BTG INTERNATIONAL LIMITED et al v. ACTAVIS LABORATORIES FL, INC. et al
Filing
571
CONSOLIDATED OPINION (Amended). Filed herewith is an amended version of the Court's 560 Opinion of October 26, 2018. Footnote 13 is revised and extended to summarize the court's reasoning on the record as to finality and section 315(e) estoppel. Signed by Judge Kevin McNulty on 10/31/18. (nic, )
UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF NEW JERSEY
BTG INTERNATIONAL LIMITED,
et al.,
Plaintiffs,
Civ. No. 15-cv-5909 (KM)(JBC)
V.
AMNEAL PHARMACEUTICALS LLC,
et al.
Defendants.
BTG INTERNATIONAL LIMITED,
et al.,
Plaintiffs
Civ. No. 16-cv-2449 (KM)(JBC)
V.
AMERIGEN PHARMACEUTICALS,
INC., and AMERIGEN
PHARMACEUTICALS LTD.,
Defendants.
BTG INTERNATIONAL LIMITED,
et al.,
Plaintiffs,
Civ. No. 17-cv-6435 (KM)(JBC)
V.
TEVA PHARMACEUTICALS USA,
INC.,
Defendant.
CONSOLIDATED OPINION
(Amended)
KEVIN MCNULTY, U.S.D.J.:
These 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
1
of abiraterone acetate and prednisone in combination. Patent exclusivity for
these medications individually is not at issue.
The 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,
ZYTIQA®.
Plaintiffs 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 (“ANDA5”). If defendants’ ANDAs are
approved, defendants will allegedly induce infringement of the asserted claims
§ 27 1(b) and contribute to infringement of
the asserted claims under 35 U.S.C. § 27 1(c). Defendants deny infringement
of the ‘438 patent under 35 U.S.C.
and claim that the patent claims are invalid for obviousness and for lack of a
written description.
On 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).
Meanwhile, on January 17, 2018, the Patent Trial and Appeal Board
(“PrAB”), in three inter partes proceedings, found the patent invalid. A motion
for reconsideration remains pending.
2
The 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.
This 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.
Essentially, I rule as follows: Like the VFAB, 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’
I.
I will cite to the record as follows:
DE
—
DBr.
=
Docket Entry in this action, Civ. No. 15-5909
=
Defendants’ Opening Post-Trial Brief (DE 533)
Def. Response
=
Defendants’ Post-Trial Response Brief (DE 552)
DPF.
=
Defendants’ Proposed Findings of Fact (DE 534)
DTX
=
Defendants’ trial exhibits
JTX
=
Parfies’joint trial exhibits
VEX
=
Plaintiffs’ trial exhibits
PBr.
=
Plaintiffs’ Opening Post-Trial Brief (DE 535)
PPF.
=
Plaintiffs’ Proposed Findings of Fact (DE 549)
P1. Response
=
Plaintiffs’ Post-Trial Response Brief (DE 552)
iT
=
July 23, 2018 Bench Trial Transcript (DE 539)
2T
=
July 24, 2018 Bench Trial Transcript (DE 540)
3T
=
July 25, 2018 Bench Trial Transcript (DE 547)
4T
=
July 26, 2018 Bench Trial Transcript (DE 541)
3
A. Procedural Background
1. On 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 acetate2 250 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. 2O8274;
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. 208371;
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; and
k. Wockhardt related to ANDA No. 208380.
ST
=
July 27, 2018 Bench Trial Transcript (DE 542)
6T
=
July 30, 2018 Bench Trial Transcript (DE 543)
7T
=
July 31, 2018 Bench Trial Transcript (DE 544)
8T
=
August 1, 2018 Bench Trial Transcript (DE 545)
9T
=
August 2, 2018 Bench Trial Transcript (DE 546)
Unless othenvise specified, abiraterone and abiraterone acetate, its prodrug, are
used interchangeably in this opinion.
2
The complaint also asserted infringement of plaintiffs’ U.S. Patent No.
5,604,213 (the “‘213 patent”) against Actavis related to Actavis’s ANDA No. 208274.
(DE 1). The ‘213 patent expired in December 2016, and on March 21, 2017, the Court
entered a stipulation dismissing, without prejudice, plaintiffs’ claims of infringement of
the ‘213 patent against Actavis. (DE 318).
On June 19, 2018, Rising Pharmaceuticals, Inc. was substituted for defendant
Citron after Citron transferred its ANDA to Rising. (DE 496, 500).
4
(DE 1).
2. The 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).
3. On April 20, 2018, plaintiffs and Apotex entered into a license
agreement for the ‘438 patent, and Apotex was dismissed from the action. (DE
467).
4. On 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).
5. On 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).
6. On 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).
7. On January 8, 2018, the 17-6435 action was consolidated with the
15-5909 action for all purposes, including trial, pursuant to Federal Rule of
5
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).
B. Metastatic Castration-Resistant Prostate Cancer
8. The invention claimed in the ‘438 patent treats metastatic castrationresistant prostate cancer (“mCRPC”) through a combination of abiraterone and
prednisone. (JTX 8000).
9. The prostate is a male genitourinaiy 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).
10. Male sex hormones, called androgens, promote the growth of prostate
cancer cells. (3T53 1:10, -22 to -24). A first-line treatment for metastatic
prostate cancer is androgen deprivation therapy (“ADT”). (iT 100:22-25;
3T532:19-20). Starting in the 1940s, the main treatment for prostate cancer
was ADT. (1T1 15:23-116: 1). ADT deprives cancer cells of androgens, like
testosterone, through either medical or surgical castration. (1T100:24-lOl:3;
3T532: 19-25).
11. ADT is not a cure for prostate cancer; in most patients, ADT
eventually loses effectiveness and the cancer may resume growing. (3T533:1325). At that point the cancer is deemed castration-resistant, as that term is
used in mCRPC.
12. Abiraterone, discovered in the early 1990s, is a second-line therapy.
(9T1 970:24). Abiraterone inhibits the 1 7a-hydroxylase/ C 17,2o-lyase (“CYP 17”)
enzyme. The CYP17 enzyme has a role in the steroid biosynthesis pathway that
leads to the production of androgens, including testosterone. (lT123:13-l8;
7T1434:4-2 1; 6T1 152:5-9, 1280:1-1281:1; see PDX7.5, chart of steroid
biosynthesis pathway and abiraterone inhibition, attached as an exhibit to this
opinion.)
6
13. Dr. 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.)
14. To combat such resistance, Dr. de Bono hypothesized, a
glucocorticoid (the family including prednisone) could be administered to
suppress those upstream steroids. (1TI 27:11-22, 129:8-24).
C. The ‘438 Patent and Asserted Claims
15. On 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 Januanr 2017.
16. The ‘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).
17. As 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).
18. The 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).
7
The ‘438 patent identifies prednisone as one such therapeutic agent that can
be combined with abiraterone acetate. (Id.)
19. 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 cancer. (3T538: 1-1 1).
20. Dependent claims 2—20 of the ‘438 patent describe additional
limitations of the method, including the amount of abiraterone acetate and the
being treated.
amount of prednisone used, and the
type
of prostate
cancer
Plaintiffs assert infringement of claims 4, 8, 11, 19, and 20 against each
defendant.
21. 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 mg/day.
b. Claim 8. The method of claim 7, wherein the therapeutically
effective amount of the prednisone is about 10 mg/day.
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
of prednisone.
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
of prednisone.
e. Claim 20. The method of claim 17, comprising administering to
said human about 1000 mg/day of abiraterone acetate or a
8
pharmaceutically acceptable salt thereof and about 10 mg/day
of prednisone.
(Id.).
D. Claim Construction
22. By Order dated June 27, 2016 (DE 208), the Court adopted the
parties’ agreed-upon constructions (DE 502, at 89, 949-51) of the following
undisputed ‘438 patent claim terms:
Claim Term
Joint Construction
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 anti
cancer 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.”
“therapeutically effective
amount”
“An amount effective for
treating cancer.”
23. On November 10, 2016, following a hearing, the Court issued its
Markman5 patent claim construction opinion and order. (DE 239, 240, reported
at BTG Int’l Ltd. v. Actavis Labs. Fl, Inc., 2016 U.S. Dist. LEXIS 157586 (D.N.J.
Nov. 10, 2016)). The parties principally disputed the terms “treatment” and
“treating.”6 Id. at 5.
See Markman v. Westvjew Instruments, Inc., 52 F.3d 967, 976-79 (Fed. Cir.
1995) (en banc), affd, 517 U.S. 370. 116 S. Ct. 1384, 134 L. Ed. 2d 577 (1996).
5
Defendants sought a broad construction of the term to encompass treatments
aimed at not only “reducing the actual prostate cancer, but also ‘reducing the pain
associated with prostate cancer and replacing the normal production of
6
9
24. The 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•
E. Clinical Trials and Data
25. 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 ZYTIQA®. (2T265:8-12; PDX 2.2
(Summary of Clinical Trials)).
26. 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).
27. In April 2004, Cougar Biotechnology7 licensed the rights to develop
abiraterone from BTG. (1T108:12-13, 230:25-231:4; 8T1817:25-1818:5).
28. In 2004 and 2005, Dr. de Bono designed the first clinical trial of
abiraterone, which became known as the COU-AA-001 trial (“001 trial”).
(lTlO8:21-23, 124: 17024; PTX 13). The purpose of the 001 trial was to
evaluate the safety and efficacy of abiraterone monotherapy in men with
mCRPC. (1T126:16-21, 127:23-25).
29. The 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).
glucocorticoids that is blocked when patients are given CYP17 inhibitors.” BTG, 2016
U.S. Dist. LEXIS 157586, at *7
Cougar Biotechnology is Janssen’s predecessor. (2T468:4-5).
10
In the Phase II portion of the 001 study, all patients received 1000 milligrams
of abiraterone acetate. (2T302:20-23).
30. For 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.8 (lTl27: 11-22, 134:5-14; 2T267: 12-18; PTX
11, at 4, 39-40; JTX 8086, at 1).
31. The 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:ll-22, 128:18129:3). 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 3T6l8:1-6; 7Tl415:5-9). The study was approved by the Institutional
Review Board and the Royal Marsden Cancer Research Committee. (lT142:68).
32. The 001 study results were published in the Journal of Clinical
Oncology. Gerhardt Attard, et al., Phase I Clinical Trial of a Selective Inhibitor of
CYP1 7, 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 CYP1 7 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”).
Dexamethasone and prednisone are both part of the same class of drugs,
known as glucocorticoids. (1T133:7-20). Dexamethasone was the steroid used by the
institution with which Dr. de Bono was then affiliated, the Institution of Cancer
Research (“ICR”), which is at the college of the University of London and the Royal
Marsden Hospital. (lTl3O:1-l2, 132:21-24). Dr. de Bono indicated that as to a
synthetic steroid, a patients’ blood test would reveal the extent to which hormones
came from the drug or from a patient’s adrenal gland. Prednisone was not then
available in the U.K. (1T140:20-25).
8
11
33. 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”)9 levels.
(1Tl43:21-23). 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 11 (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
therapy.
34. 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.).1°
35. The second clinical study submitted to the FDA, the COU-AA-002
trial (“002 trial”), was similar to COU-AA-001. (2T268:l2-13). The 002 trial,
which was conducted in the United States, received FDA approval. (2T269:8PSA is one of the modalities used to observe anti-tumor activity for hormone
therapy. (1T149:23-25; 2T378:5-18). It is used as a measure of cancer progression.
Rising levels of PSA are associated with advancing prostate cancer, while falling levels
are associated with control of prostate cancer.
9
Several peer-reviewed articles addressed this finding. See Gerhardt Attard et a).,
Antiwmor Activity with CYPI 7 Blockade Indicates that Castration-Resistant Prostate
Cancer Frequently Remains Hormone Driven, Cancer Research (2009) (VFX 461, at
4939); Daniel Danila et al., Phase ilMulticenter Study of Ahiraterone Plus Prednisone
Therapy in Patients with Docetaxel-Treated Castrate-Resistant Prostate Cancer, 28 J. of
Clinical Oncolo 1496, 1497 (2010) (JTX 8090); Oliver Sartor et al., Novel Therapeutic
Strategies for Metastatic Prostate Cancer in the Post-Docetaxel Setting, The Oncologist
(2011) (PTX 344, at 1495).
12
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, 272:1).” Under that amended Phase II
protocol, abiraterone and prednisone would be jointly administered. (2T268:2 123). 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 H Study of Abiraterone Acetate in ChemotherapyNaive Metastatic Castration-Resistant Prostate Cancer Displaying Bone Flare
Discordant with Serologic Response, Clinical Cancer Research (2011). (JTX
8093).
36. A clinical study report of the 002 trial was submitted to the FDA for
its consideration in approving ZYTIGA®. (2T3l2:16-3l3:2; 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 P0 or dexamethasone (0.5
mg once daily) with abiraterone acetate to better manage mineralocorticoid side
effects.” (Id.).
37. The 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
The 001 trial, recall, tended to confirm the hypothesis that the disease
progression on abiraterone monotherapy was due to an increase in upstream
corticosteroids, and that the effect of this increase could be moderated by the addition
of a glucocorticoid. (2T273:8- 16).
1
There was some debate at trial as to whether prednisone was added, not in
response to the 001 results, but rather in response to a patient’s death from a heart
attack associated with hypokalemia in March of 2008. (2T274:19; DTX 1354, at 5).
The decision to add prednisone in the 002 trial, however, was made in 2007, nearly a
year before that patient’s death. (2T275:3-4).
13
PSAWO 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 at 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 1000mg/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).
38. Dr. Robert Charnas, ZYTIQA®’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).
39. The 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 Antiw mor Activity in Post-Docetaxel, Castration-Resistant Prostate
Cancer with the CYPI 7lnhibitorAbiraterone Acetate, 20 J. of Clinical Oncology
1(2010). (DTX 1185).
40. The COU-AA-004 Phase II trial (“004 trial”) used the combination of
abiraterone and prednisone in post-docetaxel mCRPC patients. (2T272:7-l9;
3T614:6-l5). 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.
(4T954:22-956:1 1). The results of the 004 trial were also published. Daniel
14
Danila et al., Phase ilMulticenter 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).
41. The 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. (2T283:56).
42. 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).
43. 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. (2T277:l2-17).
44. The 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).
45. The 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).
46. The 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
15
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 administered.
(2T279: 1-3).
47. In 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 20).
48. The 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).
F. Prior Art
49. The priority date is August 2006. (Dl?? at 64, ¶249; PFF at 154,
¶764).
50. Before 2006, there was a significant divergence of opinion within the
scientific community as to whether prostate cancer was androgen dependent or
independent. (1T1 16:9-18). However, the prevailing belief was that, once the
cancer resumed growing after ADT, the cancer became androgen independent.
(1T1 16: 16-18).
51. 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).
52. The relevant prior art consists of the following:
a) Glenn Gerber et al., Prostate SpecficAntigenforAssessing
Response to Ketoconazole and Prednisone in Patients with Hormone
Refractory Metastatic Prostate Cancer, 144 J. of Urology 1177
(1990) (DTX 1059) (hereinafter “Gerber 1990”);
16
b) S.E. Barrie et al., Pharmacology of Novel Steroidal Inhibitors of
Cytochrome P450170 (1 7a-Hydroxylase/C1 7-20 Lyase), 50 J.
Steroid Biochem. Molec. Biol. 267 (1994) (DTX 1062) (hereinafter
“Barrie 1994”);
c) Gerald Potter et al., Novel Steroidal Inhibitors of Human
Cytochrome P450170 (1 7a-Hydroxylase-C 17,o-lyase): Potential
Agents for the Treatment of Prostatic Cancer, 38 J. Med. Chem.
