EXHIBIT 1023
`
`EXHIBIT 1023
`
`

`

`Serum levels of d-norgestrel, luteinizing hormone,
`follicle-stimulating hormone, estradiol, and progesterone
`in women during and following ingestion of con1bination
`oral contraceptives containing dl-norgestrel
`
`PAUL F. BRENNER, M.D .
`DANIEL R. MISHE L L, jR., M.D.
`FRANK Z. STANCZYK, PH.D.
`UWE GOEBELSMANN, M.D.
`Los Angel!;s, California
`
`Three formulations of d/-norgestrel were administered dally to groups of three women for
`five consecutive days. The serum levels of d-norgestrel were related to the dosage of
`d/-norgestrel ingested. Peak concentrations in the circulation of synthetic gestagen were
`attained a half hour to three hours after oral administration, followed by a rapid and sharp
`decline in levels until the next dose. Three women recelve'd 500 J.L9 of dl-norgestrel and 50
`Mg of ethinyl estradiol for 21 days followed by six to seven days of no me·dication tor two
`consecutive cycles. The gonadotropins remained suppressed tor four 1o six days when
`therapy was discontinued. The daily concentrations of estradiol varied from less than 5 to
`81 pg. per milliliter, and there was no difference In estrogen values during the nontreatment
`and treatment days. Due to the long half life of. norgestrel, the one-week pill-free interval is
`not long enough for the complete recovery of the reproductive axts from the inhibition of
`oral contraceptives. (AM. J. OBSTET. GYNECOL. 129: 133, 1977.)
`
`to det.ermine rJ-nor(cid:173)
`RAD I OIMMUNOASSAY (RIA)
`gestrel has been used to measure serum concentra·
`tions of this gestagen following oral, intramuscular,
`
`subdermal, and ·intravaginal administ:ration. 1- 8 Direct
`measurement of the cono·aceptive agent in the circula(cid:173)
`tion has become an importas,lt adjunct in the develop(cid:173)
`ment and evaluation of new contraceptive modalities.
`In conjunctimi wiU1 rhe measurement of luteinizing
`hormone (LH), follicle-stimulating hormone (F$1-1), es-
`
`From the Department of Obstetrics a.nd Gynecology,
`University of Soutllern California Sclwnl nf Medicine,
`and Lo.1 Angeles County-University of Southern
`California Medical Center Women's Hospital.
`Supported by a grant frorn the FOt·d Foundation.
`Receivedjo1· publication Felmtary 2.5, 1977.
`RevisedAprilll, 1977.
`AcceptedApri/27, 1977
`Reprint requests: Dr. Paul F. Brenner, Department of
`Obstetrics and Gynecology, 1240 N. Mission Rd., Lns
`Angeles, California 90033.
`
`tradiol, and progesterone levels, RIA of the circulating
`gestagen le.vels facititat.es a correlation with the func(cid:173)
`tion of the hypothalamus-pituitary and the ovary.
`This study was undertaken to determine the profile
`and absolute leve.ls of circulating d-norgeslrel, the
`biologically active enantiomer, following ingestion of
`(racemic) dl-norgestrel at tliree commonly used dos(cid:173)
`age levels. Another aim of this investigation was to
`measure serum cl-norgestrel levels in women during
`and after daily ingestion of0.5 mg. of dl-norgestrel and
`0.05 mg. of ethinyl estradiol (Ovral*) ~or two 21 day
`periods interrupted by a six- tO seven-day pill-free
`interval. The purpose of this study was to correlate
`serum d-norgestrel levels with circulating LH, FSH, es(cid:173)
`tradiol, and progesterone levels in order to assess. the
`relationship of serum levels of this drug to suppression
`of hypothalamic-pituitary-ovarian function, particu(cid:173)
`larly d uring· the pill-free interval.
`
`*Wyeth Labs., Philadelphia, Pennsylvania.
`
`133
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`134 Brenner et al.
`
`September 15, 1977
`Am. J. Obstct. Cynecnl.
`
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`Fig. 1. Serum d-norgestrel levels in three subjects receiving
`500 J.Lg ot dl-norgestrel and 50 J.Lg of ethinyl estradiol (Ovnl).
`Arrows indicate lime of ingestion.
