Case 2:11-cv-01241-FSH-MAH Document 415 Filed 05/21/14 Page 1 of 57 PageID: 16164
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`NOT FOR PUBLICATION
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`UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
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`PROMETHEUS LABORATORIES INC.,
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`: Civil Case No. 11-230 (FSH)
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`Plaintiff,
` Civil Case No. 11-1241 (FSH)
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`ROXANE LABORATORIES, INC., et al.,
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` Date: May 21, 2014
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`Defendants.
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`HOCHBERG, District Judge:
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`FINDINGS OF FACT &
`CONCLUSIONS OF LAW
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`I.
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`INTRODUCTION
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`The disease known as irritable bowel syndrome (“IBS”) is defined by a constellation of
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`symptoms that causes suffering among those who have it. There is no diagnostic test, nor any
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`organic change to tissue of the body that can be examined for a diagnosis. (See, e.g., Trial Tr.
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`2/20/14 20:24-21:24; DTX 1 at 1:53-55; Dkt. No. 385,1 ¶ 35.) The doctors who treat these
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`patients are highly trained and committed professionals, dedicated to relieving these symptoms.
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`Several of these excellent doctors testified in this case, which concerns a patent claiming a
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`treatment method for doctors to use with certain patients who have a form of IBS.
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`While the patent claims a treatment method using the drug alosetron (which goes by the
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`brand name Lotronex), the patent on the medical compound itself has expired. This case,
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`brought under the Hatch-Waxman Act, asks whether Defendants’ abbreviated new drug
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`application (“ANDA”) for generic Lotronex will result in infringement of the asserted method
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`claims. Specifically, the questions at issue are whether the label on the generic drug will induce
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`1 All docket numbers refer to docket entries in Civ. No. 11-1241 unless otherwise noted.
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`doctors to treat their patients in a manner that uses the method of treatment claimed by the
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`patent, whether Defendants contributorily infringe that patent, and whether that patent is valid.
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`The issue of validity will be analyzed first.
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`Lotronex, as well as the patent claiming a method of patient treatment using alosetron
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`(the method claimed in U.S. Patent No. 6,284,770, “the ’770 patent”), have a long and complex
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`history. The active ingredient in Lotronex is alosetron hydrochloride, a drug that treats diarrhea-
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`predominant IBS. The expired patent on the drug itself is not before this Court, except to the
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`extent that it is relevant evidence as to the validity of the method-of-treatment patent. Lotronex
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`launched in 2000 and, shortly thereafter, had to be taken off the market due to serious side
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`effects, including ischemic colitis, severe constipation, and death. Lotronex relaunched in 2002
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`with a new, more restrictive label, and continues to be used to treat some patients with severe
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`diarrhea-predominant IBS. It is used by doctors when other medicaments with fewer
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`complications have not worked. (DTX 140 at PLI-*132; see also PTX 198 at PLI-*278 (“Last
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`line product positioning”); Trial Tr. 2/11/14 PM 19:21-20:5.) Dr. Susan Lucak, one of
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`Prometheus Laboratories Inc.’s (“Prometheus” or “Plaintiff”) gastroenterology experts, testified
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`that Lotronex is considered by many physicians to be a drug of “last resort.” (Trial Tr. 2/11/14
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`AM 52:12-23.)
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`In resolving this case, the Court has faced questions involving novelty, obviousness, and
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`patentable subject matter, among others. Throughout the process, it has kept in mind that “a
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`typical patent on a new drug or a new way of using an existing drug” where the patent claims
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`confine their reach “to particular applications of [natural] laws” may be patentable. Mayo
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`Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1302 (2012). A short summary
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`of the history of the ’770 patent and Lotronex follows.
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`2
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`Alosetron hydrochloride was originally patented by Glaxo Group Limited (“GSK”)2 in
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`U.S. Patent No. 5,360,800 (“the ’800 patent”), which issued on November 1, 1994 and has now
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`expired. The ’800 patent also claimed a method of treating IBS using alosetron hydrochloride.
