Obviousness

Under 35 U.S.C. § 103, an invention is considered obvious if the differences between the claimed invention 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 (PHOSITA). The analysis involves identifying relevant prior art, determining the differences between the prior art and the claimed invention, and articulating a motivation to combine or modify the prior art to arrive at the claimed invention with a reasonable expectation of success.

The independent claims of US Patent 8,377,903 (Claims 1 and 17) describe a method for treating relapsing-remitting multiple sclerosis (RRMS) or early secondary progressive multiple sclerosis (SPMS) using an orally administered cladribine formulation in a sequential regimen comprising an induction period, a cladribine-free period, a maintenance period, and another cladribine-free period, with specific dose ranges and durations for each period.

Identified Prior Art and Their Teachings:

1. Grieb et al. (1995, Archivum Immunologiae et Therapiae Experimentalis, 43 (5-6), 323-327): This is a highly relevant prior art reference, describing an oral cladribine regimen for RRMS. It disclosed "6 monthly courses of 5 days at a total dose of about 4-5.7 mg/kg" (over 6 months) and included a "single re-treatment of 5 days at a cumulative dose of 0.4-0.66 mg/kg after a cladribine free-period of 3 or 6 months." However, Grieb et al. noted that while side effects were less severe than IV infusion, they were "still present," and the "therapeutic efficacy of the oral regimen above versus the i.v. infusion therapy was questioned."
2. U.S. Pat. No. 5,506,214 and EP 626853B1: These references suggest cladribine's usefulness in treating MS generally.
3. Selby et al. (1998), Romine et al. (1999), Rice et al. (2000), Beutler et al. (1996): These references collectively establish the efficacy of cladribine in treating various forms of MS (including RRMS, SPMS, and chronic progressive MS) via intravenous (IV) or subcutaneous (SC) administration, often in repeated or pulsed regimens.
4. Beutler et al. (1994, 1996): These articles highlight adverse effects (AEs) of cladribine, such as increased incidence of infections or myelosuppression, particularly with higher doses. Beutler et al. (1996) went as far as "excluded the oral route for the treatment of multiple sclerosis with Cladribine" due to the narrow safety margin.
5. WO 2004/087100 and WO 2004/087101: These documents describe representative oral formulations of 2-CdA (cladribine), indicating that oral formulations were known and available.

Differences Between the Claims and the Prior Art:

The key differences between the claimed regimens (Claims 1 and 17) and Grieb et al. (1995) lie primarily in the specific durations of the induction and cladribine-free periods, and the structure and dosage of the maintenance period:

• Induction Period Duration: Claims 1 and 17 specify an induction period of "about 2 months to about 4 months." Grieb et al. describes "6 monthly courses," totaling a 6-month induction.
• Cladribine-Free Period Duration: Claims 1 and 17 specify a cladribine-free period of "about 8 months to about 10 months." Grieb et al. described "3 or 6 months" for this period.
• Maintenance Period Structure and Dose: Claims 1 and 17 define a structured "maintenance period lasting from about 2 months to about 4 months," with the total dose being "lower than the total dose of cladribine reached at the end of the induction period" (Claim 1) or specifically "about 1.7 mg/kg" (Claim 17). Grieb et al. described a "single re-treatment of 5 days" at a very low cumulative dose.

Motivation to Combine/Modify the Prior Art:

The patent itself clearly articulates the problems and desires that would motivate a PHOSITA to combine and modify the existing prior art. The "Summary of the Invention" states, "Therefore, it would be desirable to have a method for treating multiple sclerosis comprising the oral administration of Cladribine that would permit the same or improved effect on MS lesions while decreasing the occurrence and/or severity adverse events. In addition, as MS is a chronic disease, it would be desirable to decrease the occurrence and/or severity adverse events in such a way that re-treatments are possible. A sustained benefit of Cladribine treatment between the treatment periods is also desirable."

A PHOSITA would be motivated to address the limitations of Grieb et al.'s oral cladribine regimen, specifically the "questioned" efficacy and the "still present" side effects, to enable safer and more effective re-treatments for a chronic disease like MS. This motivation would lead a PHOSITA to:

1. Shorten the Induction Period: Knowing cladribine's myelosuppressive effects (Beutler et al.) and the desire to reduce adverse events, a PHOSITA would be motivated to explore shorter initial induction periods (e.g., 2-4 months as claimed, compared to Grieb's 6 months) to minimize early cumulative drug exposure while aiming for an effective initial depletion of lymphocytes. The patent's own Example 1 demonstrates 2-month and 4-month induction periods, indicating these durations were considered viable.
2. Lengthen the Cladribine-Free Periods: To allow for greater immune recovery and further reduce adverse events, a PHOSITA would be motivated to extend the cladribine-free period beyond Grieb's 3 or 6 months to, for example, 8 to 10 months. This would directly address the stated need for reduced adverse effects to allow re-treatments.
3. Optimize Maintenance Dosing and Duration: Given Grieb's questioned efficacy for a single low-dose re-treatment, a PHOSITA would be motivated to explore more robust maintenance regimens that could provide a "sustained benefit" and address the chronic nature of MS. This would involve structuring a maintenance "period" (e.g., 2-4 months) with a total dose that is still lower than the induction dose for safety (as in Claim 1), but potentially higher than Grieb's minimal re-treatment to improve efficacy. For Claim 17's specific maintenance dose of about 1.7 mg/kg, a PHOSITA would be motivated to consider doses known to be effective from other short induction regimens, such as the 2-month induction period total dose of 1.75 mg/kg (effective dose 0.7 mg/kg) used in Group 2 of Example 1.

The selection of specific dose ranges (1.7-3.5 mg/kg for induction) and durations for the various periods, when viewed in light of the prior art (Grieb et al. establishing oral administration and repeated dosing, and other references establishing cladribine's efficacy and side effect profile), represents routine optimization. A PHOSITA would systematically adjust these parameters to achieve an improved balance of efficacy and safety, particularly for a chronic disease requiring re-treatment. The oral formulations described in documents like WO 2004/087101 would be readily available for use in such optimized regimens.

Therefore, a combination of Grieb et al. (1995), which teaches oral cladribine for RRMS with pulsed dosing and re-treatment but notes limitations, in view of the general knowledge of cladribine's efficacy and adverse effects (e.g., Selby et al., Beutler et al., Rice et al.), and the availability of oral formulations (WO 2004/087101), would render the claimed regimens obvious to a PHOSITA. The motivation would be to optimize the oral cladribine regimen to improve efficacy, reduce adverse events, and enable sustained re-treatment for MS patients.