PCTIE
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`P02/07348
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`UNITED STATES DEPARTMENT OF COMMERCE
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`United States Patent and Trademark Office
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`July 16, 2003
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`RECORDS OF THIS OFFICE OF:
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`Replacement Filing Receipt
`SERIAL NUMBER
`60/394,612
`July 09, 2002
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`FILING DATE
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`PRIORITY DOCUMENT ©
`SUBMITTED OR TRANSMITTED IN
`COMPLIANCE WITH
`RULE17.1(a) OR (b)
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`By Authority of the
`COMMISSIONER OF PATENTS AND TRADEMARKS
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`UNITED STATES DEPARTMENT OF COMMERCE
`Unjird Studs Potant and Prsduoark OFfiie
`Addrem: COMMISSIINER OF PATENTS AND TRADEMARKS:
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`erat eyVeniney! Feoroxanis 2OR1d-143G
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`—areaouNMaEe”RUNSOATE[GRPanTONT|ALSERESD[aryyBoogeTNOToRnaves[rorcus[inpclans|
`60/394,612
`07/09/2002
`210
`G-32574P1
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`CONFIRMATION NO. 4521
`001095
`REPLACEMENTFILING RECEIPT
`roeTIS. CORPORATE INTELLECTUALPROPERTY CAAN
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`THOMAS HOXIE
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`ONE HEALTH PLAZA 430/2
`EAST HANOVER, NJ 07936-1080
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`Date Mailed: 07/16/2003
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`Receipt is acknowledged of this provisional Patent Application. !t will not be examined for patentability and will
`become abandoned notlater than twelve months afterits filing date. Be sure to provide the U.S. APPLICATION
`NUMBER, FILING DATE, NAME OF APPLICANT, and TITLE OF INVENTION wheninquiting about this
`application. Fees transmitted by check or draft are subject to collection. Please verify the accuracy of the data
`presented on this receipt.
`If an error is noted on this Filing Receipt, please write to the Office of Initial
`Patent Examination’s Filing Receipt Corrections, facsimile number 703-746-9195. Please provide a copy of
`this Filing Receipt with the changes noted thereon. {f you received a "Notice to File Missing Parts" for this
`application, please submit any corrections to this Filing Receipt with your reply to the Notice. When the
`USPTO processes the reply to the Notice, the USPTO will generate anotherFiling Receipt incorporating
`the requested corrections{if appropriate).
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`Appiicant(s)
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`Michael Betz, Kund!, AUSTRALIA;
`John Stevens, GB-Surrey, UNITED KINGDOM;
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`lf Required, Foreign Filing License Granted: 09/11/2002
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`Projected Publication Date: None, application is not eligible for pre-grant publication
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`Non-Publication Request: No
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`Early Publication Request: No
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`Title
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`High concentration hGH formulations comprising phenol
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`ereangetangentperenneAERCPee
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`LICENSE FOR FOREIGN FILING UNDER
`Title 35, United States Code, Section 184
`Title 37, Code of Federal Regulations, 5,11 & 5,15
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`GRANTED
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`nt has been granted a license under 35 U.S.C. 184, ifthe phrase "IF REQUIRED, FOREIGN FILING
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`2 ANTED" followed by a date appears onthis form. Such licenses are issuedin all applications where
`the co
`for issuance of a license have been met, regardless of whetheror not a license may be required as
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`CFR 5.15, The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
`set fort
`license has been issued under 37 GFR 5.15(b). Thelicenseis subject to revocation upon written notification, The
`date indicated is the effective date of the license, unless an earlier license of similar scope has been granted
`under 37 CFR 5,13 ar 5.14.
`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof
`unless it is revoked. This license is automatically transferred to any related applications(s) filed under 37 CFR
`1,53(d). This license is not retroactive.
`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject
`matter as imposed by any Government contract or the provisions of existing laws relating to espionage and the
`national security or the export of technical data. Licensees should apprise themselves of current regulations
`especially with respect to certain countries, of other agencies, particularly the Office of Defense Trade Controls,
`Department of State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Office of
`Export Administration, Department of Commerce (15 CFR 370.10 @)); the Office of Foreign Assets Control,
`Departmentof Treasury (31 CFR Parts 500+) and the Departmentof Energy.
