EXHIBIT 1022
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`EXHIBIT 1022
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`Page 1
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`1 of 1 DOCUMENT
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`Copyright 2000 The Conde Nast Publications, Inc.
`The New Yorker
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`March 13, 2000
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`SECTION: ANNALS OF MEDICINE; Pg. 52
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`LENGTH: 7194 words
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`HEADLINE: JOHN ROCK'S ERROR WHAT THE CO-INVENTOR OF THE PILL DIDN'T KNOW: MENSTRUA-
`TION CAN ENDANGER WOMEN'S HEALTH.;
`BY MALCOLM GLADWELL
`
`BODY:
`John Rock was christened in 1890 at the Church of the Immaculate Conception in Marlborough, Massachusetts, and
`married by Cardinal William O'Connell, of Boston. He had five children and nineteen grandchildren. A crucifix hung
`above his desk, and nearly every day of his adult life he attended the 7 a.m. Mass at St. Mary's in Brookline. Rock, his
`friends would say, was in love with his church. He was also one of the inventors of the birth-control pill, and it was his
`conviction that his faith and his vocation were perfectly compatible. To anyone who disagreed he would simply repeat
`the words spoken to him as a child by his home-town priest: "John, always stick to your conscience. Never let anyone
`else keep it for you. And I mean anyone else." Even when Monsignor Francis W. Carney, of Cleveland, called him a
`"moral rapist," and when Frederick Good, the longtime head of obstetrics at Boston City Hospital, went to Boston's
`Cardinal Richard Cushing to have Rock excommunicated, Rock was unmoved. "You should be afraid to meet your
`Maker," one angry woman wrote to him, soon after the Pill was approved. "My dear madam," Rock wrote back, "in my
`faith, we are taught that the Lord is with us always. When my time comes, there will be no need for introductions."
`In the years immediately after the Pill was approved by the F.D.A., in 1960, Rock was everywhere. He appeared in
`interviews and documentaries on CBS and NBC, in Time, Newsweek, Life, The Saturday Evening Post. He toured the
`country tirelessly. He wrote a widely discussed book, "The Time Has Come: A Catholic Doctor's Proposals to End the
`Battle Over Birth Control," which was translated into French, German, and Dutch. Rock was six feet three and rail-thin,
`with impeccable manners; he held doors open for his patients and addressed them as "Mrs." or "Miss." His mere associ-
`ation with the Pill helped make it seem respectable. "He was a man of great dignity," Dr. Sheldon J. Segal, of the Popu-
`lation Council, recalls. "Even if the occasion called for an open collar, you'd never find him without an ascot. He had
`the shock of white hair to go along with that. And posture, straight as an arrow, even to his last year." At Harvard Med-
`ical School, he was a giant, teaching obstetrics for more than three decades. He was a pioneer in in-vitro fertilization
`and the freezing of sperm cells, and was the first to extract an intact fertilized egg. The Pill was his crowning achieve-
`ment. His two collaborators, Gregory Pincus and Min-Cheuh Chang, worked out the mechanism. He shepherded the
`drug through its clinical trials. "It was his name and his reputation that gave ultimate validity to the claims that the pill
`would protect women against unwanted pregnancy," Loretta McLaughlin writes in her marvellous 1982 biography of
`Rock. Not long before the Pill's approval, Rock travelled to Washington to testify before the F.D.A. about the drug's
`safety. The agency examiner, Pasquale DeFelice, was a Catholic obstetrician from Georgetown University, and at one
`point, the story goes, DeFelice suggested the unthinkable-that the Catholic Church would never approve of the
`birth-control pill. "I can still see Rock standing there, his face composed, his eyes riveted on DeFelice," a colleague
`recalled years later, "and then, in a voice that would congeal your soul, he said, 'Young man, don't you sell my church
`short.' "
`In the end, of course, John Rock's church disappointed him. In 1968, in the encyclical "Humanae Vitae," Pope Paul
`VI outlawed oral contraceptives and all other "artificial" methods of birth control. The passion and urgency that ani-
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`Petitioner Exhibit 1022
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
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`Page 2
`JOHN ROCK'S ERROR WHAT THE CO-INVENTOR OF THE PILL DIDN'T KNOW: MENSTRUATION CAN
`ENDANGER WOMEN'S HEALTH.;BY MALCOLM GLADWELL The New Yorker March 13, 2000
`
`mated the birth-control debates of the sixties are now a memory. John Rock still matters, though, for the simple reason
`that in the course of reconciling his church and his work he made an er- ror. It was not a deliberate error. It became
`manifest only after his death, and through scientific advances he could not have anticipated. But because that mistake
`shaped the way he thought about the Pill-about what it was, and how it worked, and most of all what it meant-and be-
`cause John Rock was one of those responsible for the way the Pill came into the world, his error has colored the way
`people have thought about contraception ever since.
