DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
1. Applicant's election with traverse of Group I, encompassing claims 1-6 and 10-17 in the reply filed on February 11, 2026 is acknowledged. The traversal is on the ground(s) that there is a technical relationship among the inventions involving one or more of the same or corresponding special technical features. This is not found persuasive because, as stated in the restriction requirement mailed on 01/08/2026, the technical feature required by Group I, i.e., the detection of the biomarker NFL, is neither recited not required by either of the claims within Groups III or IV. Additionally, prior art was cited in the restriction requirement that broke unity of invention a priori between Groups I and II (Hrusovsky et al. WO 2019/199871 A1). And because the technical feature linking the inventions of Groups I and II does not define a contribution over the prior art, the technical feature does not constitute a special technical feature as defined by PCT Rule 13.2.
The requirement is still deemed proper and is therefore made FINAL.
2. Claims 18-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on February 11, 2026.
3. Accordingly, claims 1-6 and 10-17 are under examination in the current office action.
Information Disclosure Statement
4. The information disclosure statements (IDSs) filed 04/21/2023 and 05/05/2023 have been considered and the references therein are of record.
Claim Objections
5. Claims 1, 3 and 5 are objected to because of the following informalities:
Claim 1 contains an additional “or” in line 1 (i.e., “…use disorder and/or or…”) (emphasis added) which appears to be a typographical error.
Claims 1 and 3 recite acronyms that are not spelled out in their first use in the claims (i.e., NFL and MPO). It would be remedial to amend the claim language in claims 1 and 3 such that the acronyms are clearly defined.
Claim 5 is missing a period “.” at the end of the claim.
Appropriate correction is required.
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.
6. Claims 1-6 and 10-17 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 recites a “method for detecting or predicting a substance use disorder and/or monitoring a progress of the substance use disorder, and/or predicting treatment response or prognosis of substance use disorder in a subject” comprising measuring the level of neurofilament light chain (NFL) in a biological sample obtained from the subject, “wherein the level of NFL at least 1.0 times higher than a level of a control is indicative of neurotoxicity severity following substance use, and/or predicting treatment responses or prognosis of substance use disorder in a subject.” However, it is unclear how “monitoring a progress of the substance use disorder” or “predicting treatment responses or prognosis of substance use disorder” can be done by performing only one measurement of NF-L and comparison to a “control”. In particular, monitoring progress of a disease or disorder, or predicting prognosis of a disorder, is typically performed over time, with two or more samples that are obtained from a subject at two or more different, sequential timepoints. Similarly, determining a response to treatment would minimally require comparison of a biomarker level prior to and following the treatment. This also then means that the recited “control” may vary depending on the intended goal of the method: the control may be a healthy subject, or the same subject at baseline (i.e., at a first timepoint or prior to treatment). The metes and bounds of the claim therefore cannot be readily determined.
Dependent claims 2-6 and 10-17 are included in this rejection because they contain all of the limitations of base claim 1, yet nothing in addition that would aid in clarifying the issue.
Claim 3 is rendered indefinite for the limitations defining the additional biomarkers. In particular, the claim recites that the method of claim 1 further comprises “one or more additional biomarkers selected from CCL11 for chronic stress following substance use, Nectin-4 for skin irritation following substance use, MPO for alcohol dependence following substance use and ADAM10 for synaptopathy following substance use.” However, it is unclear whether this recitation means: (a) the biomarker X means the subject has Y, which is a result of Z (i.e., any and all subjects having Z are tested for biomarker X to determine if they also have Y); or if (b) in the case of a subject having Y following Z, the biomarker X should be selected (i.e., only those subjects having Y following X are tested for biomarker X). Additionally, there is no measurement or determination (of a level/concentration/amount, etc.) of a biomarker in this claim.
The metes and bounds of the claim therefore cannot be readily determined.
Claims 2 and 6 each recite the limitation "the plasma or serum level". There is insufficient antecedent basis for this limitation in the claims.
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.
7. Claims 1-6 and 10-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for detecting a substance use disorder in a subject suspected of having a substance use disorder, comprising obtaining a biological sample from the subject and detecting a level of neurofilament light chain (NF-L) in the sample, wherein a level of NF-L in the sample at least 1.0 times higher than a level of a healthy control is indicative of neurotoxicity severity following substance use, wherein the substance is alcohol, ketamine or a combination thereof, and wherein the biological sample is plasma or serum,
does not reasonably provide enablement for a method for predicting a substance use disorder, monitoring a progress, and/or predicting treatment response or prognosis of a substance use disorder in any individual based upon a determination made by detecting a level of NFL in any biological sample and comparing it to a control sample. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and, (8) the breadth of the claims. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The claims are broadly drawn to a method for detecting or predicting a substance use disorder and/or monitoring a progress of the substance use disorder, and/or predicting treatment response or prognosis of substance use disorder in a subject” comprising measuring the level of neurofilament light chain (NFL) in a biological sample obtained from the subject, wherein a level of NFL at least 1.0 times higher than a level of a control is indicative of neurotoxicity severity following substance use, and/or predicting treatment responses or prognosis of substance use disorder in a subject.
