In re application of
`
`Shirou SAW A et al.
`
`Serial No. 10/525,006
`
`Filed March 28, 2005
`
`Confirmation No. 1756
`
`Attorney Docket No. 2005 _ 0232A
`
`Group Art Unit 1614
`
`Examiner Timothy P. Thomas
`
`AQUEOUS LIQUID PREPARATION
`CONTAINING 2-AMIN0-3-
`(4-BROMOBENZOYL)PHENYLACETIC ACID Mail Stop: Amendment
`
`AMENDMENT
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`Responsive to the Official Action dated July 18, 2007, the time for responding thereto
`
`being extended for three months in accordance with a petition for extension submitted
`
`concurrently herewith, please amend the above-identified application as follows:
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`Page 1 of 17
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`SENJU EXHIBIT 2243
`LUPIN v. SENJU
`IPR2015-01100
`
`

`
`Amendments to the Claims
`
`1-18. (Cancelled)
`
`19. (Currently amended) An aqueous liquid preparation comprising at least the
`
`following two components, the first component comprising 2-amino-3-( 4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof, and the second component comprising an alkyl aryl polyether alcohol type polymer or a
`
`polyethylene glycol fatty acid ester, wherein said liquid preparation is in the form of an eye drop.
`
`20. (Previously presented) The aqueous liquid preparation according to claim 19,
`
`wherein the alkyl aryl polyether alcohol type polymer is tyloxapol;
`
`wherein the concentration ofthe tyloxapol is selected from a range of about 0.01 w/v%
`
`to about 0.5 w/v %; and
`
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`
`pharmacologically acceptable salt thereof or a hydrate thereof is selected from a range of about
`
`0.01 to about 0.5 w/v %.
`
`21. (Previously presented) The aqueous liquid preparation according to claim 20,
`
`wherein the pharmacologically acceptable salt of 2-amino-3-( 4-bromobenzoyl)phenylacetic acid
`
`is a sodium salt.
`
`22. (Previously presented) The aqueous liquid preparation according to claim 21,
`
`wherein the concentration of the 2-amino-3-( 4-bromobenzoyl)phenylacetic acid sodium salt is
`
`selected from a range of about 0.05 to about 0.2 w/v %.
`
`- 2-
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`Page 2 of 17
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`

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`23. (Previously presented) The aqueous liquid preparation according to claim 22,
`
`wherein the concentration ofthe tyloxapol is selected from a range of about 0.01 w/v% to about
`
`0.3 w/v %.
`
`24. (Previously presented) The aqueous liquid preparation according to claim 23,
`
`wherein the concentration ofthe 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`
`about 0.1 w/v %.
`
`25. (Previously presented) The aqueous liquid preparation according to claim 24,
`
`wherein the concentration of the tyloxapol is about 0.02 w/v %.
`
`26. (Previously presented) The aqueous liquid preparation according to claim 25,
`
`wherein the formulation further includes one or more additives selected from the group
`
`consisting of a preservative, buffer, thickener, stabilizer, chelating agent, and pH controlling
`
`agent.
`
`27. (Previously presented) The aqueous liquid preparation according to claim 26,
`
`wherein said preservative is benzalkonium chloride; wherein said buffer is boric acid and/or
`
`sodium borate; wherein said thickener is polyvinylpyrrolidone; wherein said stabilizer is sodium
`
`sulfite; wherein said chelating agent is sodium edetate; and wherein said pH controlling agent is
`
`sodium hydroxide.
`
`28. (Previously presented) The aqueous liquid preparation according to claim 27,
`
`wherein the pH is from about 7 to about 9.
`
`29. (Previously presented) The aqueous liquid preparation according to claim 28,
`
`wherein the pH is from about 7.5 to about 8.5.
`
`- 3-
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`Page 3 of 17
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`

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`30. (Cancelled)
`
`31. (Previously presented) The aqueous liquid preparation according to claim 23,
`
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`
`about 0.2 w/v %.
`
`32. (Previously presented) The aqueous liquid preparation according to claim 31,
`
`wherein the concentration ofthe tyloxapol is about 0.3 w/v %.
