EXHIBIT 1025
`
`EXHIBIT 1025
`
`

`

`Journal of The
`American College
`of Obstetricians
`and Gynecologists
`
`Volume 59
`
`June 1982
`
`Number 6
`
`Biologic Effects of Various Doses of Ethinyl
`Estradiol in Postmenopausal Women
`
`FRED P. MANDEL, MD, FLOR L. GEOLA, MD, JOHN K. H. LU, PhD,
`PETER EGG~NA, PhD, MOHINDER P. SAMBHI, MD,
`JEROME M. HERSHMAN, MD, AND HOWARD L. JUDD, MD
`
`To determine which dosage of estrogen might provide
`physiologic replacement while minimizing adverse effects,
`20 postmenopausal women were studied before and after
`oral administration of elhinyl estradiol. Twenty premeno(cid:173)
`pausal women studied in the early and late follicular phases
`of the menstrual cycle were presumed to reflect normal
`physiologic function. Variable responses of the different
`biochemical and biologic markers to the actions of ethinyl
`estradiol were observed. Liver protein synthesis was the
`most sensitive measure of the action of ethinyl estradiol. In
`comparing the relative potencies of ethinyl estradiol with
`previously reported results observed with the usage of
`conjugated equine estrogens, the actions of 10 pg ethinyl
`estradiol were approximately equivalent to the biologic
`effects of 1.25 mg conjugated estrogens. The results suggest
`that ethinyl estradiol is far more potent than previously
`believed and that the daily administration of 10 pg, a dose
`lower than currently available commercial preparations,
`may be adequate for relief of symptoms of vaginal atrophy
`
`From the Departments of Obstetrics and Gynecology and Medicine,
`University of California; 1/w Medical Services of Wadsworth Veterans
`Administration Hospital, Los Angc/es;mrd Sepulveda Vctcrmrs Admin(cid:173)
`istration Hospital, Sepulveda, California.
`Supported in part by Public Healt/r Service grnuts CA-23093, AC-
`01512, RR-865, and HD-7181 and V. A. Medical Research Funds.
`Submitted for publication fmrrtan; 4, 1982.
`
`and may provide protection from the occurrence of osteopor(cid:173)
`otic fractures. (Obstet Gy11ecol 59:673, 1982)
`
`The postmenopausal syndrome is characterized by a
`constellation of symptoms which are endocrinologic,
`somatic, and psychologic in nature. Estrogen replace(cid:173)
`ment therapy has been shown to be effective for the
`relief of hot flashes and symptoms associated with
`vaginal atrophy and for the prevention of osteoporo(cid:173)
`sis. l-6 Adverse effects include hypertension/ cardio(cid:173)
`vascular illness, 8-ll gallbladder disease, 12 endometrial
`17 and, less well documented, breast can(cid:173)
`cancer, 13-
`cer. ns.r 9 Some of these complications have been shown
`to be dose dependent. 1s·20·21
`Recently Geola et al22 reported the effects of various
`doses of conjugated equine estrogens on several bio(cid:173)
`chemical or biologic parameters of the action of estro(cid:173)
`gen and observed different sensitivities of the various
`target organs. To date, similar information is not
`available concerning the most commonly used synthet(cid:173)
`ic estrogen, ethinyl estradiol (EE). The present study
`was undertaken t6 examine the biologic effects of
`various doses of EE and to compare the results with
`the values reported previously for conjugated equine
`estrogens.
`
`VOL. 59, NO. 6."JUNE 1982
`
`0029-7844/821060673-07$02.50 673
`
`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`Materials and Methods
`Subjects
`
`Twenty postmenopausal patients who had experi(cid:173)
`enced their last menstrual period at least 1 year before
`study and 20 premenopausal women in the early and
`late follicular (vaginal cytology only) phases of the
`menstrual cycle were studied. Some of the results
`observed in the premenopausal subjects have been
`reported previously. 22 None of the subjects had re(cid:173)
`ceived sex steroids for at least 6 weeks before evalua(cid:173)
`tion.