2463 (1995) (JTX 8037) (hereinafter “Potter 1995”);
d) Ian F. Tannock et al., Chemotherapy with Mitoxantrone Plus
Prednisone orPrednisone 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 1996”);
e) Oliver Sartor, et al., Effect of Prednisone on Prostate-SpecJic
Antigen in Patients with Honnone-Refractonj Prostate Cancer, 52(2)
UROLOGY 252 (1998) (DTX 1087) (hereinafter “Sartor 1998”);
f) Michael Jarman et al., The 16,17-Double Bond Is Needed for
Irreversible Inhibition of Human Cytochrome P450170 by Abiraterone
(1 7-(3-Pyridyl,)androsta-5, 1 6-dien-3J3-ol) and Related Steroidal
Inhibitors, 41 J. Med. Chem. 5375 (1998) (DTX 1085) (hereinafter
“Jarman 1998”);
g) F.D. Fossa et al., Flutamide Versus Prednisone in Patients with
Prostate Cancer Symptomatically Progressing After Androgen
Ablative Therapy: A Phase 1ff 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) Manvan Fakih et al., Glucocorticoids and Treatment of Prostate
Cancer A Preclinical and Clinical Review, 60 Urology 553 (2002)
(DTX 1104) (hereinafter “Fakih 2002”);
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 2002”);
A. O’Donnell at al., Hormonal Impact of the 1 7aHydroxylase/ C1 7,2o-lyase Inhibitor Abiraterone Acetate (CB7630 in
Patients with Prostate Cancer, 90 British J. Can. 2317 (2004) (DTX
1129) (hereinafter “O’Donnell 2004”);
j)
k) L. Vidal et al,, Reversing Resistance to Targeted Therapy, 16 J.
Chemo. 7 (2004) (DTX 1135) (hereinafter “Vidal 2004”);
1) Gerhardt Attard et al., Selective Blockade of Androgenic Steroid
Synthesis By Novel Lyase Inhibitors As A Therapeutic Strategy For
17
Treating Metastatic Prostate Cancer, Urological Oncology (2005)
(JTX 8072) (hereinafter “Attard 2005”);
m) Oliver Sartor, The Continuing Challenge of Honnone-Refractonj
Prostate Cancer, Clinical Genitourinaiy Cancer (2006) (VFX 108)
(hereinafter “Sartor 2006”); and
n) Marc B. Qarnick & Camille Motta, Androgen Deprivation
Therapy, the Future, Prostate Cancer Principles and Practice (2006)
(DTX 1157) (hereinafter “Qarnick 2006”).
53. The prior art is further summarized and discussed at Section II.A.2,
infra.
G. FDA Approval
54. The 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).
55. 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. (2T41 1:3-5).
The application received priority review as requested.’2 (2T284:22-286:13).
56. On 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
The standard timeline for review of an NDA was approximately ten months.
Priority review expedites that process, resulting in completion in about six months.
(2T285: 1-6).
12
18
sponsor to inform the FDA about the NDA; and for the FDA to provide initial
feedback that would aid in the NDA review process. (2T334:15-23).
57. The 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 11-14). That scientific rationale was described as
follows:
Based on our understanding of abiraterone acetate’s mechanism of
action and as predicted by the syndrome of congenital deficiency of
CYP17, we anticipated that a state of mineralocorticoid excess
mediated by increased deoxycorticosteron could occur after
pharmacologic inhibition of CYP17, resulting in hypertension,
hypokalemia and fluid retention. Indeed, these mechanism-based
toxicities were observed in Phase 1 and 2 studies. Accordingly, the
Phase 1 studies were designed to allow administration of low dose
corticosteroids for disease progression or for palliation of
symptoms. The improved tolerability of abiraterone acetate after
concomitant administration of low-dose corticosteroids was
associated with suppression of ACTH and upstream adrenal
steroids, including mineralocorticoids, suggesting that the
combination may be better tolerated and safer regimen in this
older prostate cancer patient population.
Thus, the regimen of low-dose prednisone 5 mg twice a day and
abiraterone acetate 1 g daily was advanced into Phase 2 and 3
testing. Prednisone was selected over other corticosteroids because
it is commonly used as standard of care in combination with
chemotherapy and often maintained as palliative treatment after
chemotherapy is discontinued in patients with advanced
metastatic prostate cancer. When abiraterone acetate was
administered in a combination with oral prednisone 5 mg twice
daily there appeared to be a decreased incidence and severity of
mineralocorticoid based side effects, including hypertension, fluid
retention and hypokalemia (Danila et al., JCO). Anti-tumor activity
was observed across all patient studies as declines in prostate
specific antigen levels, and in objective radiographic responses in
the subset of men who had measureable disease.
(DTX 1331, at 12).
58. The NDA as submitted included a “summary of clinical efficacy,” i.e.,
a summary of the clinical trials discussed above that established ZYTIGA®’s
efficacy. (2T352: 16-353:6; JTX 8187). In comparing the various clinical trials
19
and addressing efficacy, the report noted that “[tihe totality of data from Phase
1/2 studies, Phase 2 studies, and pivotal Study COU-AA-301 consistently
demonstrates the benefit of abiraterone acetate and prednisone treatment for
patients with mCRPC.” (JTX 8187, at 52; 2T375:8-17).
59. The summan’ of clinical efficacy explained the specific dosing
recommendations of 1000mg/day of abiraterone and 10 mg/day of prednisone.
(JTX 8187, at 54). In addressing prednisone, the recommendation provided
that “concurrent treatment with prednisone” was “administered to ameliorate
mineralocorticoid-related toxicity that was observed with abiraterone acetate in
early Phase 1/2 studies.” (Id.). It noted that when abiraterone was
administered alone, “[hjypertension, hypokalemia, and peripheral edema were
observed frequently, and were managed with the mineralocorticoid receptor
antagonist eplerenone or with low-dose glucocorticosteroids.” (Id.).
60. On April 26, 2011, the FDA completed its medical
review,
which is
the FDA’s analysis and interpretation of the data presented in the clinical
section of the NDA. (2T342:17-343:2; DTX 1333). In addressing the potential
for overdose, drug abuse and withdrawal, the medical review included the
following comment: “Abiraterone acetate is given concurrently with 10mg of
prednisone once daily in order to attenuate mineralocorticoid excess resulting
from reduced feedback inhibition of ACTH.” (DTX 1333, at 107; 2T344:8-12).
61. The FDA approved the NDA on April 28, 2011. (2T286:19).
Specifically, the FDA approved ZYTIGA® in combination with prednisone for
the treatment of mCRPC. (2T393: 12-17).
62. The FDA publishes Approved Drug Products with Therapeutic
Equivalence Evaluations in the “Orange Book.” (DE 502, at 97, ¶90). The FDA
requires NDA holders to identify in the Orange Book “each patent that claims
the drug or a method of using the drug that is the subject of the NDA
...
and
with respect to which a claim of patent infringement could reasonably be
asserted if a person not licensed by the owner of the patent engaged in the
manufacture, use, or sale of the drug product.” (Id. at ¶9 1).
20
63. The ‘438 patent is listed in the Orange Book in connection with NDA
No. 202379. (Id. at ¶92). Each defendant had knowledge of the ‘438 patent and
its listing in the Orange Book when each respective defendant filed its
Paragraph IV certification for its ANDA. (Id. at 98, ¶93-94).
H. ZYTIGA Labeling
64. A medication’s product label is an FDA-approved document.
(2T390:2). The label contains information that the FDA believes is necessary in
order for the physician to prescribe a medication properly. (2T390:2-8). The
label also reflects the FDA’s views about the medication and how it should be
used. (2T391:14-17).
65. Physicians look to the Indications and Usage section of a label to
determine why a particular therapy is being used. (3T543:8-9). The Warnings
and Precautions section of a label provides information about adverse reactions
that may occur when using the drug product. (2T420:4-7; PDX 406, at 4). The
Dosing and Administration section of a label provides the recommended dose
for each indication and subpopulation. (2T4 12:1-5; 3T543:18-22).
66. On April 28, 2011, the FDA approved NDA 202379, with FDAapproved labeling. (DE 502, at 90, ¶55). The Indications and Usage section
provided that, “ZYTIQA is a CYP17 inhibitor indicated for use in combination
with prednisone for the treatment of patients with metastatic castrationresistant prostate cancer who have received prior chemotherapy containing
docetaxel.” (Id. at 90,
¶55).
67. On December 12, 2012, the FDA again approved NDA 202379, with
FDA-approved labeling stating in the Indications and Usage section that
“ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the
treatment of patients with metastatic castration-resistant prostate cancer.” (DE
502, at 90, ¶56).
68. On February 7, 2018, the FDA approved NDA 202379, with FDA
approved labeling stating in the Indications and Usage section that:
ZYTIGA is indicated in combination with prednisone for the treatment of
patients with
21
•
•
Metastatic castration-resistant prostate cancer (CRPC)
Metastatic high-risk castration-sensitive prostate cancer (CSPC)
(PTX 406; emphasis added). This Indications and Usage Section is
representative of the Indications and Usage section on the current ZYTIGA®
label. (PPF. at 14, ¶68). The Indications and Usage section of the label does not
identify any other disease or condition, other than mCRPC and metastatic
high-risk CSPC. (4T845:15-17).
69. The approved “Dosage and Administration” section of the 2018
ZYTIGA® label reads, in part:
2.1 Recommended Dose for metastatic CRPC
The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets
or four 250 mg tablets) administered orally once daily in
combination with prednisone 5 mg administered orally twice daily.
2.2 Recommended Dose for metastatic high-risk CSPC
The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets
or four 250 mg tablets) orally once daily with prednisone 5 mg
administered orally once daily.
(PTX 406). These are the doses that the FDA has approved for the treatment of
these diseases. (2T412:1-2).
70. Section 5 of the ZYTIGA® label, “Warnings and Precautions,” warns
that it may cause hypertension, hypokalemia, and fluid retention due to
mineralocorticoid excess. (PDX 406, at 4). In the 2018 label, the FDA removed
the following warning: “[cjo-administration of a corticosteroid suppresses
adrenocorticotropic hormone (ACTH) drive, resulting in the reduction in the
incidence and severity of these adverse reactions.” (2T42 1:13-19).
71. Section 14 of the label highlights some of the clinical studies that
were completed and demonstrated efficacy. (2T415:20-22). This section
specifies that “[t]he efficacy and safety of ZYTIGA with prednisone was
established in three randomized, placebo-controlled, international clinical
studies.” (PDX 406, at 21; 2T4l8:1-4).
22
I. Defendants’ Labels
72. Each defendant has filed an ANDA seeking approval to market a
generic form of ZYTIGA®, i.e., abiraterone acetate tablets. (DE 502, at 91,
¶65). The FDA requires that a drug manufacturer, when filing for such an
application, to prepare a side-by-side comparison of its proposed labels to the
brand name labels. (2T398:10-13). Typically, a proposed generic’s drug label is
substantively the same as the approved branded drug’s label. (3T393:10-l3).
73. Defendants’ proposed ANDA product labels recite the same mCRPC
indication as the ZYTIGA® label, except that defendants’ labels substitute
“abiraterone acetate” for “ZYTIGA.” (2T396:18-21, 407:22-24; 3T541:2-24; JTX
8011 (Amerigen’s proposed label); VEX 359 (Amneal proposed label); VEX 367
(DRL); VEX 372 (Mylan); VEX 383 (Teva); VEX 393 (West-Ward/Hikman); VEX
397 (Wockhardt)).
74. The proposed Indications and Usage sections of defendants’ labels
entail that they wish to market abiraterone plus prednisone for the treatment
of mCRPC only. (2T408:3-5). The defendants’ proposed labels do not contain
the mCSPC indication that was added to the ZYTIGA® label in its 2018 version.
(2T396:22-397: 1).
75. The Dosage and Administration sections of defendants’ labels all
recommend administering 1000mg/day of abiraterone acetate, and 10mg/day
of prednisone. (DE 502, at 4,
¶
73).
76. Amerigen’s, Mylan’s, and West-Ward/Hikman’s Dosing and
Administration sections are identical to the ZYTIGA® pre-2018 labels insofar
as they state that the “recommended dosage” is 1,000 milligrams of abiraterone
acetate tablets administered orally once daily in combination with 10
milligrams of prednisone administered orally twice daily. (2T413: 18-23; JTX
8011; PDX 393).
77. Amneal’s, DRL’s, Teva’s, and Wockhardt’s proposed Dosage and
Administration sections, like the ZYTIGA® 2018 label, state the same
23
l000mg/ 10mg “recommended dosage,” while adding the words “for mCRPC.”
(2T4 13:23-414:3).
78. The defendants’ labels that are based on the ZYTIGA® 2015 label still
contain the warning, dropped from the ZYTIQA® 2018 label, that “[c]o
administration of a corticosteroid suppresses adrenocorticotropic hormone
(ACTH) drive, resulting in the reduction in the incidence and severity of these
adverse reactions.” (2T422: 16-23). The FDA has already instructed Teva to
remove this language from its label. (2T424:20-2l).
J. ZYTIGA Marketing
79. The FDA requires pharmaceutical companies to submit marketing
materials. (2T483:8-10). The materials do not have to be approved in advance,
but they cannot mischaracterize a drug’s indication. (2T483:23-484: 1). Several
of ZYTIGA®’s marketing documents discuss the role of prednisone.
80. In a marketing document related to the 2011 indication (i.e., prior to
the removal of the warning language related to the “[cjo-administration of a
corticosteroid”) the role of prednisone was described as reducing “the incidence
and severity of mineralocorticoid-related adverse reactions” with ZYTIGA®.
(DTX 1260; 2T484:7-23).
81. A ZYTIGA® brochure dedicated to explaining the role of prednisone
also notes that prednisone “reduces the incidence and severity of
mineralocorticoid-related adverse reactions associated with ZYTIGA.” (DTX
1276; 2T488:8-22).
82. A third marketing document explaining the role of prednisone
explains that prednisone lessens the system’s response to a net cortisol deficit
due to abiraterone. (2T489:7-12; DTX 1276).
83. Other ZYTIGA® marketing materials, however, promote ZYTIGA® in
combination with prednisone solely as a means to treat prostate cancer. (PDX
424 (stating that “ZYTIGA plus prednisone achieved a statistically significant
median overall survival difference”); PDT 447 (stating that “ZYTIGA plus
24
prednisone significantly increased median radiographic progression for
survival”)).
II.
CONCLUSIONS OF LAW
The Hatch-Waxman Act strikes a balance between two competing policy
interests: “(1) inducing pioneering research and development of new drugs and
(2) enabling competitors to bring low-cost, generic copies of those drugs to
market.” AndrxPhanns., Inc. v. Biovail Corp., 276 F.3d 1368, 1370-7 1 (Fed. Cir.
2002). A brand name drug manufacturer seeking FDA approval must submit
an NDA that includes, among other things, a statement of the drug’s
components, proposed labeling describing the uses for which the drug may be
marketed, and scientific data showing that the drug is safe and effective. 21
U.S.C.
§
355(b)(l); Caraco Pharm. Labs., Ltd. v. Novo NordiskA/S, 566 U.S.
399, 404, 132 S. Ct. 1670, 1676 (2012).
The Hatch-Waxman Act streamlines the FDA approval process for generic
manufacturers, who can “bring their products to market without submitting all
of the extensive drug and clinical data ordinarily required of an NDA under 21
U.S.C.
