EXHIBIT 1018
`
`
`
`EXHIBIT 1018EXHIBIT 1018
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`

`
`Progestogen-only pills and bleeding disturbances
`
`Gab Kovacs
`
`Monash Medical School, Box Hill Hospital, Melbourne, Australia
`
`Downloaded from
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`http://humrep.oxfordjournals.org/
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` by guest on January 21, 2015
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`The progestogen-only pill (POP), minipill, is
`quite an effective second line contraceptive.
`Despite this, it is used relatively infrequently
`except during lactation. The main reason for
`this is that women on POP often have abnormal
`bleeding patterns, with an increased frequency
`of bleeding, lengthened cycles, breakthrough
`bleeding, spotting and prolonged bleeding.
`These menstrual disturbances are the most com(cid:173)
`mon quoted reason for discontinuation in up to
`25% of users.
`Key words: bleedinglminipilllprogestogen-only
`pill/spotting
`
`Although the mini pill (progestogen-only pill; POP)
`was once hailed as a possible successor to the
`combined oral contraceptive, it has failed to live
`up to its expectations. By 1975 it was used by a
`few hundred thousand women out of the more than
`50 million women using some form of oral con(cid:173)
`traception (Rinehart, 1975). POP were developed
`in the mid-1960s, when it was discovered that
`small doses of progestogens could prevent preg(cid:173)
`nancy, even though they did not always prevent
`ovulation. Its mechanism of action may include
`changes to the cervical mucus, endometrium, cor(cid:173)
`pus luteu~ function and tubal motility, and in
`some cases prevention of ovulation (Graham and
`Fraser, 1982). The POP is less effective in pre(cid:173)
`venting pregnancy than the combined pills, and
`forgetting just one or two pills may be enough to
`cause a loss of contraceptive efficacy.
`Although the first orally active POP preparation
`that was shown to be effective was chlormadinone
`acetate (Martinez-Manautou et al., 1966), the first
`
`oral POP preparations to receive US Federal Drug
`Agency approval were the norethisterone prepara(cid:173)
`tions of 0.35 mg daily Micronor (Ortho) and Nor
`Q-D (Syntex), which were approved in December
`1972. The dl-norgestrel preparation (0.075 mg)
`Ovrette (Wyeth) was approved in January 1973.
`The first detailed review of POP was in 1975
`(Rinehart, 1975). This review reported on three
`studies with norethisterone, and eight with nor(cid:173)
`gestrel. The efficacy varied from 0.0 to 4.3 pregnan(cid:173)
`cies per 100 woman years. 'This review highlighted
`the fact that although the side-effects associated
`with the combined pill, such as dizziness, nausea,
`headaches and breast tenderness, were decreased,
`this was heavily outweighed by the disadvantage
`of alterations and disturbances of menstrual flow.
`Of eight studies in which women used norethis(cid:173)
`terone (a total of 1253 women), it was found that
`between 30 and 50% of women maintained a
`normal cycle length, but that up to 70% complained
`of breakthrough bleeding/spotting in one or more
`cycles. With respect to duration of bleeding, one(cid:173)
`third to one-half of women had prolonged menstru(cid:173)
`ation. In a summary of 14 reports of norgestrel
`use in a total of 5500 women, it was found that
`35-70% maintained normal cycles, with up to 39%
`of cycles having breakthrough bleeding and 17-
`35% having prolonged bleeding. The review con(cid:173)
`cluded that <50% of women were still continuing
`with the method 12 months later, a continuation
`rate which is much lower than for combined pills,
`and that women more often abandoned POP use
`because of menstrual disturbances and less often
`because of non-menstrual side-effects.
`The next major review of POP was in 1982
`(Graham and Fraser, 1982). Although this review
`
`20
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`C Ewopean Society for Hwnan Reproduction & Embryology
`
`Hwnan Reproduction ~lume 11 Supplemau 2 1996
`
`Petitioner Exhibit 1018
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
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`