`John Rock believed that the Pill was a "natural" method of birth control. By that he didn't mean that it felt natural,
`because it obviously didn't for many women, particularly not in its earliest days, when the doses of hormone were many
`times as high as they are today. He meant that it worked by natural means. Women can get pregnant only during a cer-
`tain interval each month, because after ovulation their bodies produce a surge of the hormone progesterone. Progester-
`one-one of a class of hormones known as progestin-prepares the uterus for implantation and stops the ovaries from re-
`leasing new eggs; it favors gestation. "It is progesterone, in the healthy woman, that prevents ovulation and establishes
`the pre- and post-menstrual 'safe' period," Rock wrote. When a woman is pregnant, her body produces a stream of pro-
`gestin in part for the same reason, so that another egg can't be released and threaten the pregnancy already under way.
`Progestin, in other words, is nature's contraceptive. And what was the Pill? Progestin in tablet form. When a woman
`was on the Pill, of course, these hormones weren't coming in a sudden surge after ovulation and weren't limited to cer-
`tain times in her cycle. They were being given in a steady dose, so that ovulation was permanently shut down. They
`were also being given with an additional dose of estrogen, which holds the endometrium together and-as we've come to
`learn-helps maintain other tissues as well. But to Rock, the timing and combination of hormones wasn't the issue. The
`key fact was that the Pill's ingredients duplicated what could be found in the body naturally. And in that naturalness he
`saw enormous theological significance.
`In 1951, for example, Pope Pius XII had sanctioned the rhythm method for Catholics because he deemed it a "nat-
`ural" method of regulating procreation: it didn't kill the sperm, like a spermicide, or frustrate the normal process of pro-
`creation, like a diaphragm, or mutilate the organs, like sterilization. Rock knew all about the rhythm method. In the
`nineteen-thirties, at the Free Hospital for Women, in Brookline, he had started the country's first rhythm clinic for edu-
`cating Catholic couples in natural contraception. But how did the rhythm method work? It worked by limiting sex to the
`safe period that progestin created. And how did the Pill work? It worked by using progestin to extend the safe period to
`the entire month. It didn't mutilate the reproductive organs, or damage any natural process. "Indeed," Rock wrote, oral
`contraceptives "may be characterized as a 'pill-established safe period,' and would seem to carry the same moral impli-
`cations" as the rhythm method. The Pill was, to Rock, no more than "an adjunct to nature."
