EXHIBIT 1013
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`EXHIBIT 1013
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`Editor: Chai'les Mitchell
`Managing Editor: Ray Reter
`Marketing Manager: Joy Stewart
`Production Editor: Robert D . Magee
`
`Copyright© 1999 Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
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`All rights reserved. This book is protected by copyright. No part of this book may be reproduced
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`retrieval system without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or otherwise) for any
`injury resulting from any material contained herein. This publication contains information
`relating to general principles of medical care which sbould not be construed as specific
`instructions for individual patients. Manufacturers' product information and package inserts
`should be reviewed for current information, including contraindications, dosages and
`precautions.
`
`Printed in the United States of America
`
`First Edition, 1973
`
`Library of Congress Cataloging-in-Publication Data
`
`Speroff, Leon, 1935-
`Clinkal gynecologic endocrinology and infertility I Leon Speroff, Robert H. Gla.~s, Nathan G.
`Kase ; illustration and page design by Lisa Million. -{'ith ed.
`p.
`em.
`Includes bibliographical references and index.
`ISBN 0-683-30379-1
`1. Endocrine gynecology. 2. Infertility-Endocrine aspects. I. Glass, Robert H.. 1932-
`ll. Kase, Nathan G., 1930-
`ill. Title.
`RG159.S62 1999
`618.l-dc21
`
`98-36104
`CIP
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If
`they have inadvertently overlooked any, they will be pleased to make the necessary arrangements
`at the first opportunity.
`
`To purchase additional copies of this book, call our customer service department at (800) 638·
`3030 or fax orders co (301) 824-7390. International customers should call {301) 714-2324.
`
`99 0001 02 03
`2 3 4 5 6 7 8 9 10
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`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
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`

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`4
`
`The Uterus
`
`atomical knowledge of the uterus was slow to accumulate. I. 2 Papyrus writings from 2500
`BC indicate that the ancient Egyptians made a distinction between the vagina anrl
`uterus. Because the dead had to be embalmed, dissection was precluded, but prolapse
`was recognized because it was important to return the uterus into its proper place prior to
`mummification. Next ro the Egyptian papyri in antiquity were I Iindu writings m wh1ch dcscrip·
`tioos of the uterus, tubes, ami vagina indicate knowledge gained fn)m dissections. This was
`probably the earliest description of the fallopian tubes_
`
`There is little information in Greek writings about femnle anatomy; however, Herophilus (4th
`century BC), Lhe great anatomist in Alexandria and U1c originator of scholarly dissection ,
`recorded the different positions of the uterus. Soranus of Ephesus (98-138 /\D) accurate!)
`descrioed the uterus (probably t.he first. to do so), obvious! y from multiple dissections of cadavers.
`He rccognii';ed thai the uterus is not essential for life, acknowledged the presence of leiomyomata,
`and treated prolapse with pessaries.
`
`Herophilus and Soranus were 11ncertain about the funcl.ion of the fallopian rubes, but G~1 len ,
`Rufus, and Aetisu guessed correctly lheir function. Galen promoted tbc practice of hlceding for
`the treatment of almost every disorder. ln his argument that nature prevented disease by
`discharging excess blood, Galen maintained that women were healthier because their superfluou~
`blood was eliminated by menslruation.J The writings of Galen ( 130-200 /\D) represented the
`knowledge of medicine for over 1000 years until the end of the med ieval dark ages. Galen's
`description of the uterus and tubes indicates that he had only seen the homed uteri of animals.
`
`In the l6th century, Berengarius, Vesalius, Rustacbi us, and Fallopius made s ignifi cant contribu(cid:173)
`tions to the anatomical study of the female genitalia. Bcrengarius (Giacomo Berengario da Carpi)
`was the first anatomist to work with an artL~il. His anatomical text. published in 1514, depicted
`dissected subjects as if they were still alive.
`
`Gabriele Pallopio (or flallopius) puhlished his work. Ohservatirmes Anatomicae, in Venice in
`1561, one year before his death from pleurisy at ago 40. He provided the first descriptions or the
`clitoris and the hymen, and the first exact descriptions of the ov:Jrics and the tubes. He named the
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
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`132
`
`Part I
`
`J<eproductive Physiology
`
`During the secretory phase, so-called K (Kornchenzellcn) cells appear, reaching a peak concen(cid:173)
`tration in the tirst trimester of pregnancy. These arc granulocytes that have an immunoprotecti ve
`role in implantation and placentation. They arc located perivascularly and arc believed to be
`derived from the blood. n y day 26-27, the endometrial stroma is infi It rated by extravasated
`polymorphonuclear leukocytes.