Dependent claims recite that: the substance use disorder is drug addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome or overdose; the substance is alcohol, ketamine, opiate, opioid, cocaine, morphine, amphetamines, nicotine, cotinine, heroin, amphetamine, methamphetamine, cannabis, cannabinoid, narcotic analgesic combinations, drug overdose, or chronic substance use; the biological sample is plasma, a tissue, cell, blood, urine or serum; and the biomarker further comprises one or more additional biomarkers selected from CCL11 for chronic stress following substance use, Nectin-4 for skin irritation following substance use, MPO (myeloperoxidase) for alcohol dependence following substance use, and ADAM10 for synaptopathy following substance use. The claimed method thus broadly encompasses the detection, prediction, prognosis, monitoring or prediction of treatment response of any condition related to substance use including, substance abuse, addiction, dependence, withdrawal or overdose for a wide range of drugs based upon a single measurement of the biomarker NFL. The specification as filed does not reasonably support the full scope of the presently claimed invention.
In contrast to the breadth of the claims, what is provided in the specification is quite narrow. With respect to the biomarker NFL, the working examples describe measuring the levels of NFL in blood samples of ketamine-dependent patients (Examples 6 and 9) and in alcohol use disorder (AUD) patients (Examples 8 and 9). The Example 6 study found that within the ketamine dependence group, age was the only clinical variable showing a significant correlation with NFL levels, and there was no significant correlation for any of the ketamine use variables, including length of use (total years of ketamine use), daily dose, or ketamine craving (see [00133]). Example 8 found that NFL, CCL11 and MPO plasma levels were all significantly elevated in AUD patients compared to age- and gender-matched control subjects, after adjustment for smoking (Table 16). And Example 9 describes risk prediction models using ROC curves for the different plasma biomarkers associated with drug use (opioid, ketamine, and alcohol dependence). For NFL, only alcohol and ketamine dependent patients were reported, with the specificity, sensitivity and AUC of NFL as a biomarker being good, but not excellent, for predicting these substance disorders (Table 17).
Note also that Nectin-4 was not assessed as a potential biomarker for alcohol-dependency, neither CCL11 nor MPO were assessed as biomarkers for ketamine dependency, and ADAM10 was not assessed at all in the working examples as being associated with any substance use disorder. Further, there are no working examples pertaining to the prediction or evaluation of a treatment response or prognosis in an alcohol- or ketamine- dependent patient using NFL as a biomarker, such as demonstrating treatment efficacy based upon reduced NFL levels. Accordingly, the guidance and working examples provided by the instant specification is limited with respect to the ability of the different biomarkers, and NFL in particular, to predict, monitor, stage or prognose any substance use disorder (other than alcohol or ketamine abuse), or treatment response in a substance use disorder patient, consistent with the breadth of the presently claimed invention.
While the skill level in the art is high, the predictability is low. The prior art recognizes NFL as a biomarker of neural injury and neurodegeneration (see, for example, US 2017/0045534 A1 by Wang et al. and WO 2019/199865 A1 by Hrusovsky et al.), and that heavy chronic or binge alcohol use can lead to debilitating diseases of the central and peripheral nervous systems (de la Monte et al. Acta Neuropathol. 2014, 127(1):71-90). De la Monte, for instance, reports that chronic alcohol abuse is associated with significant structural and functional injury to the brain, including neurotoxic injury, degeneration of cortical and subcortical areas of the brain, and white matter (myelin) degeneration. However, the prior art also recognizes unpredictability with respect to the biomarker NFL in different substance use patients. In particular, Garcia-Sevilla et al. (NeuroReport, 1997, 8:1561-1570) found that NFL levels were significantly reduced in postmortem frontal cortex samples from opiate addicts (who had died of drug overdose) compared to control subjects (see Fig. 1A). And even amongst the opiate abusers, Garcia-Sevilla observed that heroin addicts had significantly lower cortical NFL levels than methadone users (Fig. 1B).