`In 1958, Pope Pius XII approved the Pill for Catholics, so long as its contraceptive effects were "indirect"-that is, so
`long as it was intended only as a remedy for conditions like painful menses or "a disease of the uterus." That ruling
`emboldened Rock still further. Short-term use of the Pill, he knew, could regulate the cycle of women whose periods
`had previously been unpredictable. Since a regular menstrual cycle was necessary for the successful use of the rhythm
`method-and since the rhythm method was sanctioned by the Church-shouldn't it be permissible for women with an irre-
`gu- lar menstrual cycle to use the Pill in order to facilitate the use of rhythm? And if that was true why not take the logic
`one step further? As the federal judge John T. Noonan writes in "Contraception," his history of the Catholic position on
`birth control:
`These arguments, as arcane as they may seem, were central to the development of oral contraception. It was John
`Rock and Gregory Pincus who decided that the Pill ought to be taken over a four-week cycle-a woman would spend
`three weeks on the Pill and the fourth week off the drug (or on a placebo), to allow for menstruation. There was and is
`no medical reason for this. A typical woman of childbearing age has a menstrual cycle of around twenty-eight days,
`determined by the cascades of hormones released by her ovaries. As first estrogen and then a combination of estrogen
`and progestin flood the uterus, its lining becomes thick and swollen, preparing for the implantation of a fertilized egg. If
`the egg is not fertilized, hormone levels plunge and cause the lining-the endometrium-to be sloughed off in a menstrual
`bleed. When a woman is on the Pill, however, no egg is released, because the Pill suppresses ovulation.The fluxes of
`estrogen and progestin that cause the lining of the uterus to grow are dramatically reduced, because the Pill slows down
`the ovaries. Pincus and Rock knew that the effect of the Pill's hormones on the endometrium was so modest that women
`could conceivably go for months without having to menstruate. "In view of the ability of this compound to prevent
`menstrual bleeding as long as it is taken," Pincus acknowledged in 1958, "a cycle of any desired length could presuma-
`bly be produced." But he and Rock decided to cut the hormones off after three weeks and trigger a menstrual period
`because they believed that women would find the continuation of their monthly bleeding reassuring. More to the point,
`
`Petitioner Exhibit 1022
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
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`

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`Page 3
`JOHN ROCK'S ERROR WHAT THE CO-INVENTOR OF THE PILL DIDN'T KNOW: MENSTRUATION CAN
`ENDANGER WOMEN'S HEALTH.;BY MALCOLM GLADWELL The New Yorker March 13, 2000
`
`if Rock wanted to demonstrate that the Pill was no more than a natural variant of the rhythm method, he couldn't very
`well do away with the monthly menses. Rhythm required "regularity," and so the Pill had to produce regularity as well.
`It has often been said of the Pill that no other drug has ever been so instantly recognizable by its packaging: that
`small, round plastic dial pack. But what was the dial pack if not the physical embodiment of the twenty-eight-day cycle?
`It was, in the words of its inventor, meant to fit into a case "indistinguishable" from a woman's cosmetics compact, so
`that it might be carried "without giving a visual clue as to matters which are of no concern to others." Today, the Pill is
`still often sold in dial packs and taken in twenty-eight-day cycles. It remains, in other words, a drug shaped by the dic-
`tates of the Catholic Church-by John Rock's desire to make this new method of birth control seem as natural as possible.
`This was John Rock's error. He was consumed by the idea of the natural. But what he thought was natural wasn't so
`natural after all, and the Pill he ushered into the world turned out to be something other than what he thought it was. In
`John Rock's mind the dictates of religion and the principles of science got mixed up, and only now are we beginning to
`untangle them.
`In 1986, a young scientist named Beverly Strassmann travelled to Africa to live with the Dogon tribe of Mali. Her
`research site was the village of Sangui in the Sahel, about a hundred and twenty miles south of Timbuktu. The Sahel is
`thorn savannah, green in the rainy season and semi-arid the rest of the year. The Dogon grow millet, sorghum, and on-
`ions, raise livestock, and live in adobe houses on the Bandiagara escarpment. They use no contraception. Many of them
`have held on to their ancestral customs and religious beliefs. Dogon farmers, in many respects, live much as people of
`that region have lived since antiquity. Strassmann wanted to construct a precise reproductive profile of the women in the
`tribe, in order to understand what female biology might have been like in the millennia that preceded the modern age. In
`a way, Strassmann was trying to answer the same question about female biology that John Rock and the Catholic
`Church had struggled with in the early sixties: what is natural? Only, her sense of "natural" was not theological but
`evolutionary. In the era during which natural selection established the basic patterns of human biology-the natural his-
`tory of our species-how often did women have children? How often did they menstruate? When did they reach puberty
`and menopause? What impact did breast-feeding have on ovulation? These questions had been studied before, but never
`so thoroughly that anthropologists felt they knew the answers with any certainty.
