DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Preliminary Amendments filed on June 18, 2024, has been received and entered.
Restriction Requirement
3. Applicant’s election of Group I (claims 1-14, 16 and 18-19) without traverse, on May 4, 2026, is acknowledged.
Claim Disposition
4. Claims 15 and 17 have been cancelled. Claims 1-14, 16 and 18-25 are pending. Claims 1-14, 16 and 18-19 are under examination. Claims 20-25 are withdrawn from further consideration pursuant to 37 CFR 1.12(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Information Disclosure Statement
5. The Information Disclosure Statements filed on June 9, 2026, March 12, 2026, December 8, 2025, September 9, 2025, June 5, 2025, March 4, 2025, December 26, 2024, September 5, 2024, June, 5, 2024 and May 8, 2024, have been received and entered. The references cited on the PTO-1449 Form have been considered by the examiner and a copy is attached to the instant Office action. Note that a few references have been lined through because of an improper date citation.
Specification Objection
6. The specification is objected to because of the following informalities:
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following is suggested: "Biomarkers for determining sustained or suspected subacute acquired brain injury (ABI)".
Claim Objection
7. Claims 1-14, 16 and 18-19 are objected to because of the following informalities:
For clarity and precision of claim language, it is suggested that claim 1 is amended to read “…(ABI), [[the method]] comprising:…”. For clarity it is suggested that claim 1 is amended to read, “…within, after or about twenty…..”; “…..if the [[subject’s]] subject…..”. The dependent claims are also included.
For clarity and consistency the acronyms should be spelled out in claim 3 (see, CT and TBI). See also claims 7 and 9.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of the first paragraph of 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.
8. Claims 1-14, 16 and 18-19 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and or use the invention.
The claimed invention is directed to a method for aiding in the diagnosis and evaluation of a subject that has sustained or may have sustained an acquired brain injury (ABI)……performing one or more assays on at least one or more samples obtained from a subject within after about twenty-four hours… to measure or detect a level of a biomarker in the sample….said biomarker comprising…GFAP and UCH-L1, GFAP or UCH-L1….(see claim 1 in its entirety). The invention is not adequately described because the language in the independent claim defines the invention more in terms of effect to be achieved (accounting for statements of the underlying problem without providing the skilled person with the technical information necessary for achieving the list of parameters claimed, see claims 1-6 for instance), as assays are needed to be performed but not defined in concrete terms. The assays are defined in such terms that raises uncertainty as to the scope and possession, since with assays data vary significantly depending on the assay matrix and/or the assay constituents (choice of sample material, buffer, choice of antibodies and signal amplification system, incubation times, to name a few). In addition, the general part of the description refers to a huge amount of available immunoassay, single molecule detection assay, point of care device. It is therefore, an undue burden based on the lack of adequate description for the skilled person to perform an immunoassay for detecting UCH-L1 alone or UCH-L1 in combination with GFAP as presently defined in the claims so as to determine which assay falls within the scope of the claims. It is therefore, an undue burden and applicant has not demonstrated possession of the entire scope of the claims.
The instant specification discloses that the claimed method surprisingly can be used to measure or assess UCH-L1 at low levels in an undiluted biological sample over a wide range of concentrations and thus provide a more versatile and sensitive assay aid in diagnosing and distinguishing TBI in a patient. It is disclosed that the claimed method surprisingly reduce the likelihood of hook effect. While hook effect (or prozone phenomena) can be avoided by other means known in the art (e.g., increasing conjugate concentration), these means often destroy low end sensitivity of an assay. In contrast, the methods encompassed by the amended claims maintain the low end sensitivity of the assay by optimization of the concentration of the reagents used in the assay. However, these limitations are not reflected in the claims. Indeed, the present wording of the independent claims do not comprise the features essential to the definition of the invention, namely the technical features essential to reduce the likelihood of hook effect.
In the light of the experimental part of the description, the antibody pair used in the methods of for example, claims 1-4 should be identified. Indeed, Example 1 points to some "initial selection criteria", which however are not identified in the claims, so that the skilled person is left guessing how to select an appropriate antibody pair. Moreover, the claims do not indicate which signal detection system is used to achieve the desired limit of detection and dynamic range. It would therefore appear that either determination of the claimed assay parameters is trivial and results from routine assay optimization, or the application does not disclose the assay in terms sufficient to enable a skilled person to perform the claimed assays with the desired parameters, absent adequate description.
The specification fails to provide any additional representative species of the claimed genus encompassed based on the breath of the claims having multiple assays, to show that applicant was in possession of the claimed genus. A representative number of species means that the species which are adequately described are representative of the entire genus. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. Moreover, Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir.1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
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.
9. Claims 1-14, 16 and 18-19 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.
Claim 1 and the dependent claims hereto are indefinite for the recitation of “performing one or more assays on at least one or more samples obtained from a subject” and the claim does not recite what assays or if the sample is a blood or cerebrospinal fluid sample, thus the claim language has ambiguity. In addition, the claim does not define the normal range or baseline of GFAP or UCH-L1 to make a comparison with the vast amounts of levels recited in the claim for suspected/sustained subjects, thus the claim language lacks clarity.
Item 1(b)(i) lacks clear antecedent basis for “…the subject’s….”.
