IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`C.A. No. 18-192 (CFC)
`CONSOLIDATED
`
`CONFIDENTIAL f SUBJECT TO
`PROTECTIVE ORDER
`
`))))))))))
`
`PHARMACYCLICS LLC and
`JANSSEN BIOTECH, INC.,
`
`Plaintiffs,
`
`v.
`
`FRESENIUS KABI USA, LLC, et al.,
`
`Defendants.
`
`EA5>CH>;;Gg ;>FGH GIEEA9B9CH5A F9GEDCG9G HD 89;9C85CHGg
`FIRST SET OF JOINT INTERROGATORIES (NOS. 1f4)
`
`Pursuant
`
`to Rules 26 and 34 of the Federal Rules of Civil Procedure, Plaintiffs
`
`K_XidXZpZc‘Zj GG> ({K_XidXZpZc‘Zj| fi {K>T>|) Xe[ EXejj\e =‘fk\Z_* DeZ, ({EXejj\e|)
`
`(Zfcc\Zk‘m\cp* {KcX‘ek‘]]j|) _\i\Yp gifm‘[\ k_\‘i ]‘ijk jlggc\d\ekXc i\jgfej\j kf ?\]\e[Xekj~ A‘ijk
`
`Set of Joint Interrogatories (Nos. 1y4), served by Defendants Fresenius Kabi USA, LLC and
`
`Ai\j\e‘lj FXY‘ JeZfcf^p G‘d‘k\[ (Zfcc\Zk‘m\cp* {Ai\j\e‘lj FXY‘|)9 Up[lj Rfic[n‘[\ ?H>>
`
`Xe[ >X[‘cX C\Xck_ZXi\ G‘d‘k\[ (Zfcc\Zk‘m\cp* {Up[lj|)9 Nle K_XidX BcfYXc AU@ Xe[ Nle
`
`Pharmaceutical Industries LTD (coll\Zk‘m\cp* {Nle|)9 Xe[ >‘gcX G‘d‘k\[ Xe[ >‘gcX PN< DeZ,
`
`(Zfcc\Zk‘m\cp* {>‘gcX|)* fe N\gk\dY\i 5* 0./6, Je N\gk\dY\i /6* 0./6* NXe[fq DeZ, Xe[ G\b
`
`K_XidXZ\lk‘ZXcj ?,?, (Zfcc\Zk‘m\cp* {NXe[fq|) af‘e\[ Xj n\cc, See C.A. No. 18-275 (CFC) (D.I.
`
`67) (D. Del. Sept. 18, 2018). Fresenius Kabi, Zydus, Sun, Cipla, and Sandoz are collectively
`
`i\]\ii\[ kf Xj {?\]\e[Xekj| _\i\‘e,
`
`

`

`IV.
`
`The Method Patents Are Valid
`
`Pursuant to Fed. R. Civ. P. 33(d), and subject to and without waiver of the foregoing
`
`objections, Plaintiffs refer Defendants to the following documents1:
`
`’ P,N, KXk\ek If, 6*532*.7. ({k_\ ~.7. KXk\ek|)
`’ P,N, KXk\ek If, 7*/03*667 ({k_\ ~667 KXk\ek|)
`’ P,N, KXk\ek If, 6*777*777 ({k_\ ~777 KXk\ek|)
`’ U.S, KXk\ek If, 7*6./*66/ ({k_\ ~66/ KXk\ek|)
`’ P,N, KXk\ek If, 7*6./*661 ({k_\ ~661 KXk\ek|)
`’ P,N, KXk\ek If, /.*...*524 ({k_\ ~524 KXk\ek|)
`’ P,N, KXk\ek If, 7*573*4.2 ({k_\ ~4.2 KXk\ek|)
`
`Plaintiffs further refer Defendants to the prosecution histories of these patents:
`
`’
`’
`’
`’
`’
`’
`’
`
`~.7. KXk\ek A‘c\ C‘jkfip
`~667 KXk\ek A‘c\ C‘jkfip
`~777 KXk\ek A‘c\ C‘jkfip
`~66/ KXk\ek A‘c\ C‘jkfip
`~661 KXk\ek A‘c\ C‘jkfip
`~524 KXk\ek A‘c\ C‘jkfip
`~4.2 KXk\ek A‘c\ C‘jkfip
`
`O_\ Xjj\ik\[ ZcX‘dj f] k_\ ~.7.* ~667* ~777* ~66/* ~661* ~524* Xe[ ~4.2 KXk\ekj
`
`(Zfcc\Zk‘m\cp* k_\ {H\k_f[ KXk\ekj|) Xi\ gi\jld\[ mXc‘[, De Zfej‘[\i‘e^ fYm‘flje\jj* k_\ >flik
`
`must assess (1) the scope and content of the prior art, (2) the differences between the claimed
`
`invention and the prior art, (3) the level of ordinary skill in the art, and (4) objective indicia of
`
`non-obviousness. To prove an invention is invalid for obviousness, defendants must demonstrate
`
`{Yp Zc\Xi Xe[ Zfem‘eZ‘e^ \m‘[\eZ\ k_Xk X jb‘cc\[ Xik‘jXe nflc[ _Xm\ Y\\e dfk‘mXk\[ kf ZfdY‘e\
`
`the teachings of the prior art references to achieve the claimed invention, and that the skilled
`
`Xik‘jXe nflc[ _Xm\ _X[ X i\XjfeXYc\ \og\ZkXk‘fe f] jlZZ\jj ‘e [f‘e^ jf,| Procter & Gamble Co.
`
`v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009). Defendants have not and will not
`
`Y\ XYc\ kf d\\k k_Xk Yli[\e, O_\‘i DemXc‘[‘kp >fek\ek‘fej ]X‘c kf X[\hlXk\cp [‘jZcfj\ ?\]\e[Xekj~
`
`1 U.S. Patent No. 9,814,721 is no longer at issue in the litigation.
`
`18
`
`

