CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`UNDER 37 CFR 1.102(e) (Page 1 of 1)
`
`PTO/AIA/424 (03-13)
`
`First Named
`Inventor:
`Title of
`Invention:
`
`Joerg Zeller
`
`I Nonprovisional Application Number (if
`
`I TBD
`
`known):
`ANTAGONIST ANTIBODIES DIRECTED AGAINST CALCITONIN GENE-RELATED PEPTIDE
`AND METHODS USING SAME
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`1. The processing fee set forth in 37 CFR 1.17(i)(1 ), the prioritized examination fee set forth in
`37 CFR 1.17(c), and if not already paid, the publication fee set forth in 37 CFR 1.18(d) have
`been filed with the request. The basic filing fee, search fee, examination fee, and any required
`excess claims and application size fees are filed with the request or have been already been
`paid.
`
`2. The application contains or is amended to contain no more than four independent claims and no
`more than thirty total claims, and no multiple dependent claims.
`
`3. The applicable box is checked below:
`1?\1 Original Application (Track One)- Prioritized Examination under§ 1.102(e)(1)
`
`I.
`
`i.
`
`(a) The application is an original non provisional utility application filed under 35 U.S.C. 111 (a).
`This certification and request is being filed with the utility application via EFS-Web.
`---OR---
`(b) The application is an original non provisional plant application filed under 35 U.S.C. 111 (a).
`This certification and request is being filed with the plant application in paper.
`
`II.
`
`ii. The executed inventor's oath or declaration is filed with the application. (37 CFR 1.63 and 1.64)
`0 Request for Continued Examination - Prioritized Examination under§ 1.1 02(e)(2)
`i. A request for continued examination has been filed with, or prior to, this form.
`ii.
`If the application is a utility application, this certification and request is being filed via EFS-Web.
`iii. The application is an original non provisional utility application filed under 35 U.S.C. 111 (a), or is
`a national stage entry under 35 U.S.C. 371.
`iv. This certification and request is being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`v. No prior request for continued examination has been granted prioritized examination status
`under 37 CFR 1.1 02( e )(2).
`
`Signature
`
`/Adam J. Cole/
`
`Name
`(Print/Typed)
`
`Adam J. Cole
`
`Date November21, 2013
`
`Practitioner
`Registration Number 71,901
`
`Note: This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4(d) for signature requirements and certifications.
`Submit multiple forms if more than one signature is required, see below*.
`
`~ *Total of _1_ forms are submitted.
`
`5939813_2.DOC
`
`1
`
`EX2035
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01710
`
`

`

`PATENT APPLICATION
`
`WSGR Docket No. 44306-701.304
`
`ANTAGONIST ANTIBODIES DIRECTED AGAINST CALCITONIN GENE-RELATED PEPTIDE AND
`METHODS USING SAME
`
`lnventor(s):
`
`Joerg Zeller
`Citizen of Germany, Residing at
`Ann Arbor, Ml48103
`United States of America
`
`Kristian T. Poulsen
`Citizen of United States, Residing at
`San Francisco, CA 94107
`
`Yasmina Noubia Abdiche
`Citizen of United Kingdom, Residing at
`Mountain View, CA 94043
`
`Jaume Pons
`Citizen of Spain, Residing at
`San Bruno, CA 94066
`
`Sierra Jones Collier
`Citizen of United States, Residing at
`Menlo Park, CA 94025
`
`Arnon Rosenthal
`Citizen of United States, Residing at
`Woodside, CA 94062
`
`Assignee:
`
`Labrys Biologics, Inc.
