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`

`PTO/SB/14 (07-07)
`Approved for use through 06/30/2010. OMB 0651-0032
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`Application Data Sheet 37 CFR 1.76
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`3205US
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`Title of Invention
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`SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
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`r
`lPPIICan t I f
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`Applicant 1
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`Prefix Given Name
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`

`PTO/SB/14 (07-07)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`Application Data Sheet 37 CFR 1.76
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`3205US
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`
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`SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
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`gregg.brown@alconlabs.com
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`Attorney Docket Number 3205US
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`SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
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`PTO/SB/14 (07-07)
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`26356
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`I 0 US Patent Practitioner IO Limited Recognition (37 CFR 11.9)
`
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`This section allows for the applicant to either claim benefit under 35 U.S.C. 119(e), 120, 121, or 365(c) or indicate National Stage
`entry from a PCT application. Providing this information in the application data sheet constitutes the specific reference required by
`35 U.S.C. 119(e) or 120, and 37 CFR 1.78(a)(2) or CFR 1.78(a)(4), and need not otherwise be made part of the specification.
`I Remove I
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`PTO/SB/14 (07-07)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`Application Data Sheet 37 CFR 1.76
`
`Attorney Docket Number
`
`3205US
`
`Application Number
`
`Title of Invention
`
`SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
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`of the CFR to have an assignment recorded in the Office.
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`TB4-8
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`Fort Worth
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`
`76134
`
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`gregg.brown@alconlabs.com
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`
`Signature
`
`/Gregg C. Brown, Reg. 30,613/
`
`Date (YYYY-MM-DD) 2007-09-20
`
`First Name Gregg C.
`
`I Last Name
`
`I Brown
`
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`
`30613
`
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`

`DECLARATION AND POWER OF ATTORNEY
`
`As a below named inventor, I hereby declare that:
`
`My residence, post office address and citizenship are as stated below next to my name.
`
`I believe I am the original, first and joint inventor of the subject matter which is claimed
`and for which a patent is sought on the invention entitled:
`
`SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`described and claimed herewith and further identified as Attorney Docket No. 3205 US the
`specification of which (check one)
`
`( X )
`
`is attached hereto.
`
`(
`
`)
`
`was filed by an authorized person on my behalf on _____ , as
`Application Serial No. ______ and was amended on ___ (if
`applicable)
`
`I hereby state that I have reviewed and understand the contents of the above-identified
`specification, including the claims as amended by any amendment referred to above.
`
`I acknowledge the duty to disclose information which is known to me to be material to
`the patentability of this application in accordance with Title 37, Code of Federal Regulations,
`Section 1.56.
`
`I hereby claim foreign priority benefits under Title 35, United States Code, Section
`119(a)-(d) or Section 365(b) of any foreign application(s) for patent or inventor's certificate, or
`Section 365(a) of any PCT international application which designated at least one country other
`than the United States, listed below and have also identified below any foreign application for
`patent or inventor's certificate having a filing date before that of the application on which
`priority is claimed:
`
`7
`
`

`

`Prior Foreign Application(s):
`
`Application Number
`
`Country
`
`Filed
`(Month!Day/Y ear)
`
`Priority Claimed
`
`Yes
`
`No
`
`I hereby claim the benefit under 35 USC §119(e) of any United States provisional
`application(s) listed below.
`
`Prior Provisional Application(s):
`
`Application Number
`
`Filed
`(Month/Day/Year)
`
`Priority Claimed
`
`Yes
`
`No
`
`60/827,411
`
`60/826,529
`
`09/28/06
`
`09/21/06
`
`X
`
`X
`
`I hereby claim the benefit under Title 35, United States Code, Section 120 of any United
`States application(s), or Section 365(c) of any PCT international application designating the
`United States, listed below and, insofar as the subject matter of each of the claims of this
`application is not disclosed in the prior United States or PCT international application in the
`manner provided by the first paragraph of Title 35, United States Code, Section 112.
`I
`acknowledge the duty to disclose material information as defined in Title 37, Code of Federal
`Regulations, Section 1.56 which occurred between the filing date ofthe prior application and the
`national or PCT international filing date of this application:
`
`Prior U.S. Application(s):
`
`Application Number
`
`Filed
`(Month/Day/Year)
`
`Status: Patent,
`Pending, Abandoned
`
`I hereby declare that all statements made herein of my own knowledge are true and that
`all statements made on information and belief are believed to be true; and further that these
`statements were made with the knowledge that willful false statements and the like so made are
`punishable by fine or imprisonment, or both, under Section 1001 ofTitle 18 ofthe United States
`Code and that such willful false statements may jeopardize the validity of the application or any
`patent issued thereon.
`
`-2-
`
`8
`
`

