REMARKS
`
`The present application is a divisional application of Serial No. 13/353,653.
`
`Original claims 1-18 are canceled without prejudice and new claims 19-48 are added.
`
`I.
`
`SUPPORT FOR NEW CLAIMS
`
`New claims 19-48 are supported by the original specification and claims.
`
`New claim 19 is supported by original claims 1 and 3; page 7lines 14-15 and lines 26-28;
`
`page 8 lines 16-18; and Experimental Example 1.
`
`New claim 20 is supported by the paragraph bridging pages 3-4.
`
`New claim 21 is supported by page 8lines 6-10.
`
`New claims 22-23 are supported by page 11 lines 1-6; and page 8 lines 19-26.
`
`New claim 24 is supported by page 6lines 8-10.
`
`New claim 25 is supported by the compositions of Tables 1 and 2 and page 12line 23.
`
`Note that sodium tetraborate is known as borax and EDT A sodium salt is known as sodium
`
`edetate.
`
`New claim 26 is supported as noted above and further supported by Table 2 on page 17 to
`
`page 18line 7.
`
`New claim 27 is supported as noted above.
`
`New claim 28 is supported as noted above and further supported by Table 2.
`
`News claims 29-31 are supported as noted above.
`
`New claim 32 is supported as noted above and further supported by page 12line 14.
`
`New claims 33-43 are supported as noted above.
`
`New claims 44-48 are supported by Experimental Example 3 on pages 18-22 of the
`
`specification.
`
`II.
`
`THE SUBJECT MATTER OF NEW CLAIMS 19-48 IS PATENT ABLE
`
`Applicant respectfully submits that the subject matter of new claims 19-48 is patentable
`
`over the prior art, particularly U.S. Patent No. 5,603,929 to Desai et al. ("Desai").
`
`As an initial matter, Applicant notes that amendments and/or arguments made in the
`
`parent applications of the present case to distinguish the prior art do not carry forward and should
`
`8
`
`

`
`not apply to the claims in this application. 1 See, Hakim v. Cannon Avent Gp., plc, 479 F.3d 1313
`
`(Fed. Cir. 2007) (permitting rescission of disclaimer and recapture of disclaimed scope so long as
`
`that rescission is made clear on the record). The present claims are different and do not, for
`
`example, recite the limitation that "when a quaternary ammonium compound is included in said
`
`liquid preparation, the quaternary ammonium compound is limited to benzalkonium chloride."
`
`Desai does not disclose the currently claimed composition, with the ingredients
`
`combined as recited in the claims. Indeed, one skilled in the art would have interpreted Desai, at
`
`a time before applicant's invention, as disclosing a narrow and specific composition that differs
`
`significantly from that currently claimed by Applicant.
`
`Desai's objective is to provide a preservative system, the efficacy of which is not
`
`degraded or reduced in the presence of an acidic drug (such as diclofenac) that is incompatible
`
`with positively charged preservatives. (Desai, column 1, lines 27-34, and column 2, lines 10-14.)
`
`Desai stated that its objective was achieved by combining a polymeric quaternary ammonium
`
`compound (also known as "polyquat") and boric acid. (Desai, column 2, lines 18-22.) The
`
`specification of the Desai patent presented preservative efficacy data for only one formulation
`
`(Formulation A). But in addition to a polyquat and boric acid, Formulation A also contained
`
`mannitol. (Desai, Example 1, cplumn 4, lines 15-33.) During prosecution, Desai submitted a
`
`declaration providing comparative data to show that only the formulation having polyquat-1,
`
`though it also contained boric acid and mannitol, satisfied the preservative efficacy criteria,
`
`whereas formulations having benzalkonium chloride or benzothenium bromide did not. (Desai's
`
`Declaration dated 2/26/1996, Table 2, a copy of which is attached hereto) Desai made a
`
`statement regarding the role of mannitol in his compositions, contending it did not have any
`
`significant effect on preservative efficacy. (Desai's Supplemental Declaration, dated 7/2/1996, a
`
`copy of which is attached hereto) Those skilled in the art, however, would have had a much
`
`different understanding of Desai's disclosure and the role of mannitol prior to the time of the
`
`present invention.
`
`That Desai's formulation satisfies the preservative efficacy was not due solely to
`
`polyquat-1 and boric acid, but to the combination ofpolyquat-1, boric acid, and mannitol. It had
`
`The parent applications are Serial No. 13/353,653, filed January 19,2012, and Serial No. 10/525,006, filed
`March 28, 2005, now issued as U.S. Patent No. 8,129,431.
`
`9
`
`