`
`The stromal cells of the e ndometrium respond to hormonal signals, synthesize prostaglandins,
`and. when transformed into decidual cells, produce an impressive a rray of substances, some of
`which are prolactin, relaxin, renin, insulin-like growth factors (lGPs), and insulin-like growth
`factor binding proteins (IGFBPs). The endometrial stromal cells, the progenitors of decidual
`cells, were originally believed to be derived from the bone marrow (from cells invading the
`endometrium), but they arc now considered to emanate from the prim itive uterine mesenchymal
`ste m cells 6
`
`The decidualir.ation process begins in the luteal phase under the influence of progesterone and
`mediated by autocrine and paracrine factors. On cycle days 22- 23, prcdccidual cells can be
`identified, initially surrounding blood vessels, characterized by cytonuclcar enlargement, in(cid:173)
`creased mitotic activity, and the formation of a basement membrane. The decidua, derived from
`stromal cells, becomes an important structural and biochemical tissue of pregnancy. Decidual
`cells control ihe invasive nature of the trophoblast, and the products of the decidua play important
`autocrinc and paracrine roles in fetal and maternal tissues.
`
`Lockwood assigns a key role to decidual cells in both the process of e ndometrial bleeding
`(menstruation) and the process of endometrial hemostasis (implantation and placcntation). 19
`Implantation requires endometrial hemostasis and the maternal uterus requires resistance to
`invasion. Inhibition of endometrial hemorrhage can be attributed, to a sign ificant degree, to
`appropriate changes in critical factors as a consequence of decidualization; e.g., lower plasmino(cid:173)
`gen activator levels, reduced expression of the en:r.ymes that degrade the stromal extracellular
`matrix (such as the metalloproteinases), and increased levels of plasminogen activator inhibitor(cid:173)
`!. Withdrawal of estrogen and progesterone support, however, leads to changes in the opposite
`directions, consistent with endometrial breakdown.
`
`The Phase of Endometrial Breakdown
`
`Predecidual transformation has formed the "compacta" layer in the upper part of the funct ional is
`layer by day 25 (3 days before menstruation). In the absence of fertilization, implantation, and
`the consequent lack of sustaining quantities of human chorionic gonadotropin from the tropho(cid:173)
`blast, the otherwise fixed life span of the corpus luteum is completed, and estrogen a nd
`progesterone levels wane.
`
`The withdrawal of estrogen and progesterone initiates important endometrial events: vasomotor
`reactions, the process of apoptosis, tissue loss, and finally, menstruation. The most prominent
`immediate effect of this hormone withdrawal is a modest shrinking of the tissue height and
`remarkable spiral arteriole vasomotor responses. The following vascular sequence has been
`constructed from direct observations of rhesus endometrium.7· 8 With shrinkage of height, blood
`flow within the spiral vessels diminishes, venous drainage is decreased, and vasodilatation
`ensues. Thereafter, the spiral arterioles undergo rhythmic vasoconstriction and relaxation. Each
`successive spasm is more prolonged and profound, leading eventually to endometrial blanching.
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 12
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`Chapter 4 The Uterus
`
`135
`
`Eventually, considerable leakage occurs as a result of diapedesis, and finally, interstitial hemor(cid:173)
`rhage occurs due to breaks in superficial arterioles and capillaries. As ischemia and weakening
`progress, the continuous binding membrane is fragmented. and inrercellular blood is elttrudcd
`into the endometrial cavity. New thrombin -platelet plugs form intravascularly upstream at the
`shedding surface, limiting blood loss. Increased blooc;lloss is a consequence of reduced platelet
`numbers and inadequate hemostatic plug formation. Menstrual bleeding is intlneoccd by activa··
`ti on of clotting and fibrinolysis. Fibrinolysis is principally the consequence of tho potent enzyme,
`plC:lsmin, formed from its inactive precursor, plasminogen. Endometrial stromal cell tissue factor
`(T F) and plasminogen activators and inhibitors arc involved in acl1kving a balance in this
`pt occss. TP stimulates coagulation, initially binding to factor Vll. TF and plasminogen act·ivator
`inhibitor- I (PAI- l ) expression accompanies decidualization, and the levels of these factors may
`govern the amount of bleeding.27 PJ\.f- 1, in particular, exerts an important restraining action on
`fibrinolys is and protcoJyt ic acti vity.28
`
`With further tissue disorganization, the endometrium shrinks even more and coiled arterioles are
`buckled. Additional ischemic breakdown ensues with necrosis of cells and defects in vessels
`adding to the menstrual effluvium. A natur al cleavage point exists between basalis and spongi··
`osum, and, once breached, the loose, vascular, edematous stroma of the spongiosum dcsquamatcs
`and collapses. The process is initiated in the fundus and inexorably extends throughout the uterus.
