CTNF 18/509,717 CTNF 89199 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Status of the Claims Claims 1-19 are pending and are examined herein. Priority This application,18/509,717 was filed 11/15/2023. This application is a CONTINUATION of PCT/US2022/080578 filed 11/29/2022, which claims benefit of Provisional Application 63/294,271 filed 12/28/2021 and is a CONTINUATION of 17/538,572, filed on 30 November 2021 (abandoned) - which claims benefit of US Provisional Applications 63/170,873, filed on May 04 2021, and 63/120,062, filed on 01 December 2020 – and claims benefit of US Provisional Application 63/284,421 filed 11/30/2021 and is a CONTINUATION of PCT/US21/61215 filed 11/30/2021. Specification 07-29 AIA The disclosure is objected to because of the following informalities: Pars. 172 and 237: “Antibody variants can also be prepared using delivering a polynucleotide encoding an antibody to a suitable host such as to provide transgenic animals or mammals, such as goats, cows, horses, sheep, and the like, that produce such antibodies in their milk.” This sentence is unclear as written and correction of the grammar and/or content is required for clarity. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see browser-executable portions of links beginning after “hypertext transfer protocol://” in par. 80). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. The use of the term "i-STAT", which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term (see par. 104). Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Applicant is advised to review the entire text of the instant patent application for proper use of trade marks. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification. Claim Objections Claim 18 is objected to because of the following informalities: Claim 18 should include the word “is” after GFAP . Appropriate correction is required. Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 Claims 1-19 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. Claims 1-3 are vague and indefinite because the term “higher than a reference level” is a relative term.. The term “higher than” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 3 is indefinite because line 2 recites “if performed” regarding the head CT scan and claim 1 has not made the CT scan an optional procedure. Claim 14 is also vague and indefinite because the phrase “low, moderate or high levels” is similarly indefinite for the same reasons. Therefore, it is not possible for one of ordinary skill in the art to clearly understand the levels of UCH-L1, GFAP or UCH-L1 and GFAP that are within the scope of the claims. Claim 16 recites the limitation: "wherein the blood sample is whole blood, serum or plasma". There is insufficient antecedent basis for this limitation since there is no prior mention of a blood sample in the claims. 07-30-01 AIA 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 1-19 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. In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a) it is necessary to understand what applicant has possession of and what applicant is claiming. Claim 1 recites that the method comprises “diagnosing the subject as more likely than not as having traumatic brain injury (TBI) if the level of the biomarker is higher than a reference level and the head CT scan is negative for a TBI”. However, the use of CT scans for TBI diagnosis is conventional and it is known in the art that “[i]maging can be used to detect the most common types and patterns of injury to help classify TBI and is the frontline for accurate diagnosis of the patient’s evolving condition” (pp. 519, col 2, lines 17-20 of Haacke et al. , Journal of Magnetic Resonance Imaging, 32(2),516-543, 2010). Several studies describing the utility of UCH-L1 and GFAP as biomarkers for TBI diagnosis disclose that rising biomarker levels are correlated with positive head CT scan results (eg. Diaz-Arrastia et al. , Journal of neurotrauma, 31(1), 19-25, 2014, Papa et al., Journal of neurotrauma, 31(22), 1815-1822, 2014 , and Papa et al., The journal of trauma and acute care surgery, 72(5),1335-1344, 2012 ). While it is accepted specifically in the case of mild TBI that “the majority of mild TBI patients have a normal head CT” ( Haacke et al. , pp. 520, col 1, lines 13-14), the cited evidence above suggests that the use of UCH-L1 and GFAP biomarker levels to diagnose TBI in the case of a negative CT scan is not conventional. Furthermore, the following disclosure highlights controversy over the use of these biomarkers: “UCH-L1 and GFAP testing has been validated only in patients with mild TBI clinically deemed to need head CT in an emergency department setting.3 Extrapolating these results to include patients with mild TBI who are initially not thought to need imaging, who present in a different care setting (e.g., primary care, urgent care, field of play), or who are outside of the 12-hour post injury window may alter the sensitivity and specificity.” (pp. 2, col 1, lines 5-12 of Middleton , American Family Physician, 105(3), 313-314, 2022) The utility of biomarker-based diagnosis