United States District Court, D. New Jersey
CONSOLIDATED OPINION AMENDED
MCNULTY UNITED STATES DISTRICT JUDGE
are consolidated Hatch-Waxman actions for infringement of
United States Patent No. 8, 822, 438 ("the '438
patent") brought by Janssen Biotech, Inc.; Janssen
Oncology, Inc.; Janssen Research & Development, LLC
(collectively, "Janssen"); and BTG International
Ltd. ("BTG"). Janssen and BTG co-own the '438
patent. The '438 patent contains twenty claims covering
methods for the treatment of prostate cancer by administering
various dosages of abiraterone acetate and prednisone in
combination. Patent exclusivity for these medications
individually is not at issue.
defendants are Amerigen Pharmaceuticals, Inc.; Amerigen
Pharmaceuticals Ltd. (collectively, "Amerigen");
Amneal Pharmaceuticals LLC; Amneal Pharmaceuticals of New
York, LLC (collectively, "Amneal"); Dr. Reddy's
Laboratories, Inc.; Dr. Reddy's Laboratories, Ltd.
(collectively "DRL"); Mylan Pharmaceuticals Inc.;
Mylan, Inc. (collectively, "Mylan"); Teva
Pharmaceuticals USA, Inc. ("Teva"); West-Ward
Pharmaceutical Corporation, and Hikma Pharmaceuticals, LLC
("West-Ward/Hikman"); Wockhardt Bio AG; Wockhardt
USA LLC; and Wockhardt Ltd. (collectively,
"Wockhardt"). The defendants are generic drug
companies who seek to engage in the commercial manufacture,
use, offer for sale, or sale of a generic version of the
plaintiffs' branded drug, ZYTIGA®.
allege infringement of claims 4, 8, 11, 19 and 20, all of
which rely on claim 1 of the '438 patent, based on the
defendants' filing of Abbreviated New Drug Applications
("ANDAs"). If defendants' ANDAs are approved,
defendants will allegedly induce infringement of the asserted
claims of the '438 patent under 35 U.S.C. § 271(b)
and contribute to infringement of the asserted claims under
35 U.S.C. § 271(c). Defendants deny infringement and
claim that the patent claims are invalid for obviousness and
for lack of a written description.
November 3, 2017, defendants moved for summary judgment as to
the induced and contributory infringement claims. (DE 364).
The Court held a hearing on that motion on February 9, 2018.
Because it appeared that there were issues of fact to be
tried in any event, and that the issues on summary judgment
would subsumed in those to be tried, the motion was
terminated without prejudice to reassertion of all
contentions therein following trial. (DE 483).
on January 17, 2018, the Patent Trial and Appeal Board
("PTAB"), in three inter partes proceedings, found
the patent invalid. A motion for reconsideration remains
Court conducted a bench trial beginning on July 23, 2018 and
concluding on August 2, 2018. The parties have submitted
post-trial briefing, as well as proposed findings of fact and
conclusions of law.
Consolidated Opinion constitutes the Court's findings of
fact and conclusions of law pursuant to Federal Rule of Civil
Procedure 52(a). The findings of fact are based on the
Court's observations and credibility determinations of
the witnesses who testified at trial and a thorough review of
all the evidence.
I rule as follows: Like the PTAB, I find that the '438
patent is invalid for obviousness. I find the patent's
written description to be adequate, however. In the
alternative, and to facilitate appellate review, I have ruled
on the infringement issues that were tried. Assuming that the
'438 patent is valid, I find based on the proposed
generic labels that the ANDA defendants' marketing of
abiraterone would infringe, on either an induced infringement
or contributory infringement theory.
