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In re Ciprodex

United States District Court, D. New Jersey

June 27, 2017

IN RE: CIPRODEX

          MEMORANDUM AND ORDER

          PETER G. SHERIDAN, U.S.D.J.

         This matter comes before the Court on a Second Amended Joint Claim Construction and Prehearing Statement (hereinafter “Joint Claim Construction”) regarding U.S. Patent Nos. 6, 284, 804 (“the '804 patent”), 6, 359, 016 (“the '016 patent”) and 9, 402, 805 (“the '805 patent”)(collectively “Patents-in-Suit”). The Joint Claim Construction is submitted by Plaintiffs Alcon Pharmaceuticals Ltd., Alcon Laboratories, Inc., and Alcon Research, Ltd. (collectively “Alcon” or “Plaintiffs”) and Defendants Dr. Reddy's Laboratories, Inc. and Dr. Reddy's Laboratories, Ltd. (collectively, “DRL”), Par Pharmaceutical Inc. (“Par”), and Watson Laboratories, Inc. (“Watson”)(DRL, Par, and Watson are collectively referred to as “Defendants”), pursuant to L. Pat. R. 4.3.

(See D.I. 84)

         The '804 and the '016 patents are directed towards topical suspension formulations containing ciprofloxacin and dexamethasone. Whereas, the '805 patent is directed towards methods of treating middle ear infections using aqueous suspension formulations containing ciprofloxacin and dexamethasone. Ciprodex®, a brand name pharmaceutical drug for treating middle ear infections (otitis media) in children with ear tubes, as well as outer ear infections (otitis externa) in children and adults, includes ciprofloxacin and dexamethasone as the active ingredients.

         In order to market and sell Ciprodex®, Alcon listed the Patents-in-Suit in the Food and Drug Association's (“FDA”) Approved Drug Products with Therapeutic Equivalence Applications, commonly known as the Orange Book. See 21 U.S.C. § 355(B)(1). Thereafter, Defendants filed an Abbreviated New Drug Application (“ANDA”) with the FDA in order to seek approval to market a generic version of Ciprodex®. See 21 U.S.C. § 355(j)(1). Accordingly, pursuant to 21 U.S.C. § 355(j)(5)(B)(iii), Alcon initiated this suit against Defendants because Defendants' request to market the generic version of Ciprodex® is done prior to the expiration of the Patents-in-Suit.

         On February 23, 2017, a stipulation and order staying the litigation between Plaintiffs and Defendant Watson was entered on the record. (See D.I. 100) Thereafter, on April 3, 2017, another stipulation and order was entered on the record between Plaintiffs and Defendant Par regarding Par's ANDA filings constituting an act of infringement of the '805 patent, and that Par will not assert any defense of non-infringement as to the '805 patent in this suit. (See D.I. 114)

         As such, the remaining disputed claim terms between Plaintiffs and Defendant DRL include-“A topically administrable suspension composition intended for application to the eye, ear or nose, ” as recited in claim 1 of the '804 patent; “A topically administrable aqueous suspension composition intended for application to the eye, ear or nose, ” as recited in claims 1, 2 and 3 of the '016 patent; and “Treating a Human Patient, ” as recited in claim 1 of the '805 patent.

         On May 8, 2017, pursuant to L. Pat. R. 4.6, a Markman hearing was conducted before the Court for the aforementioned terms. These terms are construed below.

         BACKGROUND

         Ciprodex® is an FDA approved pharmaceutical product that includes two active ingredients-ciproflaxcin and dexamethasone. Ciprofloxacin is an antibiotic that treats infections caused by bacteria. And, dexamethasone is a steroid that reduces the actions of chemicals in the body that cause inflammation.

         I. The Patent Family

         The Patents-In-Suit include the '804 patent, the '016 patent and the '805 patent. The '016 patent is a continuation[1] of the '804 patent, and as such shares the same specification and inventive entity as the '804 patent. Both, the '804 and the '016 patents, are directed towards suspension formulations containing dexamethasone and ciprofloxacin. The formulation contains a nonionic polymer, a nonionic surfactant and an ionic tonicity agent. The formulations are physically stable and easily re-suspended, and are intended for topical application to the eye, ear or nose. (See Abstract of the '804 patent and the '016 patent).

