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`EXHIBIT 1028
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`EXHIBIT 1028
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`(cid:3)
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.
`Petitioner
`v.
`WARNER-CHILCOTT COMPANY LLC.
`Patent Owner
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`U.S. Patent No. 7,704,984 to Boissonneault
`Issue Date: April 27, 2010
`Title: Extended Estrogen Dosing Contraceptive Regimen
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`Inter Partes Review No. Unassigned
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`Declaration of Michael A. Thomas, M.D.
`in Support of the Petition for
`Inter Partes Review of U.S. Patent No. 7,704,984
`Under 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
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`I.
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`II.
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`QUALIFICATIONS ....................................................................................... 1
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`SCOPE OF WORK......................................................................................... 5
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`III. OVERVIEW OF THE ’984 PATENT ........................................................... 5
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`IV. PROSECUTION HISTORY OF THE ’984 PATENT ................................... 9
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`V.
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`LEGAL STANDARDS ................................................................................ 12
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`VI. LEVEL OF ORDINARY SKILL AND THE RELEVANT TIME ............. 15
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`VII. CLAIM CONSTRUCTION ......................................................................... 16
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`VIII. THE STATE OF THE PRIOR ART ............................................................ 17
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`IX. CERTAIN REFERENCES DISCLOSE OR SUGGEST EACH OF
`THE CLAIMED FEATURES OF THE ’984 PATENT .............................. 27
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`X.
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`CONCLUDING STATEMENTS ................................................................. 90
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`XI. APPENDIX A – LIST OF EXHIBITS ......................................................... 92
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`XII. APPENDIX B – CURRICULUM VITAE ................................................... 95
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`i
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
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`I, Michael A. Thomas, M.D., declare as follows:
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`I.
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`QUALIFICATIONS
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`1.
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`I received my B.S. in 1980 from Northwestern University and my
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`M.D. from the University of Illinois College of Medicine in 1984. After medical
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`school, I was a resident in obstetrics and gynecology at Wayne State University in
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`Detroit. After a successful 4 years in residency, I received a competitive position
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`as a Fellow in the Section of Reproductive Endocrinology and Infertility at
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`Northwestern University under the mentorship of Dr. Robert W. Rebar. My
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`fellowship program relocated to the University of Cincinnati College of Medicine
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`when Dr. Rebar became the Chairman of the Department of Obstetrics and
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`Gynecology.
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`2.
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`Since 1990, I have been a practicing obstetrician, gynecologist, and
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`reproductive endocrinologist at the University of Cincinnati College of Medicine
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`and see patients regularly to this day.
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`3.
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`In addition, I was appointed to numerous administration positions
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`during my tenure at the University of Cincinnati College of Medicine. For
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`example, in 1997, I was selected to be the Associate Director of Reproductive
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`Medicine Research (Clinical Trial Unit). I also served as Co-Director, Center for
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`Reproductive Health from 1998-1999; Director, Center for Reproductive Health
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`from 1999-2002; and Associate Chairman for Clinical Affairs from 2004-2005. I
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`1
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
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`have also served in a number of other leading roles in the field of obstetrics and
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`gynecology
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`including acting as
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`the Co-Medical Director, IVF (In-Vitro
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`Fertilization) Program, Health Alliance of Greater Cincinnati from 2000-2002. I
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`am currently the Division Director and Fellowship Director, Division of
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`Reproductive Endocrinology and Infertility, Department of Obstetrics and
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`Gynecology (a position I have held since 2001); Director, Reproductive Medicine
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`Research (a position I have also held since 2001); and Vice Chair, Clinical
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`Research, Division of Obstetrics and Gynecology (a position I recently was
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`appointed to in 2014).
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`4.
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`In addition to my medical practice, I also teach on the topics of
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`contraception and reproductive endocrinology at the University of Cincinnati
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`College of Medicine where I began as an Assistant Professor in 1990 and steadily
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`rose in the ranks to become a fully tenured Professor in 2006.
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`5.
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` In addition to teaching and mentoring medical students, residents and
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`fellows at the University on reproductive endocrinology and contraception, I am
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`also regularly invited to speak both nationally and internationally, on varied topics
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`in and related to the these areas. These include the endocrinology of contraception,
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`the history of contraceptive development, innovations in contraception and how to
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`design, implement, and interpret the results of a contraceptive clinical trial.