`In the end, the typical det1ated, shallow, dense, menstrual e!Jdoroetrium results. Within 13 hours,
`the endometrial height shrinks from 4 mm to 1.25 mm.1z Menstrual 11ow stops as a result of the
`combined effects of prolonged vasoconsiliction, tissue collapse, vascul ar stasis, and estrogen·~
`induced " healing." In contrast to postpartum bleeding, myometl'ial contractions arc not important
`for control of menstrual bleeding. Thrombin generation in the basal endometrium in response to
`extravasation of blood is essential f(lr bcmostasJs. Thrombin promotes the generation o1' fihdn ,
`the activation of platelets and clotting cofact.ors, and angiogenesis.
`
`The basalis endometrium remains during menses, and repair takes place from this layet. This
`endometrium is protected fi·om the lytic enzymes in the menstrual fluid by a mucinous layer of
`carbohydrate products l.ha! are discharged from the glandular and stromal cel1s.29
`
`Normal Menses
`
`Ap proximately 50% of the mcustruaJ detritus is e.xpellod in tJ1e first 24 hours of menstrual flow.
`Tbc menstrual fluid is composed of the autoJysed functionalis, inflammatory exudate, red blood
`cells, and proteolytic cn~ymes (}tl least one of Which, p lasmin, lyses f ibrin clots as they form).
`Tl'J.c high fi br inolytic activity advances emptying of the uterus by tiqucfaction of tissue and fibrin .
`If the Jaic of flow is great, clotting can and does occur.
`
`Most women (90%) have menstrua·! cycles with an interval of 24 to 35 days (Chapter 6).30• ;J I
`Menarche is followed by apptoximately 5- 7 yoars of increasing regularity as cycles shorten to
`reach the usual reproductive age pattern. l n !he 40s, cycles begin to lengthen again . The usuul
`duration of flow is tl--6 days, but many women flow as little as 2 days and as much as g days. Tho
`normal volume of mcnsll"ual blood loss is 30 rnL; greater than SO mL is abnormal (Chapter 15).
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 15
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`IJlJ
`
`Part I Reproductive Physiology
`
`lipids
`
`Cytokines
`
`Prostaglandins
`
`lnter\evkin-1 a.
`
`Thromboxanes
`
`lnterleukin-1\3
`
`leukotrienes
`
`lnterleukin-6
`
`I nterferon-y
`
`Peptides
`
`Prolactin
`
`Relaxin
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`Prorenin and renin
`
`Endorphin
`
`Colony-stimulating factor- I
`
`Endothelin-1
`
`Tumor necrosis factor-a.
`
`Cort:icotropin-rcleasi ng hormone'
`
`Leukemia-Inhibiting factor
`
`Fibronectin
`
`Uteroglobin
`
`Lipocorlin-1
`
`Parathyroid hormone-like protein
`
`lntegrins
`
`Epidermal growth factor family
`
`EGF
`
`Heparin-binding EGF
`
`TGF-a
`
`Insulin-like growth factor family
`
`IGF-11
`
`IGFBPs 1-6
`
`Platelet-derived growth factor
`
`Transforming growth factor-~
`
`Fibroblast growth factor
`
`Vascular endothelial growth factor
`
`The presence of the cytokinc family, involved in inflammation and immune responses, is not
`surprising in a tissue that undergoes cyclic degeneration. The intcrleukins stimulate prostaglan(cid:173)
`din production as well as other cytokines.34 Colony-stimulating factor-! is a cytokine that
`influences cellular proliferation and tllc presence of macrophages. Interferon-"( is produced by
`activated T-lymphocytcs and inhlbits endometrial epithelial proliferation. Leukemia-inhibiting
`factor (U F) is expressed in response to a variety of other cytokines and growth factors. Like the
`interleukins, LIF is most abundant during the progesterone-dominated secretory phase and early
`decidua, and may have a role i.n embryo implantation.35· 36 Tumor necrosis factor-a (TNF-a) gene
`expression is present in endometrium, and its activity is increased during the proliferative phase,
`decreased early in the secretory phase, and increased again in the midsecretory phase.J? TNF-cx.
