Case Information
*3 Before L OURIE , S CHALL , and P ROST , Circuit Judges . L OURIE , Circuit Judge .
In these consolidated patent infringement actions, ge-
neric pharmaceutical manufacturers Watson Pharmaceu-
ticals, Inc., Watson Laboratories, Inc., Sandoz, Inc., Lupin
Ltd., and Lupin Pharmaceuticals, Inc. (collectively, the
“Defendants”) appeal from the final judgments of the
United States District Court for the District of Nevada in
favor of Plaintiffs-Appellees Bayer Healthcare Pharma-
ceuticals, Inc. and Bayer Schering Pharma AG (collective-
ly, “Bayer”). In particular, the Defendants challenge the
district court’s entry of summary judgment that asserted
claims 13 and 15 of Bayer’s U.S. Patent RE37,564 (the
“’564 patent”) are not invalid for obviousness in view of
numerous cited prior art references.
Bayer Schering
Pharma AG v. Watson Pharm., Inc.
, Nos. 2:07-cv-01472,
2:08-cv-00995,
B ACKGROUND
This case concerns pharmaceutical formulations and dosing regimens for combined oral contraceptive (“COC”) products. First introduced in 1960, COCs, better known as birth control pills, deliver synthetic hormones that regulate the natural ovariаn cycle and prevent pregnancy. Specifically, COCs comprise a progestin and an estrogen that together inhibit folliculogenesis—a stepwise, hor- mone-directed process in which an ovarian follicle con- taining an immature oocyte ( i.e. , an egg cell) grows and develops for approximately the first two weeks of an ovarian cycle, culminating in the release of a fertile oocyte at ovulation. The synthetic progestin and estrоgen pro- vided in a COC suppress production of the natural hor- mones that drive folliculogenesis, thus inhibiting ovulation and reducing the incidence of pregnancy in COC users. The contraceptive effects depend on the continued presence of the inhibitory synthetic hormones; folliculo- genesis will commence if the synthetic progestin and estrogen are withdrawn but can be abrogated if the hor- mones are reintroduced before ovulation occurs.
To maintain synthetic hormone concentrations suffi- cient for sustained follicular suppression, COCs are typically taken once daily, and since their introduction, most COCs have been provided in 28-day, 28-pill packs that align with the approximate length of a natural ovarian cycle. Early COCs relied on a 21/7 dosing regi- men in which each monthly pill pack would include twen- ty-one active pills containing synthetic progestin and estrogen followed by seven placebo pills containing no hormones. The seven-day placebo period, also known as the pill-free interval, was originally included because it (i) triggered a “withdrawal bleed” that mimicked natural menstrual bleeding and was presumed to improve ac- ceptance among COC users, and (ii) provided a regular break from synthetic hormone exposure that was thought to mitigate potential side effects. The 21/7 regimen persists in most COCs on the market today.
In addition to maintaining a pill-free intervаl, another strategy to reduce side effects has been to reduce the hormone dose provided in each pill. For example, the first COCs provided relatively high daily doses of synthetic estrogen, up to approximately 150 µg per active pill. Deleterious side effects of COC use, including thrombo- embolism, nausea, and bloating, have been most strongly associated with synthetic estrogen exposure, so the estro- gen dose in particular has been progressively reduced over time. The first COC containing the synthetic estro- gen ethinylestradiol (“EE”) at only 20 µg per pill was approved for sale in the United States in 1976.