`Strassmann, who teaches at the University of Michigan at Ann Arbor, is a slender, soft-spoken woman with red
`hair, and she recalls her time in Mali with a certain wry humor. The house she stayed in while in Sangui had been used
`as a shelter for sheep before she came and was turned into a pigsty after she left. A small brown snake lived in her la-
`trine, and would curl up in a camouflaged coil on the seat she sat on while bathing. The villagers, she says, were of two
`minds: was it a deadly snake-Kere me jongolo, literally, "My bite cannot be healed"-or a harmless mouse snake? (It
`turned out to be the latter.) Once, one of her neighbors and best friends in the tribe roasted her a rat as a special treat. "I
`told him that white people aren't allowed to eat rat because rat is our totem," Strassmann says. "I can still see it. Bloated
`and charred. Stretched by its paws. Whiskers singed. To say nothing of the tail." Strassmann meant to live in Sangui for
`eighteen months, but her experiences there were so profound and exhilarating that she stayed for two and a half years. "I
`felt incredibly privileged," she says. "I just couldn't tear myself away."
`Part of Strassmann's work focussed on the Dogon's practice of segregating menstruating women in special huts on
`the fringes of the village. In Sangui, there were two menstrual huts-dark, cramped, one-room adobe structures, with
`boards for beds. Each accommodated three women, and when the rooms were full, latecomers were forced to stay out-
`side on the rocks. "It's not a place where people kick back and enjoy themselves," Strassmann says. "It's simply a
`nighttime hangout. They get there at dusk, and get up early in the morning and draw their water." Strassmann took urine
`samples from the women using the hut, to confirm that they were menstruating. Then she made a list of all the women
`in the village, and for her entire time in Mali-seven hundred and thirty-six consecutive nights-she kept track of everyone
`who visited the hut. Among the Dogon, she found, a woman, on average, has her first period at the age of sixteen and
`gives birth eight or nine times. From menarche, the onset of menstruation, to the age of twenty, she averages seven pe-
`riods a year. Over the next decade and a half, from the age of twenty to the age of thirty-four, she spends so much time
`either pregnant or breast-feeding (which, among the Dogon, suppresses ovulation for an average of twenty months) that
`she averages only slightly more than one period per year. Then, from the age of thirty-five until menopause, at around
`fifty, as her fertility rapidly declines, she averages four menses a year. All told, Dogon women menstruate about a hun-
`dred times in their lives. (Those who survive early childhood typically live into their seventh or eighth decade.) By con-
`trast, the average for contemporary Western women is somewhere between three hundred and fifty and four hundred
`times.
`Strassmann's office is in the basement of a converted stable next to the Natural History Museum on the University
`of Michigan campus. Behind her desk is a row of battered filing cabinets, and as she was talking she turned and pulled
`
`Petitioner Exhibit 1022
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
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`

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`Page 4
`JOHN ROCK'S ERROR WHAT THE CO-INVENTOR OF THE PILL DIDN'T KNOW: MENSTRUATION CAN
`ENDANGER WOMEN'S HEALTH.;BY MALCOLM GLADWELL The New Yorker March 13, 2000
`
`out a series of yellowed charts. Each page listed, on the left, the first names and identification numbers of the Sangui
`women. Across the top was a time line, broken into thirty-day blocks. Every menses of every woman was marked with
`an X. In the village, Strassmann explained, there were two women who were sterile, and, because they couldn't get
`pregnant, they were regulars at the menstrual hut. She flipped through the pages until she found them. "Look, she had
`twenty-nine menses over two years, and the other had twenty-three." Next to each of their names was a solid line of x's.
`"Here's a woman approaching menopause," Strassmann went on, running her finger down the page. "She's cycling but is
`a little bit erratic. Here's another woman of prime childbearing age. Two periods. Then pregnant. I never saw her again
`at the menstrual hut. This woman here didn't go to the menstrual hut for twenty months after giving birth, because she
`was breast-feeding. Two periods. Got pregnant. Then she miscarried, had a few periods, then got pregnant again. This
`woman had three menses in the study period." There weren't a lot of x's on Strassmann's sheets. Most of the boxes were
`blank. She flipped back through her sheets to the two anomalous women who were menstruating every month. "If this
`were a menstrual chart of undergraduates here at the University of Michigan, all the rows would be like this."
