IN THE UNITED STATES PATENT AND TRADEMARK
`
`In re: Desai et al.
`
`Serial No. 08/340,763
`
`Filed: November 16, 1994
`
`Group Art Unit: 1502
`
`Examiner: S. Howard
`
`For: PRESERVED OPHTHALMIC DRUG COMPOSITIONS
`CONTAINING POLYMERIC QUA TERNARY AMMONIUM
`COMPOUNDS
`
`DECLARATION UNDER 37 CFR §1.132
`
`Honorable Commissioner
`of Patents and Trademarks
`Washington, D.C. 20231
`
`Dear Sir:
`
`I, Suketu D. Desai, Ph.D., hereby say and declare as follows:
`
`I received my B.S. in Pharmacy from the University of Bombay in Bombay,
`I.
`India in 1984, my M.S. in Phannacology from the University of Bombay in 1986, and my
`Ph.D. in Pharmaceutical Sciences from the University of Arizona, Tucson, Arizona, in 1992.
`Since 1992, I have worked in the field of ophthalmic product research and development.
`
`I have been employed by Alcon Laboratories, Inc. since 1992. My current
`2.
`position at Alcon is Sr. Scientist II in the Drug Delivery Group. I am responsible for
`designing, synthesizing, and characterizing ophthalmic formulations, including formulations
`
`that are required to pass compendia preservative efficacy standards.
`
`Metrics EX1024, Page 1
`
`

`
`U.S. Serial No. 081340, 76J
`Filed: November 16, 1994
`
`As a result of my educational and work-related experiences, I am generally
`3.
`knowledgeable in the field ofphannaceutical formulation science, particularly as related to
`ophthalmic formulations.
`
`4.
`
`I am one of the inventors of the subject matter claimed in U.S. Patent
`
`Application Serial No. 08/340,763 filed on November 16, 1994, and understand that this
`
`Application sets forth claims to ophthalmic compositions comprising a therapeutically
`
`effective amount of one or more acidic ophthalmic agents, a preservative-effective amount of
`
`a combination of an antimicrobial polymenc quaternary ammonium compound and boric
`acid, and an ophthalmically acceptable vehicle.
`
`5.
`
`I am familiar with the Office Action dated September 26, 1995, in which
`
`claims l-19 and 25 of the pending application were rejected under 3 5 USC §I 03 as
`unpatentable over Chandrasekaran CWO 89/06964) in combination with Chowhan (U.S.
`Patent No. 5,342,620). I believe that this rejection is based in part on a misunderstanding
`concerning the nature of the invention and the cited art.
`
`6. As part of my responsibilities at Alcon, I have designed, conducted and reviewed
`studies to compare the preservative efficacy ofPolyqua&® (a polymeric quaternary
`ammonium preservative, also known as "polyquatemium 1 ") to that of the following
`conventional ophthalmic preservatives: benzalkonium chloride (a quaternary ammonium
`compound, but not a polymeric quaternary aminonium compound),
`benzyldimethyldodecylammonium bromide (a quaternary ammonium compound, but not a
`polymeric quaternary ammonium compound), sorbic acid, and thimerosal. These studies
`
`evaluated the preservative efficacy of combinations of boric acid and the identified
`
`preservatives in acidic ophthalmic drug formulations. I am f3miliar with the results of these
`
`studies.
`
`2
`
`Metrics EX1024, Page 2
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`