In the early 1990s, Bayer began developing a low-dose COC containing 20 µg EE and the synthetic progestin drospirenone (“DRSP”) to be administered with a reduced pill-free interval. Lowering EE dosage to 20 µg per pill limits undesirable side effects, but it also results in weak- er ovarian suppression compared to higher-dose COCs. As such, some ovarian activity and follicular maturation can persist in users of low-dose COCs, and any intake errors ( i.e. , missed pills), especially those that effectively lengthen the unregulated pill-free interval, could result in “escape” ovulation and unintended pregnancy. ’564 patent col. 2 l. 38 – col. 3 l. 6. To address the risk of escape ovulation for users of low-dose COCs, Bayer im- plemented 23/5 and 24/4 dosing regimens, reducing the pill-free interval to five or four days, respectively, and increasing the number оf active pills per cycle accordingly. Bayer demonstrated that shortening the pill-free interval to four or five days improved the contraceptive efficacy of low-dose COC formulations. Accordingly, Bayer filed its first patent application directed to such low-dose, extend- ed-regimen COCs on December 22, 1993, and that appli- cation eventually led to the ’564 patent. [1] The ’564 patent includes 15 claims reciting various COC preparations; claims 13 and 15 read as follows: 13. A combination product for oral contraception, comprising
(a) 23 or 24 daily dosage units, each containing 0.020 mg of ethinylestradiol, and 2.5 to 3.0 mg of drospirenone, and
(b) 5 or 4, respectively, active ingredient-free pla- cebo pills or other indications to show that the daily administration of the 23 or 24 dosage units, respectively, is to be followed by 5 or 4, respectively, pill-free or placebo pill days, wherein each of the dosage units containing dro- spirenone contains the same amount of dro- spirenone.
. . . . 15. A combination preparation of claim 13, which comprises 24 dosage units and 4 placebo pills or other indications to show that no dosage unit or placebo pill is administered during the last 4 days of the menstrual cycle.
’564 patent col. 6 l. 57 – col. 8 l. 4. Bayer markets a COC product that embodies claims 13 and 15 under the brand name YAZ ® . That product includes four placebo pills and twenty-four aсtive pills each containing 20 µg EE and 3 mg DRSP. Bayer received final approval to market YAZ ® in the United States on March 16, 2006.
The Defendants filed Abbreviated New Drug Applica- tions (“ANDAs”) with the U.S. Food and Drug Admin- istration (“FDA”) seeking approval to market generic versions of YAZ ® . Those ANDA filings included Para- graph IV certifications asserting that the ’564 patent is invalid. See 21 U.S.C. § 355(j)(2)(A)(vii)(IV) (2006). Bayer responded by bringing patent infringement actions alleg- ing that the Defendants’ ANDA filings infringed claims 13 and 15 of the ’564 patent under 35 U.S.C. § 271(e)(2). [2]
Before the district court, the Defendants conceded
that their ANDAs infringed the ’564 patent under
§ 271(e)(2).
Bayer Schering Pharma AG v. Watson
Pharm., Inc.
, No. 2:07-cv-01472,
The Defendants now appeal. We have jurisdiction under 28 U.S.C. § 1295(a)(1). [3]
D ISCUSSION
Summary judgment is appropriate “if the movant
shows that there is no genuine dispute as to any material
fact and the movant is entitled to judgmеnt as a matter of
law.” Fed. R. Civ. P. 56(a). We apply regional circuit law,
in this case the law of the Ninth Circuit, when reviewing
a district court’s grant or denial of a motion for summary
judgment.
Teva Pharm. Indus. v. AstraZeneca Pharm.
LP
, 661 F.3d 1378, 1381 (Fed. Cir. 2011). The Ninth
Circuit reviews summary judgment rulings without
deference, “asking ‘whether there are any genuine issues
of material fact’ while ‘[v]iewing the evidence in the light
most favorable to the nonmoving party.’”
Dealertrack,
Inc. v. Huber
,
The sole issue before us is whether the district court erred in granting summary judgmеnt in favor of Bayer and holding that asserted claims 13 and 15 of the ’564 patent are not invalid for obviousness in light of the presented prior art.
