EXHIBIT 1016
`
`
`
`EXHIBIT 1016EXHIBIT 1016
`
`

`
`35
`The forgotten pill-and the paramount importance of the
`pill-free week
`
`John Guillebaud, FRCSE, FRCOG
`
`Medical Director, Margaret Pyke Centre for Study and Training in Family Planning, London
`
`I !
`
`i
`I
`. l
`
`Summary
`It is now well established that in many women on
`current low dose pills there is a variable degree of
`restoration of endogenous ovarian/unction during
`the pill-free interval, as shown by rising levels of
`gonadotrophins plus oestradiol and also by serial
`ultrasound scanning of the ovaries. It follows that
`breakthrough ovulation is most likely to occur at
`the end of any lengthened pill-free interval, the
`lengthening being caused by omitted pills either
`just prior to the seven day break or immediately
`following it.
`Following discussions between the Medical
`Advisory Bodies of the Family Planning
`Association and the National Association of
`Family Planning Doctors new advice has been
`agreed and pilot testing proved satisfactory.
`Simplified wording to be used in leaflets remains to
`be finalised, but the content is as follows.
`If you forget a pill
`Take it as soon as you remember, and the next
`one at your normal time. If you are 12 or more
`hours late with any pill, especially the first in
`the packet, the pill may not work. As soon as
`you remember, continue normal pill taking.
`However, you will not be protected for the
`next seven days and must either not have sex
`or use another method such as the sheath. If
`these seven days run beyond the end of the
`packet, start the next packet at once when you
`have finished the present one, ie do not have a
`gap between packets. This will mean you may
`not have a period until the end of two packets
`but this does you no harm. Nor does it matter
`it you see some bleeding on tablet taking days.
`If you are using everyday (ED) pills-miss
`out the seven inactive pills.
`It is believed that seven days gives sufficient time
`for restoration of contraception
`in
`the vast
`majority of cases. When pills are omitted at the
`end of a packet, the new advice also avoids the
`illogicality of permitting the woman to take a
`further seven day break from the contraceptive
`effects of her method on top of the break she has
`
`already inadvertently taken (by the missed pills).
`The same advice is recommended, modified as
`in other situations where
`the
`appropriate,
`bioavailability of contraceptive
`steroids
`is
`reduced: such as vomiting, severe diarrhoea, and
`drug interactions.
`Devised originally by Pincus, it is clear that the
`pill-free interval potentially impairs the efficacy of
`the combined contraceptive pill. It can also be
`associated with certain side-effects, such as
`withdrawal headaches. On the other hand there are
`both proven and probable benefits.
`There is the regular reassurance of a withdrawal
`bleed. Secondly, a lesser total quantity of artificial
`steroids is ingested per year. But, possibly most
`significant, is the .finding that certain metabolic
`variables altered by the combined pill show a
`tendency to return to normal by the end of the
`pill-free week. This may imply an important
`benefit to health, and possibly to reversibility, by
`the monthly 'rest' from its systemic actions.
`However, there exist special indications for either
`eliminating the pill-free interval, or for reducing it
`to four or five days.
`
`Introduction
`During the 30 years since the combined oral
`contraceptive pill (COC) or pill was first
`introduced, the question has often been asked, by
`researchers
`'Why
`is
`it
`that
`women and
`conception can apparently follow the missing of
`just one pill, when the overwhelming majority of
`women routinely miss seven pills in each 28 day
`cycle with impunity?>~ I have been arguing since
`the beginning of this decade that 'it is precisely
`because of this seven day break that most
`pregnancies occur,'2 and that the pill omissions
`of greatest concern are those that lead to a
`lengthening of the pill-free interval (PFI). The
`time of risk is at the end of the lengthened PFI,
`but the causation of the lengthening can either be
`by delay in re-starting a new packet or by
`omissions at the end of the previous packet if
`these are nevertheless followed by the usual seven
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`
`36
`day break.
`The evidence for these statements is presented
`below and is becoming stronger with better
`research design and the use of new tools such as
`ultra-sound scanning. However, the 'acid test',
`namely the occurrence of pregnancy following
`missed pills, is extremely difficult to apply(cid:173)
`chiefly because the worst pill-takers are also
`those who are worst at recalling which particular
`pills they omitted. In addition, until recently they
`the
`would not even have been asked by
`investigator about missed pills at the end of the
`packet before their last 'period' (withdrawal
`bleed). Yet available ancedotal evidence (see for
`example Table I) links in well with what is now
`known about the pharmacology.
