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
`61/137,714
`
`FILING or
`37l(c)DATE
`08/01/2008
`
`140
`LADAS & PARRY LLP
`26 WEST 61ST STREET
`NEW YORK, NY 10023
`
`FIL FEE REC'D
`105
`
`ATTY.DOCKET.NO
`
`u 017361-7
`
`CONFIRMATION NO. 2070
`FILING RECEIPT
`
`111111111111111111111111]~!1]~~~~~~~~~~ jiiU~ I~UIIIIIIIIIIIIIIIIIIIIIIIII
`
`Date Mailed: 08/25/2008
`
`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: 08/22/2008
`
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/137,714
`
`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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`. "
`
`..
`
`..
`
`......
`
`0
`
`== ~
`oo== ~
`:::
`Practitioner's Docket No. u 017361-7
`~
`~
`g
`-i o.
`In re application of:
`
`U.S. PTO
`61/137714
`08/01/2008
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Gerald HORN
`
`For:
`
`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§ 1.5/(c)(J) 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}(J) .. See also M.P.E.P. § 201.04(b), 6'h ed., rev. 3.
`
`CERTIFICATION UNDER37 C.F.R. 1.10*
`(Express Mail/abel 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 August l. 2008, in an envelope as "EXPRESS MAIL POST OFFICE T ADDRESSEE"
`service under 37 C.F.R- 1.10 Mailing Label Number EV 926371480 US addressed to the Commissio
`r or Patents, P. 0.
`Box 1450, Alexandria, VA 22313-1450.
`
`Signature of perso
`
`WARNING:
`
`Certificate of mailing (first class) or facsimile transmission procedures of37 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 label
`placed thereon prior to mailing. 37 C.F.R. 1./0(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 1101 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 of6) 23-1
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`f
`\,
`
`Practitioner's Docket No. U 017361-7
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`Application No.:
`Filed:
`For:
`
`Group No.:
`Examiner:
`TOPICAL VASOCONSTRICTOR COMPOSITION AND METHODS OF USING THE SAME
`
`Gerald HORN
`
`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 14 between lines
`16 and
`17 ).
`
`"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
`
`08/05/2008 HDESTA1 00000057 61137714
`02 FC:1464
`130.00 OP
`
`(Petition to Accept Color Drawings or Photographs (37 C.F.R. l.84(a)(2) and (b)(2)}--page l of2) 9-30
`
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`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)
`
`(type or print name of practitioner)
`
`Customer No.: 00140
`
`P.O. Address
`
`11111111111111111111111111111111111
`00140
`
`PATENT TRADEMARK OFFICE
`
`c/o Ladas & Parry LLP
`26 West 61 st Street
`New York, N.Y. 10023
`
`Date
`
`AUGUST 1 2008
`
`(Petition to Accept Color Drawings or Photographs (37 C.F.R. 1.84(a)(2) and (b)(2)}---page 2 of2) 9-30
`
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`NOTE: "A complete provisional application does not require claims since no 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 U.S. C. 119 or 365(a) or§ 1.55, or to
`the benefit of an earlier filing date under 35 U.S. C. 120, 121 or 365(c) or§ /. 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§ /.293 for a statutory invention registration may be filed in a provisional application. The
`requirements of§§ 1.821 through 1.825 regarding application disclosures containing nucleotide and/or amino
`acid sequences are not mandatory for provisional applications." 37 C.P.R. 1.53(c)(3).
`
`NOTE: "No information disclosure statement may be filed in a provisional application." 37 C.F.R. § 1.5/(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 U.S. C. 119(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 3 7 C.F .R.
`§ 1.51 ( c )(1 )(i).
`
`1.
`
`2.
`
`The following comprises the information required by 37 C.F.R. § 1.51(c)(l):
`
`The name(s) of the inventor(s) is/are (37 C.F.R. § l.51(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)(J), the later submission of a cover sheet under§ 1.51(c)(1) 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 et a/. '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§ 1 .17(i) is filed which 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 U.S. C. 1 ll(a){.] application
`must have at least one inventor in common with the provisional application." Notice of April/4, /995, 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 1.45(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§ 1.45(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 applicant has determined what the invention is by the filing of the 35 U.S. C.
