A
`CLINICAL GUIDE
`FOR
`CoNTRACEPTION
`THIRD EDITION
`
`Leon Speroff, M.D.
`Professor of Obstetrics and Gynecology
`Oregon Health Sciences University
`Portland, Oregon
`
`Philip D. Darney, M.D., M.Sc.
`Professor and Chief
`Obstetrics, Gynecology and Reproductive Sciences
`San Francisco General Hospital
`University of California, San Francisco
`San Francisco, California
`
`Ulustration by Lisa Million and Becky Slemmons
`Page Design by Becky Slemmons
`Portland, Oregon
`
`~t~ LIPPINCOTT WILLIAMS & WILKINS
`
`•
`
`A Wolters Kluwer Company
`Philadelphia • Baltimore • New York • London
`Buenos Aires • Hong Kong • Sydney • Tokyo
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`Case No. ll· CV·OS048·JAP·TJ8
`Case No. 12·cv·02928·JAP· TJ8
`
`PTX 082A
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 1
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`

`
`Acqumtiom Edittn: Liu McAIIist~r
`D~tlnpmmtal Edirnr: Lisa Consoli
`Produaion Editor: Ca..sic Moore
`Marmfot:turing Matlllgrt: Benjamin Rivera
`Compo1itor. Lippinron Williams & Willcios Desktop Division
`
`© 2001 by UPPfNCOTT WILLIAMS & WILKINS
`530 Walnut Stre~t
`Phil~dclphia. PA 19106 USA
`LWWcom
`
`All rights resaved. This book is prorccrcd by copyrighr. No pan of chis book roay be reproduc:W in
`any form or by any means, including phococopying, or ur.ilized by any informacion 5to(agc and rcaieval
`sysc.:m withouc wricccn permis.ion &om the coprriglu owner, accpr for brief quotat:.ions embodi~d in
`critical arrides and reviews. Maruials appeas-ing in this book prep<Ucd by individuals as pan of chcir offi(cid:173)
`cial dut.i<'S as U.S. governmcoc employccs ore nor co~d by the abavt>-matcioncd copyright.
`
`Dedication
`This book is dedicated ro o
`As Sherlock Holmes said: "Yo
`
`Princecl in China
`
`Libr:ay of Congr= Catal.oging-in-Pub!ic:aion Dat2
`
`Speroff, uon, 193>---
`A clinical guide for concracepcion I Leon Spcroff, Philip D. Damcy. -3rd cd.
`p. ;em.
`Includes bibliographical ref~renccs and index.
`ISBN 0-7817-29&4-X
`I . Con((aceprion. I. Darnry, Philip D. 0 . Tide.
`IDNLM: I. Concraccprion-nmhods. WP 630 S749c 2000)
`RG 136 .S63 2000
`6l3.9'4-dc21
`
`00-063972
`
`Care Ius been taken co conftrm chc accuracy of ch~ informar.ioo prescnrcd and co describe gener:Uiy
`accr:pa:d pracci=. However, the author3, ~ditors, and publisher are nor resporuible for errors or om.i.!(cid:173)
`sioru or lOr any coosequcna:s from application of the informacion in chis book and m:<ke no warranry,
`expressed or implied, wich rcspecr ro the currency, e<>mplcten=, or .:accuracy of che conrencs of the pub(cid:173)
`lication. Applicarioo of chiJ informacion in a panicular siruat.ion rr:ma.in.t the professional responsibilicy
`of the p.raccitioo~r.
`The authors, editors, and publi.her h~vc o:en:cd evuy cffon: co ensure that drug sdccrion and dosage
`ser for.h in this car ...rc in accord.>oc~ wit:h currenc =ommc.ndarions and practice at the uo1c of publi(cid:173)
`cation. However, in view of ongol!lg research, changes in govcrnmcnc regulations, Md the constant flow
`of information rdacing to drug therapy and dru.g reactions, tb.e reader is urged to dlcck rhc pacbgc lnscrc
`for each drug for any d1ange in indications and doS2gc and for added warnings and pr=ut.ion.s. This is
`parricularly impon.aoc when the recommended agcnr is a new or infrequc:.ocly employed drug.
`.
`Som~ drugs and medical devices pres<:nrcd in this publicacioo have Food and Drug Adrnin.i.n.rarion
`(FDA) clearance for li.cn.icccl use in resuicrcd research sctciogs. Ic is tb.c resporuibilily of the health =c
`provida co ascertain che FDA sta<US of each drug or device planned for usc in their clinical practice.