`An elementary point is also worth making,
`which is valid without any assumptions about
`mechanisms. During the PFI, each day by which
`the interval is lengthened distances a woman's
`genital tract further from the last pill taken and
`hence from
`its contraceptive effects. Thus,
`lengthening the PFI must always increase the
`conception risk. In fact by the end of any
`lengthened pill-free
`interval not only
`is
`breakthrough ovulation more likely, but also the
`well known adjunctive contraceptive actions,
`particularly on the cervical mucus,3 will be
`exerting their least effect.
`
`Physiology and pharmacodynamics
`Until recently, few researchers took account of
`the PFI, whether in devising or analysing their
`studies. As early as 1980 we showed how
`endogenous gonadotrophin and oestradiol levels
`tend to rise during the PFI from the very low
`levels found during pill taking, the rise bein§
`much more marked in some women than others.
`Indeed it has been shown that by the seventh
`pill-free day some women have gonadotrophin
`and oestradiol levels similar to those seen in
`untreated women in the earlr follicular phase of a
`normal menstrual cycle. Other endocrine
`studies~ 12 have confirmed that in some women,
`especially on low dose pills, there is a tendency
`for regular restoration of pituitary and ovarian
`activity.
`There is naturally biological variation, many
`cycles showing quiescence of the ovaries at all
`times, but others showing sufficient ovarian
`activity to cause concern that for them, the seven
`days may be close to the limit that could be
`tolerated before ovulation might occur. Wang et
`
`alii identified a sub-group of five out of 31
`subjects in which plasma oestradiol (E2) levels
`rose as high as 1200 pmol/1. In both this group
`and the remainder they found a statistically
`significant linear increase with time in E2 levels
`during the pill-free week. This rise would
`obviously
`be
`of greater
`relevance
`to
`contraception in the high E2 group, and in a later
`study 12 the same researchers were able to show in
`one subject out of .I 0 that prolongation of the
`pill-free period from seven to nine days led to
`surges of luteinising hormone and marked
`follicular plus (inadequate) luteal activity in two
`of three cycles. The remaining cycles in that study
`were characterised by a varying degree of
`foJlicular activity with no luteal function. None
`of the subjects with a lengthened PFI had a
`normal ovulatory cycle in this small study, but
`the results were interpreted as 'suggesting that
`repeated
`prolongation
`of
`the
`pill-free
`period ... might result in a gradual increase in
`ovarian activity. '
`The hormone studies in this area up to 1983 were
`reviewed by Fraser and Jansen (59 references). 13
`They reached the conclusion that 'the most
`hazardous times to miss pills are at the beginning
`or the end of a monthly course.'
`More recently, these observations have been
`confirmed by ultrasound (U/ S) scanning for
`ovarian follicular activity. Nine Van de Vange
`and her co-workers 14 showed that with modern
`ultra-low
`dose
`pills,
`particularly
`the
`levonorgestrel triphasics, there was evidence of
`the growth of follicles in over half the normal
`COC-cycles studied. Pre-ovulatory size follicles
`(diameter 18 mm or more) were detected in no
`less than 27- 31 per cent of cycles, and follicular
`cysts were observed in I 4 out of 210 cycles.
`Unfortunately they did not specifically relate
`these findings to the pill-free interval. But they
`found a highly significant correlation between
`maximum follicular diameter and maximum E2
`level measured, implying follicular activity as the
`basis for the rising oestradiol levels previously
`shown during the PFI.4-12
`Molloy et a/15 found multiple ovarian follicles
`by the end of the PFI in every one of 19 women.
`However, by the seventh day of the new pill pack
`the follicular appearances had returned to the
`dormant condition shown in the first scan, just
`before the PFI (apart from one subject whose
`largest follicle had reduced in size from 8 to
`5 mm). Individual variation was still a feature,
`
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`
`Table 1 Some relevant cases of unplanned pregnancy in users of combined pills at the Margaret Pyke Centre
`
`Pills omitted or Causation
`affected
`(O=day)
`
`LMP
`
`Remarks
`
`MsGE
`(Ovranette)
`
`Ms LC
`
`0 I , D2, 0 3
`
`For got to take her pills
`when she went away
`
`28.12.80 (Previous to
`pill omissions)
`
`12! /52 gestation on
`13.3.8 1
`
`01 , D2, 0 3, D4 Forgot to take her pills
`when she went away
`
`23.5.81 (Previous to pill
`omissions)
`
`11 / 52 gestation on 5.8.8 1
`
`37
`
`Ms KL
`(Microgynon)
`
`01-5
`
`MsLJ
`
`01 , 0 2, 0 3
`
`MsNB
`(Brevi nor)
`
`0 19, D20
`
`Antibiotic treatment
`(Doxycycline) for
`sinusitis, from D23
`through WTB, to DS of
`new packet
`
`She had got the
`message to wait for
`WTB to finish after
`each cycle of pill(cid:173)
`taking, leading to 9- 10
`day gaps between
`packets.