§
355(b)(1).” TakedaPharm. U.S.A., Inc. z’. W-WardPharm. Corp., 785
F.3d 625, 629 (Fed. Cir. 2015). A generic drug applicant seeking approval to
market may file either an ANDA or “505(b)(2) application.” 21 U.S.C.
355(b)(2),
U).
§
An ANDA allows generic drug applicants seeking approval “to rely
on the safety and efficacy information for an approved drug listed in the
Approved Drug Products with Therapeutic Equivalence Evaluations, or the
‘Orange Book.” Takeda, 785 F.3d at 629.
After consulting the Orange Book, a generic company filing an ANDA is
required to assure “the FDA that its proposed generic drug will not infringe the
brand’s patents.” Caraco Phann. Labs., 566 U.S. at 406. To achieve this, a
generic manufacturer can file a “paragraph IV certification,” which states that a
listed patent “is invalid or will not be infringed by the manufacture, use, or sale
of the [generic] drug.” 21 U.S.C.
§
355(j)(2)(A)(vii)(IV). The Act treats such a
filing as an act of infringement, providing the brand with a right to sue
25
immediately. See 35 U.S.C.
§ 27l(e)(2)(A). Assuming the brand does so, the
FDA may not approve the ANDA until thirty months pass, or until the court
finds the patent invalid or not infringed. See 21 U.S.C.
§ 355W(5)(B)(iii).
Once invalidity is asserted in a paragraph IV certification, the ANDA
applicant takes on the burden of establishing it. In re Cyclobenzeprine
Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1078
(Fed. Cir. 2012). A patent and each of its claims are presumed to be valid, even
where those claims may be dependent upon other invalid claims in the patent.
35 U.S.C.
§ 282(a). A party may rebut this presumption of validity only by clear
and convincing evidence. Sciele Pharma Inc. v. Lupin Ltd., 684 F.3d 1253, 1260
(Fed. Cir. 2012) (citing 35 U.S.C.
§ 282; Microsoft Corp. v. i4i Ltd. P’ship, 564
U.S. 91, 131 5. Ct. 2238, 2245 (2011)).
Once non-infringement is asserted in a paragraph IV certification, the
patentee takes on the burden of establishing infringement by a preponderance
of the evidence. See SmithKline Diagnostics, Inc. v. Helena Labs. Corp., 859 F.2d
878, 889 (Fed. Cir. 1988); Kegel Co., Inc. v. AMF Bowling, Inc., 127 F.3d 1420,
1425 (Fed. Cir. 1997). To prove infringement, the patentee must show that it is
more likely than not that the proposed ANDA product would, if commercially
marketed, meet the claim limitations of the patent-in-suit. See Adams
Respiratory Therapeutics, Inc. a Pethgo Co., 616 F.3d 1283, 1287 (Fed. Cir.
2010); Abbott Labs. a TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002).
Plaintiffs allege two kinds of infringement: “induced” and “contributory.”
See 35 U.S.C.
§ 27 1(b), (c). Defendants assert the defense of patent invalidity,
based on lack of a sufficient written description and obviousness.
I discuss the validity issues first, in section II.A. In subsection II.A. 1, I
conclude that the ‘438 patent contains an adequate description. In subsection
II.A.2, I hold that the ‘438 patent is invalid for obviousness. In section 11.3, I
consider in the alternative whether, if the patent were valid, defendants’
activities would infringe. In subsection 11.3.1, I hold that the defendants’ labels
26
would result in induced infringement. In subsection 11.3.2, I hold that there
would be contributory infringement.
A. Validity
As a defense to infringement, defendants assert that the ‘438 patent is
invalid for lack of a written description and for obviousness. Although asserted
as a defense, the issue of patent validity is most profitably discussed in
advance of the infringement contentions. The defendants prevailed on those
invalidity contentions in three inter partes review proceedings (“IPR”) before the
PTAB. The parties state that the PTAB decisions, dated January 17, 2018, are
subject to a pending motion for reconsideration. (DTX 1562 (Mylan decision);
see also DE 393 (Amerigen and Wockhardt decisions).)’3
Defendants do not seek to estop the plaintiffs’ litigation of the validity issues
that they lost before the PTAB. Rather, the plaintiffs seek to estop defendants from
asserting the invalidity of the patent, an issue on which the defendants prevailed
before the PEAS. That argument was raised in limine and previously rejected by this
Court. (1T25:24-28:12). I consider (a) the purpose of the statute and (b) the meaning of
the term “final.”
The relevant estoppel provision, 35 U.S.C. § 315(e)(2), concededly maybe read
in the manner that plaintiffs propose. The manifest statutory intent, however, is to
prevent abuse of inter partes proceedings, for example through the withholding of
grounds and presentation of serial challenges. As I stated on the record, § 315(e)(2) is
“designed to prevent parties from using multiple, possibly inconsistent and wasteful
means of attacking a patent
I get it that a party to an IPR has to assert all of its
invalidity contentions or risk losing the opportunity to do so.”
.
.
.
.
I do not accept, however, that Congress intended to require a party to stand
mute in court because it previously prevailed on the same issue before the PEAS. The
result would be a decision reached without consideration of legally relevant facts and
issues. And if these Court proceedings overtook review of the PTAB decision, this
Court could find itself in the position of being required to enter an injunction against
infringement based on a patent already found invalid. See lT25:5—8 (“THE COURT:
You’re
Let’s just say hypothetically that there was prior art squarely on point.
could come here and
saying that having lost in an inter pafles proceeding, you
prevail? MR. TRELA: We could prevail until the inter partes proceeding runs its
course.”)
.
.
.
The case law contains no deep analysis of the issue, but it appears to reflect the
[fn. 13 cont’d on following page]
27
[fn. 13 continued]
concept that only unsuccessful or unsubmitted arguments are subsequently barred.
See Milwaukee Elec. Tool Corp. u. Snap-On Inc., 271 F. Supp. 3d 990, 1027 (E.D. Wis.
2017) (Section 315(e) (2) prohibits an unsuccessftullPR petitioner from asserting in the
district court “that the claim is invalid on any ground that the petitioner raised or
reasonably could have raised during that inter partes review.”)(emphasis added);
Depomed Inc. v. Purdue Phanna LP, 2014 WL 3729349, at *5 (D.N.J. July 25, 2014)
(Bongiovanni, M.J.). On October 30, 2018, I expanded on this discussion on the record
in connection with plaintiffs motion for a stay pending appeal.
In connection with the plaintiffs motion for a stay pending appeal, I further
discussed on the record the issue of finality. For convenience, I summarize my
reasoning here. The issue is whether the PTAB’s decision, which is subject to a
pending motion for reconsideration, is “final” for purposes of 3 15(e). I conclude that
it is not, and for this reason, too, my consideration of validity issues is not estopped. I
think finality, for these purposes, should track the concept as it is used in the closely
related context of exhaustion and appealability. “The parties to an appeal to the Board
may not appeal to the U.S. Court of Appeals for the Federal Circuit under § 1.983 of
this title lAppeal to the United States Court of Appeals for the Federal Circuit in inter
partes reexamination] until all parties’ rights to request rehearing have been
exhausted, at which time the decision of the Board is final and appealable by any
party to the appeal to the Board.” 37 C.F.R. § 41.81 (emphasis added). See 37 C.F.R.
90.3(b)(1) (deadline to appeal runs from PTAB’s action on request for rehearing).
A contrary view of finality would lead to the same conundrum identified above—
i.e., the possibility of issuance of a mandatory injunction based on a PTAB decision
treated by the plaintiff as “final,” but only for purposes of § 315(e) estoppel (because
the plaintiff itself sought reconsideration).
I observe that these are issues which will tend to arise in the interim when the
PTAB and court proceedings are not synchronized. All matters in dispute are likely to
converge before the Federal Circuit when my decision is appealed and the VPAB IPR
decision becomes ripe for review. In the meantime, my goal has been to hear all claims
and compile the fullest possible record on the matters submitted to me for decision.
2 7a
1.
Written Description
Defendants allege that the asserted claims in the ‘438 patent do not meet
the written-description requirement of 35 U.S.C.
In pertinent part, 35 U.S.C.
§ 112. 1 disagree.
§ 112 provides:
The specification shall contain a written description of the
invention and of the manner and process of making and using it,
in such full, clear, concise and exact terms as to enable any person
skilled in the art to which it pertains, or with which it is most
nearly connected, to make and use the same, and shall set forth
the best mode contemplated by the inventor of carrying out his Lor
her] invention.
“The purpose of this provision is to ensure that the scope of the right to
exclude, as set forth in the claims, does not overreach the scope of the
[inventionj as described in the patent specification.” Reiffin
i.’.
Microsoft Corp.,
214 F.3d 1342, 1345 (Fed. Cir. 2010); see also Abh Vie Deutschland GmbH &
Co., KG
ii.
Janssen Biotech, Inc., 759 F.3d 1285, 1298 (Fed. Cir. 2014). “[T]he
test requires an objective inquiry into the four corners of the specification from
the perspective of a person of ordinary skill in the art. Based on that inquiry,
the specification must describe an invention understandable to that skilled
artisan and show that the inventor actually invented the invention claimed.”
Ariad Phann., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010).
To begin with, the ‘438 patent clearly sets forth the metes and bounds of
the invention. It teaches the administration of a specified dosage of two
specified drugs for the treatment of a specified condition in a specified, narrow
class of patients, i.e., those suffering from mCRPC. Not even minimal
adjustment or experimentation is suggested; a skilled practitioner (assuming
regulatory approval) would need little if any additional instruction to practice
the method.
28
In defendants’ view, however, the specification is inadequate because it
fails to disclose test results showing that prednisone itself provides an anti
cancer benefit. Nor, they say, does it provide sufficient information to permit a
POSA to understand that both agents, abiraterone and prednisone, “treat”
prostate cancer. (DEr. at 68; Def. Response at 38). These challenges fit only
awkwardly within a contention that the method is not described so that a
practitioner could practice it. Nevertheless, I address them.
First, I find that the specification in the ‘438 patent sufficiently identifies
prednisone as an anti-cancer agent for purposes of the 35 U.S.C.
§ 122
written-description requirement. As stated in my Markman opinion, that is
what “treatment,” as used here, means. The specification is directed to the
administration of abiraterone acetate with “at least one additional therapeutic
agent, such as an anti-cancer agent or a steroid.” (JTX 8000). The specification
defines “anti-cancer agent” as “any therapeutic agent that directly or indirectly
kills cancer cells or directly or indirectly prohibits, stops or reduces the
proliferation of cancer cells.” (Id. at 4). The ‘438 patent provides a list of anti
cancer agents, including mitoxantrone, paclitaxel, docetaxel, leuprolide,
goserelin, triptorelin, seocalcitol, bicalutamide, and flutamide. (Id. at 3). It
further identities additional “anti-cancer” agents as “hormone ablation agents,
anti-androgen agents, differentiating agents,
.
.
.
antibiotic agents
.
.
.
and anti
androgens.” (Id. at 7). Thus, an antibiotic agent is defined as an anti-cancer
agent, and prednisone is explicitly identified as an antibiotic agent. (Id. at 9).
Second, the specification provides a list of steroids, including
hydrocortisone, prednisone, and dexamethasone. (Id. at 3, 10). In discussing
the administration of steroids, the specification provides that the “amount of
the steroid administered to a mammal having cancer is an amount that is
sufficient to treat the cancer whether administered alone or in combination
with a 17a-hydroxylase/C17,2o-lyase inhibitor.” (Id. at 10). Thus, whether
identified as either an “anti-cancer agent” or a “steroid,” prednisone is
sufficiently identified in the specification as an agent that “treats” cancer.
29
To this extent, the patent drafter is privileged to act as his or her own
lexicographer. “The specification acts as a dictionary when it expressly defines
terms used in the claims or when it defines terms by implication.” Novartis
Corp. v. Teua Phanns. USA, Inc., 565 F.Supp.2d 595, 604 (D.N.J. 2008) (quoting
Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996)).
Taking the patent’s own definitions of terms as my guide, I find that the
written description is adequate.
2.
Obviousness
Defendants allege that the combination therapy claimed in the ‘438
patent would already have been obvious to a person of ordinary skill in the art
(“POSA”) under 35 U.S.C.
§
103. The burden here, as in other validity
challenges, is proof by clear and convincing evidence. See p. 26, supra, and
cases cited. The parties agree that August 25, 2006 is the priority date for the
prior art analysis. Defendants assert that, as of that date, a POSA familiar with
the prior art would have been motivated to combine abiraterone acetate with
prednisone for three reasons: (1) for its anti-cancer effects; (2) to mitigate
abiraterone’s side effects; or (3) for prednisone’s palliative properties. (DBr. at
33).
A patent claim is invalid as “obvious” where the “differences between the
claimed invention and the prior art are such that the claimed invention as a
whole would have been obvious before the effective filing date of the claimed
invention to a person having ordinary skill in the art to which the claimed
invention pertains.” 35 U.S.C.
§
103. “[O]bviousness cannot be avoided simply
by a 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) (citing In re Gorkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985)
(“Although [the inventorj declared that it cannot be predicted how any
candidate will work in a detergent composition, but that it must be tested, this
does not overcome [the prior art’s] teaching that hydrated zeolites will work.”)).
30
Four factors guide the obviousness inquiry under
§
103: (1) the scope
and content of the prior art; (2) the differences between the prior art and the
claims at issue; (3) the level of ordinary skill in the field of the invention; and
(4) objective considerations such as commercial success, long felt need, and the
failure of others to develop the invention. KSR Int’l Co. v. Teleflex Inc., 550 U.s.
398, 406, 127 S. Ct. 1727 (2007) (quoting Graham v. John Deere Co., 383 U.S.
1, 17-18, 86 S. Ct. 684 (1966)). The evidence at trial focused on factors 1, 2,
and 4, the prior-art and objective-considerations factors.’4
The parties make short work of factor 3, the level of skill possessed by a POSA.
Under either side’s analysis, that level of skill is quite high. A POSA would be a
physician specializing in medical oncology or urology with significant practical
experience and with access to individuals with expertise in endocrinology,
biochemistry, pharmacology, or other related fields of science.
14
In determining the level of ordinary skill in the an, the following factors may be
considered: “(1) the educational level of the inventor; (2) type of problems encountered
in the art; (3) prior art solutions to those problems; (4) rapidity with which innovations
are made; (5) sophistication of the technology; and (6) educational level of active
workers in the field.” EnvtL Designs, Inc. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir.
1983) (citing Orthopedic Equip. Co., Inc. v. All Orthopedic Appliances, Inc., 707 F.2d
1376, 1382 (Fed. Cir. 1983)), ced. denied, 464 U.S. 1043, 104 S. Ct. 709, 79 L. Ed. 2d
173 (1984).
Defendants offered the following definition of a POSA:
Physician specializing in medical oncology or urology, having an M.D.
and/or Ph.D. in pharmacology, biochemistn’, or related discipline.
Significant practical experience (e.g., 5-6 years’ worth) in medical
oncology or urology could substitute for an advanced degree. It is
understood that the POSA would have access to individuals having
expertise in pharmacology, biochemistry, endocrinology, enzvmology,
and/or molecular biology, and would collaborate with them as necessary.
(DTX 2400). Plaintiffs offered the following definition of a POSA:
A person of ordinary skill would be a physician specializing in urology or
medical oncology who has significant practical experience in the
treatment of patients with prostate cancer. Such a person would’ve
worked in a team or setting that includes access to one or more
individuals who have expertise in endocrinology, biochemistry,
pharmacology and/or molecular biology, or related field of science, and
who has experience in prostate cancer treatments or androgen synthesis
and action.