`
`Material and methods
`Sul>jects. Twelve healthy women between 23 and 35
`years of age who had regular menstrual cycles and had
`not used contraceptive sterojds for at least three
`months prior to en~ering this study volunteered for
`
`this investigation. All 12 women ovulated during the
`pretreatment cycle as indicated by normal luteal phase
`serum progesterone concentrations.
`Tablets containing 0.5, 0.3, or 0.075 mg. of dl(cid:173)
`norgestrel were administered to three women every
`morning prior to breakfast for five consecutive days,
`beginning on menstrual cycle Day 5. The two higher
`dl-norgestrel doses given consisted of combination
`formulations (Ovral and Lo/Ovral*) containing 0.05
`mg and 0.03 mg of ethinyl estradiol, respectively, while
`the lowestdl-norgestrel dose (Ovrette*) did not contain
`any estrogen. Antecubital venous blood was drawn
`prior tO and 1;'2, 1, l Y2, 2, 3, 4, 6, 8, and 12 hours after
`ingestion of the first dl-norgestrel dose as well as prior
`to and three hours following oral intake of each o f the
`four additional doses. Venous blood samples \Vere also
`obtained each morning for the next five days from
`those six women who had received either one of the
`two combination pills.
`Three other volunteers, beginning on the fifth day
`after the onset of menses, ingested a combination of
`0.5 mg. of dl-norgestrel and 0.05 mg. of ethinyl es(cid:173)
`tradiol (Ovral) each morning for two consecutive 21
`day periods interrupted by a six- to seven-day pill-free
`interval. Antecubital venous blood was d rawn daily
`three hours after oral intake or, during pill-free inter(cid:173)
`vals, at the same time of the day, starting the day the
`first Ovral tablet was ingested and ending seven days
`after the last tablet of the second 21 day period of oral
`contraceptives had been ingested. All blood samples
`were allowed to clot, the sei'Um was separated by cen(cid:173)
`trifugation and stored at - 15° C. until it was analyzed.
`Hormone assays. Serum LH and FSH con cen(cid:173)
`trations were determined by double-antibody RIA's ac(cid:173)
`cording to previously described methods.0
`10 A
`'
`postmenopausal seru m standard was used, and the re(cid:173)
`sults were expressed as milli-Internatiorial Units per
`milliliter (Second International Reference Preparation
`qfhuman men opausal gonadotropin).11 Serum prog es(cid:173)
`terone was measured by RIA as previously reporled
`from this laboratory.12 Our serum estradiol RIN 3 ~vas
`modified in order to avoid measut'ing ethinyl estradiol
`in addition to estradiol. Ethiny! estradiol was found to
`cross react with the anti-estradiol - 17{3 -hemisuccin atc
`- bovine serum albumin serum employed in out· stan(cid:173)
`dard estradiol RlA. Tile serum estradiol RIA used in
`th is study consisted of diethyl ether extraction, micr o(cid:173)
`Celite column partition ch romatography (which failed
`to separate ethinyl estradiol from the estradiol frac(cid:173)
`tion), and utilization of an antiserum which we raised
`
`*Wyeth Labs., Philadelphia, Pennsylvania.
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`Volume 129
`Numbtr 2
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`Serum hormones following d/-norgestrel ingestfon 135
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`Fig. 3. Scwm d-norgestr cl levels in three subjects receiving 75
`p.g dl-nor gestrcl (Ovrette). Arrows indicate time of ingestion.
`
`Table I. Ranges of maximum serum cl-norgesu·el
`levels and levels 24 hours after ingestion observed
`in th ree groups o f three women each who received
`various dosages of dl-norgestrel
`
`dl-Norgcstrel
`dose (1ng.)
`
`M(lximum d-norgestrel
`levels (ng.lml.)
`
`24-hour d-norgestrel
`/evcLf (ng.lml.)
`
`0.5
`0.3
`0.075
`
`6.3-8.0
`3.6-4.2
`1.5-1.9
`
`1.6- 1.9
`0.6-0.9
`0.2-0.5
`
`levels. T he concentrations of circulating d-norgestrel
`observed after oral intake of 0.5, 0.3, and 0.075 mg.