`
`·,·
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`Dedication
`This book is dedicaced to our children, one son and seven daugbccrs.
`As She.rlock Holmes said: "You know my merhods, usc them!"
`
`vision
`
`ht. No pare of this book may be reprodu""d in
`tr.ilizod by any information s.:oragc and recricval
`>wner, cxcepc for brief quotations embodied in
`~ok prep:u-ed by individuals as pare of their offi-
`1 by the abo""-mcncioned copyright.
`
`D . Darney. -3rd od.
`
`c 2000]
`
`00-063972
`
`nfo.-macion presented md co d<:<cribc genero.Uy
`ublisher arc not rr:<ponsible for errors or omis(cid:173)
`tfonnarion in rhis l>ook and make no warranry,
`lercness, or accuracy of cl>e contenu of the pub(cid:173)
`;iru'l.cion tcrruins the prof=ional retporuibUtry
`
`• clfon to ensure rh:a drug sdeaion and donge
`mmendariom and practice at the time of P"bli(cid:173)
`, government rcguhciom, •nd rhe constant flow
`.6, the rc-adc.r ia urged ro check the pac.kge insert
`..,d for added worning:s and l?recautions. This is
`l new or iofuquently employed drug.
`tblic:~cion luve Food and Drug Ad.miniscrarion
`n:ing.>. It is dJc re!ponsibi\ity of the health C2!C
`iu planned for use in their dinical practice.
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`
`r .
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`·.·'·
`.. ~
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`·'
`..
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`·~t :· .-··
`-~t ;}~:
`-~:~: Contents
`:j
`.l
`] l ,-.,
`'
`,
`···:
`
`Preface . ...... . . . . . .... ... .... .. . . .. . .............. IX
`
`1. Contraception in the U.S.A. .. ...... . . . . . .......... ... 1
`
`2. Oral Conraception .. . ..... , .. ... .... . ............. 21
`
`3. Special Uses of Oral Contracepcion ................... 139
`The Progescin-Only Minipill
`Emergency Conrraceptiou
`
`4. Implant Contraception . . ... . ... . .... . . .......... .. 153
`
`5. Injecrable Contraception . ... .. .... . . . . . : ....... . ... 199
`
`6. Intrauterine Contracepcion: The ruo ... .. ... .. ... . . . . 22 1
`
`7. Barrier Methods ........... . ....... .. ..... . ...... 259
`
`8. Periodic Abstinence . ... . ... .. . .... . .... .. . ... ... .. 297
`
`9. The Posrparrum Period,
`
`Brcasdeeding and Contraception . ... ... . .. . .. . .. . .... 309
`
`10. Clinical Guiddines for Comraception
`a~ Different Ages: Early and Late . . ..... . . ............ 333
`
`11. Sterilization ..... . . . ..... .. . . .......... . .. . ..... 363
`
`12. Induced Aborri.on ... .. . . .. . . . ... . ................ 393
`
`13. Interpreting Epidemiologic Reporu ... .. . . .. ... . . . .. . .425
`
`Epilogue . .. . .... . .. ...... .. . .. .. ... ... . . . . .. .. .431
`
`Index . . .. . . . . .. .. . . . ..... . .. . .... . ... .. . . .... .433
`
`ix
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`2
`
`Oral
`Contraception
`
`.,
`i
`!
`
`C ONTRACEPTION is commonly viewed as a modern event, a
`
`recent developmem in hwnan history. On me conrrary, cffons to
`limir reproduction predate our ability co write about ir. Ir is only
`hormonal conuaccption wim synthetic sex steroids that is recent.
`
`3
`
`History1
`•
`lr wasn't uncil the early 1900s chat inhibition of ovulacion was observed co
`be linked to pregnancy and the corpus lutewn. Ludwig Haherlandt,
`professor of physiology ac the University of Innsbruck, Austria, was me
`first co demonstrate rhat ovarian exrracrs given orally could prevent fenil(cid:173)
`icy (in mice) . In the 1920s, Habeda.o.dc an4 a Vi~ese gynecologist,
`Otfried Ouo Fellner, were adm.i.o.ist:ering steroid exuaccs to a variery of
`an.i.rnal.s and reporting the inhibition offerriiicy. By 1931, H.aberlandt was
`proposing the administration of hormones for birth conuol. An extract
`was produced, named Infecuodin, ready co be used, bur Haberl.andr's early
`dearh in 1932, at: age 47, broughc an end to this effort. Fdlner disappeared
`after r:he annexation of Ausuia to Hider's Germany.