`

`obviousness theories, let alone establish obviousness by the requisite clear and convincing
`
`evidence. The asserted claims of the Method Patents would not have been obvious to a person of
`
`fi[‘eXip jb‘cc ‘e k_\ Xik ({KJN<|),
`
`1.
`
`FQ_\[Z_Q H[ 8QRQZPMZ‘_g E[_U‘U[Z DZ HTQ AQbQX DR D^PUZM^e GWUXX >Z HTQ
`Art
`
`Issues of obviousness are viewed from the perspective of the hypothetical POSA as of the
`
`time of ‘em\ek‘fe, ?\]\e[Xekj~ DemXc‘[‘kp >fek\ek‘fej [f efk ‘[\ek‘]p X gligfik\[ KJN< ]fi k_\
`
`asserted claims of the Method Patents. Defendants reference such a person throughout their
`
`contentions, but have not specified the level of ordinary skill on which their Invalidity
`
`>fek\ek‘fej Xi\ YXj\[, O_\p j‘dgcp jkXk\ k_Xk {X KJN< nflc[ ^\e\iXccp ‘eZcl[\ ‘e[‘m‘[lXcj*
`
`either alone or collectively, having experience in and/or an understanding of the treatment of
`
`cancer patients and other disorders associated with treat‘e^ ZXeZ\i gXk‘\ekj,| ?\]\e[Xekj~
`
`contentions are therefore deficient. In any event, under any appropriate definition of a POSA the
`
`asserted claims of the Method Patents would not have been obvious as of their priority date.
`
`2.
`
`The PTO Considered The Subject BM‘‘Q^ DR BMZe DR 8QRQZPMZ‘_g 7U‘QP
`References
`
`?\]\e[Xekj~ fYm‘flje\jj Xi^ld\ekj i\^Xi[‘e^ k_\ H\k_f[ KXk\ekj Xi\ gi‘dXi‘cp YXj\[ fe
`
`references which were considered by the examiner during prosecution, including at least: the
`
`Archive History for NCT00849652* P,N, IXk‘feXc G‘YiXip f] H\[‘Z‘e\ ({k_\ ~432 >c‘e‘ZXc
`
`Oi‘Xc|)9 Kfccp\X \k Xc,* A phase I dose escalation study of the Btk inhibitor PCI-32765 in relapsed
`
`and refractory B cell non-Hodgkin lymphoma and use of a novel
`
`fluorescent probe
`
`pharmacodynamics assay, 114 BLOOD 15/1 (0..7) ({Kfccp\X|)9 {K_XidXZpZc‘Zj* DeZ, <eefleZ\j
`
`Presentation of Interim Results from Phase I Trials of Its First-In-Human Btk Inhibitor PCI-
`
`10543*| KMI\njn‘i\ (?\Z\dY\i 5* 0..7) ({KM I\njn‘i\|)9 {K_XidXZpZc‘Zj De‘k‘Xk\j K_Xj\ /
`
`Clinical Trial of Novel Oral Btk Inhibitor for Refractory B-cell Non-Cf[^b‘e~j Gpdg_fdX*|
`
`19
`
`

`

`KMI\njn‘i\ (<gi‘c /1* 0..7) ({KM I\njn‘i\ <gi‘c 0..7|)9 <[mXe‘* Effect of Btk Inhibitor PCI-
`
`32765 monotherapy on responses in patients with relapsed aggressive NHL: Evidence of
`
`antitumor activity from a phase I study, J. CLIN. ONCOLOGY (HXp 0./.) ({<[mXe‘|)9 <iZ_‘m\
`
`C‘jkfip ]fi I>O.//.3025* P,N, IXk‘feXc G‘YiXip f] H\[‘Z‘e\ ({k_\ ~025 >c‘e‘ZXc Oi‘Xc|)9 k_\
`
`<KD KXk\ekj9 P,N, KlYc‘j_\[ KXk\ek <ggc‘ZXk‘fe If, 0..6-..5470/ ({k_\ ~70/ KlYc‘ZXk‘fe|)9 KXe
`
`et al., ;YcS_fUbi _V IU\USdYfU @bbUfUbcYR\U @^XYRYd_bc V_b 8bed_^lc Jib_cY^U BY^QcU, 2
`
`CHEMMEDCHEM 36 (0..5) ({KXe|)9 ?Xm‘j \k Xc,* Chronic Active B Cell Receptor Signaling in
`
`Diffuse Large B Cell Lymphoma, 463 NATURE 66 (0./.) ({?Xm‘j 0./.|)9 BcXjjdXe \k Xc,* The
`
`Value of Fluorescence In Situ Hybridization in the Diagnosis and Prognosis of Chronic
`
`Lymphocytic Leukemia, 158 CANCER GENETICS & CYTOGENETICS 66 (0..3) ({BcXjjdXe|)9 Xe[
`
`Hagemeister, Rituximab for the Treatment of Non-?_TW[Y^lc Ci]‘X_]Q Q^T 9Xb_^YS
`
`Lymphocytic Leukaemia, 70 DRUGS 04/ (0./.) ({CX^\d\‘jk\i|),
`
`Patent examiners are presumed to have considered prior art references listed on the face
`
`of the patent. Shire LLC v. Amneal Pharm., LLC, 802 F.3d 1301, 1307 (Fed. Cir. 2015). Because
`
`the PTO considered the subject matter of these references during the prosecution of the Method
`
`KXk\ekj* ?\]\e[Xekj _Xm\ efk d\k Xe[ n‘cc efk d\\k {k_\ X[[\[ Yli[\e f] fm\iZfd‘e^ k_\
`
`deference that is due to a qualified governmeek X^\eZp gi\jld\[ kf _Xm\ gifg\icp [fe\ ‘kj afY,|
`
`Id. The additional references Defendants cite would not in any way change the conclusion the
`
`examiner reached regarding the non-obviousness of the claims.
`
`3.
`
`The Asserted Claims Would Not Have Been Obvious To A Person of
`Ordinary Skill In The Art
`
`The asserted claims of the Method Patents would not have been obvious to a POSA.
`
`?\]\e[Xekj~ fYm‘flje\jj k_\fi‘\j* Xj [‘jZcfj\[ ‘e k_\‘i KXiX^iXg_ DQ c\kk\ij Xe[ De‘k‘Xc DemXc‘[‘kp
`
`Contentions, are hindsight-driven and unsupported. A POSA would have had no reason to focus
`
`20
`
`

