Endo Pharmaceuticals Solutions Inc. et al v. Paddock Laboratories LLC et al

Filing 85

OPINION. Signed by Judge Sue L. Robinson on 2/10/2017. (nmfn)

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE

ENDO PHARMACEUTICALS SOLUTIONS
INC., BAYER INTELLECTUAL PROPERTY
GMBH, and BAYER PHARMA AG,
Plaintiffs,

)
)
)
)
)
)

v.

)

CUSTOPHARM, INC.,
Defendant.

Civ. No. 14-1422-SLR

)
)
)
)

Jack B. Blumenfeld, Esquire and Derek J. Fahnestock, Esquire of Morris, Nichols, Arsht
& Tunnell LLP, Wilmington, Delaware. Counsel for Plaintiffs. Of Counsel: Adam K.
Mortara, Esquire, J. Scott McBride, Esquire, Nevin M. Gewertz, Esquire, Faye E. Paul,
Esquire, and Taylor A.R. Meehan, Esquire of Bartlit Beck Herman Palenchar & Scott
LLP.
Richard L. Horwitz, Esquire, David E. Moore, Esquire, and Bindu A. Palapura, Esquire
of Potter Anderson & Corroon LLP, Wilmington, Delaware. Counsel for Defendant. Of
Counsel: Douglass C. Hochstetler, Esquire, Constantine Koutsoubas, Esquire, Mark J.
Scott, Esquire, Beth D. Jacob, Esquire, and Clifford Katz, Esquire of Kelley Drye &
Warren LLP.

OPINION

Dated: February ft>, 2017
Wilmington, Delaware

I. INTRODUCTION
This action arises out of the filing of Abbreviated New Drug Application ("ANDA")
No. 207583 by defendant Paddock Laboratories, LLC seeking to produce and market a
generic testosterone undecanoate intramuscular injection. (D.I. 67at1l 10) On
November 20, 2014, plaintiffs Endo Pharmaceuticals Solutions Inc., Bayer Intellectual
Property GmbH, and Bayer Pharma AG (collectively "plaintiffs") brought this action
alleging infringement of U.S. Patent Nos. 7,718,640 (the '"640 patent") and 8,338,395
(the "'395 patent") (collectively, "the patents-in-suit"). 1 (D.I. 1) Defendants Paddock
Laboratories, LLC and Perrigo Company (collectively, "Paddock") 2 answered the
complaint and counterclaimed alleging invalidity of the patents-in-suit on December 23,
2014. (D.I. 11) Plaintiffs answered the counterclaims on January 16, 2015. (D.I. 14)
Thereafter, Paddock stipulated to infringement of certain claims. (D. I. 30) The court
held a final pretrial conference on September 7, 2016, and a four-day bench trial from
September 26 to 29, 2016 on invalidity. The parties have since completed post-trial
briefing. The 30-month stay of FDA final approval on Paddock's ANDA expires on April
9, 2017. (D.I. 3, 17) The court has jurisdiction over this matter pursuant to 28 U.S.C.

§§ 1331 and 1338(a), and venue is proper pursuant to 28 U.S.C. §§ 1391 (b) and (c)
and 1400(b). Having considered the documentary evidence and testimony, the court

1

In the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations"
("Orange Book"), the '640 and '395 patents are listed in the entry for Aveed® ("Aveed").
2

Paddock was substituted with new defendant Custopharm, Inc. ("defendant"). (D.I. 79,
so ordered January 13, 2017)

makes the following findings of fact and conclusions of law pursuant to Federal Rule of
Civil Procedure 52(a).
II. FINDINGS OF FACT AND CONCLUSIONS OF LAW
A. Technology at Issue
The '640 patent was filed on March 12, 2004 and issued on May 18, 2010. (JTX
1) The '395 patent was filed on February 24, 2009 and issued on December 25, 2012. 3
(JTX 2) The patents-in-suit are titled "Methods and Pharmaceutical Compositions for
Reliable Achievement of Acceptable Serum Testosterone Levels." (JTX 1, 2) Male
hypogonadism is a condition characterized by a deficiency of endogenous testosterone
production resulting in abnormally low levels of serum testosterone. ('640 patent, 1:3234) Men with this condition generally experience symptoms including sexual
dysfunction, reduced muscle mass and strength, depression, and osteoporosis. (Id. at
1:48-50) In 2003, the standard therapy required frequent doctors' visits to receive
intramuscular injections administered every two to three weeks. "[P]atients
complain[ed] about variations in well-being due to short-term fluctuations of serum
testosterone levels resulting from the pharmacokinetic profile after intramuscular
injection of ... testosterone enanthate." (Id. at 1:51-62) A need existed for "reliable
standard regimens acceptable for a broad population of men, ... without the need of
occasional control of serum testosterone levels, and ... where[] steady state conditions
are achieved within a shorter time period." (Id. at 2:49-54)
The invention is directed to injectable compositions using long-term acting
testosterone esters for testosterone replacement therapy. After injection,

3

The patents-in-suit have a priority date of March 14, 2003.