`
`33. (Previously presented) The aqueous liquid preparation according to claim 32,
`
`wherein the formulation further includes one or more additives selected from the group
`
`consisting of a preservative, buffer, thickener, stabilizer, chelating agent, and pH controlling
`
`agent.
`
`34. (Previously presented) The aqueous liquid preparation according to claim 33,
`
`wherein said preservative is benzalkonium chloride; wherein said buffer is boric acid and/or
`
`sodium borate; wherein said thickener is polyvinylpyrrolidone; wherein said stabilizer is sodium
`
`sulfite; wherein said chelating agent is sodium edetate; and wherein said pH controlling agent is
`
`sodium hydroxide.
`
`35. (Cancelled)
`
`36. (Previously presented) The aqueous liquid preparation according to claim 31,
`
`wherein the concentration of the tyloxapol is about 0.02 w/v %.
`
`37. (Previously presented) The aqueous liquid preparation according to claim 36,
`
`wherein the formulation further includes one or more additives selected from the group
`
`- 4-
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`Page 4 of 17
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`consisting of a preservative, buffer, thickener, stabilizer, chelating agent, and pH controlling
`
`agent.
`
`38. (Previously presented) The aqueous liquid preparation according to claim 3 7,
`
`wherein said preservative is benzalkonium chloride; wherein said buffer is boric acid and/or
`
`sodium borate; wherein said thickener is polyvinylpyrrolidone; wherein said chelating agent is
`
`sodium edetate; and wherein said pH controlling agent is sodium hydroxide.
`
`39. (Withdrawn-currently amended)
`
`A method for stabilizing 2-amino-3-( 4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof in an aqueous liquid preparation, which comprises incorporating tyloxapol or
`
`polyethylene glycol monostearate into an aqueous liquid preparation containing 2-amino-3-( 4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof, to obtain an aqueous liquid preparation comprising at least the following two
`
`components, the first component comprising 2-amino-3-(4- bromobenzoyl)phenylacetic acid or a
`
`pharmacologically acceptable salt thereof or a hydrate thereof, and the second component
`
`comprising tyloxapol or polyethylene glycol monostearate, wherein said liquid preparation is in
`
`the form of an eye drop.
`
`40. (Withdrawn-currently amended)
`
`A method for inhibiting decrease in
`
`preservative effect of a preservative in an aqueous liquid preparation of 2-amino-3-( 4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof, which comprises incorporating tyloxapol or polyethylene glycol monostearate into an
`
`aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`
`pharmacologically acceptable salt thereof or a hydrate thereof and a preservative, to obtain an
`
`aqueous liquid preparation comprising at least the following two components, the first
`
`component comprising 2-amino-3-(4- bromobenzoyl)phenylacetic acid or a pharmacologically
`
`acceptable salt thereof or a hydrate thereof, and the second component comprising tyloxapol or
`
`- 5-
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`Page 5 of 17
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`

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`polyethylene glycol monostearate, together with a preservative, wherein said liquid preparation is
`
`in the form of an eye drop.
`
`41. (Currently amended) An aqueous liquid preparation consisting essentially of at
`
`least-the following two components, wherein the first component comprising is 2-amino-3-(4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof, and the second component comprising is an alkyl aryl polyether alcohol type polymer or
`
`a polyethylene glycol fatty acid ester, wherein said liquid preparation is in the form of an eye
`
`drop.
`
`42. (Previously presented) The aqueous liquid preparation according to claim 41,
`
`wherein the alkyl aryl polyether alcohol type polymer is tyloxapol;
`
`wherein the concentration of the tyloxapol is selected from a range of about 0.01 w/v%
`
`to about 0.5 w/v %; and
`
`wherein the concentration ofthe 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`
`pharmacologically acceptable salt thereof or a hydrate thereof is selected from a range of about
`
`0.01 to about 0.5 w/v %.
`
`43. (Previously presented) The aqueous liquid preparation according to claim 42,
`
`wherein the pharmacologically acceptable salt of 2-amino-3-( 4-bromobenzoyl)phenylacetic acid
`
`is a sodium salt.
