2 ARE ANTICIPATED BY NCT00849645

A patent claim is said to be anticipated, and thus invalid, if a single prior art

reference discloses, or a single prior art product or process embodies, each and

every element of the claimed invention. Glaxo Gp., Ltd. v. Apotex, Inc., 376 F.3d

1339, 1348 (Fed. Cir. 2004). These elements must be either expressly disclosed or

inherent. Elan Pharms. v. Mayo Found. for Med. Educ. & Research, 304 F.3d

1221, 1227 (Fed. Cir. 2002). Here, NCT00849654 meets the test for anticipation

of claims 1 and 2, rendering those claims invalid.

23

A. Claim 1: A method for treating mantle cell lymphoma in an individual who has already received at least one prior therapy for mantle cell lymphoma

NCT00849654 discloses this claim element. NCT00849654 is a Phase I

clinical study recruitment document involving the administration of PCI-32765 to

patients with recurrent B-cell lymphoma. (Ex. 1002.) Recurrent B-cell

lymphoma meant that patients enrolling in the study were required to have failed

1 previous treatment for lymphoma. (Id.) Recurrent B-cell lymphoma includes relapsed or refractory MCL (Ex. 1001

at col. 36:4-5), and a POSA would know this. (Ex. 1021 at 57.) Indeed,

NCT00849654 states that it defined recurrent B-cell lymphoma according to

WHO classification. (Ex. 1002 at 2.) The 2008 WHO classification of

lymphomas identifies MCL as one of 38 subtypes of B-cell lymphoma. (Ex. 1013

at 524.) As POSA would immediately envision each B-cell lymphoma subtype,

including MCL. Thus, this limitation is met. AbbVie, Inc. v. Mathilda and

Terrence Kennedy Inst. of Rheumatology Trust, 763 F.3d 1366, 1379-80 (Fed. Cir.

2014). Further, MCL accounts for 3-10% of all NHL. (Ex.1010 at1488.)

Consequently, a POSA would expect that at least some patients enrolled in the

Phase I clinical trial contemplated in NCT00849654 had refractory or relapsed

MCL. (Ex. 1021 at 58.)

24

Although it is not clear whether at the time NCT00849654 was published the

enrolled patients had received doses of PCI-32765, NCT00849654 meets the

treating element because it is inherent in the administration of PCI-32765. In re

Montgomery, 677 F.3d 1375, 1381-1382 (Fed. Cir. 2012) In Montgomery, the

Federal Circuit found that a prior art clinical trial document describing the design

of the clinical trial, but not providing results met the claim limitation for the

treatment or prevention of stroke, on the basis that even if the claim includes an

efficacy requirement, efficacy is inherent carrying out the claim steps. Id. at 1381.

The ability of PCI-32765 in treating MCL is inherent in its administration to

patients, which is described in NTC00849654.

Thus, NCT00849654 discloses a method for treating MCL, in patients that

have previously received at least one prior therapy. (Ex. 1021 at 56-59.)

B. Claim 1: Administeringan inhibitor of Bruton's tyrosine kinase (Btk) having the structure:

25

NCT00849654 discloses that it is a Phase I Dose-Escalation Study of

Brutons Tyrosine Kinase (Btk) Inhibitor PCI-32765. A POSA would have

known from other prior art references that PCI-32765 was either Compound 4

from the 582 Publication, or its R-enantiomer, Compound 13 (ibrutinib). (Ex.

1021 at 46-48, 74.)

As explained earlier, the combination of Pan, MacPartlin and Blood 2007

disclose PCI-32765 as ibrutinib, the structure set forth in claims 1 and 2 of the 090

Patent. These references can properly be used in an anticipation analysis to show

what a POSA would have understood PCI-32765 to be. In Re Samour, 571 F.2d

559, 563 (C.C.P.A. 1978). The 582 Publication and PubMed 2007 disclose that

PCI-32765 is Compound 4 from the 582 Publication, which is a racemic mixture

that would contain the ibrutinib, its R-enantiomer. A POSA seeking to determine

the structure of PCI-32765 would therefore understand that it is one of these two

26

compounds. (Ex. 1021 at 46-48, 60-61, 74.) Since a POSA would have

understood that PCI-32765 was one of two compounds, one of which is the

claimed structure (Compound 13) and the other of which is a racemic mixture

containing the claimed structure (Compound 4), this limitation is met by

NTC00849564. See In re Petering, 301 F.2d 676 (C.C.P.A. 1962) (explaining that

a prior art genus of compounds can anticipate a claimed species if the genus is

small enough that a POSA would immediately envisage all the members of the

genus).

