`{
`;;:t Under the
`I
`
`...... "''
`UTILITY
`c:
`~I PATENT APPLICATION
`cJ I
`TRANSMITTAL
`
`, Ar.t of 1995. no no•••
`
`U.S. PTO
`12/460941
`07/27/2009
`PTO/SBI05 (08-08)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`'reauired tore ;oand to a collection
`1 unless it disolavs a valid OMB control number.
`
`Attorney Docket No.
`
`ASD10554P0070US
`
`First Inventor
`
`Title
`
`Gerald Hom
`
`Preferential Vasoconstriction ...
`
`(Only for new non provisional applications under 37 CFR 1.53(b))
`
`Express Mail Label No.
`
`EV 955717223 US
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`1. 0 Fee Transmittal Form (e.g., PTOISB/17)
`2.0
`Applicant claims small entity status.
`See 37 CFR 1.27.
`3.0
`[Total Pages
`49
`Specification
`Both the claims and abstract must start on a new page
`(For information on the prefened arrangement, see MPEP 608.01(a))
`4. 0
`Drawing(s) (35 U.S. C. 113)
`(Total Sheets
`7
`(Total Sheets
`5. Oath or Declaration
`2
`a. lZ] Newly executed (original or copy)
`b. D A copy from a prior application (37 CFR 1.63(d))
`.....J!.or continuation/divisional with Box 18 completed)
`i.J_j DELETION OF INVENTORISl
`Signed statement attached deleting inventor(s)
`name in the prior application, see 37 CFR
`1.63(d)(2) and 1 .33(b).
`
`6. 0
`7. 0
`
`Application Data Sheet. See 37 CFR 1.76
`
`CD-ROM or CD-R in duplicate, large table or
`Clmlputer Program (Appendix)
`U Landscape Table on CD
`
`ADDRESS TO:
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`
`ACCOMPANYING APPLICATION PARTS
`9. 0 Assignment Papers (cover sheet & document(s))
`
`Name of Assignee Alpha Synergy Development, Inc.
`
`10. 0 37 CFR 3.73(b) Statement
`I]]Powerof
`(when there is an assignee)
`Attorney
`11. 0 English Translation Document (if applicable)
`
`12.12] lnfo~tion Disclosure Statement (PTO/SBI08 or PT0-1449)
`Wcopies of citations attached
`
`13. D Preliminary Amendment
`14. 0 Return Receipt Postcard (MPEP 503)
`(Should be specifically itemized)
`15. D Certified Copy of Priority Document(s)
`(if foreign priority is claimed)
`16. 0 Non publication Request under 35 U.S.C. 122(b)(2)(8)(i).
`Applicant must attach form PTOISB/35 or equivalent.
`17. 0 Other: Petition to Accept Color Drawings or
`
`8. Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a. -c. are required)
`a. D Computer Readable Form (CRF)
`b.
`Specification Sequence Listing on:
`i. D
`CD-ROM or CD-R (2 copies); or
`ii.O
`Paper
`c. D Statements verifying identity of above copies
`Photographs
`18. If a CONTINUING APPLICATION, check appropriate box, and supply the requisite information below and in the first sentence of the
`specification following the title, or in an Application Data Sheet under 37 CFR 1. 76:
`D Continuation-in-part (CIP)
`0 Continuation
`D Divisional
`Examiner ____________ _
`Prior application information:
`
`of prior application No.: ............................... ..
`
`Art Un i t : - - - - - - - - - - - - -
`
`19. CORRESPONDENCE ADDRESS
`
`[{]The address associated with Customer Number: I
`Name
`
`Wood Phillips Katz Clark & Mortimer
`
`32116
`
`OR 0 Correspondence address below
`
`500 West Madison Street
`
`Chicago
`
`US
`
`/L
`
`I State
`I Telephone
`
`Illinois
`
`(312) 876-1800
`
`Address
`
`City
`
`Country
`
`Signature
`
`Name
`IPrinVTvoel
`
`Zip Code soss1
`docketing@woodphillips.com
`I Date July 27, 2009
`Registration No. I
`(Attorney/Agent) 54•377
`
`This collection of information is required by 37 CFR 1.53(b). The information is required to obtain or retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to
`complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any
`comments on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer,
`U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
`FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313·1450.