`
`U.S, Serial No. 08/340,763
`Filed: November 16, 1994
`
`7. Briefly, the formulations identified in Table 1 b~low were subjected to a
`
`preservative efficacy screen based on the United States Pharmacopeia and European
`
`Pharmacopeia (Ph.Eur.) preservative efficacy standards for ophthalmic products. These
`
`standards are given in the specification at page 8, lines 5-21. The preservative efficacy screen
`
`involved inoculating the formulations identified in Table 1 to known levels of the gram(cid:173)
`
`positive bacteria, Staphylococcus aureus (S. aureus); the gram-negative bacteria,
`
`Pseudomonas aeruginosa (P. aeruginosa); and the mold, Aspergillus niger, (A. niger). These
`
`inoculated formulations were then sampled at specified intervals of 6 hr, 24 hr, and 7 days to
`
`determine whether the antimicrobial preservative_ system present in the formulation was
`
`capable of killing or inhibiting the growth of organisms purposely introduced into the
`
`formulation. The magnitude of antimicrobial activity of the formulation determined
`
`compliance with the USP and Ph.Eur. preservative efficacy standards for ophthalmic
`
`products. The results of these screening tests are presented in Table 2 below.
`
`Table 1: Formulation Ingwiients
`
`Formulation
`
`A
`
`B
`
`c
`
`D
`
`E
`
`Preservative Benzalkonium
`Chloride
`
`Benzyldlmethyl-
`dodecylammooium
`bromide
`
`Polyquaternium 1
`
`Sorbic Acid
`
`Thimerosal
`
`Composition (o/o w/w)
`
`Sodium
`Diclofenac
`VitaminE
`TPGS
`Preservative
`
`Boric Acid
`
`HPMC
`
`EDTA
`
`Mannitol
`
`·HCI!NaOH
`
`0.1
`
`3
`
`o.oi
`1.2
`
`0.1
`
`0.1
`
`4
`
`0.1
`
`3
`
`0.0125
`
`1.2
`
`0.1
`
`--
`
`I
`
`0.1
`
`4
`
`0.001
`
`1.2
`
`---
`--·
`
`3.5
`
`0.1
`
`3
`
`0.2
`
`1.2
`
`---
`--
`
`1.2
`
`0.1
`
`3
`
`0.005
`
`1.2
`
`--
`
`0.1
`
`3.5
`
`q.s. to pH 7.4
`
`q.s. to pH7.4
`
`q.s. to pH 7.4
`
`q.s. to pH 7.4
`
`q.s. to pH 7.4
`
`q.s. to 100%
`
`q.s.to 100%
`
`Purified
`Water
`..
`V1tamm E TPGS: V1tamm E Tocophcryl Polyethylene Glycol 1000 Succmate
`HPMC: Hydroxypropyl methyl cellulose
`EDT A: cdctic acid or its disodium salt
`
`q.s. to 1000/o
`
`q.s. to 100%
`
`q.s. to 100%
`
`3
`
`Metrics EX1024, Page 3
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`

`
`U.S. Serial No. 08/340,763
`Filed: November 16, 1994
`
`Table 2; Preseaattye Efficacy Results For Fqrmulations ofTabJe 1
`
`FORMULATION
`of Example 1
`A
`(Benzalkonimn chloride)
`B
`(Benzyldimethyldodecyl-
`ammonlwn bromide)
`c
`(Polyquaternium I)
`D
`(Sorbic Acid)
`E
`(Thimerosal)
`
`USP
`
`Fail
`
`Fail
`
`Pass
`
`Fail
`
`Pass
`
`Preservative Efficacy Screen Results
`Ph.Eur.A
`Ph.Eur.B
`
`Fail
`
`Fail
`
`Pass
`
`Fail
`
`Fail
`
`Fail
`
`Fail
`
`Pass
`
`Fail
`
`Fail
`
`8.
`
`The results shown in Table 2 above demonstrate the disparity between the
`
`preservative efficacy of polquaternium I, a polymeric quaternary ammonium antimicrobial
`
`compound, and other, conventional, preservatives of the type disclosed or suggested by the
`
`WO 89/06964 and the Chowhan references. In fact, the results show that, among the
`combinations tested, only the combination ofpolyquaternium l and boric acid was able to
`
`effectively preserve the indicated formulation of an acidic ophthalmic drug such that the
`preservative efficacy standards of the U.S. anq Ph.Eur. were met. (These preservative
`
`efficacy standards are listed in the Specification at p. 8, lines 5- 21.) Moreover, only one of
`the formulations containing conventional ophthalmic preservatives was able to pass even the
`
`U.S. preservative efficacy standards (the formulation containing thimerosal). This disparity
`in results is not suggested by either the WO 89/06964 or the Chowhan references, alone or m
`combination.
`
`4
`
`Metrics EX1024, Page 4
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`