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`(DTX 6 at claims 17, 27, and 29.)
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`GSK applied for the ’770 patent in the late 1990s. Specifically, the ’770 patent issued
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`from United States Application No. 09/529,050 (the “’050 application”), filed on April 5, 2000
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`as a 35 U.S.C. § 371 national stage application of PCT/EP98/06278, filed on October 5, 1998.
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`The ’050 application claims foreign priority to GB 9721139, filed on October 7, 1997. The
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`United States Patent and Trademark Office issued the ’770 patent on September 4, 2001. Allen
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`Mangel and Allison Northcutt are listed as the inventors of the ’770 patent. When the ’770
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`patent issued in 2001, it was assigned to GSK.
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`GSK launched Lotronex in 2000. Later the same year, GSK withdrew Lotronex from the
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`market after serious side effects came to light, including ischemic colitis, severe constipation,
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`and death. (Trial Tr. 2/10/14 PM 12:20-23; Trial Tr. 2/11/14 AM 9:9-19; Dkt. No. 385, ¶ 17.)
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`Because there exists a cohort of patients who cannot abate their suffering by using medications
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`with fewer deleterious complications, GSK re-launched Lotronex in 2002 with a new label, new
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`warnings about possible side effects, and a risk management program (referred to as a REMS).
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`(Trial Tr. 2/11/14 AM 9:23-10:3.) At that point, the ’800 and ’770 patents were both listed in the
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`Orange Book. (Trial Tr. 2/10/14 AM 92:12-13.) In 2005, GSK delisted the ’770 patent from the
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`Orange Book for unknown reasons. (Trial Tr. 2/10/14 AM 92:12-93:4.)
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`Prometheus acquired the Lotronex franchise from GSK on October 31, 2007. (Trial Tr.
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`2/10/14 PM 9:10-11.) This purchase included the ’800 patent, the ’770 patent, other additional
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`2 The various incarnations of Glaxo are referred to as GSK herein.
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`3
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`patents, as well as the right to sell Lotronex, all of the training materials, copyrights, trademarks,
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`websites, and other items related to the Lotronex franchise. (Trial Tr. 2/10/14 PM 27:8-20; PTX
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`6.) Due to the GSK transaction, Prometheus holds an approved New Drug Application (“NDA”)
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`under § 505(a) of the FFDCA, 21 U.S.C. § 355(a), for alosetron hydrochloride tablets (NDA No.
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`21-107).
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`Following its purchase of the Lotronex franchise, on August 3, 2009, Prometheus
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`initiated an ex parte reexamination of the ’770 patent and, as a result of the reexamination,
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`cancelled, revised, and added claims to the ’770 patent. (PTX 1; DTX 1.) The USPTO issued
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`the ’770 patent’s reexamination certificate on October 19, 2010. (PTX 1; DTX 1.)
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`Prometheus now asserts reexamined claims 5, 6, 10, 13, and 14 of the ’770 patent against
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`Defendants.3 The Court’s claim constructions, which it applied herein, issued September 23,
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`2013. (Dkt. No. 332 & 333.) Claims 5, 10, and 13 are reproduced below: 4
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`5. A method for treating a diarrhea-predominant female IBS
`patient, while excluding those with predominant constipation,
`said method comprising:
`assessing whether said diarrhea-predominant female IBS patient
`has experienced symptoms for at least six months; and
`administering an effective amount of alosetron or a
`pharmaceutically acceptable derivative thereof to said patient
`who has experienced symptoms for at least six months,
`wherein said effective amount is dependent on the condition of
`the patient and is at the discretion of the attendant physician.
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`3 Prometheus initially asserted claims 5, 6, and 10-16 of the ’770 patent against defendants, but
`the parties did not present evidence of infringement related to claims 11, 12, 15, or 16 at trial,
`and any such claims are therefore waived.
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` Original claim 5 of the ’770 patent claimed: “A method of treatment of diarrhea-predominant
`female IBS which comprises administering an effective amount of alosetron or a
`pharmaceutically acceptable derivative thereof.” (PTX 1 at original claim 5; DTX 1 at original
`claim 5.) Reexamined claim 5 is reproduced above.
