EXHIBIT 1017
`
`EXHIBIT 1017
`
`

`

`CONTRACEPTION
`
`VAGINAL BLEEDING PATTERNS M10NG WOMEN
`USING ONE NATURAL AND EIGHT HORMONAL METHODS OF CONTRACEPTION
`
`E.t-1. Belsey*
`Epidemiology Unit, Pan American Health Organization
`
`and
`
`Task Force on Long-Ac t ing Systemic Agents
`for Fertility Regulation
`Special Programme of Research, Development and
`Research Training in Human Reproduction
`World Health Organization
`
`ABSTRACT
`
`Menstrual diary records were obtained from a total of 5257 women
`using nine differ ent met hods of contraception , one natura l and e ight
`hormonal. This paper pr esents a comparative analys is of t heir v agi nal
`bleeding patterns. The analytic procedures follow the recommendations
`of a recent WHO workshop on bleeding pattern analysis, which involve
`dividing each subject's diary into successive 90-day reference periods,
`calcula ting ten indices for each peri od, and classifying women
`according to whether they have "clinically important" bleeding
`disturbances.
`
`In general, the findings of this analysis confirm those of previous
`studies. Women using the natural method, who were deliber ately
`selected for the regularity of their menstrual cycles, averaged three
`bleeding/spotting episodes of length 5 days in each 90-day period, with
`very litt l e variability within or between women. Subjects given a
`combined oral contr aceptive had more regular patterns than any other
`treated group, with shor t (4- day) episodes and 23- 24 day bleeding-free
`intervals. ProgP.stogen -only pill users had more f r equent , longer
`episodes and shorter, less predictable intervals than combined pill
`users. Contrary to widely-held beliefs, the progestogen-only pills
`produced fewer spotting days than the combined pills, and almost no
`Ne~rly half of vaginal ring users
`spo~ting episodes~~ ~1 1 .
`experienced some menstrual disturbance in each period; their most
`common problems were irregular, infrequent or prol onged b leeding.
`Women using the long-acting injectable, depot medroxyprogesterone
`acetate, had totally unpredictable patterns, with infrequent but
`prol onged bleeding/spotting episodes . The incidence of amenorrhea rose
`from just under 10% in their fi rst injection interval to over 40% in
`their fourth.
`
`*Present address: Special Programme of Research,
`Development and Research Training in Human Reproduction
`
`Address for correspondence: C. d'Arcangues, Special Programme of
`Research, Development and Research Training in Human Reproduction,
`World Heal t h Organization, 1211 Geneva 27, Switzerland.
`
`AUGUST 1988 VOL. 38 NO. 2
`
`181
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`CONTRACEPTION
`
`The methods of anal ysis recommended by WHO in 1985 still require
`substantial refinement. Nevertheless, they are more sensitive than
`those used previous ly for WHO trials and produce an easily understood,
`cl inically meaningful charac terization of bleeding patterns.
`
`INTRODUCTION
`
`The disturbance i n vaginal bleeding induced by many methods of
`contraception is an i mportant s ide effect beca use of its potential
`impact on acceptability. For more than a decade, therefore, women
`participating in clinical trials of new contraceptive methods have been
`routinely requested to keep a menstrual diary, or daily record of the
`occurrence of bleeding. Attempts to describe the bleeding patterns
`associated with various methods, however, have been hindered by
`difficulties in the a nalysis of the data obtained . At a recent
`workshop on the analysis of vaginal bleeding patterns organized by the
`Special Programme of Research, Development and Research Training in
`Human Reproduction of the World Health Organization , it was agreed that
`deficiencies in the available methods of analy sis should not be allowed
`to delay more detaile d analy ses of the large number of menstrual
`diaries accumulated in a series of clinical trials conducted by the
`Special Programme. Presentation of the findings of even simple
`analyses would supply information badly needed by clinicians. Although
`the effects of varying dosages of the same type of contracept ive method
`have been examined previously, a comparat ive study of the bleeding
`patterns induced by several different types of hormonal contraception
`has never been undertaken. The bleeding patterns experienced by women
`who give some menstrual disturbance as their reason tor discontinuing
`method use have not been objectively analyzed and described; nor h ave
`the relationships between bleeding patterns and subject characteri st i cs
`which could be expected to influence them, such as age , parity and
`previous contracep tive me thod.
`
`In this paper, the patterns o f blood loss recorded by women using
`one of t hree combined oral pills, two progestogen- only pills, two
`dosages of a long-acting injectable , or a vaginal ring are describe d.
`A 8roup of women using a non-hormonal method of contraception, the
`ovulation method, is included for comparison.
`
`The analytic procedures follow the recommendations of the WHO group
`convened in 1985 to discuss this topic (1) . The results t herefore
`serve also to illustrate and test the usefulness and interpretability
`of t he bleeding pattern indices suggested i n their report, a nd provide
`baseline data against which to compare the resul ts of any methods of
`analysis which may be developed in the fu ture .
`
`Tri als and recor ds
`
`METHODS
`
`Menstr ual diary records were obta ined from 5257 women admitted to
`six clinical trials:
`
`182
`
`AUGUST 1988 VOL. 38 NO. 2
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`CONTRACEPTION
`
`1. A study of the use- effectiveness of a natural method of
`contraception (the ovulation method), in which subjects were taught
`to recognise mid-cycle changes in their cervical mucus, so that
`they could avoid intercourse during the fertile phase of the cycle.
`Women were only recruited to this trial if they had regular
`menstrual cycles.
`
`2. A clinical trial of three combined oral contraceptives:
`norethisterone acetate 1.0 mg 1 ethinyl estradiol 0.05 mg
`(NA 1.0 + EE 0.05);
`levonorgestrel 0.25 mg + ethinyl estradi ol 0 . 05 mg
`(LNG 0.25 + EE 0.05);
`levonorgestrel 0.15 mg + ethinyl estradiol 0.03 mg
`(LNG 0 . 15 + EE 0.03).
`
`3. A clinical trial to compare two presentations (paper and tablet) of
`an oral contraceptive containing levonorgestrel 0.15 mg + ethinyl
`estradiol 0.03 mg.
`
`4. A clinical trial of three low-dose oral preparations :
`levonorgestrel 0.15 mg + ethinyl estradiol 0.03 mg;
`norethisterone acetate 0.35 mg (NA 0.35) ;
`levonorgestrel 0.03 mg (LNG 0.03).
`
`5. A Phase II clinical trial to estimate the contraceptive efficacy
`and determine the type and incidence of side effects of a vaginal
`ring releasing 20 ug of levonorgestrel daily.
`
`6. A clinical trial of the effectiveness of depob-medroxyprogesterone
`acetate given every three months in dosages of 100 mg (DMPA 100)
`and 150 mg (DMPA 150).
`
`Thus, nine methods of contraception were used in the six trials.
`Subj ects given LNG 0.15 + EE 0.03 in trials 2, 3 and 4 are combined in
`the analy~cs dc~cribcd below .
`
`The trials were conducted in a total of 34 centres. There was no
`centre in which all six trials were conducted. The number of
`contraceptive methods studied varied from one, in 18 centres, to seven
`(all five oral preparations and both dosages of DMPA) in one centre.
`Conversely, the number of centres in which each contraceptive method
`was used ranged from 3 to 17.
`
`Women using an oral contraceptive, a vaginal ring or DMPA were
`asked to complete a menstrual diary card for the duration of their
`tria l, and to different iate between hleerline rl~y~ (thns~ on which blood
`loss requiring menstrual protection occurred) and spotting days (those
`on which blood loss insufficient to require protection occurred).
`Subjects using the ovulation method were followed-up monthly, and the
`date of their last menstrual period, the length of bleeding and the
`length of the cycle were recorded. Artificial diaries have been
`constructed from this information.
`In this group, however , no
`distinction can be made between bleeding days and spotting days.
`
`AUGUST 1988 VOL. 38 NO. 2
`
`183
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`CONTRACEPTION
`
`Description of the incti vidurtl subjnct's menstrual bleeding pattern
`
`The reference period method (2 ) was used to analyze the menstrual
`diary records. Although all three o ral contraceptive studies cont inued
`for two years, the trials of the ovulation method, vaginal ring and
`DMPA were only one year in length. Analysis of all groups of subjects
`was therefore confined to events occurring in the first 360 days of
`method use.