(3T537:4-l2).
31
Principles specifically governing the application of those factors to a
combination patent, especially a combination-therapy patent, are as follows.
The novelty of a combination therapy in relation to prior art may consist
in the idea of putting two known elements together. The POSA’s motivation to
combine prior art teachings to achieve the “claimed invention does not have to
be found explicitly in the prior art references sought to be combined, but rather
may be found in any number of sources, including common knowledge, the
prior art as a whole, or the nature of the problem itself.” Pfizer, 480 F.3d at
1362 (internal quotation and citation omitted). Accord Dystar Textilfarben
GmbH v. C.H. Patrick Co., 464 F.3d 1356, 1361 (Fed. Cir. 2006) (stating that
motivation to modif prior art to arrive at claimed invention “may be found in
any number of sources, including common knowledge, the prior art as a whole,
or the nature of the problem itself.”) Thus the mix of information available to a
POSA must be considered.
Relevance, however, has its limits. There must be “a nexus between the
claimed invention and the [objective indicia].” In reAffinity Labs of Tex., LLC,
856 F.3d 883, 901 (Fed. Cir. 2017) (quoting Onnco Corp. z.’. Align Tech., Inc.,
463 F.3d 1299, 1312 (Fed. Cir. 2006)). The evidence, moreover, “must be
reasonably commensurate with the scope of the claims.” In re Huai-Hung Kao,
639 F.3d 1057, 1068 (Fed. Cir. 2011). To determine whether the necessary
nexus exists, “[o]ur cases require consideration of whether ‘the marketed
product embodies the claimed features.” ClassCo, Inc. v. Apple, Inc., 838 F.3d
1214, 1222 (Fed. Cir. 2016) (quoting Brown & Williamson Tobacco Corp. v.
Philip Morris
ma,
229 F.3d 1120, 1130 (Fed. Cir. 2000)); see also Pro-Mold &
Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573 (Fed. Cir. 1996)
(noting that whether requisite nexus exists is a question of fact).
In reviewing all these factors, courts use an approach that is not
formulaic, but “expansive,” “flexible,” or “functional.” KSR, 550 U.S. at 415; see
The two sides’ experts agreed that the discrepancies between their definitions
would not affect their opinions.
32
alsoAlza Corp. v. My/an Labs., Inc., 464 F.3d 1286, 1291 (2006) (“There is
flexibility in our obviousness jurisprudence because a motivation may be found
implicitly in the prior art. We do not have a rigid test that requires an actual
teaching to combine.”). In describing this flexible approach, the Supreme Court
noted that, although “[a] factfinder should be aware, of course, of the distortion
caused by hindsight bias” in evaluating obviousness, the proper approach
must allow for “recourse to common sense.” KSR, 550 U.S. at 421 (citing
Graham, 383 U.S. at 36 (warning against “temptation to read into the prior art
the teachings of the invention in issue” and instructing courts to “guard
against slipping into use of hindsight”)).
The crux of defendants’ argument is that the prior art would have
motivated a POSA to combine abiraterone with prednisone with a reasonable
expectation of success. One component of the defendants’ obviousness
argument is that the anti-cancer role of prednisone in actual “treatment” of
mCRPC could have been anticipated. A second component of the defendants’
argument, however, is that the role of prednisone in palliation or reducing side
effects would also have motivated a POSA to combine it with abiraterone.
Implicit in that second component is the idea that the motivation to combine
therapies need not have been entirely congruent with the patented idea as
conceived by the inventor. See KSR, 550 U.S. at 420 (stating that it is error to
look “only to the problem the patentee was tiying to solve”); In re Kahn, 441
F.3d 977, 990 (Fed. Cir. 2006) (“IT]he skilled artisan need not be motivated to
combine [the prior art] for the same reason contemplated by [the inventor]”
(quoting In re Beattie, 974 F.2d 130g, 1312 (Fed. Cir. 1992) (“[TIhe law does not
require that the references be combined for the reasons contemplated by the
inventor.”)). Thus defendants rely in part on these other effects of prednisone
because those effects lent a separate impetus to the administration of
abiraterone and prednisone in combination.
The argument can be pushed too far; the proverbial blind pig must at
least have been searching for an acorn. The case law does not suggest that
33
obviousness must be found because an inventor, ignorant of the relevant
science and considering an entirely different problem, could have stumbled on
the patented method. This case, however, is close to the other end of the
spectrum.
The combination therapy, it is true, is patented as a “treatment.” But
even prednisone’s effects as a palliative and a side-effect minimizer would
furnish a powerful motivation to combine it with abiraterone. And the idea for
such a combination, even if initially motivated only by those two effects, would
have gotten the POSA to the same place. That road led straight to the practice
of the patented method: the target condition would be prostate cancer; the
target population would be the subset of patients who had mCRPC; the dosage
would be 1000mg of abiraterone and 10mg of prednisone daily; the object
would be to slow the spread of the disease by hormone deprivation; the clinical
results would be the same, and would be measured by prolongation of life (or,
in the interim, by proxy metrics such as reduction of PSA levels). In short, the
anticipated combination therapy—irrespective of what was in the POSA’s mind
as to the exact mechanism—would have looked precisely the same. So
understood, this begins to look less like serendipity and more like inevitability.
I first review the prior art evidence as to abiraterone, prednisone, and
combination therapy (subsections a, b, & c). I then review the secondary
considerations evidence (subsection d). Finally, I state my overall conclusions
as to obviousness (subsection e).
a. Prior art: abiraterone
Barrie l994,’ a published study involving mice, disclosed that
ketoconazole is a non-selective inhibitor that was used as a treatment for
hormone-dependent prostate cancer. As a result, efforts were then being
undertaken to discover a more potent and selective inhibitor. (DTX 1062, at 1).
In that regard, Barrie 194 concluded that abiraterone was “worthy of further
IS
Full citations and abbreviations for the prior art are at Section IF, supra.
34
study” as a potential agent “for the treatment of hormone-dependent prostate
cancer.” (7T1563:7-9; DTX 1062, at 5).
Potter 1995 explained that abiraterone is a “strong candidate for further
development as a potential drug for the treatment of prostatic carcinoma in
humans.” (JTX 8037, at 7; 7T1563:10-13). Abiraterone was also noted as an
inhibitor of both the hydroxylase and the lyase function of the CYP17 enzyme.
(JTX 8037, at 6; 6T1316:6-16; see PDX 7.5, chart attached to opinion). A few
years later, Jarman 1998 indicated that abiraterone had been selected for
clinical evaluation based on animal testing: “its marked reduction of circulating
testosterone levels in the male rat and mouse and of androgen-dependent
organ weights in the mouse.” (DTX 1085, at 5375).
The first human trial of abiraterone, reported in O’Donnell 2004, began
in 1997. (lTlO9:12-110:1, 209:11-13; DTX 1129). The Institute of Cancer
Research tested abiraterone in a Phase I clinical trial. (lT205:24-206:6). No
patient was given a glucocorticoid during testing. O’Donnell did, however,
discuss co-administration of a glucocorticoid with abiraterone. (lT214:9; DTX
1129; see mfra at 43).
The O’Donnell 2004 trial comprised of multiple parts. (1T211:3-5). In the
first portion of the trial, a population of castrate made patients received a single
dose of abiraterone, at varying dosage levels, and were monitored for the
following ten days. (1T2 11:15-20; DTX 1129, at 2319). All patients in this
portion of the study experienced a reduction in testosterone levels below
castrate levels. (1T2 14:14-16). The second portion of the trial administered a
single dose of abiraterone, at various dosages, in non-castrate males. (1T212:57; DTX 1129, at 2319). Testosterone levels were reduced there as well, but not
to below-castrate levels. (1T215:4-5). In the third and final portion of the study,
non-castrate males were given a single dose of 500 milligrams of abiraterone
every day for twelve days. (1T212:8-18, -21). Testosterone suppression was not
sustained in that non-castrate portion of the study. (1T214:20-21).
The O’Donnell 2004 triad determined that abiraterone was safe.
(1T2 14:11). But because of the failure to attain sustained testosterone
35
suppression in non-castrate patients, the results suggested that abiraterone
was suitable as a second-line (i.e., post-castration) treatment. (1T216:12-19;
DTX 1129, at 2317 (“The enhanced testosterone suppression achieved in
castrate men merits further clinical study as a second-line hormonal treatment
for prostate cancer.”)). Specifically, O’Donnell 2004 found that testosterone
levels would be suppressed below castrate levels by a daily dose of abiraterone
in the amount of 800 milligrams. (DTX 1129, at 2317; see also Garnick 2006
(DTX 1157, at 9 19-20 (recognizing that abiraterone “shows potential in the
treatment of cancer,” and “has demonstrated [an] ability to selectively inhibit
the target enzyme, resulting in inhibition of testosterone production in both the
adrenals and the testes”))). After a series of rejections, the O’Donnell results
were eventually published in the British Journal of Cancer, four years after the
close of the underlying study. (1T208:2, 222:6-227:17, 239:19-240:1).
O’Donnell 2004 specifically compares ketoconazole to abiraterone. (DTX
1129, at 2318). O’Donnell notes that”[i]n addition to ketoconazole,
aminoglutethimide and abiraterone, other compounds designed to inhibit
general androgen production have been developed and show promise.” (DTX
1129, at 2321). In addressing ketoconazole, O’Donnell 2004 observes that it is
an “unselective” inhibitor, that it has an antitumor effect (measured by clinical
benefit as well as reduction in PSA), and that a more “selective” (i.e., CYP-17)
inhibitor, abiraterone, could be used as a second-line agent. (DTX 1129, at
2318).
b. Prior art: prednisone
Tannock 1996 was a palliation study involving patients having refractory
prostate cancer with pain. They received mitoxantrone, a chemotherapy drug
(not a CYP17 inhibitor) with prednisone, or else prednisone alone. (7T1609:212; DTX 1076, at 1756; 8T1742:14-18). Tannock 1996 disclosed that
prednisone, dosed at 10 milligrams per day, would provide palliation to
hormone-resistant prostate cancer patients, when used with mitoxantrone.
(7T1609: 1-15; DTX 1076, at 1756). Defendants’ expert testified that prednisone
36
was administered to alleviate the “known effects of mitoxantrone” including
nausea, vomiting, hair loss, low blood counts, and neuropathy. (ST 1743:2-8).
Sartor 1998 evaluated the effects of prednisone on PSA levels in patients
with hormone-refractory prostate cancer. (DTX 1087, at 252). Twenty-nine
patients were given ten milligrams of prednisone daily. (Id.; 7T1575:5-1l). Of
those twenty-nine patients, fourteen (48%) achieved a PSA decline of at least
25%, ten (34%) achieved a PSA decline of at least 50%, and four (14%) achieved
a PSA decline of at least 75%, measured from baseline. (DTX 1087, at 254).
Sartor 1998 reported that four patients (14%) had a duration of response
greater than six months. (Id. at 254; 7T1575:17-1576:2).
Thus, Sartor 1998 concluded that prednisone could decrease PSA levels.
(DTX 1087, at 255; DE 393-3 (“Sartor reasonably stands for the proposition
that administration of prednisone is tolerated and effective in a subset of
patients, and at the time it was published, indicated some measure of efficacy
for certain mCRPC patients.”). Sartor 1998 hypothesized that “PSA declines of
greater than 50% may be useful in predicting a relatively prolonged survival.”
(Id. at 256).
Fossa 2001 evaluated 201 patients, all of whom had metastatic disease
that had progressed after castration. (JTX 8048, at 63). Of those patients, 101
received prednisone and 100 received flutamide, an antiandrogen. (Id. at 62).
Of the 101 patients treated with twenty milligrams of prednisone per day,
twenty-one (20.8%) had a PSA decline of greater than 50%. (7T1578:8-10; JTX
8048, at 63, 67). There was no difference in median overall survival between
the two groups of patients, however. (JTX 8048, at 70). Fossa 2001 concluded
that “[m]onotherapy with low-cost prednisone should be considered as firstline, standard hormonal manipulation of HRPC, but the combination with
tolerable cytotoxic treatment should be explored further.” (SEX 8048, at 70).
Fakih 2002, a clinical review article that evaluated “the mechanisms
underlying glucocorticoid antitumor effects in prostate cancer,” concluded that
“[gjlucocorticoids may exert an antitumor effect on androgen-independent
prostate cancer by suppression of adrenal androgens. Low-dose glucocorticoids
37
produce negative feedback on the pituitary gland, leading to a decrease in both
testicular and adrenal androgens.” (DTX 1104, at 553).
Harris 2002 was a prospective phase II study conducted on twenty-eight
men with androgen-independent cancer. It evaluated the efficacy and safety of
administering 200 milligrams of ketoconazole, three times a day, with
replacement doses of hydrocortisone. (JXT 8053, at 542). Harris 2002 noted
that “[g]lucocorticoids alone may have antiwmor effects mediated either by
direct interaction with androgen receptors or by feedback inhibition of the
hypothalamic-pituitary-adrenal axis.” (Id, at 544).
c. Prior art: combination therapy
The study published in Gerber 1990 evaluated PSA level changes in
fifteen men with hormone refractory metastatic prostate cancer that were
treated with a combination of ketoconazole and prednisone. (DTX 1059, at
1177). The action of ketoconazole is not as focused as that of abiraterone.
Abiraterone acetate is a selective drug that inhibits CYP17, one enzyme with
two functions: 17 alpha-hvdroxvlase and 17,20-lyase. (1T123:l3-20;JTX 8072,
at 3). Ketoconazole is a non-specific inhibitor; it acts on the CYP17 enzyme, but
also on other points in the pathways of adrenal steroid synthesis. (1T105:2;
6T1262:10-17, 1326:4-19). Ketoconazole inhibits adrenal steroid synthesis and
causes adrenal insufficiency. (6T 1276:3-6).
The patients in the Gerber 1990 study were treated with 600 to 900
milligrams of ketoconazole daily and five milligrams of prednisone twice per
day. (DTX 1059, at 1177-78). Of the fifteen patients, twelve (80%) had a
decrease in PSA levels with a median duration of response of three months.
(DTX 1059, at 1177). The other three patients had a prolonged response,
greater than eight months, of decreased PSA levels and improvement in bone
pain. (DTX 1059, at 1177). Ultimately, Gerber 1990 concluded that “there
appears to be a small subgroup of patients with progressive prostate cancer
despite androgen ablation who will benefit from ketoconazole and
glucocorUcoid treatment.” (DTX 1059, at 1177).
38
O’Donnell 2004, discussed in the preceding section, reported promising
results for abiraterone. It also indicated, however, that the treated patients
experienced a reduced adrenal reserve. (Id.; see also Attard 2005 (JTX 8072)
(noting that all six patients in O’Donnell 2004 “had a reduced cortisol response
to ACTH stimulation on the 11th day after dosing, suggesting reduced
adrenocortical reserve.”). Researchers speculated that such a deficiency could
be addressed with a dose of a steroid, either concomitantly or during times of
stress. (1T220:24, 221:7-22, 244: 12-19, 249:5-9; DTX 1129, at 2317
(“Adrenocortical suppression may necessitate concomitant administration of
replacement glucocorticoid.”)). In considering the use of a glucocorticoid,
O’Donnell 2004 noted that it was “common practice” to administer
supplementary hydrocortisone with aminoglutethimide and ketoconazole. (DTX
1129, at 2323).