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` 4
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`4
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`10. The method for treating according to claim 5, further
`comprising assessing whether said female IBS patient has
`experienced at least moderate pain prior to administration of
`alosetron.
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`13. A method for treating a diarrhea-predominant female IBS
`patient, while excluding those with predominant constipation,
`said method comprising:
`assessing whether said diarrhea-predominant female IBS patient
`has experienced symptoms for at least six months;
`assessing whether said nonconstipated female IBS patient
`experiences at least moderate baseline pain from IBS; and
`administering an effective amount of alosetron or a
`pharmaceutically acceptable derivative thereof to said patient
`who has experienced symptoms for at least six months and who
`experiences at least moderate baseline pain from IBS, wherein
`said effective amount is dependent on the condition of the
`patient and is at the discretion of the attendant physician.
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` (PTX 1, reexamined claims 5, 10, & 13; DTX 1, reexamined claims 5, 10, & 13.) Claims 6 and
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`14 limit alosetron to its hydrochloride salt. As shown above, the ’770 patent is generally directed
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`to a method of treating female IBS-D5 patients with 6 months or more of IBS-D symptoms using
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`alosetron. (PTX 1 at abstract (“This invention relates to the use of 5-HT3 receptor antagonists in
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`the treatment of nonconstipated female IBS patients.”).) The claims of the ’770 patent do not
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`contain an affirmative exclusion for men. (PTX 1; Trial Tr. 2/11/14 AM 35:11-22.) Nor do they
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`affirmatively require the exclusion of patients with fewer than 6 months of IBS-D symptoms.
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`(PTX 1; Trial Tr. 2/11/14 AM 37:16-19.) The only affirmative exclusion is “excluding those
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`with predominant constipation.” (PTX 1.)
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`Meanwhile, on August 19, 2009, Cipla Ltd. (“Cipla”) submitted, through Byron
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`Chemical Company, Cipla’s Drug Master File (“DMF”) to the FDA for the purpose of selling
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`alosetron hydrochloride for use in the United States. Cipla’s DMF, as amended, contains a
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`5 IBS-D refers to diarrhea-predominant irritable bowel syndrome, IBS-C refers to constipation-
`predominant irritable bowel syndrome, and IBS-A/IBS-M refers to mixed or alternating irritable
`bowel syndrome. (Dkt. No. 385, ¶ 36.)
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`5
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`description of the process for manufacturing the alosetron hydrochloride used in Roxane
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`Laboratories, Inc.’s (“Roxane”) ANDA Products. Roxane filed its ANDA in October 2009.
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`Following reexamination, Prometheus relisted the ’770 patent in the Orange Book in
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`2010. After its relisting, Roxane submitted to the FDA a paragraph IV certification, dated
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`December 2, 2010, in its ANDA concerning the ’770 patent. Roxane sent notice, dated
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`December 6, 2010, to Prometheus of its paragraph IV certification concerning the ’770 patent in
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`ANDA No. 200-652.
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`On January 14, 2011, Prometheus filed a complaint alleging infringement of the ’770
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`patent against Roxane (Civil Action No. 11-230). Roxane sent notice to Prometheus of its
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`paragraph IV certification in ANDA No. 200-652, dated January 21, 2011, concerning the
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`reexamined ’770 patent. On March 4, 2011, Prometheus filed a complaint alleging infringement
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`of the ’770 patent against Roxane (Civil Action No. 11-1241). On November 18, 2011,
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`Prometheus filed a First Amended Complaint in Civil Action No. 11-1241 for patent
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`infringement of the ’770 patent against Roxane and Cipla. Plaintiff alleges that Defendants will
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`infringe the ’770 patent under 35 U.S.C. §§ 271(a), 271(b), 271(c), and 271(e)(2)(A). (Am.
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`Compl. ¶¶ 38, 42-44 (Dkt. No. 67).)
