UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.goV
`
`APPLICATION NO.
`
`F ING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONF {MATION NO.
`
`10/500,354
`
`06/30/2004
`
`Masayo Higashiyama
`
`2004_1016A
`
`2612
`
`WENDEROTH,LIND&PONACK,L.L.P.
`1030 15th Street, N.W.,
`Suite
`East
`
`FRAZIER, BARBARA s
`ART UNIT
`PAPER \1Ul\/IBER
`1611
`
`04/30/2014
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on aboVe—indicated "Notification Date" to the
`following e—mail address(es):
`ddalecki @Wender0th.c0m
`e0a@ Wender0th.c0m
`
`PTOMOA (KW 04,07)
`
`MYLAN Ex. 1033, Page 1
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`MYLAN Ex. 1033, Page 1
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`

`
`Application No.
`10/500,354
`
`App|icant(s)
`HIGASHIYAMA, MASAYO
`
`0ffiCe ACtiOn Summary
`
`AIA (First Inventor to File)
`Art Unit
`Examiner
`iltgtus
`1611
`BARBARA FRAZIER
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE § MONTHS FROM THE MAILING DATE OF
`THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR1.136(a).
`after SIX (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`—
`— Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1 .704(b).
`
`In no event, however, may a reply be timely filed
`
`Status
`
`1)|Z| Responsive to communication(s) filed on 28 February 2014.
`El A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on
`
`2b)I:I This action is non—final.
`2a)IXI This action is FINAL.
`3)I:I An election was made by the applicant in response to a restriction requirement set forth during the interview on
`; the restriction requirement and election have been incorporated into this action.
`
`4)|:I Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`
`closed in accordance with the practice under Exparte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims*
`
`5)|X| Claim(s) 13 5-9 and 12-15 is/are pending in the application.
`5a) Of the above claim(s)
`is/are withdrawn from consideration.
`
`
`1 3 5-9 12 13 and 15is/are rejected.
`
`)
`
`8 |:I Claim s) j is/are objected to.
`
`9)|:I Claim(s) j are subject to restriction and/or election requirement.
`* If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
`
`participating intellectual property office for the corresponding application. For more information, please see
`
`
`h/indexfis or send an inquiry to PPl-ifeedbackf,<‘Bus§to.Gov.
`
`://www.us:>to. ow atents/init events/
`
`hit
`
`Application Papers
`
`10)|:l The specification is objected to by the Examiner.
`11)I:l The drawing(s) filed on
`is/are: a)I:I accepted or b)I:I objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`
`Priority under 35 U.S.C. § 119
`
`12)I:I Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`
`a)|:l All
`
`b)|:| Some** c)|:l None of the:
`
`1.I:I Certified copies of the priority documents have been received.
`2.I:| Certified copies of the priority documents have been received in Application No. _.
`3.|:| Copies of the certified copies of the priority documents have been received in this National Stage
`
`application from the International Bureau (PCT Rule 17.2(a)).
`** See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment(s)
`
`1) D Notice of References Cited (PTO-892)
`3) g jme,-View summary (PTQ.413)
`_
`_
`Paper No(s)/Mail Date. 4/24/14.
`2) D Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date 4) D other: H‘ .
`
`
`U.S. Patent and Trademark Office
`
`PTOL—326 (Rev. 11-13)
`
`Office Action Summary
`
`|J!agC(g120424
`
`MYLAN Ex. 1033, Page 2
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`

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`Application/Control Number: 10/500,354
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`Page 2
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`Art Unit: 1611
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`DETAILED ACTION
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`1.
`
`The present application is being examined under the pre-AIA first to invent
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`provisions.
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`Examiner’s Remarks
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`2.
`
`The Examiner notes that the proper status of claim 14 was inadvertently omitted
`
`from the previous Office action mailed 23 April 2014. The Office action mailed 23 April
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`2014 is hereby vacated; a corrected Office action follows.
`
`3.
`
`Claims 1, 3, 5-9, and 12-15 are pending in this application, and are examined.
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`Status of Claims
`
`Claim Rejections - 35 USC § 103
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`4.