`or dl-norgestrel in three women at each dosage level
`arc depicted in Figs. I to 3. A similar profile of sentm
`d-norgestrel concentr ations was observed following in(cid:173)
`gestion of all three dosages. This pattern is charac(cid:173)
`terized by a rapid r ise to peak levels which were at(cid:173)
`tained within a half hour to th ree hours after ingestion
`in all but one of the nine volunteers studied. Serum
`d-norgestrel levels feU almost as promp tly as they rose,
`once the peak was reached, aver aging 19.5 to 25.6 per
`cent of the initial peak level 24 hours after ingestion of
`the first tablet and 28.6 to 54.1 per cent of the last peak
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`~ 5
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`Fig. 2 . Serum cl-norgcstrel levels in three subjects receiving
`3 00 p.g of dl-norgcstrcl and 30 p.g of cthinyl cstl'adiol (Lo/
`Ovral). Arrows indicate time of ingestion.
`
`again st estradiol-6-(0-carboxymethyl) oxime-bovine
`serum albumin. The latter a ntiserum cross-reacted less
`than 0.1 per cent with ethinyl estradiol. The sensitivity
`of th is RIA was 5 pg. of estradiol per milliliter of
`sci·um. Intra- and inter-assay coefficients of variation
`were Jess than l 0 per cent.
`Serum d-norgestrel levels were assayed by a RIA
`p r eviously developed in this laboratory.' ln this RIA,
`an antiserum against d-norgestrcl-3-(0-carboxymetbyl)
`oxime-e-arninocaproic acid-bovine serum albumin'
`and
`d-norgesu·el-3-(0-carboxymethyl)
`imino-(1251)(cid:173)
`iodohistamine is used . This 1~1-labeled d-norgestrel
`derivative renders this RIA parlicularly sensitive:
`6 pg. of d-nm·gestrel can be measured in 0.1 mi. of
`serum with great precision. Intra- and inter-assay co(cid:173)
`efficients of variation were 4.4 and 4.9 per cent,
`respectively.
`
`Results
`Serum d -norge strel levels following ingestion of
`five d a ily dl-norgestrel doses at three different
`
`

`

`136 Brenner et al.
`
`SeptcmbeJ· 15, 19?7
`Am. J. Obstet. Gynccol.
`
`<W*A
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`Fig. 4.. Subject J.: Sertun d-norgestrel, FSH, LH, estradiol, and progesterone levels during and
`following oral administration of 500 1-1-g of dl-norgcstrel and 50 1-1-g of ethinyl estradiol (Ovral) for two
`subsequent 2 1 day periods interrupted by a six-day pill-free interval.
`
`level 24 hours after the fourth tablet of 0.5, 0.3, and
`0.075 mg. of dl-norgestrel was ingested. In the m~jority
`of Lhc nine subjects studied, the d-norgestrel levels
`measured three and 24 hours after oral dl-norgestrcl
`intake increased in a stepwise manner gradually during
`the five days of study.
`While the profiles of circulating d-norgestrel levels
`were similar, different levels of serum d-norgestrcl
`were measured after administration of the three dif(cid:173)
`ferent dl-norgestrel dosages. As indicated in Table l,
`peak as well as 24 hour d-norgestrellevcls were related
`to the amount of dl-norgestrel ingested. Differences in
`drug levels at these two time intervals were distinct and
`did not overlap foJiowing administration of each of the
`three doses of the pharmacologic agent. For three days
`following ingestion of the last tablet of 0.5 mg. of dl(cid:173)
`norgestrel, serum d-norgcstrel levels exceeded 1 ng.
`per milliliter in all three women while five days after
`
`the last tablet levels were still greater than 0.2 ng. per
`milliliter. ln all women measurable amounts of serum
`d-norgestrel were present five days after ingestion of
`the last tablet of each dosage (see Table I and Figs.
`1 to 3).