`
`been known even before Desai2 that borate/polyol complexes worked as preservative systems.
`See, e.g., U.S. Patent No. 5,342,620 to Chowhan, cited by the examiner of the Desai's patent.
`
`Borate/polyol co,mplexes enhance the preservative efficacy of a weak preservative, or a
`
`preservative amount; that otherwise would not satisfy the preservative efficacy standards.
`
`(Chowhan '620, column 1, line 67 to column 2, line 7.) Reading the Desai patent with the
`
`knowledge available in the art before Applicant's invention, the skilled artisan would have
`
`recognized that the borate/polyol complex, as a whole, contributed to increase the preservative
`
`efficacy of polyquat-1-not just boric acid.
`
`Indeed, at the time Desai filed his application for patent, it was already known that
`
`mannitol acted to enhance the preservative efficacy of a weak preservative. For example, U.S.
`
`Patent No. 5,505,953 issued to Chowhan ("Chowhan '953") provided a comparison of the
`
`preservative efficacy of formulations with and without mannitol. (Chowhan '953, column 9, line
`
`15 to column 10, line 26.) The formulations without mannitol failed to meet the British
`
`Pharmacopeia (1988) standards. (Chowhan '953, column 9, lines 44-48, and column 10, lines
`
`21-25.) To the best of Applicant's knowledge, the preservative efficacy acceptance criteria of
`
`British Pharmacopeia and European Pharmacopeia are similar. Therefore, Chowhan '620 and
`
`Chowhan '953 showed that, without mannitol, Desai's objective of meeting the preservative
`
`efficacy standard of both US Pharmacopeia XXII and European Pharmacopeia would not have
`
`been achieved.
`
`Applicant has experimental results that corroborate what those skilled in the art already
`
`knew at the time of Desai and certainly before Applicant's invention: 1) that without mannitol,
`
`Desai's combination of only polyquat-1, at a concentration typically used in ophthalmic
`
`formulations, and boric acid does not satisfy preservative efficacy criteria, even for the US
`
`Pharmacopeia, and 2) that the Desai patent would have been interpreted as requiring the presence
`
`of mannitol in addition to boric acid to achieve the touted preservative efficacy.
`
`In this regard, Applicant presents Tables 1 and 2. Table 1 provides the compositional
`
`details of six diclofenac formulations, some of which contain mannitol with polyquat-1 and boric
`
`acid, and some ofwhich do not contain mannitol. Table 2 provides the preservative efficacy of
`
`the preservative in each formulation in Table 1.
`
`2
`
`2003.
`
`Desai published in February 1997, well before the present application's Japanese priority filing in January
`
`10
`
`

`
`In Table 1, DBP-1 corresponds closely to Desai's Formulations Band C. It also contains
`
`3.5%w/v of mannitol, whereas Formulation B of Desai contains 1.6 %w/v of mannitol. The
`
`0.005% w/v ofpolyquat-1 used in Desai's Formulations Band C, as well as in DBP-1, is a
`
`typical concentration for this preservative. Desai's Formulation A, on the other hand, has a
`
`much higher concentration-4% polyquat-1, a level not typically used in commercial ophthalmic
`
`products. Conducting the experiments, therefore, at 0.005% polyquat-1 more' effectively shows
`
`the importance of mannitol in achieving Desai's stated purpose.
`
`f)BP-2 is the same as DBP-1, except it had a pH of7.8 to discern any effect of pH.
`
`· DBP-3 and DBP-4 correspond to DBP-1 and DBP-2, respectively, without mannitol. The
`
`results for these formulations show the requirement of mannitol in Desai's formuation.
`
`DBP-5 and DBP-6 correspond to DBP-1 and DBP-2, respectively, without mannitol, but
`
`with tyloxapol. Tyloxapol is not a polyol but a polyether.
`
`Table 1.
`
`Diclofenac/boric acid/polyol matrix
`
`Ingredient
`
`DBP-1
`
`DBP-2
`
`DBP-3
`
`DBP-4
`
`DBP-5
`
`DBP-6
`
`(%w/v)
`
`(%w/v)
`
`(%w/v)
`
`(%w/v)
`
`(%w/v)
`
`(%w/v)
`
`Sodium Diclofenac
`
`HPMC (E4M)
`
`Tromethamine
`
`Boric Acid
`
`Vitamin E TPGS
`
`Mannitol
`
`Polyquatemium-1
`
`Tyloxapol
`
`HCl/NaOH
`
`Purified Water
`
`0.1
`
`0.1
`
`2.0
`
`1.2
`
`3.0
`
`3.5
`
`0.1
`
`0.1
`
`2.0
`
`1.2
`
`3.0
`
`3.5
`
`0.005
`---
`pH to 7.4
`
`0.005
`---
`pH to 7.8
`
`qs to
`
`100%
`
`qs to
`
`100%
`
`0.1
`
`0.1
`
`2.0
`
`1.2
`
`0.1
`
`0.1
`
`2.0
`
`1.2
`
`3.0
`---
`0.005
`---
`pH to 7.4
`
`qs to
`
`100%
`
`3.0
`---
`0.005
`---
`pH to 7.8
`
`qsto
`
`100%
`
`0.1
`
`0.1
`
`2.0
`
`1.2
`
`3.0
`---
`0.005
`
`0.02
`
`0.1
`
`0.1
`
`2.0
`
`1.2
`
`3.0
`---
`0.005
`
`0.02
`
`pH to 7.4
`
`pH to 7.8
`
`qs to
`
`100%
`
`qs to
`
`100%
`
`Table 2 is a collection of tables presenting the preservative efficacy testing results for
`
`each of the foregoing formulations.
`
`11
`
`

