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Endo Pharmaceuticals Solutions Inc. v. Custopharm, Inc.

United States District Court, D. Delaware

February 10, 2017

CUSTOPHARM, INC., Defendant.

          Jack B. Blumenfeld, Esquire and Derek J. Fahnestock, Esquire of Morris, Nichols, Arsht & Tunnell LLP, Wilmington, Delaware. Counsel for Plaintiffs. Of Counsel: Adam K. Mortara, Esquire, J. Scott McBride, Esquire, Nevin M. Gewertz, Esquire, Faye E. Paul, Esquire, and Taylor A.R. Meehan, Esquire of Bartlit Beck Herman Palenchar & Scott LLP.

          Richard L. Horwitz, Esquire, David E. Moore, Esquire, and Bindu A. Palapura, Esquire of Potter Anderson & Corroon LLP, Wilmington, Delaware. Counsel for Defendant. Of Counsel: Douglass C. Hochstetler, Esquire, Constantine Koutsoubas, Esquire, Mark J. Scott, Esquire, Beth D. Jacob, Esquire, and Clifford Katz, Esquire of Kelley Drye & Warren LLP.


          ROBINSON, Senior District Judge


          This action arises out of the filing of Abbreviated New Drug Application ("ANDA") No. 207583 by defendant Paddock Laboratories, LLC seeking to produce and market a generic testosterone undecanoate intramuscular injection. (D.I. 67 at ¶ 10) On November 20, 2014, plaintiffs Endo Pharmaceuticals Solutions Inc., Bayer Intellectual Property GmbH, and Bayer Pharma AG (collectively "plaintiffs") brought this action alleging infringement of U.S. Patent Nos. 7, 718, 640 (the "'640 patent") and 8, 338, 395 (the'"395 patent") (collectively, "the patents-in-suit").[1] (D.I. 1) Defendants Paddock Laboratories, LLC and Perrigo Company (collectively, "Paddock")[2] answered the complaint and counterclaimed alleging invalidity of the patents-in-suit on December 23, 2014. (D.I. 11) Plaintiffs answered the counterclaims on January 16, 2015. (D.I. 14) Thereafter, Paddock stipulated to infringement of certain claims. (D.I. 30) The court held a final pretrial conference on September 7, 2016, and a four-day bench trial from September 26 to 29, 2016 on invalidity. The parties have since completed post-trial briefing. The 30-month stay of FDA final approval on Paddock's ANDA expires on April 9, 2017. (D.I. 3, 17) The court has jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331 and 1338(a), and venue is proper pursuant to 28 U.S.C. §§ 1391 (b) and (c) and 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a).


          A. Technology at Issue

         The '640 patent was filed on March 12, 2004 and issued on May 18, 2010. (JTX 1) The '395 patent was filed on February 24, 2009 and issued on December 25, 2012.[3](JTX 2) The patents-in-suit are titled "Methods and Pharmaceutical Compositions for Reliable Achievement of Acceptable Serum Testosterone Levels." (JTX 1, 2) Male hypogonadism is a condition characterized by a deficiency of endogenous testosterone production resulting in abnormally low levels of serum testosterone. ('640 patent, 1:32-34) Men with this condition generally experience symptoms including sexual dysfunction, reduced muscle mass and strength, depression, and osteoporosis. (Id. at 1:48-50) In 2003, the standard therapy required frequent doctors' visits to receive intramuscular injections administered every two to three weeks. "[P]atients complain[ed] about variations in well-being due to short-term fluctuations of serum testosterone levels resulting from the pharmacokinetic profile after intramuscular injection of . . . testosterone enanthate." (Id. at 1:51-62) A need existed for "reliable standard regimens acceptable for a broad population of men, . . . without the need of occasional control of serum testosterone levels, and . . . where[] steady state conditions are achieved within a shorter time period." (Id. at 2:49-54)

         The invention is directed to injectable compositions using long-term acting testosterone esters for testosterone replacement therapy. After injection, "physiologically normal levels of testosterone in serum are reached within a short time period . . . [and] maintained for an extended period of time, without showing fluctuations in the hypogonadal range." (Id. at 2:57-64) Claim 2 of the '640 patent provides for a 750 mg version of the composition of claim 1, which recites "[a] composition formulated for intramuscular injection in a form for single injection which contains 250 mg/ml testosterone undecanoate in a vehicle containing a mixture of castor oil and benzyl benzoate wherein the vehicle contains castor oil in a concentration of 40 to 42 vol %." Claim 18 of the '395 patent provides for a 750 mg version of the composition and method described by claim 14, which recites:

A method of treating a disease or symptom associated with deficient endogenous levels of testosterone in a man, comprising administering by intramuscular injection a composition comprising testosterone undecanoate (TU) and a vehicle consisting essentially of castor oil and a co-solvent, the castor oil being present in the vehicle at a concentration of 42 percent or less by volume, the method further comprising:
(i) an initial phase comprising 2 initial intramuscular injections of a dose of TU at an interval of 4 weeks between injections, each dose including 500 mg to 1000 mg of TU, followed by,
(ii) a maintenance phase comprising subsequent intramuscular injections of a dose of TU at an interval of 10 weeks between injections, each dose including 500 mg to 1000 mg of TU.

