Obviousness

Obviousness Analysis of US Patent 7713947 Under 35 U.S.C. § 103

US Patent 7713947B2 claims a method of treating multiple sclerosis (MS) through the oral administration of cladribine, following a specific sequential regimen. This regimen includes an induction period with a total cladribine dose of about 1.7 mg/kg to about 3.5 mg/kg, followed by a cladribine-free period of 8 to 10 months. Subsequently, a maintenance period with a total cladribine dose lower than the induction dose is administered, which is then followed by another cladribine-free period.

A person having ordinary skill in the art (POSITA) would have been motivated to combine existing prior art references to arrive at the claimed invention, particularly in light of the known challenges with cladribine treatment for MS, such as adverse effects and the need for re-treatment in a chronic disease.

Prior Art Combination and Motivation

A strong argument for obviousness can be made by combining the teachings of Grieb et al. (1995) with the general knowledge of cladribine's adverse effects (e.g., Beutler et al., 1994) and the availability of oral cladribine formulations (e.g., WO 2004/087101A2), alongside the clear motivation articulated within the background of US7713947B2 itself.

1. Oral Administration of Cladribine for MS

• Grieb et al. (1995) explicitly teaches the oral administration of cladribine for treating relapsing-remitting multiple sclerosis. This reference describes an oral regimen of cladribine given during 6 monthly courses of 5 days, achieving a total dose of about 4-5.7 mg/kg.
• The feasibility of orally administering cladribine was further established by formulations described in prior art such as WO 2004/087101A2, which details oral cladribine formulations, including cyclodextrin formulations, some of which are used in the examples of US7713947B2.

2. Induction Period Total Dose (1.7 mg/kg to 3.5 mg/kg)

• Grieb et al. (1995) disclosed an initial oral cladribine regimen with a total dose of about 4-5.7 mg/kg. However, the background of US7713947B2 acknowledges that prior cladribine regimens, including both intravenous and subcutaneous administrations, had observed adverse effects (AEs) such as increased infections and myelosuppression, particularly with higher doses (e.g., Selby et al., 1998; Beutler et al., 1994).
• The US7713947B2 patent itself states that "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." Given these known adverse effects, a POSITA would have been motivated to explore lower, yet still effective, total doses to improve the safety and tolerability profile of oral cladribine. Reducing the dose from Grieb's 4-5.7 mg/kg to a range of 1.7-3.5 mg/kg would represent a routine optimization in drug development aimed at mitigating known side effects while maintaining therapeutic benefit.

3. Cladribine-Free Period of 8 to 10 Months

• Grieb et al. (1995) teaches the concept of cladribine-free periods, mentioning "a cladribine free-period of 3 or 6 months" before re-treatment. Similarly, other cladribine regimens for MS (e.g., Selby et al., 1998; Romine et al., 1999) involved repeated courses over consecutive months, inherently implying drug-free intervals between treatment cycles.
• Faced with the objective of decreasing adverse events, particularly those related to immune suppression, and enabling re-treatments for a chronic disease, a POSITA would have found it obvious to extend the cladribine-free periods. Extending these periods from 3 or 6 months (as taught by Grieb) to 8-10 months would be a predictable adjustment to allow for better immune recovery and reduced cumulative toxicity, thereby improving patient safety and enabling long-term management of MS.

4. Maintenance Period with a Lower Total Dose

• Grieb et al. (1995) already demonstrates the principle of a reduced dose for subsequent treatments. It describes a "single re-treatment of 5 days... at a cumulative dose of 0.4-0.66 mg/kg" following an initial regimen of 4-5.7 mg/kg. This clearly teaches that subsequent courses of cladribine can be administered at a lower dose than the initial treatment.
• Therefore, the claim that the total dose during the maintenance period is lower than the total dose during the induction period is directly taught by Grieb et al. (1995) or would be an obvious application of known dosing strategies to manage chronic diseases.

5. Subsequent Cladribine-Free Period

• The inclusion of a subsequent cladribine-free period is a natural and obvious component of any pulsed or cyclical drug regimen, particularly for a chronic condition requiring repeated treatments. The concept of drug-free intervals is well-established in the prior art, including Grieb et al. (1995) and other cladribine studies.

Conclusion on Obviousness

A POSITA, motivated by the known need to reduce adverse effects and enable re-treatment for chronic MS (as articulated in US7713947B2 itself), would have found it obvious to modify the oral cladribine regimen described by Grieb et al. (1995). These modifications would include adjusting the induction dose to a lower range (1.7-3.5 mg/kg) from the 4-5.7 mg/kg of Grieb to improve tolerability, and extending the cladribine-free periods from 3 or 6 months to 8-10 months to allow for immune recovery. The concept of a lower dose for maintenance treatment was also taught by Grieb. The availability of oral cladribine formulations (WO 2004/087101A2) would make these modifications readily implementable.

The previous PTAB decisions, which resulted in claims of US7713947B2 being found unpatentable on grounds of obviousness (e.g., IPR2023-00480 citing Bodor & Stelmasiak), further support this analysis. The challenge specifically targeting a "lower-dose maintenance regimen" aligns with the obviousness arguments presented here.