Bayer Pharma AG et al v. Watson Laboratories Inc.
Filing
153
MEMORANDUM OPINION re bench trial decision. Signed by Judge Leonard P. Stark on 7/18/16. This order has been emailed to local counsel. (UNSEALED by the Court on July 20, 2016) (ntl) Modified on 7/20/2016 (ntl).
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
BAYER PHARMA AG, BAYER
INTELLECTUAL PROPERTY GMBH,
and BAYER HEALTHCARE
PHARMACEUTICALS, INC.,
Plaintiffs,
Civil Action No. 12-1726-LPS
FILED UNDER SEAL
V.
WATSON LABORA TORIES, INC.,
Defendant.
Jack B. Blumenfeld, Derek J. Fahnestock, MORRIS , NICHOLS, ARSHT & TUNNELL, LLP,
Wilmington, DE
Adam K. Mortara, J. Scott McBride, Cindy L. Sobel, BARTLIT BECK HERMAN
PALEN CHAR & SCOTT LLP, Chicago, IL
Attorneys for Plaintiff.
Dominick T. Gattuso, PROCTOR HEYMAN ENERIO LLP, Wilmington, DE
George C. Lombardi, Michael K. Nutter, James M. Hilmert, WINSTON & STRAWN LLP,
Chicago, IL
Attorneys for Defendant.
MEMORANDUM OPINION
July 18, 2016
Wilmington, Delaware
Bayer Pharma AG, Bayer Intellectual Property GmbH, and Bayer Healthcare
Pharmaceuticals Inc. (collectively, "Bayer" or "Plaintiffs") allege that Watson Laboratories, Inc.
("Watson" or "Defendant") infringes United States Patent No. 8,071 ,577 ("the ' 577 patent" or
"the patent-in-suit"). (D.I. 1) The ' 577 patent relates to a multiphasic regimen and method for
oral contraception containing estradiol valerate ("EV") and dienogest ("DNG"). (D.I. 1-1 ) EV
and DNG are the active ingredients of Bayer' s Natazia® product. (D.I. 1 if 17)
In September 2014, the Court construed the disputed terms of the patents-in-suit. 1 (D .I.
99, 11 1) The Court then held a four-day bench trial in December 2014. (See D.I. 125, 126, 127,
128) ("Tr.") After several extensions, the parties completed post-trial briefing on July 2, 2015 .
(D.I. 136, 138, 141 ) In connection with the briefing, the parties submitted proposed findings of
fact (D.I. 135, 137, 139), as well as a Stipulation of Uncontested Facts ("SUF") (D.I. 142).
Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire
record in this case and the applicable law, the Court concludes that: (1) Defendant has stipulated
that its proposed products infringe claims 1-3 of the ' 577 patent; (2) Defendant has failed to
prove by clear and convincing evidence that claims 1-3 of the ' 577 patent are invalid for
obviousness-type double patenting; and (3) Defendant has failed to prove by clear and
convincing evidence that claims 1-3 of the ' 577 patent are invalid for obviousness. The Court' s
findings of fact and conclusions of law are set forth in detail below.2
1
Neither party objected to the Report and Recommendations regarding Claim Construction
prepared by Magistrate Judge Burke.
2
At the conclusion of trial, the parties proposed a stipulation by which post-trial briefing would
have been completed by April 3, 2015. (See D.I. 120) Thereafter, on February 17, March 2, and
1
FINDINGS OF FACT
This section contains the Court' s findings of fact ("FF") on disputes raised by the parties
during trial, as well as the facts stipulated to by the parties. Certain findings of fact are also
provided in connection with the Court' s conclusions oflaw.
A.
The Parties
1.
Plaintiff Bayer Pharma AG ("Bayer Pharma"), formerly known as Bayer Schering
AG, is a corporation organized and existing under the laws of the Federal Republic of Germany,
having a principal place of business at Mullerstrasse 178, 13353 Berlin, Germany. (SUF ii 1)
2.
Plaintiff Bayer HealthCare Pharmaceuticals Inc. ("Bayer HealthCare"), formerly
known as Berlex, Inc., is a corporation organized and existing under the laws of the State of
Delaware, having a principal place of business at 100 Bayer Boulevard, Whippany, New Jersey,
07981 USA. (Id.
3.
ii 2)
Plaintiff Bayer Intellectual Property GmbH ("Bayer IP") is a corporation
organized and existing under the laws of the Federal Republic of Germany, with a place of
business at Alfred-Nobel-Strasse 10, 40789 Monheim, Germany. (Id. ii 3)
4.
Defendant Watson Laboratories, Inc. is a corporation organized and existing under
the laws of the State of Nevada, having a principal place of business at 132 Business Center
Drive, Corona, California 92880 USA. (Id.
ii 4)
April 2, 2015, the parties stipulated to extensions, such that the first of their briefs was not filed
until May 15, 2015 and briefing was not completed until July 1, 2015. (See, e.g. , D.I. 129, 131 ,
132) On September 11 , 2015, the Court held a teleconference to assess the time sensitivity of the
case. (See D.I. 146) Among other things, the parties advised the Court that there is no automatic
30-month stay of United States Food and Drug Administration ("FDA") approval of Watson' s
proposed generic product. (See id. at 3) On May 13, 2016, Bayer advised the Court that on May
6, 2016 Watson had received FDA approval for its generic version ofNatazia®. (D.I. 151 )
2
B.
The Menstrual Cycle and Combined Oral Contraceptives
5.
The menstrual cycle is the biological process where, over the course of a month, a
woman produces a follicle that then ovulates. Ovulation occurs when a dominant follicle
develops, ruptures, and releases an egg. (DDX108 ; Simon Tr. at 101-02)3 If a woman does not
become pregnant during that month, she will menstruate and begin the cycle again. (Barnhart Tr.
at 367-68)
6.
The initial phase of the menstrual cycle is called the proliferative phase, during
which the endometrial lining of the uterus thickens under the dominant influence of estrogen.
After ovulation, progesterone levels increase. Progesterone is anti-proliferative and acts to stop
the endometrium from further thickening and, if no pregnancy occurs, initiates the sloughing of
the uterine lining and bleeding that characterizes menstruation. (Barnhart Tr. at 368-69; Simon
Tr. at 102)
7.
The menstrual cycle changes considerably in the presence of a combined oral
contraceptive ("COC"). A COC is a drug that combines an estrogen hormone with a synthetic
progesterone, or progestin, hormone (also known as a gestagen or gestogen) to provide a
contraceptive effect. (Simon Tr. at 99-100) In a COC, the estrogen component is primarily
responsible for providing cycle control, while the progestin hormone suppresses the growth of
follicles, preventing ovulation, and thereby providing contraception. (Simon Tr. at 100-04;
Barnhart Tr. at 372)
8.
The hormone levels associated with a natural menstrual cycle are considerably
3
Citations to the trial transcript (which can be found at D.I. 125, 126, 127, 128) are in the form
of: ("[Witness last name] Tr. at [page]").
3
lower, almost flat-lined, when a woman is taking a COC. The endometrial lining of the uterus
when a woman is taking a COC is also considerably different from the natural menstrual cycle.
In the initial proliferative phase of the menstrual cycle of a woman taking a COC, there is less
proliferation, and the lining of the uterus is much thinner than in the natural menstrual cycle.
(Barnhart Tr. at 370-72)
9.
It is necessary that a COC promote enough proliferation, however, to maintain a
stable endometrial lining during the menstrual cycle, in order to avoid intracyclic bleeding. (Id.
at 370-71) If the endometrium becomes too thin under the influence of the COC or is otherwise
unstable, the result is undesirable intracyclic bleeding and inadequate cycle control. (Id. at 3 7172)
10.
At trial, both sides ' experts agreed that cycle control is an important feature of a
successful COC. (Simon Tr. at 100-01 ; Barnhart Tr. at 372) Cycle control refers to avoiding
unscheduled bleeding during a contraceptive cycle. (Simon Tr. at 100-01; Barnhart Tr. at 372)
Cycle control is important because unscheduled bleeding and spotting negatively affect women
and their contraceptive use. (Simon Tr. at 100-01 ) Poor cycle control can be inconvenient, and
this may lead to a failure to take all required doses, which can result in a pregnancy. (Barnhart
Tr. at 372)
C.
Selecting the Components and Dosages for a COC
11 .
Historically, the estrogen component in COCs has been nearly universally a
synthetic estrogen called ethinylestradiol ("EE"). (JTX3 at 105-06; Simon Tr. at 111; Holtz Tr.
at 330) In general, EE is highly effective for preserving cycle control. (Simon Tr. at 112)
However, EE, at certain doses, is associated with a risk of venous thromboembolism, or blood
4
clotting. (Id. at 112-13) To minimize this side effect, over the course of decades drug
manufacturers systematically reduced the dose of EE in COCs. (Id. at 113)
12.
As an alternative to reducing EE doses, drug manufacturers attempted to replace
the EE component with natural estrogens, such as estradiol valerate ("EV"). (Id. at 114)
13.
EE behaves differently than EV with respect to cycle control. (Simon Tr. at 242)
The differences between EE and EV with respect to cycle control resulted in 30-40 years of
failures caused by poor cycle control in efforts to develop a COC with natural estrogen.
(Barnhart Tr. at 420)
14.
Prior art references disclosed COCs using daily doses of EE in the amounts of 3,
2, and 1 mg, including embodiments using daily doses of 3-2-1 mg on different days of a single
cycle. (JTX14 at 3:1 6-53; DTX74 at 3-4; JTX68 at 3; JTX3 at 108 ; JTX2 at 460)
15.
A progestin' s effect of inhibiting follicular development and ovulation depends on
the dose in which it is given, such that ovarian suppression increases with increasing absolute
doses of progestin. (JTX4 at 277 (" [T]he ovulation inhibitory effects of dienogest are directly
related to the dose received."); JTX20 at 2 (Endrikat declaration submitted in prosecution of
' 577 patent, stating "it was commonly known to one of ordinary skill in the art that higher
progestin doses provide higher ovarian suppression with increasing absolute doses"); Barnhart
Tr. at 479-80 (discussing dose-response relationship around anti-ovulatory dose); Simon Tr. at
105-06, 146-47 (discussing JTX215 at depo. tr. p. 59))
16.
One progestin that had been commonly used in prior art COCs is dienogest, or
"DNG". (JTX3 at 8; Simon Tr. at 119) DNG had been used safely since 1995 in a prior art
COC, Valette®, with a daily dose of 2 mg. (JTXl 73 at 534)
5
17.
The prior art includes a dose-ranging study by Dr. Claudia Moore, aimed at
determining the minimum dosage ofDNG alone required for consistent ovulation inhibition.
(JTX4) Moore determined that 1.0 mg of DNG "reliably inhibited ovulation." (Id. at 277)
Moore ' s study was art ofrecord before the Examiner during the prosecution of the ' 577 Patent.
(JTXl ; JTX265 at 20, 131 )
18.
Persons of ordinary skill in the art ("POSA") understand that a COC will
sometimes utilize the minimum single-agent ovulation inhibition dose of a progestin and double
it as a maximum daily dose for the COC. This typical "rule of thumb" applicable to COCs
accounts for the facts that a pill must be dosed in a one-size-fits-all manner and that patients are
known to sometimes miss pills. (Simon Tr. at 126-30; Barnhart Tr. at 458-59 (discussing
estimates of 30% of women missing at least one pill in a cycle)) POSAs would generally
understand this potential two-times the minimum ovulation inhibition dose to be a ceiling for
potential COCs. (Barnhart Tr. at 420-21 ) POSAs would also understand that COCs can have
progestin dosing below the minimum single-agent dose. (Id. at 312, 428, 430-31 )
19.
Another guiding principle in COC development has been the trend to lower
hormone doses. (Barnhart Tr. at 398) Over the past 40 years, the doses of estrogen and progestin
used in COCs have gradually declined. (JTX136 at 185; JTXl 73 at 518 ; Barnhart Tr. at 399;
Simon Tr. at 171 ) This development trend is also part of the FDA' s labeling guidance to
pharmaceutical companies. (JTX133 at 47; JTX134 at 4; Barnhart Tr. at 400-01 ; Allen Tr. at
583)
20.
The historical trend towards lowering hormone doses over time would have taught
a POSA that it would be appropriate to use less than 2 mg of DNG in a COC. (Barnhart Tr. at
6
421-22)
21.
COCs are typically monophasic, meaning "the amount of each particular hormone
in each day of use is the same," but there are also biphasic, triphasic, and a few multiphasic
contraceptive regimens in which the amount of each hormone differs at different phases of a
cycle. (Simon Tr. at 96)
D.
Assessing the Effectiveness of COCs
22.
In 1993, a prior-art article by Hoogland described a method to evaluate the
effectiveness of contraceptives by assessing residual ovarian activity. (JTX214; Simon Tr. at
107-10) The method utilizes ultrasound to assess follicular growth in women taking a
contraceptive progestin. (Simon Tr. at 107)
23.
Hoogland describes a six-point scale to characterize residual ovarian activity,
ranging from no ovarian activity (at the low end) to an ovulation (at the high end). (JTX214 at
585; Simon Tr. at 107-08) A score of three on a scale starting with zero (or four on a scale
starting with one (this latter scale indicated in parentheses going forward)) is an active
follicular-like structure ("FLS"), which is greater than 13 millimeters in size and begins to
produce estradiol. (Simon Tr. at 108; Barnhart Tr. at 511) A score of four (or five) is a
luteinized unruptured follicle ("LUF"), which indicates further activity where the follicle
produces progesterone and estradiol. (Simon Tr. at 108) Active FLSs and LUFs represent
residual ovarian activity. (JTX214 at 585; JTX12 at 109; Simon Tr. at 142-43 ; Barnhart Tr. at
513-14) A score of five (or six) is ovulation. (JTX214 at 585)
24.
The rationale for Hoogland' s method of characterizing ovarian activity into six
categories was an observation that " [t]he trend towards changing the composition of the
7
contraceptive pill in order to decrease side effects might lead to increased ovarian activity. This
may decrease reliability." (Id. at 583) Hoogland taught "that the degree ofresidual ovarian
activity under oral contraceptives should be regarded as the best possible parameter of medicine
dependent efficacy," and that "follicular growth and ovulation are significant parameters to
define pill reliability." (Id. at 587 (emphasis omitted); Simon Tr. at 111)
25.
Other than being labels assigned to categories, the numbers in the Hoogland scale
have no meaning. (Simon Tr. at 230-32) That is, there is no mathematical relationship between
a 3 and a 4, for example, on the Hoogland scale. (Barnhart Tr. at 373) Moreover, each menstrual
cycle is characterized by one and only one Hoogland score; it is not as if every month a cycle
passes through lower number stages on the way to higher number stages. (Id. at 373-76)
26.
While contraceptive efficacy must ultimately be determined by a large Phase III
clinical trial, a common method for determining the potential efficacy of a COC is a smaller
Phase II ovulation inhibition study, typically involving 10-30 women. (Allen Tr. at 564-65)
Ovulation inhibition studies measure the degree of ovarian suppression. (Id. at 562-64; Barnhart
Tr. at 373-77)
27.
Another measure of contraceptive effectiveness is called the "Pearl Index."
(Simon Tr. at 173; Allen Tr. at 566) A Pearl Index is a calculation of the number of pregnancies
per 100 woman years based on data from a Phase III clinical trial. (Simon Tr. at 173 ; Allen Tr. at
567) COCs on the market at the time of the invention of the patent-in-suit had Pearl Index values
of 2.92 or less. (Allen Tr. at 568-69)
28.
The principal end point being measured in any study of contraceptive efficacy is
ovulation. (Barnhart Tr. at 3 79-80)
8
E.
Bayer's Natazia®
29.
Bayer is the holder of New Drug Application ("NDA") No. 22-252, which relates
to an oral contraceptive regimen known by and sold in the United States under the trademark
Natazia®. (SUP ifif 5, 8)
30.
On May 6, 2010, the FDA approved the marketing of the product described in
NDA No. 22-252 for the prevention of pregnancy in women who choose to use an oral
contraceptive. (Id. if 6)
31 .
On March 14, 2012, the FDA further approved the marketing of the product
described in NDA No. 22-252 for the treatment of heavy menstrual bleeding ("HMB") in women
without organic pathology who choose to use an oral contraceptive as their method of
contraception. (Id.
32.
if 7)
Natazia® is a multiphasic COC that uses EV as the estrogen component and DNG
as the progestin component. (JTXl ; Simon Tr. at 97-98) The Natazia® regimen involves daily
doses of EV of 0, 1, 2, and 3 mg, depending on the phase of the cycle, and daily doses ofDNG of
0, 2, and 3 mg, again depending on the phase of the cycle. (JTXl ; Zelano Tr. at 278)
33.