`Strassmann does not claim that her statistics apply to every preindustrial society. But she believes-and other an-
`thropological work backs her up-that the number of lifetime menses isn't greatly affected by differences in diet or cli-
`mate or method of subsistence (foraging versus agriculture, say). The more significant factors, Strassmann says, are
`things like the prevalence of wet-nursing or sterility. But over all she believes that the basic pattern of late menarche,
`many pregnancies, and long menstrual-free stretches caused by intensive breast-feeding was virtually universal up until
`the "demographic transition" of a hundred years ago from high to low fertility. In other words, what we think of as nor-
`mal-frequent menses-is in evolutionary terms abnormal. "It's a pity that gynecologists think that women have to men-
`struate every month," Strassmann went on. "They just don't understand the real biology of menstruation."
`To Strassmann and others in the field of evolutionary medicine, this shift from a hundred to four hundred lifetime
`menses is enormously significant. It means that women's bodies are being subjected to changes and stresses that they
`were not necessarily designed by evolution to handle. In a brilliant and provocative book, "Is Menstruation Obsolete?,"
`Drs. Elsimar Coutinho and Sheldon S. Segal, two of the world's most prominent contraceptive researchers, argue that
`this recent move to what they call "incessant ovulation" has become a serious problem for women's health. It doesn't
`mean that women are always better off the less they menstruate. There are times-particularly in the context of certain
`medical conditions-when women ought to be concerned if they aren't menstruating: In obese women, a failure to men-
`struate can signal an increased risk of uterine cancer. In female athletes, a failure to menstruate can signal an increased
`risk of osteoporosis. But for most women, Coutinho and Segal say, incessant ovulation serves no purpose except to in-
`crease the occurence of abdominal pain, mood shifts, migraines, endometriosis, fibroids, and anemia-the last of which,
`they point out, is "one of the most serious health problems in the world."
`Most serious of all is the greatly increased risk of some cancers. Cancer, after all, occurs because as cells divide and
`reproduce they sometimes make mistakes that cripple the cells' defenses against runaway growth. That's one of the rea-
`sons that our risk of cancer generally increases as we age: our cells have more time to make mistakes. But this also
`means that any change promot- ing cell division has the potential to increase cancer risk, and ovulation appears to be
`one of those changes. Whenever a woman ovulates, an egg literally bursts through the walls of her ovaries. To heal that
`puncture, the cells of the ovary wall have to divide and reproduce. Every time a woman gets pregnant and bears a child,
`her lifetime risk of ovarian cancer drops ten per cent. Why? Possibly because, between nine months of pregnancy and
`the suppression of ovulation associated with breast-feeding, she stops ovulating for twelve months-and saves her ovari-
`an walls from twelve bouts of cell division. The argument is similar for endometrial cancer. When a woman is menstru-
`ating, the estrogen that flows through her uterus stimulates the growth of the uterine lining, causing a flurry of poten-
`tially dangerous cell division. Women who do not menstruate frequently spare the endometrium that risk. Ovarian and
`endometrial cancer are characteristically modern diseases, consequences, in part, of a century in which women have
`come to menstruate four hundred times in a lifetime.
`In this sense, the Pill really does have a "natural" effect. By blocking the release of new eggs, the progestin in oral
`contraceptives reduces the rounds of ovarian cell division. Progestin also counters the surges of estrogen in the endome-
`trium, restraining cell division there. A woman who takes the Pill for ten years cuts her ovarian-cancer risk by around
`seventy per cent and her endometrial-cancer risk by around sixty per cent. But here "natural" means something different
`from what Rock meant. He assumed that the Pill was natural because it was an unobtrusive variant of the body's own
`processes. In fact, as more recent research suggests, the Pill is really only natural in so far as it's radical-rescuing the
`ovaries and endometrium from modernity. That Rock insisted on a twenty-eight-day cycle for his pill is evidence of just
`how deep his misunderstanding was: the real promise of the Pill was not that it could preserve the menstrual rhythms of
`the twentieth century but that it could disrupt them.