`If you need assistance in completing the form. ca/11-800-PT0-9199 and select option 2.
`
`Page 1 of 54
`
`SLAYBACK EXHIBIT 1010
`
`
`
`PTO/SB/17 (10-08)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995 no persons are required to respond to a collection of information unless it displays a valid OMB control number
`Complete if Known
`
`,
`
`Effective on 1210812004.
`Fees pursuant to the Consolidated Appropriations Act. 2005 (HR. 4818).
`
`"
`
`.J
`
`FEE TRANSMITTAL Filing Date
`For FY 2009
`[i] Applicant claims small entity status. See 37 CFR 1 .27
`\.TOTAL AMOUNT OF PAYMENT I ($)
`METHOD OF PAYMENT (check all that apply)
`
`Application Number
`
`First Named Inventor Gerald Horn
`Examiner Name
`
`765
`
`Art Unit
`Attorney Docket No. ASD1 0554P00070US
`
`0 Check D Credit Card D Money Order 0None Oother (please identify):
`0 Deposit Account Deposit Account Number: 23-0785
`D Charge fee(s) indicated below
`
`Deposit Account Name: Wood/Phillips
`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`
`0 Charge fee(s) indicated below, except for the filing fee
`
`[{] Credit any overpayments
`
`EXAMINATION FEES
`Small Enti~
`.E22..W
`.E22..W
`220
`110
`140
`70
`170
`85
`650
`325
`0
`0
`
`[{]Charge any additional fee(s) or underpayments of fee(s)
`under 37 CFR 1.16 and 1 . 17
`WARNING: Information on this form may become public. Credit card Information should not be included on this form. Provide credit card
`information and authorization on PT0-2038.
`FEE CALCULATION
`1. BASIC FILING, SEARCH, AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Entitll
`Small Enti~
`Agelication TJlj2e ~ fi!Ull
`E!Ui1 EWil
`Utility
`330
`165
`540
`270
`Design
`220
`110
`100
`50
`Plant
`220
`110
`330
`165
`Reissue
`330
`165
`540
`270
`Provisional
`220
`110
`0
`0
`2. EXCESS CLAIM FEES
`Fee Descri12tion
`Each claim over 20 (including Reissues)
`Each independent claim over 3 (including Reissues)
`Multiple dependent claims
`Total Claims
`Extra Claims
`-20 or HP =
`12
`0
`X
`HP =highest number of total claims paid for, if greater than 20 .
`.E22..W
`Extra Claims
`lndej2. Claims
`=
`j :10
`-3 or HP =
`5
`2
`X
`HP highest number of independent claims paid for, if greater than 3.
`3. APPLICATION SIZE FEE
`If the specification and drawings exceed 100 sheets of paper (excluding electronically filed sequence or computer
`listings under 37 CFR 1.52(e)), the application size fee due is $270 ($135 for small entity) for each additional 50
`sheets or fraction thereof. See 35 U.S.C. 41~)(1)(G) and 37 CFR 1.16~s).
`Num er of each additional 50 or raction thereof
`Total Sheets
`Extra Sheets
`49
`- 100 =
`Q
`(round up to a whole number) X
`/50=
`4. OTHER FEE(S)
`Non-English Specification, $130 fee (no small entity discount)
`Other (e.g., late filing
`
`Fees Paid (~}
`
`54:2
`
`Small Entitv
`.EwUll
`.E!!ltl
`26
`52
`110
`220
`195
`390
`Multigle De12endent Claims
`fi!Ull
`Fee Paid {~l
`
`.E22..W
`
`=
`
`Fee Paid m
`
`Fee Paid lil
`22Q
`
`.E22..W
`
`=
`
`Fee Paid {~l
`
`Fees Paid {~}
`
`SUBMITTED BY
`
`Signature
`
`~
`
`J. Registration No.
