-
`
`PCT/E? o 3 / o 7 3 L. 9
`
`REC'D O 1 SEP 2003
`i-----·---....
`PCT
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`July 18, 2003
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF:
`
`CORRECTED FILING RECEIPT
`SERIAL NUlVIBER: 60/394,699
`FILING DATE: July 09, 2002
`
`PRIORITYD
`SUBMITTED OR. T OCflMENT
`COMPLIAN~NSMITTBD IN
`WITI:r
`RVLB
`17.l(a) OR (b)
`
`Certifying Officer
`
`MYLAN INST. EXHIBIT 1103 PAGE 1
`
`

`

`Page 2 ot .t.
`
`rhe applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`~.
`GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
`·
`· ons for issuance of a license have been met, regardless of whether or not a license may be required as
`s
`~n 37 CFR 5.15. The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
`license has been issued under 37 CFR 5.1 S(b). The license is 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 or 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 transferrec1 to any related applications(s) filed under 37 CFR
`1.53(d). This license is not retroactive.
`
`ihe 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 (i)); the Office of Foreign Assets Control,
`Department ofl'reasury (31 CFR Parts 500-t-) and the Department of Energy.
`
`NOTJ;RANTED
`
`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 on this form. Applicant may still petition for a license under 37 CFR
`5.12, if a license is desired before the expiration of 6 months frorn the tiling date of the application. If 6 months
`has lapsed from the 'liling date of this application and the licensee has not received any indication of a secrecy
`order under 35 U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
`MYLAN INST. EXHIBIT 1103 PAGE 2
`
`

`

`U//.LO/UJ
`
`u::ir 1u u1.ru
`
`Page 1 of2
`
`\
`
`UNITED STATES PATENT AND TRADEMARl{. OFFICE
`
`UKI'J'EJ) STATES 'DEPAR'J'M.E.'-l'f OF co:r.11vn,rn.ci;:
`1.Jnit~,1 Ri11L.,~~ Puu~nt. und 'rr'JJdt,ndlr~ om,,1-1
`A~•lt•,o: CO!v!MiliSIONr.R OF' l'ATIJN"l'S J\NIJ Tlt,\11&:MJ\Rl:.S
`r•.o. a.,. 1 ,so
`Ah:Allltl..h'Ua.. Vll}9uiu 2.:Z:}l:\-14)~1
`WV,W,L111plo.gin·
`
`Fil.ING PATI; I GRP ART LINIT j FtL FEE REC'D ! ATTY.DOCKET.No I DRAWINGS ! TOT CLAIMS ! IND cl.AIMS I
`
`APPLICATION NUMBf:R
`60/394,699
`
`07/09/2002
`
`210
`
`G-32575P1
`
`001095
`THOMAS HOXIE
`NOVARTIS, CORPORATE INTELLECTUAL PROPERTY
`ONE HEAL TH PLAZA 430/2
`EAST HANOVER, NJ 07936-1080
`
`CONFIRMATION NO. 4455
`CORRECTED FILING RECEIPT
`I llllllll Ill llll lllll 1111111111 m1 m1 11111 11111111111111111111 lllll !1111111111111111111111
`•ocooooooo1 os22924•
`
`Date Mailed: 07/18/2003
`
`Receipt is acknowledged of this provisional Patent Applicat,nn. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Be sure to provide the U.S. APPLICATION
`NUMBER, FILING DATE, NAME OF APPLICANT, and TITLE OF INVENTION when inquiring 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. If 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
`USPiO processes the reply to the Notice, the USPTO will generate another Filing Receipt incorporating
`the requested corrections (if app-ropriate),
`
`Applicant(s)
`
`Michael Betz, Kundl, AUSTRIA;
`John Stevens, GB-Surrey CR7 7LP, UNITED KINGDOM;
`
`If Required, Foreign Filing License Granted: 07/26/2002
`Projected Publication Date: None, application is not eligi.:ile for pre-grant publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`
`Title
`
`High concentration hGH formulations comprising 1,2-propylene glycol
`
`LICENSE FOR FOREIGN FILING UNDER
`Title 35, United States Code, Section 184
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`GRANTED
`
`j
`
`MYLAN INST. EXHIBIT 1103 PAGE 3
`
`