`Serum d -norgestrel, LH, FSH, estradiol, and pro·
`gesterone levels in thr ee women during a nd following
`ingestion of 0.5 mg. of dl-norgestrel a nd 0.05 m g. of
`ethinyl estrad iol over two 21 day periods interrupted
`by six or seven pill-free days. Daily LH, FSH, es(cid:173)
`tradiol, and d-norgcsu·eJ levels and weekly serum pro(cid:173)
`gesterone concentrations measured in three women
`during and following the oral administration of 0.5
`mg. of dl-norgestrel and 0.05 mg. of ethinyl estradiol
`(Ovral) for two subsequent 21 day periods interrupted
`by a six- to seven-day pill-free interval are depicted in
`Figs. 4 to 6. Daily serum d-norgestrel levels rose g1·adu(cid:173)
`ally, reaching a plateau which ranged between 4 and 8
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`Volume 129
`Nwnbet· 2
`
`Serum hormones following d/-norgestrel ingestion 137
`
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`CYCLE DAYS
`
`Fig. 5. Subject K.: Serum cl-norgestrel, FSH, LH, estradiol, and progesterone levels during and
`following oral administration of 500 JLg of dl-norgestrel and 50 JLg of ethinyl estradiol (Ovral) for two
`subsequent 21 day periods intenupted by a seven-day pill-free interval.
`
`ng. per milli liter about seven days after ingestion of the
`first tablet While in Volunteer J. (Fig. 4) variation of
`serum d-norgestrel concentrations was modest, wide
`variations were observed in Subjects K. and L. (Figs. 5
`and 6). d-Norgestrel levels declined during the pill(cid:173)
`f,·ce period but remained above 1 ng. per milliliter for
`three to six days after the last dose. Seven days after
`ingestion of the last tablet, d-norgestrel levels were
`0.25 and 0.19 ng. per milliliter and undetectable,
`respectively, in the three subjects.
`Serum LH and FSH levels were suppressed during
`each of the six cycles of drug administration. Midcycle
`LH and FSH peaks were consistently absent. Begin(cid:173)
`ning three to eight days after ingestion of the first tab(cid:173)
`let, LH and FSH levels were suppressed below normal
`levels in the early follicular phase. This suppre~sion
`appeared to be mosl profound seven to 19 days after
`the first dose. Suppression of serum L.H and FSH was
`sustained longer during the second 21 day period of
`oral contraceptive medication than in the first one.
`
`Serum LH and FSH levels did nol rise until three to six
`clays after the last pill.
`Levels of serum estradiol we•·c consistently similar to
`or lower than those observed during the early follicular
`phase of ovulatory cycles. During the second treatment
`cycle. serum estradiol concentrations tended to be even
`lowe•· than during the fi1-st 2 I day period of pill intake.
`ln one cycle (Fig. 6; second cycle), serum e-s[radiol
`levels were consistently within the postmenopausal
`range. No preovulatory serum estradiol or luteal phase
`rise was observed. Serum estradiol levels also remained
`low dul'ing the six-
`to seven-day pill-free interval.
`Serum progesterone concentrations, measured once
`every week, were consistently below 1 ng. per milliliter,
`indicating absence or ovulation (see Figs. 4 to 6).
`
`Comment
`The wide fluctuations or Sel·um d-norgestrel levels
`observed during a 24 hour peri()d rollowing the inges(cid:173)
`tion of dl-norgestrel arc most striking. The rapid rise to
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`138 Brenner et al.
`
`Septemb<:r 16, 197?
`Am. J, Obstct. GynL'COI.
`
`ovUL
`
`L.
`
`~ 12
`
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`
`Fig. 6. Subject L.: Seru m d-norgestrel, FSH, LH, estradiol, and progesterone levels during and after
`oral administration of 500 J.l.g of dl-norgestrcl and 50 p.g of ethinyl estradiol (Ovral) for Lwo sub(cid:173)
`sequent 21 day periods interrupted by a six-day pill-free interval.
`
`maximum levels attained between a half hour to three
`hours after oral intake is followed by a sharp decline of
`circulating d-norgestrel to considerably lower levels
`which prevail during the second half of the 24 hom·
`interval between dl-norgestrel ingestions. When the
`progestogen is administered in a small amount without
`estrogen, levels may fall below those necessary to in(cid:173)
`hibit ovulation during the latter half of the 24 hour
`period between dosages. This may account for rhe
`higher failure rates of this method of contraception.