FINDINGS OF FACT 
July 31, 2015, plaintiffs filed a complaint for infringement
of the '438 patent based on defendants' ANDA filings,
which sought approval to market generic abiraterone
mg tablets. (Civil Action No. 15-5909, DE 1). Plaintiffs
filed suit against the following ANDA defendants:
a. Actavis Laboratories FL, Inc., Actavis Pharma, Inc., and
Actavis, Inc. ("Actavis"), related to ANDA No.
b. Amneal related to ANDA No. 208327;
c. Apotex Corp. and Apotex Inc. ("Apotex") related
to ANDA No. 208453;
d. Citron Pharma LLC ("Citron") related to ANDA No.
e. DRL related to ANDA No. 208416;
f. Mylan related to ANDA No. 208446;
g. Par Pharmaceutical, Inc. and Par Pharmaceutical Companies,
Inc. ("Par") related to ANDA No. 208168;
h. Sun Pharmaceuticals Industries, Ltd. and Sun
Pharmaceuticals Industries, Inc. ("Sun") related to
ANDA No. 208440;
i. Teva and Teva Pharmaceuticals Industries Limited related
to ANDA No. 208432;
j. West-Ward/Hikma, The Arab Pharmaceutical Manufacturing Co.
and Hikma Pharmaceuticals, PLC, related to ANDA No. 208339;
k. Wockhardt related to ANDA No. 208380.
complaint was dismissed against certain defendants without
prejudice, after they all agreed to be bound by any judgment
rendered in the 15-5909 action. Those dismissed defendants
are Teva Pharmaceuticals Industries Limited; Arab
Pharmaceutical Manufacturing Co.; Hikma Pharmaceuticals, PLC;
Actavis Pharma, Inc.; Actavis, Inc.; Par; and Citron. (DE 41,
44, 46, 103, 117).
April 20, 2018, plaintiffs and Apotex entered into a license
agreement for the '438 patent, and Apotex was dismissed
from the action. (DE 467).
September 28, 2015, plaintiffs filed a first amended
complaint against Hetero USA Inc., Hetero Labs Limited
Unit-V, and Hetero Labs Limited, asserting infringement of
the '438 patent related to Hetero's filing of ANDA
No. 208349, which sought approval to market generic
abiraterone acetate 250 mg tablets. Hetero subsequently
withdrew its ANDA, and on March 13, 2017, the Court entered a
stipulation dismissing without prejudice plaintiffs'
complaint against Hetero. (DE 308).
May 2, 2016, plaintiffs filed a separate action against
Amerigen, asserting infringement of the '438 patent
related to Amerigen's filing of ANDA No. 208027, which
also sought approval to market generic abiraterone acetate
250 mg tablets. (Civ. No. 16-02449, DE 1). This action was
consolidated with the 15-5909 action on July 29, 2016 for
discovery purposes. (Civ. No. 16-2449, DE 16).
August 25, 2017, plaintiffs filed a separate complaint
against Teva and Teva Pharmaceuticals Industries, Ltd.,
asserting infringement of the '438 patent related to
Teva's filing of ANDA No. 210726 for approval to market
generic abiraterone acetate 500 mg tablets. (Civ. No.
17-6435, DE 1). Teva Pharmaceuticals Industries, Ltd. was
dismissed from this action after it agreed to be bound by any
judgment. (Civ. No. 17-6435, DE 10).
January 8, 2018, the 17-6435 action was consolidated with the
15-5909 action for all purposes, including trial, pursuant to
Federal Rule of Civil Procedure 42(a). (Civ. No. 15-5909. DE
381). Teva's ANDA No. 208432 (at issue in the Civ. No.
15-5909 action) is substantively identical to Teva's ANDA
No. 210726 (at issue in the Civ. No. 17-6435 action).
Metastatic Castration-Resistant Prostate Cancer
invention claimed in the '438 patent treats metastatic
castration-resistant prostate cancer ("mCRPC")
through a combination of abiraterone and prednisone. (JTX
prostate is a male genitourinary organ located in the pelvis.
(3T530:24-25). Prostate cancer arises when there is an
uncontrollable proliferation of prostate tissue. (3T531:2-4).
Metastatic prostate cancer occurs when the cancer tumor
spreads from the prostate to another organ, such as the
bones, liver, or lungs. (3T531:6-8).