Consistent with the findings of Garcia-Sevilla, Samantaray et al. (Brain Res. 2015, 1622:7-21) reported that in a mouse model of alcohol dependence, chronic intermittent ethanol exposure and withdrawal (CIE), there was significant loss of axonal proteins (such as NFL; see Fig. 3) and myelin in the brain and spinal cord. Taken together, these findings are in direct opposition to the presently claimed method which encompasses, for example, the detection of opiate addiction (or alcohol dependence/withdrawal) in a tissue sample (i.e., brain tissue) by detecting an increase in NFL levels compared to a control sample. Given such unpredictability in the art, undue experimentation would be required of the skilled artisan in order to determine how NFL levels are a related to different substances (alcohol, ketamine, opiates, cannabis, narcotics, etc.) under different conditions (chronic use, acute use, addiction, dependence/tolerance, withdrawal, overdose, etc.) and within different biological samples (blood, tissue, cells, urine, plasma, serum, cerebrospinal fluid, etc.) in order to perform the detection method as claimed.
The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In view of the breadth of the claims, the limited guidance and working examples provided in the specification, the high level of unpredictability as evidenced by the prior art, and the amount of required experimentation, it is the examiner’s position that undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to practice the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir., 1988).
Claim Rejections - 35 USC § 101
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.
8. Claims 1-6 and 10-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) a method for detecting or predicting a substance use disorder and/or monitoring a progress of the substance use disorder, and/or predicting a treatment response or prognosis of a substance use disorder in a subject, comprising detecting the level of a biomarker neurofilament light chain (NFL) in a biological sample obtained from the subject, wherein a level of NFL that is at least 1.0 times higher than a level of a control is indicative of neurotoxicity severity following substance use, and/or predicting treatment responses or prognosis of substance use disorder in a subject. The claims are directed to a series of steps and are a process and, therefore a statutory category. The answer to Step 1 of the analysis is yes.
The claims are also directed to natural phenomenon correlation judicial exception (wherein a level of NFL that is at least 1.0 times higher than a level of a control is indicative of neurotoxicity severity following substance use, and/or predicting treatment responses or prognosis of substance use disorder in a subject) which is the natural correlation between the level of a biomarker (NFL) and the presence of a disease or disorder (substance use disorder). The limitations of detecting, predicting or prognosing, as drafted and under their broadest reasonable interpretation, cover performance of the limitations in the mind, and thus fall within the “mental processes” grouping of abstract ideas judicial exceptions. Therefore, the answer to Step 2A, Prong 1, is also yes. The claims recite the judicial exceptions of a natural phenomenon and an abstract idea.
These judicial exceptions are not integrated into a practical application. In particular, the claims recite an obtaining step (obtaining a biological sample) and a detection step (detecting the level of a biomarker NFL, or additional biomarkers CCL11, Nectin-4, MPO and/or ADAM10). The obtaining and detecting steps must be performed in order to accomplish the diagnostic method, and therefore are considered data gathering steps. These additional elements therefore do not integrate the judicial exception(s) into a practical application because they do not impose any meaningful limits on practicing the method. Thus, the answer to Step 2A, Prong 2, is no, the judicial exception(s) is/are not integrated into a practical application.
Finally, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As discussed above with respect to the integration of the natural correlation/abstract idea into a practical application, the additional elements of obtaining a biological sample and detecting a level of NFL within the sample amount to routine and conventional activity that is performed by those of ordinary skill in the art in order to apply the natural correlation. In particular, the prior art recognizes that NF-L is a biomarker of neural injury or damage, and can be detected by immunoassay in blood serum or plasma samples. For example, Weston et al. (Neurology, 2017, 99:2167-2175; listed on 05/05/2023 IDS) detected higher levels of NFL within serum samples from individuals that were PSEN1 or APP mutation carriers (which are associated with familial Alzheimer’s disease (AD)) compared to non-carriers. And both Hruovsky et al. (WO 2019/199865 A1) and Wang et al. (US 2017/0045534 A1) disclose that NF-L is a biomarker that is diagnostic of nerve cell injury and/or neuronal disorders, including addiction (Hruovsky [00236]) and alcohol addiction or alcoholism (Wang [0013], [0124]), and can be detected in blood samples such as serum or plasma, as well as cerebrospinal fluid (CSF) samples. Thus, the obtaining of a biological sample from a subject and the detection and measurement of biomarker levels within the sample, such as by using an antibody-based assay, were concepts that were well-understood, routine and conventional within the art at the time of filing, particularly in association with the diagnosis or detection of neural injuries, diseases or disorders. See also, for instance, paragraphs [00122] and [00154] of the instant specification teaching the use of a commercially available immunoassay kit to measure NF-L levels in serum or plasma samples.
Accordingly, when all of the elements are considered, both individually and in combination, the claims as a whole do not amount to significantly more than the judicial exceptions. Therefore, the answer to Step 2B is no, the claims are not patent eligible.
Conclusion
9. No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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, Jeffrey Stucker can be reached at 571-272-0911. 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.
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
Prosecution Insights