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
`61/203,120
`
`FILING or
`37l(c)DATE
`12/18/2008
`
`140
`LADAS & PARRY LLP
`26 WEST 61ST STREET
`NEW YORK, NY 10023
`
`FIL FEE REC'D
`110
`
`ATTY.DOCKET.NO
`
`u 017579-0
`
`CONFIRMATION NO. 6278
`FILING RECEIPT
`
`llllllllllllllllllllllll]~!l]~~~~~~~~l~jl~~~~~~llllllllllllllllllllllllll
`
`Date Mailed: 01/27/2009
`
`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: None
`
`If Required, Foreign Filing License Granted: 01/23/2009
`
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/203,120
`
`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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`f\:)
`f\:)
`.....
`-...J
`(...)
`Practitioner's Docket No.
`c
`!n
`
`u 017579-0
`
`U.S. PTO
`61/203120
`12/18/2008
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`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
`
`11111111111111111111111111111111111
`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){l) or a cover letter
`identifying the application as a provisional application. Otherwise, the application will be treated as an
`application filed under paragraph (b) [nonprovisiona/ application] of this section." 37 C.F.R. §
`1.53(c)(l).. See also M.P.E.P. § 201.04(b), 6'h ed., rev. 3.
`
`CERTIFICATION UNDER 37 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 December 18, 2008 in an envelope as "EXPRESS MAIL POST OFFICE TO
`ADDRESSEE" service under 37 C.F.R. 1.10 Mailing Label Number EV 926371635 US addressed to the Commissioner
`for Patents, P. 0. Box 1450, Alexandria, VA 22313-1450.
`
`I
`
`Signature of per n mailing paper
`
`WARNING:
`
`Certificate of mailing (first class) or facsimile transmission procedures of 37 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 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 of 7) 23-1
`
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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 foe 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 April 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 U.S. C. I 20; 121 or 365(c) or§ 1. 78 of any other application. No claim
`for priority under§ I. 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 1.825 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. "37
`C.F.R. § 1.53(c).
`
`NOTE: 35 U.S. C. 1 19(e) provides that "{i}fthe day that is 12 months after the filing date of a provisional application fa/Is
`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.
`§ 1.5l(c)(l)(i).
`
`1.
`
`2.
`
`The following comprises the information required by 37 C.F.R. § l.Sl(c)(l):
`
`The name(s) ofthe inventor(s) is/are (37 C.F.R. § l.Sl(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)(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 al. '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 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 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
`
`(Cover Sheet for Filing Provisional Application-page 2 of?) 23-1
`
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`applicant has determined what the invention is by the filing of the 35 U.S. C. lll(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. J II (a) application to be entitled to claim the benefit of
`the provisional application under 35 U.S. C. 119(e). Notice of Apri/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 of 7) 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. § l.51(c)(l)(iii)):
`
`1150 HEATHER ROAD DEERFIELD. ILLINOIS 60015
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`4.
`
`The title of the invention is (37 C.F.R. § 1.51(c)(l)(iv)):
`
`TOPICAL VASOCONSTRICTOR COMPOSITION AND METHODS OF USING THE
`SAME
`
`5.
`
`The name, registration, customer and telephone numbers of the practitioner (if applicable)
`are (37 C.F.R. § l.51(c)(l)(v)):
`
`Name ofpractitioner:
`
`JOHN RICHARDS
`
`Reg.No.-=3~1=05=3~-----
`
`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)(l)(vi)):
`
`Docket No. U 017579-0
`
`(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. § 1.51(c)(l)(vii)):
`
`Optional Customer No. Bar Code
`
`11111111111111111111111111111111111
`00140
`
`PATENT TRADEMARK OFFICE
`
`which is Ladas & Parrv LLP. 26 West 6P1 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 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 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:
`Claims:
`Drawings:
`
`B.
`
`Additional documents:
`
`No. of pages _4.!....4,___ __
`No. of pages ---'9~--
`No. of sheets ~1....:4 _ _ _
`
`[v']
`
`Claims:
`
`No. of claims ----.!.7~0 _ _ _
`
`Note:
`
`See 37 C.F.R.- § 1.51.