`exerts multiple influences on cellular growth .
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 18
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`740
`
`Part I Reproductive Physiology
`
`The insulin~ like growth factors promote cellular mitosis and differentiation. They are expressed
`in a pattern controlled by estrogen and progesterone. IGF-I is predominant in proliferative and
`early secretory endometrium, while IGF-II appears in the mid to late secretory phase and persists
`in early pregnancy decidua.43 Endomctl'ial IGF-1 expression is correlated with the circulating
`estrogen levels during the menstrual cycle.1111 This suggests that IGF-1 synthesis is regulated by
`estrogen and mediates estrogen-induced growth of the endometrium, and IGF-II is involved in
`differentiation in response to progesterone. Evidence in the monkey indicates that JGF-I is the
`primary regulator of myometrial growth in response to estrogen as well as to estrogen plus
`progesrerone.45
`
`As elsewhere in the body, the myometrial IGF activity is modulated by the IGF binding proteins,
`which respond to the sex steroids in a differential manner; IGFBP-2 parallels IGP-1 response,
`whereas IGFBP-3 is decreased in muscle but increased in vascular endothelium by estrogen.46
`IGFBP-4 and IGFBP-5 respond to estrogen but are unaffected by the addition of progesterone.
`IGFBP- l, as discussed later, is a major product of decidualized endometrium.
`
`Humari myometrial smooth muscle and endometrial stromal cells express mRNA for parathyroid
`hormone-like protein, the function of which is unknown.47 Transforming growth factor-~ (TGF(cid:173)
`P) stimulates the production of the parathyroid hormone-like protein. TGF-P production is
`greatest in the secretory phase and may inhibit cellular proliferation by increasing IGFBP-3
`synthesis.
`
`Prostaglandins are produced by both epithelial and stromal cells, and the prostaglandin content
`in the endometrium reaches a peak level in late secretory endometrium. The predominant
`prostaglandin produced by endometrium is prostaglandin F2o:, a potent stimulus for myometrial
`contractions.118 Endometrial prostaglandin production decreases dramatically after implantation,
`suggesting the presence of an active mechanism for suppression. 49 The production of prostaglan(cid:173)
`dins requires estrogen support, but the increased production by secretory endometrium suggests
`progesterone enhancement, and acute withdrawal of progesterone promotes a further increase.48
`Endometrial stromal cells produce prostacyclin and thromboxane in response to estrogen, a
`response that can be blocked by progestins.50 The myometrium principally produces prosta(cid:173)
`cyclin, utilizing precursors derived from the endometrium. However, receptors for all members
`of the prostaglandin family are present on human myometrial cells, and contraction of the
`myometrium is a major consequence of prostaglandin F2cx.5 1
`
`Thromboxane is synthesized by uterine tissues. Gene expression for the thromboxane synthase
`and for the thromboxane receptor can be identified in endometrial glands, stromal cells, myome(cid:173)
`trial smooth muscle, and uterine blood vessels.52 ThromboxaneA2 is a potent vasoconstrictor and
`stimulator of smooth muscle cells. Because of its rapid metabolism, it is limited to autocrine and
`paracrine activity.
`
`Women with excessive menstrual bleeding have alterations in the normal rates of prostaglandin
`production. For this reason, effective reductions in menstrual blood loss can be achieved with
`treatment utilizing one of the nonsteroidal anti-inflammatory agents that inhibit prostaglandin
`synthesis. These agents are also effective treatment for prostaglandin-mediated dysmenorrhea.