Prior to the discovery ofNatazia®, all prior art describing specific examples of
DNG-containing COC regimens recommended a daily dose of2 mg or less, including the Moore
article, the Hoffmann articles, the Dittgen patents and applications, and the Gast patent. (All of
this prior art is addressed in greater detail below.)
34.
Natazia® is the first "natural" estrogen COC marketed in the United States.
(JTX265 at 1313-14; Holtz Tr. at 330; Barnhart Tr. at 434)
35.
Natazia® was launched in Europe under the name "Qlaira®" in May 2009 and in
9
the United States in July2010. (Holtz Tr. at 329)
F.
The Patent-in-Suit: U.S. Patent No. 8,071,577
36.
The patent-in-suit is the '577 patent. (JTXl ) Jan Endrikat and Bernd Dilsterberg
are identified as inventors on the ' 577 patent, which was filed on April 15, 2005 and claims
priority to a German patent filing on April 20, 2004. (SUP
~
9) The '577 patent was issued
December 6, 2011. (Id.) Bayer IP is the current owner of the '577 patent. (Id.)
37.
The '577 patent is directed to multiphasic regimens for oral contraception
involving the estrogen EV, the progestin DNG, and placebo. (JTXl ) The '577 patent has two
examples and three claims. (Id. at cols. 3-4) Each claim relates to a particular contraceptive
regimen, as presented in the table below:
Table 1. '577 Patent/Natazia® Regimen
Phase
Days
Dose Elements
Phase 1
2 daily doses
3mgEV
Phase 2, group 1
5 daily doses
2 mg EV and 2 mgDNG
Phase 2, group 2
17 daily doses
2 mg EV and 3 mg DNG
Phase 3
2 daily doses
1 mg EV
Phase 4
2 daily doses
Placebo
38.
As displayed in Table 1 above, the claimed regimen has three basic components.
First, the claims involve a particular phasic pattern - that the Court will refer to as the
"2-5-17-2-2" dosing pattern - which represents the calendar days EV, DNG, and placebo are to
be given. Second, the claims require daily doses of EV at 3 mg in the first phase, 2 mg in the
second phase, and 1 mg in the third phase. Third, the claims require daily doses ofDNG at 2 mg
10
during Phase 2, group 1 and 3 mg during Phase 2, group 2. (Id. ; Simon Tr. at 121)
39.
Natazia® is a commercial embodiment of the claims of the '577 patent. (JTXl ;
Zelano Tr. at 278)
40.
The '577 patent, which expires on May 13, 2026, is listed in the entry for
Natazia® in the FDA' s "Approved Drug Products with Therapeutic Equivalence Evaluations"
("Orange Book"). (SUF ~ 10) Previously, Bayer had listed U.S. Patent No. 6,133,251 ("the '251
patent") and U.S. Patent No. 6,884,793 ("the ' 793 patent") in the FDA' s Orange Book as
protecting Natazia®, until 2011 when it disclaimed all interest in these patents. (DTX 42 at
4-11 ; DTX43 ; DTX44; Matthey Tr. at 316-17, 320-21 )
G.
Bayer's Prior Patents Covering Natazia®
41.
The ' 577 patent is the third patent that Bayer has owned that covers the Natazia®
regimen. (Id. ; JTX14; JTX19; JTXl)
42.
Bayer' s corporate representative witness, Anthony Zelano, the attorney who
prosecuted the ' 577 patent, testified about the prosecution of all three patents. (See generally
Zelano Tr. at 278-313)
1.
The '251 patent and its prosecution
43 .
On October 25 , 1996, Bayer' s subsidiary, Jenapharm, filed U.S. Patent
Application No. 08/738,314 ("the ' 314 application"), naming Michael Dittgen and others as
inventors ("the Dittgen group"). (DTX69; Zelano Tr. at 280) The ' 314 application issued as the
'251 patent on October 17, 2000. (JTX14) The ' 251 patent involves a "Combination Compound
for Contraception Based on Natural Estrogen." (Id. )
44.
The '251 patent describes and claims a genus of multiphasic regimens effective
11
for oral contraception. (Id. at 1) The scope of the regimens claimed in the '251 patent is as
follows :
Table 2. '251 Patent Regimen
Phase
Days
Dose Elements
Phase 1
2-4 daily doses
Natural estrogen compound
Phase 2, group 1
3-5 daily doses
Natural estrogen compound
and synthetic or natural
gestogen
Phase 2, group 2
13-17 daily doses
Natural estrogen compound
and synthetic or natural
gestogen (more gestogen than
in Phase 1)
Phase 3
2-4 daily doses
Natural estrogen compound
(less than in Phase 1)
Phase 4
2-4 daily doses
Placebo
(Id. at 6:31 -64 (emphasis added); Simon Tr. at 115-16) As shown above in bold, the ' 251
patent' s claimed range of days includes the 2-5-17-2-2 daily dosing regimen of the ' 577 patent.
45.
The ' 251 patent specification describes that increasing the DNG dose by 1.5 to 3
times in Phase 2, group 2 - in comparison to Phase 2, group 1 - is advantageous for use in the
multiphasic regimens described and claimed in the patent. (JTX14 at 3:34-43 ("Advantageously
the gestogen content of the individual portions of the second group amounts to 1.5 to 3 times the
gestogen content of the individual portions of the first group."); id. at 6:65-7:2 (claiming such
12
dosing) ; Simon Tr. at 154)
46.
The ' 251 patent contains five examples utilizing natural estrogens in a multiphasic
regimen having positive results for cycle control. (JTX 14 at 4:28-6:7) Example 1 of the ' 251
patent specification describes the 3-2-1 mg dosing pattern of EV (in conjunction with the
progestin desogestrel), and teaches that it offered good cycle control. (Id. at 4:28-30 ("The
improvement of the cyclic bleeding behavior in women is also proven."); id. at 4:46-50; Simon
Tr. at 116) Example 5 of the '251 patent specification describes the use of 1 mg DNG and 2 mg
DNG given in Phases 2 and 3, respectively, of a five-phase regimen. (JTX14 at 5:53-61; JTX5 at
3)
47.
To overcome an overbreadth rejection under 35 U.S.C. § 112, Jenapharm told the
Patent Office that "the amount of experimentation to obtain exemplary compositions based on
amended claim 8 and methods of administration according to claim 12 is reasonably limited."
(DTX71 at 10; DTX 72; Zelano Tr. at 283-84) Natazia® was such an "exemplary composition"
and a member of the claimed genus. (Zelano Tr. at 281-84)
48 .
To overcome an obviousness rejection to amended claim 8, Jenapharm submitted
a declaration from Michael Dittgen and others, dated April 10, 2000. (JTX5 ; DTX74) This
declaration, which published in the prior art as part of the file history of the ' 251 patent,
describes an additional regimen, apart from the patent' s five examples, that falls within the scope
of the '251 patent's claims (the "Dittgen Regimen"). (Id. ) The Dittgen Regimen involves the 32-1 mg EV dosing pattern, 1 mg and 2 mg DNG, and placebo in a 3-4-16-2-3 multiphasic
regimen:
13
Table 3. Dittgen Regimen
Phase
Days
Dose Elements
Phase 1
3 daily doses
3mgEV
Phase 2, group 1
4 daily doses
2 mg EV and 1 mg DNG
Phase 2, group 2
16 daily doses
2 mg EV and 2 mg DNG
Phase 3
2 daily doses
1 mg EV
Phase 4
3 daily doses
Placebo
49.
The results of a phase II ovulation inhibition study of the Dittgen Regimen were
reported in a Declaration ("Dittgen Declaration") to the United States Patent and Trademark
Office ("PTO") that is part of the prior art. (JTX5 at 6; DTX74 at 6; Simon Tr. at 117) The
Dittgen Declaration reports Hoogland results for a group of 21 women following the Dittgen
Regimen. (JTX5) The results showed that none of the 21 women participating in the study
ovulated. (JTX5 at 6; DTX74 at 6) However, 9 out of the 21 women (43 %) showed active FLSs
or LUFs in at least one of the three cycles tested. (Id. ; Simon Tr. at 138-39)
50.
The '25 1 patent was set to expire in 2016 (Matthey Tr. at 317); however, Bayer
disclaimed all interest in the patent on March 4, 2011 (DTX44; Matthey Tr. at 321 ).
51.
Bayer owned the ' 251 patent prior to acquiring the ' 577 patent. (Matthey Tr. at
2.
The '793 patent and its prosecution
52.
On September 12, 2001 , Bayer' s subsidiary, Jenapharm, filed U.S. Patent
279)
Application 09/950,915 ("the ' 915 application"), naming the same Dittgen group from the ' 251
patent as the inventors. (JTX228) The ' 915 application claimed priority to the ' 314 application
14
and shared the same written description as the ' 314 application. (Id.)
53.
The ' 915 application published on August 8, 2002. (DTX81; Zelano Tr. at
291-92) At the time of the application' s publication in 2002, the application and its file history
became open to the public. (Zelano Tr. at 292) Following that publication, all subsequent
documents filed with the PTO during prosecution of the '915 patent would also be public. (Id. at
291-92)
54.
On December 18, 2003 - several months before the April 2004 priority date of the
' 577 patent- Jenapharm filed an Amendment cancelling all previously pending claims in the
' 915 application and substituting application claim 15 ("New Claim 15") as the sole prosecution
claim. (JTX68) The Amendment was available online through the PTO' s Patent Application
Information Retrieval ("PAIR") system for accessing published file histories, on or about the
time it was filed . (Zelano Tr. at 293)
55.
In New Claim 15, Jenapharm specifically claimed a multiphasic 2-5-17-2-2
pattern of EV, DNG, and placebo consistent with, though broader than, that used in Natazia®.
(JTX68; DTX82; Zelano Tr. at 294-99) The regimen of New Claim 15 is presented in the table
below:
15
Table 4. New Claim 15 Regimen
Phase
Days
Dose Elements
Phase 1
2 daily doses
Effective amount of EV
Phase 2, group 1
5 daily doses
Combination of EV and DNG
Phase 2, group 2
17 daily doses
EV and DNG, with more
DNG than in group 1
Phase 3
2 daily doses
Effective amount of EV,
lower than in Phase 1
Phase 4
2 daily doses
Placebo
(JTX68 ; Simon Tr. at 153)
56.
In presenting New Claim 15 to the PTO, Jenapharm stated it was "very similar" to
the Dittgen Regimen, and further that " [t]he showing in the previously filed [Dittgen]
Declaration proves that the claimed contraceptive preparation of new claim 15 has unexpectedly
improved properties in comparison to the closest prior art." (JTX68 at 6) The regimen described
in New Claim 15 was different, however, from the Dittgen Regimen: the "length of the first and
additional stages differs by one day in the case of claim 15 from the example in the Declaration."
(Id.) Jenapharm did not, at that time, present the PTO with any claim that covered the 3-4-16-2-3
Dittgen Regimen. (Id. at 1-3)
57.
In fact, by the time that Jenapharm presented New Claim 15 in December 2003 , it
had, more than two years earlier, prematurely terminated a Phase III clinical trial of the Dittgen
Regimen. (JTX20 at 3 ("[T]his Phase III study had to be prematurely terminated due to a Pearl
Index of 4.3 (48 pregnancies in 12, 125 cycles); cycle control was also unsatisfactory compared to
16
current commercial 20µg EE preparations."), 34 ("Because of the unexpectedly high number of
pregnancies registered, the study was prematurely terminated (Letter of termination to the
Investigators on 22 Jan 2001 ; last patient out on 15 Sep 2001)")) Jenapharm, however, did not
disclose this "shocking" failure to the PTO when presenting New Claim 15. (JTX68; Allen Tr. at
592-93) Rather, it presented the Dittgen Regimen as a basis for allowing New Claim 15.
(JTX68)
58.
On August 19, 2004, after the claimed April 2004 priority date for the ' 577 patent
but before the ' 577 patent issued, Jenapharm amended New Claim 15 to "further distinguish it
from the cited prior art" (DTX78 at 176), by specifying that the DNG dosage be increased 1.5 to
3 times in Phase 2, group 2 as compared to Phase 2, group 1 (id. at 174).
59.
On April 26, 2005 , the '915 application issued as the ' 793 patent. (JTX19) The
amended New Claim 15 of the ' 915 application issued as claim 1 of the ' 793 patent. (Id. )
60.
As shown below, the only difference between New Claim 15 and issued claim 1
of the ' 793 patent is that the latter contains the additional, narrowing requirement that the DNG
dose be 1.5 to 3 times higher in Phase 2, group 2 than in Phase 2, group 1. (Compare JTX68 at 3
with JTX19 at 6:50-7:13; Simon Tr. at 153)
17
Table 5. '793 Patent Claim 1 Regimen
Phase
Days
Dose Elements
Phase 1
2 daily doses
Effective amount of EV
Phase 2, group 1
5 daily doses
Combination of EV and DNG
Phase 2, group 2
17 daily doses
EV and DNG, with 1.5 to 3X
more DNG than in group 1
Phase 3
2 daily doses
Effective amount of EV,
lower than in Phase 1
Phase 4
61.
2 daily doses
Placebo
The ' 793 patent was set to expire on October 25, 2016. (DTX43 ; Zelano Tr. at
290) However, Bayer disclaimed all interest in the patent on March 4, 2011. (Matthey Tr. at
321)
62.
Bayer owned the ' 793 patent prior to acquiring the '577 patent. (Id. at 318-19;
Zelano Tr. at 279, 310)
H.
Prosecution History of the '729 Application and the '577 Patent
63.
Shortly after Bayer presented New Claim 15 in the prosecution leading to the ' 793
patent, Bayer filed two patent applications disclosing an example containing the 2-5-17-2-2
regimen and the precise dosages used in Natazia®, but claiming two different inventive entities
were responsible for the invention. (DTX86 at 18; JTX265 at 13; Zelano Tr. at 301-02)
64.
Bayer filed the first application, U.S . Patent Application 10/891 ,729 ("the ' 729
application"), on July 15, 2004, attributing the Natazia® example to the same Dittgen group
identified as inventors of the ' 251 and ' 793 patents. (DTX86 at 4, 18) Amended claim 8 of the
18
'729 application differs from the ' 577 patent only in that it provides for DNG doses of 2-3 mg
and 3-4 mg instead of the precise amounts found in Natazia® of2 mg and 3 mg. (Compare
DTX93 at 3 with JTXl at 4:16-28) Because the co-inventorship of the ' 729 application and the
'793 patent was clear in the ' 729 application, the PTO rejected claims that were "specific to
Natazia®" for double patenting over claims 1-5 of the ' 793 patent. (DTX94 at 9; Zelano Tr. at
306-09) Bayer overcame that double patenting rejection by terminally disclaiming its application
to the ' 793 patent's 2016 expiration, before abandoning that application altogether by failure to
pay the filing fee. (DTX95 at 4; Zelano Tr. at 308-09)
65.
In the second application, U.S. Application No. 111578,771 ("the '771
application"), which led to the ' 577 patent-in-suit, Bayer identified different inventors - Jan
Endrikat and Bernd Diisterberg- as being responsible for the Natazia® example. (JTX265 at 13;
JTXl) Because Endrikat and Duesterberg were not identified as inventors in the ' 793 patent,
there was no co-inventorship. (Compare JTX19 with JTXl) The co-ownership of the '771
application and the ' 793 patent was not obvious on the face of the '771 application, because the
'793 patent issued in the name of Bayer' s subsidiary, Jenapharm, while Bayer filed the '771
application in its own name. (Id.) However, by the time that the '771 application was being
substantively prosecuted in 2009, Bayer owned the ' 793 patent and had listed it in the FDA's
Orange Book. (DTX43; Matthey Tr. at 318)
66.
The same Examiner, San-Ming Hui, examined the applications leading to the ' 793
patent and the '577 patent, but a different Examiner, Samira Jean-Louis, examined the '729
application. (Compare JTXl and JTX19 with JTX265 at 1622)
67.
On November 12, 2009, Bayer filed- in the ' 314 patent application (which had
19
issued as the ' 251 patent), the '915 patent application (which had issued as the '793 patent), the
'729 application (which had not issued), and the ' 771 application (which had not yet issued as the
' 577 patent)- a Revocation of Power of Attorney and Appointment of New Attorney, identifying
Bayer as the assignee of these patent applications. (JTX265 at 259-60; DTX78 at 203-04)
68.
On January 27, 2010, during the prosecution of the '577 patent, Bayer filed an
Identification of Related Applications listing eleven patent applications - including the ' 314
application (and the resulting '251 patent), the ' 915 application (and the resulting '793 patent),
and the ' 729 application (indicating it was "now allowed and to be abandoned") - as related to
the '577 patent. (JTX265 at 315-16)
69.