`
`NOT. GRANTEDoe
`No license under 35 U.S.C, 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear onthis fori. Applicant may still petition for a license under 37 CFR
`5.12, if a license is desired before the expiration of 6 months fram the filing date of the application. If 6 months
`has lapsed from the filing date of this application and the licensee has not received any indication of a secrecy
`order under 35 U.S.C. 181, the licensee mayforeign file the application pursuant to 37 CFR 5.15(b).
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`TOALE,TOWHOMTHESE; PRHSENDS; SHALE, COMM:
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`June 03, 2003
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`FILING DATE: July 09, 2002
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`UNITED STATES DEPARTMENT OF COMMERCE
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`United States Patent and Trademark Office
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`THIS IS TO CERTIFY THAT ANNEXED HERETOIS A TRUE COPY FROM
`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTSTO BE GRANTED A
`FILING DATE UNDER35 USC 111.
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`APPLICATION NUMBER: 60/394,612
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`By Authority of the
`LCOMMISSIONER OF PATENTS AND TRADEMARKS
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`20/60/10.-Aa
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`EV 090859869 US
`Express Mail Label Number
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`duly 9, 2002
`Date of Deposit
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`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
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`Address to: Assistant Commissioner for Patents
`Box Provisional Patent Application
`Washington, DC 20234
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`&
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`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
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`Transmitted herewith forfiling under 37 CFR §1.53(c) is the PROVISIONAL APPLICATIONfor patent of
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`Given Name(first and middle[if any])
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`Family Name or Surname
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`Residence (City and either State or Foreign Country)
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`TITLE OF THE INVENTION (280 characters max)
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`HIGH CONCENTRATION hGH FORMULATIONS COMPRISING PHENOL
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`
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`Directall correspondence to the address associated with Customer No. 001095, whichis currently:
`Thomas Hoxie
`Novartis Corporation
`Patent and Trademark Dept.
`564 Morris Avenue
`Summit, NJ 07901-1027
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` &
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` ENCLOSED APPLICATION PARTS(checkail that apply)
`of Novartis Corporation.
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`asTaney72072.
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`Specification (Including Any Claims and Abstract) - 20 pages
`bd
`(J Drawings~-
`sheets
`(1=Other(specify):
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`The Commissioneris hereby authorized to chargefiling fee and any
`additional fees required to Deposit Account Number: 19-0134 in the name
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`PROVISIONALFILING FEE AMOUNT:$160
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`(if the invention was made by an agency of the United States Government
`1 U.S. Government agency and contract number:
`or undera contract with an agency of the United States Government.)
`
`Date: July 9, 2002
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`Respectfully, submitted,
`
`Diane E. Furman
`Attorney for Applicant
`Reg. No. 37,104
`Tel. No. (908) 522-6924
`
`
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` Copy provided by USPTO from the PACR Image Database on 05/30/2003
`MYLANINST. EXHIBIT 1104 PAGE6
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`Case G-32574P1/PROV/BCK
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`High concentration hGH formulations comprising phenol
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`The presentinvention relatesto liquid formulations of human growth hormone (hGH,
`somatropin) which are storage stable, show reduced or no crystallization on storage and are
`suitable for administration to the humanor animal body. More particularly, the invention
`relates to liquid formulations of human growth hormonewhich are stable and exhibit minimal
`or no crystallization when stored at least for a time at temperatures aboverefrigeration
`temperatures.
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`_ Native hGHis a single polypeptide chain protein consisting of 191 amino acids. The protein
`is internally cross-linked by two disulphide bridges and in monomeric form exhibits a
`molecular weight of about 22kDa.
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`A majorbiological effect of hGHis to promote growth throughout a range of organs and
`tissues in the body. hGHis secreted in a pulsatile manner from thepituitary gland throughout
`life. The major biological effect of hGH is to promote growth. hGH responsive organs or
`tissues include the liver,intestine, kidneys, muscles, connective tissue and the skeleton. hGH
`deficiency can occurin all age groups. The consequences of hGH deficiency include
`reduction in bone density, shortness in stature in children, reduction in lean body mass and
`extracellular volume and increase in cardiovascularrisk factors. Replacement therapy with
`recombinant hGH has proven safe and effective in reversing these effects, but requires
`repeated injections at regular intervals.