         The embodiment of the invention is Aveed, which contains testosterone undecanoate (TU) as an active ingredient. It is approved by the FDA as a testosterone replacement therapy in adult males for conditions associated with testosterone deficiency or absence of endogenous testosterone. Aveed is sold in the United States as a series of 3 ml (750 mg) intramuscular injections given at initiation, at four weeks, and then every 10 weeks thereafter. Each vial of Aveed contains 750 mg testosterone undecanoate dissolved in a mixture of 885 mg castor oil and 1500 mg benzyl benzoate. (D.I. 67, ex. 1 at ¶¶ 6-7) Hypogonadism is a chronic condition requiring lifelong therapy. (D.I. 73 at 524:12-18)

         B. Obviousness Standard

         "A patent may not be obtained ... if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art." 35 U.S.C. § 103(a). Obviousness is a question of law, which depends on underlying factual inquiries.

Under § 103, the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background the obviousness or nonobviousness of the subject matter is determined. Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented.

KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966)).

         "[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art." KSR, 550 U.S. at 418. Likewise, a defendant asserting obviousness in view of a combination of references has the burden to show that a person of ordinary skill in the relevant field had a reason to combine the elements in the manner claimed. Id. at 418- 19. The Supreme Court has emphasized the need for courts to value "common sense" over "rigid preventative rules" in determining whether a motivation to combine existed. Id. at 419-20. "[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." Id. at 420. In addition to showing that a person of ordinary skill in the art would have had reason to attempt to make the composition or device, or carry out the claimed process, a defendant must also demonstrate that "such a person would have had a reasonable expectation of success in doing so." PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed. Cir. 2007).

         A combination of prior art elements may have been "obvious to try" where there existed "a design need or market pressure to solve a problem and there [were] a finite number of identified, predictable solutions" to it, and the pursuit of the "known options within [a person of ordinary skill in the art's] technical grasp" leads to the anticipated success. Id. at 421. In this circumstance, "the fact that a combination was obvious to try might show that it was obvious under § 103." Id.

         A fact finder is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a "check against hindsight bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed. Cir. 2012). "Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented." Graham, 383 U.S. at 17-18.

         "Patents are presumed to be valid, and overcoming that presumption requires clear and convincing evidence." 35 U.S.C. § 282; Spectrum Pharm., Inc. v. Sandoz Inc., 802 F.3d 1326, 1333 (Fed. Cir. 2015) (citing Microsoft Corp. v. 141 Ltd. P'ship., 564 U.S. 91, 95 (2011) (holding that an invalidity defense must be proved by clear and convincing evidence)). In conjunction with this burden, the Federal Circuit has explained that,

[w]hen no prior art other than that which was considered by the PTO examiner is relied on by the attacker, he has the added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job, which includes one or more examiners who are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art and whose duty it is to issue only valid patents.

PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (citations omitted).

         C. Prior Art

         A trio of prior art scientific articles - Behre, [4] Nieschlag, [5] and von Eckardstein[6](collectively "the Articles") - describe small clinical studies using an injectable composition of 250 mg/ml TU in castor oil dosed at 1000 mg injections.[7] The Articles report that the 250 mg/ml of TU was dissolved in castor oil, but do not disclose or describe the use of a co-solvent. (JTX 3, 4, 5; D.I. 67, ex. 1 at ¶15; D.I. 72 at 81:2-19, 92:19-23; D.I. 73 at 463:6-14) The compositions described by the Articles are TU dissolved in 40% castor oil and 60% benzyl benzoate (the "vehicle"). The parties agree that the vehicle was unknown to the person of ordinary skill in the art in 2003.[8] (D.I. 72 at 107:5-108:6; D.I. 73 at 338:5-22, 393:24-394:8, 463:9-20)

         Behre compared the half-life of a single dose of 1, 000 mg TU in castor oil with a single dose of 1000 mg TU in tea seed oil. (JTX 3) Nieschlag investigated the suitability of using four intramuscular injections of 1000 mg TU in castor oil at six week intervals. (JTX 4) von Eckardstein described a clinical trial investigating the efficacy and safety of prolonged TU treatment at extended injection intervals over a 3.2 year period. Seven patients (who had participated in the study described in Nieschlag) received four injections at six week intervals, followed by a gradual increase in the interval between the fifth and tenth injections. After the tenth injection, the interval was increased to twelve weeks. (JTX 5)

         Pushpalatha[9] described a commercially marketed product Proluton Depot ("Proluton"), an injectable composition of hydroxyprogesterone dissolved in a mixture of 40% castor oil and 60% benzyl benzoate. Proluton is administered weekly to pregnant women to prevent miscarriage. (JTX 42, 38 at 73; D.I. 72 at 86:10-87:17) Riffkin[10]described using castor oil for the parenteral administration of steroids. (JTX 6) It refers to using a castor oil/benzyl benzoate vehicle to "increase the solvent power of the oil." (Id. at 892; 87:18-89:2)

         The 2002 guidelines of the American Association of Clinical Endocrinologists (AACE) ("the AACE guidelines") describe a normal testosterone range as "generally between 280 and 800 ng/dl" (9.7 to 27.7 nmol/l). (JTX 41 at 448) The FDA refers to a normal testosterone range of 300-1000 ng/dl.[11] (JTX 49 at 18, 104) The Articles also describe a normal range of testosterone as 10-25 nmol/l (300-1000 ng/dl). (JTX 3 at 416, JTX 4 at ...

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