Mr. Zelano, the prosecuting attorney, testified that he did not recall having
apprised the "Examiner that the ' 793 patent was owned by Bayer at the time of the '577
prosecution," but "the Patent Office, of course, has databases indicating current ownership."
(Zelano Tr. at 311) Moreover, that there was co-ownership of the ' 771 application and the '793
patent was discernable from the record before the PTO because the ' 251 patent, the ' 793 patent,
and the ' 915 application (including New Claim 15) were "cited references" on the face of the
'771 application considered by the Examiner. (JTXl; JTX265 at 2215-19; Barnhart Tr. at 22324) Additionally, there is no evidence in the record that Bayer falsely denied joint ownership or
affirmatively misled the PTO about ownership.
70.
During prosecution of the ' 577 patent, Bayer told the Examiner:
Both the original and allowed claims of the ' 729 are drawn to
essentially the same invention as the instant application. The
persons who signed the declaration in the ' 729 (Michael Dittgen
. . . ) are not the same as the inventors of the instant application. It
is the current inventors, Endrikat and Diisterberg, who are the true
inventors of the claimed subject matter in the instant application.
20
(JTX265 at 313-14)
71.
On July 14, 2011 , Bayer confirmed:
As noted in . .. Applicants ' response of January 27, 2010, an
inventive entity different from that of this application previously
filed a U.S. application (10/891 ,729 ... ) claiming the same
subject matter as this application. This was a result of a mistake on
the part of the other inventive entity. . . . The examiner is referred
to the file history of the mentioned '729 application since the
claims of the latter were allowed. The office actions and responses
filed in ' 729 are being filed herewith for the examiner' s
convenience. However, because of the mentioned mistake in the
filing of such application by its inventors, the issue fee was never
paid. Nevertheless, the examiner may be interested in the nature of
the proceedings which led to the allowance in the ' 729 application.
These included the publication of the application and filing of a
terminal disclaimer over the US '793 patent ofrecord to render
moot an obviousness-type double patenting rejection. Because the
current claims are not obvious over the claims of the US '793
patent, or its parent US '251 patent, no terminal disclaimer is
necessary.
(Id. at 1533-34)
72.
During the prosecution of the ' 577 patent, the Examiner rejected the claims
multiple times in light of the Dittgen Regimen, which combined 3 mg, 2 mg, and 1 mg EV doses
with 1 mg and 2 mg DNG doses in a 3-4-16-2-3 daily dosing pattern. (Id. at 246-54 (7/27/2009
Office Action), 896-903 (4/27/2010 Office Action), 1221 -25 (12/08/2010 Office Action))
Following the submission of three declarations from Jan Endrikat (JTX20 at 2-3 (explaining why
arriving at Natazia® was not a matter of "routine optimization" ofDittgen Regimen and noting
Dittgen Regimen' s Phase III contraceptive efficacy failure and "unsatisfactory" cycle control);
JTX265 at 1523 (correcting misstatement from first declaration); id. at 2172 (correcting
misstatement from second declaration)), and additional remarks regarding the evidence of the
Dittgen Regimen' s failure, along with argument that "only hindsight leads a skilled worker to
21
select Example 5 of the Dittgen EP ' 388 [the Dittgen Regimen] as a starting point" (id. at 130912), the Examiner allowed the claims because of "the unexpected effectiveness of the herein
claimed specific contraception regimen" (id. at 2194-96).
73.
Rather than expiring in 2016 - as did the ' 251 and ' 793 patents before Bayer
disclaimed all interest in them, and as the ' 729 application would have done had Bayer not
abandoned it after terminally disclaiming it to the ' 793 patent - the '577 patent issued with a
term extending until 2026. (DTX43; DTX95 at 4; Zelano Tr. at 308-09, 322)
74.
The list of "cited references" on the face of the '577 patent includes, among other
things, the '251 patent, the ' 793 patent, the Schmidt-Gollwitzer patent, the Kullman patent, the
Dittgen Declaration, the Hoffman article, the Moore articles, and the Graser article. (JTXl at 14)
I.
Scope and Teachings of the Prior Art
75.
Claim 1 of the ' 793 patent, discussed above, is not in the prior art. The prior art
of record on which Watson relies is summarized below.
1.
Dittgen Materials
76.
As noted above, the Dittgen Declaration reports Hoogland results for a group of
21 women following the Dittgen Regimen (with 1 mg and 2 mg DNG doses). The results
showed that, while none of the 21 women ovulated, 9 of them (43%) showed active FLSs or
LUFs in each of the three cycles tested. (JTX5 at 6; Simon Tr. at 138-39)
77.
Dr. Allen testified "that the developmental studies of the Dittgen Regimen
[including the Hoffman articles, discussed below] would have provided the FDA with more than
sufficient information to take that product into Phase ill clinical trials." (Allen Tr. at 545-46)
22
78 .
However, Watson' s expert, Dr. Simon, analogized the Hoogland results reported
in the Dittgen Declaration to those found in a paper by Liidicke and others, which published in
the prior art in 2001. The Liidicke authors used the Hoogland scoring system to compare and
evaluate two contraceptive regimens, each containing different doses of the progestin gestodene.
(JTX217; Simon Tr. at 140) The regimen containing a lower dose of progestin showed one
ovulation and several active FLSs and LUFs, thus showing insufficient ovarian suppression.
(Simon Tr. 140-42; JTX217 at 245)
79.
While the Hoogland scores for the Dittgen Regimen were broadly similar to the
results for the regimen Liidicke determined to have insufficient ovarian suppression (Simon Tr.
at 142), the presence of one ovulation in the Liidicke regimen compared to no ovulations
observed in those following the Dittgen Regimen is a material difference relevant to whether or
not to pursue further development (Barnhart Tr. at 404-09). Dr. Barnhart testified credibly and
persuasively that a POSA would not consider the failure of the Liidicke regimen to be
comparable to the success of the 1 mg/2 mg DNG regimen ofDittgen because there was an
ovulation with Liidicke, and none with the Dittgen Regimen. (Id.) As Dr. Barnhart noted, the
presence of an ovulation with Liidicke in an ovulation inhibition study is a failure, and makes the
regimen not worth pursuing further. (Id. ) Statistically, the presence of a single ovulation tells a
POSA that the possible range of actual ovulation could be as high as 20-25 % (while zero
ovulations means the actual ovulation rate is less than approximately 15%, which would be
comparable to existing successful contraceptives). (Id. at 407-10)
2.
Hoffman Articles
80.
Dr. Herbert Hoffmann and others published two articles ("the Hoffmann
23
Articles"), in 1998 and 1999, that tested a series of CO Cs utilizing Moore ' s recommended
maximum dose of 2 mg DNG in combination with EV, in an effort to find an effective natural
estrogen COC. (JTX2; JTX3) The Hoffinann Articles, which are prior art, were authored by the
same Dittgen group responsible for the ' 251 and ' 793 patents. (Compare JTX2 and JTX3 with
JTX14 and JTXl9)
81.
Hoffinann experimented with a biphasic regimen of 2 mg of EV with 2 mg of
DNG and a triphasic regimen of2 mg, 4 mg, and 2 mg of EV with 2 mg ofDNG. (JTX2 at 460;
JTX3 at 108) Hoffinan found that " [w ]hereas both combinations were capable of completely
inhibiting the ovulation, the resulting bleeding pattern was not acceptable by the women." (JTX2
at 460; JTX3 at 108)
82.
After presenting these failures, the Hoffman Articles reported the results of a pilot
study of the Dittgen Regimen in 100 women over six menstrual cycles, with a total of 573 cycles
ultimately documented. (JTX2 at 461 ; JTX3 at 109) Zero pregnancies occurred across the 573
cycles, and there was sufficient cycle control. (Id. ) Hoffman referred to the 1 mg dose ofDNG
used as "borderline" and said that the 1 mg and 2 mg DNG doses were "regarded as effective for
contraception." (Id.) Hoffmann concluded that the pilot study results justified starting a Phase
III trial of the Dittgen Regimen. (JTX3 at 110)
83 .
Hoffinan found that the cycle control of the Dittgen Regimen "might be
acceptable" to women. (Id. at 109; JTX2 at 461) He explained that the descending 3-2-1 EV
dosing pattern was expected to be responsible for the increased cycle stability of the Dittgen
Regimen over the other two regimens that were tested. (JTX3 at 108 ; see also JTX2 at 460)
24
3.
Bayer's '722 Patent ("Schmidt-Gollwitzer")
and Kullman Patent Application
84.
U.S. Patent No. 6,312,722 ("the ' 722 patent"), Bayer' s Schmidt-Gollwitzer patent,
which issued in November 2001 , is prior art. (JTX210) The Schmidt-Gollwitzer patent
described COCs including EV and DNG: "Preferably, in the present invention the oestrogen of
the first hormone component is contained in each daily unit dose in a dose of . . . from 1.0 to 4.0
mg of 17B-oestradiol valerate and the gestagen is contained in each daily unit dose in a dose of
from 1.0 to 3.0 mg of dienogest . . . ." (Id. at 6:35-40; Simon Tr. at 133 ; Barnhart Tr. 471 )
85.
The Schmidt-Gollwitzer patent taught that " [t]he daily dosage amount of [the
progestin] component corresponds at least to the threshold dose considered necessary for the
[progestin] in question to inhibit ovulation." (JTX210 at 1:52-55)
86.
Bayer' s Kullmann patent application, WO 02/22110 A2, which was published on
March 21 , 2002, is prior art. (JTX205) It described "estradiol (as a representative of natural
estrogen) 0.25 to 4 mg inclusive" and "dienogest 1 to 3 mg inclusive." (Id. at 4; Barnhart Tr. at
472-73)
4.
Oettel and Moore Articles
87.
An article by Oettel and others, published in 1995, concluded that "the ovulation-
inhibiting dose [ofDNG] in cyclic women amounts to about lmg/day." (JTXl 73 at 529 table
VII) Oettel, which is prior art, compared the cycle control of a very low dose ofDNG (0.225 mg,
below the ovulation inhibition dose) with a 2.0 mg dose ofDNG, where both doses were given
with 0.05 mg EE (i.e., the synthetic estrogen ethinylestradiol). (Id. at 529-30) Whereas the low
DNG dose resulted in "bad cycle control and poor ovulation inhibition," with 71.2% bleeding
disturbances and two pregnancies, "[e]levating the dienogest dose to 2 mg/day resulted in better
25
cycle control without pregnancies." (Id. at 530; see also Barnhart Tr. at 464)
88.
Oettel also set forth ovulation inhibition data for 0.5 mg, 1 mg, 1.5 mg, and 2 mg
doses ofDNG. (JTXl 73 at 529 table VII)
89.
A prior art article by Moore and others, published in 1999, described a
dose-ranging study ofDNG to determine its minimum ovulation inhibitory dose. (JTX4) The
authors tested DNG at increments of 0.5 mg, 1 mg, 1.5 mg, and 2 mg, and found that
"[d]ienogest 1.0 mg is the minimal daily dose needed to inhibit ovulation in healthy individuals
with normal ovulatory cycles." (JTX4 at Abstract; id. at 276 (describing 1 mg dose as ''the
threshold dose" for ovulation inhibition)) However, because"[ o]ral contraceptives usually
contain double the determined ovulation inhibitory dose of the progestin," Moore
"recommended" using "dienogest 2.0 mg." (Id. at 277; see also Simon Tr. at 130 (explaining
that, as typical rule of thumb, person having ordinary skill in art would dose progestin in COC at
double the dose of progestin that has been shown to inhibit ovulation))
90.
Moore explained that "the ovulation inhibitory effects of dienogest are directly
related to the dose received." (JTX4 at 277) Moore further reported that "dienogest was well
tolerated" up to 2 mg. (Id. ) In the tested doses of DNG from 0.5 mg to 2 mg, "dienogest alone
improved menstrual complaints and shortened the duration of progestin withdrawal bleeding in a
dose-dependent manner." (Id.)
5.
Valette® and other prior art products
91.
Consistent with the teachings of Moore and Oettel, a prior-art product known as
Valette® was marketed in Europe, containing 2 mg DNG in conjunction with 0.03 mg EE.
(JTXl 73 at 534 ("Dienogest in combination with ethinyl estradiol (2 mg dienogest and 0.03 mg
26
ethinyl estradiol/day over 21 days) has been on the market in Germany as an oral contraceptive
since March 1995."); Simon Tr. at 136-37)
92.
Only four marketed drugs (and their generic equivalents where available) -
Natazia®, Valette®, Climodien® (a hormone replacement therapy), and Visanne® (a treatment
for pelvic pain associated with endometriosis) - contain DNG, and only two of those are COCs :
Natazia® and Valette®. (Holtz Tr. at 333) Other than Natazia®, every other drug containing
DNG has a maximum daily dose of 2 mg. (Simon Tr. at 192; Holtz Tr. at 335-36)
6.
Gast application
93 .
The Gast application, W098/04268, specifies a range of 0.25 mg to 4 mg daily
DNG doses for use with EE. (JTX201 at 8; see also Simon Tr. at 269) The preferred regimens
described in the Gast application' s examples have a daily dose of 500 µg (i.e., 0.5 mg) to 1 mg
DNG per day. (JTX201 at 1O Simon Tr. at 186-87)
;
94.
The Gast application, which is prior art, does not disclose any clinical data.
(Simon Tr. at 269-70)
7.
Graser article
95 .
A prior art article by Graser, published in 2000, studied the ratio of atrophic to
proliferative endometrial material in post-menopausal women to determine the optimal DNG
dose for producing an atrophic endometrium and a favorable bleeding profile. (JTX225) Graser
compared combinations of2 mg EV with DNG doses of0.5 mg, 1mg, 2 mg, 3 mg, and 4 mg for
use in continuous-combined hormone replacement therapy. (Id. )
96.
Graser found that "the two lowest dosages of dienogest evaluated in this study
(0.5 and 1.0 mg) are unsuitable for use in a continuous-combined therapy for the treatment of
27
postmenopausal women." (Id. at 259) The 2, 3, and 4 mg doses were suitable with this
population for this purpose. (Id.)
97.
Graser further concluded that the "most favourable bleeding profile was seen in
the 3.0 mg dienogest group." (JTX225 at Abstract)
98.
Relying in part on Graser, Watson ' s Dr. Simon opined that the prior art taught that
2 mg and 3 mg doses ofDNG were well tolerated without any dose dependent side effects.
(Simon Tr. at 147) Dr. Simon explained Graser' s conclusion that there was "no
dose-dependency in terms of adverse events," and that 2 mg and 3 mg DNG "are the optimal
doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone
replacement therapy." (Simon Tr. at 148-49)
99.
Bayer's Dr. Allen testified that the Graser article ' s conclusions cannot be applied
to pre-menopausal women - i.e., those women who can become pregnant and who may choose to
use a COC - because they are a different patient population. (Allen Tr. at 607-09)
8.
Endrikat article
100.
In a 2003 article in the prior art, Endrikat - a co-inventor on the ' 577 patent -
published a meta-analysis of clinical trials, assessing the correlation between higher degrees of
ovarian suppression and cycle control. (JTX12; Simon Tr. at 144) For purposes of his
publication, Endrikat considered the first three Hoogland categories "as indicative of sufficient
ovarian suppression." (JTX 12 at 109)
101.
Based on his analysis, Endrikat concluded that "higher ovarian suppression
measured by the Hoogland Score is correlated with improved cycle control." (Id. at 112) He
further concluded that contraceptive "formulations with higher ovarian suppression are expected
28
to provide less intermenstrual bleeding." (Id.)
102.
Consistent with his publication, Endrikat, told the PTO in a declaration:
"According to the knowledge at the filing date, a person of ordinary skill in the art would
consider the absolute amount of 4 mg of dienogest in Regimen 2C clinically tolerable in young
women, as the examiner alleges." (JTX20 at 5; Simon Tr. at 147-48)
J.
Estrogen Dominance
103.
Bayer' s expert, Dr. Barnhart, testified credibly and persuasively that "estrogen
dominance" was an important concept in the prior art, and, accordingly, at the date of the ' 577
patent' s invention a POSA would have believed that an effective COC had to be estrogen
dominant. He explained that estrogen dominance refers to the competition between the
proliferative effect of estrogen in a COC- which increases the uterine lining' s thickness - and the
anti proliferative effect of progestins in a COC - which stops the proliferation of the uterine
lining. (Barnhart Tr. at 410)
104.
An estrogen dominant pill has sufficient estrogen relative to progestin to promote
proliferation of the uterine lining. (Id.) Estrogen dominance is important during the proliferative
phase (of the endometrius) of a cycle - that is, the first seven to nine days or so of a cycle - when
the daily dose of EV should exceed the daily dose ofDNG. (Id. at 414-15)
105 .