`
`[ ]
`[ ]
`[ ]
`
`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 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 $125.00 for a small entity.
`
`B.
`
`[ ]
`[wl']
`
`Applicant is not a small entity.
`Applicant is a small entity.
`
`NOTE: "A ... statement in compliance with existing§ 1.27 is required to be filed in eaclt provisional application in which
`it is desired to pay reduced fees." Notice of Apri/14, 1995, 60 Fed Reg. 20, 195, at 20,197.
`
`11.
`
`Small entity assertion
`
`[ ]
`
`[wl']
`
`A Statement or Written Assertion that this is a filing by a small entity under 37
`C.F.R. § 1.27(c)(l) is attached.
`
`Small entity status is asserted for this application by payment of the small entity filing
`fee under§ l.l6(d). 37 C.F.R. § l.27(c)(3).
`
`WARNING:
`
`"Small entity status must not be established unless the person or persons signing the ... statement can
`unequivocally make the required self-certification." MP.E.P. Section 509.03, 6th ed, rev. 2, July 1996
`(emphasis added).
`
`12.
`
`Fee payment
`
`[-!]
`
`Fee payment in the amount of$ 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
`
`[vi']
`[ ]
`
`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: December 18, 2008
`
`Reg. No.: 31053
`
`Signature of submitter
`
`OR
`
`Tel. No.: (212) 708-1915
`
`(type or print name of practitioner)
`
`Customer No.: 00140
`
`P.O. Address
`
`11111111111111111111111111111111111
`00140
`
`PATENT TRADEMARK OFFICE
`
`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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`DOCKET NO.: U 017579-0
`
`Topical Vasoconstrictor Composition and Methods of Using the Same
`
`-1-
`
`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 receptor has been
`
`further differentiated pharmacologically into alpha 1 and alpha 2 receptors, both of which
`
`have properties ofvasoconstriction of vascular smooth muscle. The a 1-adrenoceptors are
`the predominant receptor lo<?ated on vascular smooth muscle. Depending on the tissue
`
`and type of vessel, there are also a2-adrenoceptors found on the smooth muscle. Prior art
`
`views all alpha agonists, whether alpha 1 selective, mixed, or alpha 2 selective as having
`
`both vasoconstrictive properties and secondary rebound hyperemia, or secondary
`
`vasodilation with any frequency of use (more than three applications). The rebound
`
`vasodilation is thought to be related to generalized ischemia and secondary release of an
`
`inflammatory cascade brought about by vasoconstriction. This general property and
`
`fundamental limitation of alpha agonist induced vasoconstriction for clinical use has been
`
`found for alpha 1 and alpha 2 receptor agonists and is clearly illustrated by application to
`
`nasal congestion. As noted by J.T. Ramey, et al, J. lnvestig Allergol Clin Immunol 2006
`
`Vol 16(3): 148- ISS:
`
`Tetrahydrozoline, Naphazoline, Oxymetazoline, and Clonidine comprise a
`
`group of alpha 1, mixed, and alpha 2 selective agonists. All have been found with repeat
`
`use to frequently cause rebound hyperemia and a condition called rhinitis medicamentosa
`
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`

`DOCKET NO.: U 017579-0
`
`in which more chronic rebound hyperemia and paradoxical swelling result, can last for
`
`many months, and require total discontinuation of these drugs
`
`-2-
`
`Vasoconstriction of arteriolar, capillary bed, and or venular networks
`
`provides potentially beneficial relief of vascular induced tissue congestion including
`
`nasal, ocular, hemorrhoidal, and epidermal tissue. It potentially provides valuable
`
`preoperative prophylaxis to minimize intraoperative hemorrhage and postoperative
`
`hyperemia. However prior art has not been able to discover any means to induce effective
`
`vasoconstriction without concomitant reduction in blood flow sufficient to cause ischemia
`
`and a cascade of inflammatory mediators. Vasoconstrictors that have been used for these
`
`purposes therefore produce suboptimal vasoconstriction with a high incidence of rebound
`
`vasodilation (hyperemia) secondary to induced ischemia and local tissue as well as
`
`systemic toxicity. The compounds clinically available belong to the general category of
`
`alpha agonists, and include alpha 1 selective, mixed, and low to moderately selective
`
`alpha 2 agonists. After as few as three doses rebound vasodilation may become
`
`pronounced, and produce long standing or chronic inflammation and vasodilation, even
`
`_more pronounced with more selective alpha 2 agonists clinically tested (see
`
`apraclonidine, bromonidine below
`
`Most importantly, prior art use of alpha I vasoconstrictors allows for only
`
`acute use and labeling - typically three to ten days at tid dosing. Many ophthalmic, ear
`
`,nose and throat ( ent) and other conditions represent chronic causes of mucosal
`
`congestion and or vasodilation/redness requiring long term use of agonists to minimize
`
`these effects and provide clinical benefit including reduction of conjunctival hyperemia,
`
`both due to cosmetic reduction of social stigma, and possibly to reduce discomfort from
`
`exposure to inflammatory mediators. Common examples would be patients with
`