in the instant claim is dependent on the reference level . The instant specification defines the reference level as “an assay cutoff value that is used to assess diagnostic, prognostic, or therapeutic efficacy and that has been linked or is associated herein with various clinical parameters” (par. 101). However, the specification is generic with regards to cutoff values, and does not provide a clear demonstration of a reference level that that can be used to diagnose likely TBI in patients with negative CT scans. Therefore, a person having ordinary skill in the art would not clearly understand that applicant has possession of a reference level applicable for UCH-L1 and/or GFAP measured from any generic sample obtained within about 24 hours that can diagnose likely TBI in patients with negative CT scans. Claim 2 is rejected based on the same analysis, as it recites similar application of a reference level , but does not require a CT scan to be performed. Claims 3-19, which are dependent on claims 1 and 2 are similarly rejected. For all the reasons cited above, 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. 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 depends on claim 1, which is limited in scope to “ a subject that has sustained or may have sustained an injury to the head ” (emphasis added). However, claim 14 cites: “The method of claim 1, wherein said method can be carried out on any subject without regard to factors selected from the group consisting of the subject's clinical condition , the subject's laboratory values, the subject's classification as suffering from mild, moderate, severe or moderate to severe traumatic brain injury, the subject's exhibition of low, moderate or high levels of UCH-L1, GFAP or UCH-L1 and GFAP, and the timing of any event wherein said subject has sustained or may have sustained an injury to the head” (emphasis added). Since the relevant subject matter of dependent claim 14 does not further limit the scope of the independent claim 1, it is improper according to the “Test for proper dependency” outlined in MPEP § 608.01(n) . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon judicial exception without significantly more. The claims recite methods for the diagnosis of traumatic brain injury (TBI) based on the relationship between changing levels of naturally occurring protein markers, which may occur in the absence of a TBI diagnosis by computerized tomography (CT) scan. This judicial exception is not integrated into a practical application because these methods do not constitute an improvement in the technological field; and the steps recited in addition to the judicial exception do not integrate detection of the natural phenomenon into a particular treatment/prophylaxis according to MPEP § 2106.04(d)(2). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements fail to provide either an inventive concept or impose meaningful limits upon the method such that the invention does not preempt every observance of the natural phenomenon itself. Claims 1-19 are directed to methods for the diagnosis of traumatic brain injury (TBI) in a subject who has sustained or may have sustained an injury to the head, based on levels of GFAP and/or UCH-L1 biomarkers obtained from assays, which may be considered in the absence of a TBI diagnosis by computerized tomography (CT) scan. Methods are one of the eligible statutory categories for invention (STEP 1: YES). The claims recite comparing measured biomarker levels to reference levels, which is an abstract mental concept that belongs to enumerated group (III) of the Abstract Idea Groupings described in MPEP § 2106.04(a)(2). Furthermore, the claims recite a natural correlation/phenomenon/law of nature whereby the diagnosis of TBI likelihood is correlated with greater than reference levels of UCH-L1 and/or GFAP. Therefore, the claims recite at least one judicial exception (STEP 2A, Prong One: YES). According to Step 2A, Prong Two, set forth in MPEP 2106.04 II A (2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. This analysis turns to the additional steps/elements recited within the claim. In independent claims 1 and 2, the additional steps/elements are: performing an assay on a subject’s sample to measure UCH-L1 and/or GFAP biomarker levels, and acknowledging the absence of a TBI diagnosis by CT scan. Dependent claims 4-14, 16-17, provide additional limitations on biomarker assay methods, sample collection, subject selection, and the considered biomarker reference levels. Dependent claim 15 adds an additional step of generic monitoring of the subject, and dependent claim 3 adds the additional step of generic treatment of the subject. Regarding the assay method for measurement of UCH-L1 and/or GFAP biomarker levels, applicant admits in the specification that, “[t]he nature of the assay employed in the methods described herein is not critical and the test can be any assay known in the art” (par. 142). For example, “chemiluminescent enzyme-linked immunosorbent assays” have been previously used to measure UCH-L1 and GFAP levels for TBI evaluation (pp. 784, col 1, lines 22-23 of Bazarian et al. , Lancet Neurol. 