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`Prometheus’s claims arise from Roxane’s filing of ANDA No. 200-652 with the FDA
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`seeking approval to engage in the commercial manufacture, use, offer for sale or sale of
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`alosetron hydrochloride tablets, 1 mg and 0.5 mg, a generic version of Prometheus’s Lotronex
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`product, prior to the expiration of the ’770 patent, even though the patent on the compound has
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`expired. The basis for Plaintiff’s infringement claim is, inter alia, that Roxane’s label will
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`encourage doctors to prescribe the compound to their patients in a manner that fits within the
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`method of treatment claimed by the patent.
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`6
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` Cipla manufactures the active pharmaceutical ingredient (“API”), i.e., alosetron
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`hydrochloride, used in Roxane’s ANDA products. Cipla has entered into supply contracts with
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`generic pharmaceutical companies in the United States, and a portion of Cipla’s export sales are
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`derived from the United States. (Cipla Answer, ¶ 7 (Dkt. No. 175).)
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`The Court held a bench trial on the issues of infringement, invalidity, and patentable
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`subject matter commencing in February 2014; summations were argued in April 2014, after the
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`parties had been given time to file proposed findings of fact and conclusions of law annotated to
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`the factual record of the trial.
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`II.
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`JURISDICTION
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`This Court has subject matter jurisdiction over this case pursuant to the patent laws of the
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`United States and 28 U.S.C. §§ 1331, 1338, 1367, 2201 and 2202. Venue is proper in this
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`District under 28 U.S.C. §§ 1391 and 1400(b). This Court has jurisdiction over the parties.
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`III.
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`ISSUES FOR TRIAL
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`Whether the ’770 patent is invalid due to obviousness, obviousness-type double
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`patenting, lack of adequate written description, or lack of patentable subject matter.
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`Whether Roxane and Cipla infringe claims 5, 6, 10, 13, or 14 of the ’770 patent.
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`IV.
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`THE EVIDENCE AT TRIAL
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`The Court’s findings of fact are stated below.6
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`6 In the event any finding of fact herein stated should be construed as a conclusion of law, or a
`conclusion of law herein should be construed as a finding of fact, the same is deemed to be such.
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`7
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`a. The Level of Ordinary Skill in the Art as of 1997
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`The parties agree that the level of ordinary skill in the art is a gastroenterologist with
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`three years of experience. (Trial Tr. 2/20/14 4:1-20.) The Court agrees with and adopts this
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`level of skill in the art.
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`b. The Knowledge of One of Ordinary Skill in the Art as of 1997
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`IBS, in 1997 as it still is today, is a disease with no structural or biochemical medical
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`diagnosis: there is nothing physically evident in the tissue or organs of a suffering patient that
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`appears diseased. No biopsy would show organic disease. Rather, it is a disease diagnosed by
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`its constellation of symptoms only. (See, e.g., Trial Tr. 2/20/14 20:24-21:24; DTX 1 at 1:53-55;
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`Dkt. No. 385, ¶ 35.)
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`As of 1997, it was routine practice for physicians to take detailed clinical histories from
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`patients when evaluating IBS.7 (Trial Tr. 2/20/14 26:2-19.) Such histories would include how
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`long a patient had been suffering from his or her symptoms as well as the type of symptoms (i.e.,
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`diarrhea predominant, constipation predominant, or mixed IBS). (Id.) According to Dr.
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`Anthony Lembo, one of Plaintiff’s gastroenterology experts, “the truth is that almost all patients,
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`or most patients will have had [IBS] symptoms for many years . . . the vast majority of people
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`are going to have symptoms for much longer.” (Trial Tr. 2/10/14 PM 104:18-105:3; see also
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`Trial Tr. 2/11/14 AM 78:8-11; Trial Tr. 2/20/14 26:25-27:2.) Dr. Colin Howden, Defendants’
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`gastroenterology expert, also noted that IBS patients typically have symptoms for a long
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`duration—many months or years. (Trial Tr. 2/20/14 26:20-24.) Dr. Howden testified that the
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`vast majority of his patients in 1997 had IBS symptoms for 6 months or longer. (Trial Tr.