`

`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`June 04, 2003
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS 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 REQUIREMENTS TO BE GRANTED A
`FILING DATE UNDER 35 USC 111.
`
`APPLICATION NUMBER: 60/394,699
`FILING DATE: July 09, 2002
`
`MYLAN INST. EXHIBIT 1103 PAGE 4
`
`

`

`01-J0-0'"'-
`
`,11:..1 •11· ij ~ ..:c; rr_u 11.J1 .. is:11 iq 1 .. n
`lL:J »...J, .... 1
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`.all
`
`I
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`J....
`
`•••
`
`~ P ... ,,i" ·11 1,1 u :111 •JLJ' Air.: 11 ·f 'D (2.. 0\
`V'lrl..
`'
`
`1111
`
`.ol'
`
`JU ll .. ,P .. 1
`
`,.p
`
`Docket Number G-32575P1/PROV/BCK
`FILING BY "EXPRESS MAIL" UNDER 37 CFR 1.10
`
`EV 090859869 US
`Express Mail Label Number
`
`July 9, 2002
`Date of Deposit
`
`Address to: Assistant Commissioner for Patents
`Box Provisional Patent Application
`Washington, DC 20231
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`Transmitted herewith for filing under 37 CFR §1.53(c) is the PROVISIONAL APPLICATION for patent of
`INVENTOR(S)
`Family Name or Surname
`I
`
`••'
`
`Given Name (first and middle [If any])
`
`Residence (City and either State or Foreign Country)
`
`'
`TITLE OF THE INVENTION (280 characters max)
`HIGH CONCENTRATION hGH FORMULATIONS COMPRISl~lG 1,2-PROPYLENE GLYCOL
`CORRESPONDENCE ADDRESS
`Direct all correspondence to the address associated with Customer No. 001095, which is currently:
`Thomas Hoxie
`Novartis Corporation
`Patent and Trademark Dept.
`564 Moms Avenue
`Summit, NJ 07901-1027
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`1ZJ Specification (Including Any Claims and Abstract) - 22 pages
`O Drawings -
`sheets
`'
`O Other (specify):
`
`';-': .. "•-. .:
`
`METHOD OF PAYMENT
`The Commissioner is hereby authorized to charge filing fee and any
`PROVISIONAL FILING FEE AMOUNT:$ 160
`additional fees required to Deposit Account Number: 19-0134 in the name
`. ._
`of Novartis Corporation.
`
`O U.S. Government agency and contract number:
`(if the invention was made by an agency of the United Slates Government
`or under a contract with an agency of the United States Government.)
`
`Date: July 9, 2002
`
`Respectfuily submitted,
`
`~01~'"-'ne E"""'~'-"'-urm-an-l--"~~~~q...w_--=--7'v,.,....,,_f "4 Z~z_
`
`Attorney for Applicant
`Reg. No. 31,104
`Tel. No. (908) 522-6924
`
`Copy provided by USPTO from the PACR Image Database on 06/02/2003
`
`MYLAN INST. EXHIBIT 1103 PAGE 5
`
`

`

`'J
`
`-1 -
`
`Case: G-32575P1/PROV/BCK
`
`High concentration hGH formulations comprising 1,2-propylene glycol
`
`The present invention relates to liquid formulations of human growth hormone (hGH,
`somatropin) which are storage stable, show reduced or no ~rystallization on storage and are
`suitable for administration to the human or animal body. More particularly, the invention
`relates to liquid formulations of human growth hormone which are stable and exhibit minimal
`or no crystallization when stored at least for a time at temperatures above refrigeration
`temperatures.
`
`Native hGH is a single polypeptide c~ain 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.
`
`I
`
`A major biological effect of hGH is to promote growth throughout a range of organs and
`tissues in the body. hGH is secreted in a pulsatile manner from the pituitary gland tt-iroughout
`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 occur in 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 cardiovascular risk factors. Replacement therapy with
`recombinant hGH has proven safe and effective in reversing these effects, but requires
`repeated injections at regular intervals
`
`For example, hypopituitary dwarfism is a condition which is readily treated by administering
`hGH to a subject suffering the condition. Prior to the production of large quantities of hGH by
`recombinant means only limited amounts of hGH could be preparod by laborious extraction
`of pituitary glands from human cadavers. This practice carried with it risks associated with
`infectious agents, eg the agent responsible for Creutzfeldt-Jakob disease (CJD), and that
`these agents might be passed to the patient receiving hGH. The isolation of the hGH gene
`and the construction of transformed host cells expressing recombinant hGH in cell culture
`has opened up not only a more reliable, safer and more cost effective treatment of
`hypo pituitary dwarfism, but the possibility of using hGH for treatment of other diseases and
`conditions as well. Accordingly, in the context of the present invention, hGH preferably
`
`Copy provided by USPTO from the PACR Image Database on 06/02/2003
`
`MYLAN INST. EXHIBIT 1103 PAGE 6
`
`