3

"physiologically normal levels of testosterone in serum are reached within a short time
period ... [and] maintained for an extended period of time, without showing fluctuations
in the hypogonadal range." (Id. at 2:57-64) Claim 2 ofthe '640 patent provides for a
750 mg version of the composition of claim 1, which recites "[a] composition formulated
for intramuscular injection in a form for single injection which contains 250 mg/ml
testosterone undecanoate in a vehicle containing a mixture of castor oil and benzyl
benzoate wherein the vehicle contains castor oil in a concentration of 40 to 42 vol %."
Claim 18 of the '395 patent provides for a 750 mg version of the composition and
method described by claim 14, which recites:
A method of treating a disease or symptom associated with deficient
endogenous levels of testosterone in a man, comprising administering by
intramuscular injection a composition comprising testosterone
undecanoate (TU) and a vehicle consisting essentially of castor oil and a
co-solvent, the castor oil being present in the vehicle at a concentration of
42 percent or less by volume, the method further comprising:
(i) an initial phase comprising 2 initial intramuscular injections of a
dose of TU at an interval of 4 weeks between injections, each dose
including 500 mg to 1000 mg of TU, followed by,
(ii) a maintenance phase comprising subsequent intramuscular
injections of a dose of TU at an interval of 10 weeks between injections,
each dose including 500 mg to 1000 mg of TU.
The embodiment of the invention is Aveed, which contains testosterone
undecanoate (TU) as an active ingredient. It is approved by the FDA as a testosterone
replacement therapy in adult males for conditions associated with testosterone
deficiency or absence of endogenous testosterone. Aveed is sold in the United States
as a series of 3 ml (750 mg) intramuscular injections given at initiation, at four weeks,
and then every 10 weeks thereafter. Each vial of Aveed contains 750 mg testosterone
undecanoate dissolved in a mixture of 885 mg castor oil and 1500 mg benzyl benzoate.

4

(D.I. 67, ex. 1 at

,m 6-7)

Hypogonadism is a chronic condition requiring lifelong therapy.

(D.I. 73 at 524:12-18)

B. Obviousness Standard
"A patent may not be obtained ... if the differences between the subject matter
sought to be patented and the prior art are such that the subject matter as a whole
would have been obvious at the time the invention was made to a person having
ordinary skill in the art." 35 U.S.C. § 103(a). Obviousness is a question of law, which
depends on underlying factual inquiries.
Under § 103, the scope and content of the prior art are to be determined;
differences between the prior art and the claims at issue are to be
ascertained; and the level of ordinary skill in the pertinent art resolved.
Against this background the obviousness or nonobviousness of the
subject matter is determined. Such secondary considerations as
commercial success, long felt but unsolved needs, failure of others, etc.,
might be utilized to give light to the circumstances surrounding the origin
of the subject matter sought to be patented.
KSR Int'/ Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v. John Deere

Co. of Kansas City, 383 U.S. 1, 17-18 (1966)).
"[A] patent composed of several elements is not proved obvious merely by
demonstrating that each of its elements was, independently, known in the prior art."
KSR, 550 U.S. at 418. Likewise, a defendant asserting obviousness in view of a

combination of references has the burden to show that a person of ordinary skill in the
relevant field had a reason to combine the elements in the manner claimed. Id. at 41819. The Supreme Court has emphasized the need for courts to value "common sense"
over "rigid preventative rules" in determining whether a motivation to combine existed.
Id. at 419-20. "[A]ny need or problem known in the field of endeavor at the time of

invention and addressed by the patent can provide a reason for combining the elements

5

in the manner claimed." Id. at 420. In addition to showing that a person of ordinary skill
in the art would have had reason to attempt to make the composition or device, or carry
out the claimed process, a defendant must also demonstrate that "such a person would
have had a reasonable expectation of success in doing so." PharmaStem

Therapeutics, Inc. v. ViaCel/, Inc., 491 F.3d 1342, 1360 (Fed. Cir. 2007).
A combination of prior art elements may have been "obvious to try" where there
existed "a design need or market pressure to solve a problem and there [were] a finite
number of identified, predictable solutions" to it, and the pursuit of the "known options
within [a person of ordinary skill in the art's] technical grasp" leads to the anticipated
success. Id. at 421. In this circumstance, "the fact that a combination was obvious to
try might show that it was obvious under§ 103." Id.
A fact finder is required to consider secondary considerations, or objective indicia
of nonobviousness, before reaching an obviousness determination, as a "check against
hindsight bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule

Patent Litig., 676 F.3d 1063, 1079 (Fed. Cir. 2012). "Such secondary considerations as
commercial success, long felt but unsolved needs, failure of others, etc., might be
utilized to give light to the circumstances surrounding the origin of the subject matter
sought to be patented." Graham, 383 U.S. at 17-18.
"Patents are presumed to be valid, and overcoming that presumption requires
clear and convincing evidence." 35 U.S.C. § 282; Spectrum Pharm., Inc. v. Sandoz

Inc., 802 F.3d 1326, 1333 (Fed. Cir. 2015) (citing Microsoft Corp. v. i4i Ltd. P'ship., 564
U.S. 91, 95 (2011) (holding that an invalidity defense must be proved by clear and

6

convincing evidence)). In conjunction with this burden, the Federal Circuit has
explained that,
[w]hen no prior art other than that which was considered by the PTO
examiner is relied on by the attacker, he has the added burden of
overcoming the deference that is due to a qualified government agency
presumed to have properly done its job, which includes one or more
examiners who are assumed to have some expertise in interpreting the
references and to be familiar from their work with the level of skill in the art
and whose duty it is to issue only valid patents.
PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (citations

omitted).