`
`Table 2.
`
`Preservative Efficacy Testing Results
`
`DBP-1: Diclofenac +Mannitol+ PQ-1 pH 7.4
`
`Time Intervals
`
`Ohr
`
`0.02
`
`1.01
`
`2.65
`
`~3.43
`
`>4.64
`
`6hr
`
`0.06
`
`2.99
`
`>4.24
`
`>4.49
`
`>4.64
`
`24 hr
`
`2.12
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`48 hr
`
`2.99
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`7 day
`
`3.10
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`14 day
`
`28 day
`
`~3.79
`
`~3.42
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`Organism
`
`A.
`
`brasiliensis
`
`C. Albicans
`
`E. coli
`
`S. aureus
`
`P.
`
`aeruginosa
`
`DBP-2: Diclofenac +Mannitol+ PQ-1 pH 7.8
`
`Organism
`
`Ohr
`
`6hr
`
`24 hr
`
`48 hr
`
`Time Intervals
`
`7 day
`
`2.28
`
`14 day
`
`28 day
`
`2.39
`
`2.59
`
`A.
`
`. 0.05
`
`0.09
`
`1.35
`
`2.82
`
`brasiliensis
`
`C. Albicans
`
`E. coli
`
`S. aureus
`
`P.
`
`aeruginosa
`
`0.83
`
`3.06
`
`~3.52
`
`>4.64
`
`3.06
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`DBP-3: Diclofenac + PQ-1 pH 7.4 (No Mannitol)
`
`Time Intervals
`
`Ohr
`
`0.03
`
`6hr
`
`0.34
`
`24 hr
`
`2.01
`
`48 hr
`
`~4.01
`
`7 day
`
`3.05
`
`14 day
`
`28 day
`
`2.95
`
`2.61
`
`Organism
`
`A.
`
`brasiliensis
`
`C. Albicans
`
`-3.48
`
`>4.51
`
`>4.51
`
`>4.51
`
`>4.51
`
`>4.51
`
`>4.51
`
`12
`
`

`
`E. coli
`
`S. aureus
`
`P.
`
`aeruginosa
`
`~3.11
`
`~3.37
`
`>4.64
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.24
`
`>4.49
`
`>4.64
`
`DBP-4: Diclofenac + PQ-1 pH 7.8 (No Mannitol)
`
`Organism
`
`A.
`
`brasiliensis
`
`Ohr
`
`0.01
`
`C. Albicans
`
`>4.51
`
`E. coli
`
`S. aureus
`
`~3.31
`
`~3.79
`
`6hr
`
`0.93
`
`>4.51
`
`>4.24
`
`>4.49
`
`Time Intervals
`
`24 hr
`
`2.04
`
`48 hr
`
`3.04
`
`7 day
`
`2.12
`
`14 day
`
`28 day
`
`1.90
`
`0.97
`
`>4.51
`
`>4.24
`
`>4.51
`
`>4.24
`
`>4.51
`
`>4.24
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.64
`
`>4.49
`
`>4.64
`
`>4.49
`
`>4.64
`
`>4.49
`
`>4.64
`
`>4.64
`
`>4.64
`
`P.
`
`aeruginosa
`
`DBP-5: Diclofenac + Tyloxapol + PQ-1 pH 7.4
`
`Organism
`
`A.
`
`brasiliensis
`
`Ohr
`
`0.06
`
`C. Albicans
`
`~3.32
`
`E. coli
`
`S. aureus
`
`P.
`
`aeruginosa
`
`2.73
`
`3.40
`
`~4.16
`
`Time Intervals
`
`6hr
`
`1.19
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`24 hr
`
`2.21
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`48 hr
`
`2.96
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`7 day
`
`3.06
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`14 day
`
`28 day
`
`2.93
`
`1.08
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`13
`
`