`

`narrowly on ibrutinibzignoring other compounds known at the time of inventionszto develop
`
`the claimed methods for once-daily oral administration at the claimed dosages. Moreover, even if
`
`a POSA were to focus on ibrutinib, a POSA would not have had a reasonable expectation of
`
`success in achieving the claimed methods, particularly in light of at least the difficulty of treating
`
`the diseases of the claims.
`
`a)
`
`No Motivation To Select Ibrutinib For Treating The Claimed Cancers Of
`The Method Patents
`
`A POSA would not have been motivated to select ibrutinib for the treatment of any of the
`
`jg\Z‘]‘Z ZXeZ\ij f] k_\ ~.7. KXk\ek (H>G)* k_\ ~667 KXk\ek (RH)* k_\ ~777 KXk\ek (i\cXgj\[*
`
`i\]iXZkfip >GG-NGG)* k_\ ~66/ KXk\ek (>GG)* k_\ ~661 KXk\ek (>GG-NGG)* Xe[ k_\ ~524 KXk\ek
`
`(>GG-NGG) (k_\ {>cX‘d\[ >XeZ\ij f] k_\ H\k_f[ KXk\ekj|), O_\i\ n\i\ mXi‘flj ZcXjj\j f] [il^j
`
`under investigation for the treatment of each of the different cancers in the claims of the Method
`
`Patents, and a POSA would have had no reason to limit the scope of compounds that they were
`
`considering developing to protein kinase inhibitors. In addition to kinase inhibitors, illustrative
`
`examples of drugs under investigation include antibodies, chemotherapies, immunomodulators,
`
`small molecule immunopharmaceuticals, and HDAC inhibitors. Many of these compounds were
`
`at a more advanced stage of investigation, and thus would have been more attractive to a POSA
`
`seeking to develop treatments for the Claimed Cancers of the Method Patents.
`
`Even if a POSA were to focus only on protein kinase inhibitors, and there was no reason
`
`to do so, there were different kinase inhibitors being pursued at the time of the invention.
`
`Inhibitors of non-tyrosine kinases, such as phosphatidylinositol 3-kinase (PI3kinase), protein
`
`kinase D, and checkpoint kinases, were being pursued for the treatment of cancer at the time of
`
`the claimed inventions. Even within the genus of tyrosine kinase inhibitors, there were many
`
`potential compounds. In fact, the specific kinase to be targeted to inhibit the B-cell receptor
`
`21
`
`

`

`pathway was not well-understood at the time. For example, scientists at the time of inventions
`
`were pursuing fostamatinib, a reversible Syk inhibitor, for the treatment of non-Hodgkins
`
`lymphoma and CLL. There was no precedent for an FDA-approved drug that inhibited BTK;
`
`Imbruvica is a first-in-class BTK inhibitor.
`
`Even if a POSA were to focus narrowly on BTK inhibitors, and there was no reason to do
`
`so, a number of different potential BTK inhibitors (e.g., LFM-A13) were disclosed in the
`
`literature at time of invention. Defendants have not established that a POSA would have selected
`
`ibrutinib out of all potential BTK inhibitors. Relatedly, a POSA would have been concerned
`
`about using ibrutinib as a therapeutic drug candidate because ibrutinib binds BTK irreversibly
`
`through covalent bonding, a characteristic generally seen as undesirable in a pharmaceutical
`
`compound. Numerous drug candidates with Michael acceptors, such as EGFR inhibitors Pelitinib
`
`(EKB-569) (Wyeth) and canertinib (CI-1033) (Parke-Davis (Pfizer)), did not progress past Phase
`
`II clinical trials. Likewise, a POSA would also not have had a reasonable expectation of success
`
`in using ibrutinib according to the Method Patents because it contains a Michael acceptor and
`
`binds covalently to its target.
`
`b)
`
`No Motivation To Select Ibrutinib For Treating cGVHD
`
`A POSA would also not have been motivated to select ibrutinib for the treatment of
`
`Z_ife‘Z BQC? ({ZBQC?|)* Xj ZcX‘d\[ ‘e k_\ ~4.2 Katent. The standard treatments for cGVHD
`
`at the time focused on inhibiting or interfering with T-cell signaling. While there was a long-felt
`
`need for better treatments, a POSA would not have selected ibrutinib from published patent
`
`applications that were not focused on cGVHD. Although there were no treatments approved by
`
`FDA specifically for cGVHD, the standard treatments used at the time of inventions were T-cell
`
`oriented. For example, corticosteroids, with or without the addition of calcineurin inhibitors
`
`22
`
`