C. Prior Art
A trio of prior art scientific articles - Behre, 4 Nieschlag, 5 and von Eckardstein 6
(collectively "the Articles") - describe small clinical studies using an injectable
composition of 250 mg/ml TU in castor oil dosed at 1000 mg injections. 7 The Articles
report that the 250 mg/ml of TU was dissolved in castor oil, but do not disclose or
describe the use of a co-solvent. (JTX 3, 4, 5; D.I. 67, ex. 1 at~ 15; D.I. 72 at 81 :2-19,
92:19-23; D.I. 73 at 463:6-14) The compositions described by the Articles are TU

4

Hermann M. Behre et al., Intramuscular injection of testosterone undecanoate for the
treatment of male hypogonadism: phase I studies, 140 Eur. J. Endocrinol. 414 (1999).
(JTX 3)

5

Eberhard Nieschlag et al., Repeated intramuscular injections of testosterone
undecanoate for substitution therapy in hypogonadal men, 51 Clin. Endocrinol. 757
(1999). (JTX 4)
6

Sigrid von Eckardstein and Eberhard Nieschlag, Treatment of Male Hypogonadism
with Testosterone Undecanoate Injected at Extended Intervals of 12 Weeks: A Phase JI
Study, 23(3) J. Androl. 419 (2002). (JTX 5)

7

The specifications of the patents-in-suit reference Behre and von Eckardstein. ('640
patent, 2:10-16, 37-44) Dr. Jan-Peter Ingwersen ("Dr. Ingwersen"), plaintiffs' 30(b)(6)
designee on issues related to the development of the product and inventor on the
patents, testified that the background section of the patent does not disclose the
particular vehicle used in Behre and he did not know why. (D.I. 72 at 207:8-208:11)

7

dissolved in 40% castor oil and 60% benzyl benzoate (the "vehicle"). The parties agree
that the vehicle was unknown to the person of ordinary skill in the art in 2003. 8 (D.I. 72
at 107:5-108:6; D.I. 73 at 338:5-22, 393:24-394:8, 463:9-20)
Behre compared the half-life of a single dose of 1,000 mg TU in castor oil with a
single dose of 1000 mg TU in tea seed oil. (JTX 3) Nieschlag investigated the
suitability of using four intramuscular injections of 1000 mg TU in castor oil at six week
intervals. (JTX 4) von Eckardstein described a clinical trial investigating the efficacy
and safety of prolonged TU treatment at extended injection intervals over a 3.2 year
period. Seven patients (who had participated in the study described in Nieschlag)
received four injections at six week intervals, followed by a gradual increase in the
interval between the fifth and tenth injections. After the tenth injection, the interval was
increased to twelve weeks. (JTX 5)
Pushpalatha 9 described a commercially marketed product Proluton Depot
("Proluton"), an injectable composition of hydroxyprogesterone dissolved in a mixture of
40% castor oil and 60% benzyl benzoate. Proluton is administered weekly to pregnant
women to prevent miscarriage. (JTX 42, 38 at 73; 0.1. 72 at 86:10-87:17) Riffkin 10
described using castor oil for the parenteral administration of steroids. (JTX 6) It refers

8

Saad 2007 disclosed for the first time that the composition used in the Nieschlag
article was what is now sold as Nebido® ("Nebido"). (D.I. 67, ex. 1 at 1J 15; D.I. 72 at
92:9-18, 185:11-188:11 ); Farid Saad et al., More than eight years' hands-on experience
with the novel long-acting parenteral testosterone undecanoate, 9(3) Asian J. Andrei
291 (2007). (DTX 20)

9

Pushpalatha, T. et al., Effect of prenatal exposure to hydroxyprogesterone on
steroidogenic enzymes in male rats, 90 Naturwissenschaften 40 (2003). (JTX 42)
10

Riffkin, C. et al., Castor Oil as A Vehicle for Parenteral Administration of Steroid
Hormones, 53(8) J. Pharm. Sci. 891 (1964). (JTX 6)

8

to using a castor oil/benzyl benzoate vehicle to "increase the solvent power of the oil."
(Id. at 892; 87: 18-89:2)

The 2002 guidelines of the American Association of Clinical Endocrinologists
(AACE) ("the AACE guidelines") describe a normal testosterone range as "generally
between 280 and 800 ng/dl" (9.7 to 27.7 nmol/I). (JTX 41 at 448) The FDA refers to a
normal testosterone range of 300-1000 ng/dl. 11 (JTX 49 at 18, 104) The Articles also
describe a normal range of testosterone as 10-25 nmol/I (300-1000 ng/dl). (JTX 3 at
416, JTX 4 at 759, JTX 5 at 422) The Aveed label references a normal range of 300 to
1000 ng/dl. (JTX 58 at 10)

