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 .
Status of the Claims
Claims 1, 4-6, and 29-41 are pending. Claims 1, 31, 32, 37, and 38 are amended. Claims 1, 4-6, and 29-41 are examined herein.
Maintained 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.
The rejections under 35 U.S.C. §101 are maintained. The rejections have been updated, where appropriate, in view of Applicant’s amendments.
Claims 1, 4-6, and 29-41 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception, specifically a law of nature (a natural correlation between chitinase biomarker concentrations and ALS progression) and an abstract idea (mental processes of evaluation and diagnosis). The claims do not integrate the judicial exception into a practical application and do not include additional elements sufficient to amount to significantly more than the judicial exception itself.
This rejection is made in accordance with Patent Subject Matter Eligibility as set forth in MPEP §2106. Analysis of subject-matter eligibility under 35 U.S.C. §101 requires consideration under these steps as followed:
Step 1: Are the claims to a statutory category (process, machine, manufacture, or composition of matter)?
Step 2A (Prong 1): Are the claims directed to a judicial exception (law of nature, natural phenomenon, or an abstract idea)?
Step 2A (Prong 2): Do the claims recite additional elements that integrate the judicial exception into a practical application?
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception (inventive concept)?
Step 1 – Statutory Category (Refer to MPEP §2106.03): Claims 1, 4-6, and 29-41 are drawn to a process, which fall within a statutory category under 35 U.S.C. §101.
Step 2A, Prong One – Recitation of a Judicial Exception (Refer to MPEP §2106.04): According to MPEP §2106.04(b), a concept that have been held by the courts to constitute law of nature/natural phenomena, wherein the correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk based on Cleveland Clinic Foundation v. True Health Diagnostics, LLC.
Claim 1 states “a method of categorizing for treatment a subject suspected of having or at risk of having Amyotrophic Lateral Sclerosis (ALS)” and “wherein an increased concentration of Chit-1 in the biological fluid sample relative to a control concentration of Chit-1, CHI3L1, or both obtained from a control biological fluid sample is indicative of fast progressing ALS in the subject and the subject is confirmed as a candidate for a neurologic treatment.” Here, claim 1 recites a naturally occurring correlation between chitinase biomarker concentration and ALS progression. This relationship exists in nature independent of human action and therefore constitutes a law of nature. Furthermore, in MPEP §2106.04(a), the courts consider mental processes (thinking) that can be performed in the human mind to be an abstract idea. Examples of mental processes include observations, evaluations, judgments, and opinions. Hence, claim 1 recites mental processes of the following: evaluating information, making a classification, and drawing a diagnostic conclusion. These actions can be performed in the human mind or by a human using a pen and paper, constituting an abstract idea.
Claims 4-6 are dependent of Claim 1 and add limitations specifying: “wherein recovery by the immunoassay to determine the concentration of Chit-1 is at least 70%, at least 80%, at least 90%, or at least 95%” (Claim 4), “wherein inter-assay variability of the immunoassay to determine the concentration of Chit-1 is less than 11%” (Claim 5), “wherein intra-assay variability of the immunoassay to determine the concentration of Chit-1 is less than 6%” (Claim 6). These claims retain the same natural correlation and mental evaluation steps recited in Claim 1. Indicating assay performance/validation parameters and revealing assay precision/repeatability metrics does not remove the claims from the recited judicial exceptions. Accordingly, claims 4-6 each recite a law of nature and an abstract idea.
Also, claims 29-41 are dependent of Claim 1 and add limitations specifying: “wherein the immunoassay comprises a goat anti-human Chit-1 antibody, and a goat anti-mouse IgG-HRP conjugate” (Claim 29), “wherein the immunoassay is performed with a Tris-based buffer solution comprising sodium chloride, ProClin 300, and BSA at a pH of 7.6” (Claim 30), “wherein a Chit-1 concentration of at least 28 ng/ml in the biological fluid sample of the subject is indicative of fast progressing ALS” (Claim 31), “wherein a CHI3L1 concentration of at least 390 ng/mL in the biological fluid sample of the subject is indicative of fast progressing ALS” (Claim 32), “determining a concentration of phosphorylated neurofilament heavy chain (pNFH) in the biological fluid sample” (Claim 33), “wherein correlation between increased Chit-1 and increased pNFH indicates neuroinflammation linked to ALS progression” (Claim 34), “determining a concentration of CHI3L2 in the biological fluid sample” (Claim 35), “wherein an increased CHI3L2 concentration is indicative of microglial activation,” (Claim 36), “wherein the subject's baseline Chit-1 concentration is at least 28 ng/mL” (Claim 37), “wherein the subject's baseline CHI3L1 concentration is at least 390 ng/mL,” (Claim 38), “wherein a decreased or maintained Chit-1 concentration during a treatment period is indicative of therapeutic efficacy,” (Claim 39), “wherein determining an increased concentration of Chit-1 distinguishes ALS from other neurological diseases selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, or neuropathy” (Claim 40), “wherein the immunoassay is capable of differentiating a bulbar-onset ALS subtype from a limb-onset ALS subtype., and the Chit-1 concentration differentiates the onset subtype” (Claim 41). Again, these claims retain the same natural correlation and mental evaluation steps recited in Claim 1. The added limitations in these dependent claims are largely reagent/buffer details, additional biomarker-based classification correlations, numeric baseline thresholds, and interpretive conclusions does not remove the judicial exceptions from the claims. Therefore, claims 29-41 each recite a law of nature and an abstract idea.
Step 2A, Prong Two – Integration into a Practical Application (Refer to MPEP §2106.04 (d)): The additional elements recited in Claim 1 include: “performing an immunoassay to determine a concentration of Chitinase 1 (Chit-1), Chitinase-3 like-protein-1 (CHI3L1), or both”; “wherein the immunoassay is a sandwich enzyme-linked immunosorbent assay (ELISA)”; “wherein the biological fluid sample is cerebrospinal fluid (CSF)”; and “wherein the limit of detection of the immunoassay for Chit-1 and/or CHI3L1 is less than 0.08 ng/mL.” These additional elements merely describe how data is acquired so that the judicial exceptions (the natural correlation and mental diagnosis) may be evaluated. The immunoassay, ELISA format, sample type, and assay sensitivity function as data-gathering steps that supply input to the natural correlation and diagnostic inference. Hence, Claim 1 does not integrate the judicial exception into a practical application.
On the other hand, MPEP §2106.04(d)(1) indicates that one way to demonstrate such integration is when the claimed invention improves the functioning of a computer or improves another technology or technology field. Although [0061] of the specifications states that “in one aspect, an improved immunoassay for detecting a chitinase protein is a sandwich enzyme linked immunosorbent assay (ELISA). Improvements over commercially available ELISA’s for chitinases include use of preferred capture antibodies and detection antibodies, and improved buffers, washes and washing agents,” MPEP §2106.04(d)(1) further highlights that if the specification sets forth an improvement in technology, the claim must be evaluated to ensure that the claim itself reflects the disclosed improvement. That is, the claim includes the components or steps of the invention that provide the improvement described in the specification. Here, claim 1 does not recite the “improved” features from the specifications. Accordingly, those improvements cannot be considered when determining whether the claim integrates the judicial exception into a practical application. The additional elements of claim 1 merely recite performing a sandwich ELISA to obtain biomarker data, which is then evaluated to determine what the data “is indicative of.” Such data-gathering and diagnostic evaluation do not integrate the judicial exception in to a practical application.
