As an essential component of the drug development process, human clinical trials assist in determining whether a given drug will serve its intended purpose, but patent applicants should consider disclosure of such trials in their overall patent strategy. Disclosure of a protocol summary of the human clinical trial to the National Institutes of Health (“NIH”) is federally mandated.[1] The NIH, in turn, must report information about the study publicly on ClinicalTrials.gov.[2] The Federal Food, Drug, and Cosmetic Act labels failing to timely submit clinical study information to the NIH as a “prohibited act” that carries criminal and potential civil liability.[3]
Innovators may face challenges when attempting to comply with these government-mandated disclosure requirements and with the rules and regulations of U.S. patent law. For example, the mandated ClinicalTrials.gov disclosures are published and publicly accessible. The America Invents Act (“AIA”) 35 U.S.C. § 102(b)(1) provides a one-year grace period after a first inventor-originated disclosure of an invention within which the inventor or assignee may file a patent application that disqualifies the disclosure as prior art.[4] However, most clinical studies take much longer than a year to complete,[5] and as such, postings on ClinicalTrials.gov frequently fall outside of the one-year grace period time frame. Not only may clinical trial disclosures be considered during prosecution, but challengers have also relied on such disclosures as art during litigation and in post-grant proceedings, including inter partes reviews (“IPRs”) before the Patent Trial and Appeal Board (“PTAB”).
A recent decision from the United States Court of Appeals for the Federal Circuit demonstrates just that. On April 11, 2024, the Federal Circuit issued a precedential decision in Salix Pharms., Ltd. v. Norwich Pharms. Inc.,[6] affirming the United States District Court for the District of Delaware’s final judgment[7] that several pharmaceutical method of treatment claims for rifaximin are invalid as obvious over a clinical study protocol published on ClinicalTrials.gov in combination with another reference. Rifaximin is the active ingredient in the commercial product Xifaxan® owned by Salix Pharmaceuticals, Ltd., Salix Pharmaceuticals, Inc., Bausch Health Ireland Ltd., and Alfasigma S.P.A. (collectively, “Salix”).
Background
Rifaximin has been widely used as an antibiotic for decades. The U.S. Food and Drug Administration (“FDA”) approved 200 mg tablets of Xifaxan® in 2004 for the treatment of travelers’ diarrhea, 550 mg tablets of Xifaxan® in 2010 for hepatic encephalopathy (“HE”), and 550 mg tablets of Xifaxan® in 2015 for irritable bowel syndrome with diarrhea (“IBS-D”).[8]
Norwich Pharmaceuticals Inc. (“Norwich”) submitted an Abbreviated New Drug Application (“ANDA”) to the FDA in 2019 for approval to market a generic 550 mg tablet version of Xifaxan® for reducing HE recurrence.
United States District Court for the District of Delaware
Salix sued Norwich for infringement of twenty-six patents covering Salix’s Xifaxan® 550 mg tablets that were narrowed to the following three groups prior to trial:
- Group 1: U.S. Patents 8,624,573; 9,421,195; and 10,335,397, directed to methods of treating HE (“the HE patents”);
Group 2: U.S. Patents 8,309,569 (“U.S. Pat. No. ’569”) and 10,765,667 (“U.S. Pat. No. ’667”), directed to methods of treating IBS-D by administering 550 mg rifaximin three times a day (1,650 mg/day) for 14 days (“the IBS-D patents”); and
Group 3: U.S. Patents 7,612,199 and 7,902,206, directed to rifaximin form β (“the polymorph patents”).
Norwich countered that the asserted patents were invalid as obvious.
This article focuses on the IBS-D patents, of which the challenged IBS-D claims include claim 2 of U.S. Pat. No. ’569[9] and claim 3 of U.S. Pat. No. ’667.[10]
Following a bench trial, the district court held that the challenged IBS-D claims were obvious over: (1) a trial protocol published on ClinicalTrials.gov (“the Protocol”)[11] in combination with (2) a scientific journal article (“Pimentel”).[12]
The Protocol outlined a Phase II clinical trial to evaluate the dose-response relationship of placebo administered for 28 days and rifaximin administered at various doses for a period of 14 days,[13] including “twice-daily doses of 550 mg (1,100 mg/day) and 1,100 mg (2,200 mg/day) for 14 and 28 days for the treatment of IBS[-]D.”[14] The Protocol also included the outcome measures of providing adequate relief of symptoms and evaluating a durability of response over a 12-week post-treatment period.[15] However, the Protocol does not disclose the 1,650 mg/day dose, thrice-daily dosing of the challenged IBS-D claims, or any outcome measures.
Pimentel discloses administration of 400 mg of rifaximin three times daily (i.e., 1,200 mg/day total) to treat IBS patients aged 18-65,[16] and explains that the “optimal dosage of rifaximin may, in fact, be higher than that used in our study.”[17]
| Total amount of rifaximin | Condition | Subject | Time period |
Claim 2 of U.S. Pat. No. ’569
| 1,650 mg (administered as 550 mg three times per day) | IBS-D |
| 14 days |
Claim 3 of U.S. Pat. No. ’667 | 1,650 mg (administered as 550 mg three times per day) | IBS-D | Subject is 65 years of age or older | 14 days |
The Protocol | 1,100 mg (administered as 550 mg two times per day)
2,200 mg (administered as 1,100 mg two times per day) | IBS-D |
| 14 days and 28 days |
Pimentel | 1,200 mg (administered as 400 mg three times per day) | IBS | Subject is 18-65 years of age | 10 days |
The court held that the challenged IBS-D claims were obvious over the Protocol in combination with Pimentel. In coming to this conclusion, the court explained that “Pimentel [] reported sustained improvement in IBS symptoms for patients aged 18-65 for at least 10 weeks on a 400 mg TID [times a day], 10-day regimen [and the] Protocol included no upper age limit, a 14-day dosing regimen of 550 to 2200 mg per day, and the treatment of patients with IBS-D in particular.”[18] Rifaximin had been shown to be effective in treating IBS in Pimentel and IBS-D in the Protocol. The court found that a person having ordinary skill in the art would have had the motivation to select an optimal dosing regimen from within the known range,[19] because “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation.”[20]
Salix appealed.
