Obviousness

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 8,664,239

This analysis assesses whether the claimed invention of US Patent 8,664,239 would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time of the invention (priority date 2007-05-30), considering combinations of the identified prior art. A PHOSITA in this field would be a pharmaceutical formulator or pharmacologist with experience in developing controlled-release drug delivery systems, particularly for immunosuppressants or drugs with narrow therapeutic windows and complex absorption profiles.

1. Obviousness of Claim 1 (Dissolution Profile)

Claim 1: A method for immunosuppressive treatment of a patient in need thereof comprising administering a once daily extended release oral dosage form comprising tacrolimus or a pharmaceutically active analogue thereof, wherein the dosage form releases the active substance over an extended period of time defined by a release of at the most 63.5% of the content of the active substance at the 12 hours time point defined by in vitro dissolution and when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.

Combination of Prior Art: WO99/49863 (Fujisawa Pharmaceutical Co.) in view of general knowledge in pharmaceutical formulation for once-daily dosing.

• WO99/49863's Disclosure: WO99/49863 explicitly describes sustained-release tacrolimus formulations characterized by a T63.2% value (time for dissolving 63.2% of tacrolimus) between 0.7 and 15 hours. While it notes that the most preferred embodiment has a T63.6 value of 2-5 hours, and examples range from 1.9 to 8.2 hours, the broad range of 0.7 to 15 hours for 63.2% release demonstrates that sustained release over a longer period was already contemplated.
• Motivation for Combination/Modification: A PHOSITA would be motivated to develop once-daily tacrolimus formulations to enhance patient compliance and convenience, thereby mitigating issues related to missed doses and variable drug concentrations. [cite: "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily without risk of lack of clinical effect due to low doses in the last past of the dosing interval.", "a further advantage of an extended-release-dosage-form invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to traditional oral treatment."] Given that WO99/49863 already teaches sustained-release tacrolimus, and its disclosed T63.2% range extends up to 15 hours, a PHOSITA would find it obvious to modify the release rate of these formulations to achieve an even more prolonged effect suitable for 24-hour dosing. Techniques for extending drug release, such as adjusting the concentration of rate-controlling excipients (e.g., polymers like hydroxypropylcellulose, which is explicitly mentioned in the patent classification A61K9/1652 and A61K9/2054, and the dissolution method of Claim 1), or modifying the matrix composition, are well-known and routinely applied in pharmaceutical formulation. [cite: "the desired release profile of the pharmaceutical composition may be provided by combining one or more of the following possibilities.", "the release may also be pH independent, e.g., by providing the composition with a controlled release coating such as, e.g. a cellulose based coating like e.g. ethylcellulose or by providing the composition in the form of a matrix composition such as, e.g., a hydrophilic cellulose polymer matrix type e.g. based on HPMC."] Achieving a dissolution profile of "at most 63.5% at the 12 hours time point" would be a predictable outcome of such routine optimization aimed at once-daily administration. The specific in vitro dissolution conditions described in Claim 1 are standard testing methodologies and do not introduce non-obviousness.

2. Obviousness of Claim 11 (Pharmacokinetic Profile)

Claim 11: A method for immunosuppressive treatment of a patient in need thereof comprising administering a once daily extended release oral dosage form comprising tacrolimus or a pharmaceutically active analogue thereof, wherein upon oral administration of a single 5 mg dose of the oral dosage form in fasted state to at least 6 healthy subjects, the mean maximal concentration (C max ) of tacrolimus in blood is at the most 15 ng/mL and the mean AUC(0-96 h) of tacrolimus in blood is at least 45 ng·h/L.

Combination of Prior Art: WO99/49863 (sustained release tacrolimus, improved bioavailability, suppressed variability) + WO 2005/020993 (improved bioavailability of tacrolimus formulations) + WO 2005/020994 (solid dispersions of tacrolimus) + general pharmacokinetic principles for controlled release drugs.