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`For example, hypopituitary dwarfism is a condition whichis readily treated by administering
`hGHto a subject suffering the condition. Prior to the production of large quantities of hGH by
`recombinant meansonly limited amounts of hGH could be prepared by laborious extraction
`of pituitary glands from human cadavers. This practice carried withit risks associated with
`‘infectious agents, e.g. the agent responsible for Creutzfeldt-Jakob disease (CJD), and that
`these agents might be passed to the patient receiving hGH. Theisolation of the hGH gene
`and the construction of transformed hostcells expressing recombinant hGHin cell culture
`has opened up notonly a morereliable, safer and more costeffective treatment of
`hypopituitary dwarfism, but the possibility of using hGH fortreatment of other diseases and
`conditions as well. Accordingly, in the context of the present invention, hGH preferably
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` e Database on 05/30/2003
`Cnnv nravided by USPTO from the PAGRWeep
`YLANINST. EXHIBIT 1104 PAGE 7
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`designates recombinant human growth hormone. However,itwill readily appreciated that
`also human growth hormoneisolated from natural sources can in principle likewise be
`included in a pharmaceutical formulation of the present invention.
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`A long appreciated problem with aqueous liquid formulations of pharmaceuticalproteins, not
`just hGH,is that of instability during storage overa periodof time. hGH in aqueous solution
`is known to undergo a variety of degradative changes. in common with most otherproteins,
`hGH hasthree main potential routes of degradation, namely hydrolysis leading to
`deamidation of free amide groups,oxidation of sulphur containing amino acids, and physical
`change of aggregation, where two or more hGH molecules physically stick together, for
`example, resulting in the formation of opaqueinsolubles. There is also the possibility of a
`clipping of the peptide backbone as a result of hydrolysis. Additionally, a major problem is
`crystallization of hGH.
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`Early suggestions about how to solve the problemsofinstability noted above included freeze
`drying, but this of course meant that the resulting lyophilised product needed reconstitution
`immediately or shortly prior to administration.
`In the circumstances of routine self-
`administration by a patient at home,this normally meansthat the patient has the task of
`reconstituting the lyophilised preparation into an aqueoussolution. This is inconvenient for
`the patient and carries with it a risk of improper reconstitution due to lack of care, lack of
`attention to detail and instructions, or simply misunderstanding on the part of the patient.
`Freeze drying of formulations also suffers from the disadvantage of beingcostly and time
`consuming from a manufacturing perspective.
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`Mucheffort is therefore expended in finding formulations which permit a simpler self-
`administration of hGH by patients. These efforts are focused on ways of providing sufficiently
`stable aqueousliquid hGH formulations in a ready to use form. Such liquid dosage forms
`offer increased convenience and hence better compliance compared to lyophilized dosage
`forms which haveto be reconstituted andfilled into a pen cartridge via an additional device.
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`However, care has to be taken that excipients which may be able to stabilize an aqueous
`formulation of hGH may carry someriskin administration to patients. Many compounds which
`may serve asstabilizers would not appearclinically acceptable and therefore would not
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` Database on 05/30/2003
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`Conv provided bv USPTOfrom the PACR ImaMVLA
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`enable a pharmaceutically acceptable formulation to be made. Furthermore, pharmaceutical
`regulatory requirementsdictate that any unnecessary additives / excipients, particularly
`synthetic additives / excipients, must be avoided in order to reduce risks to patients.
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`Conveniently, aqueous pharmaceutical formulations of hGH should be offered as multi-
`dosage formulations to the patient, who will administer such a formulation by means of an
`injector device. Such multi-dosage pharmaceutical formulations usually require an
`appropriate preservative to be present.
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`Commonliquid formulations of hGH are knownto contain the drug at a low concentration,
`e.g. about 3.33 mg / ml, which, however, upon administration may cause certain
`disadvantagesfor the patient.