`
`The concepr was arutundated by Haherlandr, bur steroid chemistry wasn't
`ready. The enraccion and isolation of a few milligrams of the sex steroids
`required scarring points measured in gallons of urine or thousands of
`poll.Jlds of orgaos. Edward Daisy processed 80,000 sow ovaries co produce
`12 rng of esrradiol.
`
`21
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`El
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`(
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`A Clinical Guide for Contraception
`
`Russell Marker
`The supply problem was solved by an eccenuic chemise, Russell E. Marker,
`who mmpleted his thesis, but not his murse work, for his Ph.D. Marker,
`born in 1902 near Hagerstown, Maryland, rece.ived his Bachelor's degree
`in orga.Wc chemistry and his Master's degree in mUoidal chemistry from
`the Universicy of Maryland. After leaving the University of .Maryland,
`Marker worked with rhe Ethyl Gasoline Corporation, md in 1926, devel(cid:173)
`oped the proet.:5S of ocrane raring, based on the dismvery that knocking in
`gasoline was due ro hydrocarbons with an uneven number of carbons.
`
`From 1927 ro 1935, Marker worked at the Rockefeller Inscirute, publish(cid:173)
`ing a meal of 32 papers on configu.racion and optical rotation as a method
`of idemifying mmpounds. He became interested in solving the problem of
`producing abundam and cheap amounts of progesterone, but he was told
`co cominue with his work in optical technology. In 1935, he moved ro
`Pennsylvania Stare University at a reduced salary, buc with the freedom to
`pursue any field of research. At thac rime, it required the ovaries from 2500
`pregnant pigs co produce 1 mg of progesterone. In 1939, Marker devised
`the method (called the Marker degradacion) to convert a sapogenin mole(cid:173)
`cule into a progesrin. Marker became convinced that the solution co the
`problem of obt::ain.ing large quantities of sceroid hormones was ro fiad
`planes (in the family that includes the lily, the agave, and the yam) that
`contained sufficient amounts of diosgenin, a plant steroid (a sapogenin)
`that muld be used as a srarcing poim for steroid hormone produaion.TIUs
`conviction was srrengchened with his discovery t.h.ar a species of Trillium,
`kncrwn locally as Belh's rooc, was mllecred in North Carolina and used in
`rhe preparation of Lydia Pinkham's Compound, popular at the time ro
`relieve menstrll:ll troubles. The plane ingredient in Beth's root was dios(cid:173)
`genin, and it is unUkdy char it ex:erced any therapeucic effect. The rhizome
`in Belli's roor was roo small ro provide sufficient amounts for commercial
`use, and Marker's search foe an appropriate plant then took him to
`California, Arizona, and Texas.
`
`On a visit ro Texas A & M University, Marker found a piecure of a large
`dioscorca (Diosco"a mexitana) in a book thar he just happened co pick up
`and browse through while spending the night at the home of a retired
`boranisc. After returning ro Pe.nnsylvania, he decided co go co Veracruz,
`Mexico (it took 3 days by ua.in), to search for !.his dioscorea. He made
`several arrempr.s in 194l and early 1942, bm was frustrated first by the lack
`of a plant-collecting permit from the Mcxician government and chen by
`his failu(e to find the plane. He remembered rhat the book with the picrure
`reponed thar this dioscorea was known locally as "cabei'...a de negro," black
`rubets that grew near Orizaba a.ml Cordoba. Marker rook a bus to
`Cordoba, md near Orizaba, an Indian who owned a small srore brought
`
`him two plants. Each ruber w: .
`material like a turnip, used by
`
`Marker managed to get one
`University and isolated diosg.
`pharmaet.:tJtical industry, Marl
`returned to Veracruz, mllected
`a syrup from the roars. Back
`syrup, Marker worked out the
`One 5-gallon can yidded 3 kg
`tical companies sUll refused 1
`refused, despite Marker's urgin
`
`Io 1943, Marker resigned from
`Mexico where he collected the
`Looking through the yellow P'
`Marker found a company ci
`lawyer, Emeric Somlo, and
`arranged a meeting. and the cl:
`produce hormones. In an old ·r·
`of l...aborarorios Hormona), in ·
`progesrerone {worth $300,000:
`had little education and spoke 1
`The two partners and Marker I
`Syncex (from synthesis and Mex
`of progesterone. The price of p
`
`During chis time, Marker rece.i'
`of the profirs or me 40% sha.J
`setcle.ment, Marker left Synre:
`company in Texcom, called
`barbasco, which gave a greater ~
`terone dropped to $10 a gram, :
`harassed (legally and physically
`reaching ownership by Or:gano·
`
`In 1949, Marker rerired co Pe1
`making replicas of antique w
`allowed him, in the 1980s,
`Pennsylvania Srace University a
`he cook his know-how wirb hirr
`a scientific dcscrip cioo of his p1
`discoveries. Synccx recruited G1
`living in Cuba, co reinscirurc rn
`{and testosterone) nom Mexic;u
`of !.he women lcfr behind by M
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`Oral Contraception
`
`him two plants. Each tuber was 9-12 inches high and consisted of whice
`material Lke a rurnip, U.5ed by local Mexicans as a poison tO catch fish.