`

`(immunosuppressants), such as tacrolimus and cyclosporine, were considered mainstay
`
`treatments.
`
`< KJN< nflc[ efk _Xm\ i\c‘\[ fe k_\ ~222 KXk\ek (i\gi\j\ekXk‘m\ f] Xcc k_\ <KD KXk\ekj)
`
`Xe[ gXk\ek Xggc‘ZXk‘fej (~.63 KlYc‘ZXk‘fe Xe[ ~./1 KlYc‘ZXk‘fe) k_Xk ]orm the foundation of
`
`?\]\e[Xekj~ fYm‘flje\jj k_\fi‘\j ]fi k_\ ~4.2 KXk\ek* Ylk ‘ejk\X[ nflc[ _Xm\ cffb\[ Xk d\[‘ZXc
`
`literature. Ibrutinib was not discussed in the medical literature as a potential treatment for
`
`cGVHD. Further, cGVHD, the type of GVHD to w_‘Z_ Xcc ZcX‘dj Xi\ [‘i\Zk\[ ‘e k_\ ~4.2 KXk\ek*
`
`‘j efk [‘jZcfj\[ ‘e k_\j\ k_i\\ i\]\i\eZ\j (k_\ ~222 KXk\ek* ~.63 KlYc‘ZXk‘fe* Xe[ ~./1
`
`Publication). In all three of these references, GVHD is mentioned alongside many other diseases
`
`and conditions for whic_ ‘Yilk‘e‘Y _Xj efk Y\\e glijl\[ Xe[ _Xj efk Y\\e Xggifm\[, ~222 KXk\ek*
`
`5:55y56, 6:59y67, 26:41y269 ~./1 KlYc‘ZXk‘fe Xk V..27W9 ~.63 KlYc‘ZXk‘fe Xk V..76W,
`
`c)
`
`No Motivation To Select The Claimed Dosages
`
`A POSA would not have been motivated to select the claimed dosages of the Method
`
`Patents. None of the references cited by Defendants taught or suggested that administering
`
`ibrutinib at the claimed dosages would successfully the Claimed Cancers of the Method Patents.
`
`The API Patents do not disclose a fixed dose, but rather a dosage range, based on patient weight,
`
`]fi X ^\elj f] Zfdgfle[j, ~222 KXk\ek* 62807y42.
`
`Alik_\i* ?\]\e[Xekj~ i\]\i\eZ\j ZfeZ\ie‘e^ k_\ K_Xj\ D [fj\ \jZXcXk‘fe Zc‘e‘ZXc ki‘Xc i\]\i
`
`to administering several different doses by weight (in mg/kg/day), rather than any fixed dose.
`
`They did not disclose the specific doses administered to any patient, did not specify patient
`
`weights, and did not specify which dose was most efficacious. See }432 >c‘e‘ZXc Oi‘Xc* Kfccp\X*
`
`PR Newswire, PR Newswire (April 2009), Advani, and Roth, ASCO Preview #1-We Expect a
`
`=‘^ NgcXj_ Aifd Jli >fm\iX^\ G‘jk* Mfk_ >Xg‘kXc KXike\ij (HXp 4* 0./.) ({Mfk_ 0./.|), R‘k_
`
`i\jg\Zk kf k_\ >GG-NGG H\k_f[ KXk\ekj (k_\ ~777* ~661* ~66/* Xe[ ~524 KXk\ekj)* k_\ ~025
`23
`
`

`

`Clinical Trial would not have motivated a POSA to treat patients with a once-daily oral dose of
`
`20. d^, O_\ ~025 >c‘e‘ZXc Oi‘Xc ‘j X [‘jZcfjli\ f] X K_Xj\ DY gcXe kf X[d‘e‘jk\i K>D-32765 to
`
`either a treatment-naïve CLL/SLL group or a relapsed-i\]iXZkfip >GG-NGG ^iflg, ~025 >cinical
`
`Trial. However, at the time of the publication, the study had not even enrolled any patients.
`
`<ZZfi[‘e^cp* ‘k nflc[ efk _Xm\ c\[ X KJN< kf [fjX^\j f] k_\ ZcX‘d\[ d\k_f[j f] k_\ ~777* ~661*
`
`~66/* Xe[ ~524 KXk\ekj,
`
`R‘k_ i\jg\Zk kf k_\ ~4.2 KXk\ek* efee of the references Defendants rely onzthe API
`
`KXk\ekj* k_\ ~.63 KlYc‘ZXk‘fe* Xe[ k_\ ~./1 KlYc‘ZXk‘fezwould have motivated a POSA to select
`
`the specific dose of the dependent asserted claims. The API Patents disclose that the dose will
`
`vary depending on many factors, such as the compound, the disease, and the patient weight,
`
`rather than teaching a particular fixed dose, and disclose dosage ranges that are neither specific
`
`kf ‘Yilk‘e‘Y efi kf ZBQC?, ~222 KXk\ek* 6281.y22 ( {.,.0-5000 mg per day or from about 1-1500
`
`d^ g\i [Xp|), O_\ ~./1 KlYc‘ZXk‘fe ZfekX‘ej k_\ jXd\ [‘jZcfjli\ Xj k_\ <KD KXk\ekj n‘k_ i\jg\Zk
`
`kf [fjX^\j, ~./1 KlYc‘ZXk‘fe Xk V.427W ({,.0-5000 mg per day, or from about 1-1500 mg per
`
`[Xp|), O_\ ~.63 KlYc‘ZXk‘fe [‘jZcfj\j X j\i‘\j f] [fjX^\ iXe^es ranging from 20 mg/day to 450
`
`d^-[Xp n‘k_ ef jl^^\jk‘fe k_Xk Xep gXik‘ZlcXi [fj\ ‘j jlg\i‘fi fi dfi\ \]]‘ZXZ‘flj, ~.63
`
`Publication (0001700) at [0022], [0030]. Moreover, the dosage ranges are not specific to
`
`cGVHD. Id.
`
`d)
`
`A POSA Would Not Have Had A Reasonable Expectation Of Success
`
`O_\ i\]\i\eZ\j Z‘k\[ ‘e ?\]\e[Xekj~ DemXc‘[‘kp >fek\ek‘fej nflc[ efk _Xm\ ^‘m\e X KJN<
`
`a reasonable expectation of success in arriving at the claimed methods. As a threshold matter,
`
`Defendants have not shown how several clinical trial references that they cite are the type of
`
`publication a POSA would have reviewed or relied upon. For example, Defendants have not
`
`j_fne n_p X KJN< nflc[ _Xm\ i\c‘\[ lgfe ?\]\e[Xekj~ Z_fj\e >c‘e‘ZXc Oi‘Xc i\]\i\eZ\j fm\i
`24
`
`