`
`The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis
`
`for all obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described
`as set forth in section 102 of this title, if the differences between the subject matter sought to
`be patented and the prior art are such that the subject matter as a whole would have been
`obvious at the time the invention was made to a person having ordinary skill in the art to which
`said subject matter pertains. Patentability shall not be negatived by the manner in which the
`invention was made.
`
`5.
`
`Claims 1, 3, 5-9, 12, 13, and 15 are rejected under 35 U.S.C. 103(a) as being
`
`unpatentable over Lehmussaari et al. (“Lehmussaari”, US Patent 5,795,913,
`
`previously cited) in view of Kita et al. (“Kita”, US Patent 6,307,052, previously
`
`cited) and optionally further in view of Araki et al. (“Araki”, WO 01/80858). US
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`MYLAN EX. 1033, Page 3
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`MYLAN Ex. 1033, Page 3
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`Application/Control Number: 10/500,354
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`Page 3
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`Art Unit: 1611
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`2003/0139436 is the national stage entry of WO 01/80858, and thus serves as an
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`English translation of WO 01/80858; accordingly, relevant passages will be taken from
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`the US '436 reference.
`
`Regarding claims 1 and 13, Lehmussaari teaches an ophthalmic composition in
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`the form of a topical aqueous solution consisting essentially of an ophthalmologically
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`active agent containing basic groups, an ion sensitive hydrophilic polymer containing
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`acidic groups, and at least one salt selected from the group of inorganic salts and
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`buffers in a total amount of from 0.01 to 2.0% by weight (abstract). The
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`ophthalmologically active agent may be an antiallergic agent containing basic groups,
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`including basic heterocycles, such as pyridine and piperidine (col. 4, lines 2-9). The
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`salt/buffer functions as a viscosity reducing agent; choices of salts include sodium
`
`chloride and potassium chloride (col. 3, lines 45-50 and claim 5). Sodium chloride is
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`exemplified in an amount of 0.9% w/v (Example 2), and therefore the skilled artisan
`
`would be sufficiently motivated to prepare the aqueous solution with sodium chloride,
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`with a reasonable expectation of forming the ophthalmic composition. The composition
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`is prepared by dissolving active ingredient(s) and inorganic salt(s) in sterile water,
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`followed by mixing with a dispersion of the polymer in sterile water, to form a
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`homogeneous solution (col. 5, lines 1-11). The composition is administered as a liquid
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`and obtains a desired beneficial effect of the active agent in the eye, while
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`simultaneously reducing any discomfort in the patient’s eye, as compared to the
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`administration of a composition in gel form. The composition also provides for an
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`MYLAN EX. 1033, Page 4
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`Application/Control Number: 10/500,354
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`Page 4
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`Art Unit: 1611
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`additional wetting effect while providing for a better contact and thus a controlled
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`absorption of active agent into the eye (col. 2, lines 10-18).
`
`While Lehmussaari teaches the steps of preparing an aqueous preparation
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`comprising an ophthalmic agent and sodium chloride, and teaches the ophthalmically
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`active agent may be an antiallergic agent containing basic groups, including basic
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`heterocycles, such as pyridine and piperidine, Lehmussaari does not specifically teach
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`that the antiallergic agent is bepotastine. Lehmussaari also does not specifically teach
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`that the amount of sodium chloride is a light-stabilizing effective amount (claim 1), or
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`that the antiallergic agent is light-stabilized (claim 13).
`
`Kita teaches that the benzenesulfonic acid salt or benzoic acid salt of (S)-4-[4-
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`[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid (i.e., bepotastine) is
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`excellent in antihistaminic activity and antiallergic activity, has little hygroscopicity and
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`excellent in physicochemical stability, so that it is particularly suitable compound as a
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`medicine. Kita et al also teach that its present invention relates to a medical
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`composition containing the compound as an effective ingredient (see col. 1, lines 10-
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`22).
`
`Araki teaches a stabilized liquid preparation having improved light stability,
`
`comprising an aqueous solution containing sitafloxacin and sodium chloride (abstract).
`
`The light stabilizing effect is enhanced with an increase of the sodium chloride
`
`concentration; a particularly high stabilizing effect is obtained at a sodium chloride
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`concentration of 0.1% or higher (paragraph [0055]). The liquid preparation is suitable
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`MYLAN EX. 1033, Page 5
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`Page 5
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`Art Unit: 1611
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`for systemic administration such as injections and drops, as well as topical
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`administration such as liquids for external use and sprays (paragraph [0063]).