C. Claim 1: Administering to the individual once per day between about 420 mg to about 840 mg of an oral dose

NCT00849654 discloses that PCI-32765 will be administered in 1.25, 2.5,

5.0, 8.3, 12.5 and 17.5 mg/kg/day dose cohorts orally once per day for 28 days in

order to establish the optimal dose of . . . PCI-32765. (Ex. 1002.)

A POSA would understand that 70 kilogram (kg) is the weight used for the

standard man in calculating drug doses. (Ex. 1011 at ch.7, p.16; Ex. 1021 at 62-

64.) This standard man construct is discussed in many publications. For example,

a January 2005 Public Health Assessment Guidance Manual (the 2005 Manual)

document explains that with respect to body weight the default assumption is that

the average adult weighs 70 kg (154 pounds). (Ex. 1011 at 7-16; Ex. 1021 at

64.) Therefore, to determine the daily dose given in NCT00849654, a person of

ordinary skill in the art would multiple the doses by 70 kg. The daily dose for the

27

8.3 mg/kg/day cohort would be 580 mg. This is within the dose range of claim 1.

It therefore anticipates the dosage of claim 1. Titanium Metals Corp. of Am. v.

Banner, 778 F.2d 775, 782 (Fed. Cir. 1985) (It is an elementary principle of

patent law that when, as by a recitation of ranges or otherwise, a claim covers

several compositions, the claim is anticipated if one of them is in the prior art.).

D. Claim 2: Wherein the once per day oral dose is about 560 mg

Claim 2 limits the dose to once per day oral dose is about 560 mg. As

explained above, NCT008849654 discloses a once daily oral dose of Compound 13

(ibrutinib) of 8.3 mg/kg/day. (Ex. 1004.) When using the standard 70 kg man

construct, this equates to 580 mg/day. A 580 mg dose differs from the claimed

dose of 560 mg by only 20 mg or 3%. A 560 mg dose in a 70 kg individual would

equate to 8.0 mg/kg/day. A POSA would understand that 580 mg/day is about

560 mg/day. (Ex. 1021 at 65-66.)

Moreover, the 090 patent says nothing about a 560 mg dose being preferred

or superior to any other disclosed dose. For example, the 090 patent also

discloses doses of 420 mg and 840 mg, but does not mention any difference in

safety or efficacy between the doses. (Ex. 1001 at 3:14-18.) Given that the patent

expresses no preference for doses that are 140 mg and 280 mg different from 560

mg, there is no reason to believe that a 580 mg dose would function any differently

than a 560 mg dose. The 090 Patent also says nothing about 560 mg being critical

28

to the invention. Therefore, for these reasons, a POSA would understand that 580

mg is about 560 mg. (Ex. 1021 at 66.)

Thus, the prior art discloses all of the elements of claims 1 and 2.Those

claims are therefore anticipated by NTC00849654.

VIII. GROUND 2: CLAIMS 1 AND 2 WOULD HAVE BEEN OBVIOUS

In addition to being anticipated, the claims of the 090 Patent would also

have been obvious. A patent may not be obtained . . . if the differences between

the subject matter sought to be patented and the prior art are such that the subject

matter as a whole would have been obvious at the time the invention was made to a

person having ordinary skill in the art to which said subject matter pertains. 35

U.S.C. 103(a). Underlying factual determinations in an obviousness analysis

include (1) the scope and content of the prior art, (2) the level of ordinary skill in

the art, (3) the differences between the claimed invention and the prior art, and (4)

secondary considerations of nonobviousness. Merck, 395 F.3d at 1369 (citing

Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)).