Furthermore, MPEP §2106.04(d)(2) indicates that another way to demonstrate such integration is when the additional elements apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. Although Claim 1 recites “categorizing for treatment” and “confirmed as candidate for a neurologic treatment,” the claim does not recite administering a treatment, selecting a specific therapy, or altering treatment based on the outcome. Instead, the claim concludes with an informational outcome based on the correlation. Therefore, Claim 1 still does not integrate the judicial exception into a practical application.
Additionally, the additional elements introduced by Claims 4-6 and 29-41 are limited to the following: assay performance characteristics (Claims 4-6); assay implementation details such as reagents and buffer compositions (Claims 29-30); numerical thresholds or baselines that quantify the same natural correlation (Claims 31-32, 37-38); additional biomarker measurements (Claims 33, 35); additional correlations or interpretive conclusions regarding disease state, progression, response, differentiation, or subtype (Claims 34, 36, 39-41). These additional elements constitute refined data gathering, measurement precision, or the articulation of the same biological correlations and diagnostic classifications. They do not apply the judicial exception in a manner that effects a particular treatment or improves another technology or technical field. Rather, the claims end in informational outcomes (e.g., “indicative of,” “distinguishes,” “differentiates”) without reciting a concrete action that uses the result in a transformative way. Accordingly, Claims 4-6 and 29-41 do not integrate the judicial exception into a practical application.
Step 2B, Inventive Concept (Refer to MPEP §2106.05): According to MPEP §2106.05(d), one consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional actional activities previously known to the industry. If, however, the additional element (or combination of elements) is no more than well-understood, routine, conventional activities previously known to the industry, which is recited at a high level of generality, then this consideration does not favor eligibility. For example, the additional elements recited in Claim 1 include: performing an immunoassay; using a sandwich ELISA format; analyzing cerebrospinal fluid; and achieving a specified limit of detection. These additional elements recited in Claim 1 were previously taken by those in field as demonstrated by Filippou et al. (A new enzyme-linked immunosorbent assay (ELISA) for human free and bound kallikrein 9. Clinical Proteomics. Vol. 14, No. 1, January 2017) and Varghese et al. (Chitotriosidase – A Putative Biomarker for Sporadic Amyotrophic Lateral Sclerosis. Clinical Proteomics. Vol. 10, No. 1, December 2013 – IDS entered 08/26/2020).
Specifically, with respect to performing an immunoassay and using a sandwich ELISA format with a defined limit of detection, Filippou et al. discloses how “a sandwich type ELISA immunoassay was developed using mouse monoclonal antibodies as capture and biotinylated detection antibodies, respectively” (page 5) and “the limit of detection (LOD) was around 15 pg/mL” (page 6). These disclosures demonstrate that performing an immunoassay, employing a sandwich ELISA, and achieving a specified detection limit were conventional laboratory practices. With respect to analyzing cerebrospinal fluid (CSF), Varghese et al. report that “the present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis, and could be associated with the pathogenesis of this disease” (page 1). Here this reveals evidence that CSF analysis for biomarkers in ALS was already routine in the field. Therefore, these additional elements do not add an inventive concept because they merely apply well-understood, routine, and conventional laboratory techniques to acquire data so that the natural correlation may be evaluated. Claim 1 does not recite a new or unconventional assay technique, nor does it improve the functioning of the immunoassay itself; hence, these elements do not transform the judicial exception into patent-eligible subject matter. Accordingly, Claim 1 does not recite additional elements that amount to significantly more than the judicial exception.
Moreover, the additional elements recited in Claims 4-6 and 29-41 consist of assay performance parameters, assay components, sample conditions, measurement steps, and biomarker thresholds, all of which constitute well-understood, routine, and conventional activities in the field of immunoassay-based diagnostics. None of these limitations introduce a non-conventional assay architecture, new detection chemistry, or technological improvement to immunoassay operation itself. Rather, they describe routine implementation details used to obtain or evaluate data related to the judicial exceptions. This is one aspect to how the additional elements of Claims 4-6 and 29-41 do not amount to significantly more than the judicial exception.
Another aspect to how the additional elements of Claims 4-6 and 29-41 do not amount to significantly more than the judicial exception is based on MPEP §2106.05(g). According to MPEP §2106.05(g), another consideration when determining whether a claim recites significantly more in Step 2B is whether the additional elements add more than insignificant extra-solution activity to the judicial exception. The term “extra-solution activity” can be understood as activities incidental to the primary process or product that are merely a nominal or tangential addition to the claim. Examples of activities that the courts have found to be insignificant extra-solution activity: performing clinical tests on individuals to obtain input for an equation, determining the level of a biomarker in blood, assessing or measuring data derived from an ultrasound scan – to be used in a diagnosis. This indicates that the additional elements in Claims 4-6 and 29-41 also constitute insignificant extra-solution activity, because they primarily relate to: data gathering (measuring biomarker concentrations), data refinement (assay precision and validation), and data evaluation (comparing values, identifying correlations, reporting what the results “indicate”). These steps do not add a new use, new transformation, or technological/therapeutic action beyond enabling the correlation to be evaluated. Thus, this is another aspect to how the additional elements of Claims 4-6 and 29-41 do not amount to significantly more than the judicial exception.
Ultimately, claims 1, 4-6, and 29-41, when considered individually and as an ordered combination are directed to a law of nature and an abstract idea, are not integrated into a practical application, and do not recite additional elements sufficient to amount to significantly more than the judicial exception.
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.
The rejection under 35 U.S.C. §102 is maintained. The rejection has been updated, where appropriate, in view of Applicant’s amendments.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Steinacker et al. (Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. Journal of Neurology, Neurosurgery and Psychiatry. Vol. 89, No. 3, published online first November 2017) as evidenced by MBL ELISA (2017, retrieved from ASIA-https://www.mblbio.com/bio/g/dtl/P/?pcd=CY-8074).