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`in particular, a patient has to receive a relatively large volume of such a low-concentration
`formulation of hGH perinjection, which may cause discomfort or even pain. For example, for
`children suffering from growth hormonedeficiency (GHD) hGH may haveto be administered
`at a dosage of about 0.1 IU / kg bodyweight / day. Accordingly, a patient having a bodyweight
`of 50 kg would have to receive about 5 IU hGH perday, which is contained in 500 pl of a
`liquid formulation comprising about 3.33 mg / ml! hGH (1 IU hGH = 0.33 mg hGH). It will
`readily be appreciated that the application of a volumeofless than 500 yl would be highly
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`desired.
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`In the alternative, such a dosage could be administered in 2 or moreinjections of such a
`low-concentrated hGH formulation, each injection having a reduced volume. However,in
`terms of application safety, the use of more than one injection per dosageis not
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`recommended.
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`Furthermore, depending on the treatment schedule and dosage, a patient may have to use
`more than one single injection of such a low-concentration hGH formulation in order to be
`able to provide the prescribed amount of hGH. This may apply for example to patients having
`growth deficiency related to the Turner-Syndrome, who because of their increased body
`weight may bein need of a high amount of hGH.In manyinstancesit will not be possible to
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` Copyprovided by USPTO from the PACR Image Database on 05/30/2003
`MYLANINST. EXHIBIT 1104 PAGE 9
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`Case G-32574P1/PROV/BCK
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`deliver the required amount of hGH to such patients with a single injection having a
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`reasonable volume of a such low-concentrated hGH formulation.
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`Therefore, there is an ongoing needfor a liquid pharmaceutical formulation containing hGH at
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`a high concentration.
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`In the course of the present invention it has been noticed that crystals tend to form in known
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`aqueous,liquid growth hormone formulationsif the concentration of hGH is adjusted to higher
`values, e.g. to 5 mg/ml hGH or more,in such formulations. This does not only apply just
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`when such formulations are stored at refrigeration temperatures, but also when they are
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`stored above refrigeration temperatures, at least for a time. The presenceof crystals in liquid
`hGH formulations is highly undesirable because prior to administration such formulations
`need to be agitated or swirled and there may be instances whencrystals are small or
`unobserved and the formulation is caused to be administered without dissolving the crystals
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`sufficiently first. There is also the obvious disadvantagein terms of the visual appearanceof
`hGH formulations when crystals have formed during storage.
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`An object of the invention is therefore to provide a multi-dosage, aqueousliquid hGH
`formulation which is stable when stored for periods of time at refrigeration temperatures, e.g.
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`for several months, or even for 1 or 2 years. Another object of the invention is to provide
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`liquid hGH formulations which are stable when storedfor at least a period of time above
`commonrefrigeration temperatures (e.g. above 2°C - 8°C) or even outside a refrigerator, e.g.
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`for periods of several hours, days, or even weeks.
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`In the context of the present application, "stable" mainly meansthat the problem of crystal
`formation is essentially avoided; preferably this problem is avoided completely. Accordingly,
`pharmaceutical formulation of the present invention exhibit minimalor no crystallization upon
`storage as described above.
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`In addition to avoiding crystallization, a stable formulation should preferably show no or
`minimal aggregation of hGH uponstorage. Likewise, a stable formulation preferably should
`not or only to a minimal extent undergo other degradation of hGH, e.g. by deamidation,
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`- oxidation and/or hydrolysis.
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`AN INST. EXHIBIT 1104 PAGE10
`Copy provided by USPTOfrom the PaCMIY LAe Database on 05/30/2003
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`MYLAN INST. EXHIBIT 1104 PAGE 10
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`Case G-32574P1/PROV/BCK
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`In the context of the presentinvention, it has been developed that the preservative to be used
`in such a multi-dosageliquid formulation containing a high concentration of hGHis a critical
`parameter regarding stability, and that phenol is the preservative to be most favourably used
`in such formulations comprising a high concentration of hGH. Furthermore, in the context of
`the presentinvention,it has been surprisingly established that a stable formulation can be
`composedof a smaller numberof excipients than previously thought.
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`Accordingly, an embodimentof the present invention relates to the use of phenol as a
`preservative in the preparation of a multi-dosage aqueous liquid pharmaceutical formulation
`comprising a high concentration of human growth hormone, wherein said formulation is
`substantially free of an amino acid excipient, as described herein.
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`In the contextof the present invention, a liquid pharmaceutical formulation is a formulation
`providedin a ready-to-use form,i.e. it is not provided in a form to be reconstituted before
`administration, like e.g. a lyophilisate.