`
`Having forgotten pills
`towards the end of a
`packet, BTB
`commenced. It merged
`with her next "period".
`
`Previous to the affected
`pills
`
`Patient a reliable pill-taker
`(midwife)
`
`! •
`
`Previous to pill
`OmiSSIOnS
`
`LMP was the WTB
`subsequent to pill
`omissions
`
`Unprotected intercourse
`took place subsequent to
`the I 0 days of BTB + WTB
`
`Ms GF
`(Eugynon 30)
`
`0 19 and 021
`
`Vomited 019 pill.
`Forgot 0 21
`
`Ms OC
`(Logynon)
`
`0 20 and 021
`
`Missed last two pills
`
`LMP was the WTB
`subsequent to pill
`omissions
`
`LMP was the WTB
`subsequent to
`
`Had serial ultrasound
`( U/S ) scans
`On 0 24 (5th day since
`last pill- 12 mm
`foll icle)
`On D 27 (8th day since
`last pill-16 mm
`follicle)
`On D 31 (12th day since
`last pill-<:orpus
`luteum on scan)
`Research case- advised but
`failed to take extra
`precautions. Pregnancy
`confirmed three weeks
`later + U/S scan.
`
`NOTE: Dl- 21 arc days on which pill-taking should take place.
`022-28 are days of the pill-free interval (PFI).
`
`with only three of 19 women producing a largest
`follicle greater than 7 mm in diameter by the end
`of the PFI. More recent unpublished studies have
`given ample confirma tion of this restora tion of
`follicular activity during the PFI: l6-l 7 indeed in a
`Margaret Pyke Centre based study, 17 of no fewer
`
`than 120 women all sca nned on the seventh day
`of their PFI, follicles greater than I 0 mm in
`diameter were identified in no less than 23 per
`cent. While it is by no means certain that these
`follicles would be capable of proceeding to
`ovulation, and some may well
`represent
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`
`38
`
`disturbed ovulation leading to functional cyst
`formation, the congruence of these ultrasound
`studies with the endocrine studies is striking, and
`the paramount significance of the pill-free
`interval when considering
`' missed pills'
`is
`confirmed.
`A most interesting new study 18 considers the
`effect on the hypothalamo-pituitary-ovarian axis
`of deliberately creating a seven day pill-free
`interval at various stages in the pill-taking cycle.
`The 36 women recruited to the study were
`types of pill
`divided equally between two
`(MicrogynonR and TrinordiotR). In Group 1
`medication was begun routinely on the day
`following the usual pill-free interval, but stopped
`after seven days; Group 2 took the pills for 14
`days and Group 3 (the control group) for 21
`days. Levels of gonadotrophins, oestradiol (E2)
`and progesterone were measur~d during the final
`week of pill therapy and daily for the seven days
`after stopping the pill. They observed, like other
`workers, 1 that E2 levels both during and after
`pill taking were higher in a sub-group than in the
`remainder of the population, and this was much
`more marked
`in users of the
`lower dose
`compound (TrinordioJR). But only one of the
`latter, in Group 1 having taken seven days of
`pills, showed a rise in plasma progesterone
`during the subsequent pill free seven days and
`this cycle was abnormal; with excessively high
`oestrogen
`levels
`and
`a peak measured
`progesterone concentration of 6.8 nmol/ 1. This is
`a low value for the relevant day of the luteal
`phase. 19 The authors conclude that ' normal
`ovulation is a rare event in the week after
`cessation of either of these pills, even if only
`seven days of medication have been taken'.