In particular, Steinacker et al. reports that “CSF was obtained by lumbar puncture, centrifuged, aliquoted and stored within 2 hours at -80 °C until analysis” (page 240) and “ELISA kits were used for CHIT1 (MBL)” (page 240). Here Steinacker et al. reveals: the use of an ELISA immunoassay for CHIT1, in CSF samples, using a commercial MBL ELISA kit. Additionally, Steinacker et. al further teaches that CHIT1 concentration is used to determine ALS progression, stating “in ALS, CHIT1 CSF levels were higher compared with controls” (page 239) and CSF “CHIT1 concentrations were correlated with ALS disease progression and severity” (page 239). Also, Steinacker et al. further discloses that CHIT1 can distinguish fast-progressing ALS patients, stating that based on CSF CHIT1 levels, the “sensitivity and specificity for discrimination of ALS cases with fast PRs (progression rates) were 88% and 90% at a cut-off of 2848 pg/mL, and for discrimination of slowly progressing cases at a cut-off of 2088 pg/mL 84% and 80%,” (page 242). These disclosures teach: detecting CHIT1 concentration and comparing to controls, using ELISA, and determining fast-progressing ALS based on the detected concentration. Since Steinacker et. al identifies MBL ELISA as the manufacturer of the CHIT1 ELISA kit used in the study – as evidenced by MBL ELISA, the documentation discloses every structural and functional element of the immunoassay. Specifically, MBL ELISA states “the MBL Research Product CircuLex Human Chitotriosidase ELISA Kit employs the quantitative sandwich enzyme immunoassay technique” (page 2). This discloses the sandwich ELISA format recited in amended Claim 1. MBL ELISA further discloses analytical sensitivity, stating that “the limit of detection is better than 48.3 pg/mL of sample” (page 10). A detection limit of 48.3 pg/mL = 0.0483 ng/mL, which is below the claimed “less than 0.08 ng/mL” threshold. Here, the exact numerical LOD recited in Claim 1 is anticipated. Therefore, Steinacker et al.’s disclosure as implemented using the identified MBL ELISA anticipates Claim 1 in its entirety.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
The rejections under 35 U.S.C. §103 are maintained. The rejections have been updated, where appropriate, in view of Applicant’s amendments.
Claims 1, 31, 33, 34, 35, 37, 39, 40, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al. (Cerebrospinal Fluid Macrophage Biomarkers in Amyotrophic Lateral Sclerosis. Annals of Neurology. Vol. 83, No. 2, January 2018 – IDS entered 08/26/2020) in view of Steinacker et al. (Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. Journal of Neurology, Neurosurgery and Psychiatry. Vol. 89, No. 3, published online first November 2017), Varghese et al. (Chitotriosidase – A Putative Biomarker for Sporadic Amyotrophic Lateral Sclerosis. Clinical Proteomics. Vol. 10, No. 1, December 2013 – IDS entered 08/26/2020), and Filippou et al. (A new enzyme-linked immunosorbent assay (ELISA) for human free and bound kallikrein 9. Clinical Proteomics. Vol. 14, No. 1, January 2017) as evidenced by MBL ELISA (2017, retrieved from ASIA-https://www.mblbio.com/bio/g/dtl/P/?pcd=CY-8074).
Regarding Claim 1, Thompson et al. teaches how “three macrophage-derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), and chitinase-3-like protein 2 (CHI3L2)” (page 258). These “chitinase levels correlated with disease progression rate” (page 258), supporting the clinical relevance of measuring “effective biomarkers to help reduce diagnostic delay, stratify, and monitor response in therapeutic trials” (page 259).
Although Thompson et al. teaches measuring CHIT1 and/or CHI3L1 in CSF for ALS progression assessment and stratification, Thompson et al. does not mention the following: the specific immunoassay format (e.g., sandwich ELISA), provide explicit fast-progressor cut-off values, and the specific limit of detection (LOD) thresholds.
While, Steinacker et al. teaches that in “ALS, CHIT1 CSF levels were higher compared with controls” (page 239) and CSF “CHIT1 concentrations were correlated with ALS disease progression and severity” (page 239). Steinacker et al. further discloses that CHIT1 can distinguish fast-progressing ALS patients, stating that based on CSF CHIT1 levels, the “sensitivity and specificity for discrimination of ALS cases with fast PRs (progression rates) were 88% and 90% at a cut-off of 2848 pg/mL, and for discrimination of slowly progressing cases at a cut-off of 2088 pg/mL 85% and 80%,” (page 242). Steinacker et al. also expressly frames CHIT1 as suitable for stratification, revealing that “CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials” (page 239). Although Steinacker et al. uses ELISA to measure CHIT1 and profoundly teaches the central inference recited in Claim 1 of an “increased concentration of Chit-1 in the biological fluid sample relative to a control concentration of Chit-1, CHI3L1, or both obtained from a control biological fluid sample is indicative of fast progressing ALS in the subject” - Steinacker et al. does not disclose measuring CHI3L1 as part of the methodology.
However, Varghese et al. discloses “the first report demonstrating an increase in the levels of four proteins namely, CHIT-1, osteopontin, CHI3L2 and CHI3L1 in the CSF of ALS patients using the novel and precise quantitative proteomics and ELISA” (page 3). Although Varghese teaches that CHIT1 and CHI3L1 are measured in ALS CSF using ELISA – confirming technical feasibility of immunoassay measurement, Varghese does not classify patients by progression rate or specific assay performance thresholds.
But, Filippou et al. teaches routine analytical validation parameters of sandwich ELISA assays and explicitly discloses limits of detection, stating that “the limit of blank (LOB) was estimated at 10 pg/mL (matrix was 6% BSA) and the limit of detection (LOD) was around 15 pg/mL (LOD = LOB + 1.64 * SD)” (page 6). Here a limit of detection of 15 pg/mL equates to 0.015 ng/mL. Although Filippou et al. discloses an LOD well below the claimed LOD of “less than 0.08 ng/mL,” Filippou et al. is not relied upon for ALS biology.
Lastly, MBL ELISA is relied upon solely as evidence of routine ELISA implementation available prior to the effective filing date of the claimed invention. The MBL ELISA product information demonstrates that quantitative ELISA measurement of human CHIT1 was commercially available and routinely implemented, and the product page expressly cites Varghese et al., confirming that such ELISA kits were actually used in ALS research well before the effective filing date. Here, MBL ELISA is used to further show that a PHOSITA had access to suitable ELISA tools for measuring CHIT1 and/or CHI3L1 .
Accordingly, it would have been obvious to a PHOSITA before the effective filing date to combine the teachings of Thompson et al., Steinacker et. al, Varghese et al., and to implement those teachings using routine sandwich ELISA techniques as evidenced by Filippou and MBL ELISA, for at least the following reasons:
First, the clinical problem and target biomarkers were clearly identified in the art. Thompson et al. teaches that CHIT1 and CHI3L1 are increased in ALS, correlate with disease progression, and are useful for patient stratification. A PHOSITA would therefore have been motivated to quantitatively measure CHIT1 and/or CHI3L1 in ALS patients in order to assess disease progression and treatment relevance. Second, Steinacker et al. establishes that CSF-CHIT1 specifically discriminates fast-progressing ALS patients, providing a further clear incentive to quantitatively measure CHIT1 in CSF for stratification. Third, Varghese et al. confirms that ELISA-based measurement of CHIT1 and CHI3L1 in ALS CSF was already practiced in the field, making ELISA the natural choice of measurement platform. Fourth, Filippou demonstrates that achieving an LOD well below 0.08 ng/mL was a predictable result of routine ELISA optimization, and MBL ELISA confirms that such assays were commercially available and actually used in ALS research prior to the filing date. Finally, the references are fully compatible and present no teaching away; rather, they collectively point toward applying routine, sensitive sandwich ELISA assays to measure CSF CHIT1 and/or CHI3L1 for ALS progression stratification, yielding predictable results. Therefore, Claim 1 represents no more than the application of known analytical techniques to known biomarkers for their known purpose.