`
`,(Attornev/Agentl 54,377
`
`d//.//:;f!t/1/Y I
`y
`f/
`Name (Print/Type) Mif(Polyal6{
`This collec~on of Information Is re uired b 37 CFR 1.136. The ir{(ormation Is re uired to obtain or retain a benefit b the ublic which is to file and b
`q
`q
`yp
`(
`y the
`y
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 30 minutes to complete,
`Including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments
`on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer. u.s. Patent
`and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS
`ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, ca/11-800-PT0-9199 and select option 2.
`
`Telephone (312) 876-2110
`
`Date July 27,2009
`
`Page 2 of 54
`
`SLAYBACK EXHIBIT 1010
`
`
`
`......
`{
`;;:t Under the
`I
`
`...... "''
`UTILITY
`c:
`~I PATENT APPLICATION
`cJ I
`TRANSMITTAL
`
`, Ar.t of 1995. no no•••
`
`U.S. PTO
`12/460941
`07/27/2009
`PTO/SBI05 (08-08)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`'reauired tore ;oand to a collection
`1 unless it disolavs a valid OMB control number.
`
`Attorney Docket No.
`
`ASD10554P0070US
`
`First Inventor
`
`Title
`
`Gerald Hom
`
`Preferential Vasoconstriction ...
`
`(Only for new non provisional applications under 37 CFR 1.53(b))
`
`Express Mail Label No.
`
`EV 955717223 US
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`1. 0 Fee Transmittal Form (e.g., PTOISB/17)
`2.0
`Applicant claims small entity status.
`See 37 CFR 1.27.
`3.0
`[Total Pages
`49
`Specification
`Both the claims and abstract must start on a new page
`(For information on the prefened arrangement, see MPEP 608.01(a))
`4. 0
`Drawing(s) (35 U.S. C. 113)
`(Total Sheets
`7
`(Total Sheets
`5. Oath or Declaration
`2
`a. lZ] Newly executed (original or copy)
`b. D A copy from a prior application (37 CFR 1.63(d))
`.....J!.or continuation/divisional with Box 18 completed)
`i.J_j DELETION OF INVENTORISl
`Signed statement attached deleting inventor(s)
`name in the prior application, see 37 CFR
`1.63(d)(2) and 1 .33(b).
`
`6. 0
`7. 0
`
`Application Data Sheet. See 37 CFR 1.76
`
`CD-ROM or CD-R in duplicate, large table or
`Clmlputer Program (Appendix)
`U Landscape Table on CD
`
`ADDRESS TO:
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`
`ACCOMPANYING APPLICATION PARTS
`9. 0 Assignment Papers (cover sheet & document(s))
`
`Name of Assignee Alpha Synergy Development, Inc.
`
`10. 0 37 CFR 3.73(b) Statement
`I]]Powerof
`(when there is an assignee)
`Attorney
`11. 0 English Translation Document (if applicable)
`
`12.12] lnfo~tion Disclosure Statement (PTO/SBI08 or PT0-1449)
`Wcopies of citations attached
`
`13. D Preliminary Amendment
`14. 0 Return Receipt Postcard (MPEP 503)
`(Should be specifically itemized)
`15. D Certified Copy of Priority Document(s)
`(if foreign priority is claimed)
`16. 0 Non publication Request under 35 U.S.C. 122(b)(2)(8)(i).
`Applicant must attach form PTOISB/35 or equivalent.
`17. 0 Other: Petition to Accept Color Drawings or
`
`8. Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a. -c. are required)
`a. D Computer Readable Form (CRF)
`b.
`Specification Sequence Listing on:
`i. D
`CD-ROM or CD-R (2 copies); or
`ii.O
`Paper
`c. D Statements verifying identity of above copies
`Photographs
`18. If a CONTINUING APPLICATION, check appropriate box, and supply the requisite information below and in the first sentence of the
`specification following the title, or in an Application Data Sheet under 37 CFR 1. 76:
`D Continuation-in-part (CIP)
`0 Continuation
`D Divisional
`Examiner ____________ _
`Prior application information:
`
`of prior application No.: ............................... ..