         The only difference between the '804 patent and the '016 patent is the claimed subject matter. The '804 patent includes one (1) claim directed to a composition that is intended for application to the eye, ear or nose. Whereas, the '016 patent includes five (5) claims, wherein claims 1, 2 and 3 are in independent form, and claims 4 and 5 depend from claim 3.

         The '804 and the '016 patents disclose a formulation that comprises two active agents- corticosteroids (dexamethasone) and antibiotic (ciprofloxacin). (See the '804 patent[2], col. 2, ll. 1 5) Dexmathasone can be present in any ophthalmic or optically acceptable form having poor water solubility such that the resulting formulation is a suspension formulation. Whereas, ciprofloxacin can also be present in any ophthalmic or optically acceptable form such that the ciprofloxacin ingredient is in solution in the final formulation. (See Id. at col. 2, ll. 10-20) In addition to these aforementioned active ingredients, the suspension formulations also contain-sodium chloride as an ionic tonicity agent, a nonionic polymer, a nonionic surfactant, a quaternary ammonium halide as a preservative, a chelating agent, and boric acid. (See Id. at col. 2, ll. 30-col. 3, ll. 11) The resultant suspension formulation has a desired pH of 4.5 and an average particle (mean volume basis) of the dexamethasone ingredient to be less than 10 µm (micro-meters) to avoid irritation or discomfort to the user. (See Id. at col. 3, ll. 10-25)

         The '804 patent discloses the different methods of forming this suspension formulation; and the different formulations A-E that were tested for resuspension time in accelerated and realtime settling studies. (See Id. at col. 4) The result of these studies illustrated that the suspension formulation can be preserved such that it meets both the United States Pharmacopeia (USP) and the European Pharmacopia (Ph. Eur.) minimum preservative requirements for ophthalmic and otic formulations. (See Id. at col. 6, ll. 25-30)

         With respect to the '805 patent, issued on August 2, 2016, it is a separate and distinct patent from the '804 patent and the '016 patent because the '805 patent is not a continuation, divisional or a continuation-in-part application of either the '804 patent or the '016 patent. As such, the '805 patent does not share the same disclosure as the '804 and the '016 patents. The earliest priority date of the '805 patent potentially dates back to September 21, 2001, from provisional application number 60/323, 951. (See Front Cover of the '805 patent)

         The '805 patent is directed towards method of treating middle ear infections in humans having an open tympanic membrane[3] by using aqueous suspension formulations, which contain dexamethasone and ciprofloxacin. (See Abstract of the '805 patent)

         The method of treatment includes topical application of a fixed combination of ciprofloxacin and dexamethasone as an adequate suspension product. Generally, the dosage regimen includes applying the suspension product twice a day. Each application involving administering three or four drops into the ear canal, and preferably pumping the tragus[4] to force product through the opening in the tympanic membrane, and in effect to the site of the infection/inflammation in the middle ear. (See the '805 patent, col. 2, ll. 20-30)

         The '805 patent discloses that in addition to the active agents-ciprofloxacin and dexamethasone-the suspension formulations include a tonicity agent. The tonicity agent may be ionic (e.g., NaCl) or nonionic (e.g., mannitol); however, NaCl is preferred as the tonicity agent. (Id. at col. 3, ll. 25-33)

         Studies of Ciprodex® were conducted on pediatric patients with acute otitis media with tympanostomy tubes. The studies indicated that this drug, which was administered twice a day in pediatric patients, was safe and tolerated well. (Id. at col. 15, ll. 15-20) The '805 patent includes twenty-two (22) claims, wherein claim 1 is an independent claim. Claim 1 is a method claim for treating a human patient, which includes the steps of-(i) diagnosing the patient having otitis media and an open tympanic membrane, and (ii) topically applying into the ear canal of the patients ear an aqueous suspension composition. (Id. at col. 15, ll. 50-62)

         II. Declaration of Dr. Michael Crowley, Dr. M. Jayne Lawrence and Dr. Soham Roy

         Dr. Crowley, on behalf of Alcon, has provided opinion concerning the meaning of certain claim terms in the Patents-in-Suit. (See Declaration of Crowley (“Decl. of Crowley”) at ¶ 1; D.I. 54-9). Dr. Crowley notes that the preamble[5] of the '804 patent, a term in dispute, which includes the term “suspension composition” means a liquid formulation in which one or more active ingredients are in suspension. (Id. at ¶ 44). That is, without the active ingredients being in suspension, no person skilled in the art would refer to a formulation as a “suspension composition.” (Id.)