`

`I hereby appoint those patent practitioners associated with Customer No. 26356 as my
`attorneys, with full power of substitution and revocation, to prosecute this application and to
`transact all business in the United States Patent and Trademark Office connected therewith.
`
`Full name of joint inventor:
`
`BHAGWATI P. KABRA
`
`Post Office/Residence Address:
`
`2205 Eagles Nest Drive
`Euless, Texas 76039
`
`Inventor's signature:
`
`Date:
`
`Citizenship:
`
`us
`
`Full name of joint inventor:
`
`MASOOD A. CHOWHAN
`
`Post Office/Residence Address:
`
`3521 Lake Tahoe Drive
`Arlington, Texas 76016
`
`Inventor's signature:
`
`Date:
`
`Citizenship:
`
`us
`
`-3-
`
`9
`
`

`

`Full name of joint inventor:
`
`L. WAYNE SCHNEIDER
`
`Post Office/Residence Address:
`
`10308 Lisa Jean Drive
`Crowley, Texas 76036
`
`Inventor's signature:
`
`Date:
`
`Citizenship:
`
`us
`
`Full name of joint inventor:
`
`WESLEY WEHSIN HAN
`
`Post Office/Residence Address:
`
`2400 Winding Hollow Lane
`Arlington, Texas 76006
`
`Inventor's signature:
`
`Date:
`
`Citizenship:
`
`Address for Correspondence:
`
`Gregg C. Brown
`Alcon Research, Ltd.
`IP Legal (TB4-8)
`6201 South Freeway
`Fort Worth, Texas 76134-2099
`(817) 551-8663
`
`Docket No, 3205 US
`
`us
`
`-4-
`
`10
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`SELF-PRESERVED AQUEOUS PHARMACEUTICAL COlVIPOSITIONS
`
`Cross-Reference to Related Applications
`
`5
`
`The present application claims priority based on U.S. Provisional Patent
`
`Application Serial Nos. 60/827,411 filed September 28, 2006, and 60/826,529, filed
`
`Septem_ber 21, 2006.
`
`w
`
`Background of the Invention
`
`self-preserved pharmaceutical
`to
`1s directed
`invention
`The present
`compositions. More specifically, the invention is directed to the provision of aqueous,
`multi-dose pharmaceutical compositions that have been formulated so as to have
`sufficient antimicrobial activity to satisfy the preservation efficacy requirements of the
`United States Pharmacopeia ("USP") and analogous guidelines in other countries,
`without requiring a conventional antim_icrobial preservative, such as benzalkonium
`chloride, polyquaternium-1, hydrogen peroxide (e.g., sodium perborate), or chorine(cid:173)
`containing agents. The ability to achieve self-preservation is based on a unique
`combination of formulation components and criteria.
`
`Many pharmaceutical cmnpositions are required to be sterile (i.e., free of
`bacteria,
`fungi and other pathogenic microorganisms).
`Examples of such
`compositions include: solutions and suspensions that are injected into the bodies of
`humans or other mammals; creams, lotions, solutions or other preparations that are
`topically applied to wounds, abrasions, burns, rashes, surgical incisions, or other
`conditions where the skin is not intact; and various types of compositions that are
`applied either directly to the eye (e.g., artificial tears, irrigating solutions, and drug
`products), or are applied to devices that will come into contact with the eye (e.g.,
`contact lenses).
`
`The foregoing types of compositions can be 1nanufactured under sterile
`conditions via procedures that are well known to those skilled in the art. However,
`once the packaging for a product is opened, such that the composition contained
`therein is exposed to the atmosphere and other sources of potential microbial
`contamination (e.g., the hands of a human patient), the sterility of the product may be
`
`15
`
`20
`
`25
`
`3o
`
`35
`
`11
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`compromised. Such products are typically utilized multiple times by the patient, and
`are therefore frequently referred to as being of a "multi-dose" nature.
`
`Due to the frequent, repeated exposure of multi-dose products to the risk of
`5 microbial contamination, it is necessary to employ a means for preventing such
`contamination from occurring. The means employed may be: (i) a chemical agent that
`prevents the proliferation of n1icrobes in a composition, which is referred to herein as
`an "antimicrobial preservative"; or (ii) a packaging system that prevents or reduces the
`risk of microbes reaching a pharmaceutical composition within a container.
`
`10
`
`15
`
`20
`
`25
`
`3o
`
`35
`
`Prior multi-dose ophthalmic compositions have generally contained one or
`more antimicrobial preservatives in order to prevent the proliferation of bacteria, fungi
`and other microbes. Such compositions may come into contact with the cornea either
`directly or indirectly. The cornea is particularly sensitive to exogenous chemical
`agents. Consequently, in order to minimize the potential for harmful effects on the
`cornea, it is preferable to use anti-microbial preservatives that are relatively non-toxic
`to the cornea, and to use such preservatives at the lowest possible concentrations (i.e.,
`the minimum amounts required in order to perform their anti-microbial functions).
`
`Balancing the anti-microbial efficacy and potential toxicological effects of anti-