2018 Sep;17(9):782-789). Regarding sample collection, applicant admits in the specification that the sample collection is generic and that, “[a] variety of cell types, tissue, or bodily fluid may be utilized to obtain a sample” (par. 111). Applicant further admits that the sample processing is generic and that, “sample can be used directly as obtained from a patient or can be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to modify the character of the sample in some manner as discussed herein or otherwise as is known in the art” (par. 110). Regarding TBI diagnosis by CT scan, applicant admits in the specification that, “[t]he CT scan may be a conventional CT scan or a spiral/helical CT scan” (par. 61). These methods are known in the art, and “[s]tructural imaging in the form of routine CT and MRI are the core neuroimaging examinations that serve as the basis for the initial evaluation of TBI” (pp. 519, col 2, lines 11-14 of Haacke et al. , Journal of Magnetic Resonance Imaging, 32(2),516-543, 2010). Regarding subject selection for diagnosis of potential head/brain injuries, the inclusion of subjects who may have suffered physical trauma, been exposed to fire, chemicals, or toxins, or suffer from various infections or diseases is already known in the art. For example, the collection of whole blood, serum, cerebrospinal fluid or plasma samples from subjects who may have suffered physical trauma, been exposed to fire, chemicals, or toxins, or suffer from various infections or diseases is disclosed in par. 16 of McQuiston 2018 (WO 2018/218169 cited on IDS filed 2/20/2024). Regarding the considered biomarker reference levels, it is known in the art that levels of GFAP and/or UCH-L1 measured by assay may be used to determine a reference level indicative of patient condition, and examples of these reference levels have been previously defined as about 20 pg/mL to about 200 pg/mL, which may correspond to a positive CT scan (in pars. 9, 19-20, and 23 of McQuiston 2018 ). The determination and application of reference levels is known in the art, and applicant admits in the specification that, “[i]t is well within the ordinary skill of one in the art to determine the sensitivity and specificity associated with a given reference level in the methods of the invention, for example by repeated statistical analysis of assay data using a plurality of different possible reference levels” (par. 63). Dependent claim 15 recites the additional step of monitoring the subject, which is recited with such a high level of generality that it encompasses any means known in the art (see MPEP 2106.05(e)), including repeat assays for GFAP and UCH-L1 levels and CT or MRI procedures, or it could be as simple as observation. Dependent claim 3 recite the additional step of “treating the subject for a TBI if the level of the biomarker is higher than a reference level”, which is recited with such a high level of generality that it encompasses any means known in the art (see MPEP 2106.05(e)). Applicant admits in the specification that, “the method further includes treating the subject, such as a human subject, with a traumatic brain injury treatment, such as any treatments known in the art” (par. 143). Since this administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way, it does not integrate the judicial exception into a practical application (see MPEP § 2106.04(d)(2)(a)). There are no additional elements that reflect an actual improvement within the technical field; there are no additional elements that apply the natural correlation/phenomena judicial exception to a particular treatment or which utilize a particular machine; there are no additional elements that effect a transformation; and, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, TBI diagnosis. In this way the claims, as a whole, amount to nothing more than a drafting effort designed to monopolize the natural correlation itself. ((STEP 2A, Prong Two: NO). Therefore, in accordance with MPEP 2106.05(d), the examiner has cited express statements in the specification indicating that the additional elements were sufficiently well-known that the specification does not need to describe the particulars thereof. In other words, the disclosure describes no new technology, but merely refers to techniques and elements that were known in the art at the time of filing. Lastly, the examiner cites publications within the field of technical expertise, that demonstrate the well-understood, routine, conventional nature of the additional element(s). The following prior art teaches it was well established in the field of technical expertise that UCH-L1 and GFAP are biomarkers of TBI ( Diaz-Arrastia et al. , Journal of neurotrauma, 31(1), 19-25, 2014). The authors teach that UCH-L1 and GFAP expression considered in isolation or in combination are useful for the diagnosis of TBI ( Diaz-Arrastia et al. , pp. 19). Methods for the selection of subjects, sample collection and processing, UCH-L1 and GFAP biomarker measurement using sandwich ELISA assays, statistical methods for the determination of correlative