PTAB

IPR2017-00854

Apotex Inc v. Novartis AG

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1. Case Identification

2. Patent Overview

  • Title: S1P Receptor Modulators for Treating Relapsing-Remitting Multiple Sclerosis
  • Brief Description: The ’405 patent claims a method of treating Relapsing-Remitting Multiple Sclerosis (RR-MS) by orally administering a daily dosage of 0.5 mg of fingolimod (also known as FTY720) or its salt form, specifically absent an immediately preceding loading dose regimen.

3. Grounds for Unpatentability

Ground 1: Obviousness over Kovarik and Thomson - Claims 1-6 are obvious over Kovarik in view of Thomson.

  • Prior Art Relied Upon: Kovarik (International Publication No. WO 2006/058316) and Thomson (a 2006 article in CORE EVIDENCE).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Kovarik taught all elements of the claims except for an explicit focus on RR-MS and a clear motivation to omit the loading dose it suggests. Kovarik disclosed treating autoimmune diseases like multiple sclerosis with fingolimod, specifically teaching a "maintenance therapy, e.g. a daily dosage of 0.5 mg." While Kovarik proposed a loading dose to achieve steady-state concentration faster, Petitioner asserted this was an optional method, not a prerequisite for the efficacy of the maintenance dose. Thomson, a literature review, supplied the express link to RR-MS, teaching that FTY720 has the potential to be an effective disease-modifying agent for treating RR-MS by reducing relapse rates.
    • Motivation to Combine: Petitioner contended a POSITA would combine Kovarik's 0.5 mg daily dose with Thomson's teachings on efficacy in RR-MS to arrive at the claimed method. The motivation to omit the loading dose stemmed from general knowledge that loading doses are not required for the efficacy of a maintenance dose and carry increased risks of adverse events. For a chronic condition like MS, unlike acute organ transplant rejection, a POSITA would prioritize safety and avoid the unnecessary risks of a loading dose, particularly the known risk of bradycardia associated with higher initial doses of fingolimod.
    • Expectation of Success: A POSITA would have a reasonable expectation of success because Kovarik taught the specific 0.5 mg effective dose, and Thomson confirmed the therapeutic benefit of FTY720 in the target RR-MS population. The art also established that the 0.5 mg/day dose corresponded to the EC50 value for fingolimod, ensuring a potent immunomodulatory effect.

Ground 2: Obviousness over Chiba, Kappos 2005, and Budde - Claims 1-6 are obvious over Chiba in view of Kappos 2005 and Budde.

  • Prior Art Relied Upon: Chiba (Patent 6,004,565), Kappos 2005 (a 2005 journal abstract), and Budde (a 2002 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Chiba taught the use of fingolimod hydrochloride to treat multiple sclerosis in a daily oral dose range of 0.01-10 mg, without mentioning a loading dose. Kappos 2005 provided results from a Phase II study showing FTY720 was an efficacious treatment for relapsing MS. Budde provided results from a human trial in renal transplant patients that taught a 0.5 mg dose was safe and effective at inducing lymphopenia (the drug's mechanism of action) and had a better safety profile (less bradycardia) than higher doses.
    • Motivation to Combine: A POSITA, starting with Chiba's broad disclosure, would be motivated to identify an optimal dose for treating MS. Kappos 2005 provided the clinical evidence of efficacy in the target patient population. Budde provided the motivation to select the specific 0.5 mg dose from within Chiba's range, as it demonstrated a favorable balance of efficacy and safety, noting "no clear dose response relationship" for efficacy above 0.5 mg but an increased risk of adverse events at higher doses.
    • Expectation of Success: The combination of references provided a strong expectation of success. Chiba disclosed the drug for the indication, Kappos 2005 confirmed efficacy in relapsing MS patients, and Budde provided clinical data supporting the specific 0.5 mg dose as both effective and safer than alternatives.

Ground 3: Anticipation by Kappos 2010 - Claims 1-6 are anticipated by Kappos 2010.

  • Prior Art Relied Upon: Kappos 2010 (a 2010 article in the NEW ENGLAND JOURNAL OF MEDICINE).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground was based on the argument that the ’405 patent was not entitled to a priority date earlier than April 21, 2014. Petitioner contended the negative limitation "absent an immediately preceding loading dose regimen" was first introduced in a 2014 amendment and lacked written description support in the priority documents. Therefore, Kappos 2010 qualified as prior art under 35 U.S.C. §102. Petitioner argued Kappos 2010, which reported the results of the pivotal Phase III FREEDOMS clinical trial, disclosed every element of the challenged claims. It described a study where RR-MS patients were administered "oral fingolimod capsules in a dose of 0.5 mg... once daily for 24 months" without any mention of a loading dose, and it concluded that this regimen significantly reduced relapse rates and progression of clinical disability.

4. Key Claim Construction Positions

  • "A method for...": Petitioner argued that the preamble language in claims 1, 3, and 5 (e.g., "A method for reducing or preventing or alleviating relapses...") merely stated the intended purpose of the method and was non-limiting. The patentee defined a structurally complete invention in the claim body, and the preamble was not needed to give life to the claims.
  • "a subject in need": Petitioner argued that, under the broadest reasonable construction, any subject with RR-MS was "a subject in need" of the claimed treatment, as the patent itself explained the progressive nature of the disease and the disabilities that accrue from relapses.

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-6 of Patent 9,187,405 as unpatentable.