`

`..
`
`,1
`
`-2-
`
`·case: G-32575P1/PROV/BCK
`
`designates recombinant human growth hormone. However, it will readily appreciated that
`
`also human growth hormone isolated from natural sources can in principle likewise be
`
`included in a pharmaceutical formulation of the present invention.
`
`A long appreciated problem with aqueous liquid formulations of pharmaceutical proteins, not
`just hGH, is that of instability during storage over a period of time. hGH in aqueous solution
`is known to undergo a variety of degradative changes. In common with most other proteins,
`
`Somatropin (recombinant human growth hormone, rhGH) has three 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 opaque
`insolubles. 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.
`
`Early suggestions about how to solve the problems of instability noted above included freeze
`
`drying, but this of course meant that the resulting Iyophilised product needed reconstitution
`
`immediately or shortly prior to administration. In the circumstances of routine self(cid:173)
`administration by a patient at home, this normally means that the patient has the task of
`reconstituting the lyophilised preparation into an aqueous solution. 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 being costly and time
`
`consuming from a manufacturing perspective.
`
`Much effort is therefore expended in finding formulations which permit a simpler self(cid:173)
`administration of hGH by patients. These efforts are focused on ways of providing sufficiently
`stable aqueous liquid 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 have to be reconstituted and filled into a pen cartridge via an additional device.
`
`However, care has to be taken that excipients which may be able to stabilize an aqueous
`formulation of hGH may carry some risk in administration to patients. Many compounds which
`may serve as stabilizers would not appear clinically acceptable and therefore would not
`
`Copy provided by USPTO from the PACR lmaqe Database 01> nRtn?t?fV1?
`
`MYLAN INST. EXHIBIT 1103 PAGE 7
`
`

`

`'l
`
`'1
`
`Case: .G-32575P1/PROV/BCK
`
`-3-
`
`enable a pharmaceutically acceptable formulation to be made. Furthermore, pharmaceutical
`
`regulatory requirements dictate that any unnecessary additives / excipients, particularly
`
`synthetic additives / excipients, must be avoided in order to reduce risks to patients.
`
`Conveniently, aqueous pharmaceutical formulations of hGH should be offered as multi(cid:173)
`
`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.
`
`Common liquid formulations of hGH are known to contain the drug at a low concentration,
`
`e.g. about 3.33 mg I ml, which, however, upon administration may cause certain
`
`disadvantages for the patient.
`
`In particular, a patient has to receive a relatively large volume of such a low-concentration
`
`formulation of hGH per injection, which may cause discomfort or even pain. For example, for
`
`children suffering from growth hormone deficiency (GHD) hGH may have to 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 per day, which is contained in'500 µI of a
`liquid formulation comprising about 3.33 mg/ ml hGH (1 IU hGH = 0.33 mg hGH). It will
`
`I
`
`readily be appreciated that the application of a volume of less than 500 µI would be highly
`
`desired.
`
`In the alternative, such a dosage could be administered in 2 or more injections 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 dosage is not
`
`recommended.
`
`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 be in need of a high amount of hGH. In many instances it will not be possible to
`
`Copy provided by USPTO from the PACR lmaqe Database nn '1Rll'!?l?M.,
`
`MYLAN INST. EXHIBIT 1103 PAGE 8
`
`