`
`Art Un i t : - - - - - - - - - - - - -
`
`19. CORRESPONDENCE ADDRESS
`
`[{]The address associated with Customer Number: I
`Name
`
`Wood Phillips Katz Clark & Mortimer
`
`32116
`
`OR 0 Correspondence address below
`
`500 West Madison Street
`
`Chicago
`
`US
`
`/L
`
`I State
`I Telephone
`
`Illinois
`
`(312) 876-1800
`
`Address
`
`City
`
`Country
`
`Signature
`
`Name
`IPrinVTvoel
`
`Zip Code soss1
`docketing@woodphillips.com
`I Date July 27, 2009
`Registration No. I
`(Attorney/Agent) 54•377
`
`This collection of information is required by 37 CFR 1.53(b). The information is required to obtain or retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to
`complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any
`comments on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer,
`U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
`FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313·1450.
`If you need assistance in completing the form. ca/11-800-PT0-9199 and select option 2.
`
`Page 3 of 54
`
`SLAYBACK EXHIBIT 1010
`
`
`
`PTO/SB/17 (10-08)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995 no persons are required to respond to a collection of information unless it displays a valid OMB control number
`Complete if Known
`
`,
`
`Effective on 1210812004.
`Fees pursuant to the Consolidated Appropriations Act. 2005 (HR. 4818).
`
`"
`
`.J
`
`FEE TRANSMITTAL Filing Date
`For FY 2009
`[i] Applicant claims small entity status. See 37 CFR 1 .27
`\.TOTAL AMOUNT OF PAYMENT I ($)
`METHOD OF PAYMENT (check all that apply)
`
`Application Number
`
`First Named Inventor Gerald Horn
`Examiner Name
`
`765
`
`Art Unit
`Attorney Docket No. ASD1 0554P00070US
`
`0 Check D Credit Card D Money Order 0None Oother (please identify):
`0 Deposit Account Deposit Account Number: 23-0785
`D Charge fee(s) indicated below
`
`Deposit Account Name: Wood/Phillips
`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`
`0 Charge fee(s) indicated below, except for the filing fee
`
`[{] Credit any overpayments
`
`EXAMINATION FEES
`Small Enti~
`.E22..W
`.E22..W
`220
`110
`140
`70
`170
`85
`650
`325
`0
`0
`
`[{]Charge any additional fee(s) or underpayments of fee(s)
`under 37 CFR 1.16 and 1 . 17
`WARNING: Information on this form may become public. Credit card Information should not be included on this form. Provide credit card
`information and authorization on PT0-2038.
`FEE CALCULATION
`1. BASIC FILING, SEARCH, AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Entitll
`Small Enti~
`Agelication TJlj2e ~ fi!Ull
`E!Ui1 EWil
`Utility
`330
`165
`540
`270
`Design
`220
`110
`100
`50
`Plant
`220
`110
`330
`165
`Reissue
`330
`165
`540
`270
`Provisional
`220
`110
`0
`0
`2. EXCESS CLAIM FEES
`Fee Descri12tion
`Each claim over 20 (including Reissues)
`Each independent claim over 3 (including Reissues)
`Multiple dependent claims
`Total Claims
`Extra Claims
`-20 or HP =
`12
`0
`X
`HP =highest number of total claims paid for, if greater than 20 .
`.E22..W
`Extra Claims
`lndej2. Claims
`=
`j :10
`-3 or HP =
`5
`2
`X
`HP highest number of independent claims paid for, if greater than 3.
`3. APPLICATION SIZE FEE
`If the specification and drawings exceed 100 sheets of paper (excluding electronically filed sequence or computer
`listings under 37 CFR 1.52(e)), the application size fee due is $270 ($135 for small entity) for each additional 50
`sheets or fraction thereof. See 35 U.S.C. 41~)(1)(G) and 37 CFR 1.16~s).