`
`Petitioner Exhibit 1022
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

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`Page 5
`JOHN ROCK'S ERROR WHAT THE CO-INVENTOR OF THE PILL DIDN'T KNOW: MENSTRUATION CAN
`ENDANGER WOMEN'S HEALTH.;BY MALCOLM GLADWELL The New Yorker March 13, 2000
`
`Today, a growing movement of reproductive specialists has begun to campaign loudly against the standard twen-
`ty-eight-day pill regimen. The drug company Organon has come out with a new oral contraceptive, called Mircette, that
`cuts the seven-day placebo interval to two days. Patricia Sulak, a medical researcher at Texas A. & M. University, has
`shown that most women can probably stay on the Pill, straight through, for six to twelve weeks before they experience
`breakthrough bleeding or spotting. More recently, Sulak has documented precisely what the cost of the Pill's monthly
`"off" week is. In a paper in the February issue of the journal Obstetrics and Gynecology, she and her colleagues docu-
`mented something that will come as no surprise to most women on the Pill: during the placebo week, the number of
`users experiencing pelvic pain, bloating, and swelling more than triples, breast tenderness more than doubles, and
`headaches increase by almost fifty per cent. In other words, some women on the Pill continue to experience the kinds of
`side effects associated with normal menstruation. Sulak's pa- per is a short, dry, academic work, of the sort intended for
`a narrow professional audience. But it is impossible to read it without being struck by the consequences of John Rock's
`desire to please his church. In the past forty years, millions of women around the world have been given the Pill in such
`a way as to maximize their pain and suffering. And to what end? To pretend that the Pill was no more than a pharma-
`ceutical version of the rhythm method?
`In 1980 and 1981, Malcolm Pike, a medical statistician at the Univer- sity of Southern California, travelled to Japan
`for six months to study at the Atomic Bomb Casualties Commission. Pike wasn't interested in the effects of the bomb.
`He wanted to examine the medical records that the commission had been painstakingly assembling on the survivors of
`Hiroshima and Nagasaki. He was investigating a question that would ultimately do as much to complicate our under-
`standing of the Pill as Strassmann's research would a decade later: why did Japanese women have breast-cancer rates six
`times lower than American women?
`In the late forties, the World Health Organization began to collect and publish comparative health statistics from
`around the world, and the breast-cancer disparity between Japan and America had come to obsess cancer specialists.
`The obvious answer-that Japanese women were somehow genetically protected against breast cancer-didn't make sense,
`because once Japanese women moved to the United States they began to get breast cancer almost as often as American
`women did. As a result, many experts at the time assumed that the culprit had to be some unknown toxic chemical or
`virus unique to the West. Brian Henderson, a colleague of Pike's at U.S.C. and his regular collaborator, says that when
`he entered the field, in 1970, "the whole viral- and chemical-carcinogenesis idea was huge-it dominated the literature."
`As he recalls, "Breast cancer fell into this large, unknown box that said it was something to do with the environ-
`ment-and that word 'environment' meant a lot of different things to a lot of different people. They might be talking about
`diet or smoking or pesticides."
`Henderson and Pike, however, became fascinated by a number of statistical pecularities. For one thing, the rate of
`increase in breast-cancer risk rises sharply throughout women's thirties and forties and then, at menopause, it starts to
`slow down. If a cancer is caused by some toxic outside agent, you'd expect that rate to rise steadily with each advancing
`year, as the number of mutations and genetic mistakes steadily accumulates. Breast cancer, by contrast, looked as if it
`were being driven by something specific to a woman's reproductive years. What was more, younger women who had
`had their ovaries removed had a markedly lower risk of breast cancer; when their bodies weren't producing estrogen and
`progestin every month, they got far fewer tumors. Pike and Henderson became convinced that breast cancer was linked
`to a process of cell division similar to that of ovarian and endometrial cancer. The female breast, after all, is just as sen-
`sitive to the level of hormones in a woman's body as the reproductive system. When the breast is exposed to estrogen,
`the cells of the terminal-duct lobular unit-where most breast cancer arises-undergo a flurry of division. And during the
`mid-to-late stage of the menstrual cycle, when the ovaries start producing large amounts of progestin, the pace of cell
`division in that region doubles.