`
`l)BP-6: Diclofenac + Tyloxapol + PQ-1 pH 7.8
`
`Organism
`
`A.
`
`brasiliensis
`
`Ohr
`
`0.01
`
`C. Albicans
`
`>4.51
`
`E. coli
`
`S. aureus
`
`P.
`
`aeruginosa
`
`~3.43
`
`~3.69
`
`>4.64
`
`Time Intervals
`
`6hr
`
`1.03
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`24hr
`
`2.70
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`48 hr
`
`2.98
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`7 day
`
`2.05
`
`14 day
`
`28 day
`
`1.95
`
`1.34
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`>4.51
`
`>4.24
`
`>4.49
`
`>4.64
`
`The following Table 3 (from the Desai patent) shows the criteria needed to pass the
`
`preservative efficacy testing under US Pharmacopeia ("USP"), European Pharmacopeia A ("EP(cid:173)
`
`A"), and European Pharmacopeia B ("EP-B"). EP-A has the most stringent criteria.
`
`Table 3. Preservative Efficacy Acceptance Criteria
`
`PI~. Eur.
`A
`('1arget)
`
`Ph. Eur.
`B
`(Min)
`
`USP
`
`6 ho~£rs
`24 hmtrs
`7 dass
`14 da)'S
`28 days
`
`7 days
`14 days
`28 days
`
`2
`3
`
`3
`Nl
`
`NI
`Nl
`
`NR
`For Fungi;
`
`2
`
`Nl
`
`l
`3
`
`1
`NI
`
`NR "" No ()rganism~ reroveted
`NI "'· No increase at. !his or any following time pulls
`-
`:No cequiretnent at this dme .rmil
`
`14
`
`

`
`In the results presented in Table 2, A. brasiliensis and C. Albicans are fungi, and E. Coli,
`
`S. aureus, and P. Aeruginosa are bacteria. The preservative efficacy against fungi, especially A.
`
`brasiliensis, is the most difficult to meet. If the preservative efficacy fails for any one
`
`microorganism, the formulation does not meet the preservation efficacy criteria.
`
`Generally speaking, a lower pH of 7.4 is more effective than a pH of 7. 8. However,
`
`whether a formulation meets the preservative efficacy criteria does not depend on pH in the
`
`range of 7.4-7.8.
`
`Only formulations containing all three ingredients, polyquat-1, boric acid, and mannitol
`
`(DBP-1 and DBP-2), meet all three preservative efficacy criteria required by Desai. None of the
`
`formulations without mannitol (DBP-3 through DBP-6) satisfies any preservative efficacy
`
`because the population of the fungus A. brasilensis shows an increase from the previous time
`
`· point. As the tables show with regard to the USP and EP-B criteria, the population of A.
`
`brasilensis at 28 days is higher than at 14 days. Similarly, with respect to the EP-A criteria, the
`
`population of A. brasilensis at 28 days is higher than at 7 days.
`
`Thus, the data prove what the skilled person would have understood all along when
`
`reading the Desai patent: that, without mannitol, the formulations having polyquat-1 and boric
`
`acid do not achieve Desai's purpose of satisfying the preservative efficacy ofUSP XXII and
`
`European Pharmacopeia and that, to be operative for its intended purpose, Desai's formulations
`
`must contain mannitol.
`
`In view of the foregoing, Desai's formulations would not have rendered the claims of the
`
`present application obvious. The Desai formulations are different from those presently claimed,
`
`and there is no suggestion to avoid degradation of acidic drugs, such as bromfenac, by using
`
`tyloxapol.
`
`15
`
`

`
`III.
`
`CONCLUSION
`
`Applicant respectfully submits that claims 19-48 are patentable over the prior art. A
`
`favorable action on the merits is solicited.
`
`J;heek!
`
`IJW<gr~~rfn(i]ti~~g~:~Y signed by !Warren M.
`DN: cn=/Warren M. Cheek/, o, ou,
`email=wcheek@wenderoth.com,
`c=US
`Date: 2012.11.28 12:02:34 -05'00'
`Warren M. Cheek
`Registration No. 33,367
`Attorney for Applicant
`
`WMC/dlk
`Washington, D.C. 20005-1503
`Telephone (202) 721-8200
`Facsimile (202) 721-8250
`November 28,2012
`
`16