Dr. Barnhart identified support for the estrogen dominance theory in the Hoffman
Articles discussing the pilot study of the Dittgen Regimen (id. at 499-501), which states:
Bearing in mind that sequential preparations are known to improve
cycle stability in women complaining of bleeding irregularities, our
efforts were directed at designing a sequential 28-day regime. To
ensure estrogen dominance in the first cycle phase, le., the stage
at which the endometrial proliferation is promoted under
estrogen influence, 17B-estradiol valerate was given on days 1-25
29
of the menstrual cycle at doses stepped from 3 mg to 1 mg.
Basically, the shortening of the hormone-free interval to only 3
cycle days and the prolongation of the estrogen phase at the end of
the progestin phase were expected to increase the cycle stability of
the ethinylestradiol-free combination considerably.
(JTX3 at 108 (emphasis added) ; JTX2 at 460)
106.
Hoffmann' s development of an estrogen dominant regimen with EV and DNG
appeared to solve the cycle control problem that had caused the failure of every other prior effort
to develop a natural estrogen COC. (Barnhart Tr. at 411)
107.
Hoffmann and his colleagues, including Dittgen, wrote similarly in the Dittgen
patents and applications, stating:
In the combination preparation according to the invention the
estrogen-gestogen balance is shifted largely in favor of the
estrogen ingredient and in a predetermined stage the gestogen is
completely eliminated from the daily dosage. Furthermore this
regimen allows an extremely high estrogen daily dosage (more than
4 mg estradiol equivalents/day).
(E.g. , JTX19 at 4:8-13) (emphasis added)
108.
Dr. Barnhart testified that a POSA would understand Hoffmann' s teachings about
the significance of estrogen dominance and its importance to the cycle control success of the 1
mg/2 mg DNG regimen. (Barnhart Tr. at 411 , 417) Dr. Barnhart went on to testify that a POSA
would recognize that making the change from 1 mg/2 mg ofDNG to higher doses ofDNG (such
as Natazia®' s 2 mg/3 mg doses) would significantly reduce and eliminate the key estrogen
dominance during the early proliferative phase. (Barnhart Tr. at 417-18) He further testified that
a POSA would not believe that Natazia® was reasonably likely to succeed in maintaining
sufficient cycle control because of its lack of estrogen dominance. (Id. )
109.
As further support for his opinion that a POSA would have believed estrogen
30
dominance was necessary for an effective COC, Dr. Barnhart pointed to the Graser 2000 paper.
(Id. at 529-30) Dr. Graser's article on the treatment of menopause with EV and DNG describes
the countervailing proliferative and antiproliferative influences of EV and DNG, respectively, at
different doses. (JTX225) Although Bayer's Dr. Allen testified that Graser is irrelevant to
contraception because it deals with hormone replacement therapy ("HRT") (Allen Tr. at 607-09),
it does show specific pharmacological interactions of EV and DNG at different doses, and the
concepts of estrogen or progestin being "dominant" as measured (at least in part) by their relative
weight amounts in a daily dose (Barnhart Tr. at 529).
110.
Graser found that, in combination with 2 mg EV:
The prevalence of proliferat~ve material and atrophic endometrium
indicated that the two lowest dosages of dienogest evaluated in this
study (0.5 and 1.0 mg) are unsuitable for use in a
continuous-combined therapy for the treatment of postmenopausal
women. The ratio of atrophic to proliferative material was 0.7 and
1.0, respectively, in the 0.5 and 1.0 mg dosage groups
demonstrating a lack of clinical efficacy at these dosages.
Conversely, the 3.0 and 4.0 mg doses of dienogest are both suitable
with atrophic:proliferative material ratios of 5.0 and 6.0,
respectively. The 2.0 mg dienogest dose is also appropriate for use
in continuous-combined HRT. The atrophic:proliferative ratio was
2.0 in this group, however, the high prevalence of nonassessable
and unavailable biopsies in this group meant that this ratio was
based on data from only 6 patients rather than 10-14 patients in the
other dosage groups.
(JTX225 at 259)
111.
Applying Graser' s findings to this case (to the extent relevant) is complicated by
the fact that Graser reports results in the form ofDNG:EV ratios, the opposite of the EV:DNG
ratios the parties and the Court have used here. (Relatedly, Graser reports the
atrophic:proliferative ratio - i.e. , breaking down:building up ratio - whereas the Court is
31
discussing its analysis in the form of proliferative: atrophic ratios, consistent with the course of a
menstrual cycle, which is characterized by the building up and later breaking down of the
endometrius.) "Translating" Graser' s results to the EV:DNG ratio used throughout this Opinion
shows the following:
Table 6. Translating Graser
Amt. EV
Amt. DNG
Atrophic:
Proliferative
Ratio
Proliferative: HRT
Suitable?
Atrophic
Ratio
Dom- EV:DNG
lilRatio
ant?
2mg
.5mg
0.7 (0.711]
1.43 (1 /0.7]
NO
Estr .
4:1
2mg
1 mg
1.0 [111]
1.0 (1 11 ]
NO
Estr.
2:1
2mg
2mg
2.0 (2/1]
0.5 [Yi ]
YES
Prog. 1:1
2mg
3mg
5.0 (5/1]
0.2 (115]
YES
Prog. 2:3
2mg
4mg
6.0 (611]
0.17 (1 /6]
YES
Prog. 1:2
112.
As Dr. Barnhart admitted, the Hoffmann paper does not compare the weights of
EV and DNG; nor does it calculate ratios between them. (Barnhart Tr. at 492) Neither the
Dittgen patent specification nor the claims of the '251 or '793 Dittgen patents recites ratios of
EV:DNG either. (JTX 14; JTX19)
113.
The ' 577 patent is silent on whether estrogen or progestin are dominant in its
examples or claims. (JTXl )
114.
However, a person of skill in the art could "do the math" and calculate the ratios
of estrogen and progestin, based on daily dose weights, even if those ratios are not expressly
disclosed in a reference. (See Barnhart Tr. at 493 , 501-02, 527)
115.
None of Endrikat' s three declarations discusses estrogen "dominance" in the first
32
phase of a cycle (or at any other point). (See JTX20 ("First Endrikat Declaration") at 1-7;
JTX265 ("Second Endrikat Declaration") at 1523 ; id. at 2172 ("Third Endrikat Declaration"))
The First Endrikat Declaration does discuss the putative importance of ratios of
estrogen:progestin, but does not identify the important part of the regimen for calculating ratios
as the first phase; rather, the First Endrikat Declaration indicates that the important point is the
second phase, the days in the middle of the regimen - i.e., days 8 to 23 ofDittgen. (JTX20 at 6,
10-16) In the Second Endrikat Declaration, Endrikat corrected his assertion about the
importance of a particular ratio in the second phase to the decision to further investigate a
particular regimen. (JTX265 (' 577 File History) at 1523) The Third Endrikat Declaration says
nothing about ratios at all. (Id. at 2172)
116.
Watson' s Dr. Simon acknowledged that it is the estrogen component of the COC
that acts to provide cycle control. (Simon Tr. at 112) He further admitted that early efforts to
develop a natural estrogen COC failed because of failures of cycle control. (Simon Tr. at 242)
117.
The Natazia® regimen-which is the regimen of the asserted claims of the ' 577
patent - is not as estrogen dominant in the proliferative phase of the menstrual cycle as the
Dittgen Regimen. (Barnhart Tr. at 417) Compared to the Dittgen Regimen (1 mg/2 mg DNG),
the Natazia® regimen: (i) shortens the initial EV-only stage from three days to two days;
(ii) doubles the DNG dose (from 1 mg to 2 mg) during the subsequent, longer, first group of
Phase 2, resulting in five days of an equal 2:2 mg EV:DNG ratio compared with Dittgen' s four
days of2:1 mg EV:DNG ratio in that same stage; and (iii) lengthens the second group of Phase 2
(to 17 days), a stage in which Natazia® doses DNG at 50% greater weight than EV, for a 2:3 mg
EV:DNG ratio, compared to Dittgen's 16 days of equal 2:2 mg EV:DNG.
33
118.
Other illustrations that the Natazia® regimen is not as estrogen dominant as the
Dittgen Regimen include: (i) during each of the first seven days of a cycle with the Dittgen
Regimen, a woman takes more EV than DNG, whereas with Natazia® a woman takes more EV
than DNG for only the first two of the first seven days; (ii) during the first seven days of a cycle
with the Dittgen Regimen, a woman takes 17 mg of EV and 4 mg of DNG, whereas with
N atazia® a woman takes 16 mg of EV and 10 mg of DN G during the first seven days of a cycle;
(iii) over an entire cycle on the Dittgen Regimen, the total amount of EV:DNG is 51:36 mg,
whereas over an entire cycle on the Natazia® regimen the total amount of EV:DNG is 52:61 mg;
and (iv) while a woman on the Dittgen Regimen never takes a greater amount ofDNG than the
amount of EV she is taking on the same day, with the Natazia® regimen a woman takes a greater
amount of DNG than EV on 17 out of 28 days of a cycle.
119.
Neither Dr. Simon nor any other Watson witness provided any persuasive
testimony or evidence in rebuttal to Dr. Bamhart' s opinions on the issue of estrogen dominance,
its significance to the success of the 1 mg/2 mg DNG regimen described in the Hoffmann
Articles, the lack of estrogen dominance in Natazia® relative to the 1 mg/2 mg DNG regimen, or
how a person of ordinary skill in April 2004 would find no reasonable expectation of success for
the Natazia® regimen based on its lack of estrogen dominance.
K.
Long-Felt But Unmet Need
120.
Bayer established that Natazia® fulfilled a long-felt unmet need for an oral
contraceptive with natural estrogen, given that previous attempts had failed due to unacceptable
bleeding problems. (See generally Barnhart Tr. at 420)
121.
Persons of ordinary skill have been trying since the 1970' s to develop a natural
34
estrogen COC. (Id. at 434)
122.
Natazia® was launched in Europe under the name "Qlaira®" in May 2009 and in
the United States in July 2010. (Holtz Tr. at 329) Natazia® was the first, and remains the only,
natural estrogen COC in the United States. Natazia® was also the first natural estrogen COC
approved anywhere in the world for use in all healthy women. (JTX265 at 1313-14; Holtz Tr. at
330; Barnhart Tr. at 434)
1.
Early Failures of Others
123 .
Early regimens using natural estrogen suffered from poor cycle control. (JTX2 at
460; JTX3 at 108 ; JTX169 at 619; JTXl 74 at 471 ; JTXl 76 at 458 ; JTXl 77 at 543 ; JTXl 78 at 9;
Simon Tr. at 114-15; Barnhart Tr. at 436-37)
124.
For instance, in 1979, Serup reported efforts to substitute natural estrogen (in the
form of estradiol and estriol) for synthetic estrogen in COCs, based on a view that "natural
oestrogens may be safer." (JTXl 74 at 471 ) Although the natural estrogen COC provided
adequate contraceptive efficacy, Serup reported that because of the "high frequency of bleeding
irregularities the natural oestrogen pill we investigated is not acceptable for general use. "
(JTXl 74 at 471 )
125.
In 1980, Koetsawang similarly reported that a natural estrogen pill was of"high
efficacy" but that the "high incidence of menstrual problems associated with the combination of
' natural ' estrogens and norethisterone acetate make it much less suitable for general use in family
planning programmes than combinations containing synthetic estrogens." (JTXl 76 at 458)
126.
In 1987, Schubert tested a natural estrogen pill utilizing estradiol cyclo-octyl
acetate with a progestin and found that, consistent with past experiments, "follicular hormonal
35
activity and ovulation was inhibited by this combination," yet "[b]leeding control was, however
unacceptable in all volunteers." (JTXl 77 at 543)
127.
In 1993, Wenzl tried to develop a natural estrogen pill utilizing micronized
estradiol together with the progestin desogestrel, but found that despite providing "complete
ovulation inhibition," the "bleeding pattern does not show an acceptable profile." (JTX169 at
616) Wenzl hypothesized: "This most probably is due to the progestogen dominance of the
combination." (JTX169 at 619; see also Barnhart Tr. at 411-12)
2.
Failure of the Dittgen Regimen
128.
As recommended by Hoffmann, the Dittgen Regimen was tested in a Phase
ill clinical study (known as AZ94). (JTX6) AZ94 was a large scale Phase ill clinical trial
enrolling approximately 1,800 women for a planned 20-cycle study. (Id. at 2; Allen Tr. at 578)
129.
The AZ94 study was stopped after only 14 cycles because of an unexpectedly high
number of pregnancies. (JTX6 at 2-3) It resulted in an adjusted "Pearl Index" of 4.3 (reflecting
the number of pregnancies per hundred woman-years not due to subject failures) and an
unadjusted Pearl Index of 5.3 (including subject failures). (Id. at 2-3 ; Allen Tr. at 567, 578-79,
597)
130.
Bayer' s regulatory expert, Dr. Allen, called the results a "shocking" failure.
(Allen Tr. at 578, 592-93) Based on the Phase II clinical study results found with the Dittgen
Regimen- reported, for instance, in the Hoffman Articles and the Dittgen Declaration (JTX3 at
110; JTX5; JTX19 at 5:20-52, 6:1-27; see also Barnhart Tr. at 386-87)- the FDA would have
expected a Pearl Index for the Dittgen Regimen of less than 2 (Allen Tr. at 579).
131.
Even though it occurred years before the priority date of the ' 577 patent, the
36
failure of AZ94 was known only to Bayer and was not known in the prior art. (Simon Tr. at 164)
3.
Failure of the "Modified Dittgen Regimen"
132.
The Modified Dittgen Regimen is a 2-5-17-2-2 regimen of EV, DNG, and placebo
that uses the 3-2-1 mg EV dosing pattern and 1 mg/2 mg doses ofDNG. (JTXl 1 at 220 Fig. 1)
As an extension of the original Dittgen Regimen, the Modified Dittgen Regimen added one day
of the phase with 2 mg EV and 1 mg DNG (at Day 3, in place of one day of unopposed 3 mg EV
in the Dittgen Regimen), and added one day of the phase with 2 mg EV and 2 mg DNG (at Day
24, extending the end of cycle by one day) . (JTXl 1 at 220 Fig. 1)
133.
The Modified Dittgen Regimen was tested in a Phase II ovulation inhibition study
initiated after the failure of AZ94. (JTX15 ; Allen Tr. at 580-81) This study enrolled 192
women, with 96 women per study arm. (JTX15 at 3)
134.
An Endrikat 2008 article, which is not prior art, describes a Phase II ovulation
inhibition study of the Modified Dittgen Regimen. (JTXl 1) The study used new parameters
Bayer set "to be on the safe side" after the failure of the Dittgen Regimen. (Id. at 223 ; Allen Tr.
at 580-83 , 614) Bayer decided to "consider a Hoogland score of 5 (LUF) to be as critical as a
Hoogland score of 6 (ovulation), since the transition from a persisting FLS into a ruptured FLS
might happen easily in subsequent cycles," and " [a]n ovulation rate of <5%" would be required
"in an effort to be ' on the safe side' before initiating a Phase III clinical trial program." (JTXl 1
at 223)
135.
The ovulation inhibition data showed an ovulation rate of approximately 5-6% for
the Modified Dittgen Regimen. (Allen Tr. at 581 ) The Phase II ovulation inhibition study results
were outside of Bayer' s "safe side" criteria. (JTXl 1 at 223) (showing ovulation/LUF rate of
37
6.38%)
136.
Dr. Simon testified that a person of ordinary skill would have expected that the
extension of the 1 mg/2 mg DNG daily dose by an additional day in the Modified Dittgen
Regimen would have improved ovarian suppression. (Simon Tr. at 244)
137.
Dr. Allen testified that without the shocking failure of the lmg/2mg DNG doses
of the Dittgen Regimen in the Phase III clinical study AZ94, the Modified Dittgen Regimen
would have been acceptable to take to Phase III trials, without concern, based on its Phase 2
ovulation inhibition results. But with the failure of AZ94, the Modified Dittgen Regimen' s
ovulation inhibition results were deemed a failure and not an acceptable candidate to take into
Phase III trials. (Allen Tr. at 581-82, 614)
L.
Watson's ANDA No. 202349
138.
Watson submitted to the FDA ANDA No. 202349 under the provisions of 21
U.S.C. § 355(j), seeking approval to engage in the commercial manufacture, use, offer for sale,
sale, and/or importation of a generic version of Bayer' s Natazia® tablets. (SUF ii 11 )
139.
Watson has amended its ANDA to include a certification under 21 U.S.C.
§ 355G)(2)(A)(vii)(IV) asserting that, in its opinion, the '577 patent is invalid, unenforceable, or
will not be infringed by the manufacture, use, offer for sale, sale, and/or importation of Watson' s
ANDA product. (Id.
