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.

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.
V.

IV.

Evidence Relied Upon to Support the Challenge ..........................10

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

CLAIM CONSTRUCTION ...................................................................................20

A.

Treating ..................................................................................................20

B.

About ......................................................................................................21

C.

Mantle Cell Lymphoma..........................................................................22

i

VII.

VII.

VIII.

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

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

CONCLUSION ......................................................................................................43

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 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

iii

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

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. 311319 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

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,

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.

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

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).

D.

Notice of Service Information

Papers concerning this matter should be served by Express Mail, handdelivery, 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)

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
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. 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).

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

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. 149:2627.)
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

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

12

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 4950.) 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.)

13

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.

14

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

15

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 PCI32765 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 lowgrade (cell line DHL-4) and high-grade (cell lines DHL-6, WSU-DLCL2, OCILy10, 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 Bcell 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 nonstereospecific enantiomer in Scheme 1 and Table 3. Further in Table 3,
Compounds 13 and 14 in Pan are distinguished from Compound 4 as specific

16

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 PCI31523. (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 Renantiomer of Compound 4 in Pan is now known as ibrutinib. Thus, the
combination of Blood 2007, Pan and MacPartlin discloses the structure of PCI32765 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

17

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 PCI32765 Racemate.) However, this is contradicted by the above-discussed
combination of Blood 2007, Pan and MacPartlin, which discloses PCI-32765 as the

18

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 PCI32765 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

19

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

20

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)

21

(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. 36:45; 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.
22

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.)

23

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:

24

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

25

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 6264.) 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
26

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

27

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 8688.) 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

28

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 Bcell 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-

29

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 nonHodgkins 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

30

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:

31

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].)

32

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 Senantiomer (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
33

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 11500 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
34

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
35

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

36

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

37

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

38

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)

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(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

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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

42

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

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