`181 0 Gateway Drive
`Suite 230
`San Mateo, CA 94404
`United States of America
`
`Entity:
`
`A large business concern
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300 (Main)
`(650) 493-6811 (Facsimile)
`
`Filed Electronically on: November 21, 2013
`
`2
`
`

`

`ANTAGONIST ANTIBODIES DIRECTED AGAINST CALCITONIN GENE-RELATED PEPTIDE AND
`METHODS USING SAME
`
`Cross Reference to Related Applications
`
`5
`
`This application is a continuation of U.S. Patent Application No. 13/870,871, filed April 25, 2013,
`
`which is a continuation of U.S. Patent Application No. 13/835,394, filed March 15, 2013, which is a
`
`continuation of U.S. Patent Application No. 13/179,846 (now U.S. Patent No. 8,586,045), filed July 11, 2011,
`
`which is a continuation of U.S. Patent Application No. 12/093,638 (now U.S. Patent No. 8,007,794), filed
`
`November 10, 2008, which is a national stage entry of PCT International Application No. PCT/IB2006/003181
`
`10
`
`filed November 2, 2006, which claim priority to U.S. Provisional Patent Application No. 60/736,623, filed
`
`November 14, 2005, all of which are incorporated herein in their entireties by reference.
`
`The instant application contains a Sequence Listing which has been submitted in ASCII format via
`
`15
`
`EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 20,
`
`2013, is named 44306-701-304-SL.txt and is 25,419 bytes in size.
`
`Sequence Listing
`
`The present invention relates to the use of anti-CGRP antagonist antibodies for the prevention,
`
`amelioration, or treatment of vasomotor symptoms, such as CGRP related headaches (e.g., migraine) and hot
`
`Field of the Invention
`
`20
`
`flushes.
`
`Background of the Invention
`
`CGRP (calcitonin gene-related peptide) is a 37 amino acid neuropeptide, which belongs to a family of
`
`peptides that includes calcitonin, adrenomedullin and amylin.
`
`In humans, two forms of CGRP (a-CGRP and
`
`13-CGRP) exist and have similar activities. They vary by three amino acids and exhibit differential distribution.
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`25
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`At least two CGRP receptor subtypes may also account for differential activities. CGRP is a neurotransmitter
`
`in the central nervous system, and has been shown to be a potent vasodilator in the periphery, where CGRP(cid:173)
`
`containing neurons are closely associated with blood vessels. CGRP-mediated vasodilatation is also
`
`associated with neurogenic inflammation, as part of a cascade of events that results in extravasation of
`
`plasma and vasodilation of the microvasculature and is present in migraine.
`
`30
`
`CGRP has been noted for its possible connection to vasomotor symptoms (Wyon et al. Scand. J.
`
`Ural. Nephrol. 35: 92-96 (2001 ); Wyon et al. Menopause 7(1 ):25-30 (2000)). Vasomotor symptoms (VMS),
`
`such as hot flushes and night sweats, are the most common symptoms associated with menopause,
`
`occurring in 60% to 80% of all women following natural or surgically-induced menopause. Hot flushes are
`
`likely to be an adaptive response of the central nervous system (CNS) to declining sex steroids (Freedman
`
`35
`
`Am. J. Human Bioi. 13:453-464 (2001)). To date, the most effective therapies for flushes are hormone-based
`
`treatments, including estrogens and/or some progestins. Hormonal treatments can be effective for alleviating
`
`flushes, but are not appropriate for all women. Psychological and emotional symptoms observed, such as
`2
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`nervousness, fatigue, irritability, insomnia, depression, memory loss, headache, anxiety, nervousness or
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`inability to concentrate are considered to be caused by the sleep deprivation following hot flush and night
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`sweats (Kramer et al., In: Murphy et al., 3.sup.rd lnt'l Symposium on Recent Advances in Urological Cancer
`
`Diagnosis and Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).
`
`5
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`Men also experience hot flushes following steroid hormone (androgen) withdrawal. This is true in
`
`cases of age-associated androgen decline (Katovich, et al., Proceedings of the Society for Experimental
`
`Biology & Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormone deprivation associated
`
`with treatments for prostate cancer (Berendsen, et al., European Journal of Pharmacology, 2001, 419(1 ): 47-
`
`54). As many as one-third of these patients will experience persistent and frequent symptoms severe enough
`
`10
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`to cause significant discomfort and inconvenience.
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`CGRP is a potent vasodilator that has been implicated in the pathology of other vasomotor
`
`symptoms, such as all forms of vascular headache, including migraines (with or without aura) and cluster
`
`headache. Durham, N. Engl. J. Med. 350:1073-1075, 2004. The serum levels of CGRP in the external
`
`jugular vein are elevated in patients during migraine headache. Goadsby et al., Ann. Neural. 28:183-7, 1990.