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`7 Similarly, there is no doubt that any competent doctor would determine an effective amount of
`a drug based on the condition of the particular patient when prescribing any drug. (Trial Tr.
`2/20/14 224:24-225:11.)
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`8
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`2/20/14 26:25-27:2.) In 1997, as now, the vast majority of patients with IBS were women, and
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`approximately 75% to 80% of IBS-D patients were, and have always been, women. (Trial Tr.
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`2/20/14 8:1-23, 27:3-5, 277:1-3.)
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`The purpose of the 6 month duration criterion in the assessment steps of the ’770 patent is
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`to consider the Rome criteria (standard criteria used by gastroenterologists to diagnose IBS
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`which generally requires at least 3 months of symptoms), allow enough time to do a workup on
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`the patient, and consider whether other medications with less severe side effects would alleviate
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`the symptoms. (Trial Tr. 2/10/14 PM 105:4-12; Trial Tr. 2/20/14 27:6-8, 64:18-65:10 (in 1997 a
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`gastroenterologist would take a conservative approach to treating IBS, try other therapies first,
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`and be cautious using a new drug), 72:9-17 (same).) There is nothing “magic” or medically
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`precise about the patent’s 6-month criterion; it is there to help ensure that patients who can be
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`successfully treated with other medications do not receive alosetron. (Trial Tr. 2/10/14 PM
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`106:9-107:11; Trial Tr. 2/11/14 AM 30:14-32:10, 40:22-41:10 (Dr. Lucak, Prometheus’s expert,
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`stating that she believes the benefit of waiting for six months of symptoms was that the doctors
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`had greater confidence in a diagnosis of IBS-D); Trial Tr. 2/20/14 74:4-75:18.)
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`Six months is also a reasonable amount of time to see if there is an organic disease
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`causing the patient’s symptoms. (Id.; see also Trial Tr. 2/10/14 PM 108:12-15 (“I think it’s to
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`ensure that the correct patient -- that a patient does not -- to ensure that a patient who has an
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`organic disease or another cause for their symptoms doesn’t get this medication.”), 143:24-
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`144:15; Trial Tr. 2/20/14 257:22-258:3.) But, as noted above, most IBS-D patients will have
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`symptoms for more than 6 months. (Trial Tr. 2/10/14 PM 129:7-9.) And it has always been true
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`that waiting a longer period of time to observe a patient’s symptoms decreases the likelihood of a
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`false positive. (Trial Tr. 2/11/14 AM 41:2-10.) It is also true that doctors always assess the
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`9
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`duration of a patient’s symptoms and have done so since far before 1997. (Trial Tr. 2/11/14 AM
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`78:1-7; Trial Tr. 2/20/14 25:25-26:24 (noting that taking patient history has been a routine
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`practice since before 1997).) It is undisputed that by October 1997, a gastroenterologist would
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`have been able to diagnose the various forms of IBS, including IBS-D, and could verify the
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`duration of a patient’s symptoms. (Dkt. No. 385, ¶ 39.) Moreover, it was understood as of 1997
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`that the longer abdominal symptoms have been present the more likely they are due to a
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`functional disorder like IBS. (Trial Tr. 2/20/14 28:18-29:10.)
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`Another key symptom of IBS as of 1997, as it is today, was abdominal pain. (Trial Tr.
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`2/10/14 PM 114:4-15.) It would have been a routine part of any clinical evaluation to determine
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`if a patient was experiencing pain because pain is a cardinal feature of IBS. (Trial Tr. 2/10/14
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`PM 114:4-115:2; Trial Tr. 2/20/14 77:4-19, 199:8-12.) For example, the Rome criteria ask many
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`questions about pain and its severity, and a doctor would always assess for abdominal pain.