`

`-4-
`
`Case: G-32575P1/PROV/BCK
`
`deliver the required amount of hGH to such patients with a single ifljection having a
`
`reasonable volume of a such low-concentrated hGH formulation.
`
`Therefore, there is an ongoing need for a liquid pharmaceutical formulation containing hGH at
`
`a high concentration.
`
`In the course of the present invention it has been noticed that crystals tend to form in known
`aqueous, liquid growth hormone formulations if 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
`
`when such formulations are stored at refrigeration temperatures, but also when they are
`stored above refrigeration temperatures, at least for a time. The presence of 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 when crystals are small or
`unobserved and the formulation is caused to be administered without dissolving the crystals
`sufficiently first. There is also the obvious disadvantage in terms of the visual appearance of
`
`hGH formulations when crystals have formed during storage.
`
`An object of the invention is therefore to provide a multi-dosage, aqueous liquid hGH
`
`· 1
`
`,
`
`formulation which is stable when stored for periods of time at refrigeration temperatures, e.g.
`for several months, or even for 1 or 2 years. Another object of the invention is to provide
`liquid hGH formulations which are staple when stored for at least a period of time above
`common refrigeration temperatures (e.g. above 2°C - 8°C) or even outside a refrigerator, e.g.
`
`for periods of several hours, days, or even weeks.
`
`In the context of the present application, "stable" mainly means that the problem of crystal
`
`formation is essentially avoided; preferably this problem is avoided completely. Accordingly,
`pharmaceutical formulation of the present invention exhibit minimal or no crystallization upon
`
`storage as decribed above.
`
`In addition to avoiding crystallization, a stable formulation should preferably show no or
`minimal aggregation of hGH upon storage. likewise, a stable formulation preferably should
`not or only to a minimal extent undergo other degradation of hGH, e.g. by deamidation,
`
`oxidation and/or hydrolysis.
`
`Copy provided by USPTO from the PACR Image Database on 06/02/200:'{
`
`MYLAN INST. EXHIBIT 1103 PAGE 9
`
`

`

`.•
`
`. ,
`
`-5-
`
`Case: G-32575P1/PROV/BCK
`
`In the context of the present invention, it has_ been developed that 1,2-propylene glycol to be
`
`used in such a multi-dosage liquid formulation containing a high concentration of hGH is a
`
`favourable parameter regarding stability. Furthermore, in the context of the present invention,
`
`it has been surprisingly established that a stable formulation can be composed of a smaller
`
`number of excipients than previously thought.
`
`Accordingly, an embodiment of the present invention relates to the use of 1,2-propylene
`
`glycol as 'a stabilizing agent in the preparation of a multi-dosage aqueous liquid
`
`pharmaceutical .formulation comprising a high concentration of human growth hormone, as
`
`described herein.
`
`During the development of the present invention it has been shown that 1,2-propylene glycol
`is capable of providing stability to the pharmaceutical formulation and, simultaneously, it
`
`contributes to the desired tonicity of the formulation.
`
`In the context of the present invention, a liquid pharmaceutical formulation is a formulation
`
`provided in a ready-to-use form, i.e. it is not provided in a form to be reconstituted before
`
`administration, like e.g. a lyophilisate.
`
`The present invention therefore provides a multi-dosage liquid pharmaceutical formulation of
`
`human growth hormone consisting essentially of human growth hormone at a concentration
`of from about 5 mg/ml to about 100 mg/ml, 1,2-propylene glycol, an aqueous buffer, a non(cid:173)
`
`ionic surfactant and a preservative, said pharmaceutical formulation having a tonicity of from
`about 100 mosm/kg to about 500 mosm/kg and having a pH of from about 6.1 to about 6.3.
`
`Where necessary, additionally a tonicity-adjusting agent may be present in such a
`
`pharmaceutical formulation such that the tonicity is from about 100 to about 500 mosm/kg.
`
`Preferably, the pharmaceutical formulation of the present invention is isotonic.
`
`Accordingly, in a further embodiment thereof, there is provided a multi-dosage liquid
`
`pharmaceutical formulation of human growth hormone consisting essentially of human
`
`growth hormone at a concentration of from about 5 mg/ml to _about 100 mg/ml, 1,2-propylene
`
`Copy provided by USPTO from the PACR Image Database on 06/0?/?flfl~
`
`MYLAN INST. EXHIBIT 1103 PAGE 10
`
`