The Defendants rely on six prior art references: Aus- tralian Patent Application 55094/90, published November 22, 1990 (“AU’094”); European Patent Application Publi- cation 0 253 607, published April 29, 1992 (“EP’607”); B.G. Molloy et al., “Missed Pill” conception: fact or fic- tion? , 290 Brit. Med. J. 1474 (1985) (“Molloy”); John Guillebaud, The forgotten pill—and the paramount im- portance of the pill-free week , 12 Brit. J. Fam. Plan. 35 (1987) (“Guillebaud”); B-M. Landgren & E. Diczfalusy, Hormonal Consequences of Missing the Pill During the First Two Days of Three Consecutive Artificial Cycles , 29 Contraception 437 (1984) (“Landgren”); and N.D. Goldstuck et al., Use and misuse of oral contraceptives by adolescents attending a free-standing clinic , 3 Advances in Contraception 335 (1987) (“Goldstuck”). According to the Defendants, the combination of AU’094 with any of EP’607, Molloy, Guillebaud, Landgren, or Goldstuck would have rendered the asserted claims of the ’564 patent obvious at the time of invention. In particular, the Defendants argue that AU’094 discloses a COC combining 20–40 µg EE and 1–10 mg DRSP per active pill—dosage ranges that encompass those recited in claims 13 and 15 of the ’564 patent. The Defendants further contend that EP’607, Molloy, Guillebaud, Landgren, and Goldstuck each disclose 23/5 and/or 24/4 dosing regimens and that those references provided motivation to combine such regimens with the low-dose COCs disclosed in AU’094 by identifying the problem of missed-pill conceptions and suggesting a shortened pill-free interval as a solution. Finally, the Defendants contend that the district court erred by misapplying and misinterpreting the cited refer- ences and by crediting legally insufficient evidence as secondary indicia of nonobviousness.
In response, Bayer argues that AU’094 and EP’607 were directed to narrow subpopulations of patients pri- marily in need of hormone-replacement therapy, so those references would not have been combined by a person of ordinary skill seeking to develop a COC in 1993. Fur- thermore, according to Bayer, the prior art as a whole taught away from the claimed COC preparations at that time in view of the entrenched use of traditional 21/7 dosing and the perceived risks from increasing total synthetic hormone administration by shortening the pill- free interval. Finally, Bayer defends the district court’s reliance on its evidence of unexpected results, expert skepticism, industry praise, and copying as secondary indicia of nonobviousnеss.
We agree with the Defendants that the district court erred in holding the claims not invalid. A claim is invalid for obviousness “if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.” 35 U.S.C. § 103(a) (2006). In this case, the cited prior art references set forth every limitation required by the asserted claims and provide express motivation to combine those teachings to derive the claimed COC products. Accordingly, the as- serted claims are invalid under § 103.
There is no dispute that claims 13 and 15 of the ’564 patent require a COC product defined by the following limitations: (1) 20 µg EE per active pill, (2) 2.5–3.0 mg DRSP per active pill, and (3) a 23/5 or 24/4 dosing regi- men. ’564 patent col. 6 l. 57 – col. 8 l. 4. Nor is it disput- ed that the cited prior art references disclose each of those limitations. For example, EP’607 discloses a combinatiоn dosage form that can provide hormonal replacement therapy and contraceptive protection, using a “preferred administration cycle [of] 24 days of the combination dosage form and 4 days of no dosage form.” EP’607 col. 1 ll. 3–18; see also id. col. 3 ll. 46–57 (describing 24/4 and 23/5 dosage regimens as “preferred”). In addition, the disclosed active dosage form includes an estrogen and a progestin; EP’607 lists EE (8–30 µg per dose) among three estrogen choices and describes several suitable progestins, but DRSP is not disclosed. Id. col. 2 l. 35 – col. 3 l. 25. AU’094, however, discloses DRSP as an additional proges- tin suitable for use “alone or in combination with estro- gens in contraceptive preparations.” AU’094 at 1. Furthermore, AU’094 indicates that EE is a preferred estrogen complement to DRSP for COC use and suggests using daily doses of 20–40 µg EE with 1–10 mg DRSP. Id. at 4–5. AU’094 even refers expressly to EP’607, stating that the disclosed EE/DRSP preparations can be used “analogously” to the EP’607 combinations and expressly inсorporating the disclosure of EP’607 by reference. Id. at 5–6. In sum, EP’607 and AU’094 disclose all three limita- tions required by the asserted claims. AU’094 discloses COC preparations that encompass the claimed doses of EE and DRSP, and EP’607 discloses similar COCs, also comprising the claimed dose of EE, administered via the claimed 24/4 and 23/5 regimens.
With every limitation of the asserted claims thus dis-
closed in the cited references, the question, as the district
court recognized, becomes whether a person of ordinary
skill in the art would have been motivated to combine
those teachings to derive the claimed subject matter with
a reasonable expectation of success.