biomarker reference levels, evaluation of CT scans, and monitoring through follow-up outcome assessments are described in detail in the Methods section ( Diaz-Arrastia et al. , pp. 20-21). These methods have been confirmed by other studies that have demonstrated the utility of GFAP ( Papa et al., Journal of neurotrauma, 31(22), 1815-1822, 2014 ) and UCH-L1 ( Papa et al., The journal of trauma and acute care surgery, 72(5),1335-1344, 2012 ) as biomarkers for the detection of TBI. The use of radiologic imaging techniques such as CT scans in the diagnosis of TBI has also been previously described in detail ( Haacke et al. , Journal of Magnetic Resonance Imaging, 32(2),516-543, 2010). Therefore, the steps/elements recited in addition to the judicial exception were all well understood, routine, conventional activities in the field of TBI diagnosis prior to filing the application at hand (STEP 2B: NO). The claimed steps/elements recited in addition to the judicial exception(s), alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to mere observation of the natural phenomenon itself, by any means known, with the words “apply it” in order to append it to the field of TBI diagnosis. For all of these reasons, claims 1-19 are directed to the judicial exception without significantly more and are rejected. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-21-aia AIA Claim s 1-2, 4-7, 9-10, 14, 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Bazarian et al (Lancet Neurol. 2018 Sep;17(9):782-789) in view of Blankenberg et al (US 2006/0105419) . Regarding claims 1-2, 5, 9, 14, 16-19, Bazarian et al teach a method for the diagnosis and evaluation of TBI based on testing for serum levels of blood-based brain biomarkers UCH-L1 and GFAP (pp. 782, Summary). They disclose a study that recruited human subjects including, “adults (≥ 18 years) presenting to participating emergency departments with suspected, non-penetrating TBI” (Bazarian et al., pp. 782, Summary, lines 7-8 after the heading). They further disclose that blood samples were obtained within 12 hours of injury, and that CT scans had been performed within 12 hours of injury as part of clinical care (Bazarian et al., pp. 783, Methods, lines 18-23 after the heading). Regarding the reference ranges of claim 1-2 and 18-19, while Bazarian et al teach that “UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively” (pp. 782, Summary, lines 10-11 after the heading), the reference does not explicitly teach all of the reference ranges of claims 1-2 and 18-19. However, it was recognized in Blankenberg that the sensitivity and specificity is a measure of the accuracy of a test, reflecting the number (if any) of false positives and false negatives. Furthermore, sensitivity and specificity may be adjusted by adjusting the value of a threshold or cutoff value, above which (or below which, depending on how a marker changes with the disease) the test is considered to be indicative of one state or condition (e.g., diseased) and below which the test is considered to be indicative of another state or condition (e.g., non-diseased). See Blankenberg et al at [0007], [0028], [0084]. Accuracy need not be 100%; however Blankenberg et al indicates that particularly preferred would be where both the sensitivity and specificity are at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, and most preferably at least about 95% [0028]. The teachings of Blankenberg et al indicate that the sensitivity and specificity of a diagnostic test was known to be a result-effective variable, impacting the number of individuals who are correctly diagnosed with disease. Furthermore, the teachings of Blankenberg et al indicate that it was known in the prior art to optimize tests for desired levels of sensitivity and specificity, by selecting appropriate threshold or cutoff values. Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate comparison to a reference and to arrive at the claimed invention by optimizing cutoff levels in order to achieve a desired sensitivity and specificity as claimed, given that such percentages were recognized in the art to be particularly preferred for diagnostic tests. One skilled in the art would have been motivated to select such levels of sensitivity and specificity out of the course of routine optimization, given that these measures of test accuracy were recognized in the prior art to be result-effective variables that impact the number of false negatives and false positives for the test. