`
`William P. Deni, Jr.
`J. Brugh Lower
`GIBBONS P.C.
`One Gateway Center
`Newark, New Jersey 07102
`Tel: (973) 596-4500
`Fax: (973) 596-0545
`
`Attorneys for Plaintiffs
`
`UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
`
`BAUSCH & LOMB, INC.;
`BAUSCH & LOMB IRELAND LIMITED;
`and EYE THERAPIES, LLC,
`
`Plaintiffs,
`
`v.
`
`SLAYBACK PHARMA LLC and
`SLAYBACK PHARMA INDIA LLP,
`
`Defendants.
`
`Civil Action No. 21-16766
`
`Document Electronically Filed
`
`COMPLAINT FOR PATENT INFRINGEMENT
`
`Plaintiffs Bausch & Lomb, Inc., Bausch & Lomb Ireland Limited, and Eye Therapies, LLC
`
`(collectively, “Plaintiffs”) by way of Complaint against Defendants Slayback Pharma LLC and
`
`Slayback Pharma India LLP (collectively, “Defendants”) allege as follows:
`
`NATURE OF THE ACTION
`
`1.
`
`This is an action for infringement of United States Patent Nos. 8,293,742 (“the ’742
`
`patent”) and 9,259,425 (“the ’425 patent”), arising under the United States patent laws, Title 35,
`
`United States Code, § 100 et seq., including 35 U.S.C. §§ 271 and 281, and for declaratory
`
`judgment of infringement under 28 U.S.C. §§ 2201 and 2202. This action relates to Slayback
`
`Pharma LLC’s filing of an Abbreviated New Drug Application (“ANDA”) under Section 505(j)
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 2 of 12 PageID: 2
`
`of the Federal Food, Drug, and Cosmetic Act (“the Act”), 21 U.S.C. § 355(j), seeking U.S. Food
`
`and Drug Administration (“FDA”) approval to market its generic Brimonidine Tartrate
`
`Ophthalmic Solution, 0.025% (“Slayback’s generic brimonidine ophthalmic solution”) prior to the
`
`expiration of the ’742 patent and the ’425 patent.
`
`THE PARTIES
`
`2.
`
`Plaintiff Bausch & Lomb, Inc. (“Bausch”) is a corporation organized and existing
`
`under the laws of New York with a place of business at 1400 N. Goodman St. Rochester, NY
`
`14609. Bausch is the registered holder of approved New Drug Application (“NDA”) No. 208144,
`
`which covers Lumify® ophthalmic solution/drops (brimonidine tartrate, 0.025%).
`
`3.
`
`Plaintiff Bausch & Lomb Ireland Limited (“Bausch Ireland”) is a company
`
`organized and existing under the laws of Ireland, having its registered office at 3013 Lake Drive,
`
`Citywest Business Park, Dublin, Ireland. Bausch Ireland exclusively licenses the ’742 patent and
`
`the ’425 patent.
`
`4.
`
`Plaintiff Eye Therapies, LLC (“Eye Therapies”) is a limited liability company
`
`organized and existing under the laws of Delaware, having its principal place of business at 26933
`
`Camino De Estrella, 2nd Fl., Dana Point, California 92624. Eye Therapies is the owner of the
`
`’742 patent and the ’425 patent.
`
`5.
`
`Upon information and belief, Slayback Pharma, LLC (“Slayback”) is a Delaware
`
`limited liability company having a principal place of business at 301 Carnegie Center, Suite 303,
`
`Princeton, NJ 08540, within this judicial district.
`
`6.
`
`Upon information and belief, Slayback Pharma India LLP (“Slayback India”) is a
`
`limited liability partnership organized under the laws of India, having a principal place of business
`
`- 2 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 3 of 12 PageID: 3
`
`at 310, 3rd Floor, Manjeera Trinity Corporate, JNTU - Hitech City Road, KPHB Phase 3,
`
`Kukutpally Hyderabad, Telangana 500072, India.
`
`7.
`
`Upon information and belief, Slayback is the parent corporation of Slayback India,
`
`and the acts of Slayback complained of herein were done with the cooperation, participation and
`
`assistance of Slayback India.
`
`JURISDICTION AND VENUE
`
`8.
`
`This Court has subject matter jurisdiction under 28 U.S.C. §§ 1331, 1338(a), 2201
`
`and 2202.
`
`9.