`

`the other clinical trials that were posted on Clinicaltrials.gov at the time of the inventions.
`
`Further, PR Newswire is a press release and Roth 2010 is a proprietary industry analysis
`
`generated for purposes of investment advice. Neither is the type of document a POSA seeking
`
`new methods of treating patients would have likely considered to be particularly relevant.
`
`Additionally, the clinical trials were ongoing and incomplete. Pollyea at 1y2; PR Newswire at 1y
`
`2; Advani at 1. Pollyea only disclosed data regarding patients in Cohort I, which were given a
`
`dose of 1.25 mg/kg/day. Pollyea at 1. Even if a POSA were to have reviewed the references
`
`asserted by Defendants, Defendants have not shown how such data would have been used to
`
`draw conclusions about efficacy, or used to arrive at the claimed methods of treatment. Finally,
`
`k_\ ‘eZclj‘fe Zi‘k\i‘X ]fi k_\ [fj\ \jZXcXk‘fe ki‘Xc i\Z‘k\[ {ViW\Zlii\ek jli]XZ\ ‘ddlef^cfYlc‘e
`
`positive B cell non-Cf[^b‘e~j cpdg_fdX*| n_‘Z_ ‘eZcl[\j ?G=>G Xe[ ]fcc‘ZlcXi cpdg_fdX*
`
`two NHL sub-types for which ibrutie‘Y _Xj efk XZ_‘\m\[ XggifmXc, ~432 >c‘e‘ZXc Oi‘Xc Xk 2, O_\
`
`]XZk k_Xk k_\j\ ZXeZ\ij n\i\ \eZfdgXjj\[ Yp k_\ ‘eZclj‘fe Zi‘k\i‘X Y\c‘\j ?\]\e[Xekj~ k_\fip k_Xk
`
`inclusion criteria can be relied upon alone as providing a reasonable expectation of success.
`
`Re^Xi[‘e^ k_\ ~4.2 KXk\ek* ?\]\e[Xekj~ i\]\i\eZ\j Xcjf [f efk jlggfik ?\]\e[Xekj~
`
`argument that a POSA would have had a reasonable expectation of success in treating cGVHD
`
`and would have selected ibrutinib to do so. None of the non-patent literature references cited by
`
`Defendants for cGVHD involve ibrutinib. None of them contain data, either clinical or
`
`preclinical, regarding the administration of ibrutinib to subjects with cGVHD. Further, none of
`
`the patent references Defendants cite specifically mention cGVHD, the type of GVHD to which
`
`Xcc ZcX‘dj f] k_\ ~4.2 KXk\ek Xi\ [‘i\Zk\[, < KJN< nflc[ efk _Xm\ Zfej‘[\i\[ X i\]\i\eZ\ XYflk
`
`cGVHD to be interchangeable with a reference about GVHD or acute GVHD (aGVHD).
`
`cGVHD and aGVHD have different disease mechanisms, originate under different
`
`25
`
`

`

`Z‘iZldjkXeZ\j* Xe[ Xi\ ki\Xk\[ n‘k_ [‘]]\i\ek i\^‘d\ej, ?\]\e[Xekj~ fne i\]\i\eZ\j fe BQC?
`
`make this clear. See, e.g., Lee, New Approaches for Preventing and Treating Chronic Graft-
`
`Versus-Host Disease, 105 BLOOD 20.. (0..3) ({G\\|); Shimabukuro-Vornhagen, The Role of B
`
`Cells
`
`in the Pathogenesis of Graft-Versus-Host Disease, 114 BLOOD 4919 (2009)
`
`({N_‘dXYlblif|),
`
`Moreover, as explained above, the references disclosing ibrutinib that Defendants rely
`
`onzk_\ ~222 KXk\ek* ~./1 KlYc‘ZXk‘fe* Xe[ ~.63 KlYc‘ZXk‘fezmention GVHD as part of a list of
`
`[‘j\Xj\j k_Xk Zflc[ Y\ ki\Xk\[ Yp k_\ Zfdgfle[j f] k_\ ‘em\ek‘fe, ~222 KXk\ek* 3833y56, 6:59y67,
`
`26:41y269 ~./1 KlYc‘ZXk‘fe Xk V..27W9 ~.63 KlYc‘ZXk‘fe Xk V..76W, O_\ ~.63 KlYc‘ZXk‘fe* ]fi
`
`example, ZfekX‘ej fecp X j‘e^c\ d\ek‘fe f] BQC? ‘e k_\ \ek‘i\ gXk\ek, ~.63 KlYc‘ZXk‘fe Xk
`
`[0098]. The lists in these references include many other diseases and conditions for which
`
`ibrutinib has not been pursued and has not been approved. For that additional reason, a POSA
`
`would not have had a reasonable expectation of success in treating cGVHD using ibrutinib.
`
`O_\ [fjX^\ iXe^\j f] k_\ ~222 KXk\ek* ~./1 KlYc‘ZXk‘fe* Xe[ ~.63 KlYc‘ZXk‘fe nflc[ efk
`
`have given a POSA a reasonable expectation of success in treating cGVHD with ibrutinib at the
`
`ZcX‘d\[ fiXc [fjX^\, <j \ogcX‘e\[ XYfm\* k_\ [fjX^\ iXe^\j f] k_\ ~222 KXk\ek Xe[ k_\ ~./1
`
`Publication are not specific to ibrutinib or GVHD, and the references explain that the dosages
`
`n‘cc mXip YXj\[ fe X mXi‘\kp f] ]XZkfij, ~224 Patent, 84:30y229 ~./1 KlYc‘ZXk‘fe Xk V.427W,
`
`G‘b\n‘j\* k_\ ~.63 KlYc‘ZXk‘fe i\]\ij kf j\m\iXc [‘]]\i\ek [fjX^\ iXe^\jzidentifying no one
`
`preferred rangez‘e X ^\e\iXc [‘jZcfjli\ efk jg\Z‘]‘Z kf ZBQC?, ~.63 KlYc‘ZXk‘fe Xk V..00W*
`
`[0030].
`
`e)
`
`The Claimed Cancers And cGVHD Were Particularly Intractable
`
`Another reason that a POSA would not have had a reasonable expectation of success in
`
`arriving at the claimed methods is that the specific Claimed Cancers of the Method Patents and
`26
`
`