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`(Trial Tr. 2/10/14 PM 114:5-24; Trial Tr. 2/20/14 24:4-18, 278:5-20 (the Rome criteria requires
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`abdominal pain or discomfort for a diagnosis of IBS).) Dr. Lembo, Plaintiff’s expert, candidly
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`stated that he “think[s] it’s pretty obvious that [doctors] will assess for at least moderate pain”
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`when the patient in question is someone with severe IBS-D. (Trial Tr. 2/10/14 PM 114:4-24.)
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`As of 1997, a person of ordinary skill in the art would have considerable knowledge
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`about IBS and how the gastrointestinal tract works. One organ that is part of the gastrointestinal
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`tract is the colon. The colon, or large intestine, performs a storage function, but it also acts to
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`reabsorb water from the contents that it receives from the small intestine. (Trial Tr. 2/20/14
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`14:3-25.) When the colon does not remove enough water from the contents of the
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`gastrointestinal tract, a patient may experience diarrhea. (Trial Tr. 2/20/14 15:3-6.) Similarly, if
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`the colon removes too much water, a patient may experience constipation. (Trial Tr. 2/20/14
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`10
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`15:7-10.) One reason the colon may not remove enough water is if its contents move too quickly
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`through the colon, allowing less time for reabsorption of water. (Trial Tr. 2/20/14 15:16-19.) At
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`a basic level, those with IBS-D experience diarrhea, among other symptoms, and one theory
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`about the cause of IBS is that there are disturbances in the normal motility of the colon. (Trial
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`Tr. 2/20/14 27:12-28:2; DTX 193 at ROX_ALOS*589.) As of October 1997, a person of
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`ordinary skill in the art would have known that colonic transit time had been recorded to be
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`accelerated in IBS-D patients and delayed in IBS-C patients. (Trial Tr. 2/20/14 287:24-288:3.)
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`The colon contains a rich network of nerves that helps control its function. (Trial Tr.
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`2/20/14 15:24-16:6.) One way to affect this system of nerves is with 5-HT3 receptor antagonists.
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`(Trial Tr. 2/20/14 17:6-11.) These drugs are designed to occupy the 5-HT3 receptors to prevent
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`serotonin from acting at the receptors. (Id.) By October 1997, 5-HT3 antagonists—including
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`alosetron and ondansetron—were being studied for the treatment of IBS. (Trial Tr. 2/20/14 38:1-
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`9.) At that time, there was evidence to indicate these drugs may be helpful in reducing visceral
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`pain and slowing colonic transit. (Trial Tr. 2/20/14 38:12-23, 279:19-22.) In other words, that
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`they would be potentially helpful for IBS-D patients and potentially harmful for IBS-C patients.
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`(Id.)
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`c. The Benefit-Risk Profile of Alosetron
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`One allegedly novel aspect of the ’770 patent is the purported clinical study result that
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`women benefitted in a statistically significant way from treatment with alosetron, whereas in
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`men, a large placebo effect meant that statistically significant results could not be claimed. (See,
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`e.g., DTX 1 at 5:45-65 (“No meaningful improvement [of pain and discomfort] relative to
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`placebo was seen in the male population with any dose of alosetron. However, the placebo
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`response in males was substantially greater than that seen in females.”), 6:53-64; Trial Tr.
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`11
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`2/20/14 132:10-134:8 (“[T]he numerical values are similar for males and females for some of the
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`doses of alosetron that were studied. The striking thing about this study is the unusually high
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`placebo response rate exhibited in the men. . . .”).) Prometheus did not introduce any evidence to
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`explain why the unusual placebo effect was shown in men at certain dosages, nor any evidence
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`about what this meant from a medical testing standpoint.8 There was an absence of proof on the
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`significance, if any, of the coexistence of this placebo effect together with medical effectiveness
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`in the same subpopulation.
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`As noted above, the vast majority of patients with IBS are women; approximately 75% to
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`80% of IBS-D patients were, and have always been, women. (Trial Tr. 2/20/14 8:1-23, 27:3-5,
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`277:1-3.) Limiting the patient population to women with severe IBS-D did not change the risk
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`profile for Lotronex. Even when limited to that cohort of the patient population, Lotronex’s
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`incidence of complications did not decrease. (Trial Tr. 2/11/14 AM 69:11-14.)