See, e.g.
,
Unigene
Labs., Inc. v. Apotex, Inc.
,
The prior art before us provides that motivation. In addition to AU’094’s express reference to EP’607, several of the cited references highlight evidence that the unregu- lated ovarian activity that occurs during a seven-day pill- free interval can achieve significant follicular develop- ment, and those references also express concern that inadvertently extending the traditional pill-free interval via one or more missed pills could lead to escape ovulation and unintended pregnancy. See, e.g. , Molloy at 1475 (“The demonstration of ovarian folliculogenesis . . . on the seventh pill free day, means that during the early days of the subsequent pill cycle, some women harbour signifi- cantly developed folliсles, ready to [ovulate] if oestrogen suppression were to fail because of a missed pill.”); Guil- lebaud at 35 (stating “that it is precisely because of this seven day break that most pregnancies occur, and that the pill omissions of greatest concern are those that lead to a lengthening of the pill-free interval”) (quotation omitted); Landgren at 444 (“These data seem to suggest that ovulation is more likely to occur when the pill is omitted during the first days of the artificial cycle. Hence, the prolongation of the pill-free week by two or more days is likely to increase the risk of ‘escape’ ovulation.”). In addition, Bayer’s expert acknowledged that one of skill in the art at the time of the invention would have expected an even greater risk of such “missed pill” ovulation for users of low-dose COCs ( i.e. , those containing 20 µg EE per active pill). J.A. 2032–35.
The evidence thus demonstrates that missed-pill ovu-
lation was a recognized concern with traditional 21/7
COCs, particularly for those on the market by 1993 that—
like the claimed COC preparations—relied on low-dose
EE. As the Supreme Court has stated, “any need or
problem known in the field of endeavor at the time of
invention and addressed by the patent can provide a
reason for combining the elements in the manner
claimed.”
KSR
,
Bayer’s arguments do not support a contrary conclu- sion. Bayer contends that EP’607 and AU’094 “are pri- marily directed to older women who have reached pre- menopause and are in need of hormone replacement therapy,” and that therefore a “skilled person setting out to design an oral contraceptive using EE and DRSP would not have used the 24/4 regimen intended to achieve effective [hormone-replacement therapy].” Appellees’ Br. 39–40. But those references plainly disclose preparations with hormone rеplacement and contraceptive applica- tions, and the product claims at issue do not distinguish between target patient populations, whether by age or otherwise.
In addition, Bayer argues that the prior art taught
away from the claimed COC preparations, focusing on
statements in Guillebaud as indicating that the “conven-
tional wisdom” in the field favored 21/7 dosing for most
patients and as suggesting that a reduced pill-free inter-
val should be used together with higher-dosе COCs for
patients perceived to be at risk of escape ovulation.
[4]
Those statements, however, do not overcome the express
teachings of multiple references, including Guillebaud,
that a shorter pill-free interval would improve COC
efficacy. Furthermore, Guillebaud may have suggested
condensing the pill-free interval while concurrently in-
creasing the hormone dose for at-risk patients, but those
two measures are never described as mutually dependent,
and each could be expected to reduce missed-pill ovulation
risks with or without the other. “[A] finding that the prior
art as a whole suggests the desirability of a particular
combination need not be supported by a finding that the
prior art suggests that the combination claimed . . . is the
preferred, or most desirable, combination.”
In re Fulton
,
Finally, Bayer’s evidence of secondary indicia of non- obviousness, including alleged unexpected results, expert skepticism, industry praise, and copying by others, is legally insufficient. To demonstrate unexpected results, Bayer relies on data showing that 23/5 administration results in reduced follicular activity compared to 21/7 dosing of the same COC formulation. But those data merely confirm that administering additional active pills results in additional follicular suppression, which would have been a matter of “common sense,” as even Bayer’s expert agreed.
As evidence of expert skepticism, Bayer cites an FDA
request for clinical safety data and data demonstrating
efficacy benefits sufficient to justify the added synthetic
hormone exposure required for the proposеd 24/4 dosing
regimen. That request in no way indicates that FDA
experts would have been surprised to receive such data.