`
`44. (Previously presented) The aqueous liquid preparation according to claim 43,
`
`wherein the concentration of the 2-amino-3-( 4-bromobenzoyl)phenylacetic acid sodium salt is
`
`selected from a range of about 0.05 to about 0.2 w/v %.
`
`- 6-
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`Page 6 of 17
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`

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`45. (Previously presented) The aqueous liquid preparation according to claim 44,
`
`wherein the concentration of the tyloxapol is selected from a range of about 0.01 w/v % to about
`
`0.3 w/v %.
`
`46. (Previously presented) The aqueous liquid preparation according to claim 45,
`
`wherein the concentration ofthe 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`
`about 0.1 w/v %.
`
`47. (Previously presented) The aqueous liquid preparation according to claim 46,
`
`wherein the concentration of the tyloxapol is about 0.02 w/v %.
`
`48. (Previously presented) The aqueous liquid preparation according to claim 4 7,
`
`wherein the formulation further includes one or more additives selected from the group
`
`consisting of a preservative, buffer, thickener, stabilizer, chelating agent, and pH controlling
`
`agent.
`
`49. (Previously presented) The aqueous liquid preparation according to claim 48,
`
`wherein said preservative is benzalkonium chloride; wherein said buffer is boric acid and/or
`
`sodium borate; wherein said thickener is polyvinylpyrrolidone; wherein said stabilizer is sodium
`
`sulfite; wherein said chelating agent is sodium edetate; and wherein said pH controlling agent is
`
`sodium hydroxide.
`
`50. (Previously presented) The aqueous liquid preparation according to claim 49,
`
`wherein the pH is from about 7 to about 9.
`
`51. (Previously presented) The aqueous liquid preparation according to claim 50,
`
`wherein the pH is from about 7.5 to about 8.5.
`
`- 7-
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`Page 7 of 17
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`

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`52. (Cancelled)
`
`53. (Previously presented) The aqueous liquid preparation according to claim 45,
`
`wherein the concentration ofthe 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`
`about 0.2 w/v %.
`
`54. (Previously presented) The aqueous liquid preparation according to claim 53,
`
`wherein the concentration of the tyloxapol is about 0.3 w/v %.
`
`55. (Previously presented) The aqueous liquid preparation according to claim 54,
`
`wherein the formulation further includes one or more additives selected from the group
`
`consisting of a preservative, buffer, thickener, stabilizer, chelating agent, and pH controlling
`
`agent.
`
`56. (Previously presented) The aqueous liquid preparation according to claim 55,
`
`wherein said preservative is benzalkonium chloride; wherein said buffer is boric acid and/or
`
`sodium borate; wherein said thickener is polyvinylpyrrolidone; wherein said stabilizer is sodium
`
`sulfite; wherein said chelating agent is sodium edetate; and wherein said pH controlling agent is
`
`sodium hydroxide.
`
`57. (Cancelled)
`
`58. (Previously presented) The aqueous liquid preparation according to claim 53,
`
`wherein the concentration of the tyloxapol is about 0.02 w/v %.
`
`59. (Previously presented) The aqueous liquid preparation according to claim 58,
`
`wherein the formulation further includes one or more additives selected from the group
`
`- 8 -
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`Page 8 of 17
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`

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`consisting of a preservative, buffer, thickener, stabilizer, chelating agent, and pH controlling
`
`agent.
`
`60. (Previously presented) The aqueous liquid preparation according to claim 59,
`
`wherein said preservative is benzalkonium chloride; wherein said buffer is boric acid and/or
`
`sodium borate; wherein said thickener is polyvinylpyrrolidone; wherein said chelating agent is
`
`sodium edetate; and wherein said pH controlling agent is sodium hydroxide.
`
`61. (Withdrawn-currently amended)
`
`A method for stabilizing 2-amino-3-( 4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof in an aqueous liquid preparation, which comprises incorporating tyloxapol or
`
`polyethylene glycol monostearate into an aqueous liquid preparation containing 2-amino-3-(4-
`
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`thereof, to obtain an aqueous liquid preparation consisting essentially of at least the following
`
`two components, the first component comprising 2-amino-3-(4- bromobenzoyl)phenylacetic acid
`
`or a pharmacologically acceptable salt thereof or a hydrate thereof, and the second component
`
`comprising tyloxapol or polyethylene glycol monostearate, wherein said liquid preparation is in
`
`the form of an eye drop.