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 20
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`Chapter 4 The Uterus
`
`111
`
`Fibronectin and laminin are extracellular matrix substances that arc secreted by stromal cells of
`the endometrium in response to progesterone. 53 These proteins are important adhesion molecules
`during implantation. Integdns are a family of glycoprotcins that function as receptors for proteins
`such as collagen, fibronectin, and laminin. The integrins are highly expressed in endometrium
`and are important for cell-to··cell and cell-to-matrix interactions.54 The expression of integrins
`appears to be regulated by cytokines and growth factors, not estrogen and progesterone. 55
`
`Uteroglobin is a small protein expressed in endometrial epithelial cclls.56 The physiologic
`function of uteroglobin is uncertain. Uteroglobin, with high affinity, binds progestins and may
`play a role in immunosuppression. Uteroglobin gene expression is stimulated by estrogen, and
`this response is enhanced by progesterone. Human endometrium can secrete ~-endorphin, yet
`another candidate for involvement in endometrial immunologic events, and its release is inhibited
`by both estrogens and glucocorticoids.57
`
`Endothelins are potent vasoconstrictors produced in the vascular endothelial cells. The vasocon(cid:173)
`strictor activity of endothel in-1, present in the endometrium, is balanced by the fact that ir
`promotes the synthesis of the vasodilators, nitric oxide and prostacyclin. Endothelin-1 is
`synthesized in endometrial stromal cells and the glandular epithelium, stimulated by both TGF ·
`~ and interleukin-1 a . 58 Endothelin-1 is at least one agent responsible for the vasoconstriction that
`shuts off menstrual bleeding. It is also a potent stimulator of myometrial contractions and can
`contribute to dysmenorrhea. Finally, cndothelin-1 is a mitogen and can promote the healing
`reepithclialization of the endometrium. Human decidual cells also synthesize and secrete cndo(cid:173)
`thelin- 1, from where it may be transported into the amniotic l'luid.s9
`
`Angiogenesis, the formation of new blood vessels, is an essential process in tissue growth and
`development. Angiogenesis is necessary for tumor growth, and in normal tissues, it is usually kept
`in check by regulating factors. The female reproductive tissues (specifically ovarian follic les, the
`trophoblast, and the endometrium), however, must experience periodic and rapid gn)\vth and
`regression. In these tissues, angiogenesis is part of normal events. The endometrium is a major
`source for angiogenic factors during the menstrual cycle and during pregnancy.()() Vascular
`endothelial growth factor, a specific mitogen for endothelial cells, is abundantly expressed in
`human endometrium, reaching a peak that correlates with the maximal angiogenesis reached
`during the secretory phase.6 1 Angiogenesis is also influenced by many of the growth factors, and
`other substances such as fibronectin and prostaglandins. Fibroblast growth factor, in particular,
`is highly mitogenic for endothelial cells as well as endometrial stromal cells.
`
`In all types of endometrial and myometrial cells, estrogen receptor expression reaches a maxi··
`mum in the late follicular phasc.62• 63 The concentration is greatest in the glandular epithelium.
`During the early luteal phase, estrogen receptor expression declines, followed by an increase in
`the mid and late luteal phases. These changes reflect the cyclic changes in estradiol (which
`increa~es estrogen receptor expression) and progesterone (which decreases estrogen receptor
`expression).
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 21
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`

`The Decidua
`
`Chapter 4 The Uterus
`
`113
`
`The decidua is the specialized endometrium of pregnancy. The biochemical dialogue between the
`fctoplacental unit and the mother must pass back and forth through the decidua. The classic view
`of the decidua conformed to its designation as a thin line in anatomical diagrams, a minor, inactive
`structural component. We now know that the decidua is a vigorous, active tissue.
`
`The glycoprotein a -subunit, common to follicle-stimul ating hormone (FSH), luteinizing hor·
`mone (LH), thyroid-stimulating hormone (TSII), and HCG, is secreted into the circulation by the
`pituitary and placenta. A specific role for the a.-subunit has not been apparent; however,
`gonadotropin receptors are present in the endometrium and in vitro, a-subunit acts synergistically
`with progesterone to induce dccidualization of endometrial cells. 65 In addition, the a -subunit
`stimulates decidual prolactin secretion.66
`
`Decidual cells arc derived from the stroma cells of the endometrium, under the stimulation or
`progesterone. Thus, they appear during the luteal phase and continue to proliferate during early
`pregnancy, eventually lining the entire uterus, including the implantation site. The decidual cell
`is characterized by the accumulation of glycogen and lipid droplets and the new expression of a
`host of substances, including prolactin, relaxin, renin, insulin-like growth factors (lGFs). and
`insulin-like growth factor binding proteins (TGFBPs). There is no evidence that these proteins are
`secreted into the circulation, therefore they serve as autocrinc and paracrinc agents.67· 68
`
`Riddick was the first to detect prolactin in the dccidualizing endometrium of the late luteal
`phase.69 The amino acid sequence and the chemical and biological properties of decidual
`prolactin are identical to those of pituitary prolactin. Decidual prolactin synthesis and release are
`controlled by the placenta, fetal membranes, and decidual factors. Dopamine, bromocriptinc, ancl
`thyroid-releasing hormone (TRH), in contrast to their action in the pituitary, have no cffCl:l on
`decidual synthesis and release of prolactin./\ protein named decidual prolactin-releasing factor
`has been purified from the placenta, and an inhibiting protein, which blocks the stimulatory
`activity of the releasing factor, has been purified from decidua. 68 fGF-·1, relaxin, and insulin all
`stimulate decidual prolactin synthesi s and release, each through its own receptor. The same
`decidual cells produce both prolactin and relaxin.