`Num er of each additional 50 or raction thereof
`Total Sheets
`Extra Sheets
`49
`- 100 =
`Q
`(round up to a whole number) X
`/50=
`4. OTHER FEE(S)
`Non-English Specification, $130 fee (no small entity discount)
`Other (e.g., late filing
`
`Fees Paid (~}
`
`54:2
`
`Small Entitv
`.EwUll
`.E!!ltl
`26
`52
`110
`220
`195
`390
`Multigle De12endent Claims
`fi!Ull
`Fee Paid {~l
`
`.E22..W
`
`=
`
`Fee Paid m
`
`Fee Paid lil
`22Q
`
`.E22..W
`
`=
`
`Fee Paid {~l
`
`Fees Paid {~}
`
`SUBMITTED BY
`
`Signature
`
`~
`
`J. Registration No.
`
`,(Attornev/Agentl 54,377
`
`d//.//:;f!t/1/Y I
`y
`f/
`Name (Print/Type) Mif(Polyal6{
`This collec~on of Information Is re uired b 37 CFR 1.136. The ir{(ormation Is re uired to obtain or retain a benefit b the ublic which is to file and b
`q
`q
`yp
`(
`y the
`y
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 30 minutes to complete,
`Including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments
`on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer. u.s. Patent
`and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS
`ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, ca/11-800-PT0-9199 and select option 2.
`
`Telephone (312) 876-2110
`
`Date July 27,2009
`
`Page 4 of 54
`
`SLAYBACK EXHIBIT 1010
`
`
`
`APPLICATION DATA SHEET
`(lnventor(s) With Representation)
`
`Inventor Information
`
`Inventor One, Given Name:
`Family Name:
`Postal Address Line One:
`Postal Address Line Two:
`City:
`State or Province:
`Postal or Zip Code:
`Citizenship Country:
`
`Correspondence Information
`
`Gerald
`HORN
`1150 Heather Road
`
`Deerfield
`Illinois
`60015
`United States
`
`Correspondence Customer Number:
`Name Line One:
`Address Line One:
`Address Line Two:
`City:
`State or Province:
`Postal Or Zip Code:
`Telephone:
`Facsimile:
`
`32116
`Wood, Phillips, Katz, Clark & Mortimer
`Citigroup Center, Suite 3800
`500 West Madison Street
`Chicago
`Illinois
`60661
`312-876-1800
`312-876-2020
`
`Application Information
`
`This Application is a:
`Title Line One:
`Title Line Two:
`Total Drawing Sheets:
`Docket Number:
`
`Claiming Priority of:
`
`Utility
`Preferential Vasoconstriction Compositions
`and Methods of Use
`7
`ASD10554P00070US
`
`US Provisional Application No. 61/137,714
`filed August 1, 2008;
`
`US Provisional Application No. 61/192,777
`filed September 22, 2008;
`
`US Provisional Application No.61/203, 120
`filed December 18, 2008; and
`
`US Provisional Application No. 61/207,481
`filed February 12, 2009
`
`Representative Information
`
`Registration Number One:
`
`54,377
`
`Page 1 of 1
`
`Page 5 of 54
`
`SLAYBACK EXHIBIT 1010
`
`
`
`I
`
`•
`
`Preferential Vasoconstriction Compositions and Methods of Use
`
`The file of this patent contains at least one drawing executed in color. Copies of
`
`this patent with color drawing(s) will be provided by the Patent and Trademark Office
`
`5
`
`upon request and payment of the necessary fee.
`
`BACKGROUND OF THE INVENTION
`
`Dilation of small blood vessels, particularly arterioles, capillaries, and venules,
`
`causes many clinically undesirable events including surface hemorrhage and hyperemia
`
`following Lasik surgery, eye redness (conjunctival hyperemia), and nasal congestion
`
`10
`
`(turbinate mucosal swelling secondary to vasodilation).