`
`Marker managed ro gee ooe bag of rubers back to Pennsylvania Stare
`
`University and isolared diosgenin. Unable to obtain support fi-om the. II
`
`pharmaceurical indusuy, Marker used his life savings, and in 1942, he
`rerurned ro Veracruz, collected the roors of che Mexican yam, aod prepared
`a syrup fi-om the roars. Back in Penosylvania wirh his 5-gallon cans of
`syrup, Marker worked ouc che degradation of diosgenin co progesterone..
`One 5-gallon can yielded 3 kg of progesterone. United Srates pharmaceu-
`cical companies scill refused to back Marker, and even the University
`refused, dc.spire Marker's urging, to patent the process.
`
`In 1943, Marker resigned from Pen.nsylvania State Universicy and went to
`Mexico where )te collected the roots of Dwscorea m~xicana, 10 tons worth!
`Looking through the yellow pages in a Merica City telephone directory,
`Marker found a company called Laboracorios Hormona, owned by a
`lawyer, Emeric Somlo, and a physician, Frederick Lehman. Marker
`arranged. a meecing. and rhe three agreed to form a Mexican company ro
`produce hormones. in an old pouery shed in Merica Cicy (the laboratories
`of Laboratories Hormona), in two mo!1r:h.s, he prepared several pounds of
`progesterone (wonh $300,000) with the hdp of four yollllg women who
`ha.d .licrle eduan:ion and spoke no Engl.i.sh (Marker did nor speak Spanish).
`The cwo partners and Marker formed a company in 1944 that they called
`Syncex (from rynthesis and Mmco). In 1944, Marker produced over 30 kg
`of progesterone. The price of progesrerone fell from $200 to $50 a gram.
`
`During this rime, Marker received expenses, bur he was not given his share
`of che profits or che 40% share of swck due w him. Failing to reach a
`seulement, Marker left Symex after only one year and started a new
`company in Texcoco, called Bocanica-Mex. He changed ro Dioscorea
`barbasco, which gave a grearer yield of diosgenin, and t:he price of proges(cid:173)
`terone dropped to $10 a gram, and larer co $5. This company was allegedly
`harassed (legally and ph~ically) by Syncex, and in 1946, sold, evenrually
`reaching ownership by Organon of Holland, which still uses ir.
`
`In 1949, Marker recired m Pennsylvania m devote che resc of his life to
`making replicas of antique works in silver, a successful business rhat
`allowed him, in the 1980s, co endow scienri.Bc lecrureships at both
`Pennsylvania Swe Un.iverury and che Un.iversicy of Maryland. However,
`he took his know-how wich him. Fortunately for Symex, he had published
`a scientific description of his process, aod there sriU was no patent on his
`discoveries. Synr.e:x recruited George Roseo.k.ranz, a Hungarian immigranr
`living in Cuba, ro reinstitute chc commercial manufaccure of progesterone
`(and testosterone) &om Moo can yams, a wk that took him (wich che help
`of the women lcfi: behind by Marker) 2 years.
`
`an eccenrric chemise, RU.5sell E. Marker,
`: h.is course work, for his Ph.D. Marker,
`vfaryland, recci1-ed bi.s Bachelor's degree
`;rcr's degree in colloidal chernisuy from
`~ leaving the Universicy of Maryland,
`!Saline Corporation, and in 1926, devel(cid:173)
`based on cite discovery chat knocking in
`with an uneven number of carbons.