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation.” Application of Aller, 220 F.2d 454,456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation .” Id. At 458,105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Application of Boesch, 617 F.2d 272,276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).Finally, one skilled in the art would have had a reasonable expectation of success in arriving at the claimed cutoffs since means of achieving desired sensitivity and specificity were known, namely by selecting an appropriate threshold or cutoff level (as taught by Blankenberg et al). Regarding claim 4, Bazarian et al teach that “UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively” (pp. 782, Summary, lines 10-11 after the heading). They further disclose their methodology for deriving these cutoff levels associated with intracranial injury (Supplemental appendix, pp. 10). Regarding claims 6-7, Bazarian et al disclose that “samples were analysed for UCH-L1 and GFAP concentration using chemiluminescent enzyme-linked immunosorbent assays” (pp. 784, Procedures, lines 6-9 after the heading). Regarding claim 10, Bazarian et al disclose that the mechanism of injury for their subjects included various forms of physical trauma such as, vehicle accident, fall, sports injury, and explosion (pp. 785, Table 1) . 07-21-aia AIA Claim s 1-7, 8-10, and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over by Hayes (US 2014/0342381 A1) in view of Blankenberg et al (US 2006/0105419) . Regarding claims 1-2, 5-7, 9-10, 14, 16-19, Hayes teaches an in vitro diagnostic (IVD) device used to detect the presence of and/or severity of neural injuries based on immunoassays that identify biological markers in samples such as whole blood (pp. 1, Abstract). Measured levels of biomarkers including GFAP and UCH-L1 were compared to “normal” levels for diagnosis of subjects (Hayes, par. 45). Hayes et al disclose, “a step of comparing the quantity of one or more biomarkers to normal levels to determine the neurological condition of the subject” (par. 96). Subjects include human adults with suspected TBI who had received closed head injuries, including injuries inflicted by blunt force mechanism, had samples collected within 4 hours of the injury, and were willing to undergo a CT scan (Hayes, par. 103). Regarding the reference ranges of claim 1-2 and 18-19, Hayes does not explicitly teach all of the reference ranges of claims 1-2 and 18-19. However, it was recognized in Blankenberg that the sensitivity and specificity is a measure of the accuracy of a test, reflecting the number (if any) of false positives and false negatives. Furthermore, sensitivity and specificity may be adjusted by adjusting the value of a threshold or cutoff value, above which (or below which, depending on how a marker changes with the disease) the test is considered to be indicative of one state or condition (e.g., diseased) and below which the test is considered to be indicative of another state or condition (e.g., non-diseased). See Blankenberg et al at [0007], [0028], [0084]. Accuracy need not be 100%; however Blankenberg et al indicates that particularly preferred would be where both the sensitivity and specificity are at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, and most preferably at least about 95% [0028]. The teachings of Blankenberg et al indicate that the sensitivity and specificity of a diagnostic test was known to be a result-effective variable, impacting the number of individuals who are correctly diagnosed with disease. Furthermore, the teachings of Blankenberg et al indicate that it was known in the prior art to optimize tests for desired levels of sensitivity and specificity, by selecting appropriate threshold or cutoff values. Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate comparison to a reference and to arrive at the claimed invention by optimizing cutoff levels in order to achieve a desired sensitivity and specificity as claimed, given that such percentages were recognized in the art to be particularly preferred for diagnostic tests. One skilled in the art would have been motivated to select such levels of sensitivity and specificity out of the course of routine optimization, given that these measures of test accuracy were recognized in the prior art to be result-effective variables that impact the number of false negatives and false positives for the test. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation.” Application of Aller, 220 F.2d 454,456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation .” Id. At 458,105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Application of Boesch, 617 F.2d 272,276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).Finally, one skilled in the art would have had a reasonable expectation of success in arriving at the claimed cutoffs since means of achieving desired sensitivity and specificity were known, namely by selecting an appropriate threshold or cutoff level (as taught by Blankenberg et al). Regarding claim 3, Hayes et al teach that the “results of such a test using an in vitro diagnostic device can help a physician determine whether the administration a particular therapeutic or treatment regimen may be effective, and provide a rapid clinical intervention to the injury or disorder to enhance a patient's recovery” (par. 97) Regarding claim 4, Hayes et al teach comparison of measured biomarkers to a cutoff level (threshold) that is correlated with head injury: “The output component relays to the display 2405 the processed measured amount, resulting from the comparison of the input to the preprogrammed threshold, in a user defined usable format. The display 2405 provides an output from which the user may determine the measured amount of the respective biomarker present in the sample, an indication of the presence or absence of neurological condition, and/or an indication of the severity of the neurological condition.” (par. 60) Regarding claim 8, Hayes et al teach that the “in vitro diagnostic device may comprise of a handheld device, a bench top device, or a point of care device” (par. 50, fig. 24). Regarding claim 15, Hayes et al teach that the “in vitro diagnostic device provides the ability to detect and monitor levels of these proteins after neurotoxicity or CNS injury” and “to continually monitor the effects of therapy by examination of these proteins in biological fluids” (par. 63) . 