Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Claims
Claims 92-93, 95-99, 105-122 are pending in the application and are the subject of this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 17 February 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 92-93, 95-99, 105-122 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass a genus of biomarkers and capture objects that associate with those biomarkers: “the biomarker is one for which a concentration of the biomarker becomes elevated in subjects only in association with neuronal damage and/or neuronal death” (claim 92); “providing a plurality of capture objects, at least some of which are associated with at least one molecule of the biomarker from the sample” (claims 92 and 122). However, the disclosure fails to demonstrate possession of all biomarkers and all capture objects having the claimed function.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include (1) Actual reduction to practice (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
The claimed invention (claim 92) is directed to a method of detection and quantification of a biomarker, wherein the biomarker is one for which a concentration of the biomarker becomes elevated in subjects only in association with neuronal damage and/or neuronal death. Thus, the claims encompass a genus of biomarkers that are defined by their association with neuronal damage and/or neuronal death, and which experience a specific change (i.e. elevation) in concentration only in association with neuronal damage and/or neuronal death. The claims (92 and 122) further recite a capture object that associates with the biomarkers from the sample, such that the claims also encompass any species of capture object which is capable of associating with any of the recited biomarkers in any way.
It is noted that this limitation regarding the claimed genus of biomarkers does not explicitly appear in the specification. The closest literal support for this limitation appears to be instant specification pg. 11, Par. 3: “as described herein, the biomarker generally undergoes a change in concentration as a result of hypoxic even. For example, the concentration of the biomarker may increase or decrease as a result of the brain injury”. Additionally, the disclosure also recites specific species of biomarkers which may be detected (see, e.g. specification Pg. 11), and provides reduction to practice for detection of tau protein.
However, this disclosure is not sufficient to support or prove possession of the entire genus of biomarkers as claimed. Neither the claims nor the specification indicate sufficient relevant identifying characteristics of the members of the genus. No specific structural or physical requirements for the claimed biomarkers are disclosed, rather they are claimed only by a specific causal and functional relationship with a particular pathology (i.e. becoming elevated only in association with neuronal damage and/or neuronal death). From the disclosure it is not clear how one of ordinary skill in the art would be able to envision what species of biomarkers do or do not fall within the recited genus without both testing each and every biomarker for specific elevation in association with neuronal damage and/or neuronal death, and also ruling out elevation of each biomarker in association with any other cause outside of neuronal damage and/or neuronal death. It is not clear how one of ordinary skill in the art would definitively determine that a given biomarker is elevated only in association with neuronal damage and/or neuronal death, and the instant disclosure does not provide evidence or guidance for making this determination.
Claim 122 is more specific and more limited regarding the species of biomarker encompassed by the claim, but is noted to still encompass some genus of biomarkers which are claimed by a particular function rather than by a specific species name or structural identity (i.e. beta amyloid precursor proteins) and the structural requirements of this genus are not particularly defined in either the claims or the specification.
Lack of description of the biomarkers themselves further contributes to lack of description of the recited capture objects. The claims provide no required structure of the capture objects, rather they are defined only by their functional ability to associate with the biomarker in any way, wherein the type of association is not limited. The specification provides limited description and reduction to practice of the structural features of a capture object that may facilitate the recited function. (Specification, Pg. 24-25: capture objects (e.g. beads) that each include a binding surface having affinity for at least one type of biomarker. For example, the capture objects may comprise a plurality of beads comprising a plurality of capture components (e.g. an antibody having specific affinity for a biomarker of interest); the specification further provides reduction to practice wherein the biomarker tau becomes associated with the capture objects via an antibody that specifically binds to tau, see, e.g. Pg. 47). As such, the specification provides discussion and reduction to practice of a single species of capture object that fulfills the recited function in the claim (i.e. an anti-biomarker antibody conjugated to a bead), however, the disclosure of a singular species is not sufficiently representative of a very broad genus of “capture objects” which may associate in any way with a broad genus of biomarkers. The description provided in the disclosure does not make it clear what physical features or structural properties are common to members of the recited genus of capture objects such that one of ordinary skill in the art could visualize or recognize all species that fall within the recited genus.
Predictability in the art is low. The determination of specific biomarkers associated with neuronal damage and/or death is an active and evolving area of research, such that one of ordinary skill in the art would not have envisioned that the inventors could recognize or have possession of all species of biomarkers encompassed by this genus at the time of filing. See, for example Avagyan et al (Immune blood biomarkers of Alzheimer disease patients. Journal of Immunology. Vol. 210. ISSN 1-2. 29 May 2009); Gresle et al (Neurofilament proteins as body fluid biomarkers of neurodegeneration in multiple sclerosis. Mult Scler Int. 2011;2011:315406.); and Spitzer et al (cNEUPRO: Novel Biomarkers for Neurodegenerative Diseases. Int J Alzheimers Dis. 2010 Sep 19;2010:548145.).