`
`ked ar cite Rockefd!er lnscirure, publish(cid:173)
`uracion and opcical ror.acion as a merhod
`:arne interested in solving the problem of
`moums of pmgesccrone, bur he was mid
`cical technology. Jn 1935, he moved ro
`1 reduced salary, hue wirh che freedom m
`ar rime, ir required che ovaries from 2500
`f progesterone. ln 1939, Marker devised
`:gradation) to convert a sapogenin mole(cid:173)
`c.;une convinced chat the solution m the
`ncicies of steroid hormones was to find
`es the lily, me agave, and me yam) that
`diosgenin, a plane steroid (a sapogenin)
`.im for sreroid hormone production. This~
`1 his discovery rhat a species of Trillium,
`collecred in North Carolina and used in
`m's Compound, popular at me rime to
`)l.anr ingredient in Beth's root was dios(cid:173)
`~ed any rherapeutic effect. The rhizome
`;ovide sufficient amounts for commercial
`n appropriate plant then rook him m
`
`1ersity, Marker found a picttue of a large
`t a book that he just happened co pick up
`ding the night at the home of a retired
`nsyivania, he decided to go to Veracruz,
`), to search for this dioscorea. He made
`y 1942, bur was frustrated fim by rhe lack
`a che Mocician government and then hy
`~embcred ilia( the book wirh the picrure
`known locally as "cabeza de negro," black
`and Cordoba. Marker rook a bus co
`Indian who owned a small score brought
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`
`A Clinical Guide for Contraception
`
`In 1970, the Mexican govenunent recognized Marker and awarded him
`the Order of me Aztec Eagle; he declined. Iu 1984, Pennsylvania Scue
`Universiry established che annual Marker Lecrurcs in Science, and in 1987,
`che Russell and Mildred Marker Professorship of Narural Product
`Chemisuy.ln 1987, Marker was granted an honorary Doctorate in Science
`from me University of M;pyland, the degree be failed to receive in 1926.
`At the age of 92, Russell Earl Marker died in Wernersville, Pennsylvania,
`in 1995, from complications after a broken hip.
`
`Carl Djerassi•
`The Djerassi family lived in Bulg:uia for hundreds of years afrer escaping
`Spain during the Inquisition. Carl Djerassi, the son of a Bulgarian physi(cid:173)
`cian, was born in Vienna (as was his physician roomer) . Dje.rassi, at the age
`of 16, and his mother emigrated to the United Scates in 1939. A Jewish
`refugee aid organization placed Djerassi with a family in Newark, New
`Jersey. Wich a scholarship ro Tarkio College in Tarkio, Missouri, he was
`exposed to middle America, where he earned his way giving talks to church
`groups about Bulgaria and Europe. His education was further supported
`by another scholarship &om Kenyon College in Ohio, where he pursued
`chemistry. After a year working for CIBA, Djerassi received his graduare
`degree from the Uuiversiry of WISconsin. Returning co CIBA and being
`somewhat unhappy, he responded to an inviration m visit Syntex.
`Rosenkranz proposed that Djerassi head a research group to concem.race
`on me synchcsis of cortisone.
`
`In 1949, it was discovered char cortisone relieved arrhricis, and the race was
`on to devdop an easy and cheap method to synthesize cortisone. Carl
`Djerassi, at age 26, joined Symex ro 'WOrk on this synthesis using the
`Mexican yam plant sreroid diosgenin as the starting poinr. This was
`quickly achieved (in 195l), bur soon after, an even better method of corci(cid:173)
`sone producrion using microbiologic fermenracioJl was discovered at
`Upjohn. This latter method used progcstemne as the starring point, and,
`therefore, Syncex fOund itself as the key supplier to oilier companies for
`rhis important process, at rhe rate of 10 tons of progesterone per year and
`a price of 48 cents per gram.
`
`Djerassi and other Synrex chemist<> then rurot::d cheir attention to che sex
`steroids. They discovered rhat the removal of the 19--carbon from yam,
`derived progescerone .increased the progestational acrivicy of che molecule.
`Ethisterone had been available for a dozen years, and me Synrex chemists
`reasoned tha[ removal of the 19-carbon would increase the proges~:arional
`potency of this oraUy active compound. In 1951, norethindrone was
`synthesized; the patcm for this drug .is the first patent for a drug listed in
`the National In.vemor's Hall of Fame in Akron, Ohio. A closcly related
`
`i
`
`·?
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`
`.I
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`1
`
`.}
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`{.
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`
`·--~
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`
`compoWld, norethynodrel, Wa.!
`tiona! agent to receive a patent
`G.D. Searle & Company.
`
`Djerassi eventually ldt Sym<
`Uo.ivcrsity. He is now a playwri1
`
`Gregory Pincus
`Gregory Goodwin (Goody) Pic
`son of Russian Jewish imm.igran
`a Ge(man-Jewish philanclu-opic
`children and grew up in a horr
`even his f.uni.ly regarded him as
`
`Pincus graduaced from CorneU
`joining Hudson Hoagland and
`Crozier in physiology, recciviJ
`Jacques Loeb who discovered a
`urchin eggs. Mosc importamly
`science to improve human life.