`

`Case: G-32575P1/PROV/BCK
`
`- 6 -
`
`glycol, an aqueous buffer, a non-ionic surfactant and a preservative, said pharmaceutical
`
`formulation having a tonicity of from about 100 mosm/kg to about 500 mosm/kg and having a
`
`pH of from about 6.2 to about 6.3, said pharmaceutical formulation additionally comprising a
`
`tonicity-adjusting agent such that the tonicity of the pharmaceutical composition is from about
`
`100 to about 500 mosm/kg.
`
`The presence of an additional tonicity-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. In particular, depending on its concentration,
`
`1,2-propylene glycol is capable to provide a substantial part of the desired tonicity.
`
`Particularly preferred are those pharmaceutical formulations according to the present
`
`invention, where 1,2-propylene glycol, together with the further excipents, is capable of
`'
`providing the desired tonicity without the need of an additional tonicity-adjusting agent to be
`
`present, thereby keeping the overall number of excipients to be used to a minimum.
`
`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
`
`pharmaceutical function to the pharmaceutical formulation, e.g. in terms of stability, pH,
`
`tonicity, and the like. This does, however, not exclude the possibility that such a formulation
`
`may comprise one or more further auxiliary agents, which do not perform a technological
`
`pharmaceutical function in the formulation. Such auxiliary agents for example may be
`
`pharmaceutically acceptable dyes which will make the liquid formulation coloured. This may
`
`e.g. help in identifying the amount of liquid in a multi-dosage injection device or assist in
`
`easily identifying whether or not crystallization has occurred.
`
`Arising out of the present invention the inventors have perceived an advantage for patients,
`
`pharmacists and medical practitioners. Hitherto it has been necessary to ensure careful
`
`storage of growth hormone formulations at refrigeration temperatures (e.g. in the range of 2°
`
`to 8°C) in order to minimize crystallization. Prior to receipt of the growth hormone by patients
`
`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 much less reliability in terms of storage temperature: Temperatures in patients'
`
`I
`I·
`
`Copy provided by USPTO from the PACR lmaqe Database 011 Of\/1'\?l?M~
`
`MYLAN INST. EXHIBIT 1103 PAGE 11
`
`

`

`-7-
`
`Case: G-32575P1/PROV/BCK
`
`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 may 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 21°c,
`frequently about 25°C) for some time. Crystallization of hGH tends to occur more readily at
`temperatures greater than 8°C, i.e. above refrigeration temperatures, with known
`
`pharmaceutical formulations of hGH.
`
`The formulations of the present invention provide a greater resistance to crystallization if
`stored for a time above refrigeration temperatures. This therefore permits patients to be
`supplied with sufficient growth hormone to provide daily doses over longer periods of time
`than was hitherto recommendable or desirable. Whereas before, patients might have kept a
`small numb.er of 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 minimal crystallization 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 or at
`
`least 1 month, preferably for at least 7 weeks, more preferably for at 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
`Pharmacopoeia and measured by reversed phase HPLC. The inventors propose a maximum
`. of 20% "related proteins" as a target at the end of the shelf life of the formulations.
`
`The degradation rate of hGH is 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 ab!)Ut 13% per month, and at 40°C
`
`Copy provided by USPTO from the PACR Image Database on 06/02/2003
`
`MYLAN INST. EXHIBIT 1103 PAGE 12
`
`