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`15
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`Intravenous administration of human a-CGRP induced headache and migraine in patients suffering from
`
`migraine without aura, suggesting that CGRP has a causative role in migraine. Lassen et al., Cephalalgia
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`22:54-61, 2002.
`
`Possible CGRP involvement in migraine has been the basis for the development and testing of a
`
`number of compounds that inhibit release of CGRP (e.g., sumatriptan), antagonize at the CGRP receptor
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`20
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`(e.g., dipeptide derivative BIBN4096BS (Boerhringer lngelheim); CGRP(8-37)), or interact with one or more of
`
`receptor-associated proteins, such as, receptor activity membrane protein (RAMP) or receptor component
`
`protein (RCP), both of which affect binding of CGRP to its receptors. Brain, S. et al., Trends in
`
`Pharmacological Sciences 23:51-53, 2002. Alpha-2 adrenoceptor subtypes and adenosine A1 receptors also
`
`control (inhibit) CGRP release and trigeminal activation (Goads by et al., Brain 125:1392-401, 2002). The
`
`25
`
`adenosine A1
`
`receptor agonist GR79236 (metrafadil), which has been shown to inhibit neurogenic
`
`vasodilation and trigeminal nociception in humans, may also have anti-migraine activity (Arulmani et al.,
`
`Cephalalgia 25:1082-1090, 2005; Giffin et al., Cephalalgia 23:287-292, 2003.)
`
`Confounding this theory is the observation that treatment with compounds that exclusively inhibit
`
`neurogenic inflammation (e.g., tachykinin NK1 receptor antagonists) or trigeminal activation (e.g., 5HT10
`receptor agonists) have been shown to be relatively ineffective as acute treatments for migraine, leading
`
`30
`
`some investigators to question whether inhibiting release of CGRP is the primary mechanism of action of
`
`effective anti-migraine treatments. Arulmani et al., Eur. J. Pharmacal. 500:315-330, 2004.
`
`Migraine is a complex, common neurological condition that is characterized by severe, episodic
`
`attacks of headache and associated features, which may include nausea, vomiting, sensitivity to light, sound
`
`35
`
`or movement. In some patients, the headache is preceded or accompanied by an aura. The headache pain
`
`may be severe and may also be unilateral in certain patients.
`
`Migraine attacks are disruptive to daily life.
`
`In US and Western Europe, the overall prevalence of
`
`migraine sufferers is 11% of the general population (6% males; 15-18% females). Furthermore, the median
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`5939827 2.DOC
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`frequency of attacks in an individual is 1.5/month. While there are a number of treatments available to
`
`alleviate or reduce symptoms, preventive therapy is recommended for those patients having more than 3-4
`
`attacks of migraine per month. Goadsby et al. New Engl. J. Med. 346(4): 257-275, 2002.
`
`The variety of pharmacologic interventions that have been used to treat migraine and the variability in
`
`5
`
`responses among patients are a testament to the diverse nature of this disorder. Thus, such relatively non(cid:173)
`
`selective drugs as ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide), which exhibit
`
`serotonergic, as well as adrenergic, noradrenergic and dopaminergic activity, have been used for over eighty
`
`years to treat migraine. Other treatments include opiates (e.g., oxycodone) and 13-adrenergic antagonists
`
`(e.g., propranolol). Some patients, usually those with milder symptoms, are able to control their symptoms
`
`10
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`with non-prescription remedies such as one or more non-steroidal anti-inflammatory agents (NSAIDs), such
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`as a combination of aspirin, acetaminophen and caffeine (e.g., Excedrin® Migraine).
`
`More recently, some migraine patients have been treated with topiramate, an anticonvulsant that
`
`blocks voltage-dependent sodium channels and certain glutamate receptors (AMPA-kainate), potentiates
`
`GABA-A receptor activity, and blocks carbonic anhydrase. The relatively recent success of serotonin 5HT-
`
`15
`
`18/10 and/or 5HT-1a receptor agonists, such as sumatriptan, in some patients has led researchers to
`
`propose a serotonergic etiology of the disorder. Unfortunately, while some patients respond well to this
`
`treatment, others are relatively resistant to its effects.