Regarding Claim 31, Steinacker et al. reports quantitative CSF CHIT1 concentrations for fast progressing ALS patients, disclosing that in fast progression ALS, CSF CHIT1 levels have a median value of 15023 pg/mL (or 15.024 ng/mL) and the range is 5,880 – 40,211 pg/mL (or 5.88 – 40.21 ng/mL) (Table 1, page 240).
Additionally, Varghese et al. independently confirms quantitative CSF CHIT 1 concentrations in ALS patients measured by ELISA, stating that “in the ALS-CSF, the level of CHIT-1 ranged between 5000 – 54,000 pg/ml (or 5 – 54 ng/mL)” (page 3).
Taken together, the prior art demonstrates that CSF CHIT1 concentrations in ALS patients routinely fall within and above the claimed threshold in claim 31, that elevated CHIT1 levels are associated with faster disease progression, quantitative ELISA-based measurement of CHIT1 in ALS CSF was routine. In view of these teachings, a PHOSITA would therefore have been motivated to select a CHIT1 concentration of at least 28 ng/mL (or 28,000 pg/mL) to identify fast-progressing ALS patients with a reasonable expectation of success. This represents routine optimization and a selection of a value from a known range yields predictable results and require no inventive skill.
Regarding Claim 33, Thompson et al. discloses that phosphorylated neurofilament heavy chain (pNFH), are measured in CSF and correlated with ALS disease progression. Specifically, Thompson et al. reveals that “the neurofilament protein, pNFH, is a marker of axonal damage, and multiple studies have shown significant elevation in ALS CSF that also show correlation with disease progression rate” (page 262). Here Thompson et. al discloses that pNFH is a known ALS biomarker, pNFH concentration is determined in CSF, and pNFH levels are used in ALS disease assessment and stratification. Once a PHOSITA is motivated, as taught by Claim 1 and its applied references, to perform ELISA-based biomarker measurements in ALS for stratification and disease-progression assessment, including an additional well-established ALS biomarker such as pNFH in the same immunoassay workflow would have been a routine and predictable variation with a reasonable expectation of success.
Regarding Claim 34, Thompson et al. already establishes that since CHIT1 levels increase with ALS progression, and reveals that “neuroinflammatory mechanisms have been consistently implicated through various experimental paradigms. These results support a key role for macrophage activity in ALS pathogenesis, offering novel target engagement and pharmacodynamic biomarkers for neuroinflammation-focused ALS therapy” (page 258). Thompson et al. also discloses “neuroinflammation undoubtedly occurs in ALS” (page 259). On the other hand, Steinacker et al. independently confirms that pNFH increases with ALS severity, highlighting that similar to CHIT1 concentrations, pNFH “correlated with ALS disease progression and severity” (page 239). Steinacker et al. further discloses that “concentrations of pNFH were significantly higher in ALS compared with controls” (page 242). Given that ALS progression is understood in the art to involve interacting neuroinflammatory and neurodegenerative mechanisms, a PHOSITA would have been motivated to interpret concurrent increases in CHIT1 and pNFH as indicative of neuroinflammation linked to ALS progression. Such interpretation represents a predictable synthesis of known biomarker information, requires no inventive step, and merely applies known biomarkers for their established purposes in ALS disease assessment.
Regarding Claim 35, Thompson et. al discloses that CHI3L2 is measured as a part of an ALS biomarker, CHI3L2 levels increased in ALS, and CHI3L2 levels “correlated with disease progression rate” (page 258). Claim 35 does not recite a new assay format, a cutoff value, or a new interpretation step. Once a PHOSITA is motivated to perform ELISA-based biomarker measurements for ALS as recited in Claim 1, extending that same assay to measure an additional known ALS-associated biomarker such as CHI3L2 would have been a routine and predictable modification with a reasonable expectation of success.
Regarding Claim 37, given that Steinacker et al. reports ALS CHIT1 concentrations spanning and exceeding 28 ng/mL, it would have been obvious to a PHOSITA before the effective filing date of the claimed invention to adopt a baseline CHIT1 concentration of at least 28 ng/mL. Such selection constitutes the use of a result-effective variable derived from known quantitative data and would have yielded predictable results with a reasonable expectation of success, consistent with routine optimization and interpretation of biomarker thresholds in the art.
Regarding Claim 39, Thompson et al. discloses that measuring CHIT1 levels can “help reduce diagnostic delay, stratify, and monitor response in therapeutic trials” (page 259). Steinacker et al. also teaches that “CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials” (page 239). Claim 39 does not require: a new assay format, a specific treatment regiment, or a novel biological mechanism. Rather, it recites a clinical interpretation step that flows directly and logically from the known relationship between CHIT1 concentration and ALS disease progression disclosed in the prior art. Thus, it would have been obvious to a PHOSITA before the effective filing date of the claimed invention to interpret decreased or maintained CHIT1 concentration during a treatment period as indicative of therapeutic efficacy. A PHOSITA would therefore reasonably expect that an effective treatment would reduce or stabilize a biomarker known to increase with disease progression, making the claimed interpretation a predictable application of established biomarker principles.
Regarding Claim 40, Steinacker et al. reports numerical median values and ranges of CSF CHIT1 concentrations for ALS and non-ALS neurological diseases, stating the following CSF CHIT1 concentrations (pg/mL): “ALS – CHIT1 (pg/mL): 115023 (5880-40211), Alzheimer’s disease – CHIT1 (pg/mL): 2470 (1523-4538), Parkinson’s disease – CHIT1 (pg/mL): 1335 (605-6045), Polyneuropathy: CHIT1 (pg/mL): 2440* (890-14280)” (Tables 1 and 2, pages 240-241). Since Steinacker et al. reports that ALS patients exhibit substantially higher CHIT1 concentrations than patients with other neurological diseases and demonstrates CHIT1 as suitable for differential diagnosis and disease characterization, a PHOSITA would therefore have been motivated to use increased CHIT1 concentration to distinguish ALS from other neurological diseases with a reasonable expectation of success, yielding predictable results. Claim 40 merely recites the application of expressly disclosed numerical CSF CHIT1 differences to the routine task of differential diagnosis. The claim does not recite a new biomarker or unexpected property.
Regarding Claim 41, Thompson et al. explicitly incorporates onset site (bulbar vs spinal) into statistical models evaluating CHIT1 levels, disclosing that “multiple linear regression models controlling for the effect of age, sex, absolute ALSFRS-R, progression rate, and site of onset (bulbar vs spinal) on chitinase protein level demonstrated significant positive correlation with disease progression rate for CHIT1, CHI3L1, and CHI3L2” (page 261) and “CHIT1, p < 0.001; gradient = 0.27 log abundance units per unit increase in log disease progression rate” (page 261-262). These disclosures demonstrate that CHIT1 concentration is analyzed in the art while explicitly accounting for onset site (bulbar vs. spinal) and that CHIT1 correlates with disease progression and survival independent of onset subtype. A PHOSITA would therefore have been motivated to apply CHIT1 concentration as a stratification parameter across onset subtypes with a reasonable expectation of success, yielding predictable results.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. as applied to Claim 1 above, and further in in view of Andreasson et al. (A practical guide to immunoassay method validation. Frontiers in Neurology. Vol. 6, August 2015) and Novus CHIT1 ELISA (2017, retrieved from https://www.novusbio.com/products/chitotriosidase-chit1-elisa-kit_nbp2-75274).
