UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Ul\TfED STI\TES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adill"'· COMMISSIO'JER FOR PATENTS
`PO Box 1450
`Alexandria, Virgmia 22313-1450
`\VVi\V.USpto.gov
`
`APPLICATION
`NUMBER
`61/192,777
`
`FILING or
`37l(c)DATE
`09/22/2008
`
`140
`LADAS & PARRY LLP
`26 WEST 61ST STREET
`NEW YORK, NY 10023
`
`FIL FEE REC'D
`105
`
`ATTY.DOCKET.NO
`
`u 017463-9
`
`CONFIRMATION NO. 2891
`FILING RECEIPT
`
`IIIIIIIIIIIIIIIIIIIIIIII]~!I]~~~~~~~~~~~IUUI~~IIIIIIIIIIIIIIIIIIIIIIIIII
`
`Date Mailed: 10/29/2008
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
`APPLICANT, and TITLE OF INVENTION. Fees transmitted by check or draft are subject to collection. Please verify
`the accuracy of the data presented on this receipt. If an error is noted on this Filing Receipt, please submit
`a written request for a Filing Receipt Correction. Please provide a copy of this Filing Receipt with the
`changes noted thereon. If you received a "Notice to File Missing Parts" for this application, please submit
`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processes the reply
`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`Applicant( s)
`
`Gerald Horn, Deerfield, IL;
`Power of Attorney: The patent practitioners associated with Customer Number 00140
`
`If Required, Foreign Filing License Granted: 10/27/2008
`
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/192,777
`
`Projected Publication Date: None, application is not eligible for pre-grant publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`** SMALL ENTITY **
`Title
`
`Topical vasoconstrictor composition and methods of using the same
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
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`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
`protection is desired.
`
`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
`application for patent in that country in accordance with its particular laws. Since the laws of many countries differ
`in various respects from the patent law of the United States, applicants are advised to seek guidance from specific
`foreign countries to ensure that patent rights are not lost prematurely.
`
`Applicants also are advised that in the case of inventions made in the United States, the Director of the USPTO must
`issue a license before applicants can apply for a patent in a foreign country. The filing of a U.S. patent application
`serves as a request for a foreign filing license. The application's filing receipt contains further information and
`guidance as to the status of applicant's license for foreign filing.
`
`Applicants may wish to consult the USPTO booklet, "General Information Concerning Patents" (specifically, the
`section entitled "Treaties and Foreign Patents") for more information on timeframes and deadlines for filing foreign
`patent applications. The guide is available either by contacting the USPTO Contact Center at 800-786-9199, or it
`can be viewed on the USPTO website at http://www.uspto.gov/web/offices/pac/doc/general/index.html.
`
`For information on preventing theft of your intellectual property (patents, trademarks and copyrights), you may wish
`to consult the U.S. Government website, http://www.stopfakes.gov. Part of a Department of Commerce initiative,
`this website includes self-help "toolkits" giving innovators guidance on how to protect intellectual property in specific
`countries such as China, Korea and Mexico. For questions regarding patent enforcement issues, applicants may
`call the U.S. Government hotline at 1-866-999-HAL T (1-866-999-4158).
`
`LICENSE FOR FOREIGN FILING UNDER
`
`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`GRANTED
`
`The applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
`the conditions for issuance of a license have been met, regardless of whether or not a license may be required as
`set forth in 37 CFR 5.15. The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
`license has been issued under 37 CFR 5.15(b). The license is subject to revocation upon written notification. The
`date indicated is the effective date of the license, unless an earlier license of similar scope has been granted under
`37 CFR 5.13 or 5.14.
`
`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof unless
`it is revoked. This license is automatically transferred to any related applications(s) filed under 37 CFR 1.53(d). This
`license is not retroactive.
`
`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject matter
`as imposed by any Government contract or the provisions of existing laws relating to espionage and the national
`security or the export of technical data. Licensees should apprise themselves of current regulations especially with
`respect to certain countries, of other agencies, particularly the Office of Defense Trade Controls, Department of
`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
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`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
`Treasury (31 CFR Parts 500+) and the Department of Energy.