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`The presentinvention therefore provides a multi-dosageliquid pharmaceutical formutation of
`human growth hormoneconsisting essentially of human growth hormoneat a concentration
`of from about 5 mg/ml to about 100 mg/ml, phenol, an aqueousbuffer, a non-ionic surfactant,
`said pharmaceutical formulation having a tonicity of from about 100 mosm/kg to about 500
`mosm/kg, having a pH of from about6.1 to about 6.3, and being substantially free of an
`amino acid excipient.
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`Where necessary, additionally a tonicity-adjusting agent may be present in such a
`pharmaceutical formulation such that the tonicity is from about 100 mosm/kg to about 500
`mosm/kg. Preferably, the pharmaceutical formulation of the present inventionis isotonic.
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`Accordingly, in a further embodimentthereof, there is provided a multi-dosageliquid
`pharmaceutical formulation of human growth hormone consisting essentially of human
`growth hormoneat a concentration of from about 5 mg/ml to about 100 mg/ml, phenol, an
`aqueousbuffer, a non-ionic surfactant, said pharmaceutical formulation having a tonicity of
`from about 100 mosm/kg to about 500 mosm/kg, having a pH of from about6.1 to about 6.3,
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`Copy provided by USPTO from the PACR ImageM YIL
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`Database on 05/30/2003
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`Case G-32574P1/PROV/BCK
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`and being substantially free of an aminoacid excipient, said pharmaceutical formulation
`additionally comprising a tonicity-adjusting agent such thatthe tonicity of the pharmaceutical
`composition is from about 100 mosm/kg to about 500 mosm/kg.
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`’
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`The presenceof an additionaltonicity-adjusting agent will be necessary if the further
`excipients of the formulation cannot contribute to the formulations’ overall tonicity to such an
`extent that the desired tonicity is achieved.
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`In the context of the present invention, the term "consisting essentially of" means that the
`pharmaceutical formulation of the present invention does not contain further excipients,
`besides the ones mentioned herein, which are capable to contribute a technological
`pharmaceuticalfunction to the pharmaceutical formulation, e.g. in termsofstability, pH,
`tonicity, and the like. This does, however, not exclude the possibility that such a formulation
`may comprise one or morefurtherauxiliary agents, which do not perform a technological
`pharmaceutical function in the formulation. Such auxiliary agents for example may be
`pharmaceutically acceptable dyes whichwill make the liquid formulation coloured. This may
`e.g. help in identifying the amountofliquid in a multi-dosage injection device or assist in
`easily identifying whetheror not crystallization has occurred.
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`In the context of the present invention,the term "substantially free of an amino acid excipient”
`meansthat the formulation does not contain an amount of an excipient being an amino acid
`capable of performing a technological pharmaceutical effect on the formulation, e.g.like
`acting as a tonicity agent, as a stabilizer or as a buffer substance. However,it will be
`appreciated that trace amounts of an amino acid, being present e.g. as a remainder from a
`former preparation or purification step, can well be containedin the pharmaceutical
`formulation according to the invention,as long as they do notinfluence the technological
`pharmaceutical behaviour of the formulation.
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`In a preferred embodiment, the pharmaceutical formulations according to the present
`invention are free of an amino acid excipient.
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`Arising out of the present invention the inventors have perceived an advantage forpatients,
`pharmacists and medicalpractitioners. Hitherto it has been necessary to ensure careful
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`Case G-32574P1/PROV/BCK
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`storage of growth hormone formulations at refrigeration temperatures (e.g. in the range of 2°
`to 8°C) in order to minimizecrystallization. Prior to receipt of the growth hormonebypatients
`the formulations can usually be reliably stored at refrigeration temperatures by manufactures
`and pharmacists. However, once received and stored by patients in domestic refrigerators
`there is muchless reliability in terms of storage temperature. Temperaturesin patients’
`domestic refrigerators may well be substantially above 2-8°C,e.g. be about 15°C,e.g.