`
`Upon information and belief, this court has jurisdiction over Slayback. Upon
`
`information and belief, Slayback is in the business of, inter alia, developing, manufacturing,
`
`marketing, importing and selling pharmaceutical products, including generic drug products. Upon
`
`information and belief, Slayback directly, or indirectly, develops, manufactures, markets, and sells
`
`generic drug products throughout the United States and in this judicial district, and this judicial
`
`district is a likely destination for Slayback’s generic brimonidine ophthalmic solution. Upon
`
`information and belief, Slayback purposefully has conducted and continues to conduct business in
`
`this judicial district. Upon information and belief, Slayback has its principal place of business at
`
`301 Carnegie Center, Suite 303, Princeton, New Jersey 08540. Upon information and belief,
`
`Slayback has previously submitted to the jurisdiction of this Court and has further previously
`
`availed itself of this Court by asserting counterclaims in other civil actions initiated in this
`
`jurisdiction.
`
`10.
`
`Upon information and belief, Slayback has taken the costly, significant step of
`
`applying to the FDA for approval to engage in future activities—including the marketing of its
`
`generic drugs—that will be purposefully directed at, upon information and belief, the State of New
`
`- 3 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 4 of 12 PageID: 4
`
`Jersey and elsewhere. Slayback’s ANDA filings constitute formal acts that reliably indicate plans
`
`to engage in marketing of the proposed generic drugs. Upon information and belief, Slayback
`
`intends to direct sales of its drugs into New Jersey, among other places, once it has the requested
`
`FDA approval to market them. Upon information and belief, Slayback will engage in marketing
`
`of its generic brimonidine ophthalmic solution in New Jersey upon approval of its ANDA.
`
`11.
`
`Upon information and belief, this court has jurisdiction over Slayback India. Upon
`
`information and belief, Slayback India is in the business of, inter alia, developing, manufacturing,
`
`marketing, importing and selling pharmaceutical products, including generic drug products. Upon
`
`information and belief, Slayback India directly, or indirectly, develops, manufactures, markets,
`
`and sells generic drug products throughout the United States and in this judicial district, and this
`
`judicial district is a likely destination for Slayback’s generic brimonidine ophthalmic solution.
`
`Upon information and belief, Slayback India purposefully has conducted and continues to conduct
`
`business in this judicial district in concert with Slayback.
`
`12.
`
`Upon information and belief, Slayback and Slayback India operate as interrelated
`
`corporate entities. Upon information and belief, Slayback is the parent corporation of Slayback
`
`India. Upon information and belief, Slayback and Slayback India each act as an agent of the other
`
`and work together to, inter alia, develop, manufacture, obtain regulatory approval, market, sell
`
`and distribute generic copies of branded pharmaceutical products throughout the United States,
`
`including in this judicial district.
`
`13.
`
`Defendants know or should know that Lumify® is manufactured for Bausch, at least
`
`because that information is included in the label for Lumify® and is publicly available.
`
`14.
`
`Upon information and belief, venue is proper in this judicial district under 28 U.S.C.
`
`§§ 1391(c) and (d), and § 1400(b).
`
`- 4 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 5 of 12 PageID: 5
`
`15.
`
`Venue is proper against Slayback Pharma, LLC, which maintains a regular and
`
`established place of business in this judicial district.
`
`16.
`
`Venue is proper against Slayback India, a foreign corporation, in any judicial
`
`district that has personal jurisdiction, including this judicial district.
`
`THE PATENTS IN SUIT
`
`17.
`
`The PTO issued the ’742 patent on October 23, 2012. The ’742 patent claims, inter
`
`alia, methods of reducing eye redness consisting essentially of administering brimonidine into
`
`ocular tissue. Plaintiffs hold all substantial rights in the ’742 patent and have the right to sue for
`
`infringement thereof. A copy of the ’742 patent is attached hereto as Exhibit 1.
`
`18.
`
`The U.S. Patent and Trademark Office (“PTO”) issued the ’425 patent on February
`
`16, 2016. The ’425 patent claims, inter alia, methods of reducing redness of an eye and/or
`
`increasing whiteness of an eye comprising administering compositions comprising brimonidine.
`
`Plaintiffs hold all substantial rights in the ’425 patent and have the right to sue for infringement
`
`thereof. A copy of the ’425 patent is attached hereto as Exhibit 2.
`
`19.
`
`Bausch is the holder of NDA No. 208144 for Lumify®, which the FDA approved
`
`on December 22, 2017. In conjunction with NDA No. 208144, the ’742 and ’425 patents are listed
`
`in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (“the Orange
`
`Book”).
`
`20.
`
`Brimonidine tartrate ophthalmic solution, 0.025%, is sold in the United States under
`
`the trademark Lumify®.
`
`SLAYBACK’S INFRINGING ANDA SUBMISSION
`
`21.
`
`Upon information and belief, Slayback filed or caused to be filed with the FDA
`
`ANDA No. 216361, under Section 505(j) of the Act and 21 U.S.C. § 355(j).
`
`- 5 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 6 of 12 PageID: 6
`
`22.