`Greater contraceptive effectiveness can be attained by
`incr easing the dose of the oral progestogen so that its
`circulating levels, even at the nadir, remain sufficiently
`high to prevent ovulation. Instead of overburdening
`the or ganism with large doses of the progesLogen, re(cid:173)
`sulting in unnecessarily high peak and barely effective
`nadir levels, g'reater contraceptive effectiveness may be
`achieved by developing delivery systems which release
`
`the biologically active progestogen at a constant rate.
`Three of the six women ingesting one tablet of dl(cid:173)
`norgestrel combined with ethinyl estradiol (O~ral or
`Lo/Ovral) for five consewtive days appeared to have
`higher circulating d-norgestrel levels each successive
`day. The three volunteers using one Ovral tablet daily
`for two consecutive 21 day 1>eriods interrupted by a
`six- to seven-day pill-free interval also had increasing
`d-norgestrel levels for the first few days but did not
`demonstrate increasing serum d-norgesLrel concen(cid:173)
`trations during the remaining days of pill ingestion.
`This finding is in disagreement with the observations
`of Weiner and associates.7 These authors found in·
`creasing plasma levels of d-norgestrel during the first
`13 to 15 days of dl-norgcstrel/ethinyl estradiol inges(cid:173)
`tion in four of six women studied. T h ey attributed this
`effect to increasing levels of sex hormone-binding
`globulin which was found to bind ri-norgestrel. 14 T he
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`

`Volu me 129
`Nu mber 2
`
`Serum hormones following d/-norgestrel ingestion 139
`
`d ifference observed among individual patients in each
`study and between both investigations may be ex(cid:173)
`p lained by the assumption that production of sex
`h ormone-binding globulin in response to estrogen
`adminisu·ation may vary among individuals.
`Comprehension of the hormonal events which occur
`dttring the pill-free interval is essential for the under(cid:173)
`standing of the virtually complete contraceptive effec(cid:173)
`tiveness of any oral contraceptive. Nevertheless, litde
`attention has been paid to the pill-free interval in the
`past. In this study, serum d-norgestrcl levels fell af(cid:173)
`ter ingestion of the last pill but remained above 1.2 ng.
`per milliliter for 72 hours thereafter in each of the six
`cycles studied. This level approaches ma.ximum serum
`d-norgcsLTcl concentrations attained during daily in(cid:173)
`gestion of 0.075 mg. of dl-norgestrel (Ovrette). Persis(cid:173)
`tence of substantial sen1m d-norgestrel levels for the
`first three to four days of the six- to seven-day pill-free
`inte1·val appea•·s
`to be responsible for continued
`gonadotropin suppression and thus conLTibutcs to the
`virtually complete effectiveness of th is contraceptive
`method. Serum LH and FSH levels, in fact, did not rise
`u n til four to six days after ingestion of the last pill.
`Follicle maturation normally begins in response to in(cid:173)
`creased ~erum FSH concentrations which start to rise
`on the day preceding the first clay of mcnscs.13 Thus,
`the failure of early follicle stimulation and develop(cid:173)
`ment observed in this study is evidenced by low serum
`estradiol levels which persist during and following the
`pill-free interval. Our findings pertaining to the oral
`contraceptive-fn:e period arc in agreement with those
`of Klein and Mishell,15 who studied serum hormone
`levels for 60 consecutive days following discontinuation
`of oral contraceptives. In the latter study, serum LH
`and FSH levels remained suppressed until the onset of
`
`the first u terine bleeding or longer. The rise in serum
`gonadotropin levels was followed by a rise in serum
`estradiol concentrations two to 12 days thereafter.
`During the six- to seven-day pill-free incerval follow(cid:173)
`ing a 21 day period of daily ingestion of 0.5 mg. of
`dl-norgestrel and 0.05 mg. of ethinyl estradiol,
`sufficiently elevated serum d-norgestrel levels pe1·sist
`long enough to delay the effective r ise of serum FSH
`and LH u n til the next 21 day course of contraceptive
`medication is started. This prolonged suppression of
`gonadotropins d uring the period when conu·aceptive
`steroids are not ingested prevents fol licle maturation.