07-21-aia AIA Claim s 3, 8, 11-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Bazarian et al (Lancet Neurol. 2018 Sep;17(9):782-789) in view of Blankenberg et al (US 2006/0105419), as applied to claims 1 above (hereinafter “Modified Bazarian”), and further in view of McQuiston 2018 (WO 2018/218169) . Modified Bazarian teach a method for the diagnosis and evaluation of TBI based on testing for serum levels of blood-based brain biomarkers UCH-L1 and GFAP (pp. 782, Summary). They disclose a study that recruited human subjects including, “adults (≥ 18 years) presenting to participating emergency departments with suspected, non-penetrating TBI” (Bazarian et al., pp. 782, Summary, lines 7-8 after the heading). They further disclose that blood samples were obtained within 12 hours of injury, and that CT scans had been performed within 12 hours of injury as part of clinical care (Bazarian et al., pp. 783, Methods, lines 18-23 after the heading). Modified Bazarian fail to teach: “treating a subject for a TBI if the level of the biomarker is higher than a reference level” (instant claim 3); that the assay is performed using a point-of-care assay or single molecule detection (instant claim 8); diagnosis from samples obtained “after the subject has ingested or been exposed to a fire, chemical, toxin or combination of a fire, chemical and toxin” (instant claim 11), “wherein the chemical or toxin is mold, asbestos, a pesticide, an insecticide, an organic solvent, a paint, a glue, a gas, an organic metal, a drug of abuse or one or more combinations thereof” (instant claim 12), or “wherein the sample is obtained from a subject that suffers from an autoimmune disease, a metabolic disorder, a brain tumor, hypoxia, a viral infection, a fungal infection, a bacterial infection, meningitis, hydrocephalus, or any combinations thereof” (instant claim 13); and “monitoring the subject” (instant claim 15). McQuiston 2018 teaches methods aiding the diagnosis of head injuries that involve: “performing an assay on a sample obtained from the subject within about 24 hours after a suspected injury to the head to measure or detect a level of an early biomarker in the sample, said early biomarker comprising ubiquitin carboxy-terminal hydrolase LI (UCH-L1), glial fibrillary acidic protein (GFAP), or a combination thereof” (par. 6). McQuiston 2018 further teaches: “treating a human subject assessed or evaluated as having a mild, moderate, severe, or a moderate to severe TBI with a treatment for TBI (e.g., a surgical treatment, a therapeutic treatment, or combinations thereof)”, and “any subject being treated for TBI can also, optionally, be monitored during and after any course of treatment.” (pars. 15, 25, 39, and 52); “the assay is a point-of-care assay”, or that “the assay is a single molecule detection assay” (pars. 18, 29, 42, and 55); and “the sample can be obtained after the subject has ingested or been exposed to a chemical, toxin or combination of a chemical and toxin. Examples of chemicals or toxins are fire, mold, asbestos, a pesticide, an insecticide, an organic solvent, a paint, a glue, a gas, an organic metal, a drug of abuse or one or more combinations thereof. Still further, the sample can be obtained from a subject that suffers from an autoimmune disease, a metabolic disorder, a brain tumor, hypoxia, a virus, meningitis, hydrocephalus or combinations thereof. (pars. 16, 27, 40, and 53) Regarding claims 3 and 15, it would have been obvious for a person having ordinary skill in the art before the effective filing date of the claimed invention to apply the method for diagnosis of brain injuries of Modified Bazarian with treatment for TBI and subject monitoring as disclosed by McQuiston 2018, because a medical test may be useful “in order to diagnose, treat, and monitor health conditions” (McQuiston 2018, par. 116). One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Bazarian et al and McQuiston 2018 are similarly drawn to methods related to the diagnosis of neural injuries based on measured levels of GFAP and/or UCH-L1. Regarding claim 8, it would have been obvious for a person having ordinary skill in the art before the effective filing date of the claimed invention to apply the method for diagnosis of brain injuries of Modified Bazarian with the point-of-care or single molecule detection assays disclosed by McQuiston 2018, because of the interchangeability of these assays and that “[i]t is known in the