Obviousness

The obviousness analysis under 35 U.S.C. § 103 requires determining whether the differences between the claimed invention and the prior art would have made the invention as a whole obvious to a person having ordinary skill in the art (POSITA) before the effective filing date. The patent specifies a prior art date of June 14, 2019.

Prior Art Context from the Patent Itself:

The patent US11878049B1, in its "Definitions" and "Non-clinical studies" sections, provides critical information that is pertinent to the state of the art before the filing date. Specifically, it states:

• "Non-clinical studies described in Example 1 show that the PKR activator, mitapivat, is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) or 3A5 (CYP3A5) enzymes (i.e., >90%), with minor contributions from other detoxification enzymes, namely CYP2C8, CYP2C9, and CYP1A2."
• "It has also been found that in a clinical trial, total exposure of mitapivat increased in the presence of itraconazole, a strong CYP3A4A and p-gp inhibitor, compared with dosing of mitapivat sulfate alone."
• "It has further been found that total exposure of mitapivat decreased in the presence of rifampin, a strong CYP3A4A and p-gp inducer, compared with dosing of mitapivat sulfate alone."

For the purpose of this obviousness analysis, we assume that these findings—mitapivat's primary metabolism by CYP3A4/5 and its significant pharmacokinetic interactions with known strong CYP3A4/5 modulators (itraconazole and rifampin, with itraconazole also being a p-gp inhibitor)—were publicly known or readily ascertainable by a POSITA prior to the priority date of June 14, 2019, as the patent presents them as established facts underlying the disclosed methods. A POSITA in this field would typically be a pharmacologist, physician, or drug development scientist familiar with pharmacokinetics and drug-drug interactions.

General Motivation for Combining Prior Art:

It is a routine and well-understood principle in drug development and clinical practice that when a drug's metabolism and elimination pathways are identified (e.g., via CYP450 enzymes and efflux transporters like p-gp), its pharmacokinetic profile can be significantly altered by co-administered drugs that induce or inhibit these pathways. The primary motivation for a POSITA to combine a drug like mitapivat with CYP3A4/5 or p-gp modulators (or administer it in their absence) would be to:

1. Optimize Therapeutic Efficacy: Ensure the drug reaches and maintains therapeutic concentrations.
2. Enhance Patient Safety: Prevent sub-therapeutic drug levels (leading to lack of efficacy) or supra-therapeutic/toxic levels (leading to adverse events).
3. Manage Concomitant Medications: Adjust dosing when patients require co-administration with other essential drugs that happen to be CYP3A4/5 or p-gp modulators.

Obviousness Analysis of Independent Claims:

The independent claims of US11878049B1 generally fall into two categories: (a) methods of treating specified diseases (PKD, sickle cell disease, thalassemia) with mitapivat in combination with a CYP3A4/5 modulator or p-gp inhibitor, and (b) methods of treating these diseases with mitapivat in the absence of such modulators/inhibitors.

1. Claims Involving Co-administration with CYP3A4/5 Inducers (e.g., Claims 1, 43, 65):

• Claim 1: A method of treating pyruvate kinase deficiency (PKD) in a subject, comprising administering an effective amount of mitapivat or a pharmaceutically acceptable salt thereof and an effective amount of an inducer of cytochrome P450 3A4/5 (CYP3A4/5).
• Obviousness Argument: Given the assumed prior knowledge that mitapivat is primarily metabolized by CYP3A4/5 and that strong CYP3A4/5 inducers (like rifampin, as mentioned in the patent) decrease mitapivat exposure, a POSITA would recognize the potential for a drug-drug interaction. If a patient receiving mitapivat for PKD (or sickle cell disease, Claim 43; or thalassemia, Claim 65, as PKR activators like mitapivat are known/intended for these conditions) also required treatment with a CYP3A4/5 inducer, a POSITA would be motivated to co-administer these drugs. The specific dosage adjustments (e.g., increasing mitapivat dose) would be a routine clinical decision aimed at counteracting the increased metabolism and maintaining therapeutic mitapivat levels. Therefore, the combination, or the administration of mitapivat in the presence of an inducer with appropriate management, would be obvious.