• Prior Art Disclosures:
  • WO99/49863: Teaches sustained-release tacrolimus formulations designed to achieve "improved bioavailability" and "suppressed variation of its absorbability."
  • WO 2005/020993 and WO 2005/020994: These references, by the same inventors, underscore the importance of improved bioavailability for tacrolimus. WO 2005/020994 specifically discusses solid dispersions as a means to enhance bioavailability, and the present patent acknowledges that solid dispersions "will contribute to a predictable and constant in vivo release of tacrolimus." [cite: "Inventors of the present application have in the patent application WO 2005/020993 also tested different formulations of tacrolimus in Beagle dogs and minipigs, however demonstrating that both a fast release tablet (Example 18) and a slow release tablet (Example 19) can result in improved bioavailability compared with Prograf®. This indicates that an improved bioavailability could be linked to having tacrolimus in a dissolved state in the dosage form which also appears from WO 2005/020994 by the same inventors relating to solid dispersions comprising tacrolimus.", "a smaller particle size in micro and nano scale and preferable a molecular solution will contribute to a predictable and constant in vivo release of tacrolimus."]
  • General Pharmacokinetic Principles: For drugs like tacrolimus, which exhibit a narrow therapeutic window and significant Cmax-related toxicities (e.g., nephro- and neuro-toxicity, GI side effects), achieving a lower Cmax while maintaining adequate overall exposure (AUC) for a once-daily regimen is a recognized and highly desirable objective in controlled-release drug design. [cite: "Tacrolimus is known to induce significant side effects, of nephro- or neuro-toxic origin, as well as GI side-effects and others.", "the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e., the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed.", "the compositions provide a significant reduction in side effects, especially side effect related to a high peak concentration (such as, e.g., nephro- and neuro-toxicity, diarrhea, constipation, abdominal pain, nausea etc) and provide for an extended release of tacrolimus leading to a better therapy."]
• Motivation for Combination/Modification: A PHOSITA would be motivated to combine sustained-release approaches (WO99/49863) with bioavailability-enhancing techniques (WO 2005/020993, WO 2005/020994) to develop a tacrolimus formulation optimized for once-daily administration. The expectation of "improved bioavailability" and "suppressed variation" from WO99/49863, combined with the goal of reducing peak concentrations to minimize side effects, would lead a PHOSITA to anticipate a pharmacokinetic profile characterized by a lower Cmax and a stable or improved AUC. [cite: 4, "the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e., the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed."] The specific numerical values for Cmax (≤15 ng/mL) and AUC(0-96 h) (≥45 ng·h/L) in Claim 11, while quantitative, represent the successful optimization of expected benefits when applying these known principles to tacrolimus for once-daily extended release, rather than an unexpected result. The patent itself highlights that such "reduced peak concentration is also observed" and that "enhanced bioavailability may also result in a more reproducible (i.e., less variable compared to that of Prograf®) release profile." [cite: "the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e., the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed.", "enhanced bioavailability may also result in a more reproducible (i.e., less variable compared to that of Prograf®) release profile."]

3. Obviousness of Claim 18 (Conversion Method)

Claim 18: A method for converting a patient undergoing immunosuppressive treatment from a twice daily immediate release oral tacrolimus regimen to a once daily extended release oral tacrolimus regimen, wherein the total daily dose of tacrolimus administered in the once daily extended release oral tacrolimus regimen is reduced by from 20% to 34% compared to the total daily dose of tacrolimus administered in the twice daily immediate release tacrolimus regimen.

Combination of Prior Art: Knowledge of Prograf® (conventional immediate-release tacrolimus) + WO99/49863 (sustained release tacrolimus with improved bioavailability) / WO 2005/020993 (improved bioavailability tacrolimus formulations) + general clinical and pharmacokinetic principles of dose adjustment.