`
`NOT GRANTED
`
`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
`if a license is desired before the expiration of 6 months from the filing date of the application. If 6 months has lapsed
`from the filing date of this application and the licensee has not received any indication of a secrecy order under 35
`U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
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`/
`
`U.S. PTO
`61/192777
`09/22/2008
`
`Practitioner's Docket No. U 017463-9
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`' ei"n re application of:
`~-
`:J·or:
`0
`
`Gerald HORN
`
`TOPICAL VASOCONSTRICTOR COMPOSITION AND METHODS OF USING THE
`SAME
`
`Commissioner for Patents
`P. 0. Box 1450
`Alexandria, VA 22313-1450
`
`Optional Customer No. Bar Code
`
`lllllllllllllllllllllllllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`COVER SHEET FOR FILING PROVISIONAL APPLICATION
`(37 C.F.R. § 1.51(c)(1))
`
`WARNING:
`
`"A provisional application must also include the cover sheet required by§ 1.51 (c)(1) or a cover letter
`identifYing the application as a provisional application. Otherwise, the application will be treated as an
`application filed under paragraph (b) [nonprovisional application] of this section." 37 C.F.R. §
`1.53(c)(l).. See also MP.E.P. § 201.04(b), 6th ed, rev. 3.
`
`CERTIFICATION UNDER37 C.F.R. 1.10*
`(Express Mail label number is mandatory.)
`(Express Mail certification is optional.)
`
`I hereby certify that this correspondence and the documents referred to as attached therein are being deposited with the
`United States Postal Service on September 22, 2008 in an envelope as "EXPRESS MAIL POST OF CE TO
`ADDRESSEE" service under 37 C.F.R. 1.10 Mailing Label Number EV 926371547 US addressed
`for Patents, P. 0. Box 1450, Alexandria, VA 22313-1450.
`
`WARNING:
`
`Certificate of mailing (first class) or facsimile transmission procedures of 3 7 C.F.R. 1.8 cannot be used
`to obtain a date of mailing or transmission for this correspondence.
`
`*WARNING:
`
`Each paper or fee filed by "Express Mail" must have the number of the "Express Mail" mailing ldbel
`placed thereon prior to mailing. 3 7 C.F.R. 1 .JO(b).
`"Since the filing of correspondence under§ 1.10 without the Express Mail mailing label thereon is an
`oversight that can be avoided by the exercise of reasonable care, requests for waiver of this
`requirement will not be granted on petition." Notice of Oct. 24, 1996, 60 Fed Reg. 56,439, at 56,442.
`
`(Cover Sheet for Filing Provisional Application-page I of7) 23-1
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`NOTE: "A complete provisional application does not require claims sinceno examination on the merits will be given to a
`provisional application. However, provisional applications may be filed with one or more claims as part of the
`application. Nevertheless, no additional claim fee or multiple dependent claims fee will be required in a
`provisional application." Notice of December 5, 1994, 59 FR 63951, at 63953.
`
`"Any claim filed with a provisional application will, of course, be considered part of the original provisional
`application disclosure." Notice of Apri/14, 1995, 60 Fed. Reg. 20,195, at 20,209.
`
`NOTE: "A provisional application is not entitled to the right of priority under 35 US. C. 119 or 365(a) or§ 1.55, or to the
`benefit of an earlier filing date under 35 US. C. 120, 121 or 365(c) or§ 1. 78 of any other application. No claim
`for priority under§ 1. 78(a)(3) may be made in a design application based on a provisional application. No
`request under§ 1.293 for a statutory invention registration may be filed in a provisional application. The
`requirements of§§ 1. 821 through 1. 82 5 regarding application disclosures containing nucleotide and/or amino
`acid sequences are not mandatory for provisional applications." 37 C.F.R. 1.53(c)(3).
`
`NOTE: "No information disclosure statement may be filed in a provisional application." 37 C.F.R. § 1.51(d). "Any
`information disclosure statements filed in a provisional application would either be returned or disposed of at the
`convenience of the Office." Notice of December 5, 1994, 59 FR 63591, at 63594.