`

`cGVHD were particularly difficult to treat. For example, it was known that MCL had the worst
`
`properties of both the indolent and aggressive NHLs,
`
`including average survival of the
`
`aggressive NHLs and yet the resistance to therapy and incurability of the indolent NHLs. With
`
`respect to CLL, the literature taught that CLL remained incurable and that relapses were
`
`‘e\m‘kXYc\, Alik_\i* n‘k_ i\jg\Zk kf Xcc k_\ H\k_f[ KXk\ekj \oZ\gk k_\ ~661 KXk\ek* k_\ gXk‘\ek
`
`populations of the claims had already been proven incurable: they had received one or more prior
`
`therapies, but their diseases were refractory or the patients relapsed despite that therapy. Thus,
`
`these patients had cancers that were particularly difficult to treat.
`
`M\^Xi[‘e^ ZBQC?* fe\ f] ?\]\e[Xekj~ fne i\]\i\eZ\j
`
`jkXk\j
`
`k_Xk* {V[Wespite
`
`improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over
`
`the last 25 years, chronic graft-versus-host disease (GVHD) remains a substantial problem with
`
`little change in the incidence, morbidity, and mortality of k_‘j Zfdgc‘ZXk‘fe,| G\\ Xk 20..,
`
`Alik_\i* ZBQC?~j {gXk_fg_pj‘fcf^p ‘j gfficp le[\ijkff[* Xe[ dXeX^\d\ek jkiXk\^‘\j Y\pfe[
`
`jpjk\d‘Z Zfik‘Zfjk\if‘[j _Xm\ efk Y\\e \jkXYc‘j_\[,| Id.
`
`For all of the foregoing reasons, a POSA would not have had a reasonable expectation of
`
`arriving at the claimed methods of treatment.
`
`V.
`
`The Formulation Patents Are Valid
`
`Pursuant to Fed. R. Civ. P. 33(d), and subject to and without waiver of the foregoing
`
`objections, Plaintiffs refer Defendants to the following documents:
`
`’ U.S. Pateek If, 7*32.*160 ({k_\ ~160 KXk\ek|)
`’ P,N, KXk\ek If, 7*5/1*4/5 ({k_\ ~4/5 KXk\ek|)
`
`Plaintiffs further refer Defendants to the prosecution histories of these patents:
`
`’ O_\ ~160 KXk\ek A‘c\ C‘jkfip
`’ O_\ ~4/5 KXk\ek A‘c\ C‘jkfip
`
`27
`
`

`

`VII. Objective Indicia Strongly Support The Non-Obviousness Of The Asserted Patents
`
`Defendants bear the burden to prove invalidity under 35 U.S.C. § 103 by clear and
`
`convincing evidence. In responding to allegations of obviousness, Plaintiffs may rely upon
`
`objective indicia of non-obviousness, including evidence of skepticism, teaching away, failure of
`
`others, long-felt but unmet need, unexpected results, acclaim or praise, recognition in the
`
`industry, licensing, commercial success, and copying. Such objective indicia support the non-
`
`obviousnejj f] k_\ <jj\ik\[ KXk\ekj* Xcc f] n_‘Z_ Xi\ \dYf[‘\[ ‘e KcX‘ek‘]]j~ [il^ gif[lZk
`
`Imbruvica® (ibrutinib) and methods of treatment using the same.
`
`1.
`
`Skepticism And Teaching Away
`
`Ibrutinib inhibits BTK by forming a covalent bond using a Michael acceptor. Both
`
`clinicians and pharmaceutical companies, including Pharmacyclics, were initially skeptical of
`
`ibrutinib because it irreversibly inhibited BTK and because it contained a Michael acceptor.
`
`Irreversible kinase inhibitors form a covalent bond with their target. Irreversible inhibitors were
`
`generally avoided in drug development because of the high risk of toxicity and adverse reactions.
`
`Use of a Michael acceptor for a potential drug therapy was also discouraged, as such compounds
`
`were considered potentially dangerous to living things and toxic and carcinogenic.
`
`Because ibrutinib irreversibly binds BTK, physicianszincluding those involved with the
`
`clinical trials for ibrutinibzwere also concerned that patients taking ibrutinib would have
`
`symptoms similar to people with the human genetic BTK disorder XLA, including weakened
`
`immunity to bacterial and viral infections.
`
`2.
`
`Failure Of Others
`
`Imbruvica succeeded where many others had failed. Imbruvica is the first FDA-approved
`
`inhibitor of BTK. Although other companies had attempted to develop treatments using tyrosine
`
`kinase inhibitors, most failed to provide any clinical benefit. Many of the BTK inhibitors under
`
`48
`
`