Additionally, predictability is low because the prior art does not provide guidance as to how one of ordinary skill in the art would be able to definitively exclude every other cause of potential elevation of a given biomarker. For example, research that shows that elevation of a particular biomarker is correlated with or even caused by neuronal damage and/or neuronal death does not necessarily exclude the possibility that the biomarker may also be elevated in association with other causes, especially because the particular relationship required by the phrasing “associated with” is vague and broad.
Additionally, the phrasing “associated with” in the recitation of capture objects is broad such that the predictability in the art regarding members of this genus is low. The specification provides examples of capture objects comprising anti-biomarker antibodies that associate with a biomarker through specific binding, but does not provide examples or description of any other type of capture object that associates with a biomarker in any other way. There are numerous ways in which a “capture object” could be understood to associate with a biomarker. For example, association could be broadly interpreted to include specific binding, electrostatic interactions, van der waals interactions, covalent bonding, non-covalent bonding, and each type of association can result from a variety of different structural features or physical properties of a capture object, such that the requirements of such a capture object are broad and unpredictable. While the art is generally predictable in indicating that there are known antibodies for binding particular known species of biomarkers, the art is not predictable regarding the structural features common to a broad genus of capture objects that can associate with a broad genus of biomarkers in any way.
As such, the information provided in the instant disclosure and the prior art does not allow one of ordinary skill in the art to visualize and recognize all members of the genus of biomarkers encompassed by the instant claims.
For all these reasons, the specification fails to provide adequate written description for the genus of the claim and does not reasonably convey to one skilled in the relevant art the that inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 92-93, 95-99, 105-121 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claim 92 recites: “the biomarker is one for which a concentration of the biomarker becomes elevated in subjects only in association with neuronal damage and/or neuronal death”. This is rejected as indefinite because the relationship required by the phrasing “in association with” is vague and unclear, such that the relationship between biomarker elevation and neuronal damage and/or death required to meet the limitation is unclear, and also the relationship between any other criteria or condition and biomarker elevation which would exclude a biomarker from falling within the recited genus is unclear.
Dependent claims 93, 95-99, 105-121 are rejected as indefinite because they depend from an indefinite claim and fail to remedy its deficiencies.
Allowable Subject Matter
Claims 92-93, 95-99, 105-122 are rejected as described above, but contain subject matter which is free of the prior art.
Regarding the independent claims 92 and 122, the closest prior art is Aizawa et al (US 2009/0068639 A1; previously cited) in view of Bitsch et al (Serum tau protein level as a marker of axonal damage in acute ischemic stroke. Eur Neurol. 2002;47(1):45-51; previously cited) and Noguchi-Shinohara et al (Serum tau protein as a marker for the diagnosis of Creutzfeldt-Jakob disease. J Neurol 258, 1464–1468 (2011).).
Aizawa teaches:
A method for determining the measure of a concentration of a biomarker in a volume of bodily fluid obtained from a subject (Abstract: quantitative determination of a biomarker in a sample; Par. 289: sample may be a fluid sample obtained from a subject such as blood serum; Table 6), the method comprising:
Performing an assay on a sample containing or derived from the volume of bodily fluid (Abstract; Example 1: assay performed on blood serum samples) wherein:
The volume of bodily fluid contains or is suspected of containing the biomarker (Table 6 shows exemplary method performed on samples containing the biomarker);
The volume of bodily fluid comprising blood or a blood component (Table 6; Par. 289: assay performed on blood serum samples); and
Providing a plurality of capture objects, at least some of which are associated with at least one molecule of the biomarker from the sample (Abstract; Par. 13: fluorescent silica particles modified with a substance capable of specifically adsorbing or binding to the target biomolecule; Par. 273-277: silica beads modified with specific binding substance mixed with sample, such that the specific binding substance binds the target biomolecule);
Passing at least some of the capture objects associated with at least one molecule of the biomarker from the sample by a detection system (Abstract; Par. 278: measurement by flow cytometry (wherein it is understood that in the process of flow cytometry, the capture objects associated with the biomarker are passed by a detector));
Individually interrogating, during the passing step, the at least some of the capture objects passed by the detection system: though not explicitly stated in Aizawa, the process of flow cytometry is understood to include individual interrogation of the capture objects as they pass by the detector in single file, as evidenced by Chandler et al (US 2005/0118574 A1; previously cited) (See Chandler, Par. 8: flow cytometry hydrodynamically focuses a fluid suspension of particles into a thin stream so that the particles flow down the stream in substantially single filed and pass through an examination zone); and
Processing the detected signal to determine a measure of the biomarker concentration in the volume of bodily fluid based at least in part on the interrogating step (Abstract: quantitative determination of biomolecule by flow cytometry; Table 6).
