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
`61/207,481
`
`FILING or
`37l(c)DATE
`02/12/2009
`
`140
`LADAS & PARRY LLP
`26 WEST 61ST STREET
`NEW YORK, NY 10023
`
`FIL FEE REC'D
`245
`
`ATTY.DOCKET.NO
`
`u 017610-2
`
`CONFIRMATION NO. 6161
`FILING RECEIPT
`
`IIIIIIIIIIIIIIIIIIIIIIII]~!I]~~~~~~~~I~JIU~ ~U] 11111111111111111111111
`
`Date Mailed: 03/31/2009
`
`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:
`John Richards--31 053
`
`If Required, Foreign Filing License Granted: 03/31/2009
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/207,481
`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
`page 1 of 3
`
`Page 1 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`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
`page 2 of 3
`
`Page 2 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`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).
`
`page 3 of 3
`
`Page 3 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`0
`ofractitioner's Docket No. U 017610-2
`....,
`
`0)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`Q\n re application of:
`
`Gerald HORN
`
`"tJ
`
`PATENT
`
`U.S. PTO
`61/207481
`02/12/2009
`
`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§ 1.5J(c)(1) or a cover letter
`identifYing the application as a provisional application. Othenvise, 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 MP.E.P. § 201.04(b), 6'h ed., rev. 3.
`
`CERTIFICATION UNDER 37 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 FEBRUARY 12, 2009 in an envelope as "EXPRESS MAIL?JO OFFICE TO
`ADDRESSEE" service under 37 C.F.R. 1.10 Mailing Label Number EV 926 371 683 US addr s
`to the Commissioner
`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 label
`placed thereon prior to mailing. 37 C.F.R. 1.10(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
`
`Page 4 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`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§ 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 1.825 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." 3 7 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. 11 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. 11 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. 11
`
`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. § 1.51(c)(l):
`
`The name(s) ofthe inventor(s) is/are (37 C.F.R. § 1.51(c)(l)(ii)):
`
`NOTE:
`
`11/fthe correct inventor or inventors are not named on filing, a provisional application without a cover sheet
`under§ 1.5/(c)(J), the later submission of a cover sheet under§ 1.5/(c)(l) during the pendency of the
`application will act to correct the earlier identification ofinventorship. II 37 C.F.R. § 1.48(1)(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 § 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 11(a){,] application
`must have at least one inventor in common with the provisional application. 11 Notice of Apri/14, 1995, 60 Fed.
`Reg. 20,195, at 20,209.
`
`The term "invention 11 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.
`111 (a) application, that is the time when the correct inventors must be named. The 35 U.S. C. 11 I (a) application
`must have an inventor in common with the provisional application in order for the 35 U.S. C. I 11 (a) application
`to be entitled to claim the benefit of the provisional application under 35 U.S. C. I /9(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 2 of7) 23-1
`
`Page 5 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`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) of the 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.
`
`The title ofthe 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. § 1.51(c)(l)(v)):
`
`Name of practitioner:
`
`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)(1)(vi)):
`
`Docket No. U 017610-2
`
`7.
`
`The correspondence address for this application is (37 C.F.R. § 1.51(c)(1)(vii)):
`
`Optional Customer No. Bar Code
`
`(Cover Sheet for Filing Provisional Application-page 3 of7) 23-1
`
`Page 6 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`-.
`
`lllllllllllllllllllllllllllllllllll
`00140
`
`PATENT TRADEMARK OFFICE
`
`which is Ladas & Parry LLP, 26 West 61 51 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. §§ 1.51(c)(2)-(3):
`
`Specification:
`Claims:
`Drawings:
`
`B.
`
`Additional documents:
`
`No.ofpages __ ~84~---­
`No.ofpages __ ~14~----
`No. of sheets ---'1._4.:...._ __ __
`
`[./"]
`
`Claims:
`
`No. of claims ---'1::....;0""'1~----
`
`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§ 1.78(a)(5)(iv).
`
`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 1 00 sheets
`(excluding sequence listing or computer program listing filed in electronic
`
`(Cover Sheet for Filing Provisional Application-page 4 of7) 23-1
`
`Page 7 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`medium). The fee is $250.00 for each additional 50 sheets paper or fraction
`thereof and $125.00 for a small entity.
`
`B.
`
`( ]
`[.1']
`
`Applicant is not a small entity.
`Applicant is a small entity.