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`It would have been obvious to a person having ordinary skill in the art at the time
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`the invention was made to select bepotastine as the antiallergic agent in the preparation
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`of Lehmussaari, with the reasonable expectation that the preparation thus prepared
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`would be light—stabilized; thus arriving at the claimed invention. First, one skilled in the
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`art would be motivated to select bepotastine as the antiallergic agent in the preparation
`
`of Lehmussaari because said compound provides the benefits of excellent
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`antihistaminic activity and antiallergic activity, little hygroscopicity and excellent
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`physicochemical stability, so that it is particularly suitable compound as a medicine, as
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`taught by Kita. Additionally, Lehmussaari teaches that the ophthalmologically active
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`agent may be an antiallergic agent containing basic groups such as pyridine and
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`piperidine, and the bepotastine compound taught by Kita contains both pyridine and
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`piperidine groups.
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`Regarding the limitations “a light—stabilizing effective amount” and “an active
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`ingredient...which is light—stabilized”, it is noted that the composition of the combined
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`references is drawn to the components as the claimed invention, i.e., a solution
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`comprising water, a water—soluble metal chloride, and an ophthalmically active agent
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`(i.e., an antiallergy agent, such as bepotastine).
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`It is also noted that the amount of
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`active agent taught by Lehmussaari is preferably in the range of 0.1 to 0.5% by weight
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`(col. 4, lines 32-35), which falls within the range taught for the active agent in the
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`claimed invention (see page 5, lines 1-9 of specification), and the amount of metal
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`Page 6
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`Art Unit: 1611
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`chloride is from 0.01 to 2.0% (abstract), with an amount of 0.9% exemplified, which is
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`comparable to that of the claimed invention (see page 5, lines 17-20 of specification).
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`Therefore, since the composition of the combined references comprises the same
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`components in comparable amounts, the skilled artisan would reasonably expect the
`
`resultant aqueous preparation to have the same effect, i.e., to be light-stabilized, absent
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`evidence to the contrary. Optionally additionally, since Araki teaches that sodium
`
`chloride is known to improve light stability of other active agents (such as sitafloxacin) in
`
`aqueous preparations, the skilled artisan would reasonably expect the amount of
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`sodium chloride in Lehmussaari to impart a light—stabilizing effect to the composition of
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`the combined references, and thus be a “light-stabilizing effective amount”, absent
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`evidence to the contrary.
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`Regarding the amount of metal chloride (claims 1, 13, and 15), Lehmussaari
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`teaches an amount of buffer/salt from 0.01 to 2.0% by weight (col. 2, lines 65-67) which
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`functions to reduce the viscosity, which is favorable for both efficacy and ease of
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`application (col. 3, lines 35-40), and Araki teaches that the light stabilizing effect is
`
`enhanced with an increase of the sodium chloride concentration, wherein a particularly
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`high stabilizing effect is obtained at a sodium chloride concentration of 0.1% or higher
`
`(paragraph [0055]) . These ranges overlap those of the claimed invention; one skilled in
`
`the art would be motivated to manipulate the amount of salt from within said ranges,
`
`including the ranges claimed, by routine experimentation, in order to optimize properties
`
`of the resultant composition, such as viscosity as taught by Lehmussaari, and/or light-
`
`stabilizing effect as taught by Araki.
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`MYLAN EX. 1033, Page 7
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`Page 7
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`Art Unit: 1611
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`Regarding the choice of metal chloride (claims 3, 12, and 15) Lehmussaari
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`teaches six choices of buffer/salt, two of which are sodium chloride and potassium
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`chloride (col. 3, lines 45-50), and exemplify sodium chloride as the salt present in the
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`composition (col. 5, Example 2).
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`Regarding claims 5, 6, and 15, Kita teaches the benzenesulfonic acid salt of
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`bepotastine (col. 1, lines 11-13).
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`Regarding claim 7, Lehmussaari teaches that the pH of the composition is
`
`suitably from 5 to 8 (col. 3, lines 59-60), which is within Applicant's range.