`
`A bleeding/spotting episode was defined as any set of one or more
`bleeding or spotting days (either consecutive or separated by only one
`bleeding-free day) bounded at each end by t wo or more consecutive
`bleeding-free days. (A bleeding-free day is one on which neither
`bleeding nor spotting was recorded). A spotting episode was defined
`similarly. A bleeding-free interval was defined as any set of two or
`more consecutive bleeding-free days bounded by bleeding or spotting
`days.
`(Thus, a single bleeding- free day was treated as part of the
`episode surrounding it . ) A bleeding/spotting segment was defi ned as
`the sum of a b l ee ding/spotting episode and the immediately following
`bleeding- free i nterval .
`
`Following the mos t recent WHO recommendations (1), 90-day reference
`periods were used, with the first reference period commencing on the
`date of treatment. Each b leeding event (episode or interval) was
`assigned to its appropriate r eference peri od according to the day on
`which it started; that is, an event which started between days l a nd 90
`inclusive was assigned to the first reference period, one which started
`during days 91 -180 was assigned to the second period, and so on. The
`following bleeding pattern indices were found for each woman f or each
`of four consecutive reference periods:
`the numbers of bleeding/
`spotting days, spotting days, bleeding/spotting episodes begun and
`spotting episodes beg,uu; al1ll tlte 111ean, range aud 1uaximwn value of
`b l eeding/spotting episode and bleeding-free interval lengths. Mean and
`maximum values were determined for all women who had a t least one
`episode (or interval) start during the reference period under
`consideration. The range of lengths could only be calculated if the
`subject had two or more episodes (or intervals) as signed to the period.
`
`Indices describing the average length and variability of episodes
`and interval s were first calculated from the even t lengths recorded,
`even if the event overlapped two or more r eference periods. The data
`were then re-analyzed using an approach recommended by the 1976 Exeter
`workshop on bleeding pat tern analysis (3) :
`that any event which is
`still incomplete 20 days after the end of the reference period during
`which it starts should be closed at the 20th day, and i ts truncated
`(rather t han actual) length included in analysis. Descriptions of
`tl.·ends in the Llt:t:Uill~ fH:tl.Lt:t:ll lmll~.,;t:~ iHt: Lii~tH.l Ull tl d.~ ~t:c uml ~t:t ur
`results .
`
`As recommended by WHO (l), subjects were also divided into six
`subgroups for each 90-day reference period, according to whether they
`had:
`
`184
`
`AUGUST 1988 VOL. 38 NO. 2
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`CONTRACEPTION
`
`1. amenorrhea throughout the reference period
`2. infrequ~nt bleeding; fewer than 3 bleeding/spotting episodes
`3.
`frequent bleeding: more than 5 bleeding/spotting episodes
`4.
`irregular bleeding: between 3 and 5 bleeding/spotting episodes with
`less than 3 bleeding-free intervals of length 14 days or more
`5. prolonged bleed ing: l or more bleeding/spo tting episodes lasting 14
`days or more
`6 . none of the above : a
`
`'normal' bleeding pattern.
`
`Although this classification is arbitrary, it produces groups with
`clinically interpretable bleeding patterns. It should be noted that
`groups 1-4 and 6 are mutually exclusive, but prolonged bleeding could
`occur in conjuncti on with any one of infrequent, frequent or irregular
`bleeding.
`
`Statistic al methods
`
`Some of t he contraceptive methods included in this analy sis result
`in bleeding pattern indices with highly skewed distributions. The
`median has the r efore been adopted as the measure of location o f the
`distributions of the i ndices f or each group of subjects, and the 5th,
`25th, 75th and 95th percentiles and smallest and largest observations
`are used to describe the variability between women. Figur es 1-8 are
`modified box - whisker plots (4) of the distributions of all but two of
`the bl eeding pattern indices (the numbers of bleeding/spotting episodes
`and spotting episodes), for each reference period and method of
`contracep t ion. The lines at either end of the smaller, outer box are
`located at t he 5th and 95th percentiles, those at either end of t he
`larger, inner box are located at the 25th and 75th p ercentiles ( lower
`and upper quartiles), and the median is represented by the heavier line
`inside the box.
`(Where the median and one of the quartiles coincide,
`the heavy line i s drawn at the appropriate end of the box. ) The
`end-points of the central horizontal lines, or '\vhiskers', extending
`from t he left-hand and right-hand sides of the outer box show the
`smallest and l a rgest obs ervations, respectively. Fewer summary
`statisti cs are presented for t he numbers of bleeding/spotting and
`spotting episodes, partl y becau se their distributions were relatively
`narrow but also because the occurrence of amenorrhea or infrequent
`bleeding is reported sop~r~t~ly.
`
`The s tatistical s ignificance of differences between study gr oups
`with respect to the indices was determined by means of Kruskal-Wallis
`nonpararnetric analysis of variance (5) .
`
`Exclusions
`
`Yomen who discontinued me thod use in l ess than 360 days or failed
`to complete their menstrual diary for the entire period of observation
`have been excluded from analysis, so that trends in bleeding patterns
`through the year may be examined free from the confounding influences
`of t he ir partial records.
`(The bleeding patterns experienced by
`subjects who discontinued are presented in a subsequent paper.) If a
`woman remained in her trial for 360 days and then discontinued before
`
`AUGUST 1988 VOL. 38 NO.2
`
`185
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`CONTRACEPTION
`
`the end of a n event (episode or interval ) which had s tarted during the
`last ur a p r l:!viou::; J:l:!(l:!!'l:!w.:e tJI:!Ciu<.l ,
`thaL c.;eusure<.l l:!venL was l:!x.clul.ll:!<.l
`from calculation of the mean and range of event lengths.
`
`RESULTS
`
`A total of 525 7 women were studi ed (Table I). Three- thousand-and(cid:173)
`thirty subjects discontinued method use in less than 360 day s, and
`another 75 did not comple te their menstrual diaries for a ful l year,
`even though they r emained in their trial. The proportion of \oomen
`excluded from analysis for any one of the reasons specified above
`ranged from 45% in the DMPA 150 group to 78% among those using the
`ovulation method.
`
`All women included in this analysis started method use within six
`days of the onset of menses. However, Table l shows that the exact day
`on which subjects commenced method use , and thus the day defined to be
`the start of the first reference period , differed between groups. The
`starting point for analysis of the menstrual diary records can affect
`the numbers of bleeding/spotting and spotting days and episodes
`recorded in the first 90 days of melhod use:
`a woman whose first
`reference period commences on the firs t day of a bleeding/spotting
`epi sode wi ll tend to have a higher number of bleeding/spotting and
`spotting days and episodes included in that period than one whose first
`reference period starts later. This means that the findings presented
`in Figures 1 and 2 and Table II-IV need to be viewed in the light of
`the data shown in Table I when comparing the first with subsequent
`reference periods.
`
`Menstrual bleeding patterns
`
`( a) Ovulation method
`
`Women using the one natural method of con traception inc luded in
`this analysis had, on average, 3 bleeding/spotting episodes in each
`90-day reference period, resulting in 15-16 bleeding/spotting days
`(Table II , Figure 1). The mean lengths of their bleeding/spotting
`episodes and bleeding-free intervals were 5 and 25-26 days,
`respectively (Figures 3 and 4), giving bleeding/spotting segments with
`an average length of 30-31 days.
`
`These subjects were deliberate ly selected f or the regularity of
`their menstrual cycles. It is therefore not surprising to f ind that at
`least 50% of women had episodes \olh ich differed in leng th by no more
`than l day, and interva l s which varied by no more than 3 - 5 days,
`depending on reference period (Figures 5 and 6). Extreme events were
`also rare:
`three-quarters of subjects had a maximum epi sode length of
`7 days , and no interval longer than 31 days (Figures 7 and 8).
`
`There was almost as little variability between women in t his group
`as within-woman. The interquartile range of the number of bleeding/
`s potting days was only 6 days. The minimum number of bleeding/spotting
`
`186
`
`AUGUST 1988 VOL. 38 NO. 2
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`