`
`NOTE: "No amendment other than to make the provisional application comply with the patent statute and all applicable
`regulations, may be made to the provisional application after the filing date of the provisional application. "3 7
`C.F.R. § 1.53(c).
`
`NOTE: 35 US. C. 1 19(e) provides that "{i}fthe day that is 12 months after the filing date of a provisional application falls
`on a Saturday, Sunday, or Federal Holiday within the District of Columbia, the period of pendency of the
`provisional application shall be extended to the next succeeding secular or business day."
`
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 C.F.R.
`§ 1.51(c)(l)(i).
`
`1.
`
`2.
`
`The following comprises the information required by 37 C.F.R. § 1.5l(c)(l):
`
`The name(s) ofthe inventor(s) is/are (37 C.F.R. § 1.5l(c)(l)(ii)):
`
`NOTE: "If the correct inventor or inventors are not named on filing, a provisional application without a cover sheet
`under§ 1.51(c)(1), the later submission of a cover sheet under§ 1.51(c)(l) during the pendency of the application
`will act to correct the earlier identification ofinventorship." 37 C.F.R. § 1.48(/)(2).
`
`NOTE: "The naming of inventors for obtaining a filing date for a provisional application is the same as for other
`applications. A provisional application filed with the inventors identified as 'Jones eta/.' will not be accorded a
`filing date earlier than the date upon which the name of each inventor is supplied unless a petition with the fee set
`forth in§ f. 1 7(i) isfiledwhich sets forth the reasons the delay in supplying the names should be excused.
`Administrative oversight is an acceptable reason. It should be noted that for a 35 U.S. C. 111 (a) application to be
`entitled to claim the benefit of the filing date of a provisional application the 35 US. C. 111 (a){,] application must
`have at least one inventor in common with the provisional application." Notice of Apri/14, 1995, 60 Fed. Reg.
`20,195, at 20,209.
`
`The term "invention" is typically used to refer to subject matter which applicant is claiming in his/her application.
`Because claims are not required in a provisional application, it would not be appropriate to reference joint
`inventors as those who have made a contribution to the "invention" disclosed in the provisional application. If the
`"invention" has not been determined in the provisional application because no claims have been presented, then
`the name(s) of those person(s) who have made a contribution to the subject matter disclosed in the provisional
`application should be submitted. Section !.45(c) states that "if multiple inventors are named in a provisional
`application, each named inventor must have made a contribution, individually or jointly, to the subject matter
`disclosed in the provisional application." All that§ /.45(c) requires is that if someone is named as an inventor,
`that person must have made a contribution to the subject matter disclosed in the provisional application. When
`
`(Cover Sheet for Filing Provisional Application-page 2 of7) 23-1
`
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`applicant has determined what the invention is by the filing of the 35 U.S. C. 1 ll(a) application, that is the time
`when the correct inventors must be named. The 35 U.S. C. lll(a) application must have an inventor in common
`with the provisional application in order for the 35 U.S. C. 111 (a) application to be entitled to claim the benefit of
`the provisional application under 35 U.S. C. 119(e). Notice of April 14, 1995, 60 Fed. Reg. 20,195, at 20,208.
`
`See 37 C.F.R. § 1.53.
`
`(Cover Sheet for Filing Provisional Application-page 3 of7) 23-1
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`l.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Gerald
`GIVEN NAME
`
`MIDDLE INITIAL OR NAME
`
`HORN
`FAMILY (OR LAST) NAME
`
`GIVEN NAME
`
`MIDDLE INITIAL OR NAME
`
`FAMILY (OR LAST) NAME
`
`GIVEN NAME
`
`MIDDLE INITIAL OR NAME
`
`FAMILY (OR LAST) NAME
`
`GIVEN NAME
`
`MIDDLE INITIAL OR NAME
`
`FAMILY (OR LAST) NAME
`
`GIVEN NAME
`
`MIDDLE INITIAL OR NAME
`
`FAMILY (OR LAST) NAME
`
`3.
`
`Residence address(es) ofthe inventor(s), as numbered above (37 C.F.R. § 1.51(c)(1)(iii)):
`
`1150 HEATHER ROAD DEERFIELD. ILLINOIS 60015
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`4.
