PETE
`
`P93/Q734g
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Hllflll
`ll
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MYLAN INST. EXHIBIT 1104 PAGE 1
`
`
`
`
`
` :1v....
`
`
`
`EL?)
`mmm
`mas « - Elm-s
`
`E
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`July 16, 2003
`
`RECORDS OF THIS OFFICE OF:
`
`Replacement Filing Receipt
`
`SERIAL NUMBER
`
`60/394,612
`
`PRIORITY DOCUMENT '
`SUBMITTED OR TRANSMITTED IN
`COMPLIANCE WITH
`
`RULE 17.1(a) OR (b)
`
`A
`
`IIl
`
`\
`
`[
`
`July 09, 2002
`
`,.
`
`23
`,m /
`y>
`S
`Hg
`
`By Authority of the
`
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`L
`
`EDELEN
`
`Certifying Officer
`
`FILING DATE
`
`
`
`
`afifilucvlla.yg.n.«iiinu....
`
`\..J.”wumuwmmwhmflfigifirewwnu
`
`
`
`MYLAN INST. EXHIBIT 1104 PAGE 1
`
`
`
`
`
`
`
`

`

`07/16/03 WED 05:55 FAA 'I‘Ué}
`
`JUDHSZZ
`
`le‘l’IU Ult’U
`
`by U U ‘I
`
`Page i of 2
`
`
`UNITEDsummits DEPAR1;MENT orcommence
`k:
`Entrants;atta'elflitntmm’étms.
`we,
`.
`.
`—m—m__mm
`60/394,612
`07/09/2002
`210
`6—32574P1
`
`001095
`NOVARTE‘ CORPORATE INTELLECTUAL PROPERTY
`THOMAS HOXIE
`
`ONE HEALTH PLAZA 430/2
`EAST HANOVER, NJ 07936—1080
`
`CONFIRMATION N0. 4521
`REPLACEMENT FILING RECEIPT
`liliiiiiliiiiiliiillitliililililliiiilllllllllllillllliilllillllllll
`
`
`
`
`,
`
`Date Mailed: 07/16/2003
`
`Receipt is acknowledged of this provisional Patent Application. 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
`USPTO processes the reply to the Notice, the USPTO will generate another Filing Receipt incorporating
`the requested corrections (if appropriate).
`
`ApplicantIs)
`
`Michael Betz, Kundl, AUSTRALIA;
`John Stevens. GB—Surrey, UNITED KINGDOM:
`
`If Required, Foreign Filing License Granted: 09/11/2002
`
`Projected Publication Date: None, application is not eligible for program publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`
`Title
`
`High concentration hGH formulations comprising phenol
`
`WWW"W‘
`
`LICENSE FOR FOREIGN FILING UNDER
`Title 35, United States Code, Section 184
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`MYLAN INST. EXHIBIT 1104 PAGE 2
`
`MYLAN INST. EXHIBIT 1104 PAGE 2
`
`

`

`07/16/03 WED 03:59 FAA 'ius uuoeazz
`
`usnu Uiru
`
`LEIJUUU
`
`Page 2 of 2
`
`nt has been granted a license under 35 U.S.C. 184, if the phrase “IF REQUIRED, FOREIGN FlLlNG
`
`‘ ANTED" followed by a date appears on this form. Such licenses are issued in all applications where
`for issuance of a license haVe been met, regardless of whether or not a license may be required as
`the on
`
`set fort
`CFR 51 5. 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 5.1503). 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 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 ceitain 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 (D); the Office of Foreign Assets Control,
`Department of Treasury (31 CFR Parts 500+) and the Department of Energy.
`
`"h..—
`up: GRANTED
`No license under 35 U.S.C. 184 has been granted at this time. if the phrase "lF REQUlRED, FOREIGN FlLlNG
`LlCENSE 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 from 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 may foreign file the application pursuant to 37 CFR 5.150)).
`
`MYLAN INST. EXHIBIT 1104 PAGE 3
`
`MYLAN INST. EXHIBIT 1104 PAGE 3
`
`