`
`Upon information and belief, Slayback’s ANDA No. 216361 seeks FDA approval
`
`to engage in commercial manufacture, use, and sale in the United States of Slayback’s generic
`
`brimonidine ophthalmic solution, intended to be a generic version of Lumify®.
`
`23.
`
`On or about August 16, 2021, Plaintiffs received a letter from Slayback dated
`
`August 13, 2021, purporting to be a Notice of Paragraph IV Certification regarding ANDA No.
`
`216361 (“Slayback’s Notice Letter”) under Section 505(j)(2)(B)(iv) of the Act and 21 § C.F.R.
`
`314.95. Slayback’s Notice Letter was addressed to Bausch and Eye Therapies.
`
`24.
`
`Slayback’s Notice Letter alleges that Slayback has submitted to the FDA ANDA
`
`No. 216361 seeking approval to engage in the commercial manufacture, use and/or sale of
`
`Slayback’s generic brimonidine ophthalmic solution, intended to be generic versions of Lumify®.
`
`25.
`
`Slayback’s Notice Letter states that Slayback’s ANDA No. 216361 contains the
`
`“required bioavailability or bioequivalence data or information with respect to brimonidine tartrate
`
`ophthalmic solution, 0.025%,” for Slayback’s generic brimonidine ophthalmic solution.
`
`26.
`
`Upon information and belief, ANDA No. 216361 seeks approval of Slayback’s
`
`generic brimonidine ophthalmic solution that is the same, or substantially the same, as Lumify®.
`
`27.
`
`Upon information and belief, Slayback’s actions related to ANDA No. 216361
`
`complained of herein were done at the direction of, with the authorization of, or with the
`
`cooperation, the participation, the assistance of, or at least in part for the benefit of Slayback India.
`
`COUNT I FOR PATENT INFRINGEMENT
`
`Infringement of the ’742 Patent Under § 271(e)(2)
`
`Paragraphs 1-27 are incorporated herein as set forth above.
`
`Under 35 U.S.C. § 271(e)(2), Defendants have infringed at least one claim of the
`
`28.
`
`29.
`
`’742 patent by submitting, or causing to be submitted to the FDA, ANDA No. 216361 seeking
`
`- 6 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 7 of 12 PageID: 7
`
`approval for the commercial marketing of Slayback’s generic brimonidine ophthalmic solution
`
`before the expiration date of the ’742 patent.
`
`30.
`
`Upon information and belief, Slayback’s generic brimonidine ophthalmic solution
`
`will, if approved and marketed, infringe at least one claim of the ’742 patent.
`
`31.
`
`Upon information and belief, Defendants will, through the manufacture, use,
`
`import, offer for sale, and/or sale of Slayback’s generic brimonidine ophthalmic solution, directly
`
`infringe, contributorily infringe, and/or induce infringement of at least one claim of the ’742 patent.
`
`32.
`
`If Defendants’ marketing and sale of Slayback’s generic brimonidine ophthalmic
`
`solution prior to the expiration of the ’742 patent is not enjoined, Plaintiffs will suffer substantial
`
`and irreparable harm for which there is no adequate remedy at law.
`
`COUNT II FOR PATENT INFRINGEMENT
`
`Declaratory Judgment of Infringement of the ’742 Patent
`
`Paragraphs 1-32 are incorporated herein as set forth above.
`
`These claims arise under the Declaratory Judgment Act, 28 U.S.C. §§ 2201 and
`
`33.
`
`34.
`
`2202.
`
`35.
`
`There is an actual case or controversy such that the Court may entertain Plaintiffs’
`
`request for declaratory relief consistent with Article III of the United States Constitution, and this
`
`actual case or controversy requires a declaration of rights by this Court.
`
`36.
`
`Defendants have made, and will continue to make, substantial preparation in the
`
`United States to manufacture, use, offer to sell, sell, and/or import Slayback’s generic brimonidine
`
`ophthalmic solution before the expiration date of the ’742 patent, including Slayback’s filing of
`
`ANDA No. 216361.
`
`- 7 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 8 of 12 PageID: 8
`
`37.
`
`Upon information and belief, any commercial manufacture, use, offer for sale, sale,
`
`and/or importation of Slayback’s generic brimonidine ophthalmic solution will directly infringe,
`
`contributorily infringe, and/or induce infringement of at least one claim of the ’742 patent.
`
`38.
`
`Plaintiffs are entitled to a declaratory judgment that future commercial
`
`manufacture, use, offer of use, sale, and/or importation of Slayback’s generic brimonidine
`
`ophthalmic solution will constitute infringement of at least one claim of the ’742 patent.
`
`COUNT III FOR PATENT INFRINGEMENT
`
`Infringement of the ’425 Patent Under § 271(e)(2)
`
`Paragraphs 1-38 are incorporated herein as set forth above.