`
`Protocol
`
`All subjects were instructed to fast for 12 hours before
`the study. At 0800 hours they voided and then drank
`250 ml distilled water. After 1 hour a urine specimen
`was collected. Four blood samples were drawn at 15-
`minute intervals beginning at 0800 hours. Vaginal
`smears then obtained from the middle third of the side
`wall of the vagina were immediately fixed with Spray(cid:173)
`Cyte. Repeat studies were performed on the last day of
`administration of each 4-week dosage cycle of EE.* The
`dosages tested were 5, 10, 20, and 50 p.g; the 5- and 10-
`p.g doses were prepared in the University of California,
`Los Angeles, Pharmacy and the 20- and 50-p.g doses
`were obtained from the manufacturer. Ten subjects
`used an increasing dosage schedule beginning with
`the lowest dosage, and the remainder used a decreas(cid:173)
`ing dosage schedule beginning with the highest dos(cid:173)
`age. Treatment was cyclic with a 1-week interval
`between test doses.
`The serum samples were assessed for luteinizing
`hormone (LH), follicle-stimulating hormone (FSH),
`thyroid-binding globulin (TBG), corticosteroid-binding
`globulin (CBG), and sex hormone-binding globulin
`(SHBG). A plasma sample was collected on ice, centri(cid:173)
`fuged within 30 minutes, and assayed for renin sub(cid:173)
`strate. Calcium, hydroxyproline, and creatinine were
`measured in the urine and the ratios of calcium and
`hydroxyproline to creatinine were calculated. It has
`been shown that in a fasting subject urinary calcium
`comes mainly from bone.23 Similarly, it has been
`demonstrated that urinary hydroxyproline in a fasting
`subject mainly reflects the breakdown of bony ma(cid:173)
`trix. 24
`•25 Based on these observations the calcium: crea(cid:173)
`tinine and the hydroxyproline: creatinine ratios were
`used as indices of bone resorption reflecting loss of
`mineral and matrix, respectively. To minimize the
`effects of pulsatile release of gonadotropins on serum
`
`• Supplied by Schering Corporation, Kenilworth, N].
`
`levels, LH and FSH were measured in all 4 blood
`samples collected, and the mean concentration was
`used as the value for that patient. Only 1 measurement
`was made for the other parameters.
`
`Measurements
`
`LH and FSH levels were measured by double antibody
`radioimmunoassay using reagents supplied by the
`27 Results were expressed
`National Pituitary Agency. 26
`•
`as nanograms of LER 907 per milliliter. SHBG levels
`were measured by a selective ammonium sulfate pre(cid:173)
`cipitation technique.28 Serum TBG levels were quanti(cid:173)
`tated by radioimmunoassay using a Corning kit
`(Corning Glass Works, Corning, NY). 22 Previously
`published radioimmunoassay methods were used for
`CBG and renin substrate. 29- 31 Urine calcium concentra(cid:173)
`tion was assessed by atomic absorption. Urine hy(cid:173)
`droxyproline and creatinine concentrations were mea(cid:173)
`sured by autoanalyzer (Technicon Instrument Co, San
`Francisco, CA). With the exception of vaginal cytology,
`all measurements were run i:n duplicate. All measure(cid:173)
`ments in a given subject were run in the same assay.
`The mean coefficient of variation was less than 17% for
`all assays measured in 2 samples obtained 6 weeks
`apart in 15 untreated postmenopausal womenY
`The Student 2-tailed t test was used to determine
`statistical differences between groups. The Student
`paired t test was employed to determine differences of
`values within subjects who were studied repetitively.
`A 99.5% confidence interval was calculated for the
`means of each parameter at each dosage and was
`compared to the confidence intervals of means for the
`premenopausal group and baseline measurements. A
`99.5% confidence level was selected as an adjustment
`for repeated measures. Biologic and statistical signifi(cid:173)
`cance at a .05 level was assumed if the 99.5% confi(cid:173)
`dence intervals did not over'Jap.
`
`Results
`For all parameters of the action of EE there were no
`significant differences between the results observed in
`subjects given an increasing and those given a decreas(cid:173)
`ing dosage schedule. Therefore, the data for all post(cid:173)
`menopausal subjects were analyzed together.