A. A POSA Would Have Been Motivated to Combine the Prior Art

Prior to June 3, 2009, a POSA would be interested in more tolerable and

efficacious treatments for relapsed or refractory B-cell NHLs. (Ex. 1021 at 86-

88.) One B-cell NHL where an improved therapy was needed was relapsed or

refractory MCL because after first-line therapy failed, few if any promising

29

treatment options existed. (Ex. 1021 at 58, 87.) Therefore, at the time of

the 090 Patent, a POSA would have been motivated to develop an effective drug

therapy for relapsed or refractory B-cell NHL, including MCL. (Id. at 87.)

Recognizing this need, a POSA would have had ample reason to combine

NCT00849654 with the 582 Publication and the 2009 Press Release in the search

for a better treatment options. (Id. at 88.) Each of those prior art references

comes directly from the Patent Owner and relates specifically to its development of

a Btk inhibitor shown to be effective for the treatment of refractory or relapsed B-

cell NHL. (Id.)

As discussed above, NCT00849654 discloses that PCI-32765 was in clinical

trials in patients with refractory or relapsed NHL, including MCL, and the 2009

Press Release discloses that promising results with respect to both efficacy and

tolerability were being obtained. (Ex. 1021 at 71.) The 582 Publication discloses

Compound 4 being PCI-32765 and that the R-enantiomer Compound 13 is

preferred over S-enantiomer based on potency data. (Ex. 1003 at [0458], Table 2.)

The 582 Publication also suggests that the compounds can be used to treat MCL.

(Ex. 1003 at [0036].) Certainly, a POSA looking for an improved therapy for

relapsed or refractory MCL would combine these teachings because they all are

from the Patent Owner and specifically describe a method that showed a promising

treatment for relapsed or refractory MCL. (Ex. 1021 at 88.) Knowing that PCI-

30

32765 was showing promise, a POSA would have been motivated to use

Compound 13, its R-enantiomer. (Id. at 75.)

B. The Prior Art Discloses the Elements of Claims 1 and 2

As shown on an element by element basis below, the prior art discloses all of

the elements of claims 1 and 2.

1. Claim 1: A method for treating mantle cell lymphoma in an individual who has already received at least one prior therapy for mantle cell lymphoma.

NTC00849564 discloses this limitation. (See Ex. 1002; see also Ex. 1021 at

68-71.) In addition, the 582 Publication teaches that the Btk inhibiting

compounds discussed therein, including Compound 13 (ibrutinib), are useful for

the treatment of mantle cell lymphoma. (Ex. 1003 at [0041].) In particular,

the 582 Publication states that [i]n further embodiments, the subject in need is

suffering from a cancer. In one embodiment, the cancer is a . . . mantle cell

lymphoma. (Id. at [0036].)

Furthermore, the 2009 Press Release discloses that the Patent Owner was

conducting a clinical study with a compound called PCI-32765 and that it is a

potential treatment for patients with relapsed or refractory B-cell non-Hodgkins

lymphoma (NHL). (Ex. 1004.) Patients with relapsed or refractory B-cell non-

Hodgkins lymphoma are those that have failed at least one previous treatment for

their disease. (Ex. 1021 at 43-44.) The Patent Owners Phase I clinical study

31

recruitment document, NCT00849654, requires that enrollees have failed 1 previous treatment for lymphoma, for study of involving recurrent B-cell

lymphoma. (Ex. 1002.) At the time, a POSA would have known that recurrent

B-cell lymphoma included relapsed or refractory MCL. (Ex. 1021 at 43-44.)

The 2009 Press Release also notes that [p]reliminary results from the Phase

I trial shows good patient tolerability under conditions of Btk-drug occupancy with

potent bioactivity in targeted cell populations derived from B-cell lymphoma

patients. (Ex. 1004.) Therefore, a POSA would understand from NCT00849654

and the 2009 Press Release that, in the Phase I trial, PCI-32765 showed both safety

and efficacy in patients with B-cell NHL. (Ex. 1021 at 71.) Thus, NCT00849654

and the 2009 Press Release disclose the claimed treating. Also, stated above, a

POSA would have expected that at least some patients enrolled in the Phase I

clinical trial contemplated in NCT00849654 had refractory or relapsed MCL

patients. (Id. at 70.)

Thus, a POSA of ordinary skill in the art would understand from the prior art

that PCI-32765 would treat B-cell NHL, including MCL, in patients that have

previously received at least one prior therapy.