`
`Under 35 U.S.C. § 271(e)(2), Defendants have infringed at least one claim of the
`
`39.
`
`40.
`
`’425 patent by submitting, or causing to be submitted to the FDA, ANDA No. 216361 seeking
`
`approval for the commercial marketing of Slayback’s generic brimonidine ophthalmic solution
`
`before the expiration date of the ’425 patent.
`
`41.
`
`Upon information and belief, Slayback’s generic brimonidine ophthalmic solution
`
`will, if approved and marketed, infringe at least one claim of the ’425 patent.
`
`42.
`
`Upon information and belief, Defendants will, through the manufacture, use,
`
`import, offer for sale, and/or sale of Slayback’s generic brimonidine ophthalmic solution, directly
`
`infringe, contributorily infringe, and/or induce infringement of at least one claim of the ’425 patent.
`
`43.
`
`If Defendants’ marketing and sale of Slayback’s generic brimonidine ophthalmic
`
`solution prior to the expiration of the ’425 patent is not enjoined, Plaintiffs will suffer substantial
`
`and irreparable harm for which there is no adequate remedy at law.
`
`- 8 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 9 of 12 PageID: 9
`
`COUNT IV FOR PATENT INFRINGEMENT
`
`Declaratory Judgment of Infringement of the ’425 Patent
`
`Paragraphs 1-43 are incorporated herein as set forth above.
`
`These claims arise under the Declaratory Judgment Act, 28 U.S.C. §§ 2201 and
`
`44.
`
`45.
`
`2202.
`
`46.
`
`There is an actual case or controversy such that the Court may entertain Plaintiffs’
`
`request for declaratory relief consistent with Article III of the United States Constitution, and this
`
`actual case or controversy requires a declaration of rights by this Court.
`
`47.
`
`Defendants have made, and will continue to make, substantial preparation in the
`
`United States to manufacture, use, offer to sell, sell, and/or import Slayback’s generic brimonidine
`
`ophthalmic solution before the expiration date of the ’425 patent, including Slayback’s filing of
`
`ANDA No. 216361.
`
`48.
`
`Upon information and belief, any commercial manufacture, use, offer for sale, sale,
`
`and/or importation of Slayback’s generic brimonidine ophthalmic solution will directly infringe,
`
`contributorily infringe, and/or induce infringement of at least one claim of the ’425 patent.
`
`49.
`
`Plaintiffs are entitled to a declaratory judgment that future commercial
`
`manufacture, use, offer of use, sale, and/or importation of Slayback’s generic brimonidine
`
`ophthalmic solution will constitute infringement of at least one claim of the ’425 patent.
`
`PRAYER FOR RELIEF
`
`WHEREFORE, Plaintiffs respectfully request that this Court enter judgment in their favor
`
`and against Defendants on the patent infringement claims set forth above and respectfully request
`
`that this Court:
`
`- 9 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 10 of 12 PageID: 10
`
`1.
`
`Enter judgment that, under 35 U.S.C. § 271(e)(2), Defendants have infringed at
`
`least one claim of the ’742 patent by submitting or causing to be submitted ANDA No. 216361 to
`
`the FDA to obtain approval for the commercial manufacture, use, import, offer for sale, and/or sale
`
`in the United States of Slayback’s generic brimonidine ophthalmic solution before the expiration
`
`of the ’742 patent
`
`2.
`
`Enter judgment that, under 35 U.S.C. § 271(e)(2), Defendants have infringed at
`
`least one claim of the ’425 patent by submitting or causing to be submitted ANDA No. 216361 to
`
`the FDA to obtain approval for the commercial manufacture, use, import, offer for sale, and/or sale
`
`in the United States of Slayback’s generic brimonidine ophthalmic solution before the expiration
`
`of the ’425 patent;
`
`3.
`
`Order that the effective date of any approval by the FDA of Slayback’s generic
`
`brimonidine ophthalmic solution be a date that is not earlier than the expiration of the ’425 patent
`
`and the ’742 patent, or such later date as the Court may determine;
`
`4.
`
`Enjoin Defendants from the commercial manufacture, use, import, offer for sale,
`
`and/or sale of Slayback’s generic brimonidine ophthalmic solution until expiration of the ’742
`
`patent and the ’425 patent, or such later date as the Court may determine;
`
`5.
`
`Enjoin Defendants and all persons acting in concert with Slayback from seeking,
`
`obtaining, or maintaining approval of Slayback’s ANDA No. 216361 until expiration of the ’742
`
`patent and the ’425 patent;
`
`6.
`
`Declare this to be an exceptional case under 35 U.S.C. §§ 285 and 271(e)(4) and
`
`award Plaintiffs costs, expenses, and disbursements in this action, including reasonable attorney’s
`
`fees; and
`
`- 10 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 11 of 12 PageID: 11
`
`7.