`
`Adrenergic receptors mediate physiological responses to the catecholamines,
`
`norephinephrine and epinephrine, and are members of the superfamily of G protein(cid:173)
`
`coupled receptors having seven transmembrane domains. These receptors, which are
`
`divided pharmacologically into a-1, a-2 and &-adrenergic receptor types, are involved in
`
`15
`
`diverse physiological functions including functions of the cardiovascular and central
`
`nervous systems. The a-adrenergic receptors mediate excitatory and inhibitory
`
`functions: a-1 adrenergic receptors are typically excitatory post-synaptic receptors
`
`which generally mediate responses in an effector organ, while a-2 adrenergic receptors
`
`are located postsynaptically as well as presynaptically, where they inhibit release of
`
`20
`
`neurotransmitters. Agonists of a-2 adrenergic receptors currently are used clinically in
`
`the treatment of hypertension, glaucoma, spasticity, and attention-deficit disorder, in the
`
`suppression of opiate withdrawal, as adjuncts to general anesthesia and in the
`
`1
`
`Page 6 of 54
`
`SLAYBACK EXHIBIT 1010
`
`
`
`treatment of cancer pain. Vascular constriction is known to be mediated by a·
`
`adrenergic receptors.
`
`a~2 adrenergic receptors are presently classified into three subtypes based on
`
`their pharmacological and molecular characterization: a·2AID (a-2A in human and a-2D
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`in rat); a·2B; and a·2C (Bylund et al., Pharmacal. Rev. 46:121-136 (1994); and Hein
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`and Kobilka, Neuropharmacol. 34:357-366 (1995)). The a-2A, a-28, and a-2C subtypes
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`appear to regulate arterial and/or venular contraction in some vascular beds, and the a(cid:173)
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`. 2A anda-2C subtypes mediate feedback inhibition of norepinephrine release from
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`sympathetic nerve endings; The a-2A subtype also mediates many of the central effects
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`10
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`of a·2 adrenergic agonists (Calzada and ArtiZano, Pharmacal. Res. 44: 195-208 (2001 );
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`Hein et al., Ann. NY Acad. Science 881:265-271 (1999); and Ruffolo (Ed.), a-
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`. Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology S. Karger
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`Publisher's Inc. Farmington, Conn. (1991 )). The a-2A subtype also mediates potent
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`constriction of the porcine, but not human, ciliary artery.
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`Many compounds having selective a-2 agonist activity are known and include
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`brimonidine (which has been used for lowering intraocular pressure in patients with
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`open-angle glaucoma or ocular hypertension), guanfacine (which has been used to
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`control high blood pressure), dexmetidomidine (which has been used as a sedative,
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`analgesic, sympatholytic and anxiolytic), and methyl dopa (which has been used as a
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`centrally -acting adrenergic antihypertensive).
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`The clinically available compounds belong
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`to
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`the general category of a
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`adrenergic receptor agonists. It is a known property of all a adrenergic receptor
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`agonists,
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`including brimonidine,
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`to cause vasoconstriction. However, known
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`formulations of brimonidine and other known a-2 adrenergic receptor agonists are
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`associated with a high incidence of rebound hyperemia, or other side effects, in clinical
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`use. For example, after as few as three doses of applying known formulations of a
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`adrenergic receptor agonists, patients may develop secondary rebound hyperemia or
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`secondary
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`vasodilation.
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`Brimonidine
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`(5-bromo-6-(2-imidazolidinylideneamino)
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`quinoxaline L-tartrate), a known selective alpha 2 agonist is associated with significant
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`rebound hyp~remia (primary or delayed onset vasodilation) in its current concentration
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`range for treating glaucoma of about 0.1% to 0:2%.
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`Commercially available general alpha agonists for topical mucosal decongestant
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`use
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`(ophthalmic and nasal applications)
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`include
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`tetrahydrozoline, naphazoline,
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`oxymetazoline, xylometazoline, methoxamine and phenylephrine. These agonists have
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`high alpha 1 receptor agonist activity and are known to cause rebound hyperemia and
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`medicamentosa. Accordingly, their clinical use is usually restricted to several hours or a
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`few days, at most. Many individuals with mucosal congestion or hyperemia from chronic
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`conditions such as dry eye, contact lens wear, allergic conjunctivitis, allergic rhinitis,
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`nonallergic rhinitis, acute or chronic sinusitis, nasal polyposis, rhinitis secondary to
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`pregnancy, or rhinitis due to nasal septal deviation or obstruction and asthma,
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`particularly, allergic asthma require longer term agonist use.