`By the time gonadotropins begin to rise, another cycle
`of oral contraceptive therapy has begun. Thus, the six(cid:173)
`to seven-day pill-free interval between 21 day periods
`of daily oral intake of 0.5 mg. of dl-norgestrel com(cid:173)
`bined with 0.05 mg. of ethinyl estradiol is not long
`enough to allow the hypothalamic-pituitary-ovarian
`axis to escape from the inhibitory mecllanisms of
`suppression. lt is conceivable, although at present
`unproved, that gonadotropin suppression and lack of
`follicle development, resulting in decreased ovarian
`estradiol production, produce alterations of the intra(cid:173)
`ovarian regulation of follicle development, rendering
`the follicles temporarily less responsive to FSH stimula(cid:173)
`tion and thus extending the recovery p~1ase of the
`hypothalamic-pituitary-ovarian axis.
`
`We thank Dipl. Ing. B. Nieuweboer , Schel'ing A. G.,
`Berlin, West Germany, for supplying the antiserum
`against d-Norgestrel-3-(0-carboxymethyl) oxime-E(cid:173)
`aminocaproic acid-bovine se1·um albumin. The expert
`technicaJ assistance of Claire E . Osborn and David P.
`Fisk in carrying out serum estradiol, progesterqne,
`FSH, and LH RIA's is acknowledged.
`
`REFERENCES
`I. Stanczyk, F. Z., Hiroi, M. , Goebelsmann, U., Brenner, P.
`F., Lumkin, M. E., and Mishell, D. R., Jr.: Radioim(cid:173)
`munoassay of serum d-norgestrel in women followi ng
`ontl and intravaginal administration, Contraception 12:
`279, 1975.
`2. Victor, A., Ecilqvist, L.-E., Lindberg, P., Elamssnn, K., and
`Johansson, E. D. B.: Peri pheral plasma levels of
`d-norgestrel
`in women after oral administration of
`d-norgestrel and when using intravaginal r ings impreg(cid:173)
`nated with dl-norgcstrcl, Contl'aception 12: 26 1, 1975.
`3 . Weiner, E., Johansson, It D. B .. and Wide, L.: Inhibition
`of the positive feedback of oestradiol during treatment
`with sub<:utaneous implant.~ of d-norgestrel, Contracep(cid:173)
`tion 13: 287, 1976.
`•1. Weiner, E., and Johansson, F.. D. B.: Plasma levels of
`d-norgestrel, estradiol, and progesterone during treat(cid:173)
`ment with Silastic implants containing d-norgestrel, Con(cid:173)
`traception 14: 81, 1976.
`
`5. Victor, A., and Johansson, E. D. B.: Plasma levels of
`d-norgestrel and ovarian function in women using intra(cid:173)
`vaginal rings impregnated with dl.-norgestrel for several
`cycles, Contraception 14: 215, 1976.
`6. Weiner, E., and Johansson, E. D. B.: Contraception with
`d-norgestrel Silastic rods. Plasm11 levels of d-norgestrel
`and influence on the ovarian function, Contraception 14:
`551, 1976.
`7. Weiner, E., Victor, A., and Johansson, E. D . B.: Plasma
`levels of d-no1·gestrel after oral adminis~:ration, Con(cid:173)
`traception 14: 563, 1976.
`8. Nilsson, S., Victor, A., Nygren, K.-G.: Plasma levels of
`d-norgestrel a nd sex hormone binding globulin d u ring
`oral d-norgestrel medication immediately after delivery
`and legal abortion, Contraception 15: 87, 1977.
`9. Midgley, A. R.,Jr.: Radioimmunoassay for human follicle
`stimulaLing hormone, j. Clin. Endocrine!. Metab. 27:
`295, 1967.
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`

`140 Brenner et al.
`
`September L5, 1977
`Am. J. Obstet. Gynecol.
`
`10. Midgley, A. R., Jr.: Radioimmunoassay: A method for
`human chorionic gonadotropin and human luteinizing
`hormone, Endocrinology 79: lQ, 1966.
`11. Nakamura, R. M., Nagata, Y., Osborn, C., and Mishell,
`D. R., Jr.: Use of a postmenopausal serum pool as a ref(cid:173)
`erence preparation for RIA of gonadotropins, AcLa En(cid:173)
`doc1inol. 75: 478, 1974.
`12. Thorneycroft, I. H., and Stone, S. C.: Radioimmunoassay
`of serl!lm progesterone in women receiving oral con(cid:173)
`traceptive steroids, Contraception 5: 129, 1972.