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`Progestogen~nly pills and bleeding disturbances
`
`Tabk 1. Srudies on bleeding patterns and progestogen~nly pillJ (norethisterone and levooorgestrel)
`
`Reference
`
`Countries nudy based in No. of women
`
`Results
`
`Korba er aL (1974)
`
`USA
`
`Lawson (1982)
`
`UK, New Zealand,
`Jamaica
`Veu.ey et aL (1972) Yugoslavia
`
`~y et aL (1985)
`
`Eo gland
`
`WHO (1982)
`
`India, Yugoslavia
`
`Bell et a1. (1991)
`
`Eo gland
`
`Bisset et aL ( 1992)
`
`Scotland
`
`England
`
`Broom~ and Fotherby
`(1990)
`Hawkins and Ben.ster England
`(1977)
`
`2202 oorgestrel
`
`913 norethisterone .
`
`7 4 nocgestrel,
`76 norethisterone
`1764 norethisterone,
`555 norgestrel
`130 norethisteroDe.
`128 levonorgestrel
`23 noretbisterone,
`23 levooorgestrel
`369 norethistcrone,
`146 levonorgestre1
`189 norcth.isterone.
`27 levonorgesttel
`200 ooretbisterone
`
`14% discontinued because of bleeding;
`70% bad 21~5 day cycle
`Breakthrough bleeding: 24% in
`cycle I. 7 .2% in cycle 12
`<5% discontinued because of bleeding
`
`More than half of discontinuatiODs
`caused by bleeding
`One-quartt::r discontinued because of
`bleeding
`No. of bleeds per month: 1.24
`norethisterone, 1.28 levonorgestrel
`15% discontinued because of bleeding;
`35% had distuJbed cycles
`Only 39% bad regular cycles; 24%
`discontinued becall!e of bleeding
`23% discontinued because of bleeding
`
`duplicated some of the 1975 review, it again made
`the point that menstrual cycle lengths were more
`variable in women taking POP than in those taking
`no form of hormonal contraceptive (and women
`on the combined pill were even more regular).
`Graham and Fraser (1982) also reported that 20-
`30% of women using minipills experienced break(cid:173)
`through bleeding and that 5.8-16.2% of cycles in
`women using mioipills bad breakthrough bleeding.
`Their review of continuation rates was based on a
`comparison of the number of women using Ovulen
`(combined pill) and ethynodial diacetate (a progest(cid:173)
`ogen-only preparation) (Paulsen etaL, 1974). This
`study showed that although there was a better
`continuation rate for the combined pill at 6 months
`(-80 versus 70%), the rates were similar, at -65%,
`at 13 months. One of the conclusions of Graham
`and Fraser (1982) stated that the progestogen only
`pill '(iii) minimises the menstrual disturbance seen
`with all progestogen-only methods', but it is
`unclear on what evidence this conclusion is based.
`The most comprehensive review of progestin(cid:173)
`only contraception was prepared by McCann and
`Potter ( 1994) from Family Health International
`(FHI). The report included 521 references with
`regard to progestogen-only contraception and a
`whole section on bleeding disturbances. The studies
`on bleeding patterns that relate to norethisterone
`and norgestrel preparations are summarized in
`
`Table I. Their studies summarized nine series
`where the POP was used by non-breastfeeding
`women. Their results showed that menstrual dis(cid:173)
`turbances were common, and were also the most
`often quoted reason for discontinuation of POP
`use, although there was quite a bit of variation in
`the incidence of menstrual distuibances, with the
`best results coming from a study in Yugoslavia in
`1972 with a <5.5% discontinuation rate (Vessey
`et al., 1972). Interestingly, a Wodd Health Organ(cid:173)
`ization ( 1982) study in Yugoslavia found more
`than half of the participants discontinuing because
`of menstrual abnonnalities. This highlights the
`difficulty of any meaningful analysis of results
`originating from different centres, sometimes
`involving small numbers and having different
`end-points.
`Interestingly, when breastfeeding women using
`POP are considered, and there are five series in
`the FHl review (Table IT), four out of the five
`series had discontinuation rates of <5%, which is
`understandable because most of these women
`would have some degree of lactational amenor(cid:173)
`rhoea. This also highlights the fact that the POP bas
`been widely accepted and marketed for lactational
`contraception.
`The mechanism of action of the POP on the
`endometrium is poorly understood, and the men(cid:173)
`strual response is unpredictable. It is generally said
`
`21
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`Petitioner Exhibit 1018
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
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`Downloaded from
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`http://humrep.oxfordjournals.org/
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` by guest on January 21, 2015
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`G.Kovaa
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`Table n. Bleeding patterns for breastfeeding women on progestogen-<lllly pill3
`
`Refuence
`
`Country study based in
`
`No. of women
`
`Results
`
`Apelo and Yeloso (1973)
`
`Philippines
`
`99 1evonorgemel
`
`Dunson n aL (1993)
`
`M ulticentre
`
`4088 norgewel
`
`McCann et aL (1989)
`
`Argentina
`
`2.50 Jevonorsestrel
`
`Moggia et aL (1991)
`
`Argentina
`
`West (1983)
`
`Scotland
`
`241 norgestrel
`
`84 oorethW:rone
`
`3% diSCQntinued because of
`bleeding
`4.9% di&continued because of
`bleeding
`1.6% discontinued because of
`bleeding
`36% with intermenstrual
`bleeding
`1.8% discontinued because of
`irregular bleeding
`
`that the POP interferes with the cyclic development
`of the endometrium. making it unsuitable for
`receiving the fertilized ovum, but ltistological find(cid:173)
`ings are confusing. A study by Vessey et al.
`( 1972) found that of 25 women sampled. most had
`proliferative changes early in the cycle. A study
`of 24 women who underwent endometrial biopsy
`(Johannisson et al. , 1982) found that proliferative
`activity was suppressed compared with pretreat(cid:173)
`ment cycles, and that patients with intermenstrual
`bleeding had a greater endometrial glandular dia(cid:173)
`meter. Further morphometric studies of endometrial
`biopsies from 35 women using POP (Kim-Bjork(cid:173)
`lund et al., 1991) have shown a varied distribution
`of irregular secretory endometrium in one-third, a
`lack of proliferation in one-quarter and suppressed
`proliferation in a further quarter, with secretory
`and atrophic changes in all three groups. This
`confirms that the response of the endometrium
`to POP is variable and unpredictable. To better
`understand the causes of bleeding, Hourihan et al.
`( 1986) studied the vascular patterns within the
`endometrium in POP users. They concluded that
`whereas the arteries at the endometrial-myometrial
`junction were decreased, the total and dilated veins
`were increased in POP users. How this affects the
`disturbance of bleeding patterns is not understood.
`In conclusion, it is apparent that the greatest
`disadvantage of POP is its unpredictable effect on
`menstrual bleeding. This is responsible for many
`women abandoning it as a method of contraception.
`This is a pity because it is an excellent second
`line method of contraception, with efficacy only
`surpassed by the combined pill, sterilization and
`intrauterine devices. It also has no contraindications
`
`22
`
`because it contains no oestrogen, and'can· therefore
`be used by women in whom oestrogens are contra(cid:173)
`indicated. Therefore new strategies must be
`developed to try to improve cycle control.
`
`Acknowledgement
`I would like to thank Lee McLaren for typing the
`manuscript.
`
`References
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`Petitioner Exhibit 1018
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

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`23
`
`Petitioner Exhibit 1018
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4