`I 1 J(a) application, that is the time when the correct inventors must be named. The 35 U.S. C. 1 I 1(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 benefilofthe provisional application under 35 U.S. C. 1 19(e). Notice of Apri/14,
`1995, 60Fed. Reg. 20,/95, at 20,208.
`
`See 37 C.F.R. § 1.53.
`
`(Cover Sheet for Filing Provisional Application-page 2 of6) 23-1
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`•
`
`I.
`
`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 of the invention is (37 C.F.R. § 1.5l(c)(l)(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. § L51(c)(1)(v)):
`
`Name of practitioner:
`
`JOHN RICHARDS
`
`Reg.No.~3~1~0~53~--------------------
`
`Tel. (212) 708-1915
`
`Customer No. _,0<--"0:...:1'-'4~0:.....---------
`
`(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.017361-7
`
`(Cover Sheet for Filing Provisional Application-page 3 of6) 23-1
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`' ..
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`I
`
`7.
`
`The correspondence address for this application is (37 C.F.R. § 1.51(c)(l)(vii)):
`
`Optional Customer No. Bar Code
`
`lllllllllllllllll IIIII lllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`which is Ladas & Parrv LLP. 26 West 61'1 Street. New York. NY 10023
`
`8.
`
`Statement as to whether invention was made by an agency of the U.S. Government or under
`contract with an agency of the U.S. Government. (37 C.F.R. § 1.51(c)(l)(viii)).
`
`This invention was made by an agency of the United States Government, or under contract
`with an agency of the 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. §§ 1.5l(c)(2)-(3):
`
`Specification:
`Drawings:
`Petition to Accept Colored Drawings
`(See attached)
`Additional documents:
`
`B.
`
`No.ofpages __ 3~0~----
`No. of sheets __ _,7 ____ __
`No. ofsheets --~3 ____ _
`
`Pages of Claims:
`[5]
`[2]
`Pages of References
`See 37 C.F.R. § 1.51.
`
`Note:
`
`No. of claims ___ 4:.=2.__ __ _
`
`[ ]
`[ ]
`[ ]
`
`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 nonprovisiona/ application. See§/. 78(a)(5)(iv).
`
`(Cover Sheet for Filing Provisional Application-page 4 of6) 23-1
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`' ..
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`'
`
`. .
`
`10.
`
`Fee
`
`The filing fee for this provisional application, as set in 37 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 $125.00 for a small entity.
`
`B.
`
`[ ]
`[x]
`
`Applicant is not a small entity.
`Applicant is a small entity.
`
`NOTE: "A ... statement in compliance with existing§ 1.2 7 is required to be filed in each provisional application in
`which it is desired to pay reduced fees." Notice of April 14, 1995, 60 Fed. Reg. 20, 195, at 20,197.
`
`11.
`
`Small entity assertion
`
`[ ]
`
`[x]
`
`A Statement or Written Assertion that this is a filing by a small entity under 37
`C.F.R. § 1.27(c)(l) is attached.
`
`Small entity status is asserted for this application by payment of the small entity
`filing fee under§ 1.16(d). 37 C.F.R. § 1.27(c)(3).
`
`WARNING:
`
`"Small entity status must not be established unless the person or persons signing the ... statement can
`unequivocally make the required self-certification." MP.E.P. Section 509.03, 6th ed., rev. 2, July
`1996 (emphasis added).
`
`12.
`
`Fee payment
`
`[x]
`
`[ ]
`
`Fee payment in the amount of$ 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 5 of6) 23-1
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`"
`
`.I
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`. . .
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`13. Method of fee payment
`
`[x]
`[ ]
`
`Check in the amount of$ 105.00.
`Charge Account No. 12-0425 , in the amount of$ _ _ _ _ _
`A duplicate of this Cover Sheet is attached.
`
`Please charge Account No. 12-0425 for any deficiency in the fee paid.