`

`
`
`MYLAN INST. EXHIBIT 1104 PAGE 4
`
`MYLAN INST. EXHIBIT 1104 PAGE 4
`
`

`

`
`
`
`
`,
`
`VA
`.“m
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`123’
`MSW 7
`V
`r_
`
`
`
`
`nunmimummimlluu mnmunn 7‘
`'
`'7 f
`‘7'
`r
`,
`A:
`II
`
`
`
`Ill
`
`
`
`
`
`1.“I
`
`mgmdwmmuflsg rwflsmg meme
`
`
`
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`June 03, 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 NUIVIBER: 60/394,612
`
`FILING DATE: July 09, 2002
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`By Authority of the
`’/V\{:\7L’L
`
`
`LLCOMMISSIONER OF PATENTS AND TRADEMARKS
`
`
`
`:7
`
`M. K. HAW
`
`
`
`
`
`
`
`
`
`
`
`Certifying Officer
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`x
`\Immlml
`Imuuu
`
`
`
`MYLAN INST. EXHIBIT 1104 PAGE 5
`
`MYLAN INST. EXHIBIT 1104 PAGE 5
`
`

`

`r Il
`
`
`
`30/00/30'-lllllllllllllllllllllllllllllllllllll
`
`Old'S'nasorL
`
`CD I "l D " 0 L
`
`333:3 :333: 0.3“: mamafijA h) m]
`
`lIII/000000000I0000
`
`EV 090859869 US
`Express Mail Label Number
`
`July 9, 2002
`Date of Deposit
`
`FILING BY “EXPRESS MAIL" UNDER 37 CFR 1.10
`
`Address to: Assistant Commissioner for Patents
`Box Provisional Patent Application
`Washington, DC 20231
`
`7
`
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`
`Transmitted herewith for filing under 37 CFR §1.53(c) Is the PROVISIONAL APPLICATION for patent of
`
`Given Name (first and middle [if any])
`
`Family Name or Surname
`
`Residence (City and either State or Foreign Country)
`
`TITLE OF THE INVENTION (280 characters max)
`
`°
`
`‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HIGH CONCENTRATION hGH FORMULATIONS COMPRISING PHENOL
`
`
`CORRESPONDENCE ADDRESS
`.
`Direct all correspondence to the address associated with Customer No. 001095. which is currently:
`Thomas Hoxie
`Novartls Corporation
`Patent and Trademark Dept.
`564 Morris Avenue
`Summit, NJ 07901-1027
`
`IQ
`
`
`
`
`
`
`
`of Novartis Corporation.
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`>11
`Specification (Including Any Claims and Abstract) - 20 pages
`El
`Drawlngs -
`sheets
`1:] Other (specify):
`METHOD OF PAYMENT
`
`The Commissioner is hereby authorized to charge filing fee and any
`additional fees required to Deposit Account Number: 19-0134 in the name
`
`PROVISIONAL FILING FEE AMOUNT: $'160
`
`(it the invention was made by an agency of the United States Government
`El U.S. Government agency and contract number:
`or under a contract with an agency of the United States Government.)
`
`Date: July 9, 2002
`
`Respectfully submitted.
`
`MM 20?).
`
`D ane E. Furman
`Attorney for Applicant
`Reg. No. 31,104
`Tel. No. (908) 522-6924
`
` Copy provided by USPTO from the PACR Image Database on 05/30/2003
`
`MYLAN INST. EXHIBIT 1104 PAGE 6
`
`MYLAN INST. EXHIBIT 1104 PAGE 6
`
`