`
`Lipocortin-1 is a calcium and phospholipid binding protein, present in the placenta and decidua,
`that inhibits phospholipase Az and responds to glucocortieoids. Lipocortin- 1 inhibits decidual
`prolactin release but in a mechanism independent of phospholipase action and independent or
`glucocorticoids. The prostaglandin system is not involved in decidual prolactin production, and
`corticoid steroids do not affect decidual prolactin release."IO
`
`There is good reason to believe that the amniotic nuid prolactin is derived from the decidua. In
`vitro experiments indicate that the passage of prolactin across the fetal membranes is in the
`direction of the amniotic cavity. The anmiotic fluid concentration correlates with the decidual
`content, not maternal circulating levels. Amniotic Ouid prolactin reaches peak levels in the first
`half of gestation (about 4000 ng/mL) when maternal plasma levels arc approximately 50 ng/mL
`and fetal levels about I 0 ng/mL. Maternal circulating prolactin reaches maximal levels ncar term.
`Finally, amniotic fluid prolactin is unaffec ted by brornocriptine treatment (which reduces both
`fetal and maternal circulating levels to baseline levels).
`
`lt is believed that decidual prolactin regulates amniotic fluid volume and electrolyte conccntra··
`tions. It can be demonstrated that prolactin regulates water and ion transport in lower animals,
`and prolactin binds to amniotic membranes. Disorders in human pregnancy associated with
`abnormal amniotic fluid volumes may be explained by thi s mechanism, especially idiopathic
`polyhydramnios (which is associated with a decrease in the number of prolactin receptors in the
`membranes). Prolactin may be involved in the regulation of surfactant synthesis in the fetus, and
`prolactin may inhibit uterine muscle contractility. Prolactin s uppresses the immune response and
`contributes to the prevention of immunologic rejection of the conceptus. Prolactin can also
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 23
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`748
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`Part I Rcproduclive Physiology
`
`premature labor)Y0 ··92 There may be a rudimentary horn present, and implantation in this horn is
`followed by a very high rate of pregnancy wastage or tubal pregnancies. A rudimentary horn can
`also be a cause of chronic pain, and surgical excision may be worthwhile. However, most
`rudimentary horns arc asymptomatic because they are non-communicating, and the endometrium
`is not functional. Because of the potential for problems, prophylactic removal of the rudimentary
`horn is recommended when it is encountered during a surgical procedure. Approximately 40% of
`patients wilh a unicornuate uterus will have a urinary tract anomaly (usually of the kidney).93
`
`Uterus Oidclphus (Double Uterus)
`Lack of fusion of the two miillerian ducts results in duplication of corpus and cervix. These
`patients usually have no difficulties with menstruation and coitus. Occasionally, one side is
`obstructed and symptomatic. In addition, a double uterus is occasionally associated with an
`obstructed hemivagina (often with ipsilateral renal agenesis); early diagnosis and excision of the
`obstructing vaginal septum will preserve fertility. Pregnancy is associated with an increased risk
`of malprcscntations and premature labor, although many patients will have no reproductive
`di fficultics.n
`
`The Bicornuate Uterus
`Partial lack of fusion of the two mtillerian ducts produces a single cervix with a varying degree
`of separation in the two uterine horns. This anomaly is relatively common, and pregnancy
`outcome has usually been reported to be near normal. Some, however, find a high rate of early
`miscarriage, pre term labor, and breech presentations. 86· 92 .