Male sex hormones, called androgens, promote the growth of
prostate cancer cells. (3T531:10, -22 to -24). A first-line
treatment for metastatic prostate cancer is androgen
deprivation therapy ("ADT"). (1T 100:22-25;
3T532:19-20). Starting in the 1940s, the main treatment for
prostate cancer was ADT. (1T115:23-116:1). ADT deprives
cancer cells of androgens, like testosterone, through either
medical or surgical castration. (1T100:24-101:3;
is not a cure for prostate cancer; in most patients, ADT
eventually loses effectiveness and the cancer may resume
growing. (3T533:13-25). At that point the cancer is deemed
castration-resistant, as that term is used in mCRPC.
Abiraterone, discovered in the early 1990s, is a second-line
therapy. (9T1970:24). Abiraterone inhibits the
17a-hydroxylase/C17, 20-lyase ("CYP17")
enzyme. The CYP17 enzyme has a role in the steroid
biosynthesis pathway that leads to the production of
androgens, including testosterone. (1T123:13-18; 7T1434:4-21;
6T1152:5-9, 1280:1-1281:1; see PDX7.5, chart of
steroid biosynthesis pathway and abiraterone inhibition,
attached as an exhibit to this opinion.)
Johann de Bono, an oncologist and coinventor on the '438
patent, hypothesized that, while abiraterone decreased the
production of androgens, it also resulted in an accumulation
of "upstream" non-androgenic steroids (i.e., those
whose production branches off from the synthesis pathway
before the point at which the CYP17 enzyme that is inhibited
by abiraterone operates). (1T127:15-16, 128:16-129:3;
3T607:12-14). Those accumulated non-androgenic steroids would
activate the androgen receptors on the prostate cancer cells,
thereby reducing abiraterone's effectiveness and causing
a resistance to abiraterone. (1T128:18-24; 3T607:17-20; see
top horizontal row of chart, PDX7.5, attached as exhibit.)
combat such resistance, Dr. de Bono hypothesized, a
glucocorticoid (the family including prednisone) could be
administered to suppress those upstream steroids.
The '438 Patent and Asserted Claims
September 2, 2014, the United States Patent and Trademark
Office issued the '438 patent. (JTX 8000). The named
inventors of the '438 patent were Alan H. Auerbach and
Arie S. Belldegrun. (DE 502, at 86 ¶28). Dr. de Bono was
added as an inventor by order of the Court in January 2017.
'438 patent, titled "Methods and Compositions for
Treating Cancer," has twenty claims and is directed at
methods of treating prostate cancer in humans. (JTX 8000).
described in the '438 patent, it is believed that
testosterone and dihydrotestosterone promote the growth of
prostate cancer. (Id. at 1). The '438 patent
further states that hormone therapy can be used to suppress
the production or block the effects of hormones like
testosterone. (Id.). It notes that CYP17 inhibitors
have been shown to be useful in the treatment of cancer, and
specifically in androgen-dependent disorders like prostate
cancer. (Id. at 5).
'438 patent discloses such methods as the administration
of a CYP17 inhibitor, like abiraterone acetate, in
combination with at least one other therapeutic agent, such
as an "anti-cancer agent or steroid." (Id.
at 2). The '438 patent identifies prednisone as one such
therapeutic agent that can be combined with abiraterone
Claim 1 of the '438 patent, the only independent claim,
claims the following:
1. A method for the treatment of a prostate cancer in a human
comprising administering to said human a therapeutically
effective amount of abiraterone acetate or a pharmaceutically
acceptable salt thereof and a therapeutically effective
amount of prednisone.