`
`62. (Currently amended) A method for inhibiting decrease in preservative effect of a
`
`preservative in an aqueous liquid preparation of2-amino-3-(4-bromobenzoyl)phenylacetic acid
`
`or a pharmacologically acceptable salt thereof or a hydrate thereof, which comprises
`
`incorporating tyloxapol or polyethylene glycol monostearate into an aqueous liquid preparation
`
`containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt
`
`thereof or a hydrate thereof and a preservative, to obtain an aqueous liquid preparation consisting
`
`essentially of at least the following two components, the first component comprising 2-amino-3-
`
`( 4- bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`
`-9-
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`Page 9 of 17
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`

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`thereof, and the second component comprising tyloxapol or polyethylene glycol monostearate,
`
`together with a preservative, wherein said liquid preparation is in the form of an eye drop.
`
`63. (Currently amended) An aqueous liquid preparation consisting of the following
`
`two components, the first component comprising is 2-amino-3-(4- bromobenzoyl)phenylacetic
`
`acid or a pharmacologically acceptable salt thereof or a hydrate thereof, and the second
`
`component eornprising is an alkyl aryl polyether alcohol type polymer or a polyethylene glycol
`
`fatty acid ester, and water, and optionally at least one preservative, isotonic, buffer, thickener,
`
`stabilizer, chelating agent, pH controlling agent, or perfume, wherein said liquid preparation is in
`
`the form of an eye drop.
`
`- 10-
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`Page 10 of 17
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`REMARKS
`
`Favorable reconsideration is respectfully solicited in view of the following remarks.
`
`Initially, Applicant wishes to express its sincere thanks for the courtesy and cooperation
`
`provided to its undersigned representative by Examiner Timothy Thomas and Supervisory
`
`Examiner Ardin Marschel during the personal interview held on November 20, 2008. The
`
`following is a summary of the items discussed during the interview.
`
`Claims 19, 39, 40, 41, 61,62 and 63 have been amended to require that the aqueous
`
`liquid preparation is in the form of an eye drop. Claims 30, 35, 52 and 57 have accordingly been
`
`cancelled.
`
`Claim 41 has been amended to delete "at least" and to change "comprising" to -is-.
`
`Claim 63 has been amended to change "comprising" to- is- and to add --and water --.
`
`Turning to the Official Action, Applicants acknowledge with thanks the Examiner's
`
`indication that numerous former grounds of rejection have been withdrawn in view of
`
`Applicants' last response.
`
`On page 3, claims 19-29, 31-34, 36-38, 41-51, 53-56, 58-60 and 63 are rejected under 35
`
`U.S.C. 103 as obvious over Gamache et al. (WO 01/15677) in view ofiSTA or Nolan et al. This
`
`ground of rejection is respectfully traversed as applied to the amended claims.
`
`Claims 19, 39, 40, 41, 61,62 and 63 have been amended to require that the aqueous
`
`liquid preparation is in the form of an eye drop according to claims 30, 35, 52 and 57. None of
`
`claims 30, 35, 52 or 57 were encompassed by the rejection.
`
`Accordingly this ground of rejection is deemed to be overcome.
`
`Furthermore, Applicants take the opportunity to provide additional remarks for the
`
`Examiner's consideration against a potential 103 rejection based upon a different combination of
`
`references.
`
`The subject matter of the claimed invention is directed to an eye drop having a specific
`
`combination of 2-amino-3-( 4- bromobenzoyl)phenylacetic acid or a pharmacologically
`
`acceptable salt thereof or a hydrate thereof, and an alkyl aryl polyether alcohol type polymer or a
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`- 11 -
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`Page 11 of 17
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`polyethylene glycol fatty acid ester.
`
`On the other hand, Gamache et al. do not disclose or suggest this specific combination.