M.
ii 12)
Infringement
140.
The parties have stipulated that the filing of Watson ' s ANDA No. 202349
constitutes an act of infringement of claims 1 through 3 of the ' 577 patent pursuant to 35 U.S.C.
§ 271(e)(2). (Id. ii 13)
38
N.
Expert Witnesses
141.
Dr. James Simon testified at trial as an expert witness in reproductive
endocrinology, gynecology, and contraception, on behalf of Watson. (Simon Tr. at 95-96) Dr.
Simon is a clinical professor of obstetrics and gynecology at George Washington University,
formerly a clinical professor at Georgetown University, and has been a practicing physician for
30 years. (Id. at 88, 90, 92; DTX122) After graduating from medical school, he completed a
post-doctoral fellowship in reproductive endocrinology and infertility. (Simon Tr. at 88, 92) He
has authored hundreds of papers and abstracts in the field of reproductive endocrinology. (Id. at
94-95) Dr. Simon has acted as principal investigator in approximately 300 clinical trials
involving women's health care products and reproductive endocrinology, including about a
dozen involving contraceptives. (Id. at 90-91)
142.
Dr. Kurt Barnhart testified as an expert witness in contraception, obstetrics,
gynecology, and reproductive endrocrinology, on behalf of Bayer. (Barnhart Tr. at 365) Dr.
Barnhart is a professor of obstetrics, gynecology, and epidemiology at the University of
Pennsylvania, and the Vice Chair for the Department of Obstetrics and Gynecology for Clinical
Research at the same institution. He has a medical degree as well as a Master of Science in
Clinical Epidemiology. (Id. at 358-60) Dr. Barnhart has approximately 300 publications and has
been involved in approximately 80 clinical trials in the field of obstetrics and gynecology. (Id. at
361-63)
143 .
Dr. Susan Allen testified as an expert witness on the FDA' s regulatory guidance
and requirements for the development and approval of a combined hormonal contraceptive, on
behalf of Bayer. (Allen Tr. at 560) Dr. Allen has a medical degree and a Master' s Degree in
39
Public Health; she is board certified in Preventative Medicine and Public Health. (Id. at 547-48)
Dr. Allen prac6ced medicine for five years and worked for the FDA for approximately eight
years. (Id. at 548-49) At the FDA, Dr. Allen worked in the Division of Reproductive and
Urologic Drug products (the division responsible for reviewing and approving COCs), ultimately
running the unit as Medical Team Leader. She also worked as the Associate Director of
Scientific and Medical Affairs in the Office of Compliance. (Id. at 549-50)
144.
The Court found each of the witnesses who testified - expert as well as fact
witnesses - to be credible.
0.
Person Having Ordinary Skill in the Art
145.
Dr. Simon explained that the POSA to whom the ' 577 patent is directed would be
a medical doctor who specializes in obstetrics, gynecology, and reproductive endocrinology,
having experience in "clinical development and prescribing hormonal contraceptives." (Simon
Tr. at 151-53) Bayer' s expert, Dr. Barnhart, agreed that a POSA would have at least these
qualifications. (Barnhart Tr. at 366-67) The Court finds that Dr. Simon has appropriately
characterized the POSA.
146.
A POSA would understand that, in order to be marketed, oral contraceptives must
be efficacious in a large and varied patient population, and that it is necessary to dose a progestin
in a way that takes into account individual variability and imperfect user compliance. (Simon Tr.
104-05; Barnhart Tr. at 458-59)
147.
A POSA would understand that a guiding principle in COC development was the
desire to use the lowest effective doses of any hormone to avoid adverse side effects. (Barnhart
40
Tr. at 398 ; Simon Tr. at 171 )4
148.
However, a person having ordinary skill in the art would not have thought there
were significant safety concerns associated with DNG or other progestins. (Simon Tr. at 113-14
("[T]here were large studies on progestin only oral contraceptives which did not show risks of
blood clotting or the downstream sequelae heart attacks, et cetera."); id. at 147-48; Allen Tr. at
604 ("[Based on] information that was publicly available prior to April of 2004 . . . I don' t recall
there being any significant safety concerns with dienogest, correct"); JTX20 at 5 (First Endrikat
Declaration during prosecution of' 577 patent: "According to the knowledge at the filing date, a
person of ordinary skill in the art would consider the absolute amount of 4 mg of dienogest in
Regimen 2C clinically tolerable in young women, as the examiner alleges."); Barnhart Tr. at 479
(agreeing that prior art did not suggest that DNG doses over 2 mg are dangerous or ineffective))
4
For example, a prior art article by Spona published in 1987 explained:
The aim of this research work was to develop new contraceptives
which contained the lowest possible dose of estrogen and
progestagen. This is in accordance with a recommendation which
was issued by the World Health Organization as early as 1978 with
the objective in mind to keep side effects on the parameters of the
hemostatic system and of metabolic functions as low as possible.
(JTX136 at 185 (citing JTX133 (World Health Organization report)); see also JTXl 73 at 51 8
(Oettel 1995 article stating: " [T]he aims of subsequent research [include :] to find the lowest
combined total dose of each steroid to inhibit ovulation and to prevent bleeding pattern
irregularities in the hope ofreducing the possibility of major complications . . . ."); JTX134 at 4
(FDA labeling guidance : "For any particular estrogen/progestin combination, the recommended
dosage regimen is that which contains the least amount of estrogen and progestin that is
compatible with a low pregnancy rate and the medical needs of the individual patient."))
41
LEGAL STAND ARDS
I.
Presumption of Validity
An issued patent is presumed to be valid. See 35 U.S.C. § 282. Therefore, to invalidate a
patent, a party must carry its burden of proof by "clear and convincing evidence." See Otsuka
Pharm. Co., Ltd. v. Sandoz, Inc. , 678 F.3d 1280, 1289-90 (Fed. Cir. 2012) (obviousness-type
double patenting); Procter & Gamble Co. v. Teva Pharm. USA, Inc. , 566 F.3d 989, 994 (Fed.
Cir. 2009) (obviousness). Clear and convincing evidence is evidence that "proves in the mind of
the trier of fact an abiding conviction that the truth of [the] factual contentions [is] highly
probable." Intel Corp. v. ITC, 946 F.2d 821 , 830 (Fed. Cir. 1991) (internal quotation marks
omitted; first modification in original). A defendant' s burden to prove invalidity is "especially
difficult when the prior art [on which it relies] was before the PTO examiner during prosecution
of the application." Hewlett-Packard Co. v. Bausch & Lamb Inc. , 909 F.2d 1464, 1467 (Fed. Cir.
1990).
II.
Obviousness Type Double Patenting
Under the doctrine of obviousness-type double patenting, a party is prohibited "from
obtaining an extension of the right to exclude through claims in a later patent that are not
patentably distinct from claims in a commonly owned earlier patent." Eli Lilly & Co. v. Barr
Labs. , Inc., 251F.3d955 , 967 (Fed. Cir. 2001). "[T]he fundamental reason for [this] rule is to
prevent unjustified timewise extension of the right to exclude granted by a patent no matter how
the extension is brought about." Id. at 968 (internal citation and quotation marks omitted). The
doctrine thus "ensures that the public gets the benefit of the invention after the original period of
monopoly expires," Abbvie Inc. v. Mathilda & Terence Kennedy Inst. Rheumatology Trust, 764
42
F.3d 1366, 1373 (Fed. Cir. 2014), and also "prevent[s] multiple infringement suits by different
assignees asserting essentially the same patented invention," In re Hubbell, 709 F.3d 1140, 1145
(Fed. Cir. 2013) .
The double patenting inquiry consists of two steps. "First, the court construes the
claim[s] in the earlier patent and the claim[s] in the later patent and determines the differences.
Second, the court determines whether those differences render the claims patentably distinct."
Abbvie, 764 F.3d at 1374 (internal citation and quotation marks omitted); see also Eli Lilly & Co.
v. Teva Parenteral Med., Inc., 689 F.3d 1368, 1377 (Fed. Cir. 2012) (applying two-step analysis).
At step two, to be "patentably distinct" and valid a claim must not be obvious over or anticipated
by an earlier claim by the same inventor. Abbvie, 764 F.3d at 1374. "The focus of the
obviousness-type double patenting doctrine thus rests on preventing a patentee from claiming an
obvious variant of what it has previously claimed, not what it has previously disclosed." Eli Lilly
v. Teva, 689 F.3d at 1379 (emphasis in original).
Whether or not a patent is invalid due to double patenting is a question of law. See In re
Hubbell, 709 F.3d at 1145 .
Ill.
Obviousness
A patent may not issue "if 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(a). Obviousness is a question of law based on
underlying factual findings concerning: (1) the scope and content of the prior art; (2) the
differences between the claims and the prior art; (3) the level of ordinary skill in the art; and
43
(4) objective considerations of nonobviousness. See Graham v. John Deere Co. , 383 U.S. 1,
17-18 ( 1966).
To prove that a patent is obvious, a party must demonstrate "that a skilled artisan would
have had reason to combine the teaching of the prior art references to achieve the claimed
invention, and that the skilled artisan would have had a reasonable expectation of success from
doing so." In re Cyclobenzaprine, 676 F.3d 1063, 1069 (Fed. Cir. 2012) (internal citation and
quotation marks omitted); see also Amgen, Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340,
1362 (Fed. Cir. 2009) ("An obviousness determination requires that a skilled artisan would have
perceived a reasonable expectation of success in making the invention in light of the prior art.").
While an analysis of any teaching, suggestion, or motivation to combine known elements is
useful to an obviousness analysis, the overall obviousness inquiry must be expansive and
flexible. See KSR Int '! Co. v. Teleflex, Inc. , 550 U.S . 398, 415, 419 (2007).
The use of hindsight is not permitted when determining whether a claim would have been
obvious to one having ordinary skill in the art. See id. at 421 (cautioning against "the distortion
caused by hindsight bias" and obviousness "arguments reliant upon ex post reasoning"). To
protect against the improper use of hindsight when assessing obviousness, the Court is required
to consider objective (or "secondary") considerations of non-obviousness, such as commercial
success, failure of others, unexpected results, and long-felt but unmet need. See, e.g., Leo
Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013). Secondary considerations
"may often be the most probative and cogent evidence in the record" relating to obviousness.
Stratoflex, Inc. v. Aeroquip Corp. , 713 F.2d 1530, 1538 (Fed. Cir. 1983).
44
DISCUSSION
Watson contends that the ' 577 patent is invalid due to obviousness type double patenting
as well as obviousness. The starting point for the double patenting analysis is claim 1 of the ' 793
patent, while the starting point for the obviousness analysis is New Claim 15. (See D.I. 138
(Watson' s Post-Trial Reply Brief) ("RB") at 6) As noted above, for both obviousness type
double patenting and obviousness, the burden is on Watson to prove invalidity by clear and
convincing evidence. See Otsuka , 678 F.3d at 1289-90; Procter & Gamble Co. , 566 F.3d at 994.
As explained below, the Court concludes that Watson has failed to meet its burden.
I.
The Double Patenting and Obviousness Analyses Will Be Undertaken Separately
Bayer argues that, in the circumstances presented here, the obviousness type double
patenting ("OTDP" or "double patenting") analysis and the obviousness analysis collapse into a
single inquiry. Bayer contends this is so because "[t]he statutory prior art for § 103
[obviousness] in this case includes the ' 793 Patent's Prosecution History (called the ' 915
Application) and its 'New Claim 15,' as well as the ' 793 Patent' s parent, the ' 251 Patent, all
three of which share the same specification . .. [, and] therefore encompasses all of the teachings
of Claim 1 of the ' 793 patent." (D.I. 141 (Bayer' s Post-Trial Answering Brief) ("AB") at 4) As
Bayer observes, the parties agree that " [t]he only difference between New Claim 15 [the primary
statutory prior art reference for obviousness] and Claim 1 of the ' 793 Patent [the basis for OTDP]
is that the latter has a limitation requiring that the second DNG dose must be 1.5-3x the first
dose," although this dosing requirement is also found in the ' 793 patent's specification, which
45
refers to it as "advantageous." (AB at 4 n.2; RB at 7 n.3) 5
By contrast, Watson urges the Court to undertake separate OTDP and obviousness
analyses, for several reasons. First, the starting point for the OTDP analysis here - claim 1 of the
' 793 patent - is not found in the prior art. (RB at 3) Second, while all of the prior art on which
Watson bases its obviousness analysis was before the PTO Examiner, claim 1 of the ' 793 patent
was not before the Examiner, suggesting it should be easier for Watson to prevail on double
patenting. See Hewlett-Packard Co. v. Bausch & Lomb Inc. , 909 F.2d 1464, 1467 (Fed. Cir.
1990) (explaining that defendant' s "burden is especially difficult when the prior art was before
the PTO Examiner during prosecution of the application"), claim 1 of the ' 793 patent was not
before the Examiner, suggesting it should be easier for Watson to prevail on double patenting.
Finally, Watson contends that while in an obviousness context the Court must consider whether a
POSA might have been motivated to modify aspects of a prior art reference that are common as
between the prior art and the patent-in-suit, an OTDP analysis is limited to consideration of the
5
None of the cases cited by Bayer stand for the proposition that obviousness and OTDP collapse
into a single inquiry when the prior art encompasses the teachings of the double patenting
reference yet that double patenting reference itself is not prior art. See, e.g., Ex parte Yokogawa ,
1999 WL 33220561 , at *2 (B.P.A.I. Feb. 11 , 1999) (" [I]n the case before us, the underlying U.S.
Patent 5,478,936 constitutes prior art ... ."); Eli Lilly & Co. v. Zenith Goldfine Pharm., Inc., 364
F. Supp. 2d 820, 910-11 (S.D. Ind. 2005), aff'd, 471F.3d1369 (Fed. Cir. 2006) ("Where the
reference patent is prior art, as in this case, the analysis for obviousness-type double patenting
and obviousness under § 103 certainly begin the same way.") ; see also Sun Pharmaceutical
Industries, Ltd. v. Eli Lily & Co., 625 F.3d 719, 721 (Fed. Cir. 2010) (Newman, J. , dissenting
from denial ofreh' g en bane) ("A double patenting analysis occurs only when the earlier patent is
not prior art against the later patent."). In re Ornitz, 376 F.2d 330, 334 (C.C.P.A. 1967), merely
explains that "[w]here it is possible to conduct the broader inquiry permitted by sections 102(e)
and 103 because the references are 'prior art,' it does not make sense to resort to the narrower
inquiry which underlies a ' double patenting' rejection." From this it does not follow that an
OTDP analysis is always narrower than an obviousness analysis, particularly where (as here) the
OTDP reference patent is not prior art.
46
differences between the reference patent and the patent-in-suit. Here, then, according to Watson,
the Court must assume that everything in common between claim 1 of the ' 793 patent and the
claims of the '5 77 patent are fixed and that a POSA would not consider modifying any of those
commonalities. See generally Eli Lilly v. Teva, 689 F.3d at 1377 (finding no error in district
court consideration of compounds as a whole and whether one of skill would be motivated to
modify compound in reference patent).
Because the Court concludes that Watson has failed to meet its burden even if the OTDP
analysis should proceed in the manner proposed by Watson, the Court need not decide if the law
compels the separate analysis being undertaken here. The Court merely assumes, arguendo, that
separate analyses are required. See generally Otsuka, 678 F.3d at 1297 ("Otsuka contends that
there is no difference between obviousness under § 103 and obviousness-type double patenting.
That is not entirely correct. ... Important differences remain .. .. [For example,] [t]he patent
principally underlying the double patenting rejection need not be prior art.") (internal citations
omitted).
II.
The Claims of the '577 Patent Are Not Invalid for Double Patenting
Watson's double patenting position is based on a comparison between the asserted claims
of the ' 577 patent and claim 1 of the ' 793 patent. Watson contends that the asserted claims of the
' 577 patent are invalid as obvious over claim 1 of the ' 793 patent. According to Watson, the
asserted claims are prima facie obvious because the whole regimen of EV and DNG in the ' 577
patent was already claimed in the ' 793 patent, and the specific doses of EV and DNG came
straight out of the prior art ranges taught to be effective. Watson further contends that Bayer
cannot overcome prima facie obviousness through secondary considerations.
47
As already noted, the double patenting analysis consists of two steps. "First, the court
construes the claim[s] in the earlier patent and the claim[s] in the later patent and determines the
differences. Second, the court determines whether those differences render the claims patentably
distinct." Abbvie, 764 F.3d at 1374 (internal citation and quotation marks omitted). The Court
now undertakes these two steps.
A.