`
`Award Plaintiffs such further and additional relief as this Court deems just and
`
`proper.
`
`Dated: September 10, 2021
`Newark, New Jersey
`
`Respectfully submitted,
`
`
`
`s/ William P. Deni, Jr.
`William P. Deni, Jr.
`J. Brugh Lower
`GIBBONS P.C.
`One Gateway Center
`Newark, New Jersey 07102
`Tel: (973) 596-4500
`Fax: (973) 596-0545
`wdeni@gibbonslaw.com
`jlower@gibbonslaw.com
`
`Of Counsel:
`
`Bryan C. Diner
`Justin J. Hasford
`FINNEGAN, HENDERSON,
`FARABOW, GARRETT & DUNNER, LLP
`901 New York Avenue, NW
`Washington, DC 20001-4413
`Tel: (202) 408-4000
`
`Jessica M. Lebeis (pro hac vice to be submitted)
`FINNEGAN, HENDERSON,
`FARABOW, GARRETT & DUNNER, LLP
`Two Seaport Lane
`Boston, MA 02210-2001
`Tel: (617) 646-1600
`
`Attorneys for Plaintiffs
`
`- 11 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1 Filed 09/10/21 Page 12 of 12 PageID: 12
`
`CERTIFICATION OF NON-ARBITRABILITY
`PURSUANT TO LOCAL CIVIL RULE 201.1(d)
`
`Pursuant to Local Civil Rule 201.1(d), the undersigned counsel hereby certifies that this
`
`action seeks declaratory and injunctive relief and, therefore, is not subject to mandatory
`
`arbitration.
`
`I hereby certify under penalty of perjury that the foregoing is true and correct.
`
`Dated: September 10, 2021
`Newark, New Jersey
`
`
`
`s/ William P. Deni, Jr.
`William P. Deni, Jr.
`GIBBONS P.C.
`One Gateway Center
`Newark, New Jersey 07102
`Tel: (973) 596-4500
`Fax: (973) 596-0545
`wdeni@gibbonslaw.com
`
`Attorneys for Plaintiffs
`
`- 12 -
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 1 of 21 PageID: 13
`Case 3:21-cv-16766-MAS Document1-1 Filed 09/10/21 Page 1 of 21 PagelD: 13
`
`EXHIBIT 1
`EXHIBIT 1
`
`Eye Therapies Exhibit 2006, Page 13 of 55
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 2 of 21 PageID: 14
`I 1111111111111111 11111 1111111111 111111111111111 IIIII IIIII IIIIII IIII IIII IIII
`US008293742B2
`
`c12) United States Patent
`Horn
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,293,742 B2
`Oct. 23, 2012
`
`(54) PREFERENTIAL VASOCONSTRICTION
`COMPOSITIONS AND METHODS OF USE
`Inventor: Gerald Horn, Deerfield, IL (US)
`(75)
`(73) Assignee: Alpha Synergy Development, Inc.,
`Dana Point, CA (US)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 385 days.
`(21) Appl. No.: 12/460,941
`Jul. 27, 2009
`(22) Filed:
`Prior Publication Data
`(65)
`
`( *) Notice:
`
`Feb. 4, 2010
`US 2010/0029659 Al
`Related U.S. Application Data
`
`Provisional application No. 61/137,714, filed on Aug.
`1, 2008, provisional application No. 61/192,777, filed
`on Sep. 22, 2008, provisional application No.
`61/203,120, filed on Dec. 18, 2008, provisional
`application No. 61/207,481, filed on Feb. 12, 2009.
`Int. Cl.
`A61K 311498
`(2006.01)
`A61P 27102
`(2006.01)
`U.S. Cl. ....................................................... 514/249
`Field of Classification Search ................... 514/249
`See application file for complete search history.
`
`References Cited
`
`(60)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`U.S. PATENT DOCUMENTS
`4,663,340 A
`5/1987 Najer et al.
`5,021,416 A
`6/1991 Gluchowski
`5,300,504 A
`4/1994 Gluchowski
`5,424,078 A
`6/1995 Dziabo et al.
`5,561,132 A
`10/1996 Burke et al.
`5,677,321 A
`10/1997 Jeon et al.
`5,756,503 A
`5/1998 Burke et al.
`5,804,587 A
`9/1998 Cupps et al.
`5,914,342 A
`6/1999 Maurer et al.
`5,916,900 A
`6/1999 Cupps et al.
`5,948,804 A
`9/1999 Jeon et al.
`5,965,595 A
`10/1999 Maurer et al.
`6,040,451 A
`3/2000 Jeon et al.
`6,087,361 A
`7/2000 Munk et al.