While Thompson et al., Steinacker et al., Varghese et al., and Filippou et al., as applied to Claim 1 above, motivate and teach quantitative immunoassay measurement of CHIT1 and/or CHI3L1 in ALS, these references do not expressly describe numerical recovery validation parameters and therefore do not address the additional limitation of Claim 4.
However, Andreasson et al. teaches that recovery testing is a known and standard validation parameter in immunoassay development, stating that “the recovery of an analyte in an assay is the detector response obtained from an amount of the analyte added to and extracted from the biological matrix, compared to the detector response obtained for the true concentration of the analyte in solvent (page 6). Andreasson et al. further discloses that recovery is determined by spiking known analyte and calculating recovery using an established %Recovery formula, and the “acceptance range for the recovery is usually 80-120%” (page 6).
Although Andreasson et al. teaches the following: recovery experiments are routine, analyte spiking is standard practice, and percent recovery is calculated as a validation metric – Andreasson et al. does not provide numerical recovery values.
On the other hand, Novus CHIT1 ELISA, which was commercially available before the effective filing date of the claimed invention- provides numerical recovery data for a CHIT1 sandwich ELISA and therefore supplies the missing evidentiary support. Specifically, Novus CHIT1 ELISA reports “the recovery of Human CHIT1 spiked at three different levels in samples throughout the range of the assay was evaluated in various matrices” (page 9) and the average recovery values include “91% in serum, 100% in EDTA plasma, with recovery ranges falling between 84-106% (page 9)” – depending on the sample type.
Accordingly, it would have been obvious to a PHOSITA, once motivated by Claim 1’s teachings to measure CHIT1 using an immunoassay in the ALS context, to perform routine recovery validation as taught by Andreasson et al., and to reasonably expect recovery values within or exceeding 70-95%, as demonstrated by Novus CHIT1 ELISA. The combination therefore represents routine assay validation using art-recognized ELISA systems, yielding predictable results, and does not require inventive skill.
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. as applied to Claim 1 above, and further in in view of Crowther (The ELISA Guidebook: Second Edition. Humana Press. 2009) and Novus CHIT1 ELISA.
As discussed above with respect to Claim 1, Thompson et al., Steinacker et al., Varghese et al., and Filippou et al., collectively teach and motivate measuring CHIT1 concentration in cerebrospinal fluid using immunoassay techniques for assessing ALS disease progression and stratification, and establish that ELISA-based measurement of CHIT1 in ALS CSF was known, feasible, and routinely practiced.
However, these references do not expressly address assay precision requirements, including inter-assay variability (Claim 5) and intra-assay variability (Claim 6).
Crowther expressly teaches that assessment of assay precision is a routine and necessary component of ELISA development, stating that “evidence that an assay is repeatable is necessary for further development. This is accomplished by calculating the intra- and inter-plate variation using the same samples run in different plates and on different days (and with different operators)” (page295) and “coefficients (CVs) of variation (standard deviation [SD] of replicates, of mean of replicates, of equal to or less than 15% for the raw OD values indicate adequate repeatability at this stage of assay development” (page 295). While Crowther describes the methodology for evaluating assay precision, it does not provide numerical precision values. Novus CHIT1 ELISA provides such numerical evidence, reporting for inter-assay precision testing in which “3 samples with low, mid-range and high level Human CHIT1 were tested on 3 different plates, 20 replicates in each plate” (page 9), with reported inter-assay %CV values of “5.08%, 5.05%, and 4.78%” (page 9); and intra-assay precision testing in which “3 samples with low, mid range and high level Human CHIT1 were tested 20 times on one plate, respectively” (page 9), with reported intra-assay %CV values of “6.09%, 5.89%, and 3.13%,” (page 9). These values are well below the variability thresholds recited in Claims 5 and 6, respectively.
Accordingly, it would have been obvious to a PHOSITA before the effective filing date of the claimed invention, to combine: the motivation to measure CHIT1 using an immunoassay in the ALS context by Claim 1’s teachings, the standard ELISA repeatability and inter- and intra-assay precision assessment taught by Crowther, and the commercially demonstrated inter- and intra-assay CV performance of the Novus CHIT1 ELISA, because once motivated to implement a CHIT1 immunoassay in the ALS context, that PHOSITA would necessarily assess inter- and intra-assay variability as part of routine validation and would have reasonably expected to achieve precision values within the claimed ranges, as expressly demonstrated by art-recognized commercial CHIT1 ELISA kits. The claimed precision limitations therefore represent routine assay optimization using result-effective variables, yielding predictable results, rather than an inventive contribution.
Claims 29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. as applied to Claim 1 above, and further in in view of Crowther and R&D Systems AF3559 (https://www.rndsystems.com/products/human-chitotriosidase-chit1-antibody_af3559?keywords=AF3559 - available at least since 2009 as evidence by the reference of Agapov et al. Macrophage Chitinase 1 Stratifies Chronic Obstructive Lung Disease. American Journal of Respiratory Cell and Molecular Biology. Vol. 41, No. 4, October 2009), R&D Systems MAB5591 (https://www.rndsystems.com/products/human-chitotriosidase-chit1-antibody-397513_mab35591?keywords=MAB35591 - available at least since 2009 as evidence by the reference of Agapov et al.), and R&D Systems HAF007 (https://www.rndsystems.com/products/mouse-igg-horseradish-peroxidase-conjugated-antibody_haf007?keywords=HAF007 - available at least since 2013 as evidence by the reference of DeVay et al. Characterization of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Trafficking Reveals a Novel Lysosomal Targeting Mechanism via Amyloid Precursor-like Protein 2 (APLP2). The Journal of Biological Chemistry. Vol. 288, No.15, April 2013).
As discussed above with respect to Claim 1, Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. collectively teach and motivate ELISA-based measurement of CHIT1 in CSF for assessing ALS disease progression and stratification, and establish that immunoassay-based quantification of CHIT1 in ALS CSF was known, feasible, and routinely practiced prior to the effective filing date of the claimed invention. However, these references do not expressly teach in-house ELISA reagent configuration, including selection of antibody species.
But, Crowther teaches that in-house immunoassays require routine selection, characterization, and maintenance of assay reagents, including antibodies, and that such activities are conventional laboratory practice. Specifically, Crowther highlights that “with in-house assays, new reagents must be thoroughly characterized, and once this is done the controls can be restricted to those used for monitoring assay performance. Regular checks are needed to examine deterioration in reagents” (page 320). Although Crowther does not prescribe any inventive antibody species or conjugation, R&D Systems product webpages publicly disclose the identity, species origin, and ELISA applicability of each antibody component recited in Claim 29.