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`To the best of the inventor's knowledge, there are currently no means to induce
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`effective vasoconstriction without concomitant ischemia caused by an excessive
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`reduction
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`in blood
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`flow and a cascade of inflammatory mediators, resulting
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`in
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`undesirable clinical sequelae of rebound hyperemia, and or medicamentosa, a
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`potentially prolonged inflammatory state that can last for several weeks or months of
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`rebound mucosal congestion.
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`Thus, there is a need for new methods and formulations that would provide safe
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`and long term vasoconstriction with reduced or minimized side effects, such as rebound
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`hyperemia.
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`SUMMARY OF THE PRESENT INVENTION
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`The present invention is generally related to compositions and methods for
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`inducing vasoconstriction. One of the key discoveries of the present invention lies in
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`10
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`using low doses of highly selective a-2 adrenergic receptor agonists to achieve
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`vasoconstriction with significantly reduced hyperemia.
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`There are a variety of applications and dosage forms that can be utilized to apply
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`the findings of the invention. For example, some applications include methods and
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`compositions
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`for:
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`treating nasal congestion;
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`inducing vasoconstriction;
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`inducing
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`preferential vasoconstriction of smaller blood vessels relative to larger blood vessels;
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`reducing capillary permeability in a pulmonary condition; reversing rebound hyperemia;
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`reducing activation of a-1 adrenergic receptors; and treating and preventing an allergic
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`response with reduced rebound hyperemia.
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`The invention also encompasses using the compositions and methods of this
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`20
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`invention for prophylactic reasons, for example, for prophylaxis of conditions including,
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`but not limited to, asthma, upper respiratory disease, acute pharyngitis, acute sinusitis,
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`acute
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`tracheobronchitis,
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`influenza,
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`lower
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`respiratory disease, acute bronchitis,
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`bronchiolitis, and community acquired pneumonia (CAP).
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`The invention also relates to a metered dose dispenser comprising the aqueous
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`compositions of the invention.
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`BRIEF DESCRIPTION OF THE FIGURES
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`5
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`Figure 1 is a graphical representation of the variation of vasoconstriction net clinical
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`effectiveness of prior art compositions comprising naphazoline,
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`oxymetazoline and tetrahydrozoline at various concentrations.
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`Figure 2 is a graphical representation of the variation of vasoconstriction clinical
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`effectiveness of compositions of the present
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`invention comprising
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`10
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`brimonidine at low concentrations.
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`Figure 3 is a graphical representation of clinical effectiveness of the compositions of the
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`present invention versus prior art compositions.
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`Figure 4A is a baseline visual appearance of two eyes of a patient with an ocular
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`condition.
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`15
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`Figure 48 depicts the eyes of the patient 180 minutes after being treated with a prior art
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`composition comprising tetrahydrozoline at 0.05% (right eye) and a
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`composition of the present invention comprising brimonidine at 0.01%
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`(left eye).
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`Figure 4C depicts the eyes of the patient 240 minutes after baseline (FIG. 4A) after
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`20
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`being treated with a prior art composition comprising oxymetazoline at
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`0.025% (right eye) and a composition of the present invention comprising
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`brimonidine at 0.02% (left eye).
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`Figure 4D depicts the eyes of the patient 240 minutes after treatment described in FIG.
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`4C after being
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`treated with a prior art composition comprising
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`naphazoline at 0.033% (right eye) and a composition of the present
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`invention comprising brimonidine at 0.02% (left eye).
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`5 Figure 4E
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`depicts the left eye of the patient 240 minutes after treatment described in
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`FIG. 40 after being treated with a composition of the present invention
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`comprising brimonidine at 0.033%.
`
`Figure 5A
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`is a baseline visual appear~nce of two eyes of a patient with an ocular
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`condition of moderate hyperemia.