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`2
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
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`6.
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`I have trained 24 fellows in Reproductive Endocrinology and
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`Infertility and I have been the Fellowship Director of 12 fellows at the University
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`of Cincinnati College of Medicine. There are only 42 fellowship training programs
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`offered in the United States for individuals interested in being certified as a
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`subspecialist in reproductive endocrinology and infertility. I have been the
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`Director of our program for 14 years.
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`7.
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`I have been honored as an oral examiner for the American Board of
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`Obstetrics and Gynecology, named Best Doctor in Newsweek Magazine,
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`Cincinnati Magazine (2000-present), Cincy Magazine (2009-present), and
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`Woodward and White (1999-present) and chosen as an ad hoc or associate editor
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`for several prestigious journals in the obstetrics and gynecology field, including
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`Contraception, Fertility and Sterility, Journal of Reproductive Medicine, Journal of
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`the National Medical Association, and OBGYN Clinical Alerts. I have also held
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`the office of Board Chair of the Association of Reproductive Health Professionals
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`and Chair of the Patient Education Committee of the American Society for
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`Reproductive Medicine. I am currently a Board Member of the Society for Family
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`Planning and a peer-elected member of the American Society for Reproductive
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`Medicine, Endocrine Society, the Society of Family Planning (charter member),
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`and the Society for Gynecologic Investigation.
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`3
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
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`8.
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`I have been a researcher in contraceptives for 25 years. Significantly,
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`since 1995, I have been a Principal Investigator of the Contraceptive Clinical Trials
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`Network (CCTN). The CCTN is an esteemed group of university investigators that
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`have been selected by the National Institute of Health through an intense
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`competitive process, to develop and test new and innovative contraceptive pills,
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`patches, rings, IUDs, and other devices in men and women.
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`9.
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`I have been the principal investigator on over 21 clinical trials, 19 of
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`which involved contraceptive methods including oral contraceptives. For example,
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`since 1988, I have been involved as a Principal Investigator or Co-Investigator in
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`the Phase 2 or Phase 3 development of later FDA-approved oral contraceptive
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`regimens, including Yasmin® and Yaz®. Currently, I continue to research
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`innovative contraceptive methods, including pills containing ulipristal acetate or
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`desogestrel-only, as well as a vaginal ring contraceptives containing nestorone and
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`ethinyl estradiol.
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`10.
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`I have authored, co-authored, or presented over 150 journal articles,
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`book chapters, review articles, or meeting presentations.
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`11.
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`I am licensed to practice medicine in Ohio and Kentucky.
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`12. A copy of my current curriculum vitae is included herein in Section
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`XII.
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`4
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
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`II.
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`SCOPE OF WORK
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`13.
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`I have been retained by McGuireWoods LLP, counsel for Mylan
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`Pharmaceuticals Inc. (“Petitioner”), as a technical expert in this matter. I receive
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`$500 per hour for my review and consulting services and $750 per hour for my
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`testifying services, but no part of this compensation is dependent on my opinions
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`or on the outcome of this or any other judicial or administrative proceeding. I have
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`no financial interest, beneficial or otherwise, in any of the parties.
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`14.
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`I have been asked by counsel for the Petitioner to offer an expert
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`opinion on the state of the art of the contraceptive field prior to the earliest filing
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`date of U.S. Patent No. 7,704,984 (“the ’984 patent”) and on the validity of all
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`claims of the ’984 patent. In connection with my analysis, I reviewed the ’984
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`patent and its prosecution history. I have also reviewed and considered various
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`other documents in arriving at my opinions, and may cite to them in this
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`declaration. For convenience, the information I considered in arriving at my
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`opinions is listed in Section XI.
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`III. OVERVIEW OF THE ’984 PATENT
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`15.
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`The ’984 patent (Ex. 1001) is entitled “Extended Estrogen Dosing
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`Contraceptive Regimen.” I have been informed and understand that the
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`application for the ’984 patent, U.S. Patent Application No. 11/112,290 (“the ’290
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`5
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
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`application”) was filed on April 22, 2005, and does not claim priority to any other
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`U.S. Patent or U.S. Patent Application.