`6,110,952 A
`8/2000 Henry et al.
`6,117,871 A
`9/2000 Maurer et al.
`6,159,998 A
`12/2000 Jeon et al.
`12/2000 Henry et al.
`6,162,818 A
`6,242,442 Bl
`6/2001 Dean et al.
`6,534,048 Bl
`3/2003 Borgman
`6,562,873 B2
`5/2003 Olejnik et al.
`6,627,210 B2
`9/2003 Olejnik et al.
`6,641,834 B2
`11/2003 Olejnik et al.
`6,673,337 B2
`1/2004 Olejnik et al.
`6,730,065 Bl
`5/2004 Horn
`6,982,079 B2
`1/2006 Huth
`7,019,149 B2 *
`3/2006 Burk et al.
`2005/0020600 Al
`1/2005 Scherer
`
`OTHER PUBLICATIONS
`
`549/228
`
`Lee, "Efficacy ofbrimonidine tartrate 0.2% ophthalmic solution in
`reducing halos after laser in situ keratomileusis", J Cataract Refract
`Surg 2008, (34), pp. 963-967.*
`Mechanism of decongestant activity of x2-adrenoceptor agnosits,
`Corboz M.R. et al., Pulmonary Pharmacology & Therapeutics 21
`(2008) 449-454.
`
`Alpha-adrenoceptor agomstJc activity of oxymetazoline and
`xylometazoline, Haenisch B. et al., Fundarn Clin Pharmacol. Dec. 17,
`2009.
`An Evaluation of Nasal Response Following Different Treatment
`Regimes of ... , Morris S. et al., American Journal Rhinology, vol. 11,
`No. 2, Mar.-Apr. 1997, pp. 109-115(7).
`Pharmacological Characterization of Postjunctional a-Adrenocep(cid:173)
`tors in ... , Corboz M.R. et al., American Jour ofRhinology, vol. 19,
`No. 5, Sep.-Oct. 2005, pp. 495-502(8).
`Postjuntional a2-adrenoceptors in blood ve3ssels of human nasal
`mucosa, Ichimura K. et al., Arch Otorhinolaryngol (1988) 245:127-
`131.
`Long-term use of oxy- and xylometazoline nasal sprays induces
`rebound swelling, tolerance, and nasal hyperreactivity, Graf P.,
`Rhinology 1996, 34( 1 ):9-13.
`Alpha 1-receptors at pre-capillary resistance vessels of the human
`nasal mucosa, Johannssen Vet al., Rhinology 1997; 35(4):161-65.
`Correspondence A Propos De L'article: <<Traitement Des
`Glaucomes Par La Brimonidine>>, M. Detry-Morel Et C. Dutrieux<
`JFr Ophtalmol.2001; 24(7): 748-9.
`by
`Vacoconstriction
`Potent
`a2A-Adrenoceptor-Mediated
`Brimonidine in Porcine Ciliary Arteries, Anna Wikberg-Matsson, et
`al., IOVS, 2001, vol. 42, No. 9, 2049-55.
`Medical Management of Chronic Rhinosinusitus-Jean P. Fong,
`MD, Matthew Ryan, MD (May 2006).
`Preven Drugs from Going Missing in Action-Mark B. Abelson,
`MD, and Sarah A. Rosner MPH; Review of Ophthalmology; www.
`revophth.com/index.asp?page~l_357.htm.
`Interactions Between CA2 + and H + and Functional Consequences in
`Vascular Smooth Muscle-C. Austin and S. Wray, Journ. of Amer.
`Heart Association (Circ Res. 2000;86:355-363).
`A Useful New Topical Treatment for Glaucoma and Ocular Hyper(cid:173)
`tension-Drug Ther Perspect 13(1):1-4, 1999.
`Brimonidine in the Treatment of Glaucoma and Ocular Hyperten(cid:173)
`sion-Louis B. Cantor, Therapeutics and Clinical Risk Management
`2006:2(4) 337-346.
`Silent Bedpartners-Nancy A. Collop, Chest 2002; 122; 1111-1112.
`Traitement Des Glaucomes Par La Brimonidine (Alphagan® 0,2
`%)-M. Detry-Morel, C. Dutrieux, J FR. Ophtalmol., 2000; 23, 8,
`763-768.
`Vasopressin-Induced Vasoconstriction: Two Concentration-Depen(cid:173)
`dent Signaling Pathways-Kyle K. Henderson and Kenneth L.
`Bryon, J Appl Physiol 102: 1402-1409, 2007.
`The Effect of Correction of Sleep-Disordered Breathing on Bp in
`Untreated Hypertension-K. Mae Hla, J. B. Skatrud, L. Finn, M.
`Palta and T. Young, Chest 2002;122; 1125-1135.