`Table I
`Numbers of subjects included in analysis and day after onset
`of menses on which method use commenced
`
`Method
`
`A l l
`Subjects
`
`Included
`No.
`(%)
`
`Minimum
`
`Median
`
`Maximum
`
`Day method use commenced
`
`Ovulation method
`NA 1.0 + EE 0 . 05
`LNG 0.25 + EE 0.05
`LNG 0 . 15 + EE 0 . 03
`NA 0.35
`LNG 0.03
`Vaginal ring
`OMPA 100
`DMPA 1 50
`
`735
`349
`339
`1 758
`1 3 2
`126
`684
`564
`570
`
`164 22.3
`140
`4 0. 1
`1 4 1
`41 • 6
`722
`41 . 1
`52 39.4
`44
`34 . 9
`284
`4 1 . 5
`291 51.6
`314 55. 1
`
`1
`4
`3
`
`1
`1
`1
`
`5
`5
`
`5
`4
`4
`
`6
`6
`6
`6
`6
`6
`6
`6
`
`All subjects
`
`5257
`
`2152 40.9
`
`(")
`
`0 z
`~ ('j
`~ -0 z
`
`tr1
`
`{Z)
`
`00
`00
`
`;J>
`c::
`0 c:
`~ -\0
`<
`0
`~
`w
`
`00 z
`0
`N
`
`-00
`
`-..J
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`