`Chowdhury et at2° however, showed elevation
`of plasma progesterones in far more women
`when pills were missed ( 10 out of35 women in the
`first cycle and five out of 19 in the second). There
`are still reasons for believing that the women
`could not have conceived, since the endometrium
`continued to be suppressed and there was a
`persistent marked progestagenic effect on the
`cervical mucus. However, the rate of elevated
`progesterones was much higher than in any other
`study (and included one case out of 10 even in the
`correctly-treated
`control
`group).
`This
`presumably reflects
`individual variation
`in
`different populations (see Conclusion I below).
`Another factor may be
`the COC used,
`I mg
`containing
`norethisterone
`acetate
`
`combined with ethinyloestradiol 30 ug, in fixed
`dose for 21 days out of 28. Norethisterone
`acetate is a pro-drug rapidly converted to
`norethisterone, and this has a much shorter
`elimination
`half-life
`(5- 12
`hours)
`than
`Jevonorgestrel (I 1- 20 hours).21 Wang et a/11
`recorded
`an
`even
`higher
`value
`after
`administration of 150 11g of the latter, and found
`measurable levels six days after the last tablet.
`
`Why do the biochemical studies to date fail to show
`any convincing return of fertility when volunteers
`deliberately miss their tablets?
`There are several answers to this important
`question. First, as just noted, many studies have
`chosen to use levonorgestrel-containing fixed
`dose brands. Because of the long half-life of
`levonorgestrel, these may well have a higher
`margin-for-error than pills containing other
`progestogens. Secondly, only a tiny minority of
`studies have
`focused
`specifically on pill
`omissions which lengthen the pill-free interval.
`But most importantly, biochemical studies are by
`the context of
`definition small studies. In
`enormous individual variation they are unlikely
`to include sufficient representatives of the only
`subjects who matter. It is well known that
`pill-omissions are extremely common as shown
`by a study of 161 women in Glasgow of whom 27
`per cent admitted missing pills in the past three
`months yet pregnancy rarely results.22 For most
`women the pill is "fail-safe''; the problem in this
`research is to identify the vulnerable minority.
`Even among them within-patient (cycle-to-cycle)
`that
`in
`any one-cycle
`vanat1on means
`biochemical study the critical observations may
`be missed.
`A tenable hypothesis is that the vulnerable
`those with
`the
`lowest blood
`minority are
`levels of the exogenous hormones.23 This group
`is probably
`largely co-incident with
`the
`sub-group4 •5 Il - t 3•1 8 with
`the highest
`levels
`of endogenous oestradiol especially at the
`end of the pill-free interval; and these are
`also
`the women whose ovaries show
`the
`the
`largest
`follicular activity and
`greatest
`individual follicle-like structures detected by
`ultrasound. 14- 17 These are the women who
`should be deliberately selected by preliminary
`screening before any future studies are started;
`and the latter should concentrate on tablet
`omissions which lengthen the PFI.
`
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`
`Ten conclusions so far
`Figure 1 summarises the present evidence. The
`well-known saw-tooth daily variation of the
`blood levels of the artificial steroids is portrayed
`schematically. The dotted line in the figure
`derives from figure 4 in the Margaret Pyke
`Centre study.4 It represents the mean and wide
`standard deviations of plasma oestradiol for
`normal pill-using controls. However, this. line
`also corresponds closely to the findings in other
`studies4•5•1 l- IJ,I& for endogenous oestrogen, for
`the gonadotrophins and thirdly for follicular
`activity as detected by ultrasound. 14-17 The
`foJlowing conclusions can be drawn.
`
`There is marked individual variation in the
`return of ovarian activity during the pill-free
`interval.
`2 For some women, the levels of oestradiol
`achieved suggest that a surge of LH might
`well be induced if the PFI were lengthened.
`Moreover, the ultrasound studies imply that
`in some cases a sufficiently ripe ovarian
`follicle would be present for fertile ovulation
`to result.
`3 The adjunctive contraceptive actions of
`exogenous steroids are also least effective at
`the end of a lengthened PFI, since by then
`the maximum time has elapsed since the last
`
`Figure I The Pill-free week
`
`39
`
`pill was swallowed.
`4 The minimum time for an ovarian follicle to
`reach
`pre-ovulatory maturity
`' from
`scratch', after tablet-taking ceases, exceeds
`seven days for most women.18 This matches
`the finding that normal menstrual cycles
`shorter than 21 days are rarely fertile. It also
`implies that the current PFI of seven (or six)
`days is acceptable for the majority of pill
`takers·24•25 but it could and should be
`'
`shortened in selected groups.26
`5 Lengthening of the pill-free interval. This can
`occur in two ways, not only (a) by omitting
`tablets at the start of a packet but also (b) if
`tablets are omitted around the end of the
`preceeding packet and the woman proceeds
`to take her usual PFI, ie starting on her
`usual starting day.