`
`U.S. Serial No. 08/340,763
`Filed: November 16, 1994
`
`I declare further that all statements made herein of my own knowledge are true
`9.
`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 wilful false statements and the like
`
`so made are punishable by fme, imprisonment, or both under Section 1001 of Title 18 of the
`United States Code and that such willful false statements may jeopardize the validity of the
`
`application or any patent issuing therefrom.
`
`Sulcetu D. Desai, Ph.D.
`
`Date: __ ~-+fj-1-/_cr _6 __
`
`Attorney Docket No. J 436
`
`5
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`Metrics EX1024, Page 5
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`P.14/1S
`
`U.S. Social No. 0$1340,763
`'Filed: NDVtlllbet 16, 1994
`
`3.
`
`Declaration. These fonnuiutions
`"Vitllmin E 'rPGS" ingredient li
`an amoUJlt equal to 3% (wlw), whc
`
`e formulations which wcl'l! tested in the original
`presented in 1'able 1 of the odgina.l Oecbuation. The
`in Tllble·l is present in Formulations A, n, 0, and E in
`llS Fonnulation C contains 4% (w/w). Formulations A,
`
`different amounts of the "Ma:nnitof' ingredi,:nt,
`
`ranging from 1 to 4 % (w/w).
`
`4.
`
`Neither the ''Vitamin E TPGS" nor the "Mannitol" ingredients liste<i. in Table
`
`1 are believed to have any sianific
`
`t effect on the preservative efficacy of the resp::c:tive
`
`formuJations. The "Vitamin E TPO " ingredient is a comfort-enhancing agent whicn abo
`
`a.ssisrs in solubilizing the tested acti e, sodium diclofen~~e. The "Mannitol" ingredient is a
`
`tonicity-adjusting a&ICnt of the type mmonly used in ophthalmic preparations to ru~c the:
`
`preparations mateb or nearly match he tonicity of the lac:rimal 'fluid. Neither the discrepancy
`in "Vitamin E TPQS'' concentration nor the discrepancy in "Mannitol" concentrati<m among
`Formulation$ A-E in Table I of the
`
`'gina.! Declaration are believed to effect the Cl.'lnclusion
`
`that is drawn from the data p~n in the original Declaration, namely that, unlike the other
`
`preservatives tested in combination
`
`'th boric: acid, Applicants cornbina.tion of an
`
`antimicrobial polymeric quaternlll)'
`
`onium compound and boric acid is etfecti ve in
`
`5.
`
`I declare furthe'r that 11 stateml.'1lts made herein of my own knowledge are U'Ue
`
`and that all statemenrs made: on info
`
`tion and belief are believed to be true; and further,
`
`that these statements were mlldc: wi
`so made: are punishable by fine, im
`
`the knowledge that wilful false statements anu the like
`'sonmcnt, or both under Section 1001 of Title 18 ofthc
`
`2
`
`Metrics EX1024, Page 7
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`

`
`JUL. 02 '96 03:41PM ALCO~ LEGAL
`
`P.lS/15
`
`U.S. Serial N<>. 081340,763
`Flied: Nc:.vcmber 16, I 994
`
`United States Code and that such wi lful false statetrumts may jeopardize the validity of the
`
`application or any patent issuing the from.
`
`Su.k:etu D. Des!li, Ph.D.
`
`(')'1 (ol.\~6
`Da~:·----~~--~----~
`
`Auorney Docket No. 1436
`
`3
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`Metrics EX1024, Page 8