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`16.
`
`Therefore, I have been informed and understand that the earliest
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`effective priority date for the ’984 patent is April 22, 2005, and that the time prior
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`to and up to this date should be the focus when considering the state of the art and
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`the validity of the claims of the ’984 patent.
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`17.
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`The ’984 patent relates to a method of contraception to a female of
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`child-bearing age comprising the sequential daily administration of three
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`compositions over a 28-day cycle: (1) a first composition containing a progestin in
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`an amount equivalent to about 0.3 to about 1.5 mg norethindrone acetate
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`(“NETA”) (claim 1 and 7) or norethindrone (“NE”) (claim 1) and an estrogen in
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`the amount of 5 to 15 (cid:541)g of ethinyl estradiol (“EE”) for about 24 days; (2) a second
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`composition containing 5 to 15 (cid:541)g of EE but without progestin for 2 days; and (3) a
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`third composition that is a placebo for 2 days. (Ex. 1001, 2:35-45). The sequential
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`administration is started on the first day of the female’s menstrual cycle. (Id.,
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`2:54-55).
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`18.
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`I understand that the ’984 patent issued with nine (9) claims, two of
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`which are independent. I further understand, as discussed below, that the
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`differences between the independent claims (claims 1 and 7) are insignificant.
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`6
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
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`19.
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`I have been advised by counsel for Petitioners that the validity of each
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`of claims 1-9 of the ’984 patent is being challenged through a petition for inter
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`partes review of the ’984 patent (“Petition”), for which my declaration including
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`the opinions therein are being proffered in support.
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`20. Claim 1 is an independent claim and recites:
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`A method of contraception comprising the steps of sequentially
`administering to a female of child-bearing age:
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`(a) a first composition containing a progestin in an amount equivalent
`to about 0.3 to about 1.5 mg norethindrone acetate wherein the
`progestin is selected from norethindrone acetate or norethindrone and
`5 to 15 mcg of ethinyl estradiol for 24 days;
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`(b) a second composition containing 5 to 15 mcg of ethinyl estradiol
`and substantially free of a progestin for 2 days; and
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`(c) a third composition that is a placebo,
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`wherein the sequential administration of the first composition, the
`second composition and the third composition, is performed on a daily
`basis over a 28 day cycle.
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`21. Claim 7 is the second independent claim and recites:
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`A method of contraception comprising the steps of sequentially
`administering to a female of child bearing age:
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`(a) a first composition containing about 0.3 to about 1.5 mg
`norethindrone acetate and 5 to 15 mcg ethinyl estradiol for 24 days;
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`7
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
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`(b) a second composition containing 5 to 15 mcg of ethinyl estradiol
`and substantially free of a progestin for 2 days;
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`(c) a third composition that is a placebo for 2 days,
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`wherein the sequential administration of the first composition, the
`second composition and the third composition is performed on a daily
`basis over a 28 day cycle.
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`22.
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`Therefore, it is my understanding that the sole differences between
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`independent claims 1 and 7 is that claim 7 recites that the progestin is NETA,
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`whereas claim 1 recites that the progestin can be NETA or norethindrone; and that
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`claim 7 affirmatively recites that the placebo is given for 2 days, whereas in claim
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`1, the 2-day administration of the placebo is implied.
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`23. Claim 2 depends from claim 1 and further recites that the sequential
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`administration is repeated beginning the day after completion of the 28-day cycle.
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`Claim 3 depends from claim 1 and further limits the progestin present in the first
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`composition to NETA. Claims 4 and 8 depend from claims 3 and 7, respectively,
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`and further limit the NETA in the first composition to a dosage of 1 mg. Claim 5
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`depends from claim 1 and further requires that the placebo contains about 75 mg of
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`ferrous fumarate. Claims 6 and 9 depend from claims 4 and 7, respectively, and
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`further required that the amount of EE in the first and second composition is the
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`same.
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`8
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
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`24.