`
`It has been postulated that a dysfunction of an ion channel in the aminergic brainstem nuclei
`
`underlies the disorder, however, the precise pathophysiology of migraine is not yet well understood. One
`
`20
`
`form of migraine, familial hemiplagic migraine, has been shown to associated with missense mutations in the
`
`a1 subunit of the voltage-gated P/Q-type calcium channel, and it is thought likely that other ion-channel
`
`mutations will also be found in other populations of patients. While dilation of blood vessels is associated
`
`with and exacerbates the pain symptoms of migraine, such neurovascular events are now thought to be a
`
`result of, rather than causative of, the condition. Overall, dysfunction of brainstem pathways modulating
`
`25
`
`sensory input is considered to be a unifying feature of migraine. Goadsby, P.J. et al., New Engl. J. Med.
`
`346(4): 257-275, 2002.
`
`Throughout this application various publications (including patents and patent applications) are
`
`referenced. The disclosures of these publications in their entireties are hereby incorporated by reference.
`
`30
`
`Brief Summary of the Invention
`
`The invention disclosed herein concerns anti-CGRP antagonist antibodies and methods of using anti(cid:173)
`
`CGRP antagonist antibodies for treating or preventing vasomotor symptoms, such as headaches, such as
`
`migraine with or without aura, hemiplegic migraine, cluster headaches, migrainous neuralgia, chronic
`
`headaches, tension headaches, and headaches resulting from other medical conditions (such as infection or
`
`35
`
`increased pressure in the skull due to a tumor). Other vasomotor symptoms include hot flushes.
`
`In one aspect, the present invention provides a method for treating or preventing at least one
`
`vasomotor symptom in an individual comprising administering to the individual an effective amount of an anti(cid:173)
`
`CGRP antagonist antibody.
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`5939827 2.DOC
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`5
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`

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`In one aspect, the present invention provides a method for treating or preventing headache (e.g.,
`
`migraine and cluster headache) in an individual comprising administering to the individual an effective amount
`
`of an anti-CGRP antagonist antibody.
`
`In another aspect, the invention provides a method for ameliorating, controlling, reducing incidence
`
`5
`
`of, or delaying the development or progression of headache (e.g., migraine and cluster headache) in an
`
`individual comprising administering to the individual an effective amount of an anti-CGRP antagonist antibody.
`
`In a further embodiment, the invention provides methods for ameliorating, controlling, reducing
`
`incidence of, or delaying the development or progression of headache (e.g., migraine and cluster headache)
`
`in an individual comprising administering to the individual an effective amount of an anti-CGRP antagonist
`
`10
`
`antibody in combination with at least one additional agent useful for treating headache. Such additional
`
`agents include 5-HT1-Iike agonists (and agonists acting at other 5-HT1 sites), and non-steroidal anti(cid:173)
`
`inflammatory drugs (NSAIDs).
`
`Examples of 5-HT1 agonists that can be used on combination with an anti-CGRP antibody include a
`
`class of compounds known as triptans, such as sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan,
`
`15
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`almotriptan, and frovatriptan. Ergot alkaloids and related compounds are also known to have 5-HT agonist
`
`activity and have been used to treat headache such as migraine.
`
`Included among these compounds are
`
`ergotamine
`
`tartrate,
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`ergonovine maleate,
`
`and
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`ergoloid mesylates
`
`(e.g.,
`
`dihydroergocornine,
`
`dihydroergocristine, dihydroergocryptine, and dihydroergotamine mesylate (DHE 45)).
`
`Examples of NSAIDs that can be used in combination with an anti-CGRP antibody include naproxen,
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`20
`
`flurbiprofen, ketoprofen, oxaprozin, etodolac, indomethacin, ketorolac, nabumetone, mefanamic acid, and
`
`piroxican. Additional NSAIDs include cyclooxygenase-2 (COX-2) inhibitors. Members of this group include:
`
`celecoxib; rofecoxib; meloxicam; JTE-522; L-745,337; NS398; and pharmaceutically acceptable salts thereof.