`
`5.
`
`The title ofthe invention is (37 C.F.R. § 1.51(c)(1)(iv)):
`TOPICAL VASOCONSTRICTOR COMPOSITION AND METHODS OF USING THE
`SAME
`
`The name, registration, customer and telephone numbers of the practitioner (if applicable)
`are (37 C.F.R. § 1.51(c)(l)(v)):
`
`Name ofpractitioner:
`
`JOHN RICHARDS
`
`Reg. No. --=3'-"1-"'-0=53"'-------
`
`Tel. (212) 708-1915
`
`Customer No. 00140
`
`(complete the following, if applicable)
`
`[ ]
`
`A power of attorney accompanies this cover sheet.
`
`6.
`
`The docket number used to identify this application is (37 C.F.R. § 1.51(c)(1)(vi)):
`
`Docket No. U 017463-9
`
`(Cover Sheet for Filing Provisional Application-page 4 of7) 23-1
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`7.
`
`The correspondence address for this application is (37 C.F.R. § l.Sl(c)(l)(vii)):
`
`Optional Customer No. Bar Code
`
`lllllllllllllllllllllllllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`which is Ladas & Parrv LLP, 26 West 61 51 Street. New York, NY I 0023
`
`8.
`
`Statement as to whether invention was made by an agency of the U.S. Government or under
`contract with an agency ofthe U.S. Government. (37 C.F.R. § 1.5l(c)(l)(viii)).
`
`This invention was made by an agency of the United States Government, or under contract
`with an agency ofthe United States Government.
`
`[x]
`[ ]
`
`No
`Yes
`
`The name of the U.S. Government agency and the Government contract number
`are:
`
`9.
`
`Identification of documents accompanying this cover sheet:
`
`A. Documents required by 37 C.F.R. §§ 1.51(c)(2)-(3):
`
`Specification:
`Claims:
`Drawings:
`
`B.
`
`Additional documents:
`
`No.ofpages __ ~4~3 ____ _
`No.ofpages __ -=6 ____ _
`No. of sheets --'1"'"'1:....._ __ _
`
`[.I']
`
`Claims:
`
`No. of claims ----=5'-'1:....._ _ _
`
`Note:
`
`See 37 C.F.R. § 1.51.
`
`[.I']
`
`[ ]
`[ ]
`[ ]
`
`Petition to Accept Colored Drawings No. of sheets __ .!..,.7 ____ _
`(Including the color drawings)
`Power of attorney
`Assignment
`English language translation of non-English provisional application and
`Statement of Accuracy thereof
`
`NOTE: A provisional application which is filed in a language other than English, does not have to have an English
`language translation. See 37 C.F.R. § 1.52(d}(2). However, if the provisional application is not in the English
`language and will later serve as a benefit of its filing date for a nonprovisional application, other than a design
`patent, or for an international application designating the U.S, then an English language translation must be filed
`in the provisional application or the later filed nonprovisional application. See§ I. 78(a)(5)(iv).
`
`(Cover Sheet for Filing Provisional Application-page 5 of7) 23-1
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`10.
`
`Fee
`
`The filing fee for this provisional application, as set in 3 7 C.F .R. § 1.16( d), is $210.00, for
`other than a small entity, and $105.00, for a small entity.
`
`A.
`
`[ ]
`
`Additional fee for specification and drawings filed in paper over 100 sheets
`(excluding sequence listing or computer program listing filed in electronic
`medium). The fee is $250.00 for each additional 50 sheets paper or fraction
`thereof and $125.00 for a small entity.
`
`B.
`
`[ ]
`[x]
`
`Applicant is not a small entity.
`Applicant is a small entity.
`
`NOTE: "A .. . statement in compliance with existing§ 1.27 is required to be filed in each provisional application in which
`itis desired to pay reduced fees." Notice of Apri/14, 1995, 60 Fed. Reg. 20, 195, at 20,197.
`
`11.
`
`Small entity assertion
`
`[ ]
`
`[x]
`
`A Statement or Written Assertion that this is a filing by a small entity under 3 7
`C.F.R. § 1.27(c)(l) is attached.