`

`consideration at the time failed to become drugs. For example, LFM-A13, a leflunomide
`
`metabolite analogue, was being developed at Parker Hughes Institute at the relevant time, but
`
`still had not entered clinical development in 2014. Another example is AVL-292/CC-292,
`
`another BTK inhibitor that has been investigated for B-cell malignancies, including CLL and
`
`NHLs, but has not been approved. In addition to BTK inhibitors, other attempts to develop
`
`kinase inhibitors as potential treatments failed as well. Examples include pelitinib (EKB-569)
`
`and canertinib (CI-1033), potential EGFR inhibitors, which failed to progress past Phase II trials
`
`for cancer.
`
`Compounds with Michael acceptors were also well-known to be undesirable. For
`
`example, Rezulin (troglitazone) and fosdevirine are compounds with Michael acceptors that were
`
`withdrawn or abandoned due to toxicity. Rezulin was withdrawn from the market after 63
`
`patients died of liver failure. Clinical studies of fosdevirine as a treatment for HIV were halted
`
`when patients unexpectedly experienced seizures.
`
`3.
`
`Long-Felt Need But Unmet Need
`
`Prior to the inventions, the Claimed Cancers of the Method Patents and cGVHD were
`
`incurable with standard treatments, which were of limited efficacy in obtaining durable
`
`remissions and associated with toxicities. There was a long-felt need for new and improved
`
`therapies.
`
`That Imbruvica met such needs is evidenced by the fact that it was the second drug ever
`
`to receive FDA approval via the Breakthrough Therapy Designation, a process that allows FDA
`
`to grant priority review to drug candidates if preliminary clinical trials indicate that the therapy
`
`may offer substantial treatment advantages over existing options for patients with serious or life-
`
`threatening diseases. Imbruvica received Breakthrough Therapy Designations for mantle cell
`
`cpdg_fdX (H>G)9 RXc[\ejkisd~j dXZif^cfYlc‘e\d‘X (RH)9 Z_ife‘Z cpdg_fZpk‘Z c\lb\d‘X
`49
`
`

`

`(CLL) or small lymphocytic lymphoma (SLL) with a deletion of the short arm of chromosome
`
`17 (del17p); and chronic graft-versus-host-disease (cGVHD); and is indicated for the treatment
`
`of CLL/SLL and marginal zone lymphoma (MZL).
`
`a)
`
`CLL/SLL
`
`As discussed further below with respect to Unexpected Results, Imbruvica filled a long-
`
`felt but unmet need for treatment of CLL and SLL, including in patients with relapsed or
`
`refractory CLL/SLL or 17p deletion. CLL/SLL is the most common form of adult leukemia in
`
`the United States. At the time of the claimed inventions, treatments for CLL/SLL were limited
`
`by inevitable relapse, toxicity and eventual resistance to therapy. Patients with the del17p
`
`chromosomal abnormality were identified as especially at high risk for relapsed or refractory
`
`disease. Prior to Imbruvica, the treatments for relapsed/refractory CLL/SLL were associated with
`
`significant toxicities and poor outcomes.
`
`b)
`
`MCL
`
`As discussed further below with respect to Unexpected Results, Imbruvica filled a long-
`
`felt but unmet need for the treatment of mantle cell lymphoma (MCL). MCL is a rare subtype of
`
`non-Hodgkin lymphoma that is both aggressive and indolent. Before the claimed inventions,
`
`median life expectancy for relapsed patients was only 1 to 2 years. At the time of the invention,
`
`common regimens used to treat relapsed or refractory MCL were associated with significant
`
`toxicities and produced low response rates. These treatments also had low medians for
`
`progression-free survival.
`
`c)
`
`MZL
`
`As discussed further below with respect to Unexpected Results, Imbruvica filled a long-
`
`felt but unmet need for the treatment of patients with marginal zone lymphoma (MZL) who
`
`require systemic therapy and have received at least one prior anti-CD20-based therapy. MZL is
`
`50
`
`

`

`an indolent lymphoma with a median survival of between 8 and 12 years depending on the
`
`subtype. Before Imbruvica, there were no anti-cancer therapies specifically approved for MZL,
`
`indicating a failure of others to develop a safe, effective treatment for the disease. Prior to
`
`Imbruvica, treatments for relapsed MZL were associated with significant toxicities.
`
`d)
`
`WM
`
`As discussed further below with respect to Unexpected Results, Imbruvica filled a long-
`
`felt but unmet need for the treatment of patients with WM. WM is a rare cancer and constitutes
`
`only 1% of hematologic malignancies in the United States. The disease is incurable and has 5-
`
`year survival rates ranging from 36% to 87% in high- and low-risk patients, respectively. Before
`
`Imbruvica, there were no approved therapeutic agents to treat this disease in the United States,
`
`indicating a failure of others to develop a safe, effective treatment for the disease.
`
`e)
`
`cGVHD
`
`As discussed further below with respect to Unexpected Results, Imbruvica filled a long-
`
`felt but unmet need for treatment of cGVHD. Although allogenic hematopoietic cell transplant
`
`(HCT) has become a standard therapy for some hematologic malignancies, it can result in
`
`chrfe‘Z ^iX]k m\ijlj _fjk [‘j\Xj\ (ZBQC?) n_\e k_\ [fefi~j ‘ddle\ jpjk\d XkkXZbj k_\
`
`i\Z‘g‘\ek~j efidXc k‘jjl\j, ZBQC? ‘j X c‘]\-threatening condition, affecting 30y70% of subjects
`
`who survive past the first 100 days after transplant. According to one of Defee[Xekj~ fne Z‘k\[
`
`i\]\i\eZ\j* ZBQC? nXj {k_\ dfjk j\i‘flj Xe[ Zfddfe cfe^-term complication of allogeneic
`
`_\dXkfgf‘\k‘Z jk\d Z\cc kiXejgcXekXk‘fe (C>O),| G\\ Xk 20.. (0..3), Alik_\i* {Z_ife‘Z ^iX]k-
`
`versus-host disease (GVHD) [was] a substantial problem with little change in the incidence,
`
`dfiY‘[‘kp* Xe[ dfikXc‘kp f] k_‘j Zfdgc‘ZXk‘fe| fm\i k_\ gi\Z\[‘e^ 03 p\Xij, Id. at Abstract.
`
`Before Imbruvica, there was no FDA-approved treatment for cGVHD, indicating a
`
`failure of others to develop a safe, effective treatment for the disease. At the time of the
`
`51
`
`