Differences between '793 patent claim 1 and '577 patent claims
The first step in the double patenting analysis is to determine the differences between the
claims of the patent-in-suit, the ' 577 patent, and the claim of the earlier patent, which here is
claim 1 of the ' 793 patent. In assessing those differences, the Court will apply the claim
constructions it adopted earlier in this case.
Claim 1 of the '577 patent claims a "multiphase product for contraception," while claim 2
claims an identical "multiphase oral contraception product" (emphasis added), each comprising:
a first phase of2 daily [oral] dosage units, each comprising 3 mg of
estradiol valerate,
a second phase of 2 groups of daily [oral] dosage units, a first
group comprising 5 daily [oral] dosage units, each of which
comprises 2 mg of estradiol valerate and 2 mg of dienogest, and a
second group comprising 17 daily [oral] dosage units, each of
which comprises 2 mg of estradiol valerate and 3 mg of dienogest;
a third phase of2 ... [6][oral] daily dosage units, each comprising 1
mg of estradiol valerate, and
a fourth phase of 2 daily [oral] dosage units, each comprising a
pharmaceutically acceptable placebo.
6
Claim 1 appears to contain a typographical error, as it redundantly states "a third phase of 2 two
daily dosage units" (emphasis added). The Court does not believe this error has any impact on
the analysis.
48
(JTXl at 4:16-41 ) Claim 3 of the ' 577 patent claims the identical regimen, restating it in terms
of a "method of oral contraception comprising orally administering to a woman" the various
"oral dosage unit[s] " containing the same amounts of EV and DNG, during the same days and
phases, as specified in the regimen of claims 1 and 2. (Id. at 4:42-53 ) 7
The Court has construed "multiphase product" to mean "product composed of multiple
sets of dosage units;" "multiphase oral contraception product" to mean "a contraception product
composed of multiple sets of oral dosage units ;" and "phase" to mean "a set of dosage units."
(D.I. 99; D.I. 111 ) "Daily dosage units" and "daily oral dosage units" are afforded their plain and
ordinary meaning. The Court further concluded that claims 1 and 2 "describe only the physical
composition of the claimed drug products." (D.I. 99 at 13-14 n.8)
Claim 1 of the ' 793 patent claims :
A combination preparation for contraception comprising
a first stage consisting of two daily dosage portions, each
consisting of an effective amount of estradiol valerate;
a second stage consisting of a first group and a second group of
daily dosage portions of a combination of said estradiol valerate
and dionogest;
a third stage consisting of two daily dosage portions, each
consisting of an effective amount of said estradiol valerate,
wherein said effective amount of said estradiol valerate in each of
said two daily dosage portions in said third stage is the same, but
smaller than said effective amount of said estradiol valerate in each
of said two daily dosage portions in said first stage; and
an additional stage consisting of two daily dosage portions, each
consisting of a pharmaceutically acceptable placebo;
7
Neither Bayer nor Watson contends there is any material difference among claims 1, 2, and 3 of
the ' 577 patent for purposes of the Court' s analysis.
49
wherein said first group of said daily dosage portions of said
second stage consists of five of said daily dosage portions of said
combination and wherein said second group of said daily dosage
portions of said second stage consists of seventeen of said daily
dosage portions of said combination; and
wherein respective amounts of said estradiol valerate in each of
said daily dosage portions of said second stage are equal and
respective amounts of said dienogest in said daily dosage portions
of said second group of said second stage are equal to 1.5 to 3
times corresponding amounts of said dienogest in said daily dosage
portions of said first group of said second stage.
(JTX19 at 6:50 - 7:13)
Plainly, much is the same between the claims of the ' 577 patent and claim 1 of the ' 793
patent. Both claim multiphase oral contraception products. The daily dosing pattern is the same
- 2:5 :17:2:2. Both use as their principal ingredients EV, DNG, and a placebo. Both also
generally claim the same combinations of these ingredients: 2 days of just EV, 5 days of EV and
DNG, 17 more days of EV and DNG, 2 days of just EV, and finally 2 days of placebo. (See
Simon Tr. at 124; Barnhart Tr. at 447 (agreeing that multiphasic regimen in ' 577 patent is "exact
same" as in '793 patent)) It is undisputed that the Natazia® regimen falls within the scope of
both the ' 577 patent' s claims and claim 1 of the ' 793 patent. (Barnhart Tr. at 451)
Yet, there are also differences between the claims. Whereas the claims of the ' 577 patent
identify a precise recipe of specific dosages, claim 1 of the ' 793 patent far more broadly claims
an unspecified genus of multiple dosages. See Abbvie, 764 F.3d at 1379 ("It is well-settled that a
narrow species can be non-obvious and patent eligible despite a patent on its genus."). 8 The
8
Bayer complains that ''. Watson improperly focuses on just the dienogest doses of the asserted
claims while excluding consideration of any features the claims have in common with cherrypicked features from the prior art .. . ." (AB at 8) Citing Teva Parenteral Meds. , Inc. , 689 F.3d
at 1377, in which the Federal Circuit stated that in a double patenting analysis "the claims must
50
differences are depicted in the table below:
Table 7. Differences Between '577 Claims and '793 Claim 1
Phase
(' 577 and ' 793
Patents)
Days
(' 577 and ' 793
Patents)
Dose Elements of
' 577 Patent Claims
Dose Elements of
' 793 Patent Claim 1
Phase 1
2 daily doses
3mgEV
Effective amount of
EV
Phase 2, group 1
5 daily doses
2 mg EV and 2 mg
DNG
Combination of EV
andDNG
Phase 2, group 2
17 daily doses
2 mg EV and 3 mg
DNG
Combination of EV
and DNG, with EV in
same amount as
Phase 2, group 1 and
with DNG 1.5 to 3
times more than in
Phase 2, group 1
Phase 3
2 daily doses
1 mg EV
Effective amount of
EV, lower than in
Phase 1
Phase 4
2 daily doses
Placebo
Placebo
The differences between the claims all relate to the breadth of EV and DNG doses they
cover. Claim 1 of the ' 793 patent recites the use of a daily "effective dose" of EV, where the
"effective dose" of EV is less in Phase 3 than in Phase 1 and the amount of EV in Phase 2
relative to the amounts of EV in Phases 1 and 3 is completely unspecified. Claim 1 of the ' 793
be considered as a whole," Bayer insists it is improper to assume that a POSA would keep
constant everything that the '577 patent claims and claim 1 of the '793 patent have in common.
The Court has already assumed, arguendo, that separate OTDP and obviousness analyses are
necessary, and that in connection with the OTDP analysis the commonalities between the
reference patent and the patent-in-suit are to be held constant. In connection with the OTDP
analysis, the Court is considering the claims as a whole and identifies all of the differences
between them.
51
patent also recites a formula for selecting DNG doses, where the dose increases 1.5 to 3 times
from the first to the second group of Phase 2. (JTX19 at claim l ; Simon Tr. at 124-25) The ' 577
patent claims particular doses of EV and DNG: descending doses of EV (3-2-1 mg) from Phase 1
to Phase 3, and ascending doses ofDNG (2-3 mg) in the two groups of Phase 2. (JTXl at claims
1-3) It is undisputed that the EV doses recited in the claims of the '577 patent are "effective"
within the meaning of the ' 793 patent and that the DNG dosages of the ' 577 patent claims "fit"
the formula set forth in the ' 793 patent. (Barnhart Tr. at 454-55)
The differences between the claims can be summarized as follows :
•
while Phase 1 of the '577 patent requires two daily doses of
3 mg EV, Phase 1 of the '793 patent requires two daily
doses of an unspecified "effective amount" of EV;
while Phase 2, group 1 of the ' 577 patent requires five daily
doses of 2 mg EV and 2 mg DNG, Phase 2, group 1 of the
' 793 patent requires five daily doses of an unspecified
"combination" of EV and DNG;
while Phase 2, group 2 of the ' 577 patent requires
seventeen daily doses of2 mg EV and 3 mg DNG, Phase 2,
group 2 of the '793 patent requires 17 daily doses of
unspecified amounts of EV and DNG, where the only limits
on selection of doses are that: (i) EV is the same
unspecified amount as in Phase 2, group 1, and (ii) DNG is
1.5 to 3 times more than the unspecified amount in Phase 2,
group l; and
•
while Phase 3 of the ' 577 patent requires 2 daily doses of 1
mg EV, Phase 3 of the ' 793 patent requires 2 daily doses of
an unspecified "effective amount" of EV, where the only
limit on selection of dose is that the amount of EV be
"smaller than" the unspecified "effective amount" of Phase
1.
B.
The differences render the claims patentably distinct
OTDP "prohibit[s] a party from obtaining an extension of the right to exclude through
52
claims in a later patent that are not patentably distinct from claims in a commonly owned earlier
patent." Barr Labs. , Inc., 251 F.3d at 967. Thus, in the second step of the analysis the Court
must determine if the differences between the claims identified just above are patentably distinct.
In the Court' s view, the differences between the claims of the ' 577 patent and claim 1 of
the ' 793 patent render the respective claims patentably distinct. Although all five of the
differences are of the same general type - differences between unspecified dosages in the ' 793
patent and specified dosages in the '577 patent - they are, in combination, patentably distinct
differences. The Court explains the reasons supporting its conclusion below.
1.
A POSA would have believed estrogen
dominance would be needed for an effective COC
In March 2004, a POSA using the ' 793 patent' s claim 1 as her starting point, and
"locking in" all of the features that are common to that claim and to the claims of the '577 patent,
would have believed that the estrogen component of a COC should "dominate" the progestin
component of the COC during the proliferative phase of a cycle. (See, e.g., Findings of Fact
("FF") ~
102) This is Dr. Barnhart' s theory of "estrogen dominance. " (Id. ) The estrogen
dominance theory posits that the proliferative effect of estrogen must dominate the antiproliferative effect of gestogen during the first seven or so days of a cycle, in order for a COC to
provide good cycle control. 9 (FF ~ 103)
9
Watson argues in its Reply Brief: "Nothing in the claims requires ' cycle control. ' Watson bore
no burden of showing a reasonable expectation in proving an unclaimed effect." (RB at 13) It is
unclear on what basis Watson makes this argument. To the extent it relies on the Court' s claim
construction opinion - which stated "the claims themselves describe only the physical
composition of the claimed drug products, a structurally complete invention" (D.I. 99 at 13-14
n.8 ; D.I. 111 ) - Watson' s contention is unavailing. The parties did not ask the Court to
determine, during claim construction or otherwise, whether cycle control is a limitation of the
claims. At claim construction, in particular, no extrinsic evidence was presented on this point.
53
Bayer relies on the Hoffman Articles ' description of why the Dittgen Regimen' s
sequentially descending EV doses were expected to improve cycle control as compared to other
regimens in which EV was held constant at 2 mg or stepped from 2 mg to 4 mg and back to 2
mg:
Bearing in mind that sequential preparations are known to improve
cycle stability in women complaining of bleeding irregularities, our
efforts were directed at designing a sequential 28-day regime. To
ensure estrogen dominance in the first cycle phase, i.e., the stage
at which the endometrial proliferation is promoted under
estrogen influence, 17jJ-estradiol valerate was given on days 1-25
of the menstrual cycle at doses stepped from 3 mg to 1 mg.
Basically, the shortening of the hormone-free interval to only 3
cycle days and the prolongation of the estrogen phase at the end
of the progestin phase were expected to increase the cycle stability
of the ethinylestradiol-free combination considerably.
(FF if 104) (citing JTX3 at 108; JTX2 at 460 (emphasis added)) As Dr. Barnhart testified,
Hoffman - that is, the Dittgen group - "is telling us the reason that this natural estrogen pill
worked when others had failed was because it was estrogen dominant." (Barnhart Tr. at 441 )
Dr. Simon did not testify to the contrary. 10 Bayer also points to the '915 application' s
explanation that "the estrogen-gestogen balance is shifted largely in favor of the estrogen
ingredient." (JTX19 at 4:9-10)
While the Court rejects Waston' s contention that Dr. Barnhart' s theory of estrogen
By contrast, at trial, there was a great deal of undisputed testimony that a successful COC
requires both contraceptive effect and good cycle control. (See, e.g., FF if 10) The claims of the
'577 patent claim a COC, and a COC requires both of these features. A POSA, thus, would
understand the claims to require effective cycle control. The Court has never been asked to make
a contrary finding and has not done so.
10
The Court is unpersuaded by Watson' s contention that Hoffman' s reference to "estrogen
dominance" refers to the phasic method of administration of estrogen compared to prior-art
regimens.
54
dominance is "factually baseless" and "manufactured" (D .I. 134 (Watson Post-Trial Opening
Brief) ("OB") at 24), the theory is not entirely invulnerable to criticism. At least once Dr.
Barnhart appeared to contradict himself. (Compare Barnhart Tr. at 527 (testifying that one could
infer from Hoffman that "ratio of 1 to 1, 2 to 2 milligrams [i.e., equal daily weights of EV and
DNG] was not progestin dominant") with id. at 416 ("The equal doses, the progestin dose is
actually outweighing the estrogen effect [i.e., equal daily weights of EV and DNG is progestin
dominant). Actually, if you have a higher dose of dienogest compared to estrogen, it' s even more
deeply progestin dominant .... "), 530 (testifying that Graser suggests " [a]t two-to-two [i.e.,
equal daily weights of EV and DNG] it' s progestin dominant")) Even then, however, Dr.
Barnhart consistently explained that any ratio in which the weight amount of EV is greater than
the weight amount ofDNG is estrogen dominant. (Id. at 530 (discussing Graser, in which
applicable ratios are DNG:EV, and explaining that " [a]nything under a two-to-two milligram or
one-to-one ratio is estrogen dominant," meaning that when weight amount ofDNG is less than
weight amount of EV the resulting combination is estrogen dominant))
Also, it is true that Bayer does not point to a great amount of prior art to support Dr.
Barnhart' s opinion. Moreover, the Graser article - which Dr. Barnhart cited on redirect as an
example of prior art supporting his theory of estrogen dominance (see id. at 529) - is not entirely
consistent with Dr. Barnhart' s theory of estrogen dominance. One of the Graser article' s
conclusions was that the ratio of atrophic (progestin-influenced) to proliferative (estrogeninfluenced) endometrial material was one-to-one (neutral) for 1 mg DNG with 2 mg EV (not
estrogen dominant, as Dr. Barnhart concluded), and two-to-one (i.e., not just marginally
progestin dominant or neutral, but progestin dominant by a factor of two) for 2 mg DNG with 2
55
mg EV - although the article provided the caveat that the latter ratio was "based on data from
only 6 patients rather than 10-14 patients in the other dosage groups." (JTX225 at 259)
Watson does not, however, point to these arguable inconsistencies in Dr. Barnhart's
testimony or the conclusion noted just above in Graser. This may be because Graser concerns a
different population (post-menopausal women) and a different goal (hormone replacement) than
the patent-in-suit and the '793 patent, which are directed to development of a natural estrogen
COC for women who can get pregnant. (See, e.g., Barnhart Tr. at 529-30 ("The idea in hormone
replacement therapy is you want to have the progestin dominant, to stop a process that's called
estrogen over growth or hypoplasia, which may lead to cancer. So a minimum dose of progestin
you want to use is the dose that counteracts the effect of estrogen .... ")) 11 Additionally, Graser
is expressly addressing the concept of estrogen and progestin dominance in the context of postmenopausal withdrawal bleeding, which at least supports a finding that issues of estrogendominance and progestin-dominance were topics of interest to those who were studying cycle
control.
There are other reasons the Court finds that Graser is, overall, more supportive of Bayer' s
position than Watson' s. Even in the different population Graser was studying, the study's results
clearly showed that the greater amount ofDNG a woman is given relative to a fixed amount of
EV, the greater the atrophic effect on the uterus, and therefore the greater amount of bleeding
observed. (See, e.g., JTX225 at 256 & Table 2) ("The frequency of uterine bleeding was lowest
11
0ther distinctions between Graser and the claims of the '577 patent are also readily apparent.
For example, Graser did not test a multiphasic regimen, but instead five different "fixed
combination treatment" regimens; that is, each subject of the Graser study was given a fixed
amount ofDNG and EV each day she participated in the study. (See JTX225 at 253)
56
in the 0.5 and highest in the 4.0 mg/day dienogest group (Fig. 1).") These findings are consistent
with the "estrogen dominance" theory which posits that the estrogen must dominate progestin in
order for there to be good cycle control. Graser generally found that the less estrogen dominant a
regimen is, the greater the incidence of uterine bleeding. 12
Ultimately, given that estrogen dominance turns out not to be necessary for good cycle
control in a natural estrogen COC (at least as a POSA would have understood it in March
2004), 13 the amount of evidence Bayer was able to muster in support of this theory is adequate to
persuade the Court that a POSA would have believed in Dr. Barnhart' s theory of estrogen
dominance at the pertinent time. In reaching this conclusion, the Court again emphasizes that
Watson produced no evidence that Dr. Barnhart' s theory of estrogen dominance had been
rejected in the prior art.