`
`In another aspect, the invention provides a method for ameliorating, controlling, reducing incidence
`
`of, or delaying the development or progression of hot flushes in an individual comprising administering to the
`
`25
`
`individual an effective amount of an anti-CGRP antagonist antibody.
`
`In another aspect, the invention provides methods for ameliorating, controlling, reducing incidence of,
`
`or delaying the development or progression of hot flushes in an individual comprising administering to the
`
`individual an effective amount of an anti-CGRP antagonist antibody in combination with at least one additional
`
`agent useful for treating hot flushes. Such additional agents include, but are not limited to, hormone-based
`
`30
`
`treatments, including estrogens and/or progestins.
`
`In one embodiment, the anti-CGRP antagonist antibody used in any of the methods described above
`
`is any of the antibodies as described herein.
`
`In some embodiments, the anti-CGRP antagonist antibody recognizes a human CGRP.
`
`In some
`
`embodiments, the anti-CGRP antagonist antibody binds to both human a-CGRP and 13-CGRP.
`
`In some
`
`35
`
`embodiments, the anti-CGRP antagonist antibody binds human and rat CGRP.
`
`In some embodiments, the
`
`anti-CGRP antagonist antibody binds the C-terminal fragment having amino acids 25-37 of CGRP.
`
`In some
`
`embodiments, the anti-CGRP antagonist antibody binds a C-terminal epitope within amino acids 25-37 of
`
`CGRP.
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`In some embodiments, the anti-CGRP antagonist antibody is a monoclonal antibody.
`
`In some
`
`embodiments, the anti-CGRP antagonist antibody is humanized.
`
`In some embodiments, the antibody is
`
`human.
`
`In some embodiments, the anti-CGRP antagonist antibody is antibody G1 (as described herein). In
`
`some embodiments, the anti-CGRP antagonist antibody comprises one or more CDR(s) (such as one, two,
`
`5
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`three, four, five, or, in some embodiments, all six CDRs) of antibody G1 or variants of G1 shown in Table 6.
`
`In still other embodiments, the anti-CGRP antagonist antibody comprises the amino acid sequence of the
`
`heavy chain variable region shown in Figure 5 (SEQ ID NO: 1) and the amino acid sequence of the light chain
`
`variable region shown in Figure 5 (SEQ ID NO: 2).
`
`In some embodiments, the antibody comprises a modified constant region, such as a constant region
`
`10
`
`that is immunologically inert (including partially immunologically inert), e.g., does not trigger complement
`
`mediated lysis, does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC), does not activate
`
`microglia, or having reduced one or more of these activities.
`
`In some embodiments, the constant region is
`
`modified as described in Eur. J. lmmunol. (1999) 29:2613-2624; PCT Application No. PCT/GB99/01441;
`
`and/or UK Patent Application No. 9809951.8. In other embodiments, the antibody comprises a human heavy
`
`15
`
`chain lgG2 constant region comprising the following mutations: A330P331
`
`to S330S331 (amino acid
`
`numbering with reference to the wildtype lgG2 sequence). Eur. J. lmmunol. (1999) 29:2613-2624.
`
`In some
`
`embodiments, the heavy chain constant region of the antibody is a human heavy chain lgG1 with any of the
`
`following mutations: 1) A327A330P331 to G327S330S331; 2) E233L234L235G236 (SEQ ID NO: 48) to
`
`P233V234A235
`
`with
`
`G236
`
`deleted;
`
`3)
`
`E233L234L235
`
`to
`
`P233V234A235;
`
`4)
`
`20
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`E233L234L235G236A327A330P331 (SEQ ID NO: 49) to P233V234A235G327S330S331 (SEQ ID NO: 50)
`
`with G236 deleted; 5) E233L234L235A327A330P331 (SEQ ID NO: 51) to P233V234A235G327S330S331
`
`(SEQ ID NO: 50); and 6) N297 to A297 or any other amino acid except N.