`
`NOTE: "A .. . statement in compliance with existing§ 1.27 is required to be filed in each provisional application in
`which it is desired to pay reduced fees." Notice of April 14, 1995, 60 Fed. Reg. 20, 195, at 20,197.
`
`11.
`
`Small entity assertion
`
`[ ]
`
`[.I]
`
`A Statement or Written Assertion that this is a filing by a small entity under 37
`C.F.R. § 1.27(c)(l) is attached.
`
`Small entity status is asserted for this application by payment of the small entity
`filing fee under§ 1.16(d). 37 C.F.R. § 1.27(c)(3).
`
`WARNING:
`
`"Small entity status must not be established unless the person or persons signing the ... statement can
`unequivocally make the required self-certification." M.P.E.P. Section 509.03, 6th ed., rev. 2, July
`1996 (emphasis added).
`
`12.
`
`Fee payment
`
`[.I]
`
`Fee payment in the amount of$ 230.00 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 of7) 23-1
`
`Page 8 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`13. Method of fee payment
`
`[tl']
`[ ]
`
`Check in the amount of$ 2./0_,~;).
`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.
`
`Signature of submitter
`
`OR
`
`Date: _ _ _ _ _ _ _
`
`Tel.: (
`
`)
`
`Date: February 12, 2009
`
`Reg. No.: 31053
`
`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 61 st Street
`New York, N.Y. 10023
`
`(Cover Sheet for Filing Provisional Application-page 6 of7) 23-1
`
`Page 9 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`DOCKET NO.: U 017610-2
`
`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
`
`Dilati<?n of mucosal blood vessels, particularly arterioles, capillaries, and venules,
`
`causes numerous clinically undesirable events including: eye redness (conjunctival hyperemia),
`•
`eye swelling and itching (allergic conjunctivitis), nasal congestion (allergic rhinitis, sleep apnea,
`
`related sleep disorders with turbinate mucosal swelling secondary to venous or other
`
`vasodilation), bronchiole congestion (bronchitis, allergic bronchitis, allergic asthma; asthma);
`
`alveolar congestion (flu and flu-like conditions); chronic mucous hypersecretion syndrome
`
`(defined as productive cough for at least 3 mo total duration in 2 successive years), chronic
`
`bronchitis (becomes chronic obstructive bronchitis if spirometric evidence of airflow obstruction
`
`develops), chronic asthmatic bronchitis, oropharyngeal conditions ("sore throat"); and
`
`hemorrhoidal swelling (venule dilation). In addition constriction of mucosal blood vessels can
`
`provide excellent hemostasis and edema prophylaxis (surface hemorrhage and hyperemia
`
`following Lasik surgery, intubation prophylaxis) and interstitial tissue vessel constriction can aid
`
`in local anesthetic injection duration of effect and reduction of systemic toxicity for the
`
`anesthetic.
`
`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 ofvascular smooth muscle. The a 1-adrenoceptors are the
`predominant receptor located on vascular smooth muscle. Depending on the tissue and type of
`
`vessel, there are also a 2-adrenoceptors found on the smooth muscle. Prior art views all alpha
`agonists, whether more alpha 1 selective, mixed, or more alpha 2 selective as having both desired
`
`vasoconstrictive properties and undesired ischemic consequences that are intrinsic to their use.
`
`The ischemia leads to a host of adverse sequelae including hyperemia after even hours of use,
`
`Page 10 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`induced inflammation, hyperemia and or rebound hyperemia, with vasodilation and congestion
`
`on discontinuation ofthe agonist, and medicamentosa, a long-term even chronic inflammatory
`
`condition in which return of the mucosal tissue to its normal decongestant state can take many
`
`weeks or even months.