`CONTRACEPTION
`
`Rgure 1: Number of llleeding/ Sponing Days
`
`Reference PeriOd I
`
`Reference PeriOd II
`
`011\llallon method
`
`--c[[_t::r----(cid:173)
`
`NA 1.1)0/U 0.05
`
`~
`
`LNG 025/EE 0.05
`
`-c:(]J:::::l- -- - -
`
`LNG 0. 1$/EE 0.03
`
`----c:[]]=:"""J,- - --
`
`NA 0.35
`
`LNG 0.03
`
`~'----------- " ---c:a=J-----------
`---QIJ==::=r--
`
`Vagin;ol ring
`
`----c::o:J:==:J~---
`
`OMPA 100
`
`DMPA 150
`
`~ ~ d[==~==;:========:r--------~ ~
`c:JCI=:!====:::::~
`r-1C::::(=r==J::===:=:JI-.1'- • d[=:!:==t:======~ ,.
`. ..
`..
`..
`···----
`"'
`"'
`,.
`
`~
`
`20
`
`10
`
`.0
`
`- .- - 0
`
`Reference Perioo Ill
`
`Reference PeriOd IV
`
`OvuloUon method
`
`-c[]].....:J---
`
`-c[]]:J--
`
`NA 1.00/EE 0.05 ~ -c::QJ=J-
`
`LNG 0.25/EE 0.05 ----c(]JJ--
`
`LNG 0. 15/EE 0.03 ---c[[}:>--
`
`NA 0.35
`
`LNG 0 .03
`
`-c:=[I]::J
`
`·cQJ::=J----
`
`-c\IP-
`-cOJ:=l-
`--cCI:P--
`
`~
`
`Vaglnalring ~ -t::[D:=-=1
`
`OMPA 100
`
`OMPA 150
`
`•
`
`,0
`
`~
`
`~
`
`~
`
`~
`
`.;- " LLJ
`LC:J~=====r---_,_ .. [CJ ~==~-----------~ ..
`.,.. .. --, --· ,..- - .-... --..
`..
`..
`..
`
`....._. eo
`
`·- '
`
`~
`
`~
`
`·a·-.. ;.---;.,
`
`·--r r-' -
`- - - -.. -··{ _j_ - -
`
`188
`
`AUGUST 1988 VOL. 38 NO. 2
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
`
`

