PTAB

IPR2025-01593

Bonerge Lifescience Hunan Co Ltd v. Nanjing Nutrabuilding Bio Tech Co Ltd

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Administration of berberine metabolites
  • Brief Description: The ’961 patent discloses methods for managing glucose tolerance in an individual by administering a pharmaceutically effective amount of dihydroberberine (dhBBR), a metabolite of berberine. The core of the invention is the administration of dhBBR within a specific dosage range of approximately 25 mg to 800 mg.

3. Grounds for Unpatentability

Ground 1: Obviousness over Turner in view of Shaw - Claims 1, 2, 5-7 are obvious over Turner in view of Shaw.

  • Prior Art Relied Upon: Turner (Nigel Turner et al., Berberine and Its More Biologically Available Derivative Dihydroberberine..., Diabetes, May 2008) and Shaw (Shannon Reagan-Shaw et al., Dose translation from animal to human studies revisited, The FASEB Journal, Mar. 2007).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Turner disclosed that dhBBR is effective for managing glucose tolerance in rodents at a dosage of 100 mg/kg/day. Turner further opined that dhBBR was an "attractive potential therapy" for type 2 diabetes in humans. Shaw taught a well-established, FDA-recommended method for translating drug dosages from animal studies to a Human Equivalent Dose (HED) using a Body Surface Area (BSA) normalization formula. Petitioner contended that applying the standard BSA conversion taught by Shaw to the effective rodent dose disclosed in Turner would yield a human dose of approximately 486 mg/day (for a 60kg person), which falls squarely within the ’961 patent’s claimed range of 25-800 mg. For dependent claim 2, Petitioner asserted that Turner's glucose tolerance test data shows dhBBR keeps blood glucose levels closer to fasting levels than berberine (BBR), meeting the claim limitation.
    • Motivation to Combine: A person of ordinary skill in the art (POSA) would have been motivated to confirm the therapeutic potential of dhBBR in humans after Turner demonstrated its efficacy in a standard animal model for diabetes. To do so, a POSA would have naturally turned to a standard, well-known, and widely accepted method like the BSA conversion taught by Shaw to determine an appropriate and safe starting dose for human clinical trials.
    • Expectation of Success: Petitioner asserted a POSA would have had a reasonable expectation of success. The animal model used in Turner (high-fat diet-induced obese mice) is a common and predictive model for human type 2 diabetes, and the BSA dose conversion method from Shaw is a validated, routine practice in pharmaceutical development, even recommended by FDA guidance.

Ground 2: Obviousness over Zhang in view of Feng - Claims 1, 2, 5, and 7 are obvious over Zhang in view of Feng.

  • Prior Art Relied Upon: Zhang (Yifei Zhang et al., Treatment of Type 2 Diabetes and Dyslipidemia with the Natural Plant Alkaloid Berberine, J. Clin Endocrinol Metab, Jul. 2008) and Feng (Ru Feng et al., Transforming berberine into its intestine-absorbable form..., Nature Scientific Reports, Jul. 2015).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Zhang established that BBR was safe and effective for treating type 2 diabetes in humans at a dose of 1,000 mg/day. However, the prior art, including Feng, recognized that BBR suffered from poor bioavailability. Feng specifically taught that dhBBR is a more absorbable form of BBR, identifying it as a "transient form of BBR in the intestinal lumen" with an intestinal absorption rate that is 5-fold to 12-fold higher than BBR. Petitioner argued that a POSA, starting with Zhang's known effective human dose of BBR, would have been motivated to use the more bioavailable dhBBR taught by Feng to achieve the same therapeutic effect at a lower dose. A 5-fold reduction of Zhang's 1,000 mg/day dose would result in a 200 mg/day dose of dhBBR, and a 12-fold reduction would result in an 83.3 mg/day dose. Both of these calculated, predictable dosages fall within the claimed range of 25-800 mg.
    • Motivation to Combine: A POSA would have been motivated to find a more bioavailable derivative of BBR to overcome the known disadvantages of the high 1,000 mg/day dose taught by Zhang (e.g., side effects, cost, patient compliance). Feng provided the clear solution by identifying dhBBR as a derivative with significantly improved absorption, making it an obvious candidate to substitute for BBR at a reduced dosage.
    • Expectation of Success: A POSA would have had a reasonable expectation of success because Feng provided strong in vivo and in vitro evidence confirming dhBBR's superior absorption. Since Feng and Turner also taught that dhBBR acts as a pro-drug that rapidly converts back to BBR after absorption, a POSA would expect it to have the same therapeutic effect as BBR, but at a predictably lower dose corresponding to its increased bioavailability.
  • Additional Grounds: Petitioner asserted additional obviousness challenges, including that claim 5 (capsule/tablet) is obvious over Turner/Shaw/Zhang, and claim 6 (food/beverage product) is obvious over Zhang/Feng/Turner. These grounds relied on the same core logic as the primary grounds, adding references to show that formulating BBR and its derivatives in tablet or food product forms was well-known and obvious.

4. Key Claim Construction Positions

  • The petition argued that the claim term "reduces fasting glucose levels" from claim 2 should be interpreted in light of the patent's specification. The only supporting disclosure is an observation from a glucose challenge test that dhBBR "may keep blood glucose levels closer to fasting blood glucose than berberine." Therefore, Petitioner contended the claim limitation would be met if a prior art reference demonstrates, via a glucose tolerance test, that dhBBR administration results in blood glucose levels that are closer to fasting levels than those resulting from BBR administration.

5. Relief Requested

  • Petitioner requests the institution of an inter partes review and cancellation of claims 1, 2, and 5-7 of the ’961 patent as unpatentable.