O’Donnell 2004 suggested that “further studies with abiraterone acetate
will be required to ascertain if concomitant therapy with glucocorticoid is
required on a continuous basis, at times of physiological stress, if patients
become symptomatic or indeed at all.” (Id.; see also Attard 2005 (JTX 8072, at
1245) (concluding that safety and efficacy of abiraterone should be undertaken
where abiraterone was administered daily “to castrate men with advanced
prostate cancer” and that patients should “be monitored for the development of
glucocorticoid insufficiency”); Garnick 2006 (DTX 1157, at 9 19-20) (noting that
abiraterone was under development “as a second-line hormonal therapy for
prostate cancer for patients who are refractory;” and that administration of 800
mg/day resulted in “hypersecretion of luteinizing hormone,” which “may
necessitate concomitant treatment with replacement glucorticoid”).
In 2004, Dr. de Bono,’6 along with Lara Vidal, published a review article
titled “Reversing Resistance to Targeted Therapy.” Its subject matter was
Defendants now request that the Court disregard parts of Dr. de Bono’s
testimony, which they say was not properly disclosed before trial. In particular,
defendants argue that Dr. de Bono offered surprise expert testimony regarding the
import of the prior art and clinical trials. Defendants did not raise this particular
16
39
methods of fighting resistance to cancer treatment and thereby maximizing the
treatment’s anti-tumor effect. (1T1 13:9-225; DTX 1135). It noted that hormone
therapy was the “mainstay” of treating metastatic prostate cancer. (DTX 1135,
at 17). Vidal 2004 further observed that circulating low levels of adrenal
androgens (i.e., those produced by the adrenal glands rather than the testes)
can result in failure to respond to hormone therapy. It further stated, however,
that adrenal androgen synthesis can be inhibited by low doses of steroids, or
through inhibition of key enzymes using either abiraterone or ketoconazole.
(DTX1 135, at 7-8).
The authors noted generally that combining drugs could improve
outcomes. (1Tl22:3-4). For example, chemotherapy drugs had been combined
to treat lymphoma. (1T122:5-6). Vidal 2004 noted that combination therapies
entail “major logistical challenge[s]” since they require “more than one industry
partner”; as a result, researchers were pursuing “less selective agents that can
hit multiple targets.” (DTX 1135, at 11).
Finally, Sartor 2006 noted that “[s]econdary hormonal manipulations (i.e,
ketoconazole, estrogens, glucocorticoids, antiandrogens, and antiandrogen
withdrawal) have long been used in [hormone refractory prostate cancer], but
because no study with these agents has demonstrated a survival advantage,
their potential role is not agreed upon by all.” (VEX 108, at 238).
d. Objective considerations
As to factor 4, objective considerations, plaintiffs raise several arguments
related to ZYTIGA®’s commercial success, failure of others, skepticism, long-
objection during trial, but I nevertheless consider it. (See DBr. at 66 (citing 1T98: 12107:7, 113:9-124:16, 130:2-132:12, 136:23-137:7, 142:4-143:15)). The objected-to
portions of Dr. de Bono’s testimony, while technical, did not exceed the bounds of his
personal observations and involvement in the development of the clinical trials. Such
testimony is helpful to the court’s understanding of the trials and was properly
admitted under Rule 701. Fed. R. Evid. 701. See generally Asplundh Mfg. Div., a Div. of
Asplundh Tree Expert Co. v. Benton Harbor Eng’g, 57 F.3d 1190, 1193 (3d Cir. 1995)
(Under Rule 701, even non-experts who possess helpful specialized knowledge may be
permitted “to testify about technical matters that might have been thought to lie
within the exclusive province of experts.”).
40
felt need, professional approval and industry praise, and unexpected results.
My assessment of these is mixed at best, and I give them correspondingly less
weight.
As of today, ZYTIGA® has achieved substantial sales and marketplace
success. From April 2011 to the end of 2017, plaintiffs estimate, ZYTIGA®
generated over $5.7 billion in net sales. (8T1790:17-20). Plaintiffs presented
evidence that approximately 85% to 95% of ZYTIGA® prescriptions were being
filled in proximity to a fill of prednisone. (8T1803:14-18).
During most of that period of ZYTIGA®’s market success there was a
blocking patent in place. Prior to the ‘438 combination-therapy patent was the
patent on abiraterone itself. That patent, U.S. Patent No. 5,604,213 (“the ‘213
patent”), titled “17-Substituted Steroids Useful in Cancer Treatment,” was
issued February 18, 1997, and expired in December 2016. (PPF at 208). The
‘213 patent discusses seventeen steroids and their use in the treatment of
androgen-dependent and estrogen-dependent disorders. (JTX 8042). The ‘213
patent specifically discloses abiraterone and suggests a method of using
abiraterone acetate for the treatment of prostate cancer. (Id.). The ‘213 patent
compares the inhibition levels of abiraterone with those of ketoconazole, and
reports that abiraterone achieves a superior reduction of testosterone levels.
(Id.). It was under the ‘213 patent that BTG granted Cougar Biotechnology an
exclusive license to develop abiraterone in 2004. (9T2044:21-25).
Plaintiffs point out that two other CYP17 inhibitors had failed to treat
advanced prostate cancer (9T1969:24-25); that various pharmaceutical
companies declined to pursue abiraterone after 1999 (1T229:10-230:17); and
that the O’Donnell 2004 authors had difficulty getting their results published.
The anti-cancer effect of abiraterone plus prednisone, then, was unexpected in
plaintiffs’ opinion. In countering that the argument that ZYTIGA® met a long
felt need, Defendants note that other treatments, in particular Taxotere and
Jevtana, had similar survival benefits.
41
e. Obviousness: Discussion and analysis
By the priority date of August 25, 2006, abiraterone had been identified
in the art as a treatment for prostate cancer. It was understood that
abiraterone selectively inhibited the CYP17 enzyme. This was seen as an
improvement on ketoconazole, a less selective agent that inhibited CYP17, but
also interfered with other metabolic steps. (See O’Donnell 2004; Barrier 1994).
Ketoconazole and aminoglutethimide were known treatments.
(6T1260:22-24, 1276:3-6, 1325: 13-14, 1327:8-15). Both ketoconazole and
abiraterone were steroid inhibitors, and both inhibited the CYP17 enzyme
(although, as stated, ketoconazole inhibited others steps as well). (6T1262:717, 1325:13-1326:19). Barrie 1994 and O’Donnell 2004 both used
ketoconazole as a starting point for their discussions regarding abiraterone and
its potential to be a more selective inhibitor.’7 (7T1563:7-9; DTX 1062, at 5;
DTX 1129, at 2318). Barrie 1994, comparing the inhibition levels of hormone
production by abiraterone with ketoconazole, concludes that abiraterone was
more effective than ketoconazole in decreasing testosterone levels. (DTX 1062,
at 270; see also Jarman 1998 (noting that abiraterone caused “marked
reduction of circulating testosterone” warranting further clinical evaluations
(DTX 1085, at 5375)). O’Donnell 2004 specifically notes that abiraterone’s
ability to sustain testosterone suppression in castrate males, when given in
500 to 800 milligram doses, suggested that it could be used as a second-line
treatment.’8 (DTX 1129, at 2317).
The ‘213 patent likewise used ketoconazole as a starting point and relevant
comparison in its discussion of abiraterone. (JTX 8042).
17
It is undisputed that publication of the study underlying O’Donnell 2004 was
delayed, and that companies did not pursue the marketing of abiraterone immediately
after that publication. I do not give weight, however, to the plaintiffs’ speculation that
those events resulted from skepticism about abiraterone therapy, a conclusion
unsupported by any first-hand testimony. (PBr. at 34, 39). Because there are many
reasons that a company decided not to pursue a particular drug or publish a study, I
cannot assume plaintiffs’ speculative explanation is the true one.
18
42
From all of this, I conclude that abiraterone had been identified in the
prior art as a second-line prostate cancer treatment. I also conclude that it was
regarded as a superior swap for ketoconazole, in that it performed a parallel
function in a more targeted manner.
As for prednisone itself, Tannock 1996 suggested that corticosteroids
provide some level of palliation to cancer patients. Sartor 1998 goes farther,
and suggests that prednisone can cause reduced PSA levels, a marker of anti
cancer effect. It further teaches the administration of 20 mg/day of prednisone
as a monotherapy in patients with mCRPC. Plaintiffs may be correct that
Sartor 1998 was flawed, in that it was not a prospective study hut a
retrospective analysis of data, and that it carried a risk of sample bias. A
reference, however, “is prior art for all that it discloses, and there is no
requirement that a teaching in the prior art be scientifically- tested
guarantee success
.
.
.
.
.
.
or even
before providing a reason to combine.” (internal
citations omitted); Duramed Pharm., Inc. v. Watson Labs., Inc., 413 F. App’x
289, 294 (Fed. Cir. 2011).
Sartor 1998 teaches that prednisone monotherapy worked to reduce PSA
levels in some mCRPC patients, and a POSA would have known that. Whether
firm or shaky, the Sartor results disclosed to a POSA that prednisone can have
an anti-cancer effect. That conclusion is supported by three other prior art
references: Fossa 2001, Fakih 2002, and Harris 2002)°
Reduced PSA levels, to be sure, do not necessarily correspond to a
survival benefit. Still, PSA levels are an accepted measure of progression of
prostate cancer. I am not convinced that PSA levels are so meaningless that
researchers would have been dissuaded from pursuing prednisone in
combination therapy.
The extent to which the biochemical basis for such an effect was understood is
less clear, however, and hindsight is not the appropriate test. See Findings of Fact ¶
34, supra (post-priority-date citations).
43
Based on the foregoing, and some additional references (especially
O’Donnell 2004), I find that there was more than sufficient motivation for a
POSA to combine abiraterone with prednisone.
Gerber 1990 suggests that a patient whose PSA levels are increasing can
be treated with a combination of ketoconazole and a glucocorticoid, which can
result in a decrease in PSA levels. Gerber 1990 also teaches that the
combination of ketoconazole and five milligrams a day of prcdnisone, twice
daily, is safe and effective for treating hormone-refractory advance prostate
cancer.
O’Donnell 2004 corroborates that in the clinical use of ketoconazole, it
was “common practice” to administer supplementary hydrocortisone. It states
cautiously that “further studies with abiraterone acetate will be required to
ascertain if concomitant therapy with glucocorticoid is required on a
continuous basis, at times of physiological stress, if patients become
symptomatic or indeed at all.” (DTX 1129, at 2323). The prior art went so far as
to identify specific dosages: between ten and twenty milligrams per day of
prednisone (Gerber 1990; Tannock 1996; Sartor 1998; Fossa 2001); and 800
milligrams of abiraterone. (Gerber 1990; O’Donnell 2004; Garnick 2006).
A POSA would have interpreted ketoconazole’s clinical use as a basis to
take the next investigative steps with abiraterone. It made sense to replace
ketoconaiole with abiraterone, as it became clear that abiraterone was a
superior, more selective inhibitor. Co-administration of 10mg per day of
prednisone would naturally carry over from the ketoconazole combination
therapy to the abiraterone combination therapy.
I believe a POSA would have been concerned about the potential
reduction in cortisol as a side effect of abiraterone’s inhibition of CYP17.
Specifically, a POSA would have seen the potential for resulting excess
mineralocorticoid (aldosterone) and adrenal insufficiency. Plaintiffs’
44
reservations about the Synacthen test for adrenal insufficiency20 are, I believe,
well-taken. They do not, however, outweigh the clear import of O’Donnell 2004.
O’Donnell 2004 states that “[s}ome impact on adrenal reserve was predic.table
from the steroid synthesis pathway.” That conclusion is consistent with
defendants’ expert’s testimony and with the literature relied upon by
defendants’ expert. (6T1287:3-1292:8; DTX 1096). O’Donnell 2004 suggests
that a practitioner could address those side effects through coadministration of
a glucocorticoid. To be sure, the paper appears to be agnostic about whether
coadministration would (or would always) be necessary. It falls far short,
however, of concluding that such coadministration is unnecessary or should be
avoided. See Depuy Spine, Inc. v. Medtronic SofamorDanek, Inc., 567 F.3d
1314, 1327 (Fed. Cir. 2009) (prior art does not teach away “if it merely
expresses a general preference for an alternative invention but does not
criticize, discredit, or otherwise discourage investigation into the invention
claimed.”). I therefore do not agree, as plaintiffs suggest, that prior art “taught
away” from the combination therapy. Plaintiffs further suggest that there were
other options and theories on how to treat mCRPC, and that there were other
anti-cancer agents, perhaps even more promising ones. Nevertheless, the prior
art clearly pointed to coadministration of abiraterone with a glucocorticoid.
See, e.g., In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) (“a finding that the
prior art as a whole suggests the desirability of a particular combination need
not be supported by a finding that the prior art suggests that the combination
claimed by the patent applicant is the preferred, or most desirable,
combination.”); In re Gurley, 27 F.3d 551, 552-53 (Fed. Cir. 1994) (upholding
obviousness finding where patent was directed to one of two alternative resins
disclosed in prior art reference, even though reference described claimed resin
as “inferior.”).
The Synacthen test evaluates adrenal insufficiency based on the measurement
of serum cortisol before and after an injection of synthetic ACTH. (DTX 1096).
20
45
Nor do I agree that prednisone’s own side effects would have discouraged
its use. The prior art establishes that, despite side effects, glucocorticoids were
reasonably well-tolerated. The mere existence of other treatments does not
suggest that a POSA would employ these alternatives to the exclusion of
prednisone.
In short, to the POSA, the prior art would suggest that abiraterone could
be combined with prednisone with a reasonable probability of success.
The factor 4 objective considerations presented by plaintiffs do not alter
my conclusion. See generally Ryko Mfg. Co. z’. Nit-Star, Inc., 950 F.2d 714, 719
(Fed. Cir. 1991) (holding that district court did not err when it determined that
secondary considerations did not carry sufficient weight to override
obviousness determination based on primary considerations).
As to the commercial success factor, there can be no dispute that
ZYTIGA® has yielded billions of dollars in sales.2’ “Commercial success is
relevant because the law presumes an idea would successfully have been
brought to market sooner, in response to market forces, had the idea been
obvious to persons skilled in the art.” Merck & Co. v. Teva Pharms. USA, Inc.,
395 F.3d 1364, 1376 (Fed. Cir. 2005). “Evidence of commercial success
.
.
.
is
only significant if there is a nexus between the claimed invention and the
commercial success.” Onnco, 463 F.3d at 13 11-12. “When a patentee can
demonstrate commercial success, usually shown by significant sales in a
relevant market, and that the successful product is the invention disclosed and
claimed in the patent, it is presumed that the commercial success is due to the
The net sales figures offered by plaintiffs, totaling $5.7 billion for 2011—17, are
for ZYTIGA® abiraterone acetate tablets alone. They do not correspond precisely to the
patented invention, i.e., ZYTIGA® plus prednisone. See Merck Sharp & Dohme Corp. v.
Sandoz Inc., 2015 U.S. Dist. LEXIS 113710, at *118 (D.N.J. Aug. 27, 2015)
(Commercial success is measured by sales of a “commercial embodiment of the
claimed compound”); Asyst Techs., Inc. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir.
2008) (noting that “failure to link that commercial success to the features of [thel
invention that were not disclosed in [the prior artj undermines the probative force of
the evidence.”). On that score, plaintiffs offer suggestive though not conclusive
evidence that approximately 85% to 95% of ZYTIGA® prescriptions were being filled at
a pharmacy in temporal proximity to a fill of prednisone.
2t
46
patented invention.” J.T. Eaton & Co.
i.’.