Specifically, the R&D Systems AF3559 product webpage (available at least as early as 2009) identifies a polyclonal goat IgG antibody recognizing human CHIT1 and validated for ELISA use, providing the complementary capture/detection antibody species recited in Claim 29. The corresponding R&D systems MAB35591 product webpage (available at least as early as 2009) identifies a monoclonal mouse IgG antibody specific for human CHIT1 and suitable for ELISA applications, confirming availability of a mouse anti-human CHIT1 antibody prior to the effective filing date of the claimed invention. Lastly, the R&D Systems HAF007 product webpage (available at least as early as 2013) discloses a polyclonal goat anti-mouse IgG antibody conjugated to horseradish peroxidase (HRP) and states that it detects mouse IgG subclasses in direct ELISAs, thereby disclosing the precise secondary antibody and enzyme conjugate recited in Claim 29.
Therefore, it would have been obvious to a PHOSITA before the effective filing date of the claimed invention, to combine: the motivation to conduct ELISA-based measurement of CHIT1 in ALS CSF by Claim 1’s teachings, the routine in-house ELISA development principles taught by Crowther, and the commercially available, ELISA-validated antibody reagents disclosed on the R&D System webpages for AF3559, MAB5591, and HAF007, because once motivated to construct an ELISA for measuring CHIT1, a PHOSITA would have routinely selected a conventional sandwich ELISA configuration employing: primary antibodies raised in different species (e.g., mouse and goat) against the same antigen, and an HRP-conjugated anti-mouse IgG secondary antibody for enzymatic detection, as revealed on the reagent webpages and corroborated by third-party, pre-filling ELISA publications. The combination represents the predictable application of known immunoassay components according to their established functions, with a reasonable expectation of success and no teaching away, and therefore does not require inventive skill.
Regarding Claim 30 and as discussed with respect to Claim 1, Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. collectively teach and motivate ELISA-based measurement of ALS-related biomarkers, in CSF, thereby establishing the overall immunoassay framework. However, these references do not explicitly disclose buffer composition, blocking agents, or preservative formulation details.
But, Crowther expressly teaches that Tris-based buffers are commonly used in ELISA assays, stating that “the coating buffers most used are 50 mM carbonate, pH 9.6; 20mM Tris-HCl, pH 8.5; and 10 mM phosphate-buffered saline (PBS), pH 7.2” (page 45). Crowther further teaches routine buffer evaluation, disclosing that “Different coating buffers should be investigated when problems are encountered or compared at the beginning of assay development” (page 45). Crowther also teaches that preservatives are routinely included in ELISA reagents and expressly recommends “a commercial product ProClin™ from Rohm and Haas, Spring House, PA” (page 321). Crowther describes ProClin™ “to be a broad-spectrum biocide, having good compatibility and stability and low toxicity at in-use levels. It eradicates bacteria, fungi, and yeast cells at very low concentration, does not interfere with enzyme reactions, and can be disposed of without restrictions” (page 321). In addition, Crowther discloses that bovine serum albumin (BSA) is a commonly used ELISA blocking agent (Table 3, page 59) and explains that its selection is a routine assay-development consideration.
Therefore, it would have been obvious to a PHOSITA before the effective filing date of the claimed invention to combine the ALS-motivated ELISA framework by Claim 1’s teachings and the routine ELISA buffer formulation, blocking, and preservation practices taught by Crowther because Crowther teaches selecting a Tris-based buffer containing sodium chloride, BSA, and ProClin™ (e.g., ProClin 300) at an appropriate pH, ultimately represents a predictable application of well-established ELISA formulation principles, yielding expected results with a reasonable expectation of success, and does not require inventive skill.
Claims 32 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. as applied to Claim 1 above, and further in in view of Crag-Schapiro et al. (YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer's Disease. Biological Psychiatry. Vol. 68. No. 10, November 2010).
As discussed with respect to Claim 1, Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. collectively teach the following: CHI3L1 is increased in ALS and correlates with disease progression – providing the biological motivation to quantify CHI3L1 ALS stratification, and confirmed technical feasibility of measuring this biomarker in the claimed disease context.
However, neither of these references disclose a specific numerical cutoff for CHI3L1 concentration.
On the other hand, Craig-Schapiro et al. reports absolute CSF CHI3L1 (YKL-40) concentrations in ng/mL, measured by ELISA, stating that “cerebrospinal fluid from the discovery cohort (CDR 0, n = 24; CDR 1, n = 23) was analyzed for YKL-40 by enzyme-linked immunosorbent assay (CDR 0 = 293.6 ± 23.9; CDR 1 = 422.2 ± 30.0, ng/mL, mean ± SEM)” (page 905) and “cerebrospinal fluid from a larger, independent sample set (n = 292) was analyzed for YKL-40 by enzyme-linked immunosorbent assay (CDR 0 = 282.1 ± 6.7; CDR 0.5 = 358.9 ± 16.9; CDR 1 = 351.7 ± 22.6, ng/mL, mean ± SEM)” (page 905). These disclosures establish that CSF CHI3L1 (YKL-40) is measured in ng/mL, values extend into and beyond the claimed “at least 390 ng/mL” range recited in Claim 32, and that ELISA-based quantification of CHI3L1 was routine.
Although Craig-Schapiro et al. is not centered around ALS biology, it would have been obvious for a PHOSITA before the effective filing date of the claimed invention to combine the motivation to measure CHI3L1 in ALS and the ELISA-based measurement of CHI3L1 in ALS CSF provided by Claim 1’s teachings, and the known quantitative CSF CHI3L1 ranges disclosed by Craig-Schapiro et al. A PHOSITA would have been motivated to select a CHI3L1 concentration threshold of at least 390 ng/mL to identify faster progressing ALS patients with a reasonable expectation of success and predictable results. Moreover, since claim 38 recites a baseline CHI3L1/YKL-40 concentration threshold of at least 390 ng/mL. Claim 38 does not introduce a new assay format, a new biomarker, or a new biological relationship; rather, it merely specifies a numerical cutoff value within the known quantitative range of CSF CHI3L1/YKL-40 concentrations. As discussed above, Craig-Schapiro et al. expressly discloses CSF CHI3L1 values measured by ELISA that meet or exceed the claimed threshold, thereby rendering the selection of a threshold of at least 390 ng/mL an obvious result-effective variable. Once a PHOSITA is motivated to measure CHI3L1 ALS progression assessment (Claim 32), further selecting a cutoff value within the expressly disclosed quantitative range would have been a routine optimization step yielding predictable results.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al., Steinacker et al., Varghese et al., and Filippou et al. as applied to Claims 1 and/or 35 above, and further in in view of Sanfilippo et al. (CHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients. Molecular and Cellular Neuroscience. Vol. 85, December 2017).
As discussed with respect to Claims 1 and/or 35, Thompson et al. expressly teaches that CHI3L2 is macrophage-derived and increased in ALS, and places these biomarkers in a neuroinflammatory context. Thompson, Steinacker, Varghese and Filippou differs from claim 36 in failing to teaching that an increased in CHI3L2 concentration is indicative of microglial activation.
On the other hand, Sanfilippo et al. discloses that “the increase CHI3L1 and CHI3L2 could be connected to the immune-activation of microglia and astrocytes. The secretion of CHI3L1 and CHI3L2 by microglia/astrocytes could increase the monocyte/macrophages infiltration, new angiogenesis and neuron death” (Figure 6, page 167).