D. Evidence
Defendant's expert, Dr. Peter Schlegel ("Dr. Schlegal"), 12 opined that it would
have been obvious from the prior art to decrease the dose of TU from 1000 to 750 mg
and to modify the dosing intervals after the dose amount was reduced to 750 mg. (D.I.
73 at 268:20-269: 1) He explained that the prior art disclosed injectable testosterone
drugs and monitoring of the patient's testosterone levels. A clinician could choose to
decrease the dose amount or change the interval between injections to maintain the
level of testosterone. A clinician would determine such routine dosing adjustments, and
might make dosing estimates outside the recommendations of the drug label. 13 (Id. at

11

A book chapter edited by defendant's expert stated that "[t]he most common
[testosterone range] in clinical practice is a Food & Drug Administration range of 300 to
1000 nanograms per deciliter." The book also refers to the AACE range. (D.I. 73 at
322:3-24)
12

A urologist.

13

Plaintiffs' expert, Dr. Anthony Sliwinski ("Dr. Sliwinski"), testified that he also made
routine dose adjustments for injectable testosterone in about 30-40% of his patients, but
did so "within the confines of the package insert." (D.I. 74 at 548:18-549:19, 528:16-24)

9

286:4-289:8, 350:3-25; PTX 166, 169) Dr. Schlegel agreed that individual dose
adjustments are different than dose determinations for an entire population, but clarified
that both are based on the same principles. (Id. at 326:7-12) He admitted that his
obviousness opinion was based on the premise that the composition of the vehicle was
known, as it was in the historical data. (Id. at 338:1-4) Defendant's expert, Dr. Ralph
Tarantino ("Dr. Tarantino"), 14 similarly opined that the disputed claims were obvious as
von Eckardstein disclosed single injections of 250 mg/ml TU; the 40/60 castor oil/benzyl
benzoate vehicle was known in the art for use with steroids in a commercial product
(Proluton); and using 750 mg of TU is a trivial change, by using 3 rather than 4 ml of
product disclosed by von Eckardstein. (D.I. 72 at 78:5-80:2, 94:10-96:23)

1. Co-solvent
Dr. Tarantino explained that although the Articles only disclosed dissolving TU in
castor oil, "the issues of viscosity and ... solubility would make it obvious that another
vehicle was being used." (D.I. 72 at 91:13-93:10; 107:13-20) He admitted that he did
not cite to any prior art data or do any testing of the solubility of TU in castor oil for his
opinions. Instead, he testified based on what he "saw here" and his knowledge of
lipidation. 15 (Id. at 116:23-117:6) He testified that a formulator would know to use
another solvent to make the castor oil less viscous to improve injectability and

14

A formulation scientist.

15

On cross-examination, Dr. Tarantino was presented with documents that he had not
seen before and asked whether such documents suggested that 250 mg TU is able to
dissolve in 1 ml of castor oil in order to "impeach" his testimony. He did not give a
definitive answer. (D.I. 72 at 123-138) The court does not find such testimony helpful
to answer the ultimate question of solubility, as plaintiffs' expert did not opine on the
disclosures of these documents.
10

manufacturability. 16 Moreover, it was known before 2003 that benzyl benzoate could be
combined with castor oil to dissolve testosterone. (Id. at 81 :5-7, 88:13-16) He agreed,
however, that the prior art described other co-solvent choices for oily injectables, but
opined that their practicality or actual usage make benzyl benzoate the "go-to" solvent
for an oil solution. 17 (Id. at 153: 12-22)
Dr. Tarantino opined that a person of ordinary skill would look to marketed
products (which provide knowledge of safety, tolerance, and injectability) first. A
formulator would be "remiss" in not trying the vehicle of Proluton since "both drugs are
closely related chemically. Sometimes even when drugs aren't closely related
chemically, co-solvent systems that were used in prior products are used." It is
"common sense from every standpoint that you can imagine." (Id. at 76:13-77:9, 86:1087:17, 89:19-91:1, 96:24-98:3, 169:7-170:13) Moreover, a formulator would expect that
the "pharmaceutical dosage form ... [of] 250 milligrams per ml testosterone ... [could]
be safely and effectively administered." (Id. at 98:4-12) He concluded that it would
have been obvious to one of ordinary skill in the art "to replace [the testosterone ester of
Proluton] with TU and test it, because you would anticipate little or no manufacturing or
regulatory difficulties." (Id. at 93:12-94:4) Dr. Tarantino also pointed to Riffkin, which
"mentions benzyl benzoate and benzyl alcohol resulting in a more favorable viscosity,
making it easier to inject." (Id. at 87:18-89:2) He testified that benzyl benzoate was the

16

He testified that it would be "next to impossible" to inject pure castor oil though a
standard syringe needle, because of the viscosity. (D.I. 72 at 140:1-141:18)
17

Defendant's citation to the testimony of Dr. Frank Diana, plaintiffs' 30(b)(6) witness,
regarding the disclosures of plaintiffs' internal information about the dissolution of TU in
castor oil is not prior art and not properly considered in the obviousness analysis. (D.I.
72 at 214:25-220:13; DTX 25, 39)
11

"go-to" excipient for reasons including safety and acceptability. (Id. at 89:24-90:2) He
concluded that any ratio of castor oil to benzyl benzoate as a vehicle for testosterone
injectables would be obvious, as the excipients "have been around a long time,"
therefore, combining and optimizing the solubility and viscosity is "what [he] did every
day." (Id. at 150:23-151: 19)
Plaintiff's expert, Dr. Robert Williams, Ill ("Dr. Williams"), 18 disagreed that the
Articles "teach[] the need for a co-solvent." He testified that "one would actually have to
confirm whether" a co-solvent was necessary for solubility and injectability reasons. 19
(D.I. 73 at 463:15-464:7) He testified that there are other co-solvents available to use.