Atlantic Paste & Glue Co., 106 F.3d
1563, 1571 (Fed. Cir. 1997). However, “if the feature that creates the
commercial success was known in the prior art, the success is not pertinent.”
Onnco, 463 F.3d at 1311-12; see also fT. Eaton, 106 F.3d at 1571 (“[Tjhe
asserted commercial success of the product must be due to the merits of the
claimed invention beyond what was readily available in the prior art”); see
Tokai Corp. v. Easton Enters., Inc., 632 F.3d 1358, 1369 (Fed. Cir. 2011) (noting
that if “commercial success is due to an element in the prior art, no nexus
exists.”).
Specifically, “where ‘market entry by others was precluded [due to
blocking patentsj, the inference of non-obviousness of [the asserted claims],
from evidence of commercial success, is weak.”’ Galdenna Labs., L.P. v. Tolmar,
Inc., 737 F.3d 731, 740 (Fed. Cir. 2013) (quoting Merck, 395 F.3d at 1377). “A
‘blocking patent’ is an earlier patent that must be licensed in order to practice
a later patent. This often occurs, for instance, between a pioneer patent and an
improvement patent.” Prima TekII, L.L.C. v. A-Roo Co., 222 F.3d 1372, 1379 n.2
(Fed. Cir. 2000). “The existence of such a blocking patent may deter nonowners and non-licensees from investing the resources needed to make,
develop, and market such a later, ‘blocked’ invention, because of the risk of
infringement liability and associated monetary or injunctive remedies.” Acorda
Therapeutics Inc u. Apotex Inc., 2011 U.S. Dist. LEXIS 102875, at *61 (D.N.J.
Sep. 6, 2011), affid, 476 F. App’x 746 (Fed. Cir. 2012); see also id. at *66 (“if all
other variables are held constant, a blocking patent diminishes possible
rewards from a non-owner’s or non-licensee’s investment activity aimed at an
invention whose commercial exploitation would be infringing, therefore
reducing incentives for innovations in the blocked space by non-owners and
non-licensees of the blocking patent.”).
To explain the commercial success of the patented ZYTIGA® combination
therapy, despite its alleged obviousness, defendants point to the exclusionary
effect of the earlier ‘213 “blocking patent.” Abiraterone was previously known in
47
the art, and indeed was taught by the ‘213 patent. From 1997 through 2016,
that patent granted its holder the exclusive right to market abiraterone. See
Galderma Labs., 737 F.3d at 740 (holding that any inference of nonobviousness gleaned from evidence of commercial success is undermined when
blocking patent precludes others from entering market).
Janssen contends that the effect of the blocking patent is overstated,
because they were willing to license the ‘213 patent rights at any time from
2000 until 2004, when Cougar Biotechnology was granted its exclusive license.
To be sure, licensing opportunities can “dilute the power of the blocking
patent” in evaluating commercial success. Accord Therapeutics, 2018 U.S. App.
LEXIS 25536, at *70. But such licensing efforts appear to have been lackluster.
Dr. Ian Judson testified that he met with three drug companies on one
occasion in an effort to partner and license abiraterone. (lT229:23-230:3). Dr.
Judson pointed to no further attempts to find a licensing partner. (1T229:1214). And starting in 2004, of course, both the blocking patent and the Cougar
license (which was exclusive) prevented non-owners or licensees from entering
the market. Between 2004 and 2006, Cougar Biotechnology was the exclusive
licensee for abiraterone. So although the commercial possibilities might
otherwise have attracted entrants, Cougar’s exclusive status surely would have
stifled such interest.
The existence of a blocking patent 1997 through 2006 (indeed, through
2016), despite some desultory licensing efforts, would have discouraged entry
at the very time when the obviousness of combination therapy was manifesting
itself. See generally Media Techs. Licensing, LLC v. Upper Deck Co., 596 F.3d
1334, 1339 (Fed. Cir.) (“Even if Media Tech could establish the required nexus,
a highly successful product alone would not overcome the strong showing of
obviousness.”), cert. denied, 562 U.S. 894, 131 S. Ct. 305 (2010). And the sales
of ZYTIGA may not be wholly attributable to the patented combination therapy.
These are powerful offsetting factors. All in all, however, I must recognize that
this abiraterone product has enjoyed commercial success.
48
I find the market-skepticism factor to be neutral. “Evidence of industry
skepticism weighs in favor of non-obviousness. If industry participants or
skilled artisans are skeptical about whether or how a problem could be solved
or the workability of the claimed solution, it favors non-obviousness.” WBIP,
LLC v. KohierCo., 829 F.3d 1317, 1335 (Fed. Cir. 2016). Plaintiff advances
arguments related to the delayed publication of the study results underlying
O’Donnell 2004, a negative comment received in response to those results, the
failure to obtain a licensing partner after 1999 and before 2004, the
uncertainty of Dr. de Bono’s colleagues in proceeding with the extension study,
and an article from 1999 that discounted hormonal therapies. Much of that
skepticism seems to be directed to abiraterone itself, rather than the claimed
combination. And the context is important: as noted above, prior art suggested
the combination of abiraterone and glucocorticoids to treat prostate-cancer,
and by 1997 industry researchers had patented abiraterone itself. By then,
multiple experts had concluded that it was worth pursuing abiraterone as a
treatment for prostate cancer. See Section II.A.2.a, supra. This skepticism
factor does not point strongly either way.
I next address the plaintiffs’ claims that the patented invention
addressed a long-felt need and had unexpected results. “[L]ong-felt need is
analyzed as of the date of an articulated identified problem and evidence of
efforts to solve that problem.” Tat Instruments, Inc. v. U.S. ITC, 988 F.2d 1165,
1178 (Fed. Cir. 1993). In practical terms, courts “look to the filing date of the
challenged invention to assess the presence of a long-felt and unmet need.”
P&G u. Teva Pharms. USA, Inc., 566 F.3d 989, 998 (Fed. Cir. 2009). “Evidence
of ‘unexpected results’ allows a patent-holder to rebut a prima facie case of
obviousness by showing that the ‘claimed invention exhibits some superior
property or advantage that a person of ordinary skill in the relevant art would
have found surprising or unexpected.”’ Daiichi Sankyo Co., Ltd. u. Mylan Phann.
Inc., 670 F. Supp. 2d 359, 382 (D.N.J. 2009) (quoting In re Soni, 54 F.3d 746,
750 (Fed. Cir. 1995), aff’d, 619 F.3d 1346 (Fed. Cir. 2010)). To establish this
49
factor, “the claimed properties or results must be different in ‘kind and not
merely in degree’ from the results of the prior art.” Id. (quoting In re Huang, 100
F.3d 135, 139 (Fed. Cir. 1996)). That is, in order for the results to be
“unexpected,” they must be proven to be surprising in relation to the closest
prior art. Id. (citing In re Baxter Tra venal Labs., 952 F.2d 388, 392 (Fed. Cir.
1991)).
Plaintiffs state that the claimed invention was an advance on the prior
art in that it had less toxicity, was better tolerated, and improved overall
survival. Defendants point to existing contemporaneous alternatives: Jevtana
was approved by the FDA in 2010, a year before ZYTIGA® was approved;
Xtandi was approved in 2012. (7T1626:13-18). Those drugs were FDAapproved and available for the treatment of prostate cancer patients. Cf Pfizer
Inc. v. Teva Phann. United States, Inc., 460 F. Supp. 2d 659, 662 (D.N.J. 2006)
(noting that failure to obtain FDA approval is “appropriate benchmark in
evaluating failure of others”). Taxotere (a chemotherapy drug) and Jevtana were
found to extend overall survival of mCRPC patients by 2.5 months, whereas
ZYTIGA®-based therapy extended survival by about four months. (7T1622: 1724). That represents a real improvement, but an incremental one. In the
context of prostate cancer patients with dire prognoses, it cannot be
discounted. Still, it does not suggest that all other efforts had failed, or that the
abiraterone/prednisone combination therapy was unexpected “in kind and not
merely in degree.” Daichi, supra. So, although there is evidence supporting the
unmet-need or failure-of-others factors, I do not find it to be powerful.
As for the professional-approval factor, plaintiff points to the 301 and
302 studies, as well as the post-priority-date Attard 2008 and 2009 references.
“Appreciation by contemporaries skilled in the field of the invention is a useful
indicator of whether the invention would have been obvious to such persons at
the time it was made.” Vulcan Eng’g Co. v. FATA Aluminium, Inc., 278 F.3d
1366, 1373 (Fed. Cir.), cert. denied, 537 U.S. 814, 123 5. Ct. 81(2002). A court
may look to “contemporaneous recognition of the achievements of the
50
[patented] system, including articles in trade journals” and testimony by those
skilled in the art that prior to the appearance of the patented technology, it was
generally believed the system could not be created. Id. This factor weighs
somewhat in plaintiffs’ favor.
All in all, however, I conclude that the patented combination here was
well foreshadowed in peer-reviewed articles. That factor outweighs the others.
Balancing all of the prior art and the other indicia, I find that the evidence
favors a conclusion of obviousness. Tokai Corp. a Easton Enters., 632 F.3d
1358, 1370 (Fed. Cir. 2011) (“However, even assuming the existence of a nexus,
we see no error in the district court’s determination that Tokai failed to
establish ‘that any of these secondary’ factors are significant,’
.
.
.
in light of the
strong showing of prima facie obviousness.”).
Defendants’ burden of proof to rebut the presumption of validity by clear
and convincing evidence is met. The ‘438 patent is declared invalid for
obviousness.
B. Infringement
In this section, I assume arguendo that the ‘438 patent is valid and
consider whether, if valid, it would have been infringed. Plaintiffs assert both
induced and contributory’ infringement. Both, I find, would be supported by a
preponderance of the evidence.
1.
Induced infringement
The gist of the induced infringement claim here is that the ANDA label,
which specifies indications and proper use of the abiraterone/prednisone
combination therapy, would induce physicians’ direct infringement of the
method claimed in the ‘438 patent. The label by definition embodies the range
of uses and indications that are approved by the FDA. Defendants argue that
because the allegedly infringing use would fall outside the scope of the FDAapproved use, the ANDA label does not induce infringement.
It’s a subtle argument. Both the patent and the label indications,
followed faithfully, would lead to the same actions, undertaken in the same
manner and for the same reason: the administration of abiraterone and
51
prednisone, in combination, to treat a class of patients who suffer from
mCRPC, with the goal of slowing the progression of the disease. The
defendants, however, argue that the 438 patent claims that each component
(abiraterone, prednisone) has an anti-cancer effect. The FDA, in contrast,
allegedly approved administration of the prednisone component of the
combination only for its palliative effect, or to address side effects. Therefore,
the argument runs, the administration of the combination therapy in
accordance with the FDA-approved label would not infringe.
Defendants ask, in effect, that the court look behind the Indications and
Usage section of the label, which provides for combination therapy and does
not segregate the contribution of each component. That would require the
Court to reanalyze the clinical data as if it were a regulatory body, and posit a
revised Indication which, in defendants’ estimation, would better fit the
underlying science. I do not sit to reconstruct a theoretical ruling by an ideal
FDA; in assessing the scope of the FDA approval, I am confined to the actual
ruling of the actual FDA. In short, this is not an appeal of the FDA’s decision,
but only an attempt to define its scope.
“Whoever actively induces infringement of a patent shall be liable as an
infringer.” 35 U.S.C.
§
27 1(b); see Wamer-Lambert Co. v. Apotex Corp., 316 F.3d
1348, 1363 (Fed. Cir. 2003). Thus infringement liability falls upon parties who,
while not directly infringing a patent themselves, induce others to infringe. See
Commil USA, LLC v. Cisco Sys., Inc., 135 S. Ct. 1920, 1926 (2015).
“A person induces infringement under
§
27 1(b) by actively and knowingly
aiding and abetting another’s direct infringement.” C.R. Bard, Inc. v. Advanced
Cardiovascular Sys., Inc., 911 F.2d 670, 675 (Fed. Cir. 1990) (emphasis
omitted). To succeed on an induced infringement claim, a plaintiff must prove
that the defendants’ “actions induced infringing acts and that [they] knew or
should have known [their] actions would induce actual infringement.” Manville
Sales Corp. v. Paramount Sys., Inc., 917 F.2d 544, 553 (Fed. Cir. 1990).
However, it is insufficient that defendants merely have “knowledge of the acts
52
alleged to constitute infringement.” Id. “[P]roof of actual intent to cause the acts
which constitute the infringement is a necessary prerequisite to finding active
inducement.” Hewlett—Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469
(Fed. Cir. 1990); see ACCO Brands, Inc. v. ABA Locks Mfrs. Co., 501 F.3d 1307,
1312 (Fed. Cir. 2007). “While proof of intent is necessary, direct evidence is not
required; rather, circumstantial evidence may suffice.” Water Techs. Corp. v.
Calco, Ltd., 850 F.2d 660, 668 (Fed. Cir. 1988).
a. FDA approval
The ‘438 patented method, say defendants, requires that each
component (abiraterone and prednisone) have an anti-cancer effect. The FDA
however, allegedly approved the prednisone component for its palliative effects
only, and the proposed ANDA labels reflect that. Thus, according to
defendants, their ANDAs do not meet the claim limitation of a “therapeutically
effective amount of prednisone,” La, an amount of prednisone that is, in itself,
therapeutically effective against prostate cancer.
How do we know that the FDA did not approve a therapy in which
prednisone, viewed separately, has an anti-cancer effect? Primarily, defendants
say, because (1) the underlying clinical trials and data provided to the FDA
would not permit such a conclusion. Relatedly, defendants cite the following
evidence: (2) the ZYTIGA® label is vague in its Indications and Usage section as
to the role of prednisone; (3) plaintiffs’ NDA submissions focused on the
efficacy of abiraterone, not prednisone, in treating cancer; (4) the FDA approval
package does not suggest that prednisone was approved for its combination
effect with abiraterone; and (SJ the FDA-approved marketing materials promote
prednisone as relieving abiraterone’s side effects.
“The FDA-approved label for an approved drug indicates whether the
FDA has approved a particular method of use for that drug.” Bayer Sche ring
Phanna AG & Bayer HealthCare Phann., Inc. v. Lupin, Ltd., 676 F.3d 1316,
1322 (Fed. Cir. 2012). Under the Food, Drug, and Cosmetics Act (“FDCA”), new
pharmaceutical drugs cannot be marketed or sold unless the sponsor of the
53
drug demonstrates to the satisfaction of the FDA that the drug is “safe for use
under the conditions prescribed, recommended or suggested” on the drug’s
label. 21 U.S.C.
§ 355(d). A drug receives FDA approval only for treatment of
specified conditions, referred to as “indications.” 21 U.S.C. § 352, 355(d).
FDA regulations provide guidance on how to interpret a label. The
“Indications and Usage” section of the label must set forth indications that are
supported by “substantial evidence of effectiveness based on adequate and
well-controlled studies.” 21 C.F.R.
§ 20l.57(c)(2)(iv). The Indications and Usage
section “must state that the drug is indicated for the treatment, prevention,
mitigation, cure, or diagnosis of a recognized disease or condition, or of a
manifestation of a recognized disease or condition, or for the relief of symptoms
associated with a recognized disease or condition.” 21 C.F.R.
§ 201.57(c)(2).
“Indications or uses must not be implied or suggested in other sections of the
labeling,” i.e., sections other than the Indications and Usage section. 21 C.F.R.