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`Instead, the goal of isolating a particular patient population for Lotronex upon its
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`reintroduction into the market was to give the drug to those who might benefit the most, thus
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`8 For example, it could mean that the testing in males was inconclusive, or that males were more
`suggestible than females, or that the sample of males had been poorly selected for the disease, or
`that it was a failed study for males in that cohort, or any number of other unexplained reasons,
`but because no evidence was introduced by Plaintiff on this point, this Court draws no factual
`conclusion about the reason why nor the significance of the placebo effect in men. Clearly, at
`certain doses identified in the patent specification, the medication is shown to cause a reduction
`of suffering in men with IBS-D; the label states that “[c]linical studies have not been performed
`to adequately confirm the benefits of Alosetron Hydrochloride Tablets in men.” (PTX 1 at 5:45-
`55; PTX 13; see also Trial Tr. 2/11/14 AM 80:11-19 (Dr. Lucak stating that she sometimes
`prescribes alosetron to men).) Prometheus is factually incorrect when it argues that alosetron
`does not work for men. The only evidence in the specification is that men did not have
`statistically significant results in the study described in the ’770 patent due to a large placebo
`effect. Indeed, at doses larger than 1 mg men and women had similar responses to the drug.
`(DTX 1 at 5:45-65.) Because no factual evidence was adduced beyond the inconclusive study
`cited in the specification, there is insufficient evidence to support a finding of fact that alosetron
`works in women but not in men. See Hoffmann-La Roche Inc. v. Apotex Inc., --- F.3d ----, 2013-
`1164, 2014 WL 1394948, at *3-*4 (Fed. Cir. Apr. 11, 2014).
`
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`making it potentially worth the risk of prescribing Lotronex despite the incidence of
`
`complications. (Trial Tr. 2/11/14 AM 81:14-25, 82:13-24.) But no data was introduced as
`
`evidence at trial to show whether only treating patients with 6 months or more of symptoms
`
`increased the average benefit for patients using Lotronex. (Trial Tr. 2/11/14 AM 39:15-40:21,
`
`42:18-22.) While the number of severe incidents associated with Lotronex has fallen, this
`
`decrease is more likely attributable to other changes in how Lotronex is prescribed. (Trial Tr.
`
`2/20/14 91:6-92:25; DTX 257.) For example, Lotronex can only be prescribed pursuant to a
`
`REMS (Risk Evaluation and Mitigation Strategies), which requires patients and doctors to
`
`complete a form that highlights the risks; Lotronex’s label now has “black box” warnings about
`
`the drug’s potential side effects and instructs doctors that it should only be prescribed to patients
`
`with severe IBS-D who have not responded to conventional therapy; and its prior removal from
`
`the market caused doctors to be more vigilant with respect to complications. (Trial Tr. 2/11/14
`
`AM 63:10-64:6, 74:6-18; Trial Tr. 2/20/14 93:1-15; PTX 13.) These cautionary steps are not
`
`claimed in the ’770 patent. (Id.; PTX 1.) Importantly, the incidence rate of adverse events such
`
`as ischemic colitis and severe constipation has not changed since Lotronex changed its label.
`
`(Trial Tr. 2/11/14 AM 69:11-14.) And, despite the methods claimed in the ’770 patent, doctors
`
`cannot predict which patients will have complications of constipation or ischemic colitis when
`
`using alosetron. (Trial Tr. 2/11/14 AM 76:12-15.)
`
`d. Commercial Success
`
`The evidence at trial showed that the market for Lotronex is very limited. More
`
`significantly, the evidence adduced by Prometheus failed to prove a link or nexus between the
`
`commercial sales of Lotronex and the ’770 patent’s method claims.