`The data for LH and FSH are shown in Figure 1. In
`premenopausal controls, mean values ( ± SEM) for LH
`and FSH were 55 ± 5 nglml and 195 ± 12 ng/ml,
`respectively. The baseline concentrations of both were
`significantly elevated in the postmenopausal patients
`(LH, 456 ± 38 ng/ml; FSH, 2064 ± 152 ng/ml). The
`levels of both hormones showed a stepwise decline
`with increasing dosages of EE. With the 50-p.g dosage
`
`674 Mandel et al Postmenopausal Etlrinyl Estradiol
`
`Obstetrics & Gynecology
`
`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`both LH (181 ± 23 ng/ml) and FSH (509 ± 52 ng/ml)
`were still significantly greater than the values observed
`in the premenopausal subjects. However, in 1 and 6
`subjects of the postmenopausal group, the levels of LH
`and FSH, respectively, fell into the early follicular
`phase range at this dosage. The smallest dosages of EE
`that elicited a significant reduction of the gonadotro(cid:173)
`pins from baseline were 20 and 10 ~J-g for LH and FSH,
`respective! y.
`Figure 2 shows the mean ( ± SEM) percentage of
`superficial and para basal cells by vaginal cytology.
`Values observed in the premenopausal women early
`and late in the follicular phase are also given. In the
`postmenopausal subjects the baseline percentage of
`parabasal cells (28.1 ± 11.4%) was significantly greater
`and the percentage of superficial cells (0.8 ± 0.4%) was
`significantly less than the values observed in the
`premenopausal subjects either early (parabasal, 4.9 ±
`3.3%; superficial, 6.3 ± 2.0%) or late (parabasal, 0;
`superficiat 42.8 ± 9.2%) in the follicular phase. Five
`micrograms of EE significantly reduced the number of
`parabasal cells (2.8 ± 1.6%) and increased the percent-
`
`2000
`
`1000
`
`0
`
`400
`
`200
`
`E
`.......
`0'1 c:
`I
`(j)
`lL
`
`E
`.......
`0'1 c:
`I
`_J
`
`0
`
`PRE(cid:173)
`MENO
`
`5 10 20 50
`0
`ETHINYL ESTRADIOL
`TREATMENT (f.Lg)
`Figure 1 . . Mean (:!: SEM) serum concentrations of luteinizing hor(cid:173)
`mone (LH) and follicle-stimulating hormone (FSH) in the premeno(cid:173)
`pausal controls (solid bars) and postmenopausal group before and
`after oral administration of various doses of ethinyl estradiol. Dot c
`significantly different (P < .05) from the premenopausal value.
`Asterisk = significantly different (P < .05) from the untreated
`postmenopausal value.
`
`*
`
`60
`
`__J- 40
`<t~ _o
`u-
`-en
`I..I.._J
`a::_J 20
`ww g,u
`
`(f)
`
`0
`
`40
`~
`~
`CD(/) 20
`
`a._J
`_J
`w
`(.)
`
`0
`
`EF LF
`PRE-
`MENO
`
`* * * *
`.........
`0 5 10 20 50
`ETHINYL ESTRADIOL
`TREATMENT (p.g)
`Figure 2. Mean (:!: SEM) for percentage of superficial and parabasal
`(PB) cells by vaginal maturation index in the 2 groups of patients.
`Asterisk = significantly different (P < .05) from the untreated
`groups; EF = early follicular phase; LF = late follicular phase.
`
`age of superficial cells (11.8 ± 3.7%) to values similar
`to those observed during the early follicular phase in
`the ovulatory subjects. Increasing dosage had no de(cid:173)
`monstrable effect on parabasal cells but progressively
`increased the percentage of superficial cells. At the 50-
`~J-g dosage the mean percentage of superficial cells
`(46.4 ± 8.1%) was similar to the value (42.8 ± 9.2%)
`observed in the late follicular phase of the younger
`subjects.
`The urinary calcium: creatinine and hydroxypro(cid:173)
`line :creatinine ratios are depicted in Figure 3. The
`mean ratios were significantly elevated in the untreat(cid:173)
`ed postmenopausal patients (0.131 ± 0.02 and 0.028 ±
`0.02, respectively) over the values in the younger
`women (0.093 ± 0.01 and 0.02 ± 0.0002, respectively).
`EE administration lowered both ratios. For cal(cid:173)
`cium :creatinine, 5 ~J-g EE decreased the ratio to a value
`similar to that observed in the younger women, but 10
`~J-g was the lowest dose that significantly reduced the
`ratio from baseline. Increasing amounts of EE had a
`minimal effect on this ratio. All doses of EE lowered
`the hydroxyproline: creatinine ratio to values interme(cid:173)
`diate between those observed in the premenopausal
`and untreated postmenopausal women.