`glaucoma or ocular hypertension, many of whom have eye redness either as a baseline
`
`component of their condition or as a secondary affect of their medication. Other examples
`
`would include chronic blepharitis; chronic dry eye; allegic conjunctivitis, contact lens
`
`wear, allergic rhinitis, sleep disorders related to swollen turbinates, asthma mucosal
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`congestion of bronchiolar lumen postoperative conjunctival hyperemia which can extend
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`for much longer than the 10 days to which alpha I agonist use is typically limited to,
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`swimming, smoking, etc. While experts are more inclines to believe rebound the etiology
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`of vasodilation secondary to agonist use topically in the eye is debated for some agonists
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`like Dr. Mark Adelson, does not like the term "rebound" for the observed induced redness
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`with topical ophthalmic agonists in use for vasoconstriction (Adelson, Ophthalmology
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`Management , September 2001, "Diagnostic Challenges in Allergy Patients"), the
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`induced redness is an accepted well recognized side effect, and the present invention is
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`the first to dramatically reduce/eliminate it. Adelson does admit to rebound when applied
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`to the eye being present with phenylephrine, Naphzoline and Tetrahydrozoline. Rebound
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`heperemia is a well documented problem with other topical use on mucosa, including
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`Oxymetrazoline, such as when applied nasally. Experts recognize current OTC agonists
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`do not provide a safe clinical treatment for other than very acute use, cause incorrect self
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`diagnosis, and it is a significant problem with the occasional longer term self-diagnosed
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`and treated use despite contraindicated labeling and is a significant problem with the
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`occasional longer term self-diagnosed and treated use despite contraindicated labeling for
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`such use. A longer lasting, safe alternative, particularly one prescribed by a physician is
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`preferred. Ophthalmology Management, September 2001, "Diagnostic Challenges in
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`Allergy Patients". The present invention lends itself to chronic use and prescription
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`labeling for such.
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`So while the labeling for agonists as vasconstrictors is acute due to their
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`clinical limitations, toxicity and rebound effects, the need for decongestant is rarely just
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`acute. Allergic rhinitis afflicts over 20% of the population- over 50,000,000 in the U.S.
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`alone. Dry eye and allergic conjunctivitis combined afflict over 20,000,000, with a high
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`prevalence of chronic red eyes. Sleep deprivation, alcohol intake, staring at computer
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`screens excessively, dandruff with deposed ocular surface debris, blepharitis, swimming,
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`smoking, exposure to noxious air pollutant particulates, drug ingestion, and low morbidity
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`viral conjunctivitis are but some of the many contributors to eye redness and or for some
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`of the above nasal congestion. Many live with chronic fatigue due to inability to obtain
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`cleared nasal passages, and the stigma of eyes that are chronically red because no known
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`agonist option has existed prior to the present invention for safe vasoconstriction with
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`much reduced risk of rebound. Just as teeth whitening has become a $1 billion industry,
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`the desire for cosmesis of red eye is important for those afflicted to minimize or eliminate
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`the social stigma of appearing to be in poor health and or having been in a situation of
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`some type of excessive abuse or unhealthy activity the night before.