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`In my opinion, as explained in further detail below, claims 1-9 of the
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`’984 patent would have been obvious to a person of ordinary skill in the art
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`(“POSA”) in the field of obstetrics and gynecology, specifically in the field of
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`contraception, prior to or at the time of filing of the earliest priority date of the
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`’984 patent, i.e., April 22, 2005.
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`IV.
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`PROSECUTION HISTORY OF THE ’984 PATENT
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`25.
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`It is my understanding that the ’290 application was filed on April 22,
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`2005, with 23 claims directed toward a contraceptive regimen comprising the
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`administration of a first composition containing a combination of an estrogen and
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`progestin for 22-26 days, followed by the administration of unopposed estrogen
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`(i.e., estrogen only and no progestin) for about 2-3 days, with or without the
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`subsequent administration of a placebo period for 1-4 days. (Ex. 1002, Original
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`Claims). The claims specified particular administration regimens depending upon
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`whether or not the placebo period was present. (Id.) By Preliminary Amendment,
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`eight claims were added, including two independent claims directed to a specific
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`24-2-2 regimen and dependent claims that narrowed the amount of EE from 5-20
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`(cid:541)g to 5-15 (cid:541)g. (Id., Oct. 29, 2008, Preliminary Amendment). It is my
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`understanding that, in response to a requirement by the Patent Office, the
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`Applicants elected to pursue the method claims and selected NETA for the
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`9
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
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`progestin and EE for the estrogen in the claims. (Id., Jan. 28, 2009, Response to
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`Restriction Requirement).
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`26.
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`It is my understanding that the Patent Office rejected claims 1-3, 5, 6,
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`9, 10, 24, and 25 as anticipated by U.S. Patent No. 5,756,490 (“the ’490 patent”).
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`(Id., Mar. 30, 2009, Office Action at 7-8). It is my further understanding the Patent
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`Office rejected claims 4, 7, 8, 11, 12, 28, and 29 as obvious over the ’490 patent in
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`view of Loose-Mitchell et al., Ch. 58 Estrogens and Progestins. Goodman &
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`Filman’s The Pharmacological Basis of Therapeutics, 10th ed., Hardman, JG,
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`Limbrid LE, and Gilman AG, eds., McGraw-Hill, pp. 1597-1634 (2001) (“Loose-
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`Mitchell”) in further view of International Publication No. WO 98/04268 (“Gast”).
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`(Id. at 8-10). In response to these rejections, it is my understanding that the
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`Applicants canceled certain claims and amended claim 1 to limit the progestin in
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`the first composition to NE or NETA and the estrogen to EE at a dosage of 5-15
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`(cid:541)g. (Id., Jul 13, 2009, Amendment at 2). Claim 1 was further amended to specify
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`that the first composition is to be administered for 24 days and that the third
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`composition, a placebo, was no longer optional but affirmatively required in the
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`regimen. It is my further understanding that, in their remarks, the Applicants noted
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`that the amendment of claim 1 results in the administration of 2 days of placebo.
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`(Id. at 5-6).
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`10
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 12
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`27.
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`It is also my understanding the Applicants argued that because the
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`’490 patent allegedly did not specifically discuss a placebo, it taught away from the
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`claimed invention. Specifically, I understand that Applicants argued that the ’490
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`patent explicitly touted the importance of maintaining a continuous dosage of
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`estrogen to avoid breakthrough bleeding. (Id. at 6-7). Therefore, the Applicants
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`argued that a POSA would not have had a reasonable expectation of success of
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`using a very low level of EE and introducing a placebo period. (Id. at 7-8). The
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`Applicants further argued that there would not have been a reasonable expectation
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`that the specific 24-2-2 regimen at the specific amounts claimed would have been
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`contraceptive effective given the “25% to 75% reduction in ethinyl estradiol used
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`in presently available commercial products.” (Id. at 8). In support of these alleged
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`unexpected results, the Applicants submitted a Declaration of Herman Ellman
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`under 37 C.F.R. § 1.132 (“Ellman Declaration”), in which he claimed that it was
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`unexpected that the alleged commercial embodiment of the claimed invention
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`maintained a Pearl Index similar to other combination oral contraceptive (“COCs”)
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`despite a reduction in EE levels in the claimed invention. (Id. at 7).
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`28.