United States Court of Appeals for the Federal Circuit
Majority
Salix did not dispute the district court’s finding that the combination of the Protocol and Pimentel “disclose all limitations of the IBS-D claims.”[21] Instead, Salix argued that even if the asserted combination of references effectively disclosed the claimed 1,650 mg/day dosage, there was insufficient evidence to support a finding of a reasonable expectation of success in using that particular dosage amount. According to Salix, “the highest prior art dosage amount that could have been supported with a reasonable expectation of success was the 1,200 mg/day dose evaluated by Pimentel.”[22]
In being “hesitant to conclude as a general matter that the disclosure of a Phase II clinical trial plan, standing alone, provides an expectation of success sufficient to render obvious a dosage that was not included within the planned clinical trial,”[23] the Federal Circuit explained that the Protocol was not asserted alone—it was asserted in combination with Pimentel.
The Federal Circuit has previously held that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious, provided there is also a reasonable expectation of success.[24] Further, conclusive proof of efficacy is not required to show a reasonable expectation of success, but at least some degree of predictability is required.[25]
According to the Federal Circuit, a person having ordinary skill in the art “would have looked to both [Protocol and Pimentel], considered their limits, and had a reasonable expectation of success as to the efficacy of 550 mg TID dosing,”[26] and there would have been a reasonable expectation of success in administering higher doses of rifaximin without an intolerable increase in negative side effects.
The Federal Circuit majority affirmed the district court’s decision, noting that disclosure of a clinical trial plan is likely insufficient alone to render obvious a dosage that was not included within the planned clinical trial, absent a showing of a reasonable expectation of success. However, a clinical trial plan, combined with another prior art reference, may tip the scale into a finding of obviousness if the additional reference demonstrates a reasonable expectation of success regarding the claimed dosage.
References
[1] See U.S. Public Law 110-85 (FDA Amendments Act of 2007 (“FDAAA”), Title VIII, Section 801) (which expanded the legal registration requirement for sponsors responsible for clinical trials of FDA-regulated drugs and biologics to register their studies to ClinicalTrials.gov).
[2] ClinicalTrials.gov is a registry of clinical trials managed by the United States National Library of Medicine at the NIH.
[3] See 21 U.S.C. § 331(jj), 21 U.S.C. § 333(a)(1), and 21 U.S.C. § 333(f)(3)(A)&(B). See also FDA, Civil Monetary Penalties Relating to ClinicalTrials.gov Data
Bank: Guidance for Responsible Parties, Submitters of Certain Applications and Submissions to FDA, and FDA Staff (Aug. 20, 2020), perma.cc/SV5N-3JUF.
[4] See 35 U.S.C. § 102(b)(1).
[5] See FDA, Step 3: Clinical Research (Jan. 4, 2018), perma.cc/23ZD-H6FN.
[6] Salix Pharms., Ltd. v. Norwich Pharms. Inc., 2024 WL 1561195 (Fed. Cir. Apr. 11, 2024).
[7] See Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 20-cv-430, 2022 WL 3225381 (D. Del. Aug. 10, 2022) (“Decision”).
[8] See Decision, 2022 WL 3225381, at *1.
[9] Claim 2 of U.S. Pat. No. ’569 is a dependent claim that includes two elements: (1) administering 1650 mg/day of rifaximin for 14 days to a subject in need thereof, where the 1650 mg is administered as 550 mg three times per day; and (2) after stopping rifaximin, achieving a durability of response that comprises about 12 weeks of adequate relief of symptoms.
[10] Claim 3 of U.S. Pat. No. ’667 is a dependent claim that includes three elements: (1) administering 550 mg of rifaximin three times a day for 14 days; (2) to treat one or more symptoms of IBS, where the IBS is IBS-D; and (3) in a subject 65 years of age or older.
[11] See ClinicalTrials.gov, History of Changes for Study: NCT00269412, Randomized, Double Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Three Different Doses of Rifaximin Administered BID either Two or Four Weeks in the Treatment of Patients with Diarrhea-Associated Irritable Bowel Syndrome (December 22, 2005).
[12] See M. Pimentel et al., The Effect of a Nonabsorbed Oral Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel Syndrome, 145 Ann. Intern. Med. 557 (2006).
[13] See the Protocol.
[14] See Salix Pharms., Ltd., 2024 WL 1561195, at *6.
[15] See Decision, 2022 WL 3225381, at *19.
[16] See id. at *18–19.
[17] See Salix Pharms., Ltd., 2024 WL 1561195, at *6. See also Decision, 2022 WL 3225381, at *20.
[18] See Decision, 2022 WL 3225381, at *19.
[19] See id.
[20] See id. at *20 (quoting In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012)).
[21] See Decision, 2022 WL 3225381, at *17.
[22] See Salix Pharms., Ltd., 2024 WL 1561195, at *7.
[23] See id. at *7–8.
[24] See In re Merck & Co., Inc., 800 F.2d 1091 (Fed. Cir. 1986).
[25] See Almirall, LLC v. Amneal Pharms. LLC, 28 F.4th 265, 275 (Fed. Cir. 2022) (“A finding of a reasonable expectation of success does not require absolute predictability of success.”).
[26] See Salix Pharms., Ltd., 2024 WL 1561195, at *8.