`Pincus, Hoagland, and Sk.i..nn.
`neurophysiology, and psycholo:
`This was co be che cornerstone
`
`Hoagland, afrer a short stay :
`England, and chen moved to C);
`co be the chair of biology ar ch
`Germany, and returned co Han
`
`Pincus performed pioneering stt
`oocyres, in both rabbit and hw
`achievement of in vitro ferriliza.
`in the New York Times chat alh
`Colliers depicted h.i.m as an e,
`Pincus's work as one of the univ
`of all time, bur Harvard denied
`
`At Clark University, Hudson r.
`president of the university, w~
`widely used textbook on geogr;
`consim:d of one faculty membe
`Hudson Hoagland. Hoagland,
`grant renure ro his &iend (st
`Scmicism), invired Pincus co joi
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 8
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`
`rr
`
`t
`j
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`l ·;
`I l
`-i
`i I
`
`~
`
`'I
`
`r recognized Marker and awarded him
`dec.li.ncd. In 1984, Pennsylvania Smre
`1arker Lectures in Science, and in 1987,
`er Professorship of Natural Product
`anted an honorary Docrorare in Science
`dte degree he failed ro receive in 1926.
`·ker died in Wernersville, Peno.sylvan.ia,
`a broken h.ip.
`
`ria for hundreds of years afrer escaping
`Dje.rassi, che son of a Bulgarian physi(cid:173)
`s physician morher). Djerassi, at rhe age
`.o the United Scares in 1939. A Jewish
`·jerassi with a family in Newark, New
`io College in Tarkio, Missouri, he was
`he earned hls.way giving calks ro church
`·. His education was further supported
`:m College in Ohio, where he pursued
`r CIBA, Djerassi received his gnduare
`consin. Returning ro CIBA and being
`:d ro an invicarion ro visir Symex,
`i bead a research group to concentrate
`
`isone relieved arthritis, and me race was
`method w symhesize cortisone. Carl
`: to work on chis syniliesis using the
`enin as me sr.aning point. This was
`n afrer, an even beaer method of ooni(cid:173)
`ogic fermentation was discovered ar
`•rogesterone as me st.art.ing point, and,
`c key supplier co oilier companies for
`,f 10 rons of progesterone per year and
`
`then rurned their actention ro che se:x
`removal of the 19-c:acbon from yam(cid:173)
`?rogest2tiorral accivicy of the molecule.
`l doz.eo years, and the Syote:x: chemists
`·bon would increase che proges-rariona1
`pound. In 1951, oorethind.rone was
`~ is the fLrSt patem for a drug lisr.ed io
`me in Akron, Ohio. A closdy rdared
`
`•
`
`Oral Contraception
`
`compound, norethyoodrd, was actually the first orally active progesta(cid:173)
`tional age.~u to receive a pare.or, assigned to Frank Cohon, a chemist ar
`G.D. Searle & Company.
`
`Djerassi evencua.lly left: Symcx to become a professor ar Sranford
`University. He is now a puywrighr and novdisr, living in San Francisco.
`
`Gregory Pincus
`Gregory Goodwin (Goody) Pincus was born in 1903 in New Jersey, the
`son of Russian Jewish immigrants who lived on a farm colony founded by
`a Ge(')JUJl-Jewish philanthropic organization. Pincus was me oldest of 6
`children and grew up in a home of imellecrual curiosity and energy, but
`even his fami1y regarded him as a genius.
`
`Pincus graduared from Cornell and went to Harvard to study generics,
`joining Hudson Hoagland and B.F. Skinner as graduate students ofW).
`Crozier io physiology, receivi.ug degrees in 1927. Crozier's hero was
`Jacques Loeb who discovered artificial parthenogenesis work.ing with sea
`urchin eggs. Most impormncly, Loeb was a srrong believer io applying
`science ro improve human life. Thus, Crozier, i.n.flueoced by Loeb, caughc
`Pincus, Hoagland, and Skinner (respecrivdy, in reproductive biology,
`neurophysiology, and psychology) to apply science ro human problems.
`This was w be the cornerstone of Pincus's own philosophy.
`
`Hoagland, after a short stay ac Harvard, spcnc a year in Cambridge,
`England, and men moved ro Clark University in Worcester, Massachuserrs,
`to be che chair of biology ar the age of 31. Pincus weor co England and
`Germany, aod recurned co Harvard as an assisrnm professor of physiology.