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`Joseph Limber, the former President and CEO of Prometheus, participated in the
`
`acquisition of the Lotronex product from GSK. (Trial Tr. 2/10/14 PM 9:2-9.) The acquisition of
`
`the Lotronex product included GSK’s ’800 patent on the compound itself. (Trial Tr. 2/10/14 PM
`
`15:12-16:7, 30:4-6; PTX 6.) The payments Prometheus made to GSK were not merely for the
`
`patents associated with Lotronex—GSK transferred everything needed to run the franchise
`
`including trademarks, copyrights, websites, and training materials, among other things. (PTX 6.)
`
`At the time Prometheus purchased the Lotronex franchise, including the ’800 and ’770
`
`patents and all the materials described above, it believed that approximately 10 million patients
`
`were good candidates for the drug. (Trial Tr. 2/10/14 PM 16:12-22.) Other Prometheus
`
`documents indicated that there were approximately 500,000 severe IBS-D patients in the United
`
`States. (Trial Tr. 2/10/14 PM 63:13-15; Trial Tr. 2/11/14 PM 14:13-19; PTX 198 at PLI-*273;
`
`DTX 138 at PLI-*589.) But by 2011, there were just over 42,000 prescriptions of Lotronex
`
`written per year for about 10,000 patients. (PTX 150; DTX 138 at PLI-*589; Trial Tr. 2/11/14
`
`PM 13:1-18.) This was only about 2,100 more prescriptions compared to its peak year of sales
`
`with GSK. (Trial Tr. 2/11/14 PM 13:11-18.) Prometheus also spent a significant amount of time
`
`at trial discussing its projections and expectations for Lotronex sales, but it did not tie those
`
`expectations to either actual sales on the market or, more significantly, the claimed inventions of
`
`the ’770 patent. Prometheus introduced evidence that sales revenue of Lotronex increased from
`
`the time of its reintroduction into the market in 2002 until 2012. (Trial Tr. 2/10/14 PM 39:4-12.)
`
`But Prometheus’s evidence did not show whether the revenue increases were due to the
`
`inventions of the ’770 patent, as distinguished from pricing changes, marketing, coupons, or the
`
`inventions claimed in the ’800 patent (i.e., the compound itself or the use of alosetron
`
`hydrochloride to treat IBS). Moreover, those sales did not meet Prometheus’s expectations of
`
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`projected sales for the drug. (Trial Tr. 2/10/14 PM 57:13-59:5, 60:22-61:9.) This problem is not
`
`due to any lack of effort by trial counsel; rather, it is simply hard to show that a treatment method
`
`that, in essence, cautions doctors to be very cautious about prescribing this drug is going to show
`
`big sales gains.
`
`Mr. Limber admitted that Prometheus’s promotional efforts contributed to increased sales
`
`of Lotronex—activity that is not attributable to the claimed inventions of the ’770 patent. (Trial
`
`Tr. 2/10/13 PM 40:2-4.) The evidence at trial also demonstrated that pricing can have a
`
`significant effect on sales and revenue. While revenue from Lotronex has generally risen since
`
`Lotronex’s reintroduction into the market, total numbers of prescriptions has grown and shrunk
`
`depending on the year. (Compare PTX 6 at PLI-*0452 and PTX 151 with PTX 150.) In other
`
`words, the total number of prescriptions written has only grown by about 2,100 prescriptions
`
`since 2005, while revenue has grown at a faster rate. The evidence supports finding that the
`
`growth in revenue is due to Prometheus’s actions in marketing, increasing the price of Lotronex,
`
`and introducing a series of rebates to stimulate sales of the drug, rather than from the treatment
`
`method claimed in the ’770 patent. (Trial Tr. 2/10/14 PM 61:10-23; PTX 151 (showing
`
`significant spending in sales and marketing); PTX 225 (the Lotronex “Savings Program”); PTX
`
`204 (showing the price changes in Lotronex from 2007 to 2012).)
`
`While Mr. Limber focused on how well he thought Lotronex fit in with the rest of
`
`Prometheus’s offerings, this justification for purchasing Lotronex does not tend to prove that the
`
`treatment methods of the ’770 patent wer