2. Claim 1: AdministeringAn inhibitor of Brutons tyrosine kinase (Btk) having the structure:

32

Assuming, for the sake of argument only, that a POSA would have

understood that PCI-32765 was Compound 4 of the 582 Publication (i.e. the

racemate), and may not have been the R-enantiomer as disclosed in Pan/Nature

2008/MacPartlin/Blood 2007, this element would have been obvious. A POSA

would have understood that PCI-32765 was in clinical trials for the treatment of

NHL, including MCL, and that it was showing promising results. (Ex. 1021 at

72-80.) The 582 Publication discloses the compounds in the application are

useful to treat MCL. (Ex. 1003.) A POSA would have also understood from

the 582 Publication that Compound 13 is the R-enantiomer of the racemate

Compound 4. (Ex. 1021 at 46.) The 582 Publication discloses that Compound

13 is the most potent Btk inhibitor tested in one of the two in vitro assays, and

further expresses a preference for Compound 13 over the S-enantiomer, Compound

14. (Ex. 1003 at [0461].)

33

Specifically, Example 2 of the 582 Publication provides potency data in the

form of Btk IC50 and Ramos Cell Ca Flux IC50 assays on twelve compounds. (Id.

at [0455-0461].) For both assays, a lower value indicates a greater potency at

inhibiting Btk. Compound 13 is the most potent compound of the twelve. (Id. at

[0458], Table 2.) Based on this data, a POSA would have found Compound 13

was the best candidate for a pharmaceutical drug.

As discussed above, a POSA would have further known that Compound 4 is

a racemate, that Compound 13 is the R-enantiomer, and it is preferred over the S-

enantiomer (Compound 14). (Ex. 1002 at Table 2; [0455-0461].) This expressed

preference for Compound 13 over Compound 14 is supported by the potency data

in Table 2. (Id. at [0455-0461].)

By this time, it was also well-known that single enantiomer formulations

can provide greater selectivities for their biological targets, improved therapeutic

indices, and/or better pharmacokinetics than a mixture of enantiomers. (Ex. 1021

at 79; Ex. 1009 at 72.) Thus, a POSA knowing that Compound 4 was in clinical

trials to treat NHL, including MCL, would have expected Compound 13 to treat

relapsed or refractory MCL at the claimed dose, and would likely be more potent

than Compound 4. As a result, a POSA would have been motivated to administer

Compound 13 to a patient to treat refractory or relapsed MCL. (Ex. 1021 at 79.)

3. Claim 1: Administering to the individual once per day between about 420 mg to about 840 mg of an oral dose

34

NCT00849654 discloses that PCI-32765 will be administered in 1.25, 2.5,

5.0, 8.3, 12.5 and 17.5 mg/kg/day dose cohorts orally once per day for 28 days in

order to establish the optimal dose of . . . PCI-32765. (Ex. 1004.) A POSA

would have understood that finding a dose that would treat the disease from the six

dose levels contemplated in NCT008849654 would have been a matter of routine

experimentation. (Ex. 1021 at 81-83; Ex. 1008.) A POSA would also have

expected at least one of the doses in the study would treat relapsed B-cell NHL.

(Ex. 1021 at 82.) In fact, a POSA would perform the same experimentation

contemplated in NCT00849654 to find a dose that treats B-cell NHL. (Id.)

Using the 70 kg person construct discussed above, the daily dose for the

17.5mg/kg/day cohort is 1225mg/day of Compound 4. A POSA would have

expected that half of this dose, 612.5mg, was the R enantiomer, Compound 13.

(Id. at 83.) This is within the dose range of claim 1.

The 582 Publication further explains that doses employed for adult human

treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-

1500 mg per day. (Ex. 1003 at [0399].) This prior art dose range encompasses

the range claimed in claim 1 of the 090 patent. The Federal Circuit has previously

held that [a] prima facie case of obviousness typically exists if the ranges of the

claimed composition overlap the ranges disclosed in the prior art. In re Peterson,

315 F.3d 1325, 1329 (Fed. Cir. 2003); Galderma Labs., L.P. v. Tolmar, Inc., 737

35

F.3d 731, 738 (Fed. Cir. 2013) ([W]here there is a range disclosed in the prior art,

and the claimed invention falls within that range, the burden of production falls

upon patentee to establish the nonobviousness of the range.). Unless the claimed

range is critical or is demonstrated that claimed method works differently at the

claimed range as compared to the prior art range, there is no considerable

difference between the claimed range and the range in the prior art. ClearValue,

Inc. v. Pearl River Polymers. Inc., 668 F.3d 1340, 1345 (Fed. Cir. 2012). During

patent prosecution of the 090 patent, the applicant failed to demonstrate any

criticality of the claimed range over the prior art range.