`

`r“; .a—mzr'u “-
`n“ “111
`13 “"u
`.11 .a'
`.1‘1' ”“4;.x “‘1sin“;
`Esau..."'1 113333-31up .1;. t::.«. .311 513.111.31.12?
`
`- 1 _
`
`Case G-32574P1/PROV/BCK
`
`High concentration hGH formulations comprising phenol
`
`The present invention relates to 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 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 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.
`
`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 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 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 dwariism 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 prepared 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
`hypopituitary 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
`
`
`
`
`
`("nnv nrovidpd bv USPTO from the PACR lmaM? Database on 05/30/2003
`LAN INST. EXHIBIT 1104 PAGE 7
`
`MYLAN INST. EXHIBIT 1104 PAGE 7
`
`

`

`,w ,._ .....
`-
`a...
`-._
`w, ”my. _.,. _,.
`wuflfimbiflmbfflwfifl
`
`- 2 -
`
`Case G—32574P1lPROV/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,
`hGH 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 lyophilised product needed reconstitution
`immediately or shortly prior to administration.
`In the circumstances of routine self—
`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-
`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
`I
`
` Database on 05/30/2003
`
`Conv provided bv USPTO from the PACE Ma?
`LAN INST. EXHIBIT 1104 PAGE 8
`
`MYLAN INST. EXHIBIT 1104 PAGE 8
`
`

`

`'1]
`
`.5“ 1:”:‘ “72.331311 as! m m;
`11:3 -!LJ‘I _...II AJI'"“!x‘i.‘31 ".53.. fix:
`
`.....
`“.2, “HT.“ 11"" _
`‘ijuji
`r-
`I‘m“ ”if: and; 11:3
`
`a,
`
`Case G-32574P1lPROV/BCK
`
`enable a pharmaceutically acceptable formulation to be made. Furthermore, pharmaceutical
`
`regulatory requirements dictate that any unnecessary additives l 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-
`
`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 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 volume of less than 500 pl 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 Image Database on 05/30/2003
`MYLAN INST. EXHIBIT 1104 PAGE 9
`
`
`
`MYLAN INST. EXHIBIT 1104 PAGE 9
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case G-32574P1IPROVIBCK
`
`deliver the required amount of hGH to such patients with a single injection 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
`
`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 stable 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 described 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.
`
`
`
`
`
`
`
`Database on 05/30/2003
`Copy provided by USPTO from the PACR lmMWAN INST. EXHIBIT 1104 PAGE 10
`
`MYLAN INST. EXHIBIT 1104 PAGE 10
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.0...
`,n-
`1...: new: m It 3!
`r
`5.1: its! “:3- w u- in .1”- u;'.'.
`
`.m,
`m
`. a...
`::. ‘13:?! 45931:} 11$ 313.! .1?"
`
`Case G-32574P1/PROV/BCK
`
`In the context of the present invention, it has been developed that the preservative to be used
`
`in such a multi-dosage liquid formulation containing a high concentration of hGH is 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 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 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.
`
`In the context of the present invention, a liquid pharmaceutical formulation is a formulation
`
`provided in a ready-to-use form, is. 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, phenol. an aqueous buffer, a non—ionic surfactant,
`
`said pharmaceutical formulation having a tonicity of from about 100 mosm/kg to about 500
`
`mosmlkg, having a pH of from about 6.1 to about 6.3, and being substantially free of an
`
`amino acid excipient.
`
`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
`
`mosmlkg. 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 mglml to about 100 mg/ml, phenol, an
`aqueous buffer, a non-ionic surfactant, said pharmaceutical formulation having a tonicity of
`
`from about 100 mosm/kg to about 500 mosmlkg, having a pH of from about 6.1 to about 6.3,
`
`
`
`
`
`
`Copy provided by USPTO from the PACRfim e Database on 05/30/2003
`LAN INST. EXHIBIT 1104 PAGE 11
`
`MYLAN INST. EXHIBIT 1104 PAGE 11
`
`