2. Claims Involving Co-administration with CYP3A4/5 Inhibitors (e.g., Claims 22, 54, 80):

• Claim 22: A method of treating PKD in a subject, comprising administering an effective amount of mitapivat or a pharmaceutically acceptable salt thereof and an effective amount of an inhibitor of cytochrome P450 3A4/5 (CYP3A4/5).
• Obviousness Argument: Similarly, with the assumed prior knowledge that mitapivat is primarily metabolized by CYP3A4/5 and that strong CYP3A4/5 inhibitors (like itraconazole, as mentioned in the patent) increase mitapivat exposure, a POSITA would anticipate a drug-drug interaction. If a patient being treated with mitapivat for PKD (or sickle cell disease, Claim 54; or thalassemia, Claim 80) also required a CYP3A4/5 inhibitor, a POSITA would be motivated to co-administer the drugs, likely reducing the mitapivat dose to prevent potential toxicity from increased exposure. The idea of combining a CYP3A4/5 substrate with a CYP3A4/5 inhibitor and adjusting doses is a standard pharmacological practice, thus rendering such claims obvious.

3. Claims Involving Co-administration with p-glycoprotein (p-gp) Inhibitors (e.g., Claims 95, 108, 117):

• Claim 95: A method of treating PKD in a subject, comprising administering an effective amount of mitapivat or a pharmaceutically acceptable salt thereof and an effective amount of a p-glycoprotein inhibitor.
• Obviousness Argument: The patent's mention of itraconazole as both a "strong CYP3A4A and p-gp inhibitor" that "increased total exposure of mitapivat" directly highlights the role of p-gp in mitapivat's pharmacokinetics. A POSITA familiar with drug transporters would understand that p-gp inhibition can increase the bioavailability and exposure of substrate drugs. Therefore, co-administering mitapivat for PKD (or sickle cell disease, Claim 108; or thalassemia, Claim 117) with a p-gp inhibitor to potentially increase mitapivat exposure (or adjusting doses if the patient is already on a p-gp inhibitor) would be an obvious strategy for managing drug levels, especially when seeking to enhance efficacy or reduce required mitapivat dosage.

4. Claims Involving Administration in the Absence of Modulators (e.g., Claims 16, 37, 50, 61, 74, 89, 102, 113, 124):

• Claim 16: A method of treating pyruvate kinase deficiency (PKD) in a subject, comprising administering to the subject an effective amount of mitapivat or a pharmaceutically acceptable salt thereof in the absence of an inducer of cytochrome P450 3A4/5 (CYP3A4/5).
• Obviousness Argument: Conversely, given the known potential for significant DDIs with CYP3A4/5 modulators and p-gp inhibitors, a POSITA would routinely consider administering mitapivat for PKD (or sickle cell disease, Claims 50, 61, 113; or thalassemia, Claims 74, 89, 124) in the absence of such modulators or ensuring adequate washout periods if they were previously administered. This approach simplifies dosing, minimizes the risk of unpredictable drug levels, and reduces the likelihood of adverse events. Avoiding known drug interactions is a fundamental principle in clinical medicine, making such a method an obvious choice for a POSITA seeking to provide safe and effective therapy.

Conclusion:

Based on the internal disclosures of US11878049B1 regarding mitapivat's metabolism and drug interaction profile, combined with the general knowledge of a person having ordinary skill in the art in pharmacology and clinical practice prior to June 14, 2019, the methods claimed in the patent would likely be considered obvious. The motivation for combining mitapivat with CYP3A4/5 or p-gp modulators (or administering it in their absence) for treating PKD, sickle cell disease, or thalassemia would be the routine clinical practice of managing drug-drug interactions to ensure optimal therapeutic outcomes and patient safety.