`
`Small entity status is asserted for this application by payment of the small entity filing
`fee under§ 1.16(d). 37 C.F.R. § 1.27(c)(3).
`
`WARNING:
`
`"Small entity status must not be established unless the person or persons signing the ... statement can
`unequivocally make the required self-certification." MP.E.P. Section 509.03, 6th ed., rev. 2, July 1996
`(emphasis added).
`
`12.
`
`Fee payment
`
`[tf]
`
`Fee payment in the amount of$ 105.00 is being made at this time.
`
`[ ]
`
`No filing fee is to be paid at this time. (This and the surcharge required by 37 C.F.R.
`§ 1.16(g) can be paid subsequently.)
`
`(Cover Sheet for Filing Provisional Application-page 6 of7) 23-1
`
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`13. Method of fee payment
`
`[tl"]
`[ ]
`
`Check in the amount of$ 105.00.
`Charge Account No. 12-0425, in the amount of$ _ _ _ _ _
`A duplicate ofthis Cover Sheet is attached.
`
`Please charge Account No. 12-0425 for any deficiency in the fee paid.
`
`Date:-------
`
`Tel.: (
`
`)
`
`Date: September 22, 2008
`
`Signature of submitter
`
`OR
`
`Reg. No.: 31053
`
`SIGNATURE
`
`Tel. No.: (212) 708-1915
`
`(type or print name of practitioner)
`
`Customer No.: 00140
`lllllllllllllllllllllllllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`P.O. Address
`
`c/o Ladas & Parry LLP
`26 West 6P1 Street
`New York, N.Y. 10023
`
`(Cover Sheet for Filing Provisional Application-page 7 of7) 23-1
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`,,
`
`Practitioner's Docket No. U 017463-9
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Gerald HORN
`
`In re application of:
`Application No.:
`Filed:
`For:
`
`Group No.:
`Examiner:
`TOPICAL VASOCONSTRICTOR COMPOSITION AND METHODS OF USING THE
`SAME
`
`Commissioner for Patents
`P. 0. Box 1450
`Alexandria, VA 22313-1450
`
`PETITION TO ACCEPT COLOR DRAWINGS
`OR PHOTOGRAPHS (37 CFR 1.84(a)(2) and (b)(2))
`
`1. This petition is for the acceptance of color:
`
`[x] drawings (37 C.F.R. § 1.84(a)(2))
`
`[ ] photographs (37 C.F.R. § 1.84(b)(2))
`
`2. Attached hereto are three (3) sets of color: [x] drawings []photographs that accurately depict,
`to the extent possible, the subject matter shown in the color drawings or photographs.
`
`3. Please amend the specification, by inserting the following language as the first paragraph of the
`specification beginning a brief description of the drawing or photograph (page 21 between lines
`14 and
`15 ).
`
`"The file of this patent contains at least one drawing or photograph executed in color. Copies of
`this patent with color drawing(s) or photograph(s) will be provided by the Patent and Trademark
`Office upon request and payment of necessary fee."
`
`4. The reason(s) for the need for color drawings or photographs in this application is/are as follows:
`
`To better understand the invention
`
`09/24/2008 "GEBREM1 00809050 ~1192777
`138.00 OP
`02 FC: 14f.4
`
`(Petition to Accept Color Drawings or Photographs (37 C.F.R. 1.84(a)(2) and (b)(2))-page I of2) 9-30
`
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`i'
`
`5. The petition fee required to waive the requirements of§ 1.84 (37 C.F.R. § 1.17(h)) is paid as
`follows:
`
`[x] Attached is a check for the sum of $130.00.
`[ ] Charge account
`the sum of$130.00.
`A duplicate of this petition is attached.