`because of frequent opening. Moreover, devices containing the liquid formulation to be
`applied maybe stored outside the refrigerator, e.g. being forgotten on the kitchen bench after
`administration, thereby being exposed to room temperature (e.g. about 20°C to about 27°C,
`frequently about 25°C) for some time. Crystallization of hGH tends to occur more readily at
`temperatures greaterthan 8°C,i.e. above refrigeration temperatures, with known
`pharmaceutical formulations of hGH.
`
`The formulations of the present invention provide a greater resistance to crystallizationif
`stored for a time aboverefrigeration temperatures. This therefore permits patients to be
`supplied with sufficient growth hormoneto provide daily doses over longer periods of time
`than was hitherto recommendable or desirable. Whereas before, patients might have kept a
`small numberof doses for use over a period of a week,with the formulations of the present
`invention patients may keep several weeks or even several months supply of growth
`hormone in domestic refrigerator with no or only minimalcrystallization taking place. The
`frequency of prescription to patients can therefore be reduced significantly by the present
`invention.
`
`Accordingly, the pharmaceutical formulations of the present invention are stable, in particular
`substantially free of crystallization, on storage at temperatures from refrigeration
`temperatures to room temperature. In particular, such formulations are stable upon storage at
`temperatures from refrigeration temperatures to room temperature for at least 4 weeks orat
`least 1 month, preferably for at least 7 weeks, more preferably forat least 13 weeks.
`
`In this context,it is to mention that prior to storage, hGH formulations may comprise about
`4% of “related proteins” being proteinaceous materials generated by degradative processes
`of deamidation and oxidation. Such “related proteins” are defined in the European
`
`Copy provided by USPTO from the PACR Image Database on 05/30/2003
`MYIi AN INST. EXHIBIT 1104 PAGE13
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`MYLAN INST. EXHIBIT 1104 PAGE 13
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`Pharmacopoiea and measured by reversed phase HPLC. The inventors propose a maximum
`of 20% “related proteins” as a target at the endof the shelflife of the formutations.
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`Case G-32574P 1/PROV/BCK
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`The degradation rate of hGHis not exactly linear and the rate of degradation increases with
`an increase in temperature. At 2° - 8°C formulations usually exhibit an increase in “related
`proteins” of about 0.8% per month. At 25°C this rises to about 13% per month, and at 40°C
`to about 70% per month. Storage at 25°C for 1 month is approximately equivalent to 17
`months storage at 2° -8°C. Storage at 15°C for 1 month is approximately equivalent to 5
`months storage at 2° - 8°C. Continuous storage at a temperature in the range of about 25° to
`40°Cis therefore impractical.
`
`Although the formulations of the presentinvention offer good resistance to crystallization
`_ even up to 40°C,particularly up to 25°C, more particularly up to 15°C, the rapid formation of
`“related proteins” at these temperatures will usually place a more immediate limit on the
`potential shelflife of formulations.
`
`Ratesof “related proteins” formation at different temperatures overtime are readily measured
`by one of average skill and with this information the optimisation and maximum storage
`time/temperature patterns may be calculated without undue burden.
`In practice, formulations
`ofthe presentinvention can readily be subjected to a daily rise in temperatureslightly above
`about 8°C due to the opening and closing of a refrigerator door or removal from a refrigerator
`for periods of an hour or so each day for the purposes administration without significant loss
`of shelf life. Advantageously, formulations of the present invention would not suffer adversely
`in terms of degradation or crystallization if left out of the refrigerator at room temperature for a
`
`dayor so.
`
`Accordingly, the pharmaceutical formulations of the present invention may be kept at
`refrigeration temperature (e.g. in the range of 2° to 8°C)all the time in a stable condition.
`Furthermore, the pharmaceutical compositions show a sufficient stability when at least some
`of the overall storage time will be at a temperature above refrigeration temperatures, possibly
`up to about a week outsidea refrigerator, possibly up to about a month or even longer
`outside a refrigerator.
`
`
`
` Copy provided by USPTO from the PACR Image Database on 05/30/2003
`MYLANINST. EXHIBIT 1104 PAGE 14
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`MYLAN INST. EXHIBIT 1104 PAGE 14
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`Case G-32574P1/PROV/BCK
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`Accordingly, at least a part of the time that the formulation is stored may be at a storage
`temperature of at least 8°C, optionally a temperature in the range selected from 8° to 40°C,
`
`8° to 25°C or 8° to 15°C.