`
`Pincus perfoWlcd pioneering studies of meiotic maturation in rruu:nmalian
`oocytcs, in both rabbir and human oocytcs. In 1934, Pincus reported the
`achievement of in viuo fertilization of nbbic eggs, earning him a hea.dl.ioc
`in me New York Times that alluded co Haldane and Huxley. An an:icle in
`Colliers depicred him as an evil scientisr. By 1936, H.uvard had cired
`Pincus's work as one of the university's outstanding scienrific ac.b..ievemeors
`of all rime, bur Harvard denied him tenure in 1937.
`
`At Clark Univcrsicy; Hudson Ho~bnd was in consl:allt confljcr wirh the
`presidcnr of the university, Wallace W. Arwood, the senior author of a
`widely used re.xtbook on geography. In 1931, che Depanrnent of Biology
`consisted of one fuculry member and his graduate srudenr, and rheir chair,
`Hudson Hoagland. Hoagland, upset and angry over Harvard's refusal w
`grant renure to his friend (suspecting chat this was because of anti(cid:173)
`Semitism), .invited Pincus to joiu bim.
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 9
`
`

`
`A Clinical Guide for Contraception
`
`Hoagland secured funds for Pincus from philanthropists i.n New York Ciry,
`enough for a laborarory aod an assiscanc. This success Unpressed che two
`men, especially Hoagland, planring che idea th.ar ir would be possible to
`supporr research wich privare money.
`
`Min-Chueh Chang received b.is Ph.D. degree from Harvard on an infa(cid:173)
`mous day, December 7, 1941, and thus he was forced ro remain in this
`counrry. He was drawn ro Pincus because of Pincus's book, The Egg.r of
`Mammals, published in 1936, a book rJur had a major impact on biolo(cid:173)
`gistS ar char cime. The successful recruirmenr ofM-C Chang by Hoagland
`and Pi.ncus was ro pay great dividends.
`
`Soon Hoagland h:~.d put together a group of outsranding sc.ienrists, bur
`because of his on-going antagonism wic:h President Atwood, che group was
`denied faculry srarus. Working in a convened barn, chey were tot:ally
`suppocred by private funds. By 1943, 12 of Clark's 60 faculry were in rhe
`Deparunent of Biology.
`
`Frusrcated by me politics of academia, Hoagland and Pincus (who both
`eo joyed srepping omside of convencion) had a vision of a privare research
`cen.rer devored ro their philosophy of applied science, Indeed, the estab(cid:173)
`lishmem of rhe Worcesrer Foundacion for ExperLmental Biology, in 1944,
`cao be auribuced directly to Hoagland and Pincus, rhcir friendship for
`each ocher, their confidence, enthusiasm, ambirioo, and drive. Ir was their
`spirit thar rurned many members of Worcester society inro financial
`supporters of biologic science. Hoagland and Pincus accomplished whar
`rhey set our to do. They created and sustained a vibrant, productive scien(cid:173)
`cific instirucion in which ic was a pleasure ro work.
`
`Although named rhe Worcesrcr Foundation for Experimental Biology, the
`Foundation was
`located
`in rbe summer of 1945 across Lake
`Quiosigamond in a house on an estate in Shrewsbury. The Board of
`Trustees was chaired by Harlow Shapley, a distinguished astronomer, vice(cid:173)
`chaired by Rabbi Levi Olan, and included 3 Nobellaureares and a group
`of Worcester businessmen.
`
`From 194 S co the dea(h of Pincus in 1967 , rhe sraff grew from 12 to 3 SO
`(scie.ncisrs and support people), 36 of whom were independently funded
`and 45 were postdoctoral feUow:s. The annual budger grew from $1 00,000
`to $4.5 million, One hundred acres of adjoining land were acquired, and
`the campus grew to ll buildings. In its fmr 25 years, approximately 3000
`scientific papers were published.
`
`.!
`i
`.i
`·l
`i
`1
`l
`.l
`i
`·'
`i
`
`·[
`1
`
`·I
`
`. ..
`' ·;
`
`i ·;
`
`Bur in those early years, Pi.ncus,
`bookkeep,;, M -C Chang was c:h
`che lawn. During the ~s o:
`combined their interests in hor
`mess and fatigue in indusrry an.
`
`The initial discoveries tim led rc
`M-C Cb.ang (also the fusr co de
`In 1951, he confirmed the wor.