Aizawa differs from the instant claim in that it does not explicitly teach that the biomarker is one for which a concentration of the biomarker becomes elevated in subjects only in association with neuronal damage and/or neuronal death. Aizawa teaches broadly that the target biomolecule may be a number of different proteins and biomolecules which are not particularly limited (Par. 230).
Both Noguchi-Shinohara and Bitsch disclose the detection of tau protein in serum samples (see Abstract of each reference).
Noguchi-Shinohara discloses measurement of serum tau protein as a marker of CJD, wherein serum tau is elevated in patients with CJD as compared to patients with AD, patients with non-CJD-RPD, and healthy controls (Abstract; Fig. 1).
Bitsch discloses measurement of tau protein in serum samples as a marker of axonal injury and teaches that serum tau levels after stroke are correlated with infarct volume and disability after 3 months (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the detection method disclosed by Aizawa for the detection and quantification of tau protein in a blood or blood component sample. One of ordinary skill in the art would be motivated to make this modification because both Bitsch and Noguchi-Shinohara teach that quantification of tau protein in the blood is a useful biomarker of neuronal damage associated with particular pathologies. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Aizawa discloses a method which can be used to detect protein biomarkers in blood samples, and Noguchi-Shinohara and Bitsch both disclose detection of tau protein in blood samples.
Aizawa in view of Bitsch and Nogushi-Shinohara differs from the instant claims in that it does not teach that the limit of quantification of the biomarker in the assay is less than about 0.2 pg/mL.
Aizawa does not explicitly teach a lower limit of detection, however the reduction to practice provided in Example 1 (Par. 260-291) gives some insight into the lower limits of detection of the assay when used to measure exemplary cytokines. Par. 273 indicates that standard samples are prepared from a stock solution containing 5 ug/mL of target analyte which is diluted at intervals from 0x to 256x to create nine standard samples (i.e. such that the most concentrated standard sample has a concentration of 5 ug/mL, and the most dilute standard sample has a concentration of about 0.02 ug/mL. Discussion of the example indicates that an exemplary standard curve for IL-2 produced using this method is displayed in Fig. 4.
It is noted that there appears to be some disagreement in the units described in Par. 273 and those displayed in Fig. 4. That is, a 5 ug/mL sample diluted 1/256 would yield a diluted standard concentration of about 0.02 ug/mL, while Fig. 4 indicates that the most diluted standard has a concentration of about 0.02 ng/mL, which would reflect a starting standard concentration of 5 ng/mL rather than 5 ug/mL. As such, it is unclear whether the stock standard solution should be correctly interpreted to have a concentration of 5ug/mL or 5 ng/mL. Since the majority of the data appears to indicate a starting concentration of 5 ng/mL (as reflected in Fig. 4 and Table 6), the stock standard solution is interpreted herein to have a starting concentration of 5 ng/mL rather than 5 ug/mL.
However, even assuming this lower starting concentration, the evidence provided in Aizawa does not indicate that the assay has a reliable limit of detection of .02 pg/mL or lower. Fig. 4 indicates that the lowest concentration standard (other than the blank sample) has a target analyte concentration of 0.02 ng/mL, which is two orders of magnitude higher than the limit of detection recited in the instant claim. Additionally, the data provided in Fig. 4 indicates a roughly linear detection range between 0.02 ng/mL and 5 ng/mL, but this linear relationship is not maintained for concentration below 0.02 ng/mL. As such, although the data provided in Table 6 indicates that the average concentration of some measured analytes is below 0.2 pg/mL, this average of multiple measurements is not a strong indication of a limit of detection below 0.2 pg/mL, given that no specific limit of detection is disclosed, and measurement of concentrations below the most diluted standard sample are not necessarily assumed to be reliable given the data provided in Fig. 4 which indicates a nonlinear detection response at concentrations lower than 0.02 ng/mL, indicating that concentrations below this threshold likely fall below the reliable limit of detection of the assay.
As such, the weight of the evidence provided in the reference does not appear to indicate that one would reasonably expect to be able to measure a neuronal biomarker such as tau using the assay disclosed by Aizawa and achieve a limit of detection at or below 0.2 pg/mL, as required by the instant claim.
Goix et al (US 2010/0329929 A1) is also noted as close prior art, however Goix fails to meet the instant claims because it requires elution of the label from the target biomarker prior to detection of the label, such that it fails to read on the instant claims which require “passing at least some of the capture objects associated with at least one molecule of the biomarker from the sample by a detection system”.
Response to Arguments
Applicant’s arguments filed 17 February 2026 have been fully considered.
Applicant’s arguments regarding the previous double patenting and prior art rejections are persuasive in view of the amendments of the claims and the reasons discussed above, and the double patenting and prior art rejections are withdrawn.
Previous grounds of 112 first and second rejections are withdrawn in view of the amendments to the claims, and new grounds of rejection are presented above which address the amended claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLIS LUSI whose telephone number is (571)270-0694. The examiner can normally be reached M-Th 8am-6pm ET.
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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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