`

`.. ‘5“:133; .m‘ 4) ~.
`.t
`‘
`4n-
`*-,-‘-nr-.1““..'«‘"-_“1IZZ‘.‘JL.\F.
`
`"“
`.
`11““ “'1'“
`u.- ztj A" tj'ffilfllw-t'
`
`'
`
`Case G-32574P1IPROVIBCK
`
`and being substantially free of an amino acid excipient. said pharmaceutical formulation
`
`additionally comprising a tonicity-adjusting agent such that the tonicity of the pharmaceutical
`composition is from about 100 mosm/kg to about 500 mosm/kg.
`
`'l
`
`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 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, eg. 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.
`
`In the context of the present invention. the term "substantially free of an amino acid excipient"
`
`means that 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 contained in the pharmaceutical
`
`formulation according to the invention, as long as they do not influence the technological
`
`pharmaceutical behaviour of the formulation.
`
`,_
`
`In a preferred embodiment, the pharmaceutical formulations according to the present
`
`invention are free of an amino acid excipient.
`
`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
`
`f
`"
`
`;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Copy provided by USPTO from the PACR Image Database on 05/30/2003
`MYLAN INST. EXHIBIT 1104 PAGE 12
`
`MYLAN INST. EXHIBIT 1104 PAGE 12
`
`

`

`
`
`- 7 _
`
`Case G—32574P1/PROV/BCK
`
`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’
`
`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 be 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 greater than 8°C, is. 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 number 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
`
`Copy provided by USPTO from the PACE lma e Database on 05/30/2003
`M LAN INST. EXHIBIT 1104 PAGE 13
`
`MYLAN INST. EXHIBIT 1104 PAGE 13
`
`

`

`
`
`
`
`
`
`_...
`w,
`.1 a...
`‘ _.,. A, M
`"1:...“ ant?“ 5.2.11...) " 31‘253‘3 1.235
`
`Case G-32574P1/PROV/BCK
`
`Pharmacopoiea 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 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°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 with 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 (eg. 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 outside a refrigerator, possibly up to about a month or even longer
`
`outside a refrigerator.
`
`
`
`
`
`Copy provided by USPTO from the PACE image Database on 05/30/2003
`MYLAN INST. EXHIBIT 1104 PAGE 14
`
`
`
`MYLAN INST. EXHIBIT 1104 PAGE 14
`
`

`

`
`
`.
`:3 {it
`
`m at,
`..
`,
`,
`«1 M5. 4;: "".!"1£il.5l..1-1‘..‘..
`
`,- .2 m,
`"2,...
`.._'-t :9" it} 33:3 at 11.5“,
`
`.2:
`
`Case G-32574P1/PROV/BCK
`
`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 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
`
`mglml. In a particularly preferred embodiment thereof, the concentration of hGH in the
`
`formulation is about 6.67 mglml.
`
`In the development of the present invention it hassurprisingly 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 mglml to about 5 mglml, more preferably from about 2mg/ml to about 3 mglml,
`
`most preferably of about 2.5 mglml. in particular 2.5 mglml.
`
`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 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 aqueous buffer is 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 which is 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 surfactant is a poloxamer,
`
`Copy provided by USPTO from the PACR Image Database on 05/30/2003
`MYLAN INST. EXHIBIT 1104 PAGE 15
`
`MYLAN INST. EXHIBIT 1104 PAGE 15
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3‘11)!” .m‘
`.u...
`.,,
`
`41 "fl.
`.2.
`.
`
`'
`
`1.11“" I‘M—31
`«21.1: 21.31114!“3:1
`
`-10-
`
`Case G-32574P1/PROV/BCK
`
`in particular poloxamer 188. Amounts of the non-ionic surfactant used may be in the range
`
`from about 0.001% (w/v) to about 10% (wlv), more preferably from about 0.005% (wlv) to
`
`about 5% (wlv), even more preferably from about 0.01% (wlv) to about 1% (wlv). In a
`
`preferred embodiment thereof, the non-ionic surfactant is 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 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