`
`In some embodiments, the heavy
`
`chain constant region of the antibody is a human heavy chain lgG4 with any of the following mutations:
`
`E233F234L235G236 (SEQ
`
`ID NO: 52)
`
`to P233V234A235 with G236 deleted; E233F234L235
`
`to
`
`25
`
`P233V234A235; and S228L235 to P228E235.
`
`In still other embodiments, the constant region is aglycosylated for N-linked glycosylation.
`
`In some
`
`embodiments, the constant region is aglycosylated for N-linked glycosylation by mutating the oligosaccharide
`
`attachment residue (such as Asn297) and/or flanking residues that are part of the N-glycosylation recognition
`
`sequence in the constant region.
`
`In some embodiments, the constant region is aglycosylated for N-linked
`
`30
`
`glycosylation. The constant region may be aglycosylated for N-linked glycosylation enzymatically or by
`
`expression in a glycosylation deficient host cell.
`
`The binding affinity (K0 ) of an anti-CGRP antagonist antibody to CGRP (such as human a-CGRP as
`measured by surface plasmon resonance at an appropriate temperature, such as 25 or 37 oc) can be about
`
`0.02 to about 200 nM.
`
`In some embodiments, the binding affinity is any of about 200 nM, about 100 nM,
`
`35
`
`about 50 nM, about 10 nM, about 1 nM, about 500 pM, about 100 pM, about 60 pM, about 50 pM, about 20
`
`pM, about 15 pM, about 10 pM, about 5 pM, or about 2 pM. In some embodiments, the binding affinity is less
`
`than any of about 250 nM, about 200 nM, about 100 nM, about 50 nM, about 10 nM, about 1 nM, about 500
`
`pM, about 100 pM, or about 50 pM.
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`The anti-CGRP antagonist antibody may be administered prior to, during and/or after headache.
`
`In
`
`some embodiments, the anti-CGRP antagonist antibody is administered prior to the attack of headache (e.g.,
`
`migraine and cluster headache). Administration of an anti-CGRP antagonist antibody can be by any means
`
`known in the art, including: orally, intravenously, subcutaneously, intraarterially, intramuscularly, intracardially,
`
`5
`
`intraspinally,
`
`intrathoracically,
`
`intraperitoneally,
`
`intraventricularly, sublingually,
`
`transdermally, and/or via
`
`inhalation. Administration may be systemic, e.g. intravenously, or localized.
`
`In some embodiments, the anti-CGRP antagonist antibody may be administered in conjunction with
`
`an another agent, such as another agent for treating headache.
`
`In another aspect, the
`
`invention provides use of an anti-CGRP antagonist antibody for the
`
`10
`
`manufacture of a medicament for use in any of the methods described herein, for example, for treating or
`
`preventing headache.
`
`In another aspect, the invention provides a pharmaceutical composition for preventing or treating
`
`headache (e.g., migraine and cluster headache) comprising an effective amount of an anti-CGRP antagonist
`
`antibody, in combination with one or more pharmaceutically acceptable excipients.
`
`15
`
`In another aspect, the invention provides a kit for use in any of the methods described herein.
`
`In
`
`some embodiments, the kit comprises a container, a composition comprising an anti-CGRP antagonist
`
`antibody described herein, in combination with a pharmaceutically acceptable carrier, and instructions for
`
`using the composition in any of the methods described herein.
`
`The present invention also provides anti-CGRP antagonist antibodies and polypeptides derived from
`
`20
`
`antibody G1 or its variants shown in Table 6. Accordingly, in one aspect, the invention is an antibody G1
`
`(interchangeably termed "G1") that is produced by expression vectors having ATCC Accession Nos. PTA-
`
`6866 and PTA-6867. For example, in one embodiment is an antibody comprising a heavy chain produced by
`
`the expression vector with ATCC Accession No. PTA-6867.
`
`In a further embodiment is an antibody
`
`comprising a light chain produced by the expression vector with ATCC Accession No. PTA-6866. The amino
`
`25
`
`acid sequences of the heavy chain and light chain variable regions of G1 are shown in Figure 5. The
`
`complementarity determining region (CDR) portions of antibody G1 (including Chothia and Kabat CDRs) are
`
`also shown in Figure 5.