`
`The cited reference is directed to compositions comprising of 5-HT10 and/or HT 18 agonists. The
`cited reference states that these agonists may be combined with an extensive list of other
`
`pharmaceutical agents, i.e. (1) anti-microbial agent, (2) anti-inflammatory agents or (3) anti(cid:173)
`
`allergy agent (please see page 6, lines 1-3 of Gamache). Gamache et al. only describes
`
`"bromfenac" as one of many examples of anti-inflammatory agents enumerated on page 12, lines
`
`11-24. Gamache et al. does not concretely describe nor suggest the claimed preparation
`
`containing bromfenac.
`
`Further, tyloxapol (0.05% w/v) is only mentioned as being added to an 1 B/1 D agonist
`
`(0.1-1.0% w/v) and moxifloxacin (0.3% w/v) in Example 4 (an Example of an otic/nasal
`
`suspension). There is no explanation about tyloxapol in the description of Gamache et al. or why
`
`it is included. Moreover in this Example, moxifloxacin is incorporated as a well-known
`
`antibacterial agent but is not an anti-inflammatory agent like bromfenac. Thus it is unclear from
`
`Gamache et al. why tyloxapol is added to the otic/nasal suspension containing 1 B/1 D agonist and
`
`moxifloxacin.
`
`"Tyloxapol" described in Example 4 is just a single word description and does not give
`
`any clues and hints to the present invention. Therefore, the word "tyloxapol" described only in
`
`Example 4 does not destroy the novelty of the present invention.
`
`Further, Gamache et al. is silent about an alkyl aryl polyether alcohol type polymer or a
`
`polyethylene glycol fatty acid ester component according to the claimed eye drop.
`
`Thus the disclosure of Gamache et al. would suggest to the skilled artisan thousands of
`
`possible combinations of ingredients to include with an IBIID agonist. Such disclosure does not
`
`lead the artisan to the claimed specific combination nor does such disclosure render the claimed
`
`combination obvious. The prior art must motivate one skilled in the art to make the claimed
`
`combination. There is no teachings or suggestion in Gamache of selecting bromfenac in
`
`combination with an alkyl aryl polyether alcohol type polymer or a polyethylene glycol fatty acid
`
`ester.
`
`- 12-
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`Page 12 of 17
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`Furthermore, Gamache et al. is directed to compositions for relieving otic pain (abstract)
`
`by apply the compositions to the ear or nasally (page 10, lines 6-9 and Example 4). There is no
`
`teaching or motivation to make the claimed eye drop.
`
`Regarding claims 41-51, 53-56 and 58-60, the claims are directed to an eye drop which
`
`consists essentially of the recited specific combination of ingredients. The claim recites the
`
`transitional phrase "consisting essentially of' means that the claim is open to include the
`
`specified ingredients and additional ingredients that do not materially affect the basic and novel
`
`characteristics ofthe claimed invention. See M.P.E.P. 2111.03.
`
`It is respectfully submitted that the principal IBIID agonist of the Gamache composition
`
`would affect the basic novel properties of the claimed preparation.
`
`One skilled in the art would not have been motivated to modify the Gamache et al.
`
`composition in view of 1ST A and Nolan, to arrive at the claimed eye drop. The primary object of
`
`Gamache et al. is to make a composition containing an IB/ID agonist. The artisan would not have
`
`been motivated by the reference to make a composition lacking the IBIID agonist. An IBIID
`
`agonist is excluded from claims 41-51, 53-56 and 58-60 by the "consisting essentially of'
`
`transitional phrase.
`
`Regarding claim 63, the claim is limited to an eye drop which "consists of' the recited
`
`bromfenac, recited an alkyl aryl polyether alcohol type polymer or a polyethylene glycol fatty
`
`acid ester, and water. Such claim explicitly excludes other ingredients, such as an IBIID agonist.
`
`For the foregoing reasons, Applicant submits that the present invention is unobvious from
`
`Gamache et al. and 1ST A or Nolan to those skilled in the art.
`
`Claims 41-60 and 63 are rejected under 35 USC 112, second paragraph, as being
`
`indefinite for the reasons set forth on pages 6-7 of the Action.
`
`Based upon the Examiner's remarks during the personal interview, it is believed that this
`
`ground of rejection is overcome by the foregoing amendments.