In the Court' s view, a POSA ' s belief in the necessity of estrogen dominance means that a
POSA - even one with the ' 793 patent' s claim 1 in hand- would not have reasonably expected
the claims of the ' 577 patent to be successful. The Court agrees with Bayer that '"the Dittgen
12
However, as Watson points out (see D.I. 138 at 27-28), Graser reported the optimal bleeding
profile was found with the 2:3 mg EV:DNG combination, a ratio that Graser found was progestin
dominant. (See JTX225 at 257)
13
At trial, Watson surprised Bayer by presenting as evidence advertising materials from Bayer's
website for Qlaira®, the European trade name for Natazia®. The Qlaira® materials explain that
its regimen (identical to that used in Natazia®) has "[e]strogen dominance in the early part of the
cycle," providing good cycle control. (DTX300 at 3; see also id. at 4 (touting that Qlaira®
regimen is consistent with Hoffman article)) The Court overruled Bayer' s objection to use of
this evidence. (See Tr. at 627-28) While the Qlaira® materials seem to be inconsistent with
Bayer' s characterization ofNatazia® as not being estrogen dominant, the materials are dated
2014- ten years after the pertinent date of 2004 - by which time a POSA' s understanding of
estrogen dominance may well have evolved, for reasons including the success of Qlaira® and
Natazia®.
57
group told the world that ' estrogen dominance ' was a key part of their cycle control solution,"
and while the Dittgen regimen is estrogen dominant in the first cycle phase, the Natazia®
invention is not. (AB at 3) There would, hence, "be no reasonable expectation of cycle control
success" with the ' 577 patent regimen. (Id. )
The assumptions Watson identifies as underlying Bayer' s estrogen dominance theory for instance, that DNG dominates combinations of equal amounts of EV and DNG - are, it is
true, not expressly stated in the prior art. But they are supported by Dr. Bamhart' s opinion, a
qualified expert whose testimony was persuasive and credible. Nor does the fact that the ' 577
patent is silent as to the "estrogen dominance" theory and as to the patent's inconsistency with it,
persuade the Court that a POSA would have failed to understand that the patent is, in fact,
inconsistent with estrogen dominance during the proliferative phase of a cycle.
Because it lacks estrogen dominance during the first cycle phase, a POSA in 2004 would
not have expected the ' 577 regimen to have provided good cycle control. In hindsight, the POSA
would have been wrong. As the '577 patent demonstrates, either estrogen dominance during the
proliferative phase of a cycle is unnecessary, or alternatively what a POSA would have
understood constituted estrogen dominance has turned out to be a mistaken understanding.
Either way, the Court' s finding remains: estrogen dominance would have been thought by a
POSA at the time of the invention of the '5 77 patent to have been necessary to cycle control; a
POSA would have understood that the ' 577 patent does not provide estrogen dominance ; and,
therefore, a POSA would not have been motivated to create the ' 577 patent regimen and would
not have expected it to succeed.
58
2.
A POSA would not have found it obvious
to select the specific doses of the '577 patent
Given a POSA ' s belief that estrogen dominance during the proliferative phase of a cycle
would be necessary for good cycle control, a POSA starting with ' 793 claim 1 would have
expected that the unspecified "effective amounts" of EV in the daily doses of Phase 2, group 1
would need to be greater than the amounts ofDNG. Because, in fact, the EV:DNG ratio in Phase
2, group 1 of the '577 patent's regimen is 2:2 mg, it would not have been obvious to move from
the ' 793 patent' s claim to the '577 patent's claims. Instead, the daily dosage differences between
the respective claims are patentably distinct.
For these reasons, the Court is not persuaded that it would have been obvious to a POSA
in 2004 to "plug in" the 3-2-1 mg descending pattern of EV doses in moving from the regimen of
claim 1 of the ' 793 patent to the claims of the '577 patent. Watson is correct that the prior art set
forth specific examples for dosing EV in a descending 3-2-1 mg pattern in a multiphasic
regimen. Examples 1 and 5 of the ' 251 patent specification described that dosing pattern of EV
and taught that it offered good cycle control. (FF if 45) The Dittgen Regimen also used that
same 3-2-1 mg pattern of descending EV. (FF if 47) And the Court recognizes that both sides '
experts agreed that it would have been obvious to a POSA to select the 3-2-1 mg descending
pattern of EV doses for use in conjunction with the 2-5-17-2-2 dosing pattern set forth in the
' 793 patent's claim 1.
Still, the 3-2-1 mg descending pattern of EV doses, in combination with the increasing
doses ofDNG called for by claim 1 of the ' 793 patent, would not have been entirely obvious to a
POSA in 2004. Notably, the Dittgen Patents and Applications also disclose higher daily dosages
of EV, above the 3 mg EV ofNatazia®. (See JTX19 at 4 ("Furthermore this regimen allows an
59
extremely high estrogen daily dosage (more than 4mg estradiol equivalents/day.")) As Bayer
writes, "[p]ermitting other EV doses exponentially increases the number of options because there
are three phases of EV dosing to relate to two phases ofDNG dosing." (AB at 22) A POSA
starting with the ' 793 patent, then, may very well have believed it would be necessary to increase
the EV daily dose over the fust seven or fourteen days of a cycle. Claim 1 of the ' 793 patent
contains no limitation as to the relative amount of EV between Phase 1 and Phase 2.
At times (at least), Dr. Barnhart' s testimony was consistent with this view, as the
following testimony demonstrates:
Q.
Now, let's say though that you did contrary to what Moore
and the other art teaches, that you did raise the dose of dienogest
like Simon said you should. What would you do to the estradiol
valerate dose in such a situation?
A.
Again, my opinion would be that you wouldn' t raise the
dose [ofDNG] to higher than two [mg], but if you were [to do so] ,
you would recognize the teaching of the estrogen dominance of
Hoffman, and if you needed to go higher in progestin [e.g., DNG] ,
then you should accommodate and go higher on the estrogen so
you could maintain the same biologic ratio and maintain the
estrogen dominance. You wouldn ' t just change the progestin.
(Barnhart Tr. at 422)
Regardless of whether the EV doses in the ' 577 patent are patentably distinct from the EV
doses in the '793 patent claim 1, the Court concludes that the differences between the two
patents ' DNG doses - and the resulting EV:DNG daily dose combinations - are patentably
distinct. No prior art disclosed any example of a dose ofDNG higher than 2 mg for use in a
COC. (FF if 32) As Bayer correctly explains, neither Schmidt-Gollwitzer (JTX210) nor
Kullman (JTX205) disclose regimens with DNG, although they state ranges of possible DNG
doses of 1-3 mg. (AB at 20 n.6) Neither discloses the high overall cycle dosage of 61 mg DNG.
60
(See id.) 14 Gast has a lower range beginning at 250 µg (i.e., 0.25 mg) well below the range that
Watson contends would be obvious to a POSA. (See JTX201 at 8) The Court agrees with Bayer
that "Gast reconfirms what the person of skill in the art would believe - that 2 mg was the
highest DNG dose that should be necessary." (AB at 20) That Gast discloses dosing regimens in
0.25 mg increments also demonstrates that a POSA would have considered a wide variety of
DNG doses, not just the 1-2-3 mg Watson theorizes would be the full range of options
considered.
A POSA would also have understood there was a general preference for minimizing a
woman' s overall dosage of estrogen and progestin. (FF
~
18) In the context of moving from the
'793 patent to the '577 patent, this preference would have proved a challenge for a POSA.
Estrogen dominance would have motivated the POSA to increase the estrogen doses, while the
limitation that the DNG amount in Phase 2, group 2 was to be 1.5 to 3 times greater than the dose
in Phase 2, group 1 would have motivated the POSA to increase the DNG dose. Because claim 1
of the '793 patent does not specify the amount of EV, and because a POSA in possession of the
'793 patent would expect an effective COC to need to be estrogen dominant at least in the
proliferative phase of a cycle, such a POSA would not have found it obvious to select EV:DNG
dose ratios of 2:2 mg and 2:3 mg in Phase 2 of the regirnen. 15
14
The high per cycle DNG dose is also contrary to what a POSA would have expected or
plannned. Natazia® involves 61 mg total DNG, as compared to 18 and 20.25mg for Gast, 36 mg
for the Dittgen Regimen, and 42 mg DNG for Valette® over the course of a cycle. (Simon Tr. at
189-90; see also generally Barnhart Tr. at 491)
15
Watson correctly states that its burden is not to prove that the specific doses of the claims of the
'577 patent are the only doses that would have been obvious to a POSA. Watson need only
prove that these doses would have been among the doses that would have been obvious. See
KSR Int 'l Co. , 550 U.S. at 420 ("One of the ways in which a patent's subject matter can be
61
3.
A POSA would have believed that the Dittgen
Regimen, with lower doses of DNG, solved the
problem of a natural estrogen COC with good cycle control
An additional reason a POSA, starting with claim 1 of the ' 793 patent, would not have
found it obvious to select the daily doses of the ' 577 patent claims - and, thus, another reason the
differences between the daily doses of the former are patentably distinct from the latter - is that a
POSA would have believed the Dittgen Regimen worked. A POSA at that time would have
thought that the Dittgen Regimen - including its Phase 2, in which the EV :DNG ratio favored
estrogen, and not progestin - constituted an effective COC with good cycle control. In fact,
however, the Dittgen Regimen was a failure . This fact contributes to the Court' s conclusion that
the differences in the claims are patentably distinct. 16
The Court agrees with Bayer that "even if Natazia® were an obvious solution to the
efficacy problem the lmg/2mg DNG Dittgen dosing suffered, the prior art did not disclose that
proved obvious is by noting that there existed at the time of invention a known problem for
which there was an obvious solution encompassed by the patent's claims."); OB at 18; see also
Galderma Laboratories, L.P. v. Tolmar, 737 F.3d 731 , 731 (Fed. Cir. 2013) ("Nothing in the
statute or our case law requires [the Defendant] to prove obviousness by starting with a prior art
commercial embodiment and then providing motivation to alter that commercial embodiment.").
While there is evidence that a POSA starting with claim 1 of the '793 patent may have
considered the specific doses of EV and DNG that ended up in the ' 577 patent' s claims, Watson
has not proven that a POSA reading the ' 793 patent would have "at once envisage[d]" every
member of the genus. See Abbvie, 764 F.3d at 1379. More fundamentally, Watson has not, on
the whole, presented clear and convincing evidence that the invention of the ' 577 patent's claims
would have been obvious to a POSA reading claim 1 of the '793 patent.
16
Although Bayer knew that the Dittgen Regimen had failed, this failure was not in the prior art.
Hence, this failure would not have been known to a POSA. While the Court' s OTDP analysis
here requires the Court to contemplate a POSA starting with the '793 patent's claim 1 "in hand"
- even though the ' 793 patent is not prior art to the '577 patent - the Court does not understand
the OTDP analysis also to require it to vest the POSA with all the knowledge Bayer had in its
possession if that knowledge was not also in the prior art.
62
problem." (AB at 11) "Even an obvious solution, however, does not render an invention
obvious ifthe problem solved was previously unknown." Novartis Pharm. Corp. v. Watson
Labs, Inc. , 611 Fed. App ' x 988, 995 (Fed. Cir. 2015); see also id. at 996 ("Although the addition
of an antioxidant would have been an obvious solution for a formulation with known oxidation
problems, here Watson failed to prove that a rivastigmine formulation was known to be
susceptible to oxidative degradation."); see also Leo Pharm. Prods. , 726 F.3d at 1353 ("[A]n
invention can often be the recognition of a problem itself."); id. at 1354 ("The ordinary artisan
would first have needed to recognize the problem, i.e. , that the formulations disclosed in [the
prior art] Dik:stein and Serup were not storage stable . .. . Only after recognizing the existence of
the problem would an artisan then tum to the prior art and attempt to develop a new formulation
for storage stability."); id. at 1357 ("Because the problem was not known, the possible
approaches to solving the problem were not known or finite, and the solution was not
predictable, it would not have been obvious for a person of ordinary skill to make the claimed
invention."); Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1377 (Fed. Cir. 2012) ("Often the
inventive contribution lies in defining the problem in a new revelatory way.").
The data in the Dittgen Declaration, which was in the prior art, showed that the Dittgen
Regimen was 100% effective in preventing ovulation. (FF ii 48) Hoffman, also prior art, further
showed that this regimen successfully prevented pregnancy in 100 women across 573 cycles. (FF
ii 81 )
That Bayer invested the money to go into Phase III trials is further strong evidence that a
POSA would have believed that the Dittgen Regimen was likely to prove to be a successful
63
natural estrogen COC. 17
The Court recognizes that this case does not line up entirely with those that Bayer relies
on because, here, it was not the inventors of the '577 patent that discovered the failure of the
Dittgen Regimen. Still, the fact that this failure was not known in the prior art supports Bayer' s
position and contributes to the Court' s conclusion that Watson has not met its burden of clear
and convincing evidence.
4.
Secondary considerations of non-obviousness support Bayer
Further supporting the Court' s conclusion is the evidence that Bayer presented of
secondary considerations of non-obviousness. Such evidence contributes to the Court' s findings
that Watson has not made a clear and convincing showing of obviousness. See In re
Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Lit. , 676 F.3d 1063, 1075-77
(Fed. Cir. 2012).
"Objective indicia can be the most probative evidence of nonobviousness in the record,
and enables the court to avert the trap of hindsight." Leo Pharm. Prods. , 726 F.3d at 1358
(internal quotation marks omitted); see also Mintz, 679 F.3d at 1378 ("These objective
guideposts are powerful tools for courts faced with the difficult task of avoiding subconscious
reliance on hindsight. . . . These objective criteria thus help turn back the clock and place the
claims in the context that led to their invention."). "For objective evidence [of secondary
considerations] to be accorded substantial weight, its proponent must establish a nexus between
17
Watson contends that because prior art showed that doses ofDNG lower than 2 mg were
"associated with significant follicular growth," a POSA "would have every reason to consider the
appropriateness of higher doses within the prior art' s preferred and limited range." (OB at 13)
The Court disagrees, given the overall highly successful results the Dittgen Regimen had
experienced in the Phase II studies and the decision to take it into Phase ill studies.
64
the evidence and the merits of the claimed invention." Jn re GPAC Inc. , 57 F.3d 1573, 1580
(Fed. Cir. 1995).
Here, Bayer proved long-standing need for a natural estrogen COC and the failure of
others to arrive at the same successful result.
The '577 patent provides a solution to a long-felt but unmet need for a natural estrogen
contraceptive. (See generally FF iii! 118-35) As Bayer puts it, "researchers had spent decades
attempting to create a workable natural estrogen oral contraceptive, because of the possibility that
they would prove to have fewer undesirable and dangerous side effects." (AB at 28) It is
undisputed that Natazia®, which embodies the claims of the '577 patent, is the first and only
natural estrogen COC approved in the United States. (FF if 120)
Bayer has proven that its success with the Natazia® regimen claimed by the ' 577 patent
came only after decades of failed attempts by others to arrive at an effective natural estrogen
COC. Bayer presented a great deal of evidence that years of attempts to make a natural estrogen
COC failed due to inadequate cycle control. (FF iii! 121-25) Although the Dittgen Regimen
purported to have solved the cycle control problem, it, too, failed, due to efficacy concerns when
tested in a Phase III clinical trial. (FF iii! 126-29) The Modified Dittgen Regimen - which was
tested by the inventors of the ' 577 patent alongside Natazia® - was not tested in Phase III
clinical trials, because the results from its Phase II ovulation inhibition studies were just outside
of new parameters Bayer set "to be on the safe side" after the failure of the Dittgen Regimen.
(FF ifif 130-35)
Watson argues: "Since the ' 793 patent already solved any long-felt need," Bayer failed to
prove that '577 patent solved any long-felt need. (OB at 28) However, as Bayer observes,
65
"Watson cites no case law to support its view that Bayer must show a failure within the scope of
Claim 1 of the ' 793 Patent." (AB at 29) 18
Bayer also provided evidence that a POSA would have been dissuaded from moving from
the daily doses of claim 1 of the ' 793 patent to those of the ' 577 patent's claims. This is because
the prior art taught "estrogen dominance" was necessary for cycle control, yet the claimed
invention would not, in 2004, have been understood to be estrogen dominant. While this
evidence does not amount to the secondary consideration of "teaching away," 19 the evidence
nonetheless helps Bayer and does not at all help Watson meet its high, clear and convincing
burden.
Hence, the Court concludes that the secondary considerations of non-obviousness support
Bayer.