(Id. at 467:19-468:2, 469:8-19; JTX 6; PTX 108, 109, 118) He also explained that other
ratios of castor oil to co-solvents are present in the prior art. (Id. at 479:19-481 :9,
481 :20-483:12, 484:3-10; JTX 6, 7; PTX 46) He explained that he did not know if 250
mg of TU could be soluble in 1 ml of castor oil or in "50 castor oil/benzyl benzoate at a
rate of 250" mg/ml. (Id. at 496:24-497:14) He testified that a person of ordinary skill
"would choose the excipient vehicle" from an approved product if the formulation was
equal in all other ways. (Id. at 503:7-504: 12) He agreed that, assuming a person of
ordinary skill could create a 250 mg/ml solution of TU in the Proluton vehicle, it could be
injected intramuscularly. (Id. at 499: 18-500: 10) Dr. Williams also agreed that a person
of ordinary skill would know that TU was compatible with castor oil and benzyl
benzoate. (Id. at 507: 18-508:4) He admitted that he did not provide an "example of a
commercialized intramuscular injectable product that used castor oil and any one of

18

A formulation scientist.

19

Dr. Ingwersen testified that the viscosity of castor oil would cause difficulties during
injection. (D.I. 72 at 203:9-204:6)
12

these [other] co-solvents." (Id. at 508:22-509:5) Dr. Williams concluded, however, that
a person of ordinary skill would not be motivated to consider the vehicle of Proluton "to
create vehicles that have long-acting activity like the patents-in-suit" because Proluton
requires weekly injections and are not directed to prolonged activity. (Id. at 488:4-20)

2. Using a lower dose of TU
Dr. Schlegel explained that "[t]he two most common changes that are made in
terms of treating patients with injectable agents are to change the dose amount or the
dose interval, frequency between injections." (D.I. 73 at 264:21-265:2, 287:1-23) Dr.
Schlegel testified that he uses the AACE guidelines (which reflected the state of the art
at that time) in his practice. (Id. at 271 :24-274:23, 308:9-13, 349: 10-350:2) He relied
on the AACE guidelines for the normal range of testosterone (280 to 800 ng/dl) to
formulate his opinions. According to Dr. Schlegel, although the FDA sometimes refers
to a 300-1000 ng/dl range, a testosterone level of 1000 ng/dl or more is "relatively
unusual" and "not a common physiologic observation." (Id. at 275:2-23)
Dr. Schlegal testified that a person of ordinary skill would not need to know the
exact composition of the formulation before modifying the dose amount because "it
[was] common practice to adjust doses based on the results that you get with serum
testosterone levels, and that is independent of the exact formulation of the medication."
(D.I. 73 at 280:9-17) He analyzed Nieschlag and explained that "a proportion of
patients who are treated with a single dose of 1000 mg [of TU] are going to have
testosterone levels above 800" ng/dl (27.7 nanomoles per liter). He observed that the
first dose provides an overdose and the subsequent injections also overdose the
patient. He concluded that it would be obvious to reduce the 1000 mg dose to get the

13

patient into normal range without "overshooting" the target. Dr. Schlegel opined that
Behre and von Eckardstein describe similar overdosing. He concluded that the
reduction from 1000 mg (given in 4 ml) to 750 mg is an obvious change as it would be
easy to draw up 3 ml ("a whole millimeter change"). 20 (Id. at 276:14-281 :16, see also
D.I. 72 at 152:6-22)
Dr. Schlegel agreed that the Articles do not suggest lowering the dose of TU from
1000 mg to 750 mg, but maintained that they "pointed out specifically overdosing"
certain patients. 21 (D.I. 73 at 300:4-23) He observed that one of the fourteen patients in
Behre exhibited a testosterone level "nowhere near an acceptable range" after
treatment. He opined that there were likely other patients "possibly in this trial, who are
out of what would be considered normal range." (Id. at 340:23-341 :9) He agreed that
the observed testosterone level, however, fell within the range of testosterone allowed
by the FDA for approved testosterone replacement therapies. (Id. at 344:4-345:2)
Dr. Sliwinski 22 testified that the "normal" testosterone range used varies with
individual laboratories and clinician patient populations. In 2003, his reference
laboratory used a range of 349-1149 ng/dl for his patient population. He used the
AACE guidelines in his practice, but did not adopt its definition of normal testosterone
levels in treating his patients. (D.I. 74 at 530:9-12, 531 :20-532:16) In 2013, he created

20

He testified that he did not rely on the underlying data (not publicly disclosed) to form
this opinion. (D. I. 73 at 351: 13-352: 12) As the underlying data is not prior art, the court
declines to discuss the opinions and arguments based thereon. (PTX 208)
21