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`Regarding the limitation that the composition is an eye drop (claims 8 and 13),
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`Lehmussaari teaches that its invention is an easy-to-use eye drop formulation with
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`improved patient compliance (col. 2, lines 3-5).
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`Regarding the limitation that the composition is a nasal drop (claim 9), said
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`limitation recites an intended use of the composition. Since the components of the
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`composition of the combined references are suitable for use in the nose, said
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`composition would be capable of use as a nasal drop.
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`6.
`
`Applicant's arguments filed 28 February 2014 have been fully considered but
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`Response to Arguments
`
`they are not persuasive.
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`Applicant first argues that the composition of Lehmussaari requires the presence
`
`of an ion sensitive, hydrophilic polymer having viscosity, such as Carbopol, to control
`
`the formation of the polymer film on the cornea of the eye, but Carbopol is degraded by
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`MYLAN EX. 1033, Page 8
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`Page 8
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`Art Unit: 1611
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`light, citing the Declaration filed September 14, 2012. Applicant asserts that the
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`Carbopol polymer would materially affect the basic and novel characteristics of the
`
`preparation because it would introduce a component that degrades in light into a
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`solution that is designed to “light-stabilize” bepotastine by using a water-soluble metal
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`chloride.
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`(Applicant’s Remarks, filed 28 February 2014, page 3, and Declaration filed
`
`14 September 2012, Section I).
`
`This argument is not persuasive. While Applicant's evidence teaches Carbopol
`
`polymers, such as those taught in Lehmussaari, degrade in the presence of light,
`
`Applicant's evidence does not show that such a polymer, when present in the
`
`composition of the combined references, would cause the composition to not be light-
`
`stable. Thus, it is not clear that such a polymer would affect the basic and novel
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`characteristics of the claimed composition.
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`It is optionally further noted that both
`
`carbopol and bepotastine contain reactive carboxyl groups; since salts of organic acids
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`are known to be more stable than the corresponding free acid, one of ordinary skill in
`
`the art would reasonably expect that a compound (such as sodium chloride) which light-
`
`stabilizes bepotastine would also light-stabilize carbopol, absent evidence to the
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`contrary.
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`Examiner’s note: objective evidence presented which shows that carbopol
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`degrades in the presence of light and sodium chloride (i.e., is not light-stabilized by a
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`metal chloride such as sodium chloride) would be sufficient to overcome the rejection.
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`Applicant further argues that there is no reason, based upon the art, to expect a
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`metal chloride to light-stabilize Carbopol, and asserts the Examiner's position is “merely
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`MYLAN EX. 1033, Page 9
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`MYLAN Ex. 1033, Page 9
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`Page 9
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`Art Unit: 1611
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`a conclusory statement.” Applicant argues that the Examiner has not articulated any
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`reason with some rational underpinning, based on the art, that the reactive carboxy
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`groups in Carbopol and bepotastine are related to light—stabilization. Applicant further
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`argues that the Examiner has made an assumption that the metal chloride light-
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`stabilizes bepotastine simply because it contains a carboxy group without any reasoning
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`based upon Lehmussaari, Kita, or Araki. Applicant further argues differences between
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`Carbopol, bepotastine, and sitafloxacin (pages 3-4 of Remarks).
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`This argument is not persuasive. The Examiner points out that the question here
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`is not one of obviousness, since the teachings of Lehmussaari and Kita (and optionally
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`Araki) already meet the limitations of the claimed invention in terms of the required
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`components of bepotastine and a water-soluble metal chloride. Rather, the question is
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`whether or not the presence of Carbopol would materially affect the basic and novel
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`characteristics of the claimed composition, and thus be excluded from the composition
`
`due to the use of the transitional language, “consisting essentially of’. To this end,
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`Applicant has not demonstrated that Carbopol degrades in the presence of light in the
`
`composition of the combined references, and therefore it has not been shown that
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`Carbopol would materially affect the basic and novel characteristics of the claimed
`
`composition. That Carbopol, bepotastine, and sitafloxacin all have reactive carboxy
`
`groups is noted merely to point out that, because the compounds contain similar
`
`reactive groups, the skilled artisan would reasonably expect the compounds to react
`
`with sodium chloride (a compound known to react with reactive carboxy groups to form
`
`the corresponding salt) in a similar fashion, absent evidence to the contrary.