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`It is my understanding the Examiner maintained his rejections, noting
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`that a placebo was obvious because “breaks in steroid administration are common
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`in the oral contraceptive art.” (Id., Nov. 2, 2009, Final Office Action at 4). I
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`further understand that the Examiner did not find the Ellman Declaration
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`11
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 13
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`persuasive because it provided several examples of COCs that included placebos
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`and “the presence of a placebo does not negatively affect the capacity of an oral
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`contraceptive to reduce pregnancy.” (Id.). I also understand that the Examiner
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`further noted that a POSA would have been motivated to use a placebo with the
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`method of the ’490 patent to induce menses. (Id. at 3).
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`29.
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`It is my understanding that after additional exchanges between the
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`Patent Office and the Applicants, the Examiner allowed the claims and provided
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`the following as his reason for allowance:
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`The prior art does not anticipate or render obvious the claimed invention.
`After an extensive search of the art, Examiner found no art that teaches or
`suggests an ultra low dose of ethinyl estradiol (5-15 (cid:541)g) and a placebo
`period of any length in a biphasic regimen lasting 28 days.
`
`(Id., Feb. 12, 2012 Notice of Allowance) (emphasis in original).
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`V.
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`LEGAL STANDARDS
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`30.
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`I have been informed that a claimed invention is not patentable under
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`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
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`prior art are such that the subject matter as a whole would have been obvious to a
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`POSA at the time the invention was made.
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`31.
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`I have been instructed that a determination of obviousness requires
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`inquiries into (1) the scope and content of the art when the invention was made; (2)
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`the difference between the art and the claims at issue; (3) the level of ordinary skill
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`12
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 14
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`in the pertinent art when the invention was made; and, to the extent they exist, any
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`secondary considerations of non-obviousness.
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`32.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art, a POSA could have combined the elements
`
`as claimed by known methods with no change in their respective functions, and the
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`combination would have yielded nothing more than predictable results.
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`33.
`
`I understand that hindsight must not be used when comparing the
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`prior art to the invention for obviousness. Thus, a conclusion of obviousness must
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`be firmly based on knowledge and of a POSA at the time the invention was made
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`without the use of post-filing knowledge.
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`34.
`
`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some supporting rationale for combining cited references as
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`proposed.
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`35.
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`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a prior
`
`art to create the patented invention. Obviousness may also be shown by
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`demonstrating that it would be have been obvious to combine the teachings of
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`more than one prior art. In determining whether the teachings of one prior art
`
`could have been combined with the teachings in other prior art or with other
`
`13
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 15
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`
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`information within the knowledge of a POSA, the following examples of
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`approaches and rationales may be considered:
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`36. Combining prior art elements according to known methods to yield
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`predictable results;
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`37.
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`Simple substitution of one known element for another to obtain
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`predictable results;
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`38. Use of a known technique to improve similar methods or products in
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`the same way;
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`39. Applying a known technique to a known method or product ready for
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`improvement to yield predictable results;
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`40. Applying a technique or approach that would have been “obvious to
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`try” (choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success);
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`41. Known work in one field of endeavor may prompt variations of it for
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`use in either the same field or a different one based on design incentives or other
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`market forces if the variations would have been predictable to a POSA;
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`42.
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`Some teaching, suggestion, or motivation in the prior art that would
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`have led a POSA to modify the prior art reference or to combine prior art teachings
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`to arrive at the claimed invention.
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`14
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 16
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`43.
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`I also understand that “secondary considerations” may be considered
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`when in evidence to rebut a conclusion of prima facie obviousness where
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`appropriate.
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`44.
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`I understand
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`that such secondary considerations
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`include: (a)
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`commercial success of a product due to the merits of the claimed invention; (b) a
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`long-felt, but unsatisfied need for the invention; (c) failure of others to find the
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`solution provided by the claimed invention; (d) deliberate copying of the invention
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`by others; (e) unexpected results achieved by the invention; (f) praise of the
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`invention by others skilled in the art; (g) lack of independent simultaneous
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`invention within a comparatively short space of time; and (h) teaching away from
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`the invention in the prior art. Secondary considerations are relevant where there is
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`a connection, or relationship, between the evidence and the claimed invention.