Hence, a PHOSITA would have been motivated to interpret increased CHI3L2 concentration is indicative of microglial activation in ALS with a reasonable expectation of success because microglial activation is well known as a hallmark of ALS and Sanfilippo clearly discloses that CHI3L1 is produced by astrocytes and activated microglia, therefore, a skilled artisan would have had a reasonable expectation of success in concluding that an increased in CHI3L2 is indicative of microglial activation. This interpretation represents a predictable application of known neuroinflammatory biology.
Ultimately, claims 1, 4-6, and 29-41 are rejected under 35 U.S.C. 103 because the claimed invention represents no more than the predictable application of known analytical techniques to known biomarkers for their established clinical purposes, with a reasonable expectation of success.
Double Patenting
The nonstatutory 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 nonstatutory 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
The rejections on the ground of nonstatutory obviousness-type double patenting are maintained. The rejections have been updated, where appropriate, in view of Applicant’s amendments.
Claim 1 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12050217 referred as ‘217, in view of Steinacker et al. as evidenced by MBL ELISA.
Patented claims 1-3 of ‘217 recites a similar method of categorizing a human subject suspected of having or at risk of ALS for treatment, comprising: determining CHI3L1 and Chit-1 optimal cutoff concentrations, performing an immunoassay to determine CHI3L1 and Chit-1 concentrations in a CSF sample, comparing the concentrations to the optimal cutoff concentrations, categorizing the subject as having fast progressing ALS, and providing a neurologic treatment by administering an anti-inflammatory agent when the cutoff conditions are met.
Instant claim 1 differs from the claims of ‘217 in that instant claim 1 specifies that the immunoassay is a sandwich ELISA and recites a limit of detection (LOD) of less than 0.08 ng/mL. However, these differences do not render the claim patentably distinct.
Steinacker et al. teaches the quantitative measurement of CHIT1 concentration and comparing to controls, using ELISA, and determining fast-progressing ALS based on the detected concentration. Since Steinacker et. al identifies MBL ELISA as the manufacturer of the CHIT1 ELISA kit used in the study – as evidenced by MBL ELISA, the documentation discloses every structural and functional element of the immunoassay. The MBL kit employs a quantitative sandwich enzyme immunoassay technique and specifies an assay detection limit of 0.0483 ng/mL. Hence, it would have been obvious to a PHOSITA, when practicing the method of claims 1-3 of ‘217, to implement the required immunoassay using a sandwich ELISA having an appropriate limit of detection, as such assay format and sensitivity constitute predictable assay performance characteristics and do not modify the underlying method steps or ALS categorization framework claimed in ‘217. Therefore, instant claim 1 is not patentably distinct from claims 1-3 of ‘217 and constitutes an obvious variation thereof.
Next, claim 4 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Novus CHIT1 ELISA and Andreasson et al.
Novus CHIT1 ELISA evidences that such recovery levels are routinely achieved, and Andreasson et al. teaches that recovery testing is a known and standard validation parameter in immunoassay development. Accordingly, specifying acceptable recovery levels represents routine assay validation and predictable optimization of the same immunoassay already required by ‘217 and does not render instant claim 4 patentably distinct from claims 1-3 of ‘217.
In addition, claims 5 and 6 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Crowther and Novus CHIT1 ELISA. Crowther teaches that precision and repeatability metrics are routinely evaluated for ELISAs, and Novus CHIT1 ELISA exemplifies that such variability levels are routinely achieved. The variability thresholds recited in instant claims 5 and 6 merely constrain how well the immunoassay performs and do not alter the method steps or clinical decision logic of ‘217.
Moreover, claim 29 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Crowther and R&D systems antibody reagents (AF3559, MAB35591, HAF007). Crowther teaches conventional sandwich ELISA architectures, and the R&D Systems reagents exemplify commercially available antibody combinations routinely used in such assays. The claimed antibody configuration recited in instant claim 29 reflects a routine and conventional immunoassay design choice when practicing the ‘217 method.
Similarly, claim 30 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Crowther. Instant claim 30 specifies a Tris-based buffer with salts, BSA, preservative, and controlled pH. Crowther teaches that such buffer systems are standard ELISA assay conditions. The claimed buffer composition represents a conventional formulation choice that does not render the method patentably distinct.
Also, claims 31 and 37 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Steinacker et al. Patented claims 1-3 of ‘217 recite categorizing ALS and ALS progression by quantitatively measuring Chit-1 in CSF using an immunoassay and applying cutoff-based interpretation, including identification of fast-progressing ALS. Instant claim 31 merely specifies that a Chit-1 concentration of at least 28 ng/mL is indicative of fast—progressing ALS, representing a particular numerical cutoff within the same quantitative framework. While, instant claim 37 recites the same Chit-1 concentration threshold, but characterizes it as a baseline measurement, which constitutes a routine temporal application of the same method. Steinacker et al. discloses CSF CHIT1 concentrations in ALS patients that extend into and beyond approximately 28 ng/mL, demonstrating that the recited threshold falls within known quantitative ranges obtained when practicing the method of ‘217. Accordingly, both the fast-progression determination of instant claim 31 and the baseline framing of instant claim 37 represent predictable numerical and temporal refinements of the same immunoassay-based method and do not render the claims patentably distinct from claims 1-3 of ‘217.
Likewise, claims 32 and 38 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Craig-Schapiro et al. Patented claims 1-3 of ‘217 teach categorizing ALS and ALS progression by quantitatively measuring CHI3L1 in CSF using an immunoassay and applying cutoff-based interpretation, including identification of fast-progressing ALS. Instant claim 32 merely specifies that a CHI3L1 concentration of at least 390 ng/mL is indicative of fast-progressing ALS, while instant claim 38 recites the same concentration threshold characterized as a baseline value. Craig-Schapiro et al. discloses CSF CHI3L1 (YKL-40) concentrations measured by ELISA that extend into and beyond approximately 390 ng/mL, demonstrating that the recited threshold falls within known quantitative ranges obtained when practicing the method of ‘217. Accordingly, both the fast-progression determination of instant claim 32 and the baseline framing of instant claim 38 represent predictable numerical and temporal refinements of the same quantitative immunoassay-based method and do not render the claims patentably distinct from claims 1-3 of ‘217.
Additionally, claim 33 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Thompson et al. Instant claim 33 merely adds determining pNFH concentration in the same CSF sample. Thompson et al. discloses measurement of pNFH as a biomarker associated with ALS progression, rendering the addition of pNFH measurement a routine multi-biomarker implementation within the same quantitative framework. Accordingly, instant claim 39 is not patentably distinct from claims 1-3 of ‘217.
Furthermore, claim 34 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Thompson et al. and Steinacker et al. Patented claims 1-3 of ‘217 teach categorizing ALS and ALS progression by quantitatively measuring Chit-1/CHI3L1 in CSF. Instant claim 34 merely interprets a correlation between increased Chit-1 and increased pNFH. Thompson et al. discloses pNFH as an ALS biomarker, and Steinacker et al. confirms that pNFH increases with ALS severity and correlates with disease progression, similar to CHIT1. Interpreting correlated increases of known ALS biomarkers is a routine clinical inference within the same framework, rendering instant claim 34 not patentably distinct from claims 1-3 of ‘217.