He described plaintiffs' disclosure to the FDA in 2013, wherein the testosterone dose
was decreased to 750 mg after a 1000 mg dose was evaluated in a study and found to
yield levels exceeding criteria set by the FDA. (D. I. 73 at 352: 13-354: 13)
22

A urologist.
14

his own guidelines for his own laboratory, based on internal testing and now uses an
upper limit of 800 ng/dl. (Id. at 550: 10-552:20) Dr. Sliwinski explained that an elevated
level of testosterone of 40.8 nmol/I (1054 ng/dl) would require consideration of factors
(including when the level was drawn during treatment or if the patient is exhibiting
symptoms) before causing concern. (D.I. 74 at 533:12-25)
Plaintiffs' expert, Dr. Hartmut Derendorf ("Dr. Derendorf'), 23 opined that during a
study it is common to have a patient who behaves differently for some reason. He
testified that "the goal of this exercise is to find the population dose, ... the best dose
for the majority of the patients." (D.I. 73 at 402:25-403:25) He explained that Nieschlag
does not disclose whether any of the patients had testosterone levels outside of the
therapeutic range after a single 1000 mg injection. From the plasma concentration
curve, he observed that after the first dose, the patients are "far away from the upper
end of the curve." The peaks after the third and fourth injection indicate that the
testosterone level is above the upper threshold. This issue "calls for a modification,"
such as "an extension of the dosing interval." (Id. at 404:21-405:21) Dr. Derendorf
agreed that four of the fourteen patients in the Behre study had testosterone values
exceeding the AACE guidelines. (Id. at 435:21-25)

3. Two-phase dosing
Dr. Schlegel pointed out that drug accumulation was noted in Nieschlag. "In
Nieschlag, without changing the interval of injections, the [authors] noticed increasing ..
. testosterone ... with subsequent injections, suggesting the need to have a second
interval of injection after ... reach[ing] a steady state." The "data on serum

23

A pharmacokinetics expert.
15

testosterone levels with increasing intervals of injection" supports the concept of a
maintenance phase. He opined that von Eckardstein "really is a two-phase treatment
regimen, [with t]he second phase of treatment ... really designed to figure out" the
appropriate interval. Further, an initial or loading dose is common. "[D]ecreasing the
amount of the initial dose would prevent the overshooting in terms of testosterone
levels." He explained that once a steady state of testosterone is reached, a clinician
"can allow a longer period of time for that testosterone to be absorbed into the body and
still maintain normal testosterone levels, [which is] observed in the increasing intervals
that are provided in von Eckardstein." (D.I. 73 at 281:18-286:3)
Dr. Derendorf explained that drug accumulation is a "normal phenomenon." (Id.
at 365: 13-22) He testified that the Articles did not disclose a different interval between
the first and second injections compared to subsequent injections. Moreover, he opined
that having a different dosing interval between the first two injections and subsequent
injections is unusual. (Id. at 406:1-17)

4. Pharmacokinetics
Dr. Derendorf explained that as a pharmacokineticist, his "role is to help ...
identify the dose and dose regimen that has the highest probability of success. [His]
role is usually to identify a population dose, something that would be used for the
approval of a product where it ends up in a label .... "24 (D.I. 73 at 358:25-359:21) Dr.
Derendorf disagreed that the disputed claims are obvious and opined that

24

On cross-examination, Dr. Derendorf agreed that claim 18 could be directed to a
population dose or individual dose. (D.I. 73 at 439:25-441:12)
16

"intramuscular depot injections are complex and very difficult to predict." 25 There is no
"motivation to shorten a dosage interval for a treatment where we really want to have
long-lasting effects and long dosing intervals. [T]hat would be counter to the intention."

(Id. at 366-368)
Dr. Derendorf explained that when trying "to identify the optimum dosing
regimen," the starting point "is the assessment of dose linearity." The use of predictive
models is easier with linear pharmacokinetics. (Id. at 368-369) He analyzed the
Articles and opined that the published data and graphs are inconsistent with linear
pharmacokinetics. He explained that "[a]n oily depot injection of a prodrug is a very
complex route of drug administration." Some sources of variability are partition
coefficient, viscosity, and patient effects. The formulation depends on what oil is used
and what co-solvent if any (and how much) is used. He opined that "the likelihood of
simple linear pharmacokinetics is not very high." (Id. at 372-389) He concluded that a
person of ordinary skill could not "extrapolate with any reasonable likelihood of success
from the prior art that a different dose and a different dosing regimen ... would result in
serum testosterone levels inside the therapeutic range." Moreover, the person of
ordinary skill would need "[a]dditional studies with different doses and different dosing
regimens in order to characterize the system[.]" (Id. at 391-392; JTX 19) Dr. Derendorf
testified that to reach the change in dose and regimen disclosed in the disputed claims
from the pharmacokinetic data in the prior art would require "complicated," "lengthy,"
and "expensive studies." (Id. at 409:17-410:2) In his opinion, Dr. Schlegel's

25

Dr. Schlegel admitted that different ratios of castor oil and co-solvent might yield
different pharmacokinetic data and different Cmax levels (highest concentration). (D.I. 73
at 334:24-335:6; see also D.I. 72 at 147:15-22)
17

suggestions assumed dose linearity. Dr. Derendorf testified that dose linearity would
need to be established with additional data before a person of ordinary skill "could start
to come up with [a] prediction." (Id. at 408:11-24)
On cross-examination, Dr. Derendorf was asked a series of questions about
certain statements made in the literature, such as, "drug absorption from an oil solution
follows first-order kinetics after intramuscular administration." He responded that such
statements were too general and explained that there were other variables to consider.
(Id. at 411-426; JTX 11, 32, 38) He was also asked about an article published in 2006.