`

`CONTRACEPTION
`
`Figure 2: Nu~r of Spotting Days
`
`Reference Period I
`
`Reference Period II
`
`NA 1.00/EE 0.05 TI==J--
`
`UIC 0.2S/EE 0.05 l[):::1--------
`
`LNG 0.15/EE 0.03 [L - -p - -
`
`[]=:.•---
`
`Q:=l ______ ...,.. .. ~
`.
`--, __ _
`
`C
`
`L.
`
`I I
`
`[p-
`
`NA O.J5
`
`LNG 003
`
`vavlnal rong
`
`OMPA 100
`
`OMPA 150
`
`..
`
`..
`
`..
`
`..
`-·-
`
`••
`
`..
`
`..
`..
`----
`
`Reference Period Ill
`
`Reference Period IV
`
`UIC 0 25, EE 0.05
`
`NA 0.35
`
`UIC 0.03
`
`NA 1.00/EE 11.05 ~ JJ=l--
`1:P-
`[J"l-
`LNG 0.15tEE 0.03 TJ_l -
`aJ=l-
`O::=J
`o==
`Vavlnal ring LC=l-
`
`~}
`
`~
`
`===:::::::r-
`-----.1- .,
`[CJ
`OMPA 100 ~
`- - r - "
`OMPA 150 ~ _,.... .. l.]::_ ====r -----------~ n
`..
`..
`..
`..
`·. --:. - ·--·
`"'
`
`.. - -io --..,
`
`-
`
`AUGUST 1988 VOL. 38 NO. 2
`
`189
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
`
`

`

`CONTRACEPTION
`
`episodes reported by any woman was 2, and no woman ever had more than
`4. More than one-half of subjects had episodes whose mean length was
`between 4 and 6 days, and intervals with mean length ranging only from
`23 to 28 days.
`
`Table IV shows that at least 83% of subjects using the ovul ation
`method had a
`'normal' bleeding pattern in each reference period. The
`most common problem in this highly selected group was infrequent
`bleeding (less than 3 episodes in 3 months). A few women (3-5~)
`suffered irregular bleeding, but prolonged bleeding (an episode lasting
`14 days or more) 111as almost unknown. The extremes of amenorrhea or
`frequent bleeding were not recorded in any of the four reference
`periods.
`
`(b) Combined oral contraceptives
`
`Women given one of the three combined oral pills, NA 1.0 + EE 0 . 05,
`LNG 0.25 + EE 0.05 and LKG 0.15 + EE 0.03, averaged 3 b l eeding/spotting
`epi sodes, producing a total of 12-14 bleeding/spotting days, per 90
`days of method use (Table II, Figure 1). Spotting days or episodes
`were rarely recorded in any group (Table III, Figure 2). However,
`women using LNG 0.25 + EE 0.05 consistently had even fe1ver spotting
`episodes than subjects given NA 1.0 + EE 0.05 or the lower dose LNG +
`EE pill (p<0.05).
`
`Combined pill users had bleeding/spotting episodes whose moan
`lengths were shorter (approximately 4 days) than those of the untreated
`women and varied little between subjects (Figure~). None of the women
`given NA 1.0 + EE 0.05 ever had episodes whose average length exceeded
`9.3 days, and in the other two groups, the occurrence of extreme values
`became less common over time. All three groups had mean interval
`lengths of 23-24 days (Figure 4). Thus , their mean length of bleeding/
`spotting segment, 28 days, was as expected in users of combined oral
`contraceptives .
`
`These subjects also had more regular bleeding patterns than any
`other treated group. On average, their bleeding/spotting episodes
`differed in length by only 1 day (Figure 5).
`In the first reference
`period, NA 1.0 + EE 0.05 and LNG 0.15 + EE 0.03 produced significantly
`more variability in both episode and interval lengths than LNG 0.25 +
`EE 0.05 (p<O.OOl ) (Figure 6). Thereafter, the median range of interval
`lengths among users of LNG 0.15 + EE 0.03 fell from 6 days to 2-3 days.
`Over the same period, the irregularity induced by NA 1.0 + EE 0.05 also
`lessened , but not to the same extent. By Lhe third period, the
`variability caused by the two LNG+ EE preparations was similar, while
`that resulting from use of NA 1. 0 + EE 0.05 was significantly greater
`(p<O.Ol).
`
`Figures 7 and 8 show the longest bleeding/spotting episode and
`bleeding-free interval experienced by each subject in the four 90 - day
`reference periods. Women using one of the combined pills were least
`likely to have a prolonged episode or interval, with median values of
`
`190
`
`AUGUST 1988 VOL. 38 NO. 2
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
`
`