`
`(Continued)
`
`Primary Examiner - Sreeni Padmanabhan
`Assistant Examiner - Sahar Javanmard
`(74) Attorney, Agent, or Firm - Wood, Phillips, Katz, Clark
`&Mortimer
`
`(57)
`
`ABSTRACT
`
`The invention generally relates to compositions and methods
`for preferential vasoconstriction of smaller blood vessels
`relative to larger blood vessels. The compositions comprise
`highly selective alpha-2 adrenergic receptor agonists, at low
`concentrations, such as below 0.05% weight by volume. The
`compositions preferably comprise brimonidine. The compo(cid:173)
`sitions preferably have pH between about 5.5 and about 6.5.
`
`6 Claims, 7 Drawing Sheets
`(5 of 7 Drawing Sheet(s) Filed in Color)
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 3 of 21 PageID: 15
`
`US 8,293,742 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Myogenic Tone and Reactivity of the Rat Ophthalmic Artery-Y. P.
`R. Jarajapu, M. B. Grant, and H. J. Knot, Invest. Ophth. & Visual
`Science, Jan. 2004, vol. 45, No. 1.
`Correspondence A Propos De L'article: <<Traitement Des
`Claucomes Par La Brimonidine>>, M. Detry-Morel Et C. Dutrieux,
`J Fr Ophtalmol. 2000; 23(8): 763-8.
`Prospective Study of the Association Between Sleep-Disordered
`Breathing and Hypertension-P. Peppard, et. al., The New England J
`of Med., vol. 342, No. 19:1378-1384 (2000).
`Catecholamines and Sympathomimetic Drugs-Goodman &
`Gilman's Pharmacology, Ch. 10; www.accessmedicine.com/popup.
`aspx?aID-9363 l 4&pringryes_chapter.
`
`Rhinitis Medicamentosa-JT Ramey, E Bailen, RF Lockey, J
`Investig Allergol Clin Immunol 2006; vol. 16(3); 148-155.
`Characterization of three inhibitors of endothelial nitric oxide
`synthase in vitro and in vivo-D.D. Rees, et al., br. J. Pharmacol.
`(1990) 101, 746-752.
`Inhibition of a-adrenergic vasoconstriction in exercising human
`thigh muscles-D. Walter Wray, et al., J Physiol 555, 2 pp. 545-264
`(2003).
`Dexmedetomidine Enhances the Local Anesthetic Action of
`Lidocaine via ... Tatsushi Yoshitomi DDS et al., Anesth Analg 2008;
`107:96-101.
`Adding Dexmedetomidine to Lidocaine for Intravenous Regional
`Anesthesia, Dilek Memis, MD et al., Anesth Analg 2004;98:835-40.
`
`* cited by examiner
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 4 of 21 PageID: 16
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 1 of 7
`
`US 8,293,742 B2
`
`FIG. l
`
`Effect
`
`Alpha2
`
`Prior Art
`
`Net Vasoconstriction Benefit
`
`{W l~
`~mi211~
`~~
`
`~-~~-~ ~ ------
`._ _____________ ....,,,,. --
`- -
`
`-
`
`-----,-
`'
`/
`
`'
`
`- ...
`
`0
`
`.001
`
`.005
`
`OJ::il
`
`0.03
`
`0 .OS
`
`0.08
`
`0 .. 10
`
`2.Agonists:
`
`1~1utiy,:tr9ietlru: < ~ < ~
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 5 of 21 PageID: 17
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 2 of 7
`
`US 8,293,742 B2
`
`FIG. 2
`
`>::> $.§ll. Alpha 2 /.\gordsts
`
`--+-·
`
`,.........
`
`te~,~
`'<'-W,Mt<i'<<Ni:~!.,:>-«·
`ti}:?- ~:ect:;ct:::.,,,,, f;';its:~:r,-::;:;,i}
`tMt' (~/! i:<:z:::;,:; \t.i::,~lt,·r-f'.
`~·~<;:;:;,,f/4:i: ~'\~mm\~·
`f~::;:t =:;::i:;:~9f;*tr:::~t~~f.: :5;ir~~t~
`
`(.j
`
`% Srimonidine
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 6 of 21 PageID: 18
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 3 of 7
`
`US 8,293,742 B2
`
`FIG. 3
`
`2
`
`Vs.<
`
`Present Invention Vs, Prior Art
`
`Effect
`
`++++
`
`Legelld
`iirjmQlllUl~ ?,,> W
`- -► ~l~<<W
`, .., Qmi:w~~ <W
`loo~r,g~Q,!it:i1; << W
`
`-
`
`/
`
`'
`
`-
`
`/
`
`'
`
`.... ._ --..
`..
`
`----....
`
`!)