(Id. at 16). Claim 1 is practiced when a
"therapeutically effective amount of abiraterone
acetate" and a "therapeutically effective amount of
prednisone" are administered to a patient with prostate
Dependent claims 2-20 of the '438 patent describe
additional limitations of the method, including the amount of
abiraterone acetate and the amount of prednisone used, and
the type of prostate cancer being treated. Plaintiffs assert
infringement of claims 4, 8, 11, 19, and 20 against each
Those dependent claims provide as follows:
a. Claim 4. The method of claim 3, wherein the
therapeutically effective amount of the abiraterone acetate
or pharmaceutically acceptable salt thereof is about 1000
b. Claim 8. The method of claim 7, wherein the
therapeutically effective amount of the prednisone is about
c. Claim 11. The method of claim 10, comprising administering
to said human about 1000 mg/day of abiraterone acetate or a
pharmaceutically acceptable salt thereof and about 10 mg/day
d. Claim 19. The method of claim 18, comprising administering
to said human about 1000 mg/day of abiraterone acetate or a
pharmaceutically acceptable salt thereof and about 10 mg/day
e. Claim 20. The method of claim 17, comprising administering
to said human about 1000 mg/day of abiraterone acetate or a
pharmaceutically acceptable salt thereof and about 10 mg/day
Order dated June 27, 2016 (DE 208), the Court adopted the
parties' agreed-upon constructions (DE 502, at 89,
¶¶49-51) of the following undisputed '438
patent claim terms:
Preamble: "a method for the treatment of a
prostate cancer in a human"
The preamble of claim 1, on which claims 2-20 depend,
is limiting and limits the claims to the treatment of
a prostate cancer in a human.
"refractory prostate cancer"
"Prostate cancer that is not responding to an
anticancer treatment or prostate cancer that is not
responding sufficiently to an anti-cancer treatment.
Refractory prostate cancer can also include recurring
or relapsing prostate cancer."
"An amount effective for treating cancer."
November 10, 2016, following a hearing, the Court issued its
Markman patent claim construction opinion and
order. (DE 239, 240, reported at BTG Int'l Ltd. v.
Actauis Labs. Fl, Inc., 2016 U.S. Dist. LEXIS 157586
(D.N.J. Nov. 10, 2016)). The parties principally disputed the
terms "treatment" and
"treating." Id. at *5.
Court construed the terms "treatment" and
"treating" as "the eradication, removal,
modification, management or control of a tumor or primary,
regional, or metastatic cancer cells or tissue and the
minimization or delay of the spread of cancer."
Id. at *54.
Clinical Trials and Data
There were a number of clinical trials of abiraterone and
prednisone. The results of those trials were submitted to the
United States Food and Drug Administration ("FDA")
to establish the safety and efficacy of abiraterone, with the
object of gaining FDA approval to market ZYTIGA®.
(2T265:8-12; PDX 2.2 (Summary of Clinical Trials)).
Clinical trials proceed in various phases. A Phase I trial is
typically the initial drug development, and seeks to
determine the safety of administering a particular drug into
a human. (2T266:9-12). A Phase II clinical trial uses the
findings from Phase I and extends testing to a larger patient
population. Those results provide a basis for conducting a
Phase III trial, which evaluates clinical efficacy and safety
for regulatory approval. (2T266:13-23).
April 2004, Cougar Biotechnology licensed the rights to develop
abiraterone from BTG. (1T108:12-13, 230:25-231:4;
2004 and 2005, Dr. de Bono designed the first clinical trial
of abiraterone, which became known as the COU-AA-001 trial
("001 trial"). (IT 108:21-23, 124:17024; PTX 13).
The purpose of the 001 trial was to evaluate the safety and
efficacy of abiraterone monotherapy in men with mCRPC.
001 trial was designed to proceed in two phases.