He explained that the Cmax are "not proportional ... after later doses" and the "data
[does not] confirm[] linearity," but conceded that the Cav9 value 26 does approximately
show linear dose proportionality. (Id. at 414: 1-421 :23; DTX 109) He admitted that a
person of ordinary skill in March 2003 would generally know how to design studies to
develop a formulation from the target profile to the final approved dosage form. (Id. at
504:14-505:16) He conceded that he did not know if Nebido has first order kinetics.
(D.I. 74 at 512:25-513:2)
Dr. Willliams explained that the iterative process of formulation development
requires that a formulator develop prototypes and then test them. If the prototype is
deemed unacceptable, the process starts anew. (D.I. 73 at 454:17-458:15) He agreed
that pharmacokinetic testing and research occurs prior to clinical testing. (Id. at 504:14505:20)

C. Motivation to Combine

26

Average steady state concentration.
18

The parties generally agree that the person of ordinary skill in the art would
consist of a team made up of a pharmacokineticist, a clinician, and a formulation
scientist. (D.I. 73 at 263:21-23, 267:8-12, 360:8-12, 452:23-453:10, 453:20-458:3)
There is no dispute that the prior art does not disclose the use of a 750 mg TU injection
dose or the specific interval regimen.
Defendant argues that plaintiffs focus on the motivation to create a long-acting
testosterone replacement therapy (a problem identified in the patent) to the exclusion of
other motivations such as problems of solubility and viscosity of a high TU concentration
formulation or providing a safe and effective therapy to patients. KSR Int'/ Co. v.
Teleflex Inc., 550 U.S. 398, 420 (2007) ("[A]ny need or problem known in the field of

endeavor at the time of invention and addressed by the patent can provide a reason for
combining the elements in the manner claimed."). Regardless, the patents and the prior
art describe solving the same problem - treating men with hypogonadism. It is
defendant's burden to prove by clear and convincing evidence that a person of ordinary
skill in the art would have been motivated to combine the Articles (and other cited prior
art) with the vehicle used in Proluton.
Defendant first argues that a person of ordinary skill would have recognized that
the formulation disclosed in the Articles must have used a co-solvent, and that such cosolvent was benzyl benzoate. The expert testimony on this point consists of opinion on
whether or not the stated concentration of TU "could" have dissolved in the volume of
castor oil. Beyond that question, the cited prior art (Riffkin and Proluton) does suggest
the use of a co-solvent. However, it is certainly not a given (as defendant argues) that a
person of ordinary skill would have understood that the particular co-solvent was benzyl

19

benzoate, as opposed to one of the other co-solvents known in the art. (JTX 6) Dr.
Williams pointed out that there are other co-solvents to choose from. Moreover, even
knowing the co-solvent would not provide a person of ordinary skill the particular ratio
disclosed by the patents-in-suit. The court concludes that the Articles do not disclose
benzyl benzoate as a co-solvent (or the particular ratio used by the patents-in-suit). 27
Dr. Schlegal used the AACE guidelines to the exclusion of other published
ranges for the normal levels of testosterone, and reached his opinion based on the
notion that the Articles suggested "overdosing" of patients. He opined that the
overdosing would provide a reason for a person of ordinary skill to reduce the TU dose
from 1000 mg to 750 mg. This reasoning is contradicted by the fact that after
Nieschlag, the same authors undertook another study (von Eckardstein) using 1000 mg
of TU. Dr. Schlegal also opined that after reducing the dose, a person of ordinary skill
would use routine experimentation to come up with the particular dosing regimen
disclosed by the patents-in-suit. He bolstered this opinion by explaining that clinicians
routinely make dose and regimen adjustments for testosterone therapies. In contrast,
Dr. Derendorf opined that such dose and regimen changes would require more than
routine experimentation. 28

27

Defendant's inherency argument is analyzed below.

28

Defendant criticizes Dr. Derendorf's testimony as not reflective of the opinions of a
person of ordinary skill. (D.I. 76 at 32-34) The court finds that Dr. Derendorf's
disagreement with certain general statements (paired with his explanations thereof) do
not discredit his opinions. Defendant also argues that an excerpt from a book (edited by
E. Nieschlag and H.M. Behre) makes it clear that pharmacokinetic computer simulation
was performed. (D.I. 76 at 31-32) The excerpt provides that "[a]s in the first study the
duration of action of intramuscular testosterone undecanoate was six to eight weeks.
Follow-up studies with multiple injections of 1000 milligram testosterone undecanoate
every six to eight weeks are currently being performed which are based on

20

The record demonstrates that there were a number of co-solvents that could
have been used for the formulation. Although defendant has successfully identified the
elements of the asserted claims (but not the specific quantities of TU and solvents) in
the prior art, defendant has not met its burden, by clear and convincing evidence, to
show that a person of ordinary skill would combine the elements in the manner claimed.