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`Page 10
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`Art Unit: 1611
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`Applicant also argues that the amount of metal chloride recited in claims 1 and
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`13 is a critical range that achieves unexpected results over the art. Applicant argues
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`that, in Experimental Example 1 of the specification, Formulation 2 comprising 0.1 W/V°/o
`
`of sodium chloride fails to light-stabilize bepotastine besilate, while Formulations 3-6
`
`comprising 0.2 to 1.18 W/V°/o of a metal chloride provide a light-stabilizing effect.
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`Applicant’s data in the specification has been fully considered, but is not
`
`sufficient for overcoming the rejection. While Applicant's data shows an optimal range
`
`in which sodium, potassium, or calcium chloride impart a light-stabilization effect to a
`
`bepotastine-containing composition (Example 1 of specification), the range of amounts
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`now claimed (i.e., 0.2 to 1.2% w/v) still sufficiently overlaps that of Lehmussaari (0.01 to
`
`2.0%, with an amount of 0.9 W/V°/o exemplified; see Example 2) and Araki (0.01°/o to
`
`0.5%; see Table 1 and paragraph [0101]), and are sufficiently close that one skilled in
`
`the art would still arrive at such a range by routine experimentation, and would be
`
`motivated to do so in order to optimize the viscosity of the composition, as taught by
`
`Lehmussaari (which would necessarily be a light-stabilizing effective amount), and/or to
`
`light-stabilize the composition, as taught by Araki. Therefore, while the data presented
`
`in the specification has been fully considered, the evidence is not sufficient to outweigh
`
`the prima facie case of obviousness, and therefore the rejection stands. Note that,
`
`while evidence pertaining to secondary eeneideretions must be taken inte aeceunt
`
`whenever present, it deee not neceeeerily control the obvieusneee eeneiueien. See
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`MPEP 2145.
`
`Therefore, it is the Examiner’s position that the claims are rendered obvious.
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`MYLAN EX. 1033, Page 11
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`Page 11
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`7.
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`Claim 14 is allowed.
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`Allowable Subject Matter
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`8.
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`Claims 1, 3, 5-9, 12, 13, and 15 are rejected; claim 14 is allowed.
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`Conclusion
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`9.
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`THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time
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`policy as set forth in 37 CFR 1.136(a).
`
`A shortened statutory period for reply to this final action is set to expire THREE
`
`MONTHS from the mailing date of this action.
`
`In the event a first reply is filed within
`
`TWO MONTHS of the mailing date of this final action and the advisory action is not
`
`mailed until after the end of the THREE-MONTH shortened statutory period, then the
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`shortened statutory period will expire on the date the advisory action is mailed, and any
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`extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of
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`the advisory action.
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`In no event, however, will the statutory period for reply expire later
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`than SIX MONTHS from the mailing date of this final action.
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`MYLAN EX. 1033, Page 12
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`Application/Control Number: 10/500,354
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`Page 12
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`Art Unit: 1611
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`Any inquiry concerning this communication or earlier communications from the
`
`examiner should be directed to BARBARA FRAZIER whose telephone number is
`
`(571)270-3496. The examiner can normally be reached on Monday—Friday 9am-2:30pm
`
`EST.
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
`
`supervisor, Daniel Sullivan can be reached on (571)272-0779. The fax phone number
`
`for the organization where this application or proceeding is assigned is 571-273-8300.
`
`Information regarding the status of an application may be obtained from the
`
`Patent Application Information Retrieval (PAIR) system. Status information for
`
`published applications may be obtained from either Private PAIR or Public PAIR.
`
`Status information for unpublished applications is available through Private PAIR only.
`
`For more information about the PAIR system, see http://pair-direct.uspto.gov. Should
`
`you have questions on access to the Private PAIR system, contact the Electronic
`
`Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a
`
`USPTO Customer Service Representative or access to the automated information
`
`system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
`
`BSF
`
`/DANIEL SULL|VAN/
`
`Supervisory Patent Examiner, Art Unit 1611
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`MYLAN EX. 1033, Page 13
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`MYLAN Ex. 1033, Page 13