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`Abelson has pointed out that vasoconstriction has clinical benefit potential
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`as well. It minimizes the effects of histamine and other components of the inflammatory
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`cascade on dilated leaky vessels, and therefore has positive therapeutic implications on
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`the treatment of inflammation and allergic reaction. (Abelson MB, Zbyszynski B.
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`Vasoconstrictors. In: Abelson MB, ed.Allergic Diseases of the Eye. London: WB
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`Saunders, 2000: 235-239.)
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`Vasoconstrictors that have been used for these purposes, including
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`tetrahydrozoline, naphazoline, and oxymetazoline, and produce suboptimal clinical
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`vasoconstriction systemic toxicity. No exceptions have been found to be generally useful
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`or otherwise noted as clinically practical via prior art. The compounds clinically available
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`all belong to the general category of alpha agonists, and include the full range of alpha
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`receptor targets as described above: alpha 1 selective, mixed, and low to moderately
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`selective or selective alpha 2 agonists. After as few as three doses rebound vasodilation
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`may become pronounced, and produce long standing or chronic vasodilation, even more
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`pronounced with more selective alpha 2 agonists clinically tested. Oxymetazoline has
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`been implicated as a primary cause of rhinitis medicamentosa - rebound hyperemia of the
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`nasal turbinates - that can take months to recover.
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`The prevailing viewpoint of prior art in summary is that rebound
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`hyperemia is a general property of all alpha agonists , and is based on the clinical finding
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`of rebound hyperemia in association with all classes of agonists - alpha 1
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`(tetrahydrozoline), mixed (- particularly with nasal use), low selective (eg clonidine,
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`apraclonidine ), and more high selective ( eg brimonidine) alpha 2 agonists. That
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`vasoconstriction reduces blood flow which creates ischemia and is therefore an
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`endogenous quality of agonist vasoconstriction has dogma status via prior art, and
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`universally prevents endorsement of this class for treatment of chronic causes of mucosal
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`congestion and or vascular dilatation. Nasal rhinitis alone is responsible for over
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`$25,000,000 per year in lost productivity and severe impairment of quality oflife (QOL).
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`Though frequently steroidal use reduces mucosal edema, onset takes many hours, and
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`peak effects many weeks, which reduces compliance and effectiveness, particularly for
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`treatment of nasal rhinitis and asthma. (Clinical TherapeuticsN olume 30, Number 4,
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`2008; The Pathophysiology, Clinical Impact, and Management ofNasal Congestion in
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`Allergic Rhinitis; Robert A. Nathan, MD). In addition to this generally held precept
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`regarding long term use of agonists for treatment of mucosal congestion as being
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`clinically ineffective and in many cases unsafe (rhinitis medicamentosa), and contrary to
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`the teachings of the present invention, rebound hyperemia is generally felt to be more
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`common with alpha 2 agonists, than alpha 1 agonists. As a result, as noted by Crassous
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`P.A. in Curr Top Med Chern 2007 vol 7(2): 187- 194, there are currently no clinical uses
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`for alpha 2 agonists as vasoconstrictors. They are largely utilized as anesthetic agents and
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`in some cases for modifying drug related addiction behaviorin fact via prior art .
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`Contrary to the teachings of the present invention, as noted in U.S. patent
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`6534048 (Borgman), it is generally thought that higher concentrations of alpha 2 agonists
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`are required for vasoconstriction. Clonidine, in particular, is a potent alpha 2 -adrenergic
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`partial agonist used primarily for the treatment of hypertension (Jarrett et al., "Clonidine:
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`Understanding its disposition, sites, and mechanism of action", Clin. Exp. Pharm.
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`Physiol., 14,471-479 (1987)). This drug Clonidine, a partially selective alpha 2 agonist,
`stimulates a.2 -adrenoceptors in the vasomotor centers, causing a reduction of sympathetic
`outflow from the central nervous system. Both cardiac output and peripheral resistance
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`are reduced resulting in a decrease in blood pressure. Higher concentrations cause a
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`vasoconstriction by activation of postsynaptic recept~ns in vascular smooth muscle.
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`There is no discussion of prevention or reduction of rebound hyperemia.
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`A commonly held clinical precept of prior art is that alpha 2 agonists are
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`even a more prominent cause of rhinitis medicamentosa (see C. F. Garfield Rhi