`char progesrerone could i.nhibir •
`and oorec:hyoodrcl becune avai
`100% effective in inhibiti.ng ovu
`
`Karherine DCJC£cr M cCormick
`married St:an..ley McCormick, cl
`of Incerna.riooal Harvester. She
`graduare from che Massachu
`conscious, and a generous c
`McCormick's husband suffered
`Neuroendocrine Research FoUJ
`Tbis brought he.r rogecher with
`done by Chang aud Pincus.
`
`Pincus aruibutc::d his inreresr in
`for the world's population pro
`Sanger, ar that time president
`America.. At that visit, Sanger
`ception could be derived from
`and Chaog.
`
`In 1952, Margaret Sanger hr•
`together. During this meeting
`from his mammalian research . :
`form as a conaaceptive, acting
`McCormick provided a researc
`time of her death. McCormid
`the Worce.~rer Foundation, anc
`book, Th~ Control of Fertility, p
`is dcd.icarcd ro Mrs. Scanley W
`scientific inquiry and her unsv,
`
`Ic was Pincus who made c:he ,
`knew hwnan experiments WOl
`cology and obstetrics at Harvat
`discovered their mutual imew
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 10
`
`

`
`r-(cid:173)
`-, -
`i
`r
`
`ts from philamhropists in New York City,
`tSsistam .. This success impressed the rwo
`ng me idea thar i[ would be possible (0
`ncy.
`
`Ph.D . degree &om Harvard on an infa(cid:173)
`nd elms he was forced to remain in this
`tS because of Pincus's book, The EggJ of
`book iliac had a major impact on biolo(cid:173)
`recruiunenc of M-C Chang by Hoagland
`lends.
`
`:r a group of outstanding scientists, but
`;m with President Arwood, the group was
`in a converted barn, they were torally
`943, 12 of Clark's 60 faculry were in the
`
`lemia, Hoagland and Pincus (who borh
`ention) had a vision of a private research _
`hy of applied science. Indeed, rhe esrab(cid:173)
`lacion for Experimental Biology, in 1944,
`)agland and Pincus, chcir friendship for
`IUsiasm, ambition, and drive. It was their
`•ers of Worcester sociecy into financial '
`foagland and Pincus accomplished whar
`md sus rained a vibrant, productive scien(cid:173)
`pleasure co work.
`
`:oundacion for Experimental Biology, che
`che summer of 1945 across Lake
`a.u estate in Shrewsbury. The Board of
`)hapley; a distinguished astronomer, vice(cid:173)
`l included 3 Nobd laureates and a group
`
`1s in 1967, the staff grew from 12 co 350
`36 of whom were independently funded
`. The annual budget grew from $100,000
`:res of adjoining land were acquired. and
`. In ics first 25 years, approximarely 3000
`
`Ll
`
`Oral Contraception
`
`But in chose early years, Pincus was me animal keeper, Mrs. Hoagland rhe
`bookkeeper, M-C Chang was me nighr watchman, and Hoagland mowed
`me lawn. During the years of World War II, Pincus and Hoagland
`combined their interests in hormones and neurophysiology ro focus on
`suess and fatigue in industry and me military.
`
`The initial discoveries mar led [0 an oral contraceptive can be attributed [0
`M-C Chang (also the fuse ro describe che capacitation process of sperm).
`In 1951, he confirmed me work of Makepeace (in 1937) demousrracing
`t:hat progesterone could inhlbic ovulation iu rabbits. When norethindrone
`and norethynodrel became available, Ch.ang foUDd them co be virtually
`100% effective in inhibiting ovularion when adminiS'Cered orally to rabbits.
`
`Karherine Dexter McCormick was a very rich woman; in 1904, she
`married Sranley McCormick, the son of Cyrus McCormick, rhe founder
`of International Harvester. She was also intelligent, the second woman to
`graduate from the Massachusetts Institute of Technology, socially
`conscious, and a generous con[[ibutor to family planning efforts.
`McCormick's husband suffered from schizophrenia, so she established rhe
`N euroendocrine Research Foundation at Harvard co srudy rhe disease.
`This brought her cogecher with Hoagland who told her of che work being
`done by Cnang and Pincus.
`
`Pincus amibured h.is imeresr in contraception to his growing appreciation
`for me world's popularion problem, and to a 1951 visir wim Margaret
`Sanger, at chat time president of rhe Planned Parenrhood Fedcrarion of
`America. At rh.at visir, Sanger expressed hope rhar a merhod of contra(cid:173)
`ception could be derived from the laboratory work be.ing done by Pincus
`and Chang.
`
`In 1952, Margaret Sanger brought Pincus and Katherine McCormick
`together. During chis meeting, Pincus foiTJiulared his thoughts derived
`f