4. Claim 2: Wherein the once per day oral dose is about 560 mg

Claim 2 limits the dose to once per day oral dose is about 560 mg. As

explained above, NCT008849654 discloses a once daily oral dose of 17.5

mg/kg/day. (Ex. 1002; see also Ex. 1021 at 84-85.) When using the standard 70

kg man construct, this equates to 1225 mg/day of Compound 4, of which

Compound 13 constitutes 612.5 mg. A 612.5 mg dose differs from the claimed

dose of 560 mg by less than 10%, and thus is about 560 mg/day.

Moreover, the 090 patent says nothing about a 560 mg dose being preferred

or superior to any other disclosed dose. For example, the 090 patent also

discloses doses of 420 mg and 840 mg, but does not mention any difference in

safety or efficacy between the doses. (Ex. 1001 at 3:14-18.) Given that the patent

36

expresses no preference for doses that are 140 mg and 280 mg different from 560

mg, there is no reason to believe that a 612.5 mg dose would function any

differently than a 560 mg dose. The 090 patent also says nothing about 560 mg

being critical to the invention. Therefore, for this additional reason a POSA would

understand that 612.5 mg is about 560 mg.

Thus, the prior art discloses all of the elements of claims 1 and 2.

C. A POSA Would Have Had a Reasonable Expectation of Success

A showing that a POSA would have had a reasonable expectation of success

in carrying out the claimed method strengthens the obviousness analysis. (Ex.

1021 at 89-97.) A reasonable expectation of success does not require conclusive

proof or certainty of success. Hoffmann La Roche, Inc. v. Apotex Inc., 748 F.3d

1326, 1331 (Fed. Cir. 2014) (Conclusive proof of efficacy is not necessary to

show obviousness. All that is required is a reasonable expectation of success.); In

re OFarrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988) (absolute predictability not

required). Nor does evidence of superior efficacy . . . undercut a showing that

there was a reasonable expectation of success . . . . Hoffmann La Roche, Inc., 748

F.3d at 1334 (finding patented invention invalid as obvious and stating that while

the evidence showed the patented invention has superior efficacy such superior

efficacy did not negate the showing that there was a reasonable expectation of

success). Even in unpredictable arts, obviousness cannot be avoided simply by a

37

showing of some degree of unpredictability in the art so long as there was a

reasonable probability of success. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,

1364 (Fed. Cir. 2007); see also In re OFarrell, 853 F.2d at 903.

Here, a POSA would have had a reasonable expectation of success that

Compound 13 would treat patients with MCL at the claimed doses. (Id. at 90.)

NCT00849654 discloses doses that would be expected to be useful in treating

the disease. (Ex. 1002.) The 2009 Press Release further touts PCI-32765 as a

potential treatment for patients with relapsed or refractory B-cell non-Hodgkins

lymphoma (NHL). (Ex. 1004.) The 2009 Press Release further notes that the

Phase I trial [with PCI-32765] shows good patient tolerability under conditions of

Btk-drug occupancy with potent bioactivity in targeted cell populations derived

from B-cell lymphoma patients. (Id.)

The 582 Publication clearly suggested Compound 13 and its use to inhibit

Btk in patients with B cell NHL, including mantle cell lymphoma. (Ex. 1003

at [0036].) Knowing this, a POSA would have also had a reasonable expectation

that Compound 13, the R-enantiomer of Compound 4 would work just as well as

Compound 4 in this regard, if not better. (Id. at 95.)