`
`Claims 19-38, 41-60 and 63 are rejected under 35 USC 103 as being unpatentable over
`
`Hellberg et al. and Nolan et al. This ground of rejection is respectfully traversed as applied to the
`
`amended claims.
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`- 13-
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`Page 13 of 17
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`The Examiner asserts that it would have been obvious to substitute the compounds having
`
`anti-inflammatory and anti-oxidant activity used in the ophthalmic compositions of Hellberg et
`
`al. with bromfenac used in the dermal applications disclosed in Nolan et al. Applicants
`
`respectfully disagree.
`
`The intended purpose of the invention disclosed in Hellberg et al. is to provide
`
`"(c]ompounds having anti-inflammatory and antioxidant activity." See Hellberg et al., Abstract
`
`(emphasis added); see also Hellberg at column 2, lines 13-18 ("The present invention provides
`
`new compounds having potent anti-inflammatory and anti-oxidant activity.") (emphasis added).
`
`Indeed, Hellberg et al. explicitly state that the principle of operation of the anti-inflammatory and
`
`antixodixant compounds is to provide a two-pronged therapeutic approach not previously
`
`available in the art:
`
`The compounds of the present invention are capable of protecting
`against cellular damage by a wide range of insults. Since the
`compounds provide this protection by decreasing free radical or
`oxidative damage, reducing cyclooxygenase or lipoxygenase
`mediated inflammation, and improving site delivery, this therapy
`represents an improved two-pronged approach to cytoprotection.
`
`See Hellberg et al. at Column 2, lines 57-63. Therefore, the intended purpose of the invention
`
`disclosed in Hellberg et al. is to provide compounds with not only anti-inflammatory activity, but
`
`also anti-oxidant activity for improved therapeutic functionality:
`
`The compounds also include an anti-oxidant component. As
`oxidative stress has been implicated in inflammatory responses, the
`presence of an anti-oxidant will further help treat the target tissue.
`
`The compounds of the present invention also exhibit properties
`present only in the combined molecule, not in the individual
`components. One such property is the inhibitory efficacy against 5-
`lipoxygenase, an enzyme known to be involved in inflammation.
`
`See Hellberg et al. at Column 2, lines 38-45 (emphasis added).
`
`The USPTO has made clear that "[i]f (the] proposed modification would render the prior
`
`art invention being modified unsatisfactory for its intended purpose, then there is no suggestion
`
`or motivation to make the proposed modification." See MPEP section 2143.01 V, citing In re
`
`- 14-
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`Page 14 of 17
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`Gordon, 733 F.2d 900 (Fed. Cir. 1984). Additionally, section 2143.01 VI ofthe MPEP plainly
`
`states: "The proposed modification cannot change the principle of operation of a reference. If the
`
`proposed modification or combination of the prior art would change the principle of operation of
`
`the prior art invention being modified, then the teachings of the references are not sufficient to
`
`render the claims prima facie obvious." See also In re Ratti, 270 F.2d 810, 123 USPQ 349
`
`(CCP A 1959).
`
`Here, the Examiner asserts that it would have been obvious to substitute the anti(cid:173)
`
`inflammatory and anti-oxidant compounds disclosed in Hellberg et al. with bromfenac as
`
`disclosed in Nolan et al. because of"the art recognized equivalent activity ofbromfenac as an
`
`anti-inflammatory agent in topical usage." See Official Action date July 18, 2008 at page 9. But
`
`as indicated in the Official Action and in Hellberg et al., bromfenac is an anti-inflammatory and
`
`not an antioxidant. The proposed substitution of the dual action anti-inflammatory and anti(cid:173)
`
`oxidant compounds disclosed in Hellberg et al. with bromfenac would render the Hellberg et al.
`
`invention unsatisfactory for its intended purpose of providing "compounds having potent anti(cid:173)
`
`inflammatory and anti-oxidant activity." The proposed substitution would result in a bromfenac
`
`composition having only anti-inflammatory activity. This proposed modification would radically
`
`change the principle of operation of Hellberg et al. from "an improved two-pronged approach to
`
`cytoprotection" to a mere one-pronged approach based on anti-inflammatory action alone.