`
`It is understood that reference to any part of or entire region of G1 encompasses
`
`sequences produced by the expression vectors having ATCC Accession Nos. PTA-6866 and PTA-6867,
`
`and/or the sequences depicted in Figure 5. The invention also provides antibody variants of G1 with amino
`
`30
`
`acid sequences depicted in Table 6.
`
`In one aspect, the invention is an antibody comprising a VH domain that is at least 85%, at least 86%,
`
`at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%,
`
`at least 95%, at least 96%, at least 97% at least 98%, at least 99% or 100% identical in amino acid sequence
`
`to SEQ ID NO: 1.
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`35
`
`In another aspect, the invention is an antibody comprising a VL domain that is at least 85%, at least
`
`86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least
`
`94%, at least 95%, at least 96%, at least 97% at least 98%, at least 99% or 100% identical in amino acid
`
`sequence to SEQ ID NO: 2.
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`In another aspect, the invention is an antibody comprising a fragment or a region of the antibody G1
`
`or its variants shown in Table 6.
`
`In one embodiment, the fragment is a light chain of the antibody G1.
`
`In
`
`another embodiment, the fragment is a heavy chain of the antibody G1.
`
`In yet another embodiment, the
`
`fragment contains one or more variable regions from a light chain and/or a heavy chain of the antibody G1. In
`
`5
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`yet another embodiment, the fragment contains one or more variable regions from a light chain and/or a
`
`heavy chain shown in Figure 5.
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`In yet another embodiment, the fragment contains one or more CDRs from a
`
`light chain and/or a heavy chain of the antibody G1.
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`In another aspect, the invention provides polypeptides (which may or may not be an antibody)
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`comprising a VH CDR3 as set forth in SEQ ID NO: 5, or a sequence that differs from SEQ ID NO: 5 by 1, 2, 3,
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`10
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`4, or 5 amino acid substitutions. In a particular embodiment, such amino acid substitutions are conservative
`
`substitutions.
`
`In another aspect, the invention provides polypeptides (which may or may not be an antibody)
`
`comprising a VL CDR3 as set forth in SEQ ID NO: 8, or a sequence that differs from SEQ ID NO: 8 by 1, 2, 3,
`
`4, or 5 amino acid substitutions. In a particular embodiment, such amino acid substitutions are conservative
`
`15
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`substitutions.
`
`In another aspect, the invention provides polypeptides (which may or may not be an antibody)
`
`comprising any one or more of the following: a) one or more CDR(s) of antibody G1 or its variants shown in
`
`Table 6; b) CDR H3 from the heavy chain of antibody G1 or its variants shown in Table 6; c) CDR L3 from the
`
`light chain of antibody G1 or its variants shown in Table 6; d) three CDRs from the light chain of antibody G1
`
`20
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`or its variants shown in Table 6; e) three CDRs from the heavy chain of antibody G1 or its variants shown in
`
`Table 6; f) three CDRs from the light chain and three CDRs from the heavy chain of antibody G1 or its
`
`variants shown in Table 6. The invention further provides polypeptides (which may or may not be an
`
`antibody) comprising any one or more of the following: a) one or more (one, two, three, four, five, or six)
`
`CDR(s) derived from antibody G1 or its variants shown in Table 6; b) a CDR derived from CDR H3 from the
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`25
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`heavy chain of antibody G1; and/or c) a CDR derived from CDR L3 from the light chain of antibody G1.
`
`In
`
`some embodiments, the CDR is a CDR shown in Figure 5.
`
`In some embodiments, the one or more CDRs
`
`derived from antibody G1 or its variants shown in Table 6 are at least about 85%, at least about 86%, at least
`
`about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about
`
`92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at
`
`30
`
`least about 98%, or at least about 99% identical to at least one, at least two, at least three, at least four, at
`
`least five, or at least six CDRs of G1 or its variants.
`
`In some embodiments, the CDR is a Kabat CDR. In other embodiments, the CDR is a Chothia CDR.
`
`In other embodiments, the CDR is a combination of a Kabat and a Chothia CDR (also termed "combined
`
`CDR" or "extended CDR").