§ 201.57(c)(2)(iv); cf Wamer-Lambert, 316 F.3d at 1356 (“The FDA does not
grant across-the-board approval to market a drug. Rather, it grants approval to
make, use, and sell a drug for a specflc purpose for which that drug has been
demonstrated to be safe and efficacious.” (emphasis added)).
The three cases cited by the defendants, Bayer Schering, supra, Warner
Lambert, supra, and Allergan, Inc. v. Alcon Labs., Inc., 324 F.3d 1322, 1324-25
(Fed. Cir. 2003), are not precisely on point. To begin with, they involve multiple
effects of a single drug, rather than a dispute over the allocation of multiple
effects as between two drugs. I take my lead, however, from those cases’ shared
reluctance to adopt the mode of analysis of the FDA approval that is employed
by the defendants here.
Because Bayer Sche ring is the most pertinent of the three, I give it the
most extended discussion. There, the defendants sought to market a generic
form of Yasmin, a branded oral contraceptive. The FDA had granted plaintiffs’
NDA seeking approval of Yasmin “for oral contraception.” 676 F.3d at 1319.
The defendants’ ANDAs sought FDA approval to market generic forms of
54
Yasmin for the same approved use, “oral contraception.” Id. Defendants filed
paragraph IV certifications, and the plaintiffs filed suit against the ANDA
applicants, alleging infringement of a method-of-use patent. That patent’s
claims recited that the drug “achieves three effects simultaneously: a
contraceptive (or gestagenic) effect, an anti-androgenic effect
.
.
.
and an anti
aldosterone effect.” Id. at 1320. Defendants filed a motion for judgment in their
favor on the pleadings; they would not infringe, they said, because they sought
to market the generic form of Yasmin “only for oral contraception and not for
the combination of uses claimed in the
[]
patent.” Id. The district court agreed.
Id.
On appeal, the plaintiffs acknowledged that both the FDA-approved label
and the proposed generic labels stated in their Indications and Usage sections
that the drug was to be used as an “oral contraceptive.” Id. at 1320. The
“Clinical Pharmacology” section of the label, however, referred to the other two
effects, i.e., the anti-androgenic and anti-aldosterone effects. Based on that
language, the plaintiffs argued that the FDA had approved “the use of Yasmin
to induce those effects” in addition to the contraceptive effect. Id. at 1322,
1324.
The Federal Circuit held that, as to this issue, it is the Usages and
Indications section that does the real work. The court expressly rejected the
notion that an indication could be implied from another section of the label, an
approach that would not make regulatory sense. A particular use or indication
for a drug is FDA-approved only when the safety and efficacy of that use has
been established. The inclusion of such a use in the label’s Indications and
Usage section constitutes the necessary “[a]cknowledgement of the safety and
efficacy of that specific method of use.” Id. at 1324.
Mention in the Clinical Pharmacology section, the court held, is not the
same thing at all:
The reference in the Clinical Pharmacology section of the label to
the anti-mineralocorticoid and anti-androgenic activity of
drospirenone is certainly not a direct indication of an appropriate
55
use for Yasmin, and even if it could be considered an “implied or
suggested” indication of an appropriate use, the regulation
expressly states that such implied or suggested uses do not
constitute approved uses.
Id. at 1323.
The Federal Circuit in Bayer Sd-ic ring discussed extrinsic evidence
submitted by the plaintiffs, including physicians’ declarations and marketing
materials. Id. at 1324. These documents, said the plaintiffs, established a
context that suggested FDA approval of Yasmin as safe and effective not just
for contraception, but for the claimed combination of three effects. Id. The
Federal Circuit demurred. This evidence, the Court held, demonstrated that the
FDA was aware that Yasmin could cause the other two effects, not that the
FDA had approved the safety and efficacy of the medication for the claimed
combination of effects. Id. Accordingly, the Court held that the FDA had
approved Yasmin for use only as an oral contraceptive, and that defendants did
not commit infringement. The defendants sought to market their drug solely for
that approved use as a contraceptive, while the patent claimed the trio of uses
in combination. Id. at 1326.
Following the lead of Bayer, I will not read an indication into the
ZYTIGA® label or ANDA labels that is not there. The Indications and Usage
section is clear that abiraterone and prednisone are to be used in combination
for the treatment of mCRPC. That indication signifies that these agents are
FDA-approved in combination to treat cancer. (2T400:16-24).
Defendants’ FDA expert, Dr. Akhilesh Nagaich, testified persuasively that
prednisone would not have been identified in the Indications and Usage section
if its sole approved purpose were the treatment of side effects, and I agree.
(4T861:21-862:2). I also credit Dr. O’Shea’s testimony, which is consistent with
the FDA regulations, that if prednisone were approved solely to treat side
effects of abiraterone, it would probably not appear in the Indications section,
but only in the label’s dosage and administration section, or the warnings and
precautions section. (2T401:19-402:1, 405:1-6). It is also likely that if
56
prednisone had been approved only to alleviate side effects, the label would
simply have said so. (2T402:2-3).
An item’s inclusion in the Indications and Usage section cannot be
brushed aside; to place it there is a critical regulatory decision. Indeed, as
noted above, it’s essentially that or nothing; indications not listed in the
Indications and Usage section cannot be derived by implication from other
sections of the labeling. 21 C.F.R.
§
201.57(c)(2)(iv) (“Indications or uses must
not be implied or suggested in other sections of the labeling”); see also Bayer
Schering, 676 F.3d at 1323—24; Wamer-Lambert, 316 F.3d at 13; Shire LLC v.
AmnealPharm., LLC, 2014 U.S. Dist. LEXIS 85369, at *18 (D.N.J. June 23,
2014) (rejecting argument that drug was FDA-approved to treat amphetamine
abuse based on studies section of label, where the Indications section clearly
stated that the drug was “indicated for the treatment of Attention Deficit
Hyperactivity Disorder”), aff’d and reversed on other grounds, 802 F.3d 1301
(Fed. Cir. 2015).22
I consider with care certain other cases in which courts were considering, inter
alia, the related but distinct issue of specific intent to induce infringement. See Section
II.C, infra. With that caveat, I have given some weight to cases that that have rejected
invitations to infer a drug’s use from sections of the label other than indications and
usage.
22
Thus, in United Therapeutics Corp. u. Sandoz, Inc., No. 12cv1617, 2014 U.S.
Dist. LEXIS 121573, at *49 (D.N.J. Aug. 29, 2014) Judge Sheridan of this court
persuasively rejected a plaintiffs argument that an infringing use could be predicated
on a label warning, as opposed to an indication. The court noted that there is a “rather
significant difference between a warning and an instruction.” Id. A “warning provides
information regarding a potential risk,” but stops short of prescribing a specific
“course of action.” Id. An instruction, on the other hand, specifically directs that a
particular action, or series of actions be taken. Id. at 49-50 (rejecting inducement
claim if patentee must engage in “scholarly scavenger hunt” through the label to
identify statements that may potentially, but not inevitably, impact a prescribing
physician’s actions).
To similar effect is Otsuka Pharm. Co., Ltd. v. Torrent Pharm. Ltd., Inc., 99 F.
Supp. 3d 461, 476, 490-93 (D.N.J. 2015) (Simandle, C.J.) (finding that warning and
safety information is insufficient to establish inducement of claimed method). See also
Sanofi v. Glenmark Pharm. Inc., 204 F. Supp. 3d 665, 674 (D. Del. 2016) (finding that
physician would look to indications and usage section, but that the indications and
usage section explicitly referred physicians to the clinical studies section, which a
physician would therefore consider as well), affd, 875 F.3d 636 (Fed. Cir. 2017).
57
Also implicit in Bayer is my refusal to give controlling weight to the other
evidence introduced by defendants. To be sure, there are indications in the
record that the FDA was aware of prednisone’s palliative benefits. To be sure,
underlying NDA submissions emphasize the anti-cancer effect of abiraterone
rather than that of prednisone. And there there are marketing materials that
tout the palliative effects of prednisone without mentioning its anti-cancer
effect. Giving these proofs due latitude, I nevertheless conclude that they do
not negate what the FDA actually did in its approval of the label’s Indications
and Uses. See Bayer Sche ring, 676 F.3d at 1323-24 (refusing to imply
indication from marketing materials, clinical pharmacology section of label at
issue, and from physician’s declarations). I cannot find that prednisone was
approved as part of ZYTIGA®’s indication solely for its benefits with respect to
palliation and side effects.
Concededly, this Court, like the parties, must wrestle with an irreducible
level of ambiguity in a combination-therapy approval. As defendants say, the
Indications and Uses do not, for example, attribute a percentage of efficacy to
each component; the most that can be said is that the FDA has approved the
combination as safe and effective. Similarly, defendants attack plaintiffs’ cited
combination-study clinical trials which, in defendants’ view, are confounded
and fail to establish the independent contribution of prednisone to the efficacy
of the combination.
Again, the fact remains that the FDA did approve the combination-based
treatment of mCRPC based on a combination study. Perhaps the studies could
have been better designed. Perhaps the researchers could have found an
ethical means of definitively isolating the contribution of each component.23
For similar reasons, I do not give weight to the warning that was omitted from
the 2018 version of the ZYTIGA® label (“Co-administration of a corticosteroid
suppresses adrenocorticotropic hormone (ACTH) drive, resulting in the reduction in
the incidence and severity of these adverse reactions.” (2T42l:13-19)).
Placebo control studies, for example, were discontinued when the combination
therapy began to show therapeutic benefit. See Section I.E., supra.
23
58
But from arguments that the FDA should not have approved an indication, I
cannot leap to the conclusion that it did not. That, to me, is an important
methodological lesson to be drawn from the approach of Bayer.
I treat defendants’ other two cited cases more briefly. In Wamer-Lambert,
the branded manufacturer held a patent for a method of “treating
neurodegenerative diseases” using a drug known as gabapentin. 316 F.3d at
1351. Its NDA, however, led to approval of gabapentin for use in “adjunctive
therapy in the treatment of partial seizure with and without secondary
generalization in adults with epilepsy.” Id. at 1352. Defendant Apotex’s ANDA
sought to market generic gabapentin for the same indication, i.e., partial
seizure. Id. The Federal Court affirmed the grant of summary judgment to
Apotex because the two indications were distinct; partial seizure is not a
neurodegenerative disease. Id. at 1353.
Finally, in Allergan, Inc. v. A/con Labs., Inc., 324 F.3d 1322, 1324-25
(Fed. Cir. 2003), the Federal Circuit held that an ANDA applicant’s labeled
indication for reducing intraocular pressure would not induce infringement of
patented methods of “protecting the optic nerve and retina” and “providing
neural protection.” Because the patent-claimed uses were not approved by the
FDA, the ANDA applicant could not be held liable for infringement even if the
proposed drug in fact had those additional protective effects in patients who
took the drug for the approved purpose. Id. at 1324.
These three cited cases, Bayer in particular, eschewed the kind of
searching review of the FDA record and regulatory “do-over” that defendants
propose. The common feature of these three cases is that, to decide the
induced-infringement issue, those courts compared the wording of the label to
the patent claims.24
What may be occurring here is a kind of category mistake. This is not an appeal
seeking affirmaxice or reversal of an FDA decision. In this context, what is significant
about an FDA approval is its existence and scope.
24
59
Following that approach, I find that the combination therapy embodied
in the label meets the claim limitations of the patent. The Indication on the
ZYTIGA® label is clear: “ZYTIGA is indicated in combination with prednisone
for the treatment of patients with Metastatic castration-resistant prostate
cancer (CRPC).” (VEX 406). That language aligns with the language of Claim 1
of the patent: “A method for the treatment of a prostate cancer in a human
comprising administering to said human a therapeutically effective amount of
abiraterone acetate
.
.
.
and a therapeutically effective amount of prednisone.”
(JTX 8000).
Although the Indications and Usage section is paramount, I observe that
the dosing section and the clinical studies section corroborate the reasoning
above. The 301 study established that the combination of the two drugs has an
anti-cancer effect. Section 14 of the label, which highlights the clinical studies
that were completed, states that “[t]he efficacy and safety of ZYTIGA with
prednisone was established in three randomized, placebo-controlled,
international clinical studies.” (PDX 406 at 21 (emphasis added); 2T418:1-4).
The effectiveness seen in the studies is attributed to abiraterone plus
prednisone, not simply abiraterone. (2T4l8:6-7; 3T588:5-7). The dosing section
recommends that both drugs be administered in specific doses for the purpose
of treating mCRPC. In short, it is the combination, and not one drug to the
exclusion of the other, that was found safe and effective as a treatment for
mCRPC. The FDA meant what it said when it listed the combination in the
approved Indications and Uses.
The ZYTIGA® Indications and Usage section encompasses an FDAapproved method, the administration of abiraterone plus prednisone for the
treatment of mCRPC. That being the patented method, I find that the labels
encompass infringement.
b. Intent to induce infringement
The next, interrelated question is whether the ANDA defendants’
proposed abiraterone labels evince a specific intent to encourage physicians to
60
infringe the ‘438 patent. To summarize, the ‘438 patent claims the
administration of a “therapeutically effective amount of abiraterone acetate”
and a “therapeutically effective amount of prednisone,” which is defined in
dependent claims as 1000mg/day of abiraterone and 10mg/day of prednisone,
to a mCRPC patient. I find that the labels embody an intent to induce a
physician to do just that.
Inducement can be established “where there is ‘[e]vidence of active steps
taken to encourage direct infringement,’ which can in turn be found in
‘advertising an infringing use or instructing how to engage in an infringing
use.”’ Takeda, 785 F.3d at 630—3 1 (quoting Metro—Goidwyn—Mayer Studios Inc.
v. Grokster, Ltd., 545 U.S. 913, 936, 125 S. Ct. 2764, 162 L.Ed.2d 781 (2005)).
“[The sale of a product specifically labeled for use in a patented method
constitutes inducement to infringe that patent, and usually is also contributory
infringement.” Eli Lilly & Co. v. Actavis Elizabeth LLC, 435 F. App’x 917, 926
(Fed. Cir. 2011) (citing Astrazeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060
(Fed. Cir. 2010) (finding intent to induce infringement based on product label
authorizing patented use, which “would inevitably lead some consumers to
practice the claimed method”); DSU Med. Corp. v. JMS Co. Ltd., 471 F.3d 1293,
1305-06 (Fed. Cir. 2006) (en banc in relevant part) (finding liability for induced
infringement when company “offers a product with the object of promoting its
use to infringe, as shown by clear expression or other affirmative steps taken to
foster infringement”)). If relying on instructions, those instructions must evince
an “intent to encourage infringement.” Vita—Mix Corp. v. Basic Holding, Inc., 581
F.3d 1317, 1329 (Fed. Cir. 2009). It is not enough that the instructions happen
to encompass an infringing mode; rather, they must “teach an infringing use
such that we are willing to infer from those instructions an affirmative intent
to infringe the patent.” Vita-Mix, 581 F.3d at 1329 n.2; see Toshiba Corp. v.
Imation Corp., 681 F.3d 1358, 1365 (Fed. Cir. 2012). When proof of intent to
encourage depends on the label, “[t]he label must encourage, recommend, or
promote infringement.” Takeda, 785 F.3d at 631 (citations omitted).
61
Mind-reading, however, is not required to establish the necessary intent.
The sale of a product specifically labeled for use via a patented method
constitutes inducement to infringe that patent. Astrazeneca, 633 F.3d at 1060
(finding intent to induce infringement based on the product label authorizing
patented use, which “would inevitably lead some consumers to practice the
claimed method.”).