`
`Date: _ _ _ _ _ _ _
`
`Tel.: (
`
`)
`
`Date:
`
`Reg. No.: 31053
`
`Signature of submitter
`
`OR
`
`Tel. No.: (212) 708-1915
`
`(type or print name of practitioner)
`
`Customer No.: 00140
`lllllllllllllllllllllllllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`P .0. Address
`
`c/o Ladas & Parry LLP
`26 West 61 51 Street
`New York, N.Y. 10023
`
`(Cover Sheet for Filing Provisional Application-page 6 of6) 23-1
`
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`u 017361-7
`
`Topical Vasoconstrictor Composition and Methods of Using the Same
`
`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: 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
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`located on vascular smooth muscle. Depending on the tissue and type of vessel, there are also
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`a2-adrenoceptors found on the smooth muscle. Prior art views all alpha agonists, whether alpha
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`1 selective, mixed, or alpha 2 selective as having both vasoconstrictive properties and secondary
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`rebound hyperemia, or secondary vasodilation with any frequency of use (more than three
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`applications). The rebound vasodilation is thought to be related to generalized ischemia and
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`secondary release of an inflammatory cascade brought about by vasoconstriction. This general
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`property and fundamental limitation of alpha agonist induced vasoconstriction for clinical use
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`has been found for alpha 1 and alpha 2 receptor agonists and is clearly illustrated by application
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`to nasal congestion. As noted by J.T. Ramey, et al, J. Investig Allergol Clin Immuno12006 Vol
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`16(3): 148- 155:
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`Tetrahydrozoline, Naphazoline, Oxymetazoline, and Clonidine comprise a group of alpha 1,
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`mixed, and alpha 2 selective agonists. All have been found with repeat use to frequently cause
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`rebound hyperemia and a condition called rhinitis medicamentosa in which more chronic
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`rebound hyperemia and paradoxical swelling result, can last for many months, and require total
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`discontinuation of these drugs
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`Vasoconstriction of arteriolar, capillary bed, and or venular networks provides potentially
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`beneficial relief of vascular induced tissue congestion including nasal, ocular, hemorrhoidal, and
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`epidermal tissue. It potentially provides valuable preoperative prophylaxis to minimize
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`intraoperative hemorrhage and postoperative hyperemia. Vasoconstrictors that have been used
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`for these purposes produce suboptimal vasoconstriction with a high incidence of rebound
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`hyperemia and systemic toxicity. The compounds clinically available belong to the general
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`category of alpha agonists, and include alpha 1 selective, mixed, and low to moderately selective
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`alpha 2 agonists. After as few as three doses rebound vasodilation may become pronounced, and
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`produce long standing or chronic vasodilation, even more pronounced with more selective alpha
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`2 agonists clinically tested.
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`A prevailing viewpoint of prior art is that rebound hyperemia is a general property of all
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`alpha agonists. In addition it is generally felt to be more common with alpha 2 agonists,
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`than alpha 1 agonists. As a result, as noted by Crassous P.A. in Curr Top Med Chern 2007 vol
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`7(2): 187- 194, there are currently no clinical uses for alpha 2 agonists as vasoconstrictors.
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`The alpha (2)-antagonists are useful antidotes for reversing the threatening effects of agonist
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`overdose, but currently there are very few indications. As noted in U.S. patent 6534048
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`(Borgman), it is generally thought that higher concentrations of alpha 2 agonists are required for
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`vasoconstriction. Clonidine, in particular, is a potent alpha 2 -adrenergic partial agonist used
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`primarily for the treatment of hypertension (Jarrott et al., "Clonidine: Understanding its
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`disposition, sites, and mechanism of action", Clin. Exp. Pharm. Physiol., 14, 471-479 (1987)).
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`This drug stimulates a.2 -adrenoceptors in the vasomotor centers, causing a reduction of
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`sympathetic outflow from the central nervous system. Both cardiac output and peripheral
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`resistance are reduced resulting in a decrease in blood pressure. Higher concentrations cause a
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`vasoconstriction by activation of postsynaptic receptors in vascular smooth muscle.
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`A commonly held clinical precept of prior art is alpha 2 agonist as even a more prominent
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`cause of rhinitis medicamentosa (see C. F. Garfield Rhinitis Medicamentosa, May 2, 2006) :
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`... theory postulates that alpha2 agonists stimulate a negative feedback loop that involves the
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`[
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`presynaptic nerve endings. With prolonged use of these agonists, a decrease in endogenous
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`noradrenaline would occur, and, once the exogenous drug disappears, a rebound congestion
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`develops.