`
`In other words, for any given embodiment containing more than one CDR, the
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`35
`
`CDRs may be any of Kabat, Chothia, and/or combined.
`
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid sequence of
`
`KASKXaaVXaaTYVS (SEQ ID NO: 53), wherein Xaa at position 5 is R, W, G, L, or N; and wherein Xaa at
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`position 7 is T, A, D, G, R, S, W, or V.
`
`In some embodiments, the amino acid sequence of
`
`KASKXaaVXaaTYVS (SEQ ID NO: 53) is CDR1 of an antibody light chain.
`
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid sequence of
`
`XaaXaaSNRYXaa (SEQ ID NO: 54), wherein Xaa at position 1 is G or A; wherein Xaa at position 2 is A or H;
`
`5
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`and wherein Xaa at position 7 is L, T, I, or S.
`
`In some embodiments, the amino acid sequence of
`
`XaaXaaSNRYXaa (SEQ ID NO: 54) is CDR2 of an antibody light chain.
`
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid sequence of
`
`EIRSXaaSDXaaXaaATXaaYAXaaAVKG (SEQ ID NO: 55), wherein Xaa at position 5 is E, R, K, Q, or N;
`
`wherein Xaa at position 8 is A, G, N, E, H, S, L, R, C, F, Y, V, D, or P; wherein Xaa at position 9 isS, G, T, Y,
`
`10
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`C, E, L, A, P, I, N, R, V, D, or M; wherein Xaa at position 12 isH or F; wherein Xaa at position 15 is E or D.
`
`In
`
`some embodiments, the amino acid sequence of EIRSXaaSDXaaXaaATXaaYAXaaAVKG (SEQ ID NO: 55) is
`
`CDR2 of an antibody heavy chain.
`
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid sequence of
`
`SEQ ID N0:1, wherein amino acid residue at position 99 of SEQ ID N0:1 is Lor is substituted by A, N, S, T,
`
`15
`
`V, orR; and wherein amino acid residues at position 100 of SEQ ID N0:1 is A or is substituted by L, R, S, V,
`
`Y, C, G, T, K, or P.
`
`In some embodiments, the antibody of the invention is a human antibody. In other embodiments, the
`
`antibody of the invention is a humanized antibody.
`
`In some embodiments, the antibody is monoclonal.
`
`In
`
`some embodiments, the antibody (or polypeptide) is isolated.
`
`In some embodiments, the antibody (or
`
`20
`
`polypeptide) is substantially pure.
`
`The heavy chain constant region of the antibodies may be from any types of constant region, such as
`
`lgG, lgM, lgD, lgA, and lgE; and any isotypes, such as lgG1, lgG2, lgG3, and lgG4.
`
`In some embodiments, the antibody comprises a modified constant region as described herein.
`
`In another aspect, the invention provides a polynucleotide (which may be isolated) comprising a
`
`25
`
`polynucleotide encoding a fragment or a region of the antibody G1 or its variants shown in Table 6.
`
`In one
`
`embodiment, the fragment is a light chain of the antibody G1.
`
`In another embodiment, the fragment is a
`
`heavy chain of the antibody G1.
`
`In yet another embodiment, the fragment contains one or more variable
`
`regions from a light chain and/or a heavy chain of the antibody G1. In yet another embodiment, the fragment
`
`contains one or more (i.e., one, two, three, four, five, or six) complementarity determining regions (CDRs)
`
`30
`
`from a light chain and/or a heavy chain of the antibody G1.
`
`In another aspect, the
`
`invention
`
`is a polynucleotide (which may be
`
`isolated) comprising a
`
`polynucleotide that encodes for antibody G1 or its variants shown in Table 6.
`
`In some embodiments, the
`
`polynucleotide comprises either or both of the polynucleotides shown in SEQ ID N0:9 and SEQ ID N0:10.
`
`In another aspect, the invention provides polynucleotides encoding any of the antibodies (including
`
`35
`
`antibody fragments) or polypeptides described herein.
`
`In another aspect, the invention provides vectors (including expression and cloning vectors) and host
`
`cells comprising any of the polynucleotide disclos