`the
`in
`6 There can be no difference
`contraceptive risk of 5 (b) as compared with
`5 (a). However, in 5 (b) any breakthrough
`ovulation will occur long after the tablets
`the end of
`the
`are missed, around
`lengthened PFI.
`7 Hence, one should ask a woman who
`conceives despite the pill about any tablets
`missed (or vomiting, diarrhoea or drug
`interaction) before her last menstrual period
`(LMP) as well as since. This is a reminder
`
`Q)
`+J
`Ill
`
`Ill
`\)
`0
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`\)
`!0
`~
`+J
`·u
`Ill
`w
`~ 0
`+J
`~
`<(
`
`!0
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`rll-
`
`,,' .. - ... - -u-
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`r'
`
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`,.4 ~ ....
`
`,.4
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`...
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`I I~ I
`
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`11
`Days of pill cycle '' 15 16 17 18 19 20 21
`
`Tablet- taking
`
`0· • ·0 0 0 0 0 0 0
`
`I
`I
`I
`I
`22 23 24 25 26 27 28
`-
`- -
`- -
`-
`-
`X X X X
`WTB
`
`I
`I
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`I
`I
`I
`2 3 4 5 6 7
`0 0 0 0 0 0 0· .•.•• ·0
`
`,_, •21
`
`Jl_
`
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`
`40
`
`that the LMP is no more than a hormone
`withdrawal bleed, from a target organ (the
`uterus) of
`the exogenous hormones,
`behaving independently of events at the
`ovary.
`8 Since Molloy et a/15 showed that seven days
`of subsequent pill-taking was sufficient to
`eliminate follicular activity, seven days of
`extra contraceptive precautions after the
`return to regular pill taking should suffice
`(see below). Most of the endocrine studies
`support this view,4-13•18 though there is a
`particular paucity of data here.
`9 We also lack data for the maximum time by
`which pill-taking can be safely delayed-for
`the 'extreme' women at highest risk and
`using the lowest-dose combined pills now
`that some
`in mind
`available. Bearing
`women can conceive without pill omissions
`at all, in the UK the definition of a missed
`pill is currently and arbitrarily held to be
`'more than 12 hours late'.
`10 However, mid-packet omissions are of very
`al18
`et
`little
`importance.
`Smith
`demonstrated an almost identical rise to
`that shown in Figure 1 during seven pill-free
`days, even when only seven pills had been
`taken from the current packet. This implies
`that there is contraceptive security when
`numerous tablets (even if not for all women
`quite as many as seven) are omitted mid(cid:173)
`packet, ie on the basis of sufficient previous
`pill-taking. Indeed the security appears to
`be not far removed from what regularly
`applies, in a normal seven day break
`following 21 pills!
`
`Current advice when pills are omitted or not
`bio-available
`the
`in
`appears
`advice
`The best-known
`manufacturers' leaflets namely to take extra
`contraceptive precautions from any error in tablet
`taking either until the end of the current packet32
`or until the next withdrawal bleed occurs.27•31 •33
`The discussion above makes it clear that this
`advice is invalid on two counts. On the one hand
`when pills are omitted at the beginning of a
`packet, it assumes loss of contraceptive efficacy
`for far longer than necessary. On the other hand,
`and more importantly, it completely fails to cater
`for lengthening of the pill-free interval when this
`is caused by omitted pills at the end of a packet.
`Dr Bye of Schering24 argues against a change
`
`in the manufacturers advice, on the basis of the
`the adjunc.tive
`presumed effectiveness of
`contraceptive mechanisms. He agrees that the
`pharmacodynamic effect of progestogens on
`cervical mucus declines rapidly, and that even
`one missed pill might result in the loss of that
`effect. However, he argues that 'a quiescent
`endometrium could not undergo proliferation
`sufficient to permit implantation because of one
`missed pill' and also believes that the recent
`shedding of the endometrium (during the PFI),
`along with the 'anti-proliferative effect of the
`progestogen', would make it 'highly improbable'
`that
`the
`endometrium would
`permit
`implantation during the first seven days of a new
`course of pills. He is, of course, correct that
`whenever a PFI is lengthened (whether by pill
`omissions before or after it), it would indeed be
`during the subsequent seven days of pill-taking
`that implantation would occur. However, he
`cites no hard evidence for his opinion that the
`endometrial effect is paramount, and this is
`refuted by the observed fact that implantation
`can certainly sometimes occur during both
`regular and irregular pill-taking; not to mention
`in totally unprepared sites such as the fallopian
`tube and the abdominal cavity.