`13. Mishcll, D. R., Jr., Nakamura, R. M., Crosignani, P. G.,
`
`Stone. S., Kharma, K., Nagata, Y., and Thorneycroft, I.
`H.: Serum gonadotropin and steroid patterns during rhe
`normal menstrual cycle, AM. J. Oa:STET. GYNECOL. Ill:
`60, 1971.
`14. Victor, A., Weiner, E .. and J ohansson, E. D . B.: Sex hor(cid:173)
`mone binding globulin: The
`t:arricr protein
`for
`d-norgestrel, J. Clin. Endocrinol. Me tab. 43: 24-'1, I 976.
`15. Klein, T . A., ;md Mishell, D . R., Jr.: Gonadotropin, pro(cid:173)
`lactin, and steroid hormone levels after disconti nuation
`of oral contraceptives, AM. j. 0BST£T. GYNF.COL. 127:
`585, 1977.
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
`
`

`

`, --
`
`September 15, 1977
`volume 129, number 2
`
`_, ..
`
`of OBSTETRiCS
`AND GYNECOLOGY
`
`Copyright© 1977 by The C. V. Mosby Company
`
`Editor in Chief
`JOH N I. BREWER
`
`Editors
`FREDERICK P. ZUSPAN • E. J, QUILLIGAN
`
`Associate Editor
`ALBERT B. GERBIE
`
`Editors Emeritus
`HOWARD C. TAYLOR, JR. • ALLAN C. BARNES
`
`Official Publication
`
`AMERICAN GYNECOLOGICAL SOCIETY
`
`AMERICAN ASSOCIATION OF OBSTETRICIANS AND GYNECOLOGISTS
`
`CENTRAL ASSOCIATION OF OBSTETRICIANS AND GYNECOLOGISTS
`
`SOCIETY OF OBSTETRICIANS AND GYNAECOLOGISTS OF CANADA
`
`SOUTH ATLANTIC ASSOCIATION OF OBSTETRICIANS AND GYNECOLOGISTS
`
`PACIFIC COAST OBSTETRICAL AND GYNECOLOGICAL SOCmTY
`
`AME.RICAN BOARD OF OBSTETRICS AND GYNECOLOGY
`
`Published by
`
`THE C . V. MOSBY COMPANY
`St. Louis, Missouri 63141
`
`AJOCAH 129 (2) 117-238 (1977)
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
`
`

`

`American Journal of Obstetrics and Gynecology
`Copyright© 1977 by The C. V. Mosby Company
`
`Clinical opinion
`
`Elective hysterectomy
`Philip Cole, M.D., and Joyce Berlin
`Boston, Massachusetts
`
`Gynecology
`
`Initial pelvic examination Instruction: The effectiveness of three
`contemporary approaches
`Gerald B. Holzman, M.D. , Dianne Singleton, Ph.D., Thomas F. Holmes, Ph.D., and
`Jack L. Maatsch, Ph.D.
`East Lansing, Michigan
`
`Effects of progesterone on some enzymes of fat and carbohydrate
`metabolism in rat liver
`Charles H. Dahm, Jr., M.D ., Junnosuke Minagawa, M.D., and Max Jellinek, Ph.D.
`St. Louis, Missouri
`
`September 15
`1977
`
`117
`
`124
`
`130
`
`(Contents continued on page 7 )
`
`Vol. 129, No. 2, September 15, 1977. The American Journal of Obstetrics and Gynecology is published semimomhly by
`The C. V. Mosby Company, ll830 Westline lndustrial Drive, St. Louis, Missouri 63141.
`Annuol subscription rates.
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`5
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
`
`

`

`Contents continued trom pages
`
`Serum levels of d·norgestrel, luteinizing hormone, follicle-stimulating
`hormone, estradiol, and progesterone in women during and following ingestion
`of combination oral contraceptives containing d/-norgestrel
`Paul F. Brenner, M.D., Daniel R. MisheU, Jr., M.D .. Frank z. Stanczyk, Ph.D., !Inti
`Uwe Gocbelsmann. M.D.