Claim 1 and the dependent claims hereto are indefinite for the recitation of vast amounts of alternatives because the claim taken as a whole does not comply with clarity and conciseness with the multiplicity of alternatives within a single claim. Further, the language of within after about with no punctuation or transitional phrase introduces inexactness into quantities or features and leave the ordinary skilled worker in doubt as to the exact meaning of the features qualified by such terms.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claim(s) 1-14, 16 and 18-19 and 8-15 is/are rejected under 35 U.S.C. 102(a)(1) and (a) (2) as being anticipated by McQuiston et al. (US 20180306812, 2018 of record in the application).
The reference teaches methods that aid in the hyperacute diagnosis and evaluation of a human subject that has sustained or may have sustained an injury to the head, such as mild or moderate, severe, or moderate to severe traumatic brain injury (TBI), using an early biomarker, such as ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) glial fibrillary acidic protein (GFAP), or a combination thereof. Also disclosed here are methods that aid in the hyperacute determination of whether a human subject that has sustained an injury or may have sustained to the head would benefit from and thus receive a head computerized tomography (CT) scan based on the levels of UCH-L1. These methods involve detecting levels of early biomarker, such as ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) glial fibrillary acidic protein (GFAP), or a combination thereof, in samples taken from a human subject at a time point within about 2 hours, such as about 10, 12, or 20 minutes, after the subject has sustained or may have sustained an injury to the head (see abstract). The reference teaches comparison with levels obtained via Glasgow Coma Scale, GFAP and UCH-L1 levels that fall within the ‘about’ range claimed, traumatic brain injury, comparison with CT scan and assay performed (and ranges of sensitivity). Immunoassay and clinical chemistry assay is disclosed, samples such as blood and solvents such as pesticide (see claims 1-46).
Therefore, the limitations of the claims are met by the reference.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
11. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. Claim(s) 1-14, 16 and 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hier et al. (2021, of record in the application) in view of WO 2023/034777 (ABBOTT, 2023, of record in the application) .
The claimed invention is directed to a method for aiding in the diagnosis and evaluation of a subject that has sustained or may have sustained ABI (see claim 1 in its entirety). The instant specification discloses that to date limited data have been available for the use of UCH-L1 and GFAP in the acute care setting to aid in patient evaluation and management (see page 2). The claims scope is not clear in the independent claim dues to use of obscure assay parameters that are influenced not only by the assay reagents but also by the choice of the assay matrix (sample material, buffer composition, dilution factors, etc.) and incubation times. The claims are given the broadest reasonable interpretation a method of using the biomarkers to evaluate, detect and diagnose.
Hier et al. discloses biomarkers used after mild traumatic brain injury (mTBI) that have been wildly studied. Hier et al. discloses GFAP and UCH-L1 as well established for usage in the capacity of aiding in diagnosing sustained or may have sustained brain injury. Hier et al. state that glial fibrillary acidic protein, a 50kDa protein, is the primary component of intermediate filaments in astrocytes and GFAP monomers homo-polymerize to form the intermediate filament cytoskeleton of astrocytes (GFAP is upregulated during astrogliosis and is released from astrocytes after traumatic brain injury; and levels of GFAP are elevated in both the cerebrospinal fluid and blood after traumatic brain injury), see page 1-2. Hier et al. also teach that Ubiquitin C-terminal hydrolase-L1 is a 25kDA enzyme that is highly expressed in neurons (involved in ubiquitination and de-ubiquitination of proteins allocated for catabolism, and cerebrospinal fluid and blood have elevated levels of UCH-L1 after traumatic brain injury (TBI), (see page 2).
Hier et al. discloses that force of impact to the head, releases the aforementioned biomarkers but the amount released does not correlate with the type of injury. Hier et al. also discloses that timing of sampling is important, if blood biomarkers are sampled too early or too late…..important elevations may be missed ( UCH-L1 between 4-12 hours and GFAP between 12-36 hours) to evaluate the predictive capacity of a diagnostic test using the biomarkers (see page 6). Hier et al. also disclose that GFAP as a predictor of CT positivity performed better when drawn at 12-18 hours instead of 0-6 hours (see page 8) and found that GFAP has a longer half-life (i.e., 30 to 90 days after injury) than other biomarkers with UCH-L1 being middle range at less than 48 hours (see page 8). Hier et al. found that GFAP showed the ability to discriminate between CT-positive and CT-negative in subjects. Hier et al. disclose studies that found a cutoff of 30pg/ml for GFAP and UCH-L1 that gave a sensitivity of 44% for GFAP; and 95% for UCH-L1 in distinguishing between no TBI and mTBI (see pages 9 and 11). Hier et al. does not disclose all the GFAP and UCH-L1 levels recited in the claims for suspected or sustained ABI, however, the art has well established normal ranges for healthy subjects being under 10 to 35 pg/ml and an ordinary skilled worker in the field would know how to compared known healthy levels to the ones tested to diagnose injury. The secondary reference discloses a method for the diagnosis whether a subject that has sustained or may have sustained an injury to the head has moderate to severe (TBI) based on a blood sample obtained from the subject withing about 48 hours after the actual or suspected injury to measure a combination of a level of GFAP and UCH-L1. The subject is diagnosed as not sustained a moderate, severe or a moderate to severe TBI when the level of GFAP in the sample is from about 105 pg/ml to about 890 pg/ml, and UCH-L1 in the sample from about 110 pg/ml to about 2000 pg/mL.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references renders the claimed invention as obvious. One of ordinary skill in the art would be motivated to combine the teaching of the references because they are analogous art. Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
Conclusion
13. No claims are presently allowable.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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