         With regards to “suspension”, Dr. Crowley notes that in chemistry, a suspension is defined as a two-phase system in which an un-dissolved compound is dispersed in a solid, liquid or a gas vehicle. In pharmaceuticals, Dr. Crowley notes, this term refers to solid particles that are dispersed within a liquid vehicle, which is generally water. (Id. at ¶ 13) Dr. Crowley notes that the suspension formulation must meet chemical and physical stability requirements sufficient to justify shelf life. Stability being defined as “the extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., its shelf life) […].” (Id. at ¶ 14, citing United States Pharmacopeia (23rd edition 1995) (“1995 USP”)) Most pharmaceutical products have a shelf life of at least two (2) years. (Id. at ¶ 15)

         A physical stability of a suspension formulation refers to the stability of the physical aspects of the composition, including-appearance, pH, viscosity, dissolution and particle size distribution for undissolved components. The size distribution of undissolved particles must remain the same for the shelf life of the suspension. (Id. at ¶ 16) A pharmaceutical suspension is acceptable even if it settles during its shelf life, so long as it is easily re-suspendible and homogeneous for a long duration to administer a uniform dose. (Id. at ¶ 17)

         Conversely, the composition would be unacceptable if over time, the particles start to clump together and settle in a loose structure, or form a dense sediment on the bottom of the container, known as “caking.” (Id. at ¶ 18) Dr. Crowley notes that this is unacceptable as it prevents an administration of a uniform dose of the active ingredient and reduces the potential shelf-life of the suspension formulation. (Id. at ¶ 19) As such, absent such physical stability and easily re-dispersibility, the FDA would not have approved this drug. (Id. at ¶ 21)

         Dr. Lawrence, on behalf of Defendant Watson Laboratories, Inc., has also provided opinion concerning the meaning of certain claim terms in the Patents-in-Suit. (See Declaration of M. Jayne Lawrence (“Decl. of Lawrence”) at ¶ 12; D.I. 55-1)

         Regarding the preamble of the '804, Dr. Lawrence notes that one skilled in the art would recognize that the asserted claims recite a list of specific ingredients with specific proportions, which includes pharmaceutical ingredients with pharmaceutical excipients. (See Decl. of Lawrence at ¶ 70) Further, Dr. Lawrence notes that the preamble of the'804-does not give additional meaning to the pharmaceutical compositions, does not add any structure to the claimed invention, and one could omit reading the preamble and still have the same complete understanding of the pharmaceutical compositions. (Id. at ¶ 72) Dr. Lawrence cautions that Actavis' proposed addition of “with at least one active ingredient in suspension” to the preamble is redundant and misleading because one skilled in the art would recognize that the particular claimed compositions are directed to two specific drugs-dexamethasone and ciprofloxacin-and not at least one active ingredient in suspension. (Id. at ¶ 77)

         Lastly, Dr. Soham Roy, on behalf of Alcon, provides his opinion on the disputed claim term “treating a human patient” as recited in the preamble of claim 1 of the '805 patent. (Declaration of Dr. Soham Roy (“Decl. of Roy”) at ¶ 1; D.I. 94) Dr. Roy notes that the term “treating” in the aforementioned claim term includes an intent requirement, such that the composition must be administered or the procedure must be performed with an intent to cause a therapeutic benefit in the subject. (See Decl. of Roy at ¶ 21) In other words, “treating a human patient” is directed towards a procedure that the composition must be performed ‘for the purpose' of effecting a therapeutic improvement in the patient. (Id. at ΒΆ 25) Dr. Roy further states, ...


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