C.
Galderma Does Not Compel a Finding of Invalidity
Watson analogizes this case to Galderma Laboratories, L.P. v. Tolmar, 737 F.3d 731 ,
738 (Fed. Cir. 2013), characterizing it as holding that "where the claimed invention involves
selecting dosages from within a prior-art range, as here, the burden falls upon the patentee to
18
While the Federal Circuit has stated that an OTDP inquiry does not require consideration of
objective indicia of non-obviousness, see, e.g., Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
566 F.3d 989, 999 (Fed. Cir. 2009); Geneva Pharm., Inc. v. GlaxoSmithKline PLC, 349 F.3d
1373 , 1378 (Fed. Cir. 2003), it has more recently clarified that such evidence is to be considered
when presented, see Eli Lilly & Co. v. Teva Parenteral Medicines, Inc. , 689 F.3d 1368, 1381
(Fed. Cir. 2012).
19
See Galderma, 737 F.3d at 738-39 ("A reference does not teach away, however, if it merely
expresses a general preference for an alternative invention but does not criticize, discredit, or
otherwise discourage investigation into the invention claimed. . . . A teaching that a composition
may be optimal or standard does not criticize, discredit, or otherwise discourage investigation
into other compositions.").
66
produce evidence of 'unexpected results,' ' teaching away' or other 'pertinent secondary
considerations' to save the claim." (OB at 3) In Galderma, 737 F.3d at 738, the Federal Circuit
stated:
[W]here there is a range disclosed in the prior art, and the claimed
invention falls within that range, the burden of production falls
upon the patentee to come forward with evidence that (1) the prior
art taught away from the claimed invention; (2) there were new and
unexpected results relative to the prior art; or (3) there are other
pertinent secondary considerations.
Galderma may extend to cases in which "the prior art does not teach [the] particular combination
of amounts [found in the asserted claims] , [but] those amounts ... fall within the ranges
disclosed in a single reference." Allergan, Inc. v. Sandoz Inc. , 796 F.3d 1293, 1304 (Fed. Cir.
2015); see also Avanir Pharm., Inc. v. Actavis South Atlantic LLC, 36 F. Supp. 3d 475, 502 n.17
(D. Del. 2014) (distinguishing Galderma because "[t]he prior art here does not disclose (i) ranges
encompassing the claimed doses of combination ofDM/Q at the claimed doses or weight ratios
(ii) for the treatment of PBA") (emphases in original), ajf'd sub nom Avanir Pharms. Inc. v. Par
Pharm. Inc., 612 Fed. App'x 613 (Fed. Cir. 2015).
Galderma, however, does not compel the Court to find the '577 patent's claims invalid
due to double patenting (or due to obviousness, with respect to which Watson again relies on
Galderma). As an initial matter, the Court has found "pertinent secondary considerations" failure of others and long-felt but unmet need - as explained above. Also, Galderma involved an
essentially "one dimensional range." (AB at 23) The invention at issue in Galderma was the
selection of a dose of one ingredient from a previously-disclosed range of that one ingredient. 20
20
The Court does not agree with Watson that "Galderma also involved a claim with multiple
elements." (RB at 9) Watson' s statement is based on Galderma' s discussion of the inactive
67
By contrast, in this case, as Bayer describes, "there are three phases of estradiol valerate dosing
and two phases of dionegest dosing even if one locks in the day structure of New Claim 15 or
Claim 1 of the ' 793 Patent. The skilled person thus has to make at least five decisions to come
up with a regimen." (AB at 23) Moreover, Galderma did not involve a solution to a problem
that was previously unknown in the prior art (i.e. , the failure of the Dittgen Regimen).
Thus, the Court' s conclusions are not inconsistent with Galderma.
D.
Doubts As to the PTO's Knowledge of
Common Ownership Do Not Alter the Outcome
The parties dispute whether the OTDP issue was considered by the PTO, which itself
turns on the parties ' dispute as to whether the PTO was aware of Bayer' s common ownership of
the ' 793 and ' 577 patents. Watson insists that Bayer failed to disclose its common ownership of
the two patents and, had it done so, the PTO would have rejected the ' 577 patent due to OTDP,
just as the PTO had rejected Bayer's '729 application for OTDP over the ' 793 patent.
As an initial matter, the resolution of the parties ' disputes on these points will not alter
the judgment the Court will enter in this case. Whether or not the PTO considered double
patenting, this Court has considered the issue (after a trial and full post-trial briefing) and is
empowered to make the decision announced in this Opinion. Watson's burden remains to show
clear and convincing evidence of invalidity either way. As importantly, Watson has not asserted
a claim that the ' 577 patent is unenforceable due to inequitable conduct committed by Bayer
ingredients in the pharmaceutical at issue there. (See id. at 9-10) The analysis from the Federal
Circuit on which Watson relies arises solely in the discussion of the selection of the specific
dosage of adapalene, the active ingredient. See Galderma , 737 F.3d at 736-37 (''Notably, on
appeal, the parties do not dispute the obviousness of the inactive ingredients of the formulation.
Rather, the sole dispute between the parties is whether it was obvious to use a 0.3% adapalene
composition for the treatment of acne.") (emphasis added).
68
during prosecution. Thus, even if Bayer did not disclose its common ownership of the ' 793
patent and the ' 577 patent to the PTO, this finding would not impact the result in this case.
In any event, on this issue the Court agrees with Bayer that it did disclose its common
ownership during prosecution of the ' 577 patent - although it is possible the PTO did not
recognize this disclosure. The evidence of disclosure consists of sparse references amongst a
large prosecution history, although there is nothing in the record indicating that Bayer ever
carefully drew the Examiner' s attention to its common ownership.
The same examiner, San-Ming Hui, examined both the ' 793 and ' 577 patents. (FF if 65)
During the prosecution of the ' 793 patent, Bayer filed a Revocation of Power of Attorney and
Appointment of New Attorney in which it notified the PTO and Examiner Hui that Bayer was the
owner of the applications that would lead to the ' 793 and '577 patents. (FF if 66) The same
power of attorney with the same list of Bayer-owned patents was also filed with the PTO during
the prosecution of the ' 577 Patent. (Id. ; see also JTX265 at 259-60)
During the prosecution of the ' 577 Patent, Bayer filed an Identification of Related
Applications in which it notified the PTO and Examiner Hui that the ' 577 patent and the ' 793
patent were related applications. (FF if 67) In this filing, Bayer also notified the PTO and
Examiner Hui that the ' 577 patent was a related application to the ' 251 patent, the ' 915
application, and the ' 729 application. (Id.) Additionally, in multiple remarks to the Examiner
during the prosecution of the ' 577 patent, Bayer notified Examiner Hui that the ' 729 application
had been filed incorrectly disclosing the same invention as the ' 577 Patent with a different (and
mistaken) inventive entity, and provided every single office action and response from the ' 729
application prosecution. (FF iii! 69-70) The ' 251 patent, the ' 793 patent, and the ' 915
69
application (including New Claim 15) were "cited references" on the face of the ' 771 application
(which became the ' 577 patent) considered by the Examiner.
(FF~
68)
While the prosecuting attorney, Mr. Zelano, testified that he could not recall telling the
Examiner about the common ownership of the ' 793 and ' 577 patents (id.) , the record evidence
cited above demonstrates that Bayer did disclose this fact during prosecution. By contrast, the
record is entirely devoid of evidence that Bayer affirmatively misled the PTO regarding its
common ownership of the '793 and ' 577 patents.
The Court recognizes the force of Watson' s suggestion that the PTO should have rejected
the ' 577 patent based on double patenting, just as it rejected the ' 577 patent based on
obviousness over the Dittgen Regimen. (RB at 4) ("Given that the Examiner repeatedly rejected
the '577 patent' s claims under the different 3-4-16-2-3 dosing pattern of the Dittgen Regimen,
the PTO surely would have issued a double patenting rejection under the ' 793 patent' s identical
2-5-17-2-2 dosing pattern, had co-ownership been apparent.") (internal citation omitted;
emphases in original) However, Watson ' s position ultimately rests on nothing more than
speculation. Based on the evidence, the Court concludes that Bayer did disclose its common
ownership to the PTO during prosecution of the ' 577 patent. Most importantly, the concerns
Watson has raised about the adequacy of Bayer' s disclosure of the common ownership do notin light of the totality of the evidence - provide a basis to invalidate the ' 577 patent for
obviousness type double patenting.
III.
Obviousness
Watson contends that the claims of the ' 577 patent are invalid as obvious over New
Claim 15 of the '915 application. It is undisputed that New Claim 15 is in the prior art.
70
Essentially all of the discussion above in the context of OTDP applies equally with
respect to obviousness. The principal differences both favor Bayer: (i) because New Claim 15
was prior art and was before the PTO during its examination of the ' 577 patent, it is more
difficult for Watson to prove obviousness than it is to prove double patenting, which was based
on the ' 793 patent, which was not before the PTO during its examination of the ' 577 patent; and
(ii) rather than "lock in" all the commonalities between the claims of the prior art patent (here
New Claim 15) and the asserted claims of the patent-in-suit (the ' 577 patent), as the Court did as
part of its OTDP analysis, with respect to obviousness and consideration of the prior art as a
whole the Court must, instead, consider whether a POSA would have been motivated to modify
even those commonalities (which, if so, would favor a finding of non-obviousness) . Perhaps
unsurprisingly, then, the Court concludes that Watson failed to meet its burden to show that the
claims of the ' 577 patent are invalid as obvious.
As previously discussed, the prior art - including the ' 251 patent, the Dittgen Declaration,
New Claim 15, and the Hoffman Articles - disclosed a combination of EV and DNG in a
multiphasic regimen (including 2-5-17-2-2) as a potential option for a natural estrogen COC with
good cycle control. (JTX14 at 3:16-53 ; DTX74 at 3-4; JTX68 at 3; JTX3 at 108; JTX2 at 460)
Even so, given the Court' s findings as to a POSA ' s understanding of "estrogen dominance," and
the historical trend oflowering doses over time, a POSA would not have been motivated to
combine the prior art to arrive at the 2-5-17-2-2 daily dosing regimen of3-2-1 mg EV and 2-3
mg ofDNG. A POSA would have had no reasonable expectation of success from such a
combination.
As is extensively explained in connection with double patenting, a POSA would not
71
expect the Natazia® regimen to have adequate cycle control, as the prior art taught that estrogen
dominance in the proliferative phase of the cycle was important for cycle control, and the '577
patent is not estrogen dominant in the first cycle phase due to its ratios of EV to DNG doses.
Thus, the Court finds that a POSA would not have had a reasonable expectation of success with
the formulation's particular ratios of EV to DNG for both contraceptive efficacy and cycle
control.
Further, none of the prior art references disclose an actual use of 3 mg DNG in a COC.
(See Simon Tr. at 189-90, 192-93, 208 ; Holtz Tr. at 335-36; JTX4 at 227; JTX2 ; JTX3 at Fig. 1;
JTX14; JTX19; JUTX228; JTX265 at 110) Only the Griiserprior art tested DNG doses greater
than 2 mg, but it did so in post-menopausal women, a different population. 21
A POSA would not have been motivated to raise daily DNG doses higher than 2 mg also
because the Dittgen Regimen - using 1 and 2 mg DNG - would have been expected to be an
effective COC. (Barnhart Tr. at 395, 397, 421-22) The Hoffman Articles describing the results
of the pilot study on the Dittgen Regimen reported zero pregnancies over a total of 573 cycles
(JTX3 at 109), and the Dittgen Declaration stated that this was "a safe preparation which
effectively inhibits ovulation" (JTX5 at 7). Peer-reviewed and published data, like the data in the
Hoffmann Articles, would be evidence a POSA would "start with" in the "hierarchy of
evidence," and real data that is not peer-reviewed, like the data in the Dittgen Declaration or in
actual patent examples, would be the "next most important data." (Barnhart Tr. at 384-85)
Given that "[a]nything short of an ovulation is an effective contraceptive regimen" (id. at 380,
21
The Gast application disclosed a DNG dose range of 0.25 mg to 4 mg, with examples of a
preferred dosing range of 0.5 mg to 1 mg, but it did not provide any clinical data associated with
these amounts. (JTX201; Simon Tr. at 269)
72
408), a POSA would have expected that the Dittgen Regimen was "at least as effective as those
[COC regimens] already on the market" (id. at 392).
Lastly, as explained in the previous section, Bayer has established the secondary
considerations of non-obviousness of failure of others and long-felt but unmet need.
For all of these reasons, the Court concludes that Watson has failed to meet its burden to
show that the claims of the ' 577 patent are invalid as obvious.
IV.
Suggestions of "Inequitable Conduct"
One final point merits discussion. Throughout this case, Watson has suggested that Bayer
has done something untoward in its prosecution decisions. Although Watson has not contended
that Bayer' s ' 577 patent is unenforceable due to inequitable conduct, it has suggested
inappropriate behavior which, the Court infers, Watson believes is pertinent to the issues the
Court must decide. While none of these allegations is, in actuality, legally relevant, the Court
briefly addresses them nonetheless.
Watson accuses Bayer of "attempt[ing] to extend its patent monopoly over the same oral
contraceptive regimen by over a decade. " (OB at 1) It emphasizes that Bayer obtained the ' 793
patent in 2005 and then, in 2012, obtained the ' 577 patent, after having disclaimed all interest in
the ' 793 patent in 2011. Allegedly, "Bayer thereby obtained an extension of patent monopoly
over the same oral contraceptive regimen that would last over 15 years if permitted to stand."
(Id. )
Preventing unwarranted patent "extensions" is the principal purpose of the OTDP
doctrine. See Eli Lilly, 251 F .3d at 968 ("[T]he fundamental reason for the rule is to prevent
unjustified timewise extension of the right to exclude granted by a patent no matter how the
73
extension is brought about."). The prohibition on double patenting is implemented through the
two-step process set out by the Federal Circuit. See id. The Court is obligated to apply that twostep OTDP legal analysis, without concern for the result or the parties ' policy arguments about it.
Having done so, the Court reiterates its conclusion that the challenged claims are not invalid due
to double patenting.
Watson further suggests there was something nefarious in Bayer' s decision to file "two
mutually exclusive applications claiming two different entities were responsible for Natazia®."
(OB at 4) Watson is referring to the ' 729 application - which listed the Dittgen group as
inventors - and the ' 77 1 application - which listed Endrikat and his team as the inventors. Bayer
explains that the reasons for its approach to prosecution are privileged (see Tr. at 730-31 ), and
Watson does not dispute this point. The Court perceives nothing in this back-and-forth that
should affect the conclusions it has drawn based on the evidence.
Finally, Watson contends that Bayer did something wrong in that " [r]ather than telling the
PTO the Dittgen Regimen ' failed,' Bayer relied on its efficacy to obtain the ' 793 patent covering
Natazia®. Having obtained that benefit, Bayer cannot justify its second, later-expiring patent on
Natazia® by claiming the opposite now. " (RB at 1 (internal citation omitted); see also id. at 6
("Bayer' s 'unknown problem ' is based on its own failure to tell the PTO the 'truth. '")) The
Dittgen Regimen' s failure in the Phase III clinical trial had occurred by January 2001. (JTX6 at
3) In prosecuting the ' 793 application as late as December 2003 , Bayer did not tell the PTO of
the failure of the Dittgen Regimen, but instead pointed to the success of that regimen to support
its argument for patentability of the ' 793 patent. (JTX68 at 6 ("[The] showing in the previously
filed [Dittgen] Declaration proves that the claimed contraceptive preparation of new claim 15 has
74
unexpectedly improved properties in comparison to the closest prior art."))
The Court is not persuaded that anything improper has occurred here. Again, there is no
claim of inequitable conduct. While Watson is perhaps suggesting the Court should estop Bayer
from arguing that the Dittgen Regimen failed, Watson makes no effort to meet the requirements
for estoppel. See McCarron v. FD.I. C. , 111 F .3d 1089, 1097 (3d Cir. 1997) ("Judicial estoppel
prevents a party from assuming a position inconsistent with one which it took in a prior
proceeding. The purpose of judicial estoppel is to prevent a party from playing ' fast and loose'
with courts by asserting contradictory positions.").
Thus, the Court concludes that Watson has failed to meet its burden with respect to
double patenting and obviousness.
CONCLUSION
Watson has failed to prove by clear and convincing evidence that claims 1-3 of the ' 577
patent are invalid due to obviousness-type double patenting or obviousness. Judgment will be
entered in favor of Bayer and against Watson.
An appropriate Order follows .
75
Disclaimer: Justia Dockets & Filings provides public litigation records from the federal appellate and district courts. These filings and docket sheets should not be considered findings of fact or liability, nor do they necessarily reflect the view of Justia.
Why Is My Information Online?