`
`That vasoconstriction decreases blood flow, and that therefore vasoconstrictors as a general class
`
`must inherently produce ischemia and adverse sequelae, particularly with use of more than a few
`
`days (three typically) is a prior art tenet that renders the present invention, whereby
`
`vasoconstriction is obtainable with less attendant ischemia and or adverse sequelae not obvious
`
`nor easily predicted by experts in the art of agonist use. Generalized ischemia and or
`
`inflammation secondary to vasoconstrictor use is understood to cause adverse sequelae,
`
`including hyperemia, rebound hyperemia (after discontinuation) and or medicamentosa as a
`
`result of ischemic induction of inflammatory mediators. Tachyphylaxis (loss of clinical
`
`effectiveness) is also particularly common. These general properties that are viewed via prior art
`
`as a fundamental limitation of alpha agonist have been associated with alpha 1, mixed, and alpha
`
`2 receptor agonists. A representative illustration ofthe state of prior art vs. the present invention
`
`is found in application of agonists to relief of nasal congestion. As noted by J.T. Ramey, et al:
`
`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 cause
`hyperemia, rebound hyperemia and a condition called rhinitis medicamentosa in which
`more chronic rebound hyperemia and paradoxical swelling result, can last for many
`months, and require total discontinuation of these drugs. (J.T. Ramey, et al: , J. lnvestig
`Allergol Clin Immunol2006 Vol 16(3): 148- 155)
`
`Vasoconstriction of arteriolar, capillary bed, and or venular networks provides
`
`potentially beneficial relief of vascular induced tissue congestion including ocular, nasal,
`
`oropharynx, laryngeal, bronchiolar, and rectal mucosal tissue, as well as epidermal tissue.
`
`However these benefits are largely moot and clinically of very limited value if ischemic adverse
`
`effects and their attendant morbidity cannot be significantly reduced. Vasoconstriction
`
`potentially provides in addition valuable preoperative prophylaxis of surgical tissue to minimize
`
`intraoperative hemorrhage and postoperative bleeding and or hyperemia (vessel dilation), as well
`
`as an improved means of reducing local anesthetic toxicity and retention of anesthetic effects
`
`(addition of epinephrine). However prior art does not provide for any means to induce effective
`
`2
`
`Page 11 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`vasoconstriction without concomitant reduction in blood flow sufficient to cause ischemia and a
`
`cascade of inflammatory mediators. Most agonists also suffer from tachyphylaxis, and have
`
`cardiovascular risk from tachycardia and hypertension due to significant alpha 1 receptor agonist
`
`stimulation, or bradycardia and or hypotension due to CNS imidazoline receptor and or
`
`histamine 1 receptor alpha 2 agonist stimulation.
`
`The clinically available agonist compounds all belong to the general category of alpha
`agonists, and include alpha 1 selective, mixed, and low to moderately selective alpha 2
`agonists. After as little as eight hours, vasodilation, rebound vasodilation, or
`medicamentosa may become pronounced, and produce long standing or chronic
`inflammation. (Soparkar et al, Arch Ophthalmol. 1997 Jan;ll5(1):34-8.)
`
`Hyperemia, and rebound hyperemia are particularly prevalent with topical alpha 2 agonists that
`
`have been clinically tested and used on mucosal surfaces such as conjunctiva and nasal mucosa,
`
`particularly apraclonidine and brimonidine (20-25% incidence). (http://www.rxlist.com/iopidine(cid:173)
`
`eye-drug.htm; http://www.alphaganp.com/ALPHGANP.pdO.
`
`Despite the chronic nature of many of the causes of mucosal congestion prior art
`
`vasoconstrictor options, due to the undesirable ischemia and its sequelae with repeat or longer
`
`duration use, are limited to acute use only -typically three days or less. Alpha 1 vasoconstrictors
`
`allows for only acute use and labeling - typically three to ten days at tid dosing. Many
`
`ophthalmic, nasal, and other conditions represent chronic causes of mucosal congestion and/or
`
`vasodilation/redness benefitting from acute use of acute exacerbations of longer than three days,
`
`and longer term use to treat the underlying chronic conditions to minimize their deleterious
`
`effects. Dry eye hyperemia (12 million US), allergic conjunctivitis (20 million plus US), chronic
`
`blepharitis, glaucoma, ocular hypertension, contact lens wear, allergic rhinitis, allergic asthma,
`
`asthma, sleep disorders frequently caused by allergic swelling of nasal turbinates, and other
`
`conditions involve mucosal edema with morbidity potentially responsive to vasoconstrictor
`
`induced decongestant activity. The social stigma of chronic red eyes, like that of yellow teeth
`
`reflecting poor dental hygiene, labels those with these conditions as if they were drug users,
`
`chronic smokers, and or otherwise lived undesirable lifestyles.