`

`Tabl~ I I
`Numbers of bleeding/spotting episodes in each 90-day reference period
`
`REFERENCE PERIOD
`
`I
`
`REFERENCE PERIOD II
`
`REFERE NCE PERIOD Ill
`
`REFE RENCE PERIOD
`
`I V
`
`Perc e ntiles
`.. ---.--.--
`75 Max
`25
`50
`
`Percentiles
`. --------- ..
`25
`50
`75
`
`Max
`
`Percentiles
`. ... --.----.
`75 Max
`50
`25
`
`Percent i l c::;
`- .... ---- ... -
`75 Max
`25
`50
`
`ovulation method
`NA LO + EE 0.05
`LNG 0.25 + EE 0. 0 5
`LNG 0.15 + EE 0.03
`NA 0.35
`LNG 0.03
`Vagina l ring
`DHPA 100
`OMPA 150
`
`3.0 3.0 4.0
`3.0 3.0 3 . 0
`3.0 3.0 3.0
`3.0 4.0 4.0
`3.0 4.0 4.8
`3.3 4 . 0 4.8
`3.0 3.0 4.0
`1.0 2.0 3 . 0
`1.0 2.0 3.0
`
`4
`6
`5
`7
`7
`8
`8
`10
`11
`
`3.0 3.0 3.0
`3.0 3.0 3.0
`3 .0 3.0 3.0
`3.0 3.0 3.0
`2.0 3.0 4.0
`3. 0 4.0 4.0
`3.0 3.0 4.0
`1.0 2.0 3.0
`1.0 2 . 0 3. 0
`
`4
`6
`5
`6
`6
`5
`1 0
`12
`1 2
`
`3.0 3.0 3.0
`3.0 3.0 3.0
`3.0 3.0 3 . 0
`3.0 3.0 3.0
`3 . 0 3.0 4.0
`3.0 3 .0 4.0
`3.0 3.0 4.0
`0.0 1.0 3.0
`0.0 1.0 2.0
`
`4
`7
`5
`5
`5
`5
`, 2
`9
`1 1
`
`3.0 3.0 3.0
`3 . 0 3 . 0 4 . 0
`3.0 3 .0 4.0
`3.0 3.0 4.0
`3.0 3.0 4.0
`3.0 3. 0 4.0
`3.0 3.0 4 . 0
`0. 0 1. 0 2.0
`0. 0 1. 0 2.0
`
`4
`5
`5
`6
`6
`6
`8
`12
`13
`
`()
`
`~
`
`0 z
`:::0 > ()
`m
`~ -0 z
`'i:1
`
`> c
`0 c
`""'i -\0
`
`til
`
`00
`00
`
`<
`0
`l'
`w
`00
`~
`
`N
`
`-\0
`
`.....
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
`
`

`

`()
`
`0 z .....,
`
`~
`)>
`()
`tTl
`""0
`
`....., -0 z
`
`Table Ill
`Numbers of spotting episodes in each 90-day reference period
`
`RE FERENCE PERIOD I
`
`REFERENCE PERIOD II
`
`REFERENCE PE RIOD Ill REFERENCE PERIOD
`
`I V
`
`Pcrccnti les
`- - ----- - ---
`95
`75
`
`Percentiles
`
`•
`
`•
`
`•
`
`• ~ ~ A
`
`A
`
`A
`
`A
`
`A
`
`Max
`
`75
`
`95
`
`Mall
`
`Percentiles
`-- - --- --- --
`75
`95
`
`M<Jx
`
`Percentile s
`-----------
`75
`95
`
`Max
`
`NA 1-0 • E E 0.05
`LNG 0.25 + EE 0 . 05
`LNG 0.15 + EE 0.03
`NA 0.35
`LNG 0.03
`Vaginal ring
`DMPA 100
`DMPA 150
`
`0.0
`0 . 0
`0.0
`0.0
`0.0
`I . 0
`1 . 0
`2.0
`
`2-0
`1 . 0
`2. 0
`3. 0
`2. 5
`2. 0
`3. 0
`4 . 0
`
`4
`2
`4
`4
`3
`6
`6
`10
`
`0- 0
`0 . 0
`0- 0
`0. 0
`0.0
`0.0
`, . 0
`2.0
`
`2- 0
`0. 0
`, . 0
`1.4
`1. 0
`2. 0
`3. 0
`4. 0
`
`3
`1
`4
`3
`2
`7
`1 5
`10
`
`0-0
`0 . 0
`0-0
`0. 0
`0. 0
`0.0
`, • 0
`1 . 0
`
`2-0
`1 . 0
`1 . 0
`2. 0
`1. 0
`2.0
`3. 0
`3. 3
`
`4
`1
`3
`3
`3
`9
`9
`11
`
`0. 0
`0.0
`0. 0
`0. 0
`0. 0
`0 . 0
`1 . 0
`, . 0
`
`1. 0
`1. 0
`1 . 0
`1 . 4
`I. 0
`2.0
`3. 0
`4. 0
`
`4
`5
`4
`4
`
`4
`1 2
`10
`
`......
`\0
`N
`
`)> c a c en
`
`...,
`......
`\0
`00
`00
`
`<
`0
`l'
`w
`00
`z
`0
`N
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 12
`
`