D. The Claimed Method Would Have Been Obvious to Try

At the very least, a POSA would have found it obvious to try to use

Compound 13 for the treatment of relapsed or refractory B-cell NHL, including

38

MCL, at the claimed doses. A method with a finite number of identified,

predictable solutions that is obvious to try based on the prior art is also likely to be

obvious. Bayer Schering Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1347-48

(Fed. Cir. 2009); In re Kubin, 561 F.3d 1351, 1359-60 (Fed. Cir. 2009). Indeed,

[m]ost inventions that are obvious are also obvious to try. Bayer Schering

Pharma AG, 575 F.3d at 1347. The only exception to this rule is where the prior

art is vague such that it does not guide the inventor toward the solution or where a

POSA would be required to vary all parameters or try each of numerous possible

choices until one possibly arrived at a successful result, where the prior art gave

either no indication of which parameters were critical or no direction as to which

of many possible choices is likely to be successful . . . . Id.; In re Kubin, 561

F.3d at 1359. Neither exception applies here.

At the time of the 090 Patent there was a recognized need for a therapy to

treat relapsed or refractory B-cell NHL, including MCL. That need was clear to

POSAs treating the disease and was documented in prior art such as the 2009 Press

Release. (Ex. 1004.) The Patent Owner provided a POSA with a finite number of

predictable solutions for the need. Specifically, the 2009 Press Release explains

that it had a compound, PCI-32765, that showed tolerability and efficacy in human

patients with refractory or relapsed B-cell NHL. (Id.) In the 582 Publication, the

Patent Owner identified a list of 12 compounds, the best of which was Compound

39

13. Finally, NCT0084964 revealed important dosing guidance for PCI-32765.

Thus, a POSA would have tried Compound 13 for the treatment of refractory or

relapsed MCL at the doses prescribed in NCT0084964.

E. There are No Secondary Considerations Rebut Obviousness

Petitioner is unaware of any secondary considerations of non-obviousness

that would rebut a finding of the obviousness of claims 1-2 of the 090 Patent.

(Ex. 1021 at 98-102.) During prosecution the examiner issued a final office

action rejecting patentees application under 35 U.S.C. 103. (Ex. 1018 at 3.) In

response the applicant did not address the substantive teachings of the art identified

by the examiner, but instead changed the focus to the clinical results achieved by

the claimed method. (Ex. 1019 at 5.) In particular, the applicant presented data

from a clinical study involving the treatment of MCL with ibrutinib and compared

the results with a prior therapy. The applicant argued that compared to the prior

therapy, the claimed method exhibited remarkable clinical results and that such

results were unexpected. (Id.) The examiner bought the applicants unexpected

results argument and allowed the claims on that basis. (Ex. 1020.)

The applicants reliance on such results is misplaced because those results

are entitled to no patentable weight for at least two reasons. First, for unexpected

results to be probative of nonobviousness, they must be in comparison to the

closest prior art. In re Baxter Travenol Labs, 952 F.2d 388, 392 (Fed. Cir. 1991)

40

(explaining the results must be shown to be unexpected compared with the closest

prior art); Pfizer, 480 F.3d at 1370-71 (holding that unexpected results must be

compared to closest prior art compound, noting that the district court had little, if

any, evidence to support its conclusion that amlodipine maleate was the closest

prior art compound, and finding patent invalid as obvious). During prosecution,

the applicant compared the claimed method to an existing treatment that was not

the closest prior art. The closest prior art is Compound 13 (ibrutinib) itself for use

in treating relapsed or refractory B-cell NHL, including MCL, and not some other

existing therapy. The Patent Owner cannot show unexpected results under the

proper comparison because the closest prior art results would be the same as the

results achieved by patented method. In other words, the use of ibrutinib to treat

MCL in the claims of the 090 Patent cannot be unexpectedly superior to the use of

ibrutinib to treat relapsed or refractory MCL as disclosed in the prior art. The 090

Patent merely claims a known utility for Compound 13treatment of MCL. That

known utility therefore cannot be unexpected. AbbVie, 764 F.3d 1011-12.

Second, the alleged unexpected results are an inherent result of a known

method. Newly discovered results of known processes directed to the same

purpose are not patentable because such results are inherent. Bristol-Myers

Squibb Co. v. Ben Venue Labs., 246 F.3d 1368, 1376 (Fed. Cir. 2001); see also,

e.g., In re Huai-Hung Kao, 639 F.3d 1057, 1069 (Fed. Cir. 2011) (an inherent

41

property adds nothing of patentable consequence); King Pharms., Inc. v. Econ

Labs., Inc., 616 F.3d 1267, 1275 (Fed. Cir. 2010) ([M]erely discovering and

claiming a new benefit of an old process cannot render the process again

patentable. Such newly discovered benefits are not patentable because they are

inherent in the prior art.). Indeed the Federal Circuit has specifically held that the

efficacy of a method of treatment with a drug is inherent carrying out the claim

steps. In re Montgomery, 677 F.3d at 1381-1382 (even if the claim includes

efficacy requirement, efficacy is inherent carrying out the claim steps.)