(2T267:3-11). In Phase I of the 001 trial, the dose
escalation phase, patients received abiraterone at doses of
250, 500, 750, 1000, or 2000 milligrams. (2T302:7-14). In the
Phase II portion of the 001 study, all patients received 1000
milligrams of abiraterone acetate. (2T302:20-23).
both phases of the 001 trial, Dr. de Bono proposed an
"extension" phase for patients whose cancer had
progressed despite the administration of abiraterone. Those
patients would receive 0.5 milligrams of a glucocorticoid,
dexamethasone. (1T127:11-22, 134:5-14; 2T267:12-18; PTX
11, at 4, 39-40; JTX 8086, at 1).
purpose of this extension study was to evaluate Dr. de
Bono's hypothesis that the addition of a glucocorticoid
could suppress the upstream steroids, and thus reduce
resistance to abiraterone. (1T127:11-22, 128:18-129:3). Dr.
de Bono opined that prednisone, another glucocorticoid, would
be just as effective as dexamethasone because all
glucocorticoids would have a similar effect in terms of
suppressing the upstream steroids. (1T132:13-133:20; see
also 3T618:1-6; 7T1415:5-9). The study was approved by
the Institutional Review Board and the Royal Marsden Cancer
Research Committee. (1T142:6-8).
001 study results were published in the Journal of Clinical
Oncology. Gerhardt Attard, et al., Phase I Clinical Trial
of a Selective Inhibitor of CYP17, Abiraterone Acetate,
Confirms that Castration-Resistant Prostate Cancer Commonly
Remain Hormone Driven, 26 J. of Clinical Oncology 4563
(2008) (JTX 8083) (hereinafter referred to as "Attard
2008"); Gerhardt Attard, et al., Selective
Inhibition of CYP17 with Abiraterone Acetate is Highly Active
in the Treatment of Castration-Resistant Prostate
Cancer, 27 J. of Clinical Oncology 3742 (2009) (JTX
8086) (hereinafter referred to as "Attard 2009").
Even though the central purpose of the Phase I trial was to
establish safety, the results of the trial showed that
abiraterone alone had anti-tumor activity, measured by a
reduction in Prostate-Specific Antigen
("PSA") levels. (1T143:21-23). The 001 trial
involved 54 patients. (1T144:1). All received abiraterone. In
phase I (abiraterone dose escalation), 15 of the subjects
received dexamethasone as well. In phase II (administration
of 1000 mg/day of abiraterone), 30 of the subjects received
dexamethasone as well. (1T144:1-4). Assuming complete
overlap, then, at least 30 patients received combination
When patients developed a resistance to abiraterone
monotherapy and a glucocorticoid was added, the anti-cancer
effect, measured by PSA declines of at least fifty percent,
returned for 10 of the 30 combination-therapy patients in the
Phase II portion of the study. (1T144:4-22; 3T588:13-24; JTX
8086). This suggested that a glutocorticoid such as
prednisone, at least when administered in combination with
abiraterone, has an anti-cancer effect. The suggested
mechanism was the suppression of the "upstream"
steroids. These upstream steroids, left unchecked, may
stimulate prostate cancer growth. [Id.; 3T604:20-24,
608:5-18, 663:12-14; 4T861:1-5; see top horizontal line of
biosynthesis chart, attached.).
second clinical study submitted to the FDA, the COU-AA-002
trial ("002 trial"), was similar to COU-AA-001.
(2T268:12-13). The 002 trial, which was conducted in the
United States, received FDA approval. (2T269:8- 18). Phase I
of the 002 trial tested abiraterone monotherapy to determine
the best dosage. (2T268:18-19). As originally designed, the
Phase II portion of the study was to consist of further
abiraterone monotherapy. (2T268:18-19). However, on May 25,
2007, after the results of the 001 study suggested the effect
of the glucocorticoid, the protocol of Phase II of the 002
trial was amended. (2T268:19-21, 271:8-12, 272:
that amended Phase II protocol, abiraterone and prednisone
would be jointly administered. (2T268:21-23). Patients
received 1, 000 milligrams of abiraterone and 10 milligrams
of prednisone per day. (2T272:4-6). The results of 002 Phase
II were published. Charles J. Ryan, et al., Phase II
Study of Abiraterone Acetate in Chemotherapy-Naive Metastatic
Castration-Resistant Prostate Cancer Displaying Bone Flare
Discordant with Serologic Response, Clinical Cancer
Research (2011). (JTX 8093).
clinical study report of the 002 trial was submitted to the
FDA for its consideration in approving ZYTIGA®.