`

`invention, primary therapies associated with significant toxicities and an increased risk of tumor
`
`relapse. After initial treatment, 50y60% of cGVHD patients eventually relapse or become
`
`refractory, thus requiring second-line treatment. There were no successful Phase III clinical
`
`studies for treatment of relapsed or refractory cGVHD.
`
`4.
`
`Unexpected Results
`
`Even though Imbruvica contains a Michael acceptor and binds to its target irreversibly, it
`
`surprisingly proved to be a safe, effective, well-tolerated, and non-toxic treatment. Further, even
`
`though it inhibits BTK, it does not cause the same symptomszsuch as immunoglobulin decline
`
`and vulnerability to infectionzas the human genetic BTK disorder XLA.
`
`In addition, Imbruvica has durable effects on BTK, yet is rapidly metabolized and
`
`eliminated. Specifically, ibrutinib fully occupies BTK for at least 24 hours, but experiences rapid
`
`clearance from plasma, with a mean apparent half-life of approximately 4 hours. Because of
`
`DdYilm‘ZX~j ]XmfiXYc\ jX]\kp gif]‘c\* ‘k ZXe Y\ kXb\e ‘e[\]‘e‘k\cp fm\i k_\ Zflij\ f] dXep p\Xij*
`
`unlike chemoimmunotherapies (in the case of B-cell cancers) or corticosteroids (in the case of
`
`cGVHD) to yield minimal residual disease.
`
`Ibrutinib also unexpectedly improves immune system function compared to the
`
`chemoimmunotherapy combinations that were standard treatments for the Claimed Cancers of
`
`the Method Patents at the time.
`
`As explained above, Imbruvica unexpectedly filled significant unmet needs in the
`
`treatment of a number of life-threatening diseases. The unexpected results of the claimed
`
`‘em\ek‘fej \m‘eZ\ dfi\ k_Xe {fecp X [‘]]\i\eZ\ ‘e X [\^i\\ f] \]]\Zk‘m\e\jj*| Xj ?\]\ndants state
`
`‘e k_\‘i DemXc‘[‘kp >fek\ek‘fej, ?\]\e[Xekj~ De‘k‘Xc DemXc‘[‘kp >fek\ek‘fej Xk /27, Ki‘fi kf k_\
`
`claimed inventions, it was not known that an irreversible BTK inhibitor like ibrutinib could be
`
`effective and well-tolerated when used to treat the Claimed Cancers of the Method Patents or
`52
`
`

`

`cGVHD. Ibrutinib opened the door to a new class of drugs for the treatment of these diseases.
`
`Following the claimed inventions, many other companies developed follow-on BTK inhibitors,
`
`but ibrutinib was the first in its class.
`
`Prior to the claimed inventions, it was not known that an irreversible BTK inhibitor like
`
`ibrutinib could be effective and well-tolerated when used to treat the Claimed Cancers of the
`
`Method Patents or cGVHD. The Patent Office noted the unexpectedly superior results of the
`
`claimed inventions over prior art methods in allowing the Method Patents to issue. For example,
`
`‘e Xccfn‘e^ k_\ ~.7. KXk\ek kf ‘jjl\* k_\ KXk\ek J]]‘Z\ jkXk\[ k_Xk {‘Yilk‘e‘Y [\dfejkiXk\j
`
`substantial improvement over existing therapies and this is not taught or suggested by the cited
`
`Xik,| ~.7. KXk\ek A‘c\ C‘jkfip* Ifk‘Z\ f] <ccfnXeZ\ (EXe, 05* 0./2), N‘d‘cXicp* ‘e Xccfn‘e^ k_\
`
`~667 KXk\ek kf ‘jjl\* k_\ KXk\ek J]]‘Z\ jkXk\[ k_Xk {VkW_\ jb‘cc\[ Xik‘jXe nflc[ efk _Xm\ \og\Zk\[
`
`k_\ i\jlckj fYkX‘e\[ Yp k_\ gi\j\ekcp ZcX‘d\[ d\k_f[,| ~667 KXk\ek A‘c\ C‘jkfip* Ifk‘Z\ f]
`
`Allowance (April 22, 2015).
`
`a)
`
`CLL/SLL
`
`Imbruvica has unexpectedly proved to be a safe, effective, well-tolerated, and non-toxic
`
`treatment for CLL/SLL. In Study PCYC-1102-CA, treatment with Imbruvica resulted in a
`
`unexpectedly high overall response rate of 78.4%, with a median time to initial response of 1.8
`
`months. IMBPCYC00149224. The overall response rate