`

`-8-
`
`Case: G-32575P1/PROV/BCK
`
`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
`'!)Onths storage at 2° - 8°C. Continuous storage at a temperature in the range of about 25° to
`40°C is therefore impractical.
`
`Although the formulations of the present invention 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 shelf life of formulations. -
`
`Rates of "related proteins" formation at different temperatures over time are readily measured
`by one of average skill and ~ith this information the optimisation and maximum storage
`time/temperature patterns may be calculated without undue burden. In practice, formulations
`of the present invention can readily be •subjected to a daily rise in temperature slightly 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
`day or 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 refrigera!ion temperatures, possibly
`up to about a week outside a refrigerator, possibly up to about a month or even longer
`outside a refrigerator.
`
`Accordingly, at least a part of the time that the formulation is stored may be at a storage
`temperature of at least ·a°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 embodiment of the pharmaceutical formulations according to the present
`invention, the concentration of hGH in the formulation is from about 6 mg/ml to about 14
`
`I.
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`Copy provided by USPTO from the PACR Image Database on 06/02/2003
`
`MYLAN INST. EXHIBIT 1103 PAGE 13
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`

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`-9-
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`Case: G-32575P1/PROV/BCK
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`mg/ml. In a particularly preferred embodiment thereof, the concentration of hGH in the
`formulation is about 6.67 mg/ml.
`
`In the development of the present invention it has surprisingly been established that
`1,2-propylene glycol is capable of providing sufficient stability to th_e formulations of the
`present invention which comprise such a high concentration of hGH. Preferably, the
`pharmaceutical formulations of the present invention comprise 1,2-propylene glycol at a
`concentration of from about 0.5 mg/ml to about 20 mg/ml, more preferably from about 5
`mg/ml to about 15 mg/ml, most preferably of from about 6 mg/ml to about 13 mg/ml.
`Preferred embodiments relate to pharmaceutical formulations according to the present
`invention which contain about 9 mg/ml and 12,4 mg/ml 1,2-propylene glycol.
`
`The aqueous buffer present in the pharmaceutical formulation of the present invention can be
`any pharmaceutically acceptable buffer. In a preferred embodiment thereof, 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 thereo( 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 1 O mM (the number 1 O mM referring to the
`concentration of the phosphate ions). Most preferably the aqueous buffer is a sodium
`phosphate buffer having a concentration of about 10 mM. Likewise preferred is a 1 O 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 which is pharmaceutically acceptable. Preferably, the non(cid:173)
`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 surfactant is a poloxamer,
`in particular poloxamer 188. Amounts of the non-ionic surfactant used may be in the range
`from about 0.001% (w/v) to about rn% (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). In a
`preferred embodiment thereof, the non-ionic surfactant is pr~sent at a concentration of from
`
`I
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`~ .
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`Copy provided by USPTO from the PACR lma<1e Datab::J!'lA nn Mll'l?l?nM
`
`MYLAN INST. EXHIBIT 1103 PAGE 14
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`Case: G-32575P1/PROV/BCK
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`about 0.05 mg/ml to about 4 mg/ml, preferably at a concentration of about 2 mg/ml. A
`preferred embodiment of 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.
`
`The preservative present in the pharmaceutical formulation of the present invention can be
`any pharmaceutically acceptable preservative. Preferably, the preservative is selected from
`the group consisting of benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, phenol,
`benzalkonium chloride, benzethonium chloride, chlorobutanol, 2-phenoxyethanol, phenyl
`mercuric nitrate and thimerosal. The concentration of the preservative will be readily available
`to those skilled in the art in agreement with requirements of health authorities regarding the
`safety of multi-dosage formulations. Accordingly, the concentration of the preservative can
`be, for example, from about 1 mg/ml to about 30 mg/ml, depending on the preservative
`actually used. More preferably, the preservative is benzyl alcohol. In a preferred embodiment
`thereof, the pharmaceutical formulation according to the present invention comprises benzyl,
`alcohol as preservative being present at a concentration of from about 7 mg/ml to about 12
`mg/ml, most preferably at a concentration of about 9 mg/ml.
`
`If in the pharmaceutical formulation according to the present inven~(on an additional tonicity(cid:173)
`adjusting agent is present for adjusting the tonicity of the formulation to a desired value from
`about 100 mosm/kg to about 500mosm/kg, such tonicity-adjusting agent can be any
`pharmaceutical acceptable tonicity-adjusting agent. Preferably, such tonicity-adjusting agent
`is selected from the group consisting of a sugar, a sugar alcohol, a further polyol, a neutral
`salt