(2T312:16-313:2; DTX 1367). That report included a section
that discussed the overall design of the study. (DTX 1367, at
19). In addressing the role of prednisone in Phase II of the
002 trial, the report noted that "all subjects were
required to receive low dose glucocorticoids such as
prednisone 5 mg twice daily PO or dexamethasone (0.5 mg once
daily) with abiraterone acetate to better manage
mineralocorticoid side effects." [Id.).
conclusion of the 002 study report provided, in full, that:
• In study COU-AA-002, abiraterone acetate demonstrated
encouraging antitumor activity as assessed by PSA response by
PSAWG criteria; objective response by RECIST criteria; and
time to PSA progression in this patient population with
advanced castration-resistant prostate cancer who had prior
hormonal therapies. Importantly, tumor responses to
abiraterone acetate were observed in castrate patients who
had prior ketoconazole medication.
• Although corticosteroids were not mandated: the
initiation of the study, the incidence of mineralocorticoid
excess with abiraterone acetate monotherapy was of sufficient
frequency to support the routine use of glucocorticosteroids.
• Although the MTD of abiraterone acetate could not be
definitely determined based on available data, the doses
administered appear to be well tolerated with no DLTs even at
l000mg/day. The results of the study support the use of the
1000 mg daily dose of abiraterone acetate in the treatment of
advanced castration-resistant prostate cancer, in view of the
antitumor activity and safety observed at this dose.
(DTX 1367, at 110).
Robert Charnas, ZYTIGA®'s global regulatory leader,
suggested that because abiraterone and prednisone were tested
in combination, their individual anti-cancer effects could
not be determined. (2T323:25-324:8).
COU-AA-003 ("003 trial") trial was another study
that evaluated 1000 mg/day or abiraterone acetate in
post-chemotherapy mCRPC patients. (DTX 1185). The patients in
the COU-AA-003 study were allowed to be on steroids. Eighteen
of forty-seven patients (38%) were on a low dose of steroids.
(DTX 1185.4). PSA declines were seen in thirty-two of the
forty-seven patients (68%). The results of this trial were
published. Reid, et al., Significant and Sustained
Antitumor Activity in Post-Docetaxel, Castration-Resistant
Prostate Cancer with the CYP17 Inhibitor Abiraterone
Acetate, 20 J. of Clinical Oncology 1 (2010). (DTX
COU-AA-004 Phase II trial ("004 trial") used the
combination of abiraterone and prednisone in post-docetaxel
mCRPC patients. (2T272:7-19; 3T614:6-15). The median time to
PSA progression reported in the COU-AA-003 trial and the
COU-AA-004 trial was the same, approximately 5.6 months.
(4T954:22-956:11). The results of the 004 trial were also
published. Daniel Danila et al., Phase II Multicenter
Study of Abiraterone Plus Prednisone Therapy in Patients with
Docetaxel-Treated Castrate-Resistant Prostate Cancer, 28
J. of Clinical Oncology 1496, 1497 (2010). (JTX 8090).
COU-AA-301 clinical trial ("301 trial") was the
registration study that compared the combination of
abiraterone plus prednisone to a control arm of prednisone
plus a placebo. (2T276:19-277:3). The 301 trial was
considered the pivotal trial showing efficacy and safety for
the NDA application. (2T283:5-6).
Like previous trials, the coadministration arm of the 301
trial involved 1000 milligrams of abiraterone and 10
milligrams of prednisone, administered daily. (2T277:6-8).
Positive effects were seen in the patients receiving
abiraterone plus prednisone. The Independent Data Monitoring
Committee, an outside committee that evaluates patient safety
throughout a clinical trial, therefore recommended that the
placebo control arm of the trial be discontinued for ethical
reasons. (2T277:12-278:6). All the participants were then
given prednisone plus abiraterone, as opposed to a placebo.