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`VI.
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`LEVEL OF ORDINARY SKILL AND THE RELEVANT TIME
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`45.
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`I have been advised that “a person of ordinary skill in the relevant
`
`field” is a hypothetical person who is presumed to have known the relevant art at
`
`the time of the invention. A POSA is also a person of ordinary creativity. I have
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`been advised that the relevant timeframe for assessing the validity of the ’984
`
`patent is the time prior and up to April 22, 2005.
`
`46. By virtue of my education, experience, and training, I am familiar
`
`with the level of skill in the art of the ’984 patent in the April 22, 2005 timeframe.
`
`15
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`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 17
`
`
`
`
`
`In my opinion, a POSA in the relevant field in April 2005, would have a medical
`
`degree and at least 5 years of experience administering or developing oral
`
`contraceptives, or alternatively, would have at least an advanced degree in
`
`pharmaceuticals sciences, medicinal chemistry, or a related field and at least 7-10
`
`years of experience in the design, formulation, or evaluation of oral contraceptive
`
`dosage forms. A POSA may work as a part of multi-disciplinary team and draw
`
`upon not only his or her own skills, but also take advantage of certain specialized
`
`skills of others in the team, to solve a given problem.
`
`VII. CLAIM CONSTRUCTION
`
`47.
`
`I have been advised that, in the present proceeding, the ’984 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification and that this standard differs from the standard used in district court
`
`patent litigation proceedings. I also understand that, at the same time, absent some
`
`reason to the contrary, claim terms are typically given their ordinary and
`
`accustomed meaning as would be understood by a POSA. I have been advised that
`
`all of the terms of the ’984 patent should be given their plain and ordinary
`
`meaning, and I have followed these principles in my analysis throughout this
`
`declaration.
`
`16
`
`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 18
`
`
`
`
`
`VIII. THE STATE OF THE PRIOR ART
`
`48.
`
`The predictable menstrual cycle of a typical female of child bearing
`
`age involves follicle development, ovulation (i.e., release of an egg), and then the
`
`preparation of the endometrium for implantation of a fertilized egg (embryo). (See
`
`Clinical Gynecologic Endocrinology and Infertility, (6th ed.) Speroff, L. and M.A.
`
`Fritz, eds., Lippincott, Williams & Williams, Baltimore, MD (1999), 123-157,
`
`201-245, 861-942 (Ex. 1013) at 125). If implantation of the fertilized egg occurs,
`
`pregnancy is initiated and the embryo begins to develop. However, if implantation
`
`does not occur or is prevented by some means (i.e., contraception), the
`
`endometrium will shed (i.e., menses). (Id. at 132). The typical menstrual cycle of
`
`women of reproductive age ranges from 25 to 32 days, with most women
`
`averaging 28 days. (Id. at 238). Menstrual cycle length is determined from the
`
`first day of the onset of menstrual bleeding until the onset of menstruation in the
`
`subsequent cycle. (Id. at 237).
`
`49.
`
`In the typical 28-day cycle, the first portion of the menstrual cycle is
`
`called the proliferative or follicular phase, which is when estradiol, the natural
`
`form of estrogen, is the predominant hormone produced by the ovary. (Id. at 127).
`
`Initiation of follicular growth, or folliculogenesis, begins during the last few days
`
`of the previous menstrual cycle and ends with ovulation. (Id. at 230). Ovulation
`
`17
`
`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 19
`
`
`
`
`
`occurs when the estradiol levels reach peak concentrations values between 250-500
`
`pg/ml. (Id. at 210).
`
`50. At the time of ovulation, when the egg is released, estrogen levels
`
`decrease and progesterone becomes the dominant hormone that is produced by
`
`what is now called the corpus luteum (which was formerly the follicle), and the
`
`second portion of the menstrual cycle, called the secretory or luteal phase, begins.
`
`(Id. at 230). During the luteal phase, progesterone stops the growth of the
`
`estrogen-stimulated endometrium, therefore allowing an environment for an
`
`embryo to implant and develop. (Id. at 129-132). This phase generally lasts 13 to
`
`14 days and continues until a pregnancy takes place. If no pregnancy occurs,
`
`menstrual bleeding takes place. (Id. at 132).