`
`.001
`
`.005
`
`0 01
`
`0.03
`
`0.05
`
`0.08
`
`0.10
`
`0.3
`
`0.5
`
`%
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 7 of 21 PageID: 19
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 4 of 7
`
`US 8,293,742 B2
`
`Fig 4b; Tdrnhydrozolin.e (i.05'% OD
`
`Fig 4c: O.xyinetazoline 0,025% OD
`
`Fig 4<l: Nupha:zolinc (}.033%, OD
`OS
`
`FIG. 4A
`
`FIG. 4C
`
`Brimon:id.ine (L02'%
`
`F.IG. 4D
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 8 of 21 PageID: 20
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 5 of 7
`
`US 8,293,742 B2
`
`Fig 4e: Brimi;midine {L03:3%s OS only; 4 hNtrs after 4d
`
`FIG. 4E
`
`(effect lusted ~.- 4 ho-1.rrs)
`
`Vs, Baseline 11 hours earlier:
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 9 of 21 PageID: 21
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 6 of 7
`
`US 8,293,742 B2
`
`.FIG. SA
`
`Right eye V!S!NE Original®
`
`lf'1t eye Brimonkiine 0.012% x1
`
`ii gtts tid, day 2 1st ir.st!ll.3t!OO
`
`FIG. 5B
`
`ii gtts tkl, day 2 1 s1 lnstil!atlon
`
`Note rebound hypererni,1
`
`Right i~ye !k1mon1dine 0,12% xl
`
`l.1:ift eve Bdrnonidine 0.012%x1
`
`ii gtts
`
`FIG. 5C
`
`ii gtts
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 10 of 21 PageID: 22
`
`U.S. Patent
`
`Oct. 23, 2012
`
`Sheet 7 of 7
`
`US 8,293,742 B2
`
`FlG. 6
`
`
`
`Case 3:21-cv-16766-MAS Document 1-1 Filed 09/10/21 Page 11 of 21 PageID: 23
`
`US 8,293,742 B2
`
`1
`PREFERENTIAL VASOCONSTRICTION
`COMPOSITIONS AND METHODS OF USE
`
`BACKGROUND OF THE INVENTION
`
`2
`a adrenergic receptor agonists, patients may develop second(cid:173)
`ary rebound hyperemia or secondary vasodilation. Brimoni(cid:173)
`dine (5-bromo-6-(2-imidazolidinylideneamino )quinoxaline
`L-tartrate ), a known selective alpha 2 agonist is associated
`5 with significant rebound hyperemia (primary or delayed
`onset vasodilation) in its current concentration range for treat(cid:173)
`ing glaucoma of about 0.1 % to 0.2%.
`Commercially available general alpha agonists for topical
`mucosa! decongestant use (ophthalmic and nasal applica-
`lO tions) include tetrahydrozoline, naphazoline, oxymetazoline,
`xylometazoline, methoxamine and phenylephrine. These
`agonists have high alpha 1 receptor agonist activity and are
`known to cause rebound hyperemia and medicamentosa.
`Accordingly, their clinical use is usually restricted to several
`15 hours or a few days, at most. Many individuals with mucosa!
`congestion or hyperemia from chronic conditions such as dry
`eye, contact lens wear, allergic conjunctivitis, allergic rhini(cid:173)
`tis, nonallergic rhinitis, acute or chronic sinusitis, nasal poly(cid:173)
`posis, rhinitis secondary to pregnancy, or rhinitis due to nasal
`20 septa! deviation or obstruction and asthma, particularly, aller(cid:173)
`gic asthma require longer term agonist use. To the best of the
`inventor's knowledge, there are currently no means to induce
`effective vasoconstriction without concomitant ischemia
`caused by an excessive reduction in blood flow and a cascade
`25 of inflammatory mediators, resulting in undesirable clinical
`sequelae of rebound hyperemia, and or medicamentosa, a
`potentially prolonged inflammatory state that can last for
`several weeks or months of rebound mucosa! congestion.
`Thus, there is a need for new methods and formulations that
`30 would provide safe and long term vasoconstriction with
`reduced or minimized side effects, such as rebound hyper-
`emia.
`
`SUMMARY OF THE PRESENT INVENTION
`
`The present invention is generally related to compositions
`and methods. for inducing vasoconstriction. One of the key
`discoveries of the present invention lies in using low doses of
`highly selective a-2 adrenergic receptor agonists to achieve
`vasoconstriction with significantly reduced hyperemia.
`There are a variety of applications and dosage forms that
`can be utilized to apply the findings of the invention. For
`example, some applications include methods and composi(cid:173)
`tions for: treating nasal congestion; inducing vasoconstric(cid:173)
`tion; inducing preferential vasoconstriction of smaller blood
`vessels relative to larger