`
`VOL. 59, NO. 6, JUNE 1982
`
`Mandel et al Postmenopausal Etlrinyl Estradiol
`
`675
`
`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`>-
`.....
`0::
`<( u
`.......
`z
`- u
`0
`0::
`~
`
`. 16
`
`.08
`
`0
`
`•
`
`•
`
`>- u .02
`a::,
`<(
`.....
`zo..
`a:: I
`~ 0
`
`0
`
`5 10 20 50
`0
`PRE-
`MENO ETH INYL ESTRADIOL
`TREATMENT l,u.g)
`Figure 3. Mean (:!: SEM) for urinary calcium :creatinine (Ca/Cr) and
`hydroxyprolinc:creatinine (OHPr/Cr) ratios in the 2 groups. See
`Figure 1 for symbols.
`
`The data on hepatic effects are shown in Figure 4.
`Baseline values of the 4 parameters were not signifi(cid:173)
`cantly different from the levels observed in the pre(cid:173)
`menopausal subjects. With the 5-J.Lg dosage renin
`substrate, TBG, and SHBG were significantly elevated
`above the levels observed in the premenopausal sub(cid:173)
`jects, ie, pharmacologic effects. The 10-J..tg dosage
`significantly increased the CBG-binding capacity. With
`increasing dosages stepwise increases were observed
`for all parameters. With the 50-J.Lg dosage, the levels of
`renin substrate and SHBG were more than 3 times
`higher than in the premenopausal women, and the
`concentrations of TBG and CBG were more than twice
`as high.
`Table 1 compares the biologic effect of 10 J.tg EE with
`the response reported previously22 from the oral ad(cid:173)
`ministration of 0.625 and 1.25 mg of conjugated equine
`estrogens (CE). Responses of each parameter are ex(cid:173)
`pressed as the percentage of change from the baseline
`value. Relative potencies of CE to EE per weight were
`calculated for each parameter and are also listed.
`ParalleE dose-response relationships could not be es(cid:173)
`tablished between the effects of EE and .CE using the
`raw data or single or double log transformations of the
`results. For this reason comparisons were made only
`between the effects of 10 J.Lg of EE and those of 0.625
`and 1.:25 mg of CE. For LH, renin substrate, and
`SHBG, the percentage of changes with EE fell between
`the values found for 0.625 and 1.25 mg of CE. For all
`other parameters the effects of 10 J.tg of EE were greater
`than those exerted with 1.25 mg of CE.
`
`Discussion
`The study was designed to identify a dose of EE that
`would provide physiologic estrogen replacement for
`postmenopausal women and to compare the relative
`potency of this synthetic estrogen preparation with the
`previously reported responses to oral CE administra(cid:173)
`tion. EE was studied because it is a commonly used
`synthetic estrogen preparation.
`The values obtained in the premenopausal women
`during the early and late follicular phases (vaginal
`cytology only) of their menstrual cycles were pre(cid:173)
`sumed to reflect normal physiologic function. If a dose
`of EE was insufficient to alter a specific marker to a
`mean value which was similar to that found in pre(cid:173)
`menopausal subjects, the dosage was considered sub(cid:173)
`physiologic. If the dose changed the marker to a value
`that was similar or greater than the mean premenopau(cid:173)
`sal value, it was considered physiologic or pharmaco(cid:173)
`logic, respectively.
`Using those criteria, no dosage of EE provided
`physiologic estrogen replacement for all parameters
`studied. In fact, each dosage was associated with
`subphysiologic, physiologic, and pharmacologic re(cid:173)
`sponses depending on which parameter was consid(cid:173)
`ered. Therefore, no one parameter could be used to
`determine the potency of EE at all of its sites of action.
`For gonadotropins, increasing doses of EE progres(cid:173)
`sively reduced LH and FSH levels, but even the 50-J.Lg
`dosage resulted in a subphysiologic response. There
`are several possible explanations for this. First, 50 J.tg
`EE may truly be a subphysiologic dose at the level of
`the hypothalamus and pituitary. Second, blood was
`sampled 24 hours after the last dose of medication;
`
`~ .