`
`The Septate Uterus
`Pmiiallack of resorption of the midline septum between the two miillcrian ducts results in defects
`that range from a slight midline septum (the arcuate, heart-shaped cavity) to a significant midline
`division of the endometrial cavity. A total failure in resorption can leave a longitudinal vaginal
`septum (a double vagina). This defect is not a cause of infertility, but once pregnant. the greater
`the septum the greater the risk of recurrent spontaneous miscarriage. The complete septate uterus
`is associated with a high risk of preterm labor and breech prescntation.86 Outcomes arc excellent
`with treatment by hysteroseopy.94· 95 Posttreatment miscarriage rates are approximately I 0% in
`contrast to the 90% pretreatment rates. A longitudinal vaginal septum usually does not have to
`be excised (unless dyspareunia is a problem). ln some reports, the arcuate uterus had no adverse
`impact on reproductive outcome.92
`
`Very Rare Anomalies
`Isolated agenesis of the cervix or the endometrium is incredibly rare. Absence of the cervix can
`lead to so much pain and obstruction that hysterectomy is the best solution. Attempts to preserve
`fertility by creating a fistu lous communication between uterus and vagina have achieved little
`success, and repeat surgery due to reappearance of obstruction is common.96 In asymptomatic
`patients, consideration should be given to preservation of structures for the possibility of
`pregnancy that can be achieved by means of one of the techniques of assisted reproduction.
`(Chapter 31 )
`
`The Diethylstilbestrol-Associated Anomaly
`We are still encountering women whose mothers were treated with high doses of estrogen during
`their pregnancies. Exposure to these high levels of estrogen during mii llerian development caused
`a variety of anomalies, ranging from the hypoplastic "T" shaped uterus to irregular cavities with
`adhesions.97 Women with uterine abnormalities usually also have cervical defects. In these
`individuals, the chance of term pregnancy is decreased because of higher risks of ectopic
`pregnancy, spontaneous miscarriage, and premature labor. An incompetent cervix is common.
`Poor outcome is correlated with an abnormal uterus on hysterosalpingography. No treatment is
`available beyond cervical cerclage.
`
`Petitioner Exhibit 1013
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 28
`
`

`

`

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`150
`
`Part I Reproductive Physiolof1y
`
`Myomas will be encountered in about l% of pregnant women. The risk of myoma is decreased
`with increasing parity and with iuGrcasing age allast term birth.105 Women wi~h at least two full
`term ptcgnancies have half th'~ risk for myomas. Smoking decreases the risk (presumably by
`decreasing estrogen levels), and obesity increases the risk (presumably by increasing estrogen
`levels). Although a lower risk for myomas is associated with f<~ctors that decrease estrogen levels,
`including leannc~s. smoking, and exercise, the use of oral contraceptives is not associated with
`an increased risk of uterine myomas, although the Nurses' Health Study reported a slightly
`increased risk when oral contraceptives were first used in early teenage yea.rs. 105- 107
`
`The hormone sensitivity of lciomyornas is indicated by the following clinical observations.
`Leiomyomas develop during the reproductive (hormonally active) years and regress after
`menopause. Occasionally, leiomyomas grow during pregnancy, and the hypogonadal state
`induced by treatment with gonadotropin-releasing hormone (GnRH) agonists often causes
`shrinkage of myomas.
`
`The environment within the leiomyoma is hypcrestTOgcnic. The estradiol concentration is
`in<:reased, and leiomyomas contain more estrogen and progesterone receprors.108~I LO Arornatasc
`gene and ent,yme expression arc present in signifit:ant levels in Jeiomyomat:a, 11 1 Indeed, lei(cid:173)
`o myoma tissue is hypersensitive to estrogen and appears to have lost a regulatory influence thal
`limits estrogen response. "?. Endometrial hyperplasia is frequently observed at the margins of
`submucous myomas. 113 In the myometrium and in leiomyomas, peak mitotic activity occurs
`during Lhe luteal phase, and mitotic activity is increased .by the administration of high doses of
`115 These facts indicate that pr<>gesterone stimulates mitotic activity in
`pi·ogestarional agenrs. 114•
`lciomyomas, but animal studies indicate both stimulation and inhibition of myometrial growth.
`Similarly, clinicians have reported both regression and gtowth with progestational treatmenl.
`Nevertheless, mosf of the evidence supports a growth-promoting role for pwgestins (the associa"
`tion with estrogen can be explained by the estrogen enhancement of progesterone. receptor
`cxprcssion). 1 16• 117 Treatment with RU486, the progesterone antagonist, is associated with a
`reduction in leiom