`More importantly, Bye admits elsewhere in his
`letter that 'missed pills at the beginning of a
`that is prolongation of the pill-free
`course-
`interval by several days- would, obviously,
`the most favourable conditions for
`create
`conception'. But surely if Figure 1 is inspected it
`is obvious that similar prolongation of the PFI
`can be caused by missed pills at the end of the
`previous packet. Since this would be followed by
`a correspondingly earlier withdrawal bleed, the
`situation is identical in all respects (except that it
`follows, say, 19 days rather than 21 days of
`pill-taking) to missing pills at the start of a
`packet. But the rule that Dr Bye favours imposes
`no restrictions on unprotected intercourse at the
`only time of risk: which is after the next
`withdrawal bleed, continuing until some time
`early in the next pill-taking week. See also Table
`I -
`the circumstances of conception in
`the
`bottom three cases in the table, especially the last
`monitored by ultrasound, emphasize the need for
`more valid advice to our patients.
`
`The fourteen day rule
`This advice was introduced by the FPA in 1980.34
`Unlike the above, it has scientific validity: since
`
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`
`41
`
`the second week of the four teen days assumed loss
`of protection in all circumstances covers the time
`of risk if, as just described, tablets are missed at
`the end of a packet. However, it causes confusion
`to many pill-takers as well as to some health care
`professionals. It is difficult to explain
`the
`persistence of contraceptive risk beyond the
`(falsely reassuring) next withdrawal bleed. The
`advice also retains an illogicality shared with the
`manufacturers' rules, in that it permits the
`woman to take a further seven day break from
`the contraceptive effects of her method on top of
`the break she has already inadvertently taken by
`her missed pills. Moreover, it advises more days
`of extra contraceptive precautions than the seven
`which are believed to be sufficient for the
`restoration of contraception in the vast majority
`of cases.
`
`or very severe diarrhoea the pill may not work.
`Continue to take it, but you may not be protected
`from the first day of vomiting or diarrhoea. Use
`another method, such as a sheath, for any
`intercourse during the stomach upset and for the
`next seven days. In addition, if these seven days
`run beyond the end of your current packet follow
`the advice given for when you forget a pill.
`If you have to take other medicines. Several
`medicines can reduce the effect of this pill. These
`include some drugs used in the treatment of
`epilepsy and tuberculosis, and some antibiotics.
`You may have to use another method such as the
`sheath as well while you are taking the medicines
`and for a further seven days-or longer- as
`advised by your doctor. In addition, follow the
`advice given for when you forget a pill. Always
`tell your doctor you are on this pill.
`
`I
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`Recommendation--the 'seven days plus follow-on
`packets' advice
`For the above reasons, the Medical Advisory
`Bodies of the UK Family Planning Association
`and
`the National Association of Family
`Planning Doctors have agreed the following
`advice, and pilot testing has proved satisfactory.
`The precise wording remains to be finalised,
`it
`is proposed
`that
`the readability,
`since
`presentation and
`'consumer-friendliness' of
`resulting
`leaflets will
`conform
`to
`the
`recommendation of a valuable FPA 'leaflet
`pretest' study by the University of Strathclyde. 35
`The current draft wording follows.
`Combined Pill
`If you forget a pill. Take it as soon as you
`remember, and the next one at your normal time.
`If you are 12 or more hours late with any pill
`(especially the first in the packet) the pill may not
`work. As soon as you remember, continue
`normal pill taking. However, you will not be
`protected for the next seven days and must either
`not have sex or use another method such as the
`sheath. IF these seven days run beyond the end of
`your packet, start the next packe.t at once when
`you have finished the present one, ie do not have
`a gap between packets. This·will mean you may
`not have a period until the end of two packets but
`this does you no harm. Nor does it matter if you
`see some bleeding on tablet taking days. If you
`are using everyday (ED) pills: miss out the seven
`inactive pills. If you are not sure which these are,
`ask your doctor.