`
`.. : r;f:
`
`,.
`
`111! • .
`
`0 5 10 20 50
`PRE-
`MENO Elhinyl Eslrodiol
`Treatment (J<g)
`
`Figure 4. Mean (± SEM) serum levels of renin substrate, sex
`hormone-binding globulin (SHBG), and thyroxine-binding globulin
`(TBG) and the serum binding capacity of corticosteroid-binding
`globulin (CBG) in the 2 groups. See Figure 1 for symbols.
`
`676 Mandel et al Postmenopausal Etlrinyl Estradiol
`
`Obstetrics & Gynecology
`
`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`greater suppression of gonadotropin might have been
`perceived had the sample been taken closer to drug
`administration. The 24-hour interval was chosen be(cid:173)
`cause it would reflect the action of the estrogen just
`before the next dose if a patient was taking the
`medication daily, the most common practice. Third,
`other ovarian factors (progesterone, inhibin, etc) might
`be necessary for physiologic gonadotropin suppres(cid:173)
`sion. Last, EE and estrogens secreted by the ovary may
`have different potencies on central feedback.
`For the other parameters, EE had profound effects.
`The 5-f.Lg dosage significantly reduced the number of
`parabasal cells and elevated the number of superficial
`cells to values similar to those reported during the
`early follicular phase in premenopausal women. Fur(cid:173)
`ther increases of EE elevated the proportion of superfi(cid:173)
`cial cells above the range seen during the follicular
`phase in ovulatory women. These data suggest that
`25% of the lowest dose of EE available commercially is
`sufficient to provide physiologic replacement to the
`vaginal epithelium if administered daily.
`The 10 f.'S dose of EE significantly lowered the
`calcium: creatinine ratio from baseline to below that
`observed in the premenopausal women. Studies have
`demonstrated that estrogen is protective to bone. Di(cid:173)
`minished rates of loss of bone density and reductions
`in the incidence of forearm, hip, and spinal fractures
`have all been reported with estrogen administration.
`This protective effect is dose dependent. Previous
`reports have suggested that protective doses of estro(cid:173)
`genic preparations include daily use of CE, 0.625 to
`1.25 mg32; mestranol, 24.833 or 27.8 f.Lg34
`
`; and EE, 25 to
`50 f.Lg. 25 These dosages were arbitrarily chosen. The
`
`Table 1. Comparison of Percent Change from Baseline of
`Parameters and Relative Potency of Ethinyl
`Estradiol and Conjugated Equine Estrogens
`Relative
`potency
`EE:CE
`
`CE
`
`0.625 mg•
`
`1.25 mg•
`
`EE
`(10 pg)
`
`224
`140
`31
`41
`-45
`-41
`-52
`
`78
`75
`>125
`> 125
`>125
`114
`>125
`
`202
`129
`45
`51
`-51
`-40
`-54
`
`134
`86
`2
`32
`-45
`-17
`-35
`
`SHBG
`RS
`CBG
`TBG
`FSH
`LH
`Ca!Cr
`Superficial
`cells1
`>125
`15.1
`12.5
`25.7
`EE = ethinyl estradiol; CE a conjugated estrogens; SHBG = sex
`hormone-binding globulin; RS = renin substrate; CBG = corticoste(cid:173)
`roid- binding globulin; TBG = thyroxine- binding globulin; FSH =
`follicle-stimulating hormone; LH = luteinizing hormone; Ca/Cr =
`urinary calcium :creatinine ratio.
`• Results reported by Geola et al.22
`1 Percentage with specific dosage of medication.
`
`present data suggest that the 10-f.Lg dosage of EE has
`an effect on the urinary calcium: creatinine ratio equiv(cid:173)
`alent to that of 1.25 mg CE (a known protective
`dosage).32 Long-term studies assessing bone density
`and the incidence of fracture must be performed to
`confirm that 10 f.'S of EE also has a protective effect.
`That EE had profound effects on hepatic protein
`synthesis was demonstrated by the doubling of renin
`substrate and SHBG concentrations and the significant
`increase in TBG after the 5-f.Lg dose. CBG was the least
`sensitive marker but was significantly increased by 10
`f.'S of EE, half the lowest commercially available dose.