`
`Reg. No.: 31053
`
`Tel. No.: (212)708-1915
`
`(type or print name of practitioner)
`
`JOHNRICHA
`
`Customer No.: 00140
`lllllllllllllllllllllllllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`P.O. Address
`
`c/o Ladas & Parry LLP
`26 West 61 51 Street
`New York, N.Y. 10023
`
`Date September 22. 2008
`
`(Petition to Accept Color Drawings or Photographs (37 C.P.R. 1.84(a)(2) and (b)(2))-page 2 of2) 9-30
`
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`•'
`
`u 017463-9
`
`FIG. 8
`
`Examples of shades of scleral whitening :
`
`off- White
`
`Bright White
`
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`u 017463-9
`
`FIG.9
`
`Examples
`
`Example 1: OD = right eye; OS = left eye Improvement relative to baseline measured + - ++++
`
`#0 Pretreatment Baseline: contact lens irritation and allergic reaction:
`
`#1 OD: Tetrahydrozoline 0.05% OS: Brimonidine 0.01%
`
`OD 5-180 min:
`
`OS 5- 180 min:
`
`+I-
`
`++Y2
`
`#2 OD: Oxymetazoline 0.025%; OS: Brim 0.02% OS
`
`(4 hrs after #labove- using #0 baseline)
`
`+
`
`+++ Y2
`
`Page 14 of 89
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`

`

`u 017463-9
`
`#3 OD: Naphazoline 0.033%; OS: Brim 0.02% OS (4 hrs after #2 above)
`
`++~
`
`+++~
`
`#4 Brimonidine 0.033% OS only, 4 hrs after #3 above (third application wlo
`rebound)
`
`+++ Yz
`
`Effectiveness in most clinical situations even greater as baseline redness was @ 4
`I 4 for this test; in average clinical situation @ 1- 1.5 I 4.
`
`Due to its high safety profile regarding adverse systemic toxicity, pharmaceuticals
`utilizing the present invention may be used every 3-4 hours with low incidence of
`hyperemia. The concentrations used should be optimized for their
`vasoconstrictive dose response curve, which may differ from other desired
`clinical effects, and in the embodiment tested (brimonidine) is 20 x less (10 -200
`x dose response range less) than currently used for glaucoma treatment as bid
`dosing.
`
`Page 15 of 89
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`SLAYBACK EXHIBIT 1013
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`

`

`u 017463-9
`
`Fig 10
`
`Baseline:
`
`Right eye Visine® Original
`ii gtts tid, day 2 1st instillation
`
`Left eye Brimonidine 0.012o/o x1
`
`ii gtts tid, day 2 1st instillation
`
`Note rebound hyperemia
`
`Right eye Brimonidine 0.12% x1
`ii gtts
`
`Left eye Brimonidine 0.012%x1
`
`ii gtts
`
`Right eye:
`
`Left eye:
`
`Note significant reversal of rebound hyperemia
`
`Note improved whitening over baseline.
`
`with single application preferred embodiment OD
`
`Page 16 of 89
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`SLAYBACK EXHIBIT 1013
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`

`

`u 017463-9
`
`Fig 11
`
`Schematic of probable cause ischemia secondary to preferential receptor distribution larger
`
`vessels (alpha 1 agonist; alpha 2 agonists concentration range 0.08% or higher): [red=
`
`vasoconstriction with ischemia due to larger vessel constriction; blue = vasoconstriction without
`
`ischemia due to proportionate smaller vessel constriction with large surface area of decongestion;
`
`I
`
`CopiUorl.s
`
`Teaching ofthe present invention: Hi selectivity alpha 2 :alpha 1 binding affinity; low
`
`concentration (just above the minimum threshold concentration for measurable vasoconstriction,
`
`preferably by typically 10% to 90% ). Note large surface area coverage with microvessel
`
`constriction, greatly improved total blood flow with greater larger vessel pretreatment lumen or
`
`CapiUarie\
`
`near lumen diameter retention.
