Citations
- 212 F. Supp. 3d 489
Full opinion text
FILED UNDER SEAL
MEMORANDUM OPINION
STARK, United States District Judge:
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 multi-phasic 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 ¶ 17)
In September 2014, the Court construed the disputed terms of the patents-in-suit. (D.I. 99, 111) 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.
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 of law.
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 Müllerstrasse 178, 13353 Berlin, Germany. (SUF ¶ 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. ¶ 2)
3. 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. ¶ 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. ¶ 4)
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) 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 endome-trium 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 gesto-gen) 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 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 prolifer-ative 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 intra-cyclic bleeding. (Id. at 370-71) If the en-dometrium 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 371-72)
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 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 3:16-53; 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. (JTX173 at 534)
17. The prior art includes a dose-ranging study by Dr. Claudia Moore, aimed at determining the minimum dosage of DNG 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 of record before the Examiner during the prosecution of the ’577 Patent. (JTX1; 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 proges-tin 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; JTX173 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 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 biphasie, 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 Hoog-land 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 lutein-ized 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 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 of residual 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 Hoog-land 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 379-80)
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®. (SUF ¶¶ 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. ¶ 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. ¶ 7)
32. Natazia® is a multiphasic COC that uses EV as the estrogen component and DNG as the progestin component. (JTX1; 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 of DNG of 0, 2, and 3 mg, again depending on the phase of the cycle. (JTX1; Zelano Tr. at 278)
33. Prior to the discovery of Natazia®, all prior art describing specific examples of DNG-containing COC regimens recommended a daily dose of 2 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 the United States in July 2010. (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. (JTX1) Jan Endrikat and Bernd Diister-berg 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. (SUF ¶ 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 multi-phasic regimens for oral contraception involving the estrogen EV, the progestin DNG, and placebo. (JTX1) 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/Nata/ia® Regimen
Phase Davs Dose Elements
Phase 1 2 daily doses 3 mg EV
Phase 2, group 1 5 daily doses 2 mg EV and 2 mg DNG
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 of DNG at 2 mg 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. (JTX1; 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 Na-tazia®, 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 Na-tazia®
41. The ’577 patent is the third patent that Bayer has owned that covers the Na-tazia® regimen. (Id.:, JTX14; JTX19; JTX1)
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 for oral contraception. (Id. at 1) The scope of the regimens claimed in the ’251 patent-⅛ 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 aboye 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 dosing); Simon Tr. at 154)
46. The ’251 patent contains five examples utilizing natural estrogens in a multi-phasic regimen having positive results for cycle control. (JTX14 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 desoges-trel), 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) Nata-zia® was such an “exemplary composition” and a member of the claimed genus. (Zela-no 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 3-2-1 mg EV dosing pattern, 1 mg and 2 mg DNG, and placebo in a 3-4-16-2-3 multiphasic regimen:
Table 3. Dittgen Regimen
Phase Days Dose Elements
Phase 1 3 daily doses 3 mg EV
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 mgEV
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 ’251 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 279)
2. The ’793 patent and its prosecution
52. On September 12, 2001, Bayer’s subsidiary, Jenapharm, filed U.S. Patent 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 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:
Table 4. New Claim 15 Regimen
Phase Davs 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.) Jenap-harm 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 current commercial 20jjug 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)
Table 5. ’793 Patent Claim 1 Regimen
Phase Davs 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 2 daily doses Placebo
61. 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. (Mat-they 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 ’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® of 2 mg and 3 mg. (Compare DTX93 at 3 with JTX1 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. 11/578,771 (“the ’771 application”), which led to the ’577 patent-in-suit, Bayer identified different inventors—Jan Endrikat and Bernd Düsterberg—as being responsible for the Natazia® example. (JTX265 at 13; JTX1) Because Endrikat and Duesterberg were not identified as inventors in the ’793 patent, there was no co-inventorship. (Compare JTX19 with JTX1) 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 JTX1 and JTX19 with JTX265 at 1622)
67. On November 12, 2009, Bayer filed— in the ’314 patent application (which had 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. (JTX1; JTX265 at 2215-19; Barnhart Tr. at 223-24) 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.