301 trial demonstrated that abiraterone and prednisone in
combination were efficacious. (3T372:5-8). The results of the
301 trial demonstrated a four month increase in median
overall survival. (2T278:9-13; 2T376:23-25).
results from the 001, 002, 003, 004 and 301 trials were
submitted to the FDA for review as part of the original NDA
application. (2T284:9-13). No. single study compared
abiraterone monotherapy to abiraterone plus prednisone
combination therapy. (2T293:5-7). Such a comparison by the
FDA would necessarily be less direct, based on a comparison
of data from different studies. (2T374:12-22).
final clinical trial was the COU-AA-302 clinical trial
("302 trial"). (2T278:16). The 302 trial was the
basis for a change to the indications on the ZYTIGA®
label in 2018. (2T308:7-8). In the 302 trial, abiraterone
plus prednisone was compared to prednisone plus a placebo.
The study subjects were patients whose disease had not
progressed to the point where chemotherapy was required.
(2T278:18-23). The same dosages, 1000 milligrams of
abiraterone and 10 milligrams of prednisone, were
the 302 trial protocol, it was noted that administration of a
corticosteroid "improved symptoms of fatigue and
tolerability of abiraterone acetate, including symptoms of
mineralocorticosteroid excess. The improved tolerability of
abiraterone acetate after concomitant administration of
low-dose corticosteroids was associated with suppression of
ACTH and upstream adrenal steroids[.]" (DTX 1358, at
comparative control arm of this study, as in the 301 study,
was discontinued for ethical reasons, to allow all the
patients to take abiraterone plus prednisone. (2T279:8-12).
The combination of abiraterone and prednisone in the 302
trial showed a sixty percent reduction in the risk of
progression or death, and an overall median survival
improvement of about four months. (2T279:23-280:2).
priority date is August 2006. (DFF at 64, ¶249; PFF at
Before 2006, there was a significant divergence of opinion
within the scientific community as to whether prostate cancer
was androgen dependent or independent. (1T116:9-18). However,
the prevailing belief was that, once the cancer resumed
growing after ADT, the cancer became androgen independent.
Prior to the invention described in the '438 patent,
there were treatment options for prostate cancer that stopped
responding to ADT, but the invention was not among them.
(8T1848:18-24; see DTX 1135).
relevant prior art consists of the following:
a) Glenn Gerber et al., Prostate Specific Antigen for
Assessing Response to Ketoconazole and Prednisone in Patients
with Hormone Refractory Metastatic Prostate Cancer, 144
J. of Urology 1177 (1990) (DTX 1059) (hereinafter
b) S.E. Barrie et al., Pharmacology of Novel Steroidal
Inhibitors of Cytochrome P450 17a
(17a-Hydroxylase/C17-20 Lyase), 50 J. Steroid Biochem.
Molec. Biol. 267 (1994) (DTX 1062) (hereinafter "Barrie
c) Gerald Potter et al., Novel Steroidal Inhibitors of Human
Cytochrome P450 17a (17a-Hydroxylase-C17,
20-lyase): Potential Agents for the Treatment of Prostatic
Cancer, 38 J. Med. Chem. 2463 (1995) (JTX 8037) (hereinafter
d) Ian F. Tannock et al., Chemotherapy with Mitoxantrone
Plus Prednisone or Prednisone Alone for Symptomatic
Hormone-Resistant Prostate Cancer: A Canadian Randomized
Trial with Palliative End Points, 14 J. Clin. Oncol.
1756 (1996) (DTX 1076) (hereinafter "Tannock
e) Oliver Sartor, et al., Effect of Prednisone on
Prostate-Specific Antigen in Patients with Hormone-Refractory
Prostate Cancer, 52(2) UROLOGY 252 (1998) (DTX 1087)
(hereinafter "Sartor 1998");
f) Michael Jarman et al., The 16, 17-Douhle Bond Is
Needed for Irreversible Inhibition of Human Cytochrome P450
17a by Abiraterone (17-(3-Pyridyl)androsta-5,
16-dien-3Ã¸-ol) and Related Steroidal Inhibitors, 41 J.