art that the values (e.g., reference levels, cutoffs, thresholds, specificities, sensitivities, concentrations of calibrators and/or controls etc.) used in an assay that employs specific sample type (e.g., such as an immunoassay that utilizes serum or a point-of-care device that employs whole blood) can be extrapolated to other assay formats using known techniques in the art, such as assay standardization” (McQuiston 2018, par. 169). Furthermore, the instant specification does not teach that the assay type is critical, and admits that the assays are obvious variants of each other wherein it states, “[t]he nature of the assay employed in the methods described herein is not critical and the test can be any assay known in the art” (par. 138). One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Bazarian et al and McQuiston 2018 are similarly drawn to methods related to the diagnosis of neural injuries based on measured levels of GFAP and/or UCH-L1. Regarding claims 11-13, it would have been obvious for a person having ordinary skill in the art before the effective filing date of the claimed invention to apply the method for diagnosis of brain injuries of Modified Bazarian with samples obtained from subjects exposed to fire, chemicals or toxins (such as mold, asbestos, a pesticide, etc.), or who suffer from a variety of disorders (such as autoimmune disease, a metabolic disorder, a brain tumor, etc.) as disclosed by McQuiston 2018, because it is known in the art that an injury to the head may be caused by these factors (McQuiston 2018, par. 118, pp. 39, lines 7-14). One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Bazarian et al and McQuiston 2018 are similarly drawn to methods related to the diagnosis of neural injuries based on measured levels of GFAP and/or UCH-L1 . 07-21-aia AIA Claim s 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Hayes (US 2014/0342381 A1) in view of Blankenberg et al (US 2006/0105419) as applied to claim 1 above (hereinafter “Modified Hayes”), and further in view of McQuiston 2018 (WO 2018/218169) . Modified Hayes teaches an in vitro diagnostic (IVD) device used to detect the presence of and/or severity of neural injuries based on immunoassays that identify biological markers in samples such as whole blood (pp. 1, Abstract). Measured levels of biomarkers including GFAP and UCH-L1 were compared to “normal” levels for diagnosis of subjects (Hayes, par. 45). Hayes et al disclose, “a step of comparing the quantity of one or more biomarkers to normal levels to determine the neurological condition of the subject” (par. 96). Subjects include human adults with suspected TBI who had received closed head injuries, including injuries inflicted by blunt force mechanism, had samples collected within 4 hours of the injury, and were willing to undergo a CT scan (Hayes, par. 103). Hayes fails to teach diagnosis from samples obtained “after the subject has ingested or been exposed to a fire, chemical, toxin or combination of a fire, chemical and toxin” (instant claim 11), “wherein the chemical or toxin is mold, asbestos, a pesticide, an insecticide, an organic solvent, a paint, a glue, a gas, an organic metal, a drug of abuse or one or more combinations thereof” (instant claim 12), or “wherein the sample is obtained from a subject that suffers from an autoimmune disease, a metabolic disorder, a brain tumor, hypoxia, a viral infection, a fungal infection, a bacterial infection, meningitis, hydrocephalus, or any combinations thereof” (instant claim 13). McQuiston 2018 teaches methods aiding the diagnosis of head injuries that involve: “performing an assay on a sample obtained from the subject within about 24 hours after a suspected injury to the head to measure or detect a level of an early biomarker in the sample, said early biomarker comprising ubiquitin carboxy-terminal hydrolase LI (UCH-L1), glial fibrillary acidic protein (GFAP), or a combination thereof” (par. 6). McQuiston 2018 further teaches: “the sample can be obtained after the subject has ingested or been exposed to a chemical, toxin or combination of a chemical and toxin. Examples of chemicals or toxins are fire, mold, asbestos, a pesticide, an insecticide, an organic solvent, a paint, a glue, a gas, an organic metal, a drug of abuse or one or more combinations thereof. Still further, the sample can be obtained from a subject that suffers from an autoimmune disease, a metabolic disorder, a brain tumor, hypoxia, a virus, meningitis, hydrocephalus or combinations thereof. (pars. 16, 27, 40, and 53) Regarding claims 11-13, it would have been obvious for a person having ordinary skill in the art before the effective filing date of the claimed invention to apply the method for diagnosis of brain injuries of Modified Hayes with samples obtained from subjects exposed to fire, chemicals or toxins (such as mold, asbestos, a pesticide, etc.), or who suffer from a variety of disorders (such as autoimmune disease, a metabolic disorder, a brain tumor, etc.) as disclosed by McQuiston 2018, because it is known in the art that an injury to the head may be caused by these factors (McQuiston 