`microbial preservatives is sometimes difficult to achieve. More specifically, the
`concentration of an antimicrobial agent necessary for the preservation of ophthaln1ic
`formulations from microbial contamination may create the potential for toxicological
`effects on the cornea and/or other ophthalmic tissues. Using lower concentrations of
`the anti-microbial agents generally helps to reduce the potential for such toxicological
`effects, but the lower concentrations may be insufficient to achieve the required level
`of biocidal efficacy (i.e., antimicrobial preservation).
`
`The use of an inadequate level of antimicrobial preservation may create the
`potential for microbial contamination of the compositions and ophthalmic infections
`resulting from such contaminations. This is also a serious problem, since ophthalmic
`infections involving Pseudomonas aeruginosa or other virulent microorganisms can
`lead to loss of visual function or even loss of the eye.
`
`Thus, there is a need for a n1eans of enhancing the activity of anti-microbial
`agents so that very low concentrations of the agents can be utilized without increasing
`the potential for toxicological effects or subjecting patients to unacceptable risks of
`microbial contamination and resulting ophthalmic infections.
`
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`12
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`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`isotonic, buffered
`Ophthalmic compositions are generally formulated as
`solutions. One approach to enhancing the anti-microbial activity of such cmnpositions
`is to include multi-functional components in the compositions.
`In addition to
`performing their primary functions, these multi-functional components also serve to
`enhance the overall anti-microbial activity of the compositions.
`
`The following publications may be referred to for further background regarding
`the use of multi-functional components to enhance the antimicrobial activity of
`ophthalmic compositions:
`
`1.
`2.
`3.
`
`4.
`5.
`
`6.
`7.
`
`U.S. Patent No. 5,817,277 (Mowrey-McKee, et al; tromethan1ine);
`U.S. Patent No. 6,503,497 (Chowhan, et al.; borate/polyol complexes);
`U.S. Patent No. 5,741,817 (Chowhan, et al.; low molecular weight amino acids
`such as glycine);
`U.S. Patent No. 6,319,464 (Asgharian; low molecular weight amino alcohols);
`U.S. Patent Application Publication No. US 2002/0122831 A1 (Mowrey(cid:173)
`McKee, et al.; bis-aminopolyols );
`U.S. Patent No. 6,348,190 (Illes, et al.; zinc); and
`JP 2003-104870 (zinc).
`
`The use of zinc to enhance the antimicrobial activity of pharmaceutical
`compositions, including ophthaln1ic solutions, is well known. See, for example, the
`following articles and patent publications, as well as U.S. Patent No. 6,348,190 and JP
`2003-104870, cited above:
`
`McCarthy, "Metal Ions and Microbial Inhibitors", Cosmetic & Toiletries, 100:69-72
`(Feb. 1985);
`
`Zeelie, et al., "The Effects of Selected Metal Salts on the Microbial Activities of
`Agents used in the Pharmaceutical and Related Industries", Metal Compounds m
`Environment and Life, 4:193-200 (1992);
`
`Zeelie, et al., "Effects of Copper and Zinc Ions on the Germicidal Properties of Two
`Popular Pharmaceutical Antiseptic Agents, Cetylpyridinium Chloride and Povidone(cid:173)
`iodine", Analyst, 123:503-507 (March 1998);
`
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`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`McCarthy, et al., "The Effect of Zinc Ions on the Antimicrobial Activity of Selected
`Preservatives", Journal ofPharmacy and Pharmacology, Vol. 41 (1989);
`
`U.S. Patent No. 6,482,799 (Tuse, et al.);
`
`5
`
`U.S. Patent No. 5,320,843 (Raheja, et al.);
`
`U.S. Patent No. 5,221,664 (Berkowitz, et al.);
`
`10 U.S. Patent No. 6,034,043 (Fujiwara, et al.);
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`20
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`25
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`30
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`35
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`U.S. Patent No. 4,522,806 (Muhlemann, et al.);
`
`U.S. Patent No. 6,017,861 (Fujiwara, et al.); and
`
`U.S. Patent No. 6,121,315 (Nair, et al.).
`
`The present invention is directed to the provision of improved preservative systems
`containing zinc ions.
`
`The compositions of the present invention are multi-dose products that do not
`require a conventional antimicrobial preservative (e.g., benzalkonium chloride), and
`yet are preserved from microbial contamination. Such compositions have been
`referred to in the art as being "preservative free" (see, e.g., U.S. Patent No. 5,597,559
`issued to Olejnik, et al.).
`Compositions that are preserved from microbial
`contamination as a result of the inherent antimicrobial activity of one or more
`components of the compositions are also referred to in the art as being "self(cid:173)
`preserved" (see, e.g., U.S. Patent No. 6,492,361 issued to Muller, et al.).
`