• Prior Art Disclosures:
  • Prograf®: Represents the widely used immediate-release tacrolimus, administered twice daily with known absorption variability, for which blood levels are routinely monitored. [cite: "Tacrolimus (Prograf®) was approved by the FDA in April of 1994 under NDA No.", "Prograf® is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants.", "Tacrolimus administered as Prograf® capsules, exhibits a large inter- and intra-individual variability of its absorption and metabolism. Because of this variability, standard dosing is not an accurate predictor of concentration. In clinical use, tacrolimus dose-adjustments are frequently required based on monitoring of tacrolimus trough blood concentrations."]
  • WO99/49863 and WO 2005/020993: These references teach the development of sustained-release tacrolimus formulations that provide improved bioavailability compared to conventional forms. The present patent itself asserts that its extended-release formulation offers "an increased bioavailability." [cite: 4, "Inventors of the present application have in the patent application WO 2005/020993 also tested different formulations of tacrolimus in Beagle dogs and minipigs, however demonstrating that both a fast release tablet (Example 18) and a slow release tablet (Example 19) can result in improved bioavailability compared with Prograf®.", "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily without risk of lack of clinical effect due to low doses in the last past of the dosing interval."]
  • General Clinical/Pharmacokinetic Principles: It is a fundamental and routine clinical practice for a PHOSITA (e.g., a physician or clinical pharmacologist) to adjust the dose of a drug when converting a patient from one formulation to another, especially if the new formulation exhibits altered bioavailability. The objective is to maintain equivalent therapeutic exposure (AUC) to ensure consistent efficacy and minimize potential toxicity. Given that tacrolimus requires careful blood level monitoring, dose adjustments are a standard part of patient management. [cite: "In clinical use, tacrolimus dose-adjustments are frequently required based on monitoring of tacrolimus trough blood concentrations.", "two compositions are regarded as bioequivalent if the value of the parameter used is within 80-125% of that of Prograf® or a similar commercially available tacrolimus-containing product used in the test."]
• Motivation for Combination/Modification: A PHOSITA would be highly motivated to transition patients from a twice-daily immediate-release tacrolimus regimen (e.g., Prograf®) to a more convenient once-daily extended-release regimen to improve patient adherence. [cite: "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily without risk of lack of clinical effect due to low doses in the last past of the dosing interval.", "the pharmaceutical compositions according to the invention provide significant higher bioavailability of tacrolimus, which may reduce the number of daily administered dosage units, and reduce or abolish the need for administration in connection with food intake, which provide for a higher degree of freedom for the recipient of the pharmaceutical compositions, and consequently the patients acceptance and/or compliance may be significantly improved."] Since the extended-release formulations are designed to offer "increased bioavailability," it would be a straightforward and obvious pharmacokinetic calculation to reduce the daily dose of the more bioavailable extended-release formulation to achieve systemic exposure comparable to the previous regimen. The specific dose reduction range of 20% to 34% (equivalent to administering 66% to 80% of the original dose) is an empirical adjustment that would directly stem from observed bioavailability differences in clinical trials. The patent itself explicitly supports this, stating that "a similar bioavailability and an improved profile after administration in a dose that is at the about most about 85% w/w such as, e.g., at the most about 80% w/w, at the most about 75%, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of tacrolimus administered in the form of Prograf®." [cite: "a similar bioavailability and an improved profile after administration in a dose is that is at the about most about 85% w/w such as, e.g., at the most about 80% w/w, at the most about 75%, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of tacrolimus administered in the form of Prograf® or a similar commercially available tacrolimus-containing product or as a commercial available extended release product including Advagraf®."] It further notes, "One method for such conversion from inter alia Prograf® to once daily regimen is decreasing the daily dosage of the tacrolimus immediate release regimen with between 25% to 50%, such as with between 30% to 40%, preferable with approximately 33%." [cite: "One method for such conversion from inter alia Prograf® to once daily regimen is decreasing the daily dosage of the tacrolimus immediate release regimen with between 25% to 50%, such as with between 30% to 40%, preferable with approximately 33%."] This explicit description within the patent demonstrates that such a dose reduction for conversion was an expected and logical consequence of the improved formulation's characteristics, thus making the claimed method obvious to a PHOSITA.