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`10
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`Figure 58
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`depicts a visual appearance of the right eye of the patient after being
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`treated with a prior art composition comprising VISINE Original®
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`(tetrahydrozoline 0.05%) and the induction of rebound hyperemia, and
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`the visual appearance of the left eye of the patient after being treated
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`simultaneously with a composition of the present invention comprising
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`15
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`brimonidine at 0.015%
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`Figure 5C
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`depicts a visual appearance of the right eye of the patient after then being
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`treated with the novel composition of the present invention comprising
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`brimonidine at 0.015%, reversing the VISINE Original® induced rebound
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`hyperemia, and a visual appearance of the left eye of the patient after
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`being treated simultaneously with an additional drop of the composition of
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`the present invention comprising brimonidine at 0.015%.
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`Figure 6
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`is another graphical representation of clinical effectiveness of the
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`compositions of the present invention versus prior art compositions.
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`DETAILED DESCRIPTION OF THE INVENTION
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`Definitions
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`For purposes of the present invention, the terms below are defined as follows.
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`The term "low concentrations" refers to concentrations from between about
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`0.0001% to about 0.05%; more preferably, from about 0.001% to about 0.025%; even
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`more preferably, from about 0.01% to about 0.025%; and even more preferably, from
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`about 0.01% to about 0.02% weight by volume.
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`The term "administered locally" refers to administering the compositions of the
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`10
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`present invention approximately at the site where they will come into contact with a-2
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`adrenergic receptors. This term specifically excludes oral administration, intravenous
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`injection, or transdermal patches which are not applied approximately at the spatial
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`location of the area which is desired to be treated by the compositions of the present
`
`invention.
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`The term "brimonidine" encompasses, without limitation, brimonidine salts and
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`other derivatives, and specifically includes, but is not limited to, brimonidine tartrate, 5-
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`bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, Alphagan™, and UK14304.
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`The term "treating" refers to reversing, alleviating, inhibiting, or slowing the
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`progress of the disease, disorder, or condition to which such term applies, or one or
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`20 more symptoms of such disease, disorder, or condition.
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`The term "preventing" refers to prophylactic use to reduce the likelihood of a
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`disease, disorder, or condition to which such term applies, or one or more symptoms of
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`such disease, disorder, or condition. It is not necessary to achieve a 100% likelihood of
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`prevention; it is sufficient to achieve at least a partial effect of reducing the risk of
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`acquiring such disease, disorder, or condition.
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`The term "swollen nasal turbinates condition" includes, but is not limited to, nasal
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`decongestion.
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`5 Vasoconstriction with Reduced Hyperemia
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`One aspect of the present invention refers to a surprising and unexpected finding
`
`that using highly selective a-2 agonists at low concentrations allows reducing,
`
`minimizing, and/or eliminating rebound hyperemia while optimally providing clinically
`
`equal or more effective vasoconstriction. Rebound hyperemia refers to induced
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`vasodilation (instead of intended vasoconstriction) occurring, often with a lag time, after
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`an application or, more typically, repeated applications of vasoconstrictors and
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`characterized by engorgement of blood vessels (such as those in the conjunctiva or
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`nasal mucosa), increased capillary permeability and leakage, and, in some cases,
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`inflammatory sequelae (medicamentosa), frequently due to the use of an alpha 1
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`15
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`constricting drug and particularly, chronic use of a vasoconstricting drug.
`
`Many, if not all, references in the prior art associated rebound hyperemia with all
`
`alpha agonists and considered the complication of rebound hyperemia to be intrinsic to
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`vasoconstriction, wherein blood flow is reduced, causing attendant ischemia with some
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`inflammatory cascade, precipitating rebound hyperemia in many cases and often
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`20
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`leading to medicamentosa.
`
`Contrary to these teachings, it was surprisingly and unexpectedly found that
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`selective alpha-2 (a-2) adrenergic receptor agonists (which are also interchangeably
`
`referred to as "a-2 agonists" throughout the application) with extremely high selectivity
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`for a-2 adrenergic receptors at low concentrations, well below those previously
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`contemplated, can induce effective vasoconstriction with low incidence of rebound
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`hyperemia as compared to the prior art, and low incidence of allergic reaction, including
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`allergic blepharitis and follicular conjunctivitis.