(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 of record 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” of Dittgen 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 select Example 5 of the Dittgen EP ’388 [the Dittgen Regimen] as a starting point” (id. at 1309-12), 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 Gráser article. (JTX1 at 1-4)
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 III clinical trials.” (Allen Tr. at 545-46)
78. However, Watson’s expert, Dr. Simon, analogized the Hoogland results reported in the Dittgen Declaration to those found in a paper by Lüdicke and others, which published in the prior art in 2001. The Lüdicke authors used the Hoogland scoring system to compare and evaluate two contraceptive regimens, each containing different doses of the progestin gesto-dene. (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 Lüdicke determined to have insufficient ovarian suppression (Simon Tr. at 142), the presence of one ovulation in the Lüdicke 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 Lüdicke regimen to be comparable to the success of the 1 mg/2 mg DNG regimen of Dittgen because there was an ovulation with Lüdicke, and none with the Dittgen Regimen. (Id.) As Dr. Barnhart noted, the presence of an ovulation with Lüdicke 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 Articles”), in 1998. and 1999, that tested a series of COCs 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 Hoffmann Articles, which are prior art, were authored by the same Ditt-gen group responsible for the ’251 and ’793 patents. (Compare JTX2 and JTX3 with JTX14 and JTX19)
81. Hoffmann experimented with a biphasic regimen of 2 mg of EV with 2 mg of DNG and a triphasic regimen of 2 mg, 4 mg, and 2 mg of EV with 2 mg of DNG. (JTX2 at 460; JTX3 at 108) Hoffman 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 of DNG 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. Hoffman 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)
3. Bayer’s ’722 Patent (“Schmidt-Goll-witzer”) 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-Gollwit-zer 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 17(3-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 [of DNG] in cyclic women amounts to about 1 mg/day.” (JTX173 at 529 table VII) Oettel, which is prior art, compared the cycle control of a very low dose of DNG (0.225 mg, below the ovulation inhibition dose) with a 2.0 mg dose of DNG, 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 die-nogest dose to 2 mg/day resulted in better 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 of DNG. (JTX173 at 529 table VII)
89. A prior art article by Moore and others, published in 1999, described a dose-ranging study of DNG 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 “dienog-est 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 0.08 mg EE. (JTX173 at 534 (“Dienogest in combination with ethinyl estradiol (2 mg dienogest and 0.03 mg ethinyl estra-diol/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)—Na-tazia®, 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, WO98/04268, 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 |xg (i.e., 0.5 mg) to 1 mg DNG per day. (JTX201 at 10; 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 of 2 mg EV with DNG doses of 0.5 mg, 1 mg, 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 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 of DNG were well tolerated without any dose dependent side effects. (Simon Tr. at 147) Dr. Simon explained Gráser’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—be-cause 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.” (JTX12 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 to provide less inter-menstrual bleeding.” (Id.)
102. Consistent with his publication, En-drikat, 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 en-dometrius) 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 of DNG. (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 fírst cycle phase, i.e., the stage at which the endometrial proliferation is promoted under estrogen influence, 17(3-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 ethiny-lestradiol-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-gesto-gen 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 of DNG to higher doses of DNG (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 dominance was necessary for an effective COC, Dr. Barnhart pointed to the Gráser 2000 paper. {Id. at 529-30) Dr. Gráser’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 Gráser 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. Gráser found that, in combination with 2 mg EV:
The prevalence of proliferative 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 Gráser’s findings to this case (to the extent relevant) is complicated by the fact that Gráser reports results in the form of DNG:EV ratios, the opposite of the EV:DNG ratios the parties and the Court have used here. (Relatedly, Gráser reports the atrophic:proliferative ratio— i.e., breaking dowmbuilding up ratio— whereas the Court is 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” Gráser’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: Atrophic Ratio HRT Suitable? Dom-in-ant? EV:DNG Ratio
2 mg .5 mg 0.7 [0.7/1] 1.43 [1/0.7] NO Estr. 4:1
2 mg 1 mg 1.0 [1/1] 1.0 [1/1] NO Estr. 2:1
2 mg 2 mg 2.0 [2/1] 0.5 [½] YES Prog. 1:1
2 mg 3 mg 5.0 [5/1] 0.2 [1/5] YES Prog. 2:3
2 mg 4 mg 6.0 [6/1] 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. (JTX1)
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 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 Endri-kat Declaration does discuss the putative importance of ratios of estrogemprogestin, 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 < Dittgen. (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 of 2:1 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 2:8 mg EV:DNG ratio, compared to Dittgen’s 16 days of equal 2:2 mg EV:DNG.
118. Other illustrations that the Nata-zia® 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 Natazia® a woman takes 16 mg of EV and 10 mg of DNG 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 of DNG 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. Barnhart’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 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; JTX174 at 471; JTX176 at 458; JTX177 at 543; JTX178 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.” (JTX174 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.” (JTX174 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 nor-ethisterone acetate make it much less suitable -for general use in family planning programmes than combinations containing synthetic estrogens.” (JTX176 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 activity and ovulation was inhibited by this combination,” yet “[breeding control was, however unacceptable in all volunteers.” (JTX177 at 543)
127. In 1993, Wenzl tried to develop a natural estrogen pill utilizing micronized estradiol together with the progestin deso-gestrel, 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 III clinical study (known as AZ94). (JTX6) AZ94 was a large scale Phase III 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;