`If you have a stomach upset. If you have vomiting
`
`Other recommendations
`1 Women will need to be advised to take an
`early morning urine sample for pregnancy
`there be no withdrawal
`testing should
`bleeding during the next PFI (which will be
`either after the current packet or the next
`packet, as per the instructions).
`2 Changing from a higher dose to a low dose pill.
`There
`are
`numerous
`ancedotes
`of
`breakthrough pregnancies occurring at this
`time, as a result of presumed 'rebound
`ovulation'. Several manufacturers suggest
`starting a new packet on the first day of the
`withdrawal bleed (WTB) but there is an
`in-built risk here, that the women may wait
`indefinitely for a WTB that happens not to
`occur in that particular cycle. Accordingly it
`is preferable to recommend (as for pill
`omissions at the end of the packet) that the
`PFI is omitted at the time of changeover.
`3 The value of 'everyday' packaging. The
`majority of women see
`it as of little
`importance to miss the pills that matter most,
`namely the first two in a packet. Too many
`women consider this as merely 'being a bit
`late in starting my new packet'. To m;nimise
`the chance that starting a new course may be
`delayed, the manufacturers are urged to
`introduce placebo packaging for many more
`varieties of the currently used pills than are at
`present available. It has been suggested that
`the seven placebos could be made of bran for
`perceived health reasons! 36 In addition, as
`discussed further below, versions with only
`Petitioner Exhibit 1016
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`
`42
`
`four or five bran tablets would be useful for
`selected women believed to be at high risk of
`breakthrough ovulation (eg past history of
`pill failure).
`
`Answers to some objections to the new advice
`A Pill omissions at the end of a packet
`Does not running on to the new packet increase the
`risk of exposure of an early pregnancy to the COC
`hormones?
`No, not in the slightest degree. Since the only
`time that ovulation may occur is around the end
`of the lengthened pill-free interval, and this is
`after the WTB, the latter would be falsely
`reassuring in any case. Hence if the woman
`follows the existing rules she will take the next
`packet
`anyway,
`thereby giving
`identical
`exposure to any breakthrough pregnancy.
`Does the new guidance apply to phqsic pills as well
`as fixed dose types?
`Yes. They are, however, more likely to be
`associated with breakthrough bleeding (BTB)
`early in the immediately-started new packet.
`Women should always be advised to disregard
`BTB, since this is more probable whenever
`tablets are missed.
`8 Pill omissions at the start of a packet
`Are seven days' extra precautions sufficient?
`Probably yes, for the majority of pill-takers who
`miss a small number of tablets. As mentioned
`above, however,
`there
`is an unwelcome
`deficiency of data on the restoration of COC
`efficacy after lengthening of the PFI-especially
`in the most vulnerable women with the most
`follicular activity even without missing pills.
`Consideration of this subgroup makes
`it
`appropriate in selected cases to advise post-coital
`contraception for major pill-omissions right at
`the start of a packet, if intercourse has already
`occurred, with immediate return to pill-taking
`(plus advising seven days' loss of protection)(cid:173)
`all on the basis of most careful counselling and
`I 00 per cent follow-up. But this would surely be
`
`Table 2 Cons and pros of the Pill-free interval
`
`Cons
`I Makes the COC less effective
`2 Causes some symptoms, especially withdrawal
`headaches and migraines+ occasionally the
`withdrawal bleeding is itself unwelcome.
`
`over-treatment in any other circumstances.
`above all at mid-packet!
`
`The cons and pros of the Pill-free interval (PFI)
`It is clear from the above that the pill-free
`interval, devised originally by Pincus, potentially
`the
`combined
`efficacy of
`impairs
`the
`contraceptive pill. It is also associated with the
`occurrence of certain side-effects, for example
`withdrawal headaches.
`However,
`the PFI has certain definite
`advantages listed on the right hand side of Table
`2. By the end of one year a pill taker has ingested
`pills from only 13 packets rather than the 17
`required if there were no breaks (or 16 if the
`tricycle regimen were employed).37 But further
`studies will perhaps show
`that
`the most
`significant benefit is that suggested by the work
`of Demacker et a/. 38 They found that HDL(cid:173)
`cholesterol concentrations, suppressed during
`pill taking, returned to initial values during the
`pill-free days. If this is confirmed and applies also
`to other important metabolic variables, this
`could imply an important benefit to health-and
`possibly also to reversibility of the COC method,
`by the monthly 'rest' from its systemic actions.
`Despite these good reasons for retaining the
`PFI for the maj