D. lnherency
Defendant's contention that the Nebido composition is inherently disclosed in the
prior art misapplies the doctrine of inherency. In the context of an obviousness inquiry,
inherency may supply a missing claim limitation only if the limitation at issue is the
"natural result" of the combination of prior art elements. PAR Pharm., Inc. v. TWI
Pharms., Inc., 773 F.3d 1186, 1194-95 (Fed. Cir. 2014) (cautioning that "the use of

inherency, a doctrine originally rooted in anticipation, must be carefully circumscribed in
the context of obviousness."); see also Continental Can Co. USA v. Monsanto Co., 948
F.2d 1264, 1268-69 (Fed. Cir. 1991) (an inherent limitation is one that is "necessarily
present" and not one that may be established by "probabilities or possibilities."). At bar,
the presence of benzyl benzoate or its ratio with castor oil is not inherent in the prior art
simply because the Nebido composition was used in the studies that formed the basis
of the Articles. (JTX 3-5) Defendant has failed to establish that the Articles barred the
possibility of an alternative vehicle being used in the prior art compositions. 29 See In re

pharmacokinetic computer simulation." (JTX 10 at 343) The court will not, absent
expert testimony, conclude that such statement undermines Dr. Derendorf's opinions.
29

In conjunction with the issue of inherency, defendant alleges that the claimed
invention is invalid because the examiner's allowance was based on his purported
misunderstanding that the concentration of castor oil in the co-solvent was not present
in the prior art. (D.I. 76 at 27-28; D.I. 68 at~ 4) Defendant's contention misses the
mark. The Articles did not teach a vehicle consisting of the claimed ratio of castor oil
21

Armodafinil Patent Litig. Inc., 939 F. Supp. 2d 456, 465 (D. Del. 2013) ("[l]f the
teachings of the prior art can be practiced in a way that yields a product lacking the
allegedly inherent property, the prior art in question does not inherently anticipate."). In
view of defendant's failure to establish inherency, the timing of the person of ordinary
skill's recognition that the Nebido composition was used in the studies described in the
Articles is irrelevant. See In re Newell, 891 F.2d 899, 901 (Fed. Cir. 1989) ("[A]
retrospective view of inherency is not a substitute for some teaching or suggestion
which supports the selection and use of the various elements in the particular claimed
combination.").

D. Secondary Considerations 30
Plaintiffs allege a long-felt but unmet need for a long-acting testosterone
replacement. Dr. Sliwinski testified that the available therapies required frequent visits
and resulted in unstable testosterone levels. The therapies also required clinicians to
adjust dosages for individual patients. (D.I. 74 at 528:16-529:17, 526:11-21,) Dr.
Sliwinski testified that he uses Aveed for certain of his patients, who find it convenient to
come for an injection just five times a year. The testosterone levels are "smooth." He
conceded that Aveed does not work for all patients. He opined that the occurrence of
pulmonary oil micro-embolisms ("POME"), which prompted additional measures by the
FDA for Aveed's administration, were likely due to improper injection technique. (Id. at

and benzyl benzoate. (JTX 3-5) The fact that the studies forming a basis for the
Articles contained a vehicle consisting of 40.7% by volume castor oil and 59.3% by
volume benzyl benzoate does not mean that the teachings in the Articles themselves
were so limited.
30

The court reads In re Cyclobenzaprine, supra, as requiring a review of such evidence
even where it is apparent that defendant cannot meet its burden to prove obviousness
by clear and convincing evidence.
22

534-538) In his opinion, in 2003, there existed a need for long term therapy,
notwithstanding the available therapies (including an implantable pellet, Testopel). (Id.
at 540-541)
Dr. Schlegel explained that Testopel was longer-acting than Aveed. Assuming
there was a need, Dr. Schlegel explained that Aveed does not fulfil it due to the
occurrence of POME and the additional measures required by the FDA. The additional
measures make it difficult for busy offices to administer the injections. He concluded
that Aveed "did and did not" meet the long felt need. The lower frequency of injections
is convenient, but the administration is cumbersome and, therefore, seldom used. (D.I.
73 at 289-293) Defendant's expert, Ivan T. Hofmann, analyzed certain financial data on
hormone and testosterone products and concluded that Aveed is not commercially
successful. 31 (D.I. 75 at 565-566, 586-590, 592, 597-599; JTX 46, 59; DTX 152, 153,
156, 167)
The court concludes that, on the record at bar, there existed a need for a longacting testosterone therapy. Defendant offers testimony (based on Aveed's commercial
success) that Aveed did not fill such need. This testimony is more indicative of a lack of
commercial success, a secondary consideration not advanced by plaintiffs.

Ill. CONCLUSION
For the foregoing reasons, the court finds that defendant has not met its burden
to prove, by clear and convincing evidence, that claim 2 of the '640 patent and claim 18
of the '395 patent are invalid for obviousness. An appropriate order shall issue.

31

The court declines to summarize the testimony herein.
23