`
`While experts accept tachyphylaxis, hyperemia, rebound hyperemia and
`
`medicamentosa as known risks of agonist use, the etiology, incidence, and pathophysiology
`
`3
`
`Page 12 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`explaining these adverse events is debated by some experts. Some experts such as Dr. Mark
`
`Abelson, dislike the term "rebound" for the observed induced redness with topical ophthalmic
`
`agonists in use for vasoconstriction (Abelson, Ophthalmology Management, September 2001,
`
`"Diagnostic Challenges in Allergy Patients"). However Dr. Abelson does admit to rebound
`
`when applied to the eye being presented with phenylephrine, Naphazoline and Tetrahydrozoline,
`
`and hyperemia and tachyphlaxis are well documented problems with topical mucosal use
`
`including Oxymetazoline, particularly when applied nasally.
`
`Experts in the use of mucosal decongestants universally recognize current
`
`generation (prior art) agonists do not provide a safe clinical treatment option, other than for very
`
`acute use, can cause adverse effects in hours. A lower morbidity acute and or longer duration use
`
`means of using agonists as mucosal decongestant is contrary to prior art and a discovery of the
`
`present invention based on a relationship between agonist selectivity and concentration range
`
`efficacy minimizing alpha 1 receptor stimulation not yielded nor predicted by prior art.
`
`Abelson has pointed out that vasoconstriction does more than just alleviate
`
`symptoms. It has clinical positive clinical benefit, minimizing the effects of histamine and other
`
`components of the inflammatory cascade on dilated leaky vessels. (Abelson MB, Zbyszynski B.
`
`Vasoconstrictors. In: Abelson MB, edAl/ergic Diseases of the Eye. London: WB Saunders,
`
`2000: 235-239. ). Agonist vasoconstrictors therefore have positive therapeutic potential for the
`
`treatment of inflammation and allergic reaction, particularly via the present invention where
`
`ischemic morbidity becomes for the first time so dramatically reduced and clinically insignificant
`
`relative to the substantial decongestant mucosal effectiveness.
`
`Vasoconstrictors have been used for these purposes (mucosal decongestants),
`
`including tetrahydrozoline, naphazoline, and oxymetazoline, and as described above produce
`
`suboptimal clinical vasoconstriction and have local as well as in some cases systemic toxicity.
`
`No exceptions have been found to the correlation between agonist vasoconstriction and ischemic
`
`effects of induced hyperemia, rebound hyperemia, medicamentosa and tachyphylaxis with their
`
`use. The compounds clinically available all belong to the category of general alpha agonists, and
`
`include the full range of alpha receptor targets as described above: more alpha 1 selective,
`
`mixed, and low to moderately selective to more highly selective alpha 2 agonists. After as few as
`
`4
`
`Page 13 of 122
`
`SLAYBACK EXHIBIT 1011
`
`

`

`three doses, or as little as eight hours hyperemia and medicamentosa may become pronounced,
`
`and produce long standing or chronic vasodilation. Hyperemia is as described above even more
`
`pronounced with more selective alpha 2 agonists in the concentration ranges clinically tested.
`
`Tetrahydrozoline, Oxymetazoline, Phenylephrine, and Clonidine have all been implicated as a
`
`primary cause of rhinitis medicamentosa - hyperemia and or rebound hyperemia of the nasal
`
`turbinates- from which it can take months to recover.
`
`That vasoconstriction reduces blood flow which creates ischemia and is therefore
`
`an endogenous quality of agonist vasoconstriction is a tenet of prior art, and restricts use of the
`
`agonist class from treatment of chronic causes of mucosal congestion and or vascular dilatation.
`
`This despite the great need for agonists that can safely be used for longer duration. Allergic
`
`rhinitis alone is responsible for over $25,000,000 per year in lost productivity and severe
`
`impairment of quality oflife (QOL). Though frequently steroidal use reduces mucosal edema,
`
`onset takes many hours, and peak effects many weeks, which reduces compliance and
`
`effectiveness, particularly for treatment of nasal rhinitis and asthma. (Clinical
`
`TherapeuticsNolume 30, Number 4, 2008; The Pathophysiology, Clinical Impact, and
`
`Management ofNasal Congestion in Allergic Rhinitis; Robert A. Nathan, MD). A topical
`
`decongestant that was effective without the ischemic complications of prior art use of agonists
`
`would greatly reduce the morbidity of these chronic causes of mucosal congestion.
`
`*While the adverse effects of agonist use are seen with all agonists as used via
`
`prior art, many experts believe alpha 2 agonists, contrary to the discoveries of the present
`
`in