Obviousness

The obviousness of US patent 11275092 can be analyzed under 35 U.S.C. § 103 by combining the disclosures explicitly described as prior art within the patent's own background section. A person having ordinary skill in the art (POSA) in this field would be a medical professional or researcher focused on neurology, critical care, or clinical diagnostics, possessing knowledge of brain injuries, biomarkers, and immunoassay techniques.

The core of the invention in US11275092 relates to methods of determining a treatment protocol and/or prognosis for a patient's recovery from a brain injury, particularly resulting from a hypoxic event, by measuring tau protein concentration in blood, plasma, or serum using highly sensitive assays and correlating these measurements with patient outcomes.

Claims of US11275092 (exemplified by Claim 1):
Claim 1 states: "A method of determining a treatment protocol for and/or a prognosis of a patient's recovery from a brain injury, comprising: (a) performing an assay on a blood sample from the patient and/or plasma and/or serum derived from the blood sample to determine a measure of the concentration of tau protein in the sample; and (b) determining a prognosis of the patient's recovery from the brain injury and/or a method of treatment based at least in part on the measured concentration of tau protein present in the sample."

Dependent claims introduce further limitations, such as the brain injury resulting from a hypoxic event (Claim 2), specific limits of detection (LOD) for the assay (e.g., less than 0.2 pg/mL in Claim 3, less than 0.02 pg/mL in Claim 5), determining the area under the curve (AUC) of tau protein concentration versus time (Claim 7), and specific timeframes for sample collection (e.g., at least 48 hours in Claim 10).

Prior Art Concepts and Motivation for Combination:

The patent's "BACKGROUND OF THE INVENTION" section explicitly describes several aspects of the prior art, outlining existing knowledge and identifying problems that the invention purports to solve:

1. Known Use of Tau as a Brain Injury Biomarker: It was known that "Tau is known to be elevated in the cerebrospinal fluid (CSF) of patients with neurodegenerative disease and head injuries." A POSA would understand that tau protein serves as an indicator of neuronal damage.
2. Desirability of Blood Samples over CSF: The patent states that "it is advantageous to determine the level of a biomarker in the blood of a patient as compared to CSF, as blood sampling is generally less invasive and may result in fewer complications as compared to CSF sampling." This highlights a clear clinical motivation to shift from CSF to blood testing.
3. Technical Challenge of Measuring Tau in Blood: The prior art recognized that tau protein, when diffusing across the blood-brain barrier, exists in "extremely low concentrations that are not reliably measurable by typical conventional immunoassays" in blood.
4. Known Link Between Hypoxic Events and Biomarker Changes (including Tau): It was understood that "Hypoxic conditions can lead to the production and/or change in the concentration of certain biomarkers," and specifically, "a cascade of biomarkers, such as tau proteins, is generated in the brain in proportion to the extent of hypoxia."
5. Uncorrelated Biomarker Data for Hypoxic Events: Despite the known increase, "the increased concentration [of some biomarkers] has not been correlated with specific diagnostic indications and/or methods of treatment" for hypoxic events. However, the patent also acknowledges that "Correlations (e.g., between the concentration and prognostic indication(s) and/or between the concentration and method(s) of treatment) have been discovered and/or are now discoverable due to recent advancements in technology which allow for the determination of the low concentrations of biomarkers in bodily fluids with sufficient accuracy and precision, thus allowing for the variations in concentration to be statistically significant and therefore, diagnostic."

Obviousness Argument:

A POSA would have been motivated to combine these known elements and address the identified problems, rendering the claims of US11275092 obvious.

• Motivation to Combine 1, 2, and 3 (Tau in Blood with Sensitive Assays):
  A POSA, aware of tau protein's established role as a biomarker for head injuries and neurodegenerative diseases (Prior Art 1), would naturally seek to leverage this biomarker in a clinically more advantageous sample type, namely blood (Prior Art 2). The recognized problem that "typical conventional immunoassays" could not reliably measure the extremely low concentrations of tau in blood (Prior Art 3) would directly motivate the POSA to pursue or adapt more sensitive assay technologies. The patent itself notes that such "recent advancements in technology" made the determination of low concentrations possible with "sufficient accuracy and precision." Therefore, applying or developing a highly sensitive immunoassay to measure tau in a blood-derived sample for brain injury assessment would be an obvious endeavor to overcome a known technical limitation and achieve a desired clinical benefit. This combination would directly render Claim 1 obvious.

• Motivation to Combine 4 and 5 (Correlation for Hypoxic Events):
  Given the knowledge that tau protein concentrations change in response to hypoxic events (Prior Art 4), and the explicit acknowledgment that these changes "has not been correlated with specific diagnostic indications and/or methods of treatment" (Prior Art 5), a POSA would be strongly motivated to establish such correlations. Once the technical hurdle of sensitive tau measurement in blood (as discussed above) was overcome through available or developing technology, the next logical step would be to perform standard biomarker research: collect serial samples, measure biomarker concentrations, and statistically correlate these measurements (e.g., using parameters like AUC, as described in dependent claims) with patient prognoses and treatment responses. The patent's statement that these correlations were "now discoverable" due to technological advancements further underscores this as a logical and obvious research direction once sensitive measurement became feasible. This addresses the obviousness of claims pertaining to hypoxic events (e.g., Claim 2) and the establishment of correlations for prognosis and treatment (e.g., Claim 7-9, 17-20).

• Motivation for Specific Assay Sensitivity (e.g., Claims 3-6):
  The need for extremely low limits of detection and quantification is explicitly articulated as a requirement to overcome the problem of low tau concentrations in blood (Prior Art 3). The patent states that "assay methods which have very low limits of quantification (LOQ) and/or limits of detection (LOD) are generally necessary" for statistically significant results. The continuous drive in diagnostic assay development is to improve sensitivity for low-abundance analytes. Therefore, striving to achieve specific, improved LODs (e.g., < 0.2 pg/mL, < 0.05 pg/mL, < 0.02 pg/mL) and LOQs (e.g., < 0.04 pg/mL) for tau in blood would be an obvious developmental goal for a POSA, leveraging the "recent advancements in technology" mentioned in the patent.

In conclusion, the combination of the known utility of tau as a brain injury biomarker, the recognized advantages of blood sampling, the acknowledged problem of low tau concentrations in blood with conventional assays, and the contemporaneous availability of (or motivation to develop) ultra-sensitive assay technologies, along with the recognized need to correlate biomarker changes with clinical outcomes for hypoxic events, would render the claims of US11275092 obvious to a person having ordinary skill in the art at the time of the invention. The specific numerical values for sensitivity, time points for sampling, and AUC thresholds would represent routine optimization and validation studies once the core method was established.