`Los A11geles, California
`
`False positive cervical cytology: An Important reason for colposcopy
`Martin J. Feldman, M.D., Carine C. Seeve, M.D., and Elena Srebnik, B.A.,
`C.T.(I.A .C.)
`lrvilte, Cal(fornia
`
`Plasma prolactin changes during the administration of human menopausal
`gonadotropins in nonovulatory women
`E. Kemmnnn, M.D., C. A. Gemzell, M.D., W. C. Beinert, 13.S., C. B. Beling, M.D.,
`and J. R . .Iones, M.D.
`Brooklyn. New York
`
`Microbiological Investigation of Bartholin's gland abscesses and cysts
`Yhu-Hsiung Lee, M.D. , Joel S. Rankin. M.D., Susan Alpert, A. Kathleen Daly, and
`William M . McCormack, M.D.
`Bosto11, Manachusens
`
`Mechanism of crystallization of purified human mldcycle cervical mucus
`Masahiko Saga, Tohru Okigaki, Val Davajan, and Robert M. Nakamura
`Los Angeles. California
`
`Obstetrics
`
`Effect of pregnancy hormones on herpesvirus and other deoxyribonucleic
`acid viruses
`Marvin S. Amstey, M.D .
`Rochester, New York
`
`Pathogenesis and management of uterine inertia complicating abruptio
`placentae with consumption coagulopathy
`Geoffrey Sher, M.B., Ch.B., M.R.C.O.G., F.C.O.G.(S.A.)
`Cape Town, Sowh Africa
`
`Lipid transport and metabolism in the postterm rabbit
`Martin I. Shapiro, Ph.D., and Jacques F. Roux, M.D.
`Montreal, Quebec, Canada
`
`d-Norgestrel concentrations in maternal plasma, milk, and child plasma
`during administration of oral contraceptives to nursing women
`Staffan Nilsson, Knrl-Gllsta Nygren, and EJof D. B. Johansson
`Uppsala, Sweden
`
`133
`
`141
`
`145
`
`150
`
`154
`
`'159
`
`164
`
`17'1
`
`178
`
`(Contents continued on page 9)
`
`7
`
`Petitioner Exhibit 1023
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
`
`

`

`Contents continued from page 1
`
`Fetus, placenta, and newborn
`
`Neonatal scalp abscess and fetal monitoring: Factors associated with Infection
`Donald M. Okada, M.D., Anthony W. Chow, M.D., and Virginia T. Bruce, P.N.P.
`Torrance, California
`
`Determining fetal lung maturity: A sensitive surfactant method
`Larry W. Johnson, Ph.D.
`St. Louis, Missouri
`
`Jsoxsuprine-induced release of pulmonary surfactant in the rabbit fetus
`G. Enhorning, D. Chamberlain, C. Contreras, R. Burgoyne, and B. Robertson
`Toronto, Omario, Canada
`
`Antenatal investigation of human fetal systolic time intervals
`Robert N. Wolfson, M.D ., Ph.D., Ivan E. Zador, M.S., Sasi K. Pillay, Ph.D.,
`llan E. Timor-Tritsch, M.D., and Roger H. Hertz, M.D.
`Cleveland, Ohio
`
`Fetal renal tubular function during late pregnancy and diabetes mellitus
`Robert J. Sokol, M.D., and Philip W. Hall III, M.D.
`Cleveland, Ohio
`
`Current investigation
`
`Presence of immunoassayable p-endorphin in human amniotic fluid :
`Elevation in cases of fetal distress
`J. P. Gautray , A. Joiivet, J. P. Vieih, and R. Guillemin
`Cretc-il, Fmnce, and La jolla, Califomia
`
`Classic pages
`
`Structure moiEiculaire du facteur hypothalamique (LRF} d'orlglne ovlne
`contr61ant Ia secretion de !'hormone gonadotrope hypophysaire de
`lutelnlsatlon (LH)
`Roger Burgus, Madalyn Butcher, Nicholas Ling, Michael Monahan, Jean Rivier,
`Robert Fellows. Max Amoss, Richard Blackwell, Wylie Vale, and Roger Guillemin
`Comptes Rendus deL' Acadhnie des Sciences (Paris), vol. 273, pp. 16/1-1613, /971
`
`Purification, Isolation, and primary structure of the hypothalamic lut