2018, par. 118, pp. 39, lines 7-14). One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Hayes and McQuiston 2018 are similarly drawn to methods related to the diagnosis of neural injuries based on measured levels of GFAP and/or UCH-L1. Double Patenting 08-33 AIA The non-statutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A non-statutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp. Claims 1-19 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-26 of US Patent 11,022,617; claims 1-31 of US Patent 12,105,098; claims 1-36 of US Patent 11,016,105; claims 1-38 of US Patent 12,105,100; claims 1-22 of US Patent 10,877,048; claims 1-24 of US Patent 12,099,069; claims 1-16 of US Patent 10,877,038; claims 1-18 of US Patent 12,085,567; claims 1-19 of US Patent 11, 016,092; claims 1-14 of US Patent 10,866,251. Although the claims at issue are not identical, they are not patentably distinct from each other because present claims and the patented claims encompass very similar methods, which recite the same steps, use the same materials and accomplish identical results. The U.S. Patents listed above all claim a version of: A method comprising performing, simultaneously or sequentially: (1) an assay on a sample obtained from the subject within about 24 hours after an actual or suspected injury to the head to measure or detect a level of a biomarker in the sample, said biomarker comprising ubiquitin carboxy- terminal hydrolase Li (UCH-L1), glial fibrillary acidic protein (GFAP), or a combination thereof; and (2) if performed, a head computerized tomography (CT) scan on the subject within a clinically-relevant time frame; and diagnosing the subject as more likely than not as having traumatic brain injury (TBI) if the level of the biomarker is higher than a reference level for GFAP and UCH-L1. Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2,7,13-15,21,28-29,31,33-34 of copending Application 17/747,397; claims 1-2,4-12,14-21 of copending Application 18/147,094; claims 1-4,6,8,12,14,16,19,35-3840,46,54-55,61,68 of copending Application 18/147,360; claims 1 and 3-28 (number erroring in recent amendment) of copending Application 18/474,826. Although the claims at issue are not identical, they are not patentably distinct from each other because present claims and the patented claims encompass very similar methods, which recite the same steps, use the same materials and accomplish identical results. The US Patent Applications listed above all claim a version of: A method comprising performing, simultaneously or sequentially: (1) an assay on a sample obtained from the subject within about 24 hours after an actual or suspected injury to the head to measure or detect a level of a biomarker in the sample, said biomarker comprising ubiquitin carboxy- terminal hydrolase Li (UCH-L1), glial fibrillary acidic protein (GFAP), or a combination thereof; and (2) if performed, a head computerized tomography (CT) scan on the subject within a clinically-relevant time frame; and diagnosing the subject as more likely than not as having traumatic brain injury (TBI) if the level of the biomarker is higher than a reference level for GFAP and UCH-L1. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M GIERE whose telephone number is (571)272-5084. The examiner can normally be reached M-F 8:30-4:30. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy L Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /REBECCA M GIERE/Primary Examiner, Art Unit 1677 Application/Control Number: 18/509,717 Page 2 Art Unit: 1677 Application/Control Number: 18/509,717 Page 3 Art Unit: 1677 Application/Control Number: 18/509,717 Page 4 Art Unit: 1677 Application/Control Number: 18/509,717 Page 5 Art Unit: 1677 Application/Control Number: 18/509,717 Page 6 Art Unit: 1677 Application/Control Number: 18/509,717 Page 7 Art Unit: 1677 Application/Control Number: 18/509,717 Page 8 Art Unit: 1677 Application/Control Number: 18/509,717 Page 9 Art Unit: 1677 Application/Control Number: 18/509,717 Page 10 Art Unit: 1677 Application/Control Number: 18/509,717 Page 11 Art Unit: 1677 Application/Control Number: 18/509,717 Page 12 Art Unit: 1677 Application/Control Number: 18/509,717 Page 13 Art Unit: 1677 Application/Control Number: 18/509,717 Page 14 Art Unit: 1677 Application/Control Number: 18/509,717 Page 15 Art Unit: 1677 Application/Control Number: 18/509,717 Page 16 Art Unit: 1677 Application/Control Number: 18/509,717 Page 17 Art Unit: 1677 Application/Control Number: 18/509,717 Page 18 Art Unit: 1677 Application/Control Number: 18/509,717 Page 19 Art Unit: 1677 Application/Control Number: 18/509,717 Page 20 Art Unit: 1677 Application/Control Number: 18/509,717 Page 21 Art Unit: 1677 Application/Control Number: 18/509,717 Page 22 Art Unit: 1677 Application/Control Number: 18/509,717 Page 23 Art Unit: 1677 Application/Control Number: 18/509,717 Page 24 Art Unit: 1677 Application/Control Number: 18/509,717 Page 25 Art Unit: 1677 Application/Control Number: 18/509,717 Page 26 Art Unit: 1677 Application/Control Number: 18/509,717 Page 27 Art Unit: 1677
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