Med. Chem. 5375 (1998) (DTX 1085) (hereinafter "Jarman
g) F.D. Fossa et al., Flutamide Versus Prednisone in
Patients with Prostate Cancer Symptomatically Progressing
After Androgen-Ablative Therapy: A Phase III Study of the
European Organization for Research and Treatment of Cancer
Genitourinary Group, 19 J. Clin. Oncol. 62 (2001) (JTX
8048) (hereinafter "Fossa 2001");
h) Marwan Fakih et al., Glucocorticoids and Treatment of
Prostate Cancer: A Preclinical and Clinical Review, 60
Urology 553 (2002) (DTX 1104) (hereinafter "Fakih
i) Katherine Harris et al., Low Dose Ketoconazole with
Replacement Doses of Hydrocortisone in Patients with
Progressive Androgen Independent Prostate Cancer, 168 J.
Urology 542 (2002) (JTX 8053) (hereinafter "Harris
j) A. O'Donnell et al., Hormonal Impact of the
17a-Hydroxylase/ C17, 20-lyase Inhibitor
Abiraterone Acetate (CB7630) in Patients with Prostate
Cancer, 90 British J. Can. 2317 (2004) (DTX 1129)
(hereinafter "O'Donnell 2004");
k) L. Vidal et al., Reversing Resistance to Targeted
Therapy, 16 J. Chemo. 7 (2004) (DTX 1135) (hereinafter
l) Gerhardt Attard et al., Selective Blockade of
Androgenic Steroid Synthesis By Novel Lyase Inhibitors As A
Therapeutic Strategy For Treating Metastatic
Prostate Cancer, Urological Oncology (2005) (JTX 8072)
(hereinafter "Attard 2005");
m) Oliver Sartor, The Continuing Challenge of
Hormone-Refractory Prostate Cancer, Clinical
Genitourinary Cancer (2006) (PTX 108) (hereinafter
"Sartor 2006"); and
n) Marc B, Garnick & Camille Motta, Androgen
Deprivation Therapy, the Future, Prostate Cancer
Principles and Practice (2006) (DTX 1157) (hereinafter
prior art is further summarized and discussed at Section
FDA will approve a new medication if there is substantial
evidence of safety and effectiveness. (2T388:21-22). In order
to obtain approval to market a new drug, a company is
required to submit a New Drug Application ("NDA")
to the FDA. (2T282:4-10, 387:19-388:4). An NDA application
contains proposed labeling, prescribing information, animal
and human studies, including phase I, II, and III clinical
trials, and toxicity data. (2T282:14-283:2, 388:5-12).
ZYTIGA® is sold in the United States pursuant to approved
NDA No. 202379. (Civ No. 15-5909, DE 502, at 90, ¶53).
The NDA application for ZYTIGA® was submitted in December
of 2010 for the use of ZYTIGA® in combination with
prednisone for the treatment of men with mCRPC. (2T283:19-20,
284:18-21, 370:9-10). The NDA was specifically submitted for
ZYTIGA®, and prednisone was considered a concomitant
therapy. (2T411:3-5). The application received priority
review as requested. (2T284:22-286:13).
November 9, 2010, the FDA and Cougar Biotechnology had a
"pre-NDA" meeting. (2T334:3-23, 335:9; DTX 1331).
The purpose of a pre-NDA meeting is for the sponsor of a drug
and the FDA to discuss the NDA; for the sponsor to inform the
FDA about the NDA; and for the FDA to provide initial
feedback that would aid in the NDA review process.
scientific rationale for developing abiraterone was addressed
in the briefing package that was submitted to the FDA for
this pre-NDA meeting. (2T336:5-7; DTX 1331, at ...