`
`Page 17 of 89
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`SLAYBACK EXHIBIT 1013
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`

`

`u 017463-9
`
`FIG. 8
`
`Examples of shades of scleral whitening :
`
`Off-White
`
`Bright White
`
`Page 18 of 89
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`SLAYBACK EXHIBIT 1013
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`

`

`u 017463-9
`
`FIG.9
`
`Examples
`
`Example 1: OD = right eye; OS = left eye Improvement relative to baseline measured + - ++++
`
`#0 Pretreatment Baseline: contact lens irritation and allergic reaction:
`
`#1 OD: Tetrahydrozoline 0.05% OS: Brimonidine 0.01%
`
`OD 5-180 min:
`
`OS 5- 180 min:
`
`+I-
`
`++~
`
`#2 OD: Oxymetazoline 0.025%; OS: Brim 0.02% OS
`
`(4 hrs after #Iabove- using #0 baseline)
`
`+
`
`+++~
`
`Page 19 of 89
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`SLAYBACK EXHIBIT 1013
`
`

`

`·-
`
`u 017463-9
`
`#3 OD: Naphazoline 0.033%; OS: Brim 0.02% OS (4 hrs after #2 above)
`
`:.
`
`....... "'":1--
`
`.
`
`;.+-t~: .,.~:
`
`;;:, -;-· .. ~~.:~~;~~ . ! .··-··~.
`
`#4 Brimonidine 0.033% OS only, 4 hrs after #3 above (third application wlo
`rebound)
`
`+++Yz
`
`+++ Yz
`
`Effectiveness in most clinical situations even greater as baseline redness was @ 4
`I 4 for this test; in average clinical situation @ 1- 1.5 I 4.
`
`Due to its high safety profile regarding adverse systemic toxicity, pharmaceuticals
`utilizing the present invention may be used every 3-4 hours with low incidence of
`hyperemia. The concentrations used should be optimized for their
`vasoconstrictive dose response curve, which may differ from other desired
`clinical effects, and in the embodiment tested (brimonidine) is 20 x less (10 -200
`x dose response range less) than currently used for glaucoma treatment as bid
`dosing.
`
`Page 20 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`u 017463-9
`
`Fig 10
`
`Baseline:
`
`Right eye Visine® Original
`
`ii gtts tid, day 2 1st instillation
`
`Left eye Brimonidine 0.012o/o xi
`
`ii gtts tid, day 2 1st instillation
`
`Note rebound hyperemia
`
`Right eye Brimonidine 0.12% xl
`
`Left eye Brimonidine 0.012%xl
`
`ii gtts
`
`ii gtts
`
`Right eye:
`
`Left eye:
`
`Note significant reversal of rebound hyperemia
`
`Note improved whitening over baseline.
`
`with single application preferred embodiment OD
`
`Page 21 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`u 017463-9
`
`Fig 11
`
`Schematic of probable cause ischemia secondary to preferential receptor distribution larger
`
`vessels (alpha 1 agonist; alpha 2 agonists concentration range 0.08% or higher): [red=
`
`vasoconstriction with ischemia due to larger vessel constriction; blue = vasoconstriction without
`
`ischemia due to proportionate smaller vessel constriction with large surface area of decongestion;
`
`I
`
`Teaching of the present invention: Hi selectivity alpha 2: alpha 1 binding affinity; low
`
`concentration Gust above the minimum threshold concentration for measurable vasoconstriction,
`
`preferably by typically 10% to 90% ). Note large surface area coverage with microvessel
`
`constriction, greatly improved total blood flow with greater larger vessel pretreatment lumen or
`
`CoplUaf'ies
`
`near lumen diameter retention.
`
`Venut&
`
`Page 22 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`..
`
`u 017463-9
`
`FIG. 8
`
`Examples of shades of scleral whitening :
`
`Off- White
`
`Bright White
`
`Page 23 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`.-
`
`Examples
`
`u 017463-9
`
`FIG.9
`
`Example 1: OD = right eye; OS = left eye Improvement relative to baseline measured + - ++++
`
`#0 Pretreatment Baseline: contact lens irritation and allergic reaction:
`
`#1 OD: Tetrahydrozoline 0.05% OS: Brimonidine 0.01%
`
`OD 5-180 min:
`
`OS 5- 180 min:
`
`+I-
`
`++~
`
`#2 OD: Oxymetazoline 0.025%; OS: Brim 0.02% OS
`
`(4 hrs after #Iabove- using #0 baseline)
`
`+
`
`+++~
`
`Page 24 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`·-
`
`u 017463-9
`
`#3 OD: Naphazoline 0.033%; OS: Brim 0.02% OS (4 hrs after #2 above)
`
`++Yz
`
`+++ Yz
`
`#4 Brimonidine 0.033% OS only~ 4 hrs after #3 above (third application wlo
`rebound)
`
`+++ Yz
`
`Effectiveness in most clinical situations even greater as baseline redness was @ 4
`I 4 for this test; in average clinical situation @ 1- 1.5 I 4.