`The effects of estrogens on the liver are important,
`because altered hepatic function is presumed to be
`responsible for several adverse effects
`including
`11
`35
`36 hyperlipidemia, 37 hypercoagula(cid:173)
`hypertension, 7
`•
`•
`•
`bility,38 and gallbladder disease. 12•39 An increase of
`renin substrate in plasma has been proposed as a
`possible reason for the elevation of blood pressure
`associated with estrogen administration through in(cid:173)
`creased generation of angiotensin40 and through the
`synthesis of abnormal and more active forms of this
`protein. 31 EE is one of the 2 estrogens used in oral
`contraceptives and is used in almost all preparations
`with less than 50 f.'S of estrogen. Oral contraceptive
`use is associated with the same adverse effects. These
`effects appear to be dose related, occurring more
`frequently with use of formulations containing more
`than 50 f.Lg of synthetic estrogen. 41
`'"""3 These complica(cid:173)
`tions are not surprising in light of the present study,
`which shows marked stimulatory effects on hepatic
`protein synthesis with doses of EE far lower than those
`available even in the lowest dose of oral contraceptive.
`These enhanced hepatic effects may be explained by
`an increased hepatic sensitivity to EE or by the fact that
`orally administered estrogens are absorbed by the
`intestines and are delivered to the liver before entry
`into the general circulation. The portal concentration of
`estrogen after oral administration is 4 to 5 times higher
`than the concentration in the general circulation. 44
`Studies are needed to determine if nonoral routes of
`administration avoid these enhanced hepatic actions.
`An attempt was made to assess the relative potency
`of EE and CE. True relative potency could not be
`determined because parallel dose-response curves
`could not be generated despite numerous transforma(cid:173)
`tions of the data. This suggested that the doses of EE
`and/or CE selected for study did not all fall on the
`linear portion of the dose-response curves. Recogniz(cid:173)
`ing this limitation, the authors found that the relative
`potency of EE and CE by weight was approximately
`125:1. There was no difference in relative potency
`between hepatic and nonhepatic parameters. It has
`been suggested that 20 f.Lg EE and 0.625 mg CE can be
`
`VOL. 59, NO. 6, JUNE 1982
`
`Mandel et al Postmenopausal Etlziuyl Estmdiol
`
`677
`
`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`used interchangeably in care of postmenopausal wom(cid:173)
`en.45'46 The present data imply that a lower dose of EE
`(approximately 5 p.g) would be equivalent to 0.625 mg
`of CE.
`In summary, it was observed that all doses of EE,
`ranging from 5 to 50 p.g, were associated with
`subphysiologic, physiologic and pharmacologic re(cid:173)
`sponses at the different sites of actions. Lower doses of
`EE than are available commercially appeared to pro(cid:173)
`vide therapeutic estrogen replacement particularly in
`regard to bone and vaginal epithelium. As with CE,
`oral administration of EE was associated with en(cid:173)
`hanced hepatic action. Other routes of administration
`may avoid excess hepatic stimulation. Investigation of
`parenteral administration is currently under way.
`
`References
`1. Mackinley SM, Jeffreys M: The menopausal syndrome. Dr J Prev
`Soc Med 28:108, 1974
`2. Meld rum DR, Shamonki IM, Frumar AM, et nl: Elevations in skin
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`3. Novak ER, Woodruff JD: Postmenopausal vaginitis, Novak's
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`1974, p 54
`4. Albright F, Smith PH, Richardson AM: Postmenopausal osteopo(cid:173)
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`11. Stem MP, Brown DW, Haskell WL: Cardiovascular risk and use of
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`N Eng! J Med 287:628, 1972
`13. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma
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`14. Smith DC, Brentice R, Thompson Dj, et al: Association of
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`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`

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`
`Address reprint requests to:
`Howard L. Judd, MD
`Division of Reproductive Endocrinologt;
`Department of Obstetrics and Gynecologtj
`UCLA Scltool of Medicine
`Los Attgeles, CA 90024
`
`Accepted for publicatiou Februan; 1, 1981.
`
`Copyright @ 1982 by The American College of Obstetricians an,~
`Gynecologists.
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`VOL. 59, NO. 6, JUNE 1982
`
`Mandel et al Postmenopausal Etltinyl Estradiol
`
`679
`
`Petitioner Exhibit 1025
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`