`

`CONT RACEPTION
`
`Figure 3: Mean Length ol Bleedln9JSponing Eplaodu
`
`Reference Period 1
`
`Reference Period II
`
`Owlotlon m•t~od
`
`NA 1.00/EE 0.05
`
`-rt-~ -
`·-{[1]::(cid:173)
`
`LNG 0.25/EE 0.05
`
`- J j J J - - -
`
`NA 0.35
`
`LNG 0.03
`
`DMPA 100
`
`OMPA 150
`
`LNG 0.15/EE 0.03 - : : [ ) : : J - - - -
`-cJJ=-----
`--D==-
`-= "[
`.: - -- --
`- _____ _
`. ..
`
`·-=~----
`
`--c'd
`·•
`
`"
`
`-m..:-
`•:j])-
`
`1,1_-- -
`
`-.. :1":}-
`
`-ru:=::~
`
`: [:-J
`
`--.11=-·-
`
`-- 0=--=====-- --- .,
`..
`·.
`"
`
`J,J
`
`.r •
`
`.. -..
`,.
`
`-
`;.
`
`Reference Period 111
`
`Reference PeriOd IV
`
`-:J]J-(cid:173)
`..:_{j >-
`
`-'.J]J:":-
`
`13.1=··
`
`NA 1.00/EI! o.os
`
`-jL-..-
`
`LNG 0.25JEE 0.05
`
`-[1~-
`
`LNG 0.15/EE 0.03
`
`-.']}::--·
`
`-:f_l;:·
`
`·Ql):J -
`
`NA 0.35
`
`LNG 0.03
`
`Vaglnol ring
`
`OMPA 100
`
`DMPA 150
`
`-c[[ - · _
`CCCt ___ ------_ -_-_-_-.._~----r- ,
`-=LO---- __}---.-- ·-
`..
`
`-QD.:J----
`
`~ [J=-=:l----- -
`
`"
`
`AUGUST 1988 VOL. 38 NO. 2
`
`193
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 13
`
`

`

`CONTRACEPTION
`
`4-5 days and 25-26 days, respectively. None of the women using one of
`the higher-dose preparatjons bled for more than 32 consecutive days or
`had an interval longer than 138 days.
`
`Table IV shows that the great majority (up to 93%) of subjects
`given one of the combined oral pills had a
`'normal' bleeding pattern,
`with predictable 26 - 30 day segments and shor t episodes of bleeding.
`Their most common problems were infrequent bleeding, which in t his
`particular g roup may be interpreted clinically as failure of the
`withdrawal bleed, and irregular , o r
`'breakthrough ' bleeding. None of
`the subjects using NA 1.0 + EE 0.05 ever had amenorrhea , nor did any
`woman us ing LNG 0.25 + EE 0.05 ever record frequent bleeding. The
`incidence of prolonged bleeding decreased from up to '•% in the first
`reference period to less t han 1% in the second and subsequent periods.
`
`(c) Progestogen-on ly oral contraceptives
`
`t\-JO progestogen- only oral pills, and LNG 0. 03 in particular,
`The
`produced hi~her numbers of bleeding/spotting days (15-18 days) and
`episodes (3- 4 episodes) than any of the combined pills (Table II, Figure 1) .
`In the second reference period, women using LNC 0.03 had even more
`freq uent bleeding/ s potting episodes than those given NA 0.35 (p<O.OOl) .
`However, these subj ects recorded less spot ling than combined pil l
`users: more than 50% of women had no spotting days at all, and spotting
`episodes occurred only rarely (Table III, Figure 2).
`
`Users of NA 0.35 had episodes whose mean lengths (4 . 7-5.0 days)
`were almost identical Lo those of the untreated women, and bleeding (cid:173)
`free intervals which, with a mean length of 23 days, were approximately
`2 days shorLer (Figures 3 and 4).
`LNG 0.03 produced somewhat shorter
`episodes and considerably shorter intervals ; and thus, shorter segments
`overall.
`In the second and third reference periods , the difference in
`mean interval length bet\~een the t1~o progestogen -only pil ls reached
`statistical significance (p<O.Ol and p<O.OS, respectively):
`the median
`value~ ~mong u~cr~ of UTC 0.03 were only 20 · 21 days, and 25% of
`subjects had intervals whose average l ength was 18 days or less.
`
`Progestogen-only pill users had more difficulty in predicting the
`onset of Lheir next bleeding/spotting episode than combined pill users.
`In the first reference period, the range of bleeding-free interval
`lengths averaged 16 days among \oJOmen using NA 0 . 35, and 14 days among
`t.hose given LNG 0.03 (Figure 6). Alt.hough their bleeding patterns
`became less irregu lar as the year progressed, 50% of subjects s t ill had
`interval s which differed by at leas t 10 a nd 8 days, respectively, in
`the four th reference period.
`
`f igures 7 and 8 show Lhat the occurrence of prolonged events was
`not an i mportant problem in either group. Their maximum bleeding/
`spotting episodes were very s i milar in length to those experienced by
`women using the ovulation method, with a median value of 5-6 days.
`Women using NA 0.35 tended to have longer maximum intervals than those
`given LNG 0.03, but even in the former group, 75% of women had no
`interval which exceeded 35 days.
`
`194
`
`AUGUST 1988 VOL. 38 NO. 2
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 14
`
`