`It made intuitive sense, then, that a woman's risk of breast cancer would be linked to the amount of estrogen and
`progestin her breasts have been exposed to during her lifetime. How old a woman is at menarche should make a big
`difference, because the beginning of puberty results in a hormonal surge through a woman's body, and the breast cells of
`an adolescent appear to be highly susceptible to the errors that result in cancer. (For more complicated reasons, bearing
`children turns out to be protective against breast cancer, perhaps because in the last two trimesters of pregnancy the
`cells of the breast mature and become much more resistant to mutations.) How old a woman is at menopause should
`matter, and so should how much estrogen and progestin her ovaries actually produce, and even how much she weighs
`after menopause, because fat cells turn other hormones into estrogen.
`Pike went to Hiroshima to test the cell-division theory. With other researchers at the medical archive, he looked
`first at the age when Japanese women got their period. A Japanese woman born at the turn of the century had her first
`period at sixteen and a half. American women born at the same time had their first period at fourteen. That difference
`
`Petitioner Exhibit 1022
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`Page 6
`JOHN ROCK'S ERROR WHAT THE CO-INVENTOR OF THE PILL DIDN'T KNOW: MENSTRUATION CAN
`ENDANGER WOMEN'S HEALTH.;BY MALCOLM GLADWELL The New Yorker March 13, 2000
`
`alone, by their calculation, was sufficient to explain forty per cent of the gap between American and Japanese
`breast-cancer rates. "They had collected amazing records from the women of that area," Pike said. "You could follow
`precisely the change in age of menarche over the century. You could even see the effects of the Second World War. The
`age of menarche of Japanese girls went up right at that point because of poor nutrition and other hardships. And then it
`started to go back down after the war. That's what convinced me that the data were wonderful."
`Pike, Henderson, and their colleagues then folded in the other risk factors. Age at menopause, age at first pregnan-
`cy, and number of children weren't sufficiently different between the two countries to matter. But weight was. The av-
`erage post-menopausal Japanese woman weighed a hundred pounds; the average American woman weighed a hundred
`and forty-five pounds. That fact explained another twenty-five per cent of the difference. Finally, the researchers ana-
`lyzed blood samples from women in rural Japan and China, and found that their ovaries-possibly because of their ex-
`tremely low-fat diet-were producing about seventy-five per cent the amount of estrogen that American women were
`producing. Those three factors, added together, seemed to explain the breast-cancer gap. They also appeared to explain
`why the rates of breast cancer among Asian women began to increase when they came to America: on an American diet,
`they started to menstruate earlier, gained more weight, and produced more estrogen. The talk of chemicals and tox- ins
`and power lines and smog was set aside. "When people say that what we understand about breast cancer explains only a
`small amount of the problem, that it is somehow a mystery, it's absolute nonsense," Pike says flatly. He is a South Afri-
`can in his sixties, with graying hair and a salt-and-pepper beard. Along with Henderson, he is an eminent figure in can-
`cer research, but no one would ever accuse him of being tentative in his pronouncements. "We understand breast cancer
`extraordinar- ily well. We understand it as well as we understand cigarettes and lung cancer."
`What Pike discovered in Japan led him to think about the Pill, because a tablet that suppressed ovulation-and the
`monthly tides of estrogen and progestin that come with it-obviously had the potential to be a powerful anti-breast-cancer
`drug. But the breast was a little different from the reproductive organs. Progestin prevented ovarian cancer because it
`suppressed ovulation. It was good for preventing endometrial cancer because it countered the stimulating effects of es-
`trogen. But in breast cells, Pike believed, progestin wasn't the solution; it was one of the hormones that caused cell divi-
`sion. This is one explanation for why, after years of study- ing the Pill, researchers have concluded that it has no effect
`one way or the other on breast cancer: whatever beneficial effect results from what the Pill does is cancelled out by how
`it does it. John Rock touted the fact that the Pill used progestin, because progestin was the body's own contraceptive.
`But Pike saw nothing "natural" about subjecting the breast to that heavy a dose of proges- tin. In his view, the amount of
`progestin and estrogen needed to make an effective contraceptive was much greater than the amount needed to keep the
`reproductive system healthy-and that excess was unnecessari