`
`in a preferred embodimentof the pharmaceutical formulations according to the present
`
`invention, the concentration of hGH in the formulation is from about 6 mg/mlto about 14
`
`mg/mi. In a particularly preferred embodiment thereof, the concentration of hGHin the
`formulation is about 6.67 mg/mi.
`
`In the developmentof the present invention it has surprisingly been established that phenol,
`being used as a preservative, is capable of providing sufficient stability to the formulations of
`the present invention which comprise such a high concentration of hGH. Preferably, the
`pharmaceutical formulations of the present invention comprise phenol at a concentration of
`from about 2 mg/ml to about 5 mg/ml, more preferably from about 2mg/mlto about 3 mg/ml,
`most preferably of about 2.5 mg/ml, in particular 2.5 mg/ml.
`
`The aqueous buffer presentin the pharmaceutical formulation of the present invention can be
`any pharmaceutically acceptable buffer. In a preferred embodimentthereof, the aqueous
`buffer is selected from the group consisting of a phosphate buffer, a citrate buffer, an acetate
`buffer and a formate buffer, preferably a phosphate buffer, more preferably a sodium
`phosphate buffer. Usually, the aqueous buffer has a concentration of from about 5 mM to
`about 100 mM. In a preferred embodiment thereof, the aqueous buffer has a concentration of
`about 10 mM. In a particularly preferred embodiment thereof, the aqueous buffer is a
`phosphate buffer having a concentration of about 10 mM (the number 10 mM referring to the
`concentration of the phosphate ions). Most preferably the aqueousbufferis a sodium
`. phosphate buffer having a concentration of about 10 mM. Likewise preferred is a 10 mM
`phosphate buffer, in particular a 10 mM sodium phosphate buffer.
`
`The non-ionic surfactant present in the pharmaceutical formulation of the present invention
`can be any non-ionic surfactant whichis pharmaceutically acceptable. Preferably, the non-
`ionic surfactant is selected from the group consisting of poloxamers, such as poloxamer 184
`or 188, and polysorbates, such as polysorbate 20 or 80, for example, and other
`__ ethylene/polypropylene block polymers. Preferably, the non-ionic surfactantis a poloxamer,
`
`Copy provided by USPTO from the PACR Image Database on 05/30/2003
`MYLANINST. EXHIBIT 1104 PAGE15
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`MYLAN INST. EXHIBIT 1104 PAGE 15
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`Case G-32574P1/PROV/BCK
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`in particular poloxamer 188. Amounts of the non-ionic surfactant used maybein the range
`from about 0.001% (w/v) to about 10% (w/v), more preferably from about 0.005% (w/v)to
`about 5% (w/v), even more preferably from about 0.01% (w/v) to about 1% (w/v). Ina
`preferred embodimentthereof, the non-ionic surfactantis present at a concentration of from
`about 0.05 mg/ml to about 4 mg/ml, preferably at a concentration of about 2 mg/ml. A
`preferred embodimentof the present invention relates to a pharmaceutical formulation
`wherein the non-ionic surfactant is poloxamer 188 present at a concentration from about 0.05
`
`mg/ml to about 4 mg/ml, preferably of about 2 mg/ml.
`
`If in the pharmaceutical formulation according to the present invention an additionaltonicity-
`adjusting agentis present for adjusting the tonicity of the formulation to a desired value from
`about 100 mosm/kg to about 500 mosm/kg, suchtonicity-adjusting agent can be any
`pharmaceutical acceptable tonicity-adjusting agent, with the exception of an aminoacid.
`Preferably, such tonicity-adjusting agent is selected from the group consisting of a sugar, a
`sugar alcohol, a polyol and a neutral salt. For example, a sugar can be a monosaccharide or
`a disaccharide, like e.g. lactose or sucrose. For example, a polyol can be a diol,like e.g. 1,2-
`propylene glycol. For example, a neutral salt can be an inorganic salt displaying an about
`neutral pH upondissolution in water,like e.g. sodium chloride or ammonium acetate. Ina
`preferred embodimentthereof, the tonicity adjusting agent is a sugar alcohol, preferably
`mannitol. The tonicity-adjusting agent preferably is present at a concentration u