Whether a property or result is inherent not only applies to anticipation, but

also to obviousness. In re Huai-Hung Kao, 639 F.3d at 1070; Santarus, Inc. v. Par

Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) (holding an obvious

formulation cannot become nonobvious simply by administering it to a patient and

claiming the resulting serum concentrations); Emi Group N. Am. v. Cypress

Semiconductor Corp., 268 F.3d 1342, 1350-51 (Fed. Cir. 2001) (discussing

inherency in the context of anticipation and obviousness); see also In re Alford,

300 F.2d 929, 931, 933 (C.C.P.A. 1962) (affirming Examiners obviousness

rejection and agreeing with Examiner that an unexpected result is not considered

persuasive since the result set forth by applicant is inherent in the obvious

combination of the references and hence does not confer patentability on the

claimed combination).

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Here, as explained above, the prior art renders the claimed method obvious.

A POSA would have expected that the administration of Compound 13 would be

useful in treating relapsed or refractory MCL. The degree of the clinical results

achieved in patients is simply the natural and necessary consequence of performing

this obvious method. (Ex. 1021 at 101). To the extent such a method produces

the claimed unexpected results, so does the prior art. (Id.)

Whether those skilled in the art would have recognized or appreciated the

extent of the efficacy is of no moment. Emi Group N. Am., 268 F.3d at 1351 (A

person of ordinary skill does not need to recognize that a method or structure

behaves according to a law of nature in order to fully and effectively practice the

method or structure.); MEHL/Biophile Int'l Corp. v. Milgraum, 192 F.3d 1362,

1365-66 (Fed. Cir. 1999); see also In re Huai-Hung Kao, 639 F.3d at 1070. The

express teachings of the relevant prior art render the claimed method of treating

refractory MCL with ibrutinib obvious, and the alleged unexpected results are

inherent to the method and add nothing of patentable consequence.

Finally, when faced with a final rejection during prosecution, the applicant

did not allege any secondary considerations other than the unexpected results

addressed above. (Ex. 1013 at 5.) The Petitioner is unaware of any arguments or

evidence supporting secondary considerations of non-obviousness. Further, any

secondary considerations asserted by the patent owner here would not be sufficient

43

to overcome the strong case of obviousness set forth above. Indeed, the claimed

subject matter is nothing more than the predictable use of a known compound

having a known function. This overcomes any evidence of secondary

considerations. See Pfizer, Inc., 480 F.3d at 1372.

IX. CONCLUSION

For at least the reasons given above, claims 1 and 2 of the 090 Patent are

unpatentable because they are anticipated by and are obvious over the prior art.

Petitioner respectfully requests that the Board institute an Inter Partes Review of

claims 1 and 2 on the grounds of obviousness set forth above.

Respectfully submitted,

Date: April 20, 2015 By: /Jeffrey S. Ward/ 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 FAX: (612) 332-9081 Counsel for Petitioner

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CERTIFICATE OF SERVICE ON PATENT OWNER

Pursuant to 37 C.F.R. 42.6(e), the undersigned certifies that on the 1st

day of April, 2015, a complete and entire copy of this Petition for Inter Partes

Review Under 37 C.F.R. 42.100, alongside an accompanying Power of Attorney,

Appendix of Exhibits, and Exhibits 1001-1023, were provided via electronic mail

and UPS, postage prepaid, to the Patent Owner by serving the correspondence

address of record for the 886 patent.

Attorney of Record Attn: Michael J. Hostetler, Ph.D. Wilson Sonsini Goodrich & Rosati 650 Page Mill Road Palo Alto, CA 94303 mhostetler@wsgr.com

Respectfully submitted, MERCHANT & GOULD P.C.

BY: /Jeffrey S. Ward/ 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 FAX: (612) 332-9081