`
`Due to its high safety profile regarding adverse systemic toxicity, pharmaceuticals
`utilizing the present invention may be used every 3-4 hours with low incidence of
`hyperemia. the concentrations used should be optimized for their
`vasoconstrictive dose response curve, which may differ from other desired
`clinical effects~ and in the embodiment tested (brimonidine) is 20 x less (10 -200
`x dose response range less) than currently used for glaucoma treatment as bid
`dosing.
`
`Page 25 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`-·
`
`Baseline:
`
`u 017463-9
`
`Fig 10
`
`Right eye Visine® Original
`ii gtts tid, day 2 1st instillation
`
`Left eye Brimonidine 0.012o/o x1
`
`ii gtts tid, day 2 1st instillation
`
`Note rebound hyperemia
`
`Right eye Brimonidine 0.12% x1
`
`Left eye Brimonidine 0.012%x1
`
`ii gtts
`
`ii gtts
`
`Right eye:
`
`Left eye:
`
`Note significant reversal of rebound hyperemia
`
`Note improved whitening over baseline.
`
`with single application preferred embodiment OD
`
`Page 26 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`...
`
`u 017463-9
`
`,.
`... .
`
`(
`
`Fig 11
`
`Schematic of probable cause ischemia secondary to preferential receptor distribution larger
`
`vessels (alpha 1 agonist; alpha 2 agonists concentration range 0.08% or higher): [red=
`
`vasoconstriction with ischemia due to larger vessel constriction; blue = vasoconstriction without
`
`ischemia due to proportionate smaller vessel constriction with large surface area of decongestion;
`
`Teaching of the present invention: Hi selectivity alpha 2 :alpha 1 binding affinity; low
`
`concentration Gust above the minimum threshold concentration for measurable vasoconstriction,
`
`preferably by typically 10% to 90% ). Note large surface area coverage with microvessel
`
`constriction, greatly improved total blood flow with greater larger vessel pretreatment lumen or
`
`Arteriole
`
`lf---:--AV.shunt
`
`Capibarie,
`
`near lumen diameter retention.
`
`Venule
`
`Page 27 of 89
`
`SLAYBACK EXHIBIT 1013
`
`

`

`DOCKET NO.: U 017463-9
`
`Topical Vasoconstrictor Composition And Methods Of Using The Same
`
`- 1 -
`
`Cross-Reference To Related Application
`
`This invention is related to that described in application Serial No 61/137,714
`
`filed on August 1, 2008 the content of which is incorporated herein by reference.
`
`The present invention relates to a topical composition for effecting
`
`vasoconstriction and methods by which it may be employed, for example in administration to
`
`the eye and for treating nasal congestion.
`
`Background of the invention
`
`Dilation of small blood vessels, particularly arterioles, capillaries, and venules, ·
`
`causes numerous clinically undesirable events including: release of inflammatory substances,
`
`spread of pathogens, surface hemorrhage and hyperemia following Lasik surgery, eye redness
`
`(conjunctival hyperemia), nasal congestion (turbinate mucosal swelling secondary to
`
`vasodilation), skin discoloration (vasodilated induced "flushing", "rosacea, psoriasis" and
`
`other vascular abnormalities/telangiectasia), and hemorrhoidal swelling (venule dilation).
`
`Vascular constriction is known to be mediated by alpha adrenoreceptors, for
`
`which alpha agonists have specificity. Further the alpha class of receptors, has been further
`
`differentiated pharmacologically into alpha 1 and alpha 2 receptors, both of which have
`properties of vasoconstriction of vascular smooth muscle. The a.1-adrenoceptors are the
`predominant receptor locate