With this framework in mind, the Court analyzes whether the ANDA
labels bespeak an intent to induce infringement by doctors. Defendants’
proposed product labels, recall, are substantively identical to the approved
ZYTIGA® label, except that the chemical name “abiraterone acetate” is
substituted for the trademark “ZYT1GA.”
Defendants’ Indications are as follows:
•
Amerigen’s Indication provides “Abiraterone acetate tablets are a
GYP 17 inhibitor indicated in combination with prednisone for the
treatment of patients with metastatic castration-resistant prostate
cancer[.]” (JTX 8011);
•
Amneal’s Indication provides “Abiraterone acetate tablets are a
CYP17 inhibitor indicated in combination with prednisone for the
metastatic castration-resistant
treatment of patients with
prostate cancer (CRPC).” (VEX 359);
.
•
DRL’s Indication provides “Abiraterone acetate is a CYP17 inhibitor
indicated in combination with prednisone for the treatment of
metastatic castration-resistant prostate cancer
patients with
(CRPC).” (VEX 367);
.
•
.
.
.
Mylan’s Indication provides “Ahiraterone acetate tablets are a
CYP17 inhibitor indicated in combination with prednisone for the
metastatic castration-resistant
treatment of patients with
prostate cancer (CRPC).” (VEX 372);
.
•
Teva’s Indication provides “Abiraterone acetate tablets are a GYP 17
inhibitor indicated in combination with prednisone for the
metastatic castration-resistant
treatment of patients with
prostate cancer (CRPC).” (PTX 383);
.
•
.
.
West-Ward/Hikman’s Indication provides “Abiraterone acetate
tablets, USP are a CYP17 inhibitor indicated in combination with
metastatic
prednisone for the treatment of patients with
castration-resistant prostate cancer (CRPC).” (VEX 393); and
.
62
.
.
Wockhardt’s Indication provides “Abiraterone acetate tablets, USP
are a CYP17 inhibitor indicated in combination with prednisone for
metastatic castration-resistant
the treatment of patients with
prostate cancer (CRPC).” (PTX 397).
•
.
.
.
The Indications and Usage section of defendants’ labels, no less than that of
the ZYTIGA® label itself, clearly express an intent that physicians be
authorized to prescribe abiraterone plus prednisone for the treatment of
mCRPC. (2T408:3-5).
Again, the Indications and Usage section is paramount, but I find
corroboration elsewhere. The approved “Dosage and Administration” section of
the 2018 ZYTIGA® label reads, in part: “Recommended Dose for metastatic
CRPC.
.
.
The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets
or four 250 mg tablets) administered orally once daily in combination with
prednisone 5 mg administered orally twice daily.” (PTX 406).
Defendants’ labels all contain Dosage sections that recommend
administering 1000mg/day of abiraterone acetate, and 10mg/day of
prednisone. (DE 502, at 94 ¶73). Amneal’s, DRL’s, Teva’s, and Wockhardt’s
proposed Dosage sections track the wording of ZYTIGA®’s 2018 label.
(2T4 13:23-3). They state the recommended “recommended dosage for mCRPC.”
(2T413:25-414:3 (emphasis added)) The other defendants’ labels track the pre
2018 ZYTIGA® label in that they state the “recommended dosage” but omit the
words “for mCRPC.” I do not regard the distinction as significant; everyone
agrees that the relevant target group for the ANDA consists of mCRPC
patients.25
The similarities between plaintiffs’ and defendants’ Indications and
Dosing sections are manifest. Defendants nonetheless contend that this, in
The 2018 ZYTIGA® label, recall, added an indication for mCSPC (i.e., the
castration-sensitive, as opposed to castration-resistant, form of the disease).
Presumably the “for mCRPC” language was felt to be necessary for clarity, since the
label now had more than one indication. I do not believe it alters the substance of the
label. At any rate, the ANDA parties do not seek to market the drug combination for
that additional mCSPC indication.
25
63
itself, is not sufficient to establish inducement because the labels do not direct
doctors to use prednisone to fight cancer, as opposed to addressing
abiraterone’s side effects. (DBr. at 27). In a similar vein, defendants argue that
they do not “know” that prednisone has anti-cancer effects. Lacking such
knowledge, defendants say, they cannot be regarded as intentionally promoting
such use. (DBr. at 29).
The intent required here is not the kind of specific intent required by the
criminal law. In the context of patent infringement litigation involving
pharmaceuticals, “the sale of a product specifically labeled for use in a
patented method constitutes inducement to infringe that patent.” Eli Lilly, 435
F. App’x at 926; see also Astrazeneca, 633 F.3d at 1060 (product label
authorizing patented use sufficient to establish intent, because it “would
inevitably lead some consumers to practice the claimed method”);
GlaxoSmithKline LLC v. Glenmaric Generics Inc., USA, 2015 U.S. Dist. LEXIS
52525, at *18 (D. Del. Apr. 22, 2015) (“there is no question that statements ‘in
a package insert that encourage infringing use of a drug product are alone
sufficient to establish intent to encourage direct infringement’ for purposes of
an induced infringement claim.” (citation omitted)).
The key question is whether the label teaches performance of an
infringing use. These cases make clear that the instructions in the label itself
are sufficient for finding the requisite specific intent. See In re Depomed Patent
Litig., 2016 U.S. Dist. LEXIS 166077, at *18182 (finding defendants possessed
specific intent based on “the instructions in the label itself’ and that
“[i)nformation outside the label (e.g., a physician’s knowledge) is not sufficient
to meet the standard.” (citation omitted)); see also Sanofi v. Watson
Laboratories
ma,
875 F.3d 636, 644-46 (Fed. Cir. 2017) (affirming verdict of
inducing infringement where label encouraged patient to use drug in manner
that infringed claims, relying on data of actual usage of drug product as further
evidence that labeling encouraged infringement, and rejecting contention that
64
because drug had substantial noninfringing uses there could not be inducing
infringement).
Here, the content of the ANDA labels virtually compels an inference of
specific intent to encourage the infringing use, and I do draw that
inference. Claim 1 of the ‘438 patent, the only independent claim, is a method
of treating prostate cancer by the administration of abiraterone and
prednisone. (JTX 8000). Dependent claims 2—20 of the ‘438 patent describe
additional limitations of the method, including the amount of abiraterone
acetate (1000mg/day) and the amount of prednisone (10mg/day) used, and the
type of prostate cancer being treated (mCRPC). (Id.). All of the defendants’ label
Indications promote that exact use. See Bone Care Int’l, L.L.C. v. Roxane Labs.,
Inc., 2012 U.S. Dist. LEXIS 80450, at *33 (D. Del. June 11, 2012) (finding
induced infringement where defendants’ proposed labels did not differ from
plaintiffs labels “in any relevant way.”).
Defendants cite cases in which intent was not inferred from the label’s
content, but in those cases the infringing use was no more than an option. In
none of those cases did the generic defendant successfully interpose an ostrich
defense to Indication and Dosing sections that directly instructed infringing
use, as they do here.
In Shire, for example, the patent claimed a method of administering a
certain drug orally, with food. 2014 U.S. Dist. LEXIS 85369 at *15. In contrast,
defendants’ ANDA labels stated that the drug could be taken with or without
food. Id. Consistent with the label, physicians could, at their option, infringe or
not infringe. The court held accordingly:
The problem is that the statement that the medication may be
taken with or without food cannot be reasonably understood to be
an instruction to engage in an infringing use. As Defendants
contend, it is indifferent to which option is selected. At most, it
may be understood to permit an infringing use, but permission is
[TJhe proposed label does not
different from encouragement
contain any instruction to take the medication with food. Plaintiffs
have failed to raise a material factual dispute over whether the
65
proposed label encourages infringement of method claims requiring
administration with food.
Id. at *16.
Similarly, in Acorda, the patent taught that a drug be taken with food.
2011 U.S. Dist. LEXIS 102875, at *2. The proposed label directed physicians to
“the pharmacokinetics section of the label for information on the differences
between the fed and fasted states with capsules and tablets,” and stated that
physicians should be “thoroughly familiar with the complex effects of food” on
the drug. Id. at *17. Finding that the labels did not infringe, the court explained
that none of the label’s statements “direct any action on the part of any
physician, but merely call attention to the pharmacokinetics section.” Id. In
addition, the label did not state “a preference of one over the other or a
direction to use the capsule form in the fed state.” Id. Here, too, the options
were “with food” or “without food,” and the label did not promote one over the
other.
The ANDA defendants’ abiraterone labels are a far cry from that. The only
way to follow these labels is to administer abiraterone, together with
prednisone, in specified doses, to a mCRPC patient.26
I am also unpersuaded by defendants’ argument that doctors will
prescribe prednisone only for the unpatented purposes of palliation or
minimizing side effects. First, this hypothetical possibility is contrary to the
labels’ explicit Indication, i.e., abiraterone plus prednisone for the treatment of
mCRPC. Second, this argument is best considered as a substantial noninfringing use under
§ 27 1(c), not as a rebuttal of intent under § 27 1(b).
See
Sanofi, 875 F.3d at 646 (“a person can be liable for inducing an infringing use
of a product even if the product has substantial noninfringing uses”) (citing
Grokster, 545 U.S. at 934-37). Third, courts have found induced infringement
Nor is there persuasive evidence that the defendants took affirmative steps to
avoid infringing uses, as in Otsuka Phamt., 99 F. Supp. 3d at 485 (‘the fact that.
Defendants actively and voluntarily removed any reference to the allegedly infringing
indication, in turn, belies any suggestion that these Defendants acted with the specific
intention to encourage infringement.”)
26
66
even in situations where a label did not track the patent’s description of an
underlying medical condition, but instead sought to treat a symptom.
Infringement was found because the use of the product would entail the
patented treatment of the underlying condition. See, e.g., L.A. Biomedical
Research Inst. at Harbor-UCLA Med. Ctr. u. Eli Lilly & Co., 2014 U.S. Dist.
LEXIS 185431, at *1344 (C.D. Cal. May 12, 2014) (noting that “a once daily
dosage of [drug] to treat [symptom] in these patients results directly in
treatment of the underlying [condition] and the performance of the patented
method.”).
Proposed labeling that instructs infringing uses is generally sufficient to
support a finding of intentional inducement. The defendants’ proposed labels
here would infringe each element of the asserted claim. They teach the reader
to perform ever-v element of the patented method. With respect to the specific
intent element, I conclude that the plaintiffs have sufficiently shown that the
defendants “knew or should have known [their] actions would induce actual
infringements.” See DSU Med. Corp., 471 F.3d at 1306. All defendants filed
ANDAs seeking approval to market abiraterone under a label which instructs
physicians and medical professionals to administer abiraterone plus
prednisone in accordance with the patented method. This indication is the
same use set forth in the patent-in-suit, and the labels of the defendants’
proposed products are the same as the ZYTIGA® labels. See 21 C.F.R.
§
3 14.94(a)(l)(8)(iv).
Accordingly, I find that plaintiffs have proven that, assuming the ‘438
patent is valid, the defendants would intentionally induce infringement if
permitted to market their ANDA products under the proposed labels.
2.
Contributory infringement
Plaintiffs also claim that abiraterone is a material part of a claimed
invention, and that defendants are thus liable for contributory infringement
(again, assuming that the ‘438 patent is valid). The parties give this claim very
little attention in their briefing, and my finding of induced infringement renders
it redundant. I therefore address it in abbreviated fashion.
67
Contributory infringement is prohibited by 35 U.S.C.
§ 27 1(c):
Whoever offers to sell or sells within the United States or imports
into the United States a component of a patented machine,
manufacture, combination or composition, or a material or
apparatus for use in practicing a patented process, constituting a
material part of the invention, knowing the same to be especially
made or especially adapted for use in infringement of such patent,
and not a staple article or commodity of commerce suitable for
substantial noninfringing use, shall be liable as a contributory
infringer.
Stated simply, “[a} party is liable for contributory infringement if that party
sells, or offers to sell, a material or apparatus for use in practicing a patented
process.” i4i Ltd. P;ship v. Microsoft Corp., 598 F.3d 831, 850-51 (Fed. Cir.
2010). To establish contributory infringement under this subsection, a patent
owner must prove the following: “1) that there is direct infringement, 2) that the
accused infringer had knowledge of the patent, 3) that the component has no
substantial noninfringing uses, and 4) that the component is a material part of
the invention.” Fujitsu Ltd. v. Netgear Inc., 620 F.3d 1321, 1326, 96 U.S.P.Q.2d
1742 (Fed. Cir. 2010).
Defendants concede, at least arguendo, elements 1, 2, and 4.
The dispute focuses on the third element. Prednisone, say defendants, has a
substantial non-infringing use as a glucocorticoid replacement. (DBr. at 32).
“[Djistribution of a component of a patented device will not violate the patent if
it is suitable for use in other ways.” Grokster, 545 U.S. at 932. “[T]he doctrine
absolves the equivocal conduct of selling an item with substantial lawful as
well as unlawful uses.” Id. A non-infringing use is substantial if it is “not
unusual, far-fetched, illusory, impractical, ‘occasional, aberrant, or
experimental.” Vita-Mix Corp., 581 F.3d at 1327.
I find defendants’ argument unpersuasive for several reasons. First,
every administration of prednisone as a glucocorticoid replacement to treat
mCRPC would factually duplicate the patented method. The noninfringing
“use,” then, is not so easily separated from the infringing one. This is not like
using a patented anvil to moor a boat. The distinction between infringement
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and noninfringement seems to turn, not on any external fact, but on the
subjective mental processes of the prescribing physician.
Defendants’ reliance on Wamer-Lamben is therefore misplaced; that case
involved an off-label use to treat a separate condition. As noted above, the
patented method of treating neurodegenerative diseases was distinct from the
FDA approval of the drug for “treatment of partial seizure” (which is not itself a
neurogenerative disease). 316 F.3d at 1352. The court explained that “it defies
common sense to expect that Apotex will actively promote the sale of its
approved gabapentin, in contravention of FDA regulations, for a use that (a)
might infringe Warner-Lambert’s patent and (b) constitutes such a small
fraction of total sales.” Id. at 1365.
There, gabapentin was not approved by the FDA for the patented use in
relation to a particular medical condition. Here, by contrast, the label-indicated
use is the patented combination use. The prednisone does not know why it was
administered, and its pharmacological effect when administered to a mCRPC
patient with abiraterone will be the same, irrespective of any mental
reservation by the physician. Cf L.A. Biomedical Research Inst., 2014 U.S. Dist.
LEXIS 185431, at *1314 (noting that “a once daily dosage of [drug] to treat [a
symptom] in these patients results directly in treatment of the underlying
[condition] and the performance of the patented method.”).
Defendants argue in the alternative that Section 5.2 of their ANDA labels,
the Warnings and Precautions Section, encourages abiraterone monotherapy.
(DPF. at 63, ¶244). I look to the Indications. Abiraterone monotherapy is an offlabel use, and there is no evidence in the record that this proposed off-label
use is or would be “substantial.”
q
Acorda Therapeutics, 2011 WL 4074116 at
**14, ig (finding substantial non-infringing use where evidence showed that
75% of the sales of the product were for non-infringing use). If anything, the
Warning section discourages such off-label use by suggests that withdrawing
the use of prednisone from the combination therapy can have detrimental
effects on a patient.
69
I therefore find that contributory infringement is present here as well.
HI.
CONCLUSION
The 438 patent is invalid for obviousness, but contains an adequate
written description. The plaintiffs have established by a preponderance of the
evidence that if the patent were valid, defendants’ activities would constitute
induced infringement and contributory infringement.
Dated:
As amended October 31, 2018
k-j*
KEVIN MCNULTY
United States District Judge
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