`

`CONTRACEPTION
`
`Figure 4: Mean umgth ol BIQedlng-Free Intervals
`
`Reference Period I
`
`Reference Period II
`
`Ovulation method
`
`NA 1.00/E E 0.05
`
`-®-
`--Cjj:J
`
`LNG 0.25/ llE 0.05
`
`--qjp-
`
`-$-(cid:173)
`
`~
`--cJJi - - - --
`
`LNG 0.15/EE 0.03
`
`~1----------.r- u·o~
`~
`
`NA 0.35
`
`LNG 0.03
`
`Vaginal ring
`
`DMPA 100
`
`DMPA 150
`
`c::Ll]:::::::J-
`
`c::::[[p-----
`-
`::JJ=::---- - -
`
`·.r- ,, ..
`
`~,___ _________ ,..
`
`~=====:::::;~"'
`---.____JL:c=J:r=---=====~::=: ... ~c::::=====~ .,
`. ..
`.--..
`..
`,.
`"
`..
`..
`..
`"'
`
`w---..-
`20
`,.
`..
`
`.--, ·
`
`Reference Period ill
`
`Reference reriod IV
`
`Ovul•tion melhod
`
`--c:tU:J-
`
`NA 1.00IEE 0.05
`
`-c [p -
`
`LNG 0.25/EE 0.05
`
`-QIP-
`
`LNG 0.15/EE 0.03
`
`-clJ:ii----------~~
`
`NA o.3s
`
`LNG 0.03
`
`Vaginal ring
`
`oMPA. 100
`
`OMPA 150
`
`-crrJ=~·-
`
`c:[j]:J--
`
`-r-1c::::::j=I===):::::::::::===::::J~ ...
`
`-L,._____J[=:::::j==r:::==::J=====:J~ 1' l
`,.
`'
`"'
`
`..
`
`..
`
`..
`
`..
`
`~
`
`10
`
`...
`
`..
`
`.. .,.
`
`10
`
`"
`
`.__.~J:- 1 - -
`
`AUGUST 1988 VOL. 38 NO. 2
`
`195
`
`Petitioner Exhibit 1017
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 15
`
`

`

`("')
`
`0 z ....,
`
`:::0
`;J>
`("')
`tT1
`"'0
`
`...., -0
`z
`
`\0
`0\
`
`!Able IV Bleeding pattern sub group ~ in ··~~ -90 · d~y referrncr period
`
`Ovulation
`method
`( n= 164 J
`X
`
`NA I . 0• LNG 0.2S •
`EE 0. OS
`EE 0.0 5
`(n= U 1 )
`<n= 1 ~0)
`X
`%
`
`LNC0.1S •
`EE 0.03
`(n =7 22)
`%
`
`N~ 0.3S
`
`LN G 0.03
`
`(n =52)
`%
`
`< n=44 J
`X
`
`Vaginal
`r ins
`(n=284)
`%
`
`O M P~ 100
`
`OMPA ISO
`
`(n=291)
`%
`
`(n= 314 )
`l
`
`REfEHHE rERIOO I
`No dis t u rbane e
`Aflenorr tle a
`Infrequent
`Fre que nt
`Irregular
`Prolon ged
`
`REFERE NCE PER IOO II
`No dist ur ba nce
`A•enorrhea
`Infrequent
`f r equent
`Ir regul ar
`Prolonged
`
`REFER EN CE P ER IOD !II
`No d;sturbanee
`AMeno r rhea
`I nfreq ue nt
`Fre que n t
`I r regular
`Pro lon ged
`
`8U~R~N~f PfRIOO IV
`No di•tur ben c o
`Aae nor rhea
`I nf r equen t
`Frequ en t
`I rregu l ar
`P rolon ged
`
`98.8
`0.0
`0.6
`0.0
`0. 0
`0.6
`
`82.9
`o.o
`12.8
`0.0
`4 . 3
`0.0
`
`82.9
`0.0
`14.0
`0.0
`3.0
`0.6
`
`84.8
`0.0
`10.4
`0.0
`4.9
`0.0
`
`86.4
`0. 0
`3.6
`1 . 4
`7.9
`1 • 4