`
`Therefore, because the proposed substitution of the anti-inflammatory and anti-oxidant
`
`compounds disclosed in Hellberg et al. with bromfenac as disclosed in Nolan et al. would render
`
`the Hellberg et al. invention unsatisfactory for its intended purpose and radically change the
`
`principle of operation of Hellberg et al., Applicants respectfully submit a prima facie case of
`
`obviousness cannot be based on the combination of Hellberg et al. and Nolan et al.
`
`In addition to the argument that the proposed modification changes the principle
`
`operation and intended purpose of Hellberg et al., Applicants submit that Hellberg et al.
`
`explicitly teach away from the use of a compound, such as bromfenac, having only anti(cid:173)
`
`inflammatory activity. Hellberg et al. clearly recite deficiencies in the use of non-steroidal anti(cid:173)
`
`inflammatory agents such as bromfenac:
`
`- 15 -
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`Page 15 of 17
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`Non-steroidal anti-inflammatory agents (NSAIA) have been used
`for the treatment of inflammatory disorders. The following
`references may be referred to for further background concerning
`this use ofNSAIAs:
`
`Ophthalmoscope, volume 8, page 257 (1910);
`
`F ASEB Journal, volume 1, page 89 (1987); and
`
`Inflammation and Mechanisms and Actions of Traditional Drugs,
`vol. I Anti-inflammatory and Anti-rheumatic drugs. Boca Raton,
`Fla., CRC Press, (1985).
`
`However, there are some problems associated with NSAIA
`treatment including delivery to the appropriate site of action and
`side effects (Goodman and Gilman's The Pharmacological Basis of
`Therapeutics, pages 638-669, Pergman Press, NY (1990)).
`
`See Hellberg et al. at Column 1, lines 28-3 7 (emphasis added).
`
`According to the USTPO guidelines, "[i]t is improper to combine references where the
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`references teach away from their combination." See MPEP § 2145, citing In re Grassel/i, 713
`
`F.2d 731,743 (Fed. Cir. 1983); see also McGinley v. Franklin Sports, Inc., 262 F.3d 1339, 1354
`
`(Fed.Cir. 2001) ("It is well-established that references which "teach away cannot serve to create a
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`prima facie case of obviousness.") (citations omitted).
`
`Here, Hellberg et al. plainly state that NSAIA treatment is associated with "problems"
`
`such as "side effects" and "delivery to the appropriate site of action." In light ofthis teaching
`
`away from the use of a non-steroidal anti-inflammatory agent (NSAIA), one skilled in the art
`
`would not substitute bromfenac, a known NSAIA, for the anti-inflammatory and anti-oxidant
`
`compounds disclosed in Hellberg et al. Therefore, because Hellberg et al. teach away from the
`
`use ofbromfenac, Applicants respectfully submit a prima facie case of obviousness cannot be
`
`based on the combination of Hellberg et al. and Nolan et al.
`
`For the reasons detailed above, Applicants respectfully request withdrawal of the
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`rejection of claims 19-38,41-60 and 63 under 35 USC 103 as being unpatentable over Hellberg
`
`et al. and Nolan et al.
`
`Lastly, claims 19-38 are provisionally rejected on the ground of non-statutory
`
`obviousness-type double patenting as being unpatentable over claims 1-43 of copending
`
`- 16-
`
`Page 16 of 17
`
`

`
`..
`
`application Serial No. 11/755,662.
`
`The Examiner is respectfully requested to hold this provisional ground of rejection in
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`abeyance until a later date. Upon overcoming all other grounds of rejection, it is respectfully
`
`submitted that this provisional ground of rejection should be withdrawn and the application
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`passed on to allowance.
`
`In summary, it is believed that each ground of rejection set forth in the Official Action
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`has been overcome, and that the application is now in condition for allowance. Accordingly such
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`allowance is solicited.
`
`Respectfully submitted,
`
`Shirou SAW A et al.
`
`By: u)~
`Warren M. Cheek
`Registration No. 33,367
`Attorney for Applicants
`
`WMC/dlk
`Washington, D.C. 20006-1021
`Telephone (202) 721-8200
`Facsimile (202) 721-8250
`January 15, 2009
`
`- 17-
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`Page 17 of 17