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`Further confirmation of the prevailing views of prior art regarding alpha agonist induced
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`rebound hyperemia being generalized can be found in "Management of Chronic
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`Rhinosinusitis" (May 9, 2006):
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`Decongestants are a-adrenergic agonists that induce a sympathetic response leading to
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`vasoconstriction of dilated mucosal blood vessels. Decongestants are best used for short (3-5
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`days) courses at the beginning of treatment for sinusitis or allergic rhinitis. Topical agents
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`include Phenylephrine and Oxymetazoline. These agents lead to a local excitation of alpha
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`adrenergic receptors leading to a localize vasoconstriction and decrease of mucosal edema. All
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`topical agents exhibit rebound vasodilation, which can be demonstrated by rhinometric analysis
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`of nasal resistance as early as 3 days after beginning therapy. Clinical rebound congestion or
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`rhinitis medicamentosa usually requires at least 10 days to 2 weeks oftopical decongestant use to
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`become apparent. This is the reasoning of using decongestants for short (3-5 days) courses at the
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`beginning of treatment for sinusitis or allergic rhinitis.
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`Despite the introduction of more selective alpha 2 agonists in 1962, via clonidine,
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`initially developed as a nasal decongestant, the prevailing view of prior art that rebound is a
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`property of alpha agonists generally is found throughout the literature: Graf, Treat Respir Med.
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`2005 4(1) 21 - 29.
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`Rhinitis medicamentosa (RM) is a drug-induced, nonallergic form of rhinitis that is
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`associated with prolonged use of topical vasoconstrictors, i.e. local decongestants.
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`Oxymetazoline, an alpha 2 agonist, is used clinically as a vasoconstrictor, with known rebound
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`(Table 9 above) further contributing to the general prevalent belief rebound is an all class alpha
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`agonist vasoconstrictor ischemia induced phenomenon. In Larygnoscope, 1 9969:
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`... the score for nasal stuffiness was significantly higher for the group treated with
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`Oxymetazoline than for those treated with Benzalkonium chloride. Oxymetazoline nasal spray
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`induced a pronounced increase in nasal reactivity, which was significantly greater than that
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`induced in the placebo group ... These factors are probably the main reasons for ... the
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`development of rhinitis medicamentosa.
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`The prevalence of accepted limitations of alpha 2 agonists in particular is again
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`highlighted in Goodman & Gilman's "The Pharmacologic Basis of Therapeutics", 11th Edition,
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`2008, noting that in clinical use only alpha 1 agonists have proven beneficial for
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`vasoconstriction.
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`Lasik surgeons have attempted to use both alpha 1 and alpha 2 agonists commercially
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`available as a prophylactic means of reducing bleeding following creation of a Lasik flap.
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`Bleeding prolongs intraoperative time, causes more manipulation; postoperative hemorrhage can
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`rarely cause staining of the lamellar flap interface and require a second procedure to flush out;
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`postoperative conjunctival hyperemia may increase inflammatory transudate and stinging. Both
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`hemorrhage and hyperemia create an appearance of more traumatic surgery and produce
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`unnecessary anxiety for many patients. Alpha 1agonists are generally not sufficiently potent
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`vasoconstrictors to offer much prophylactic benefit, epinephrine has high systemic
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`cardiovascular event toxicity, and alpha 2 agonists produce not only rebound with frequent
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`instillation preoperatively in some cases, but cause corneal endothelial cell pump inhibition as
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`well as lowering of intraocular pressure, neither ofwhich is a desirable clinical effect for these
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`purposes. In fact the endothelial cell pump reduction increases the frequency of Lasik flap
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`dislocation the first 24 hours postoperatively. Both Iopidine (apraclonidine) and Alphagan
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`(brimonidine) have been tried and rejected as useful prophylactic agents for this purpose ..
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`Lasik is a procedure in which excimer laser vision correction is used to create a new
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`corneal curvature under a corneal flap of thickness ranging typically from 80 u to 160 u using an
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`oscillating blade precision instrument known as a keratome, or about 80 u to 120 u using a
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`femtosecond solid state laser. Adherence of the flap begins immediately post procedure as the
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`endothelial cells begin to pump fluid out ofthe cornea. Failure to adequately pump out fluid
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`results in increased incidence of postoperative movement of the flap over the first postoperative
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`night, clinically visible as striations within the flap postoperatively known as striae, or if more
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`extensive, actual flap dislocation. In such circumstances the flap must be reset.
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`Typical vascular injection after preoperative topical anesthetics, normal vasculature,