Obviousness

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 10,278,961

This analysis evaluates the obviousness of US Patent 10,278,961 under 35 U.S.C. § 103, considering the prior art cited within the patent itself. To establish obviousness, it must be shown that a person having ordinary skill in the art (PHOSITA) would have been motivated to combine existing prior art references to arrive at the claimed invention, with a reasonable expectation of success.

The independent claims of US 10,278,961 are:

• Claim 1: A method of managing glucose tolerance in an individual, the method comprising: administering, to an individual, a pharmaceutically effective amount of dihydroberberine, wherein the pharmaceutically effective amount of dihydroberberine comprises approximately 25 mg to approximately 800 mg of dihydroberberine.
• Claim 9: A method of increasing blood ketone levels in an individual, the method comprising: administering, to an individual, a pharmaceutically effective amount of dihydroberberine, wherein the pharmaceutically effective amount of dihydroberberine comprises approximately 25 mg to approximately 800 mg of dihydroberberine.

The relevant prior art identified from the patent document, with publication dates prior to the priority date of April 19, 2016, includes:

1. US20100113494A1 (Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences): Published May 6, 2010, titled "13,13a-Dihydroberberine Derivatives For Use In Pharmaceutical Compositions." This reference explicitly teaches dihydroberberine derivatives for pharmaceutical applications.
2. Yin et al. (2008): "Efficacy of Berberine in Patients with Type 2 Diabetes,” Metabolism. 2008 May; 57(5): 712-717. This non-patent literature highlights berberine's potential for lowering fasting blood glucose but notes accompanying adverse gastrointestinal effects when administered in effective amounts.
3. Chen et al. (2011): "Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats. Aaps Pharmscitech, 12(2), 705-711." This non-patent literature discusses the bioavailability of traditional berberine, noting it can be below 70% in animal models.
4. US20140350105A1 (University Of South Florida): Published November 27, 2014, titled "Compositions and methods for producing elevated and sustained ketosis." This patent application teaches methods and compositions for inducing and maintaining ketosis.

Obviousness Analysis for Claim 1

Combination: US20100113494A1 in view of Yin et al. (2008) and Chen et al. (2011), along with general knowledge in medicinal chemistry.

Rationale:
Claim 1 describes a method of managing glucose tolerance by administering 25-800 mg of dihydroberberine.

• Prior Art Teachings:

  • Yin et al. (2008) teaches that berberine has the potential to lower fasting blood glucose, but its administration is accompanied by adverse gastrointestinal effects.
  • Chen et al. (2011) indicates that traditional berberine has limited bioavailability.
  • US20100113494A1 teaches dihydroberberine derivatives for use in pharmaceutical compositions. Dihydroberberine is a known derivative of berberine.

• Motivation to Combine: A PHOSITA would be aware of the known therapeutic effects of berberine on glucose management (Yin et al.) and its associated drawbacks, such as poor bioavailability (Chen et al.) and gastrointestinal side effects (Yin et al.). The patent itself acknowledges that "Dihydroberberine may be more biologically available to humans than berberine." Faced with these problems, a PHOSITA would be motivated to seek improved forms or derivatives of berberine that could enhance efficacy, improve bioavailability, or reduce side effects for glucose management. US20100113494A1 explicitly teaches dihydroberberine as a pharmaceutical derivative. It would be an obvious step for a PHOSITA to investigate dihydroberberine, a known derivative of berberine, for its potential to manage glucose tolerance, particularly given its anticipated improved bioavailability and reduced side effects compared to berberine. The specific dosage range of approximately 25 mg to 800 mg for dihydroberberine would be a matter of routine pharmaceutical optimization, given the known therapeutic window for berberine and the expectation that a more bioavailable derivative might be effective at different (potentially lower) doses. The patent itself demonstrates this dose optimization in Example 2, where 250 mg of dihydroberberine performed better than 500 mg for some individuals.

Obviousness Analysis for Claim 9

Combination: US20100113494A1 in view of Yin et al. (2008), US20140350105A1, and general knowledge regarding metabolic pathways.

Rationale:
Claim 9 describes a method of increasing blood ketone levels by administering 25-800 mg of dihydroberberine.

• Prior Art Teachings:

  • US20140350105A1 teaches compositions and methods for producing elevated and sustained ketosis, demonstrating a known desire and existing methods to achieve increased ketone levels.
  • Yin et al. (2008) indicates berberine's effect on lowering blood glucose levels.
  • US20100113494A1 teaches dihydroberberine derivatives for use in pharmaceutical compositions.

• Motivation to Combine: A PHOSITA would understand the fundamental relationship between glucose metabolism and ketosis; typically, conditions of lower glucose availability or utilization promote fat metabolism and ketone body production. Given the teachings of US20140350105A1 regarding the benefits and methods of inducing ketosis, a PHOSITA would be actively seeking compounds that could influence this metabolic state. Concurrently, a PHOSITA would be aware of berberine's established role in glucose management (Yin et al.). It would be an obvious hypothesis ("obvious to try") for a PHOSITA to investigate whether a known glucose-regulating compound like dihydroberberine (from US20100113494A1), a derivative with potentially improved metabolic effects (as discussed in relation to Claim 1), could also impact ketone levels by shifting metabolic pathways towards fat oxidation and ketogenesis. While the patent asserts that the increase in blood ketone levels from dihydroberberine administration is "unexpectedly increased", the underlying motivation to test a metabolically active compound (dihydroberberine, known for glucose effects) for an impact on a related metabolic pathway (ketosis) would exist. The specific dosage range (25-800 mg) would again be a matter of routine optimization for achieving a desired metabolic effect.