See Dow Jones & Co. v. Ablaise Ltd.
,
Nеxt, Bayer claims that its invention “was widely praised by experts in the COC field.” Appellees’ Br. 61. In making that claim, Bayer relies on journal citations that reference the findings stated in Bayer’s published efficacy studies or discuss possible non-contraceptive indications for 24/4 COC regimens. Another article describing Bayer’s 24/4 COC regimen as an “innovative strategy” was authored by the first-named inventor of the ’564 patent. Such bare journal citations and self- referential commendation fall well short of demonstrating true industry praise. Furthermore, industry praise of what was clearly rendered obvious by published refer- ences is not a persuasive secondary consideration.
Lastly, we reject Bayer’s contention that copying of its
COC preparations by the Defendants and other generic
manufacturers supports its validity position. Such evi-
dence of copying in the ANDA context is not probative of
nonobviousness because a showing of bioequivalence is
rеquired for FDA approval.
Purdue Pharma Prods. L.P. v.
Par Pharm., Inc.
,
C ONCLUSION
We have considered Bayer’s remaining arguments and find them unpersuasive. Accordingly, nothing Bayer has presented overcomes the plain disclosures and ex- press motivation to combine those disclosures in the prior art. We therefore conclude that claims 13 and 15 of the ’564 patent are invalid for obviousness in view of the cited references, and we reverse the judgment of the district court.
REVERSED
[1] The December 1993 application was a foreign pri- ority application filed in Germany. Bayer filed its first corresponding U.S. application in June 1994 and obtained U.S. Patent 5,824,667 (the “’667 patent”) as a continua- tion of that first U.S. application on October 20, 1998. The asserted ’564 patent, issued on February 26, 2002, arose as a reissue of the ’667 patent.
Notes
[2] Bayer filed suit against Watson on November 5, 2007, and against Sandoz on August 1, 2008. The district court consolidated those actions on November 4, 2008. Bayer Schering Pharma AG v. Watson Pharm., Inc. , Nos. 2:07-cv-01472, 2:08-cv-00995 (D. Nev. Nov. 4, 2008), ECF No. 43 (Order to Consolidate Related Cases). Bayer initiated parallel infringement proceedings against Lupin on July 15, 2010.
[3] Bayer has suggested that we lack jurisdiction to entertain this appeal. Appellees’ Br. 3–4. Specifically, Bayer contends that it has unresolved claims for damages relating to alleged at-risk launches of infringing generic products by Watson and/or Sandoz that preclude appel- late jurisdiction under 28 U.S.C. § 1292(c)(2). We need not address that argument, however, because our jurisdic- tion over this appeal does not depend on § 1292(c)(2). The district court granted summary judgment against the Defendants on their invalidity counterclaims and, pursu- ant to Federal Rule of Civil Procedure 54(b), entered partial final judgment that the ’564 patent was not inva- lid for obviousness. Bayer Schering Pharma AG v. Watson Pharm., Inc. , No. 2:07-cv-01472 (D. Nev. May 29, 2012), ECF No. 354 (Partial Final Judgment). The district court did not abuse its discretion in applying Rule 54(b), and its judgment in that part of the case is final. See Sun Pharm. Indus. v. Eli Lilly & Co. , 611 F.3d 1381, 1384 (Fed. Cir. 2010). We therefore have jurisdiction to review the dis- trict court’s partial final judgment undеr 28 U.S.C. § 1295(a)(1).
[4] Bayer also contends that Goldstuck “endorsed” Guillebaud’s suggestion to use a higher-dose formulation with a 24/4 or 23/5 regimen and therefore teaches away on the same basis. Appellees’ Br. 47–48. In citing Guil- lebaud, however, Goldstuck makes no mention of hormone dose: “The suggestion that manufacturers make 28-day packages consisting of 24 active tablets and 4 bran [place- bo] tablets is of considerable merit [Guillebaud]. This would both maintain a 28-day regimen and help reduce the pill-free interval in those women who inadvertently miss a pill.” Goldstuck at 338. Goldstuck thus offers little support for Bayer’s position.