`
`51. Oral contraceptives (OCs) are medicines designed
`
`to prevent
`
`pregnancy by using exogenous hormones
`
`(e.g., progestin
`
`(a synthetic
`
`progesterone) with or without estrogen) to disrupt the menstrual cycle and prevent
`
`a woman’s egg from developing each month. OCs accomplish this physiologically
`
`by mimicking pregnancy and suppressing the ability of the pituitary gland to make
`
`follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in
`
`a suppression of the endogenous estradiol, and in turn, prevents ovulation. (See
`
`Murphy, AA et al., “Effect of low-dose oral contraceptive on gonadotropins,
`
`18
`
`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 20
`
`
`
`
`
`androgens, an sex hormone binding globulin in nonhirsute women,” Fertil. Steril,
`
`53(1):35-39 (1990) (Ex. 1014); Ex. 1013 at 873).
`
`52.
`
`Since its introduction in 1960, the standard OC pill contained a
`
`combination of a supraphysiologic (i.e., higher than normal) dose of a progestin (a
`
`synthetic progesterone) and a synthetic estrogen (i.e., a “COC”), or a progestin
`
`alone. The progestin is the primary component of the two hormones that confers
`
`the contraceptive effect. (Ex. 1013 at 873; Hatcher, R.A. and A. Nelson,
`
`“Combined hormonal contraceptive methods,” in Contraceptive Technology, (18th
`
`ed.), Hatcher, R.A. et al., eds., Ardent Media, Inc., New York, NY (2004), 391-460
`
`(Ex. 1019) at 392). Most progestins are derived from the same structure as an
`
`androgen, for example testosterone, and each progestin has similar side effects and
`
`contraceptive failure rates. (Ex. 1013 at 867, 874; Coenen, C.M.H. et al.,
`
`“Changes in androgens during treatment with four low-dose contraceptives,”
`
`Contraception, 53:171-176 (1996) (Ex. 1015)). Estrogen alone has little direct
`
`contraceptive effect in the COC, which is why there can be progestin-only
`
`contraceptives, such as Micronor® and Nor-QD®, each of which was approved in
`
`the 1970s and contains only 0.35 mg of NE administered for 28 days. (Physicians’
`
`Desk Reference, 56th ed. (2002) (Ex. 1010) at 2543-2546, 3423-3424). In general,
`
`only a minimal pharmacological level of estrogen is necessary to maintain efficacy
`
`of the COC regimens and to minimize the risk of occurrence of a breakthrough
`
`19
`
`Petitioner Exhibit 1028
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 21
`
`
`
`
`
`ovulation when a woman missed taking a low-dose COC pill just prior to the HFI.
`
`(See, e.g., Guillabaud, J., “The forgotten pill - and the paramount importance of the
`
`pill-free week,” Brit. J. Fam. Plan., 12(4):35-43 (1987) (Ex. 1016)). The more
`
`important function of the estrogen in the COC is to provide stability to the
`
`endometrium and reduce the frequency of unwanted bleeding (commonly referred
`
`to as “cycle control”). (Ex. 1013 at 901-911; Ex. 1019 at 392). Most
`
`commercially-available COCs use EE as the synthetic estrogen component.
`
`53.
`
`Progestin-only OCs (e.g., NE 0.35 mg) are taken daily without a break
`
`and are associated with longer and frequent episodes of irregular bleeding
`
`compared to COCs. (See Belsey, E.M., “Vaginal bleeding patterns among women
`
`using one natural and eight hormonal methods of contraception,” Contraception,
`
`38(2):181-206 (1988) (Ex. 1017)). While progestin-only OCs are used worldwide,
`
`American women appear not to tolerate the irregular bleeding issues associated
`
`with progestin-only OCs and have a higher discontinuation rate (14%) compared to
`
`women in other countries, such as in Eastern Europe (<5%). (See Kovacs, G.,
`
`“Progestogen-only pills and bleeding disturbances,” Human Reprod., 11(2):20-23
`
`(1996) (Ex. 1018)). Thus, for American women, the addition of estrogen, typically
`
`EE, to the progestin in COCs
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