`The following publication may be referred to for further background regarding
`pharmaceutical compositions that are "preservative-free" or "self-preserving": Kabara,
`et al., Preservative-Free and Self-Preserving Cosmetics and Drugs - Principles and
`Practice, Chapter 1, pages 1-14, Marcel Dekker, Inc. (1997).
`
`The multi-dose compositions of the present invention, which do not contain a
`conventional anti1nicrobial preservative, are referred to herein as being "self(cid:173)
`preserved".
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`Docket No. 3205 US
`
`Summary of the Invention
`
`Filed Electronically
`September 20, 2007
`
`5
`
`The present invention is directed to the self-preservation of aqueous ophthalmic
`compositions via the use of very low concentration of zinc ions. The present
`invention is based in part on the finding that in order to utilize low concentrations of
`zinc ions to self-preserve multi-dose ophthalmic compositions having ophthalmically
`acceptable pH and osmolality values, certain fonnulation parameters must be
`maintained. Specifically, the concentration of buffering anions utilized to maintain
`the pH within an ophthalmically acceptable range must be limited to an amount of 15
`10 millimolar ("mM") or less in order to avoid interfering with the anti-microbial activity
`of the zinc ions.
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`In addition, it has been determined that the antimicrobial activity of the zinc(cid:173)
`containing compositions of the present invention can be further enhanced by the use
`of zinc ions in combination with borate or a borate/polyol complex, and that if such a
`combination is utilized, the use of propylene glycol is strongly preferred, so as to
`avoid ionic interactions between anionic species generated by other polyols (e.g.,
`sorbitol) and the zinc cations.
`
`It has also been determined that the performance of the zinc-based preservative
`systems of the present invention is further enhanced by: (i) limiting the amount of
`multivalent metal cations other than zinc (e.g., calcium and magnesium) in the
`compositions of the present invention; and (ii) limiting the amount of ionized salts
`(e.g., sodium chloride and potassium chloride) in said compositions. As described in
`greater detail below, the compositions of the present invention are preferably free of
`or substantially free of both ionized salts and multivalent metal cations other than
`zmc.
`
`The self-preserved, multi-dose compositions of the present invention have
`several advantages over existing ophthalmic fonnulations that are either: (i) packaged
`as a "single dose" or "unit of use" product, so as to avoid the inclusion of any
`antimicrobial preservative (e.g., BION®TEARS Lubricant Eye Drops, which is
`marketed by Alcon Laboratories, Inc.), or (ii) preserved by means of a so-called
`"disappearing" preservatives, such as the chlorite-based system described in U.S.
`Patent Nos. 5,424,078; 5,736,165; 6,024,954; and 5,858,346 (e.g., the artificial tears
`product "REFRESH™ Tears", which is marketed by Allergan), or the peroxide(cid:173)
`containing system described in U.S. Patent Nos. 5,607,698; 5,683,993; 5,725,887; and
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`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`5,858,996 (e.g., the artificial tear product "GenTeal™ Tears", which is marketed by
`CIBA Vision).
`
`Unlike these existing products, the multi-dose ophthalmic compositions of the
`present invention are able to satisfy the USP preservative efficacy requirements, as
`well as analogous
`requirements
`in other countries,
`including
`the Japanese
`Pharmacopoeia ("JP") and European Pharmacopoeia (''EP") preservative efficacy
`standards, without employing any conventional antimicrobial preservatives, such as
`chlorite or hydrogen peroxide.
`
`The above-discussed findings regarding the zinc may be applied to enhance the
`antimicrobial activity of various types of pham1aceutical compositions. However, the
`present invention is particularly directed to the provision of aqueous ophthalmic
`solutions that are effective in preventing microbial contamination in the absence of
`conventional antimicrobial preservatives, such as benzalkonium chloride ("BAC"),
`polyquaternium-1, chlorite or hydrogen peroxide.
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`Brief Description of the Drawings
`
`20
`
`Figures 1-3 are graphs showing the interaction of boric acid and vanous
`polyols.
`
`Detailed Description of the Invention
`
`25
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`3o
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`The pharmaceutical con1positions of the present invention contain zinc ions at a
`concentration of 0.04 to 0.9 millimoles/liter ("mM"), preferably 0.04 to 0.4 mM and
`most preferably 0.1 to 0.4 mM. The use of this very low concentration is particularly
`desirable in ophthalmic pharmaceutical compositions containing therapeutically active
`agents, such as prostaglandin analogues used t