Also, claim 35 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Thompson et al. Instant claim 35 merely adds the step of determining a concentration of CHI3L2 in the same CSF sample. Thompson et al. discloses measurement of chitinase-family biomarkers in CSF, including CHI3L2, and their association with ALS disease status and progression, making the addition of CHI3L2 a routine biomarker expansion within the same quantitative framework already claimed in ‘217. Accordingly, claim 35 is not patentably distinct from claims 1-3 of ‘217.
Moreover, claim 36 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Sanfilippo et al. Instant claim 36 merely interprets an increased CHI3L2 concentration as being indicative of microglial activation. Sanfilippo et al. discloses that increased CHI3L2 levels could be connected to microglial activation, making this interpretation a known biological inference when practicing the same quantitative immunoassay-based method claimed in ‘217. Accordingly, instant claim 36 is not patentably distinct from claims 1-3 of ‘217.
In addition, claim 39 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Thompson et al. Instant claim 39 merely interprets a decreased or maintained Chit-1 concentration during a treatment period as indicative of therapeutic efficacy. Thompson et al. discloses that measuring CHIT1 levels can be used to reduce diagnostic delay, stratify ALS patients, and monitor response in therapeutic trials, demonstrating that longitudinal assessment of CHIT1 levels is a known and predictable application of the same biomarker measurement already claimed in ‘217. Accordingly, instant claim 39 is not patentably distinct from claims 1-3 of ‘217.
Furthermore, claim 40 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Steinacker et al. Instant claim 40 recites distinguishing ALS from other neurological diseases using Chit-1. Steinacker et al. teaches biomarker-based differentiation of ALS from other neurological conditions, demonstrating that applying the chitinase measurement of ‘217 for differential diagnosis represents a predictable clinical application of ‘217 for differential diagnosis represents a predictable clinical application of the same biomarker framework. Thus, instant claim 40 is not patentably distinct from claims 1-3 of ‘217.
Lastly, claim 41 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of ‘217 in view of Thompson et al. Instant claim 41 recites differentiation of bulbar-onset versus limb-onset ALS based on Chit-1. Thompson et al. teaches that CHIT1 levels differ by ALS onset subtype, demonstrating that using chitinase levels to distinguish bulbar and limb onset ALS is a known and predictable stratification within the same biomarker-based framework already claimed in ‘217. Accordingly, instant claim 41 is not patentably distinct from claims 1-3 of ‘217.
Therefore, the instant claims 1, 4-6, 29-41 merely recite routine assay optimizations, conventional immunoassay configurations, additional known biomarkers, or predictable clinical interpretations of the same immunoassay-based ALS categorization method claimed in ‘217. The differences between the instant claims and the claims of ‘217 are obvious variations in scope that do not render the claims patentably distinct.
Response to Amendment
Applicant’s remarks filed 05/26/2026 have been fully considered. The amendments and arguments are persuasive only to the extent that the objections to the specification and abstract and the rejection under 35 U.S.C. § 112(b) are withdrawn. Applicant’s arguments are not persuasive as to the rejections under 35 U.S.C. §§ 101, 102, and 103, and the nonstatutory obviousness-type double patenting rejection. The rejections are maintained for the reasons set forth in the present Final Office Action and as further explained below.
Amendments to the Specification and Abstract
Applicant amended paragraph [0027] of the specification to identify the referenced longitudinal CSF Chit-1 ELISA data as corresponding to FIGS. 3A and 3B. Applicant also amended the Abstract to recite “one or more chitinase proteins” rather than “a one or more chitinase proteins.” These amendments correct the previously identified informalities and do not appear to add new matter. Accordingly, the objection to the specification and the objection to the Abstract are withdrawn.
Rejection Under 35 U.S.C. § 112(b)
Applicant’s arguments, with respect to claims 31, 32, 37, and 38 have been fully considered and are persuasive. The rejection under 35 U.S.C. § 112(b) of claims 31, 32, 37, and 38 has been withdrawn. Applicant amended claims 31, 32, 37, and 38 to remove the relative term “about.” Specifically, claims 31 and 37 now recite a Chit-1 concentration of “at least 28 ng/mL,” and claims 32 and 38 now recite a CHI3L1 concentration of “at least 390 ng/mL.” Because the amended claims no longer include the phrase “at least about,” the indefiniteness issue identified in the prior Office Action has been resolved.
Rejection Under 35 U.S.C. § 101
Applicant argues that claims 1, 4-6, and 29-41 are not directed to a judicial exception because claim 1 allegedly recites a concrete laboratory process, including a CSF biological fluid sample, a sandwich ELISA format, and an immunoassay limit of detection of less than 0.08 ng/mL. Applicant further argues that the claims integrate the alleged natural correlation into a practical application because the claimed assay allegedly provides a specific improved immunoassay context for categorizing ALS subjects. Applicant’s arguments have been fully considered but they are not persuasive. The claims remain directed to a judicial exception because the focus of the claims is the naturally occurring relationship between chitinase biomarker concentrations and ALS progression, treatment candidacy, therapeutic efficacy monitoring, distinguishing ALS from other neurological diseases, or ALS onset subtype. The recited immunoassay steps merely obtain the biomarker information used to apply that natural relationship.
Claim 1 recites performing an immunoassay to determine a concentration of Chit-1, CHI3L1, or both in a CSF sample, wherein increased Chit-1 relative to a control is indicative of fast progressing ALS and the subject is confirmed as a candidate for neurological treatment, and wherein the immunoassay is a sandwich ELISA having a limit of detection of less than 0.08 ng/mL. The immunoassay, CSF sample, sandwich ELISA format, and limit of detection limitations do not transform the claim into patent-eligible subject matter because they are conventional data-gathering and measurement steps used to observe the natural biomarker correlation.
Applicant’s argument that the claim does not merely recite a natural correlation in isolation is acknowledged but not persuasive. The eligibility inquiry considers whether the additional elements integrate the exception into a practical application and whether the claims recite significantly more than the judicial exception. Here, the additional elements do not impose a meaningful limit beyond measuring the naturally occurring biomarker and using the result for diagnostic or prognostic categorization. The claims do not recite a specific treatment administered to the subject, a change in treatment regimen, a new assay architecture, a new antibody structure, a new detection chemistry, or any technical improvement to ELISA technology itself.
Applicant also argues that the specification describes an improved immunoassay, including improved capture antibodies, detection antibodies, buffers, washes, washing agents, and recovery from CSF. However, limitations from the specification are not read into the claims. Claim 1 does not recite the full allegedly improved assay described in the specification. Claims 4-6 recite recovery and variability requirements, and claims 29 and 30 recite particular antibody and buffer features, but these are assay-performance and assay-component limitations that remain ancillary to the judicial exception and are routine in immunoassay validation and optimization.
Claims 39-41 also remain ineligible for similar reasons. Although these claims recite therapeutic efficacy monitoring, distinguishing ALS from other neurological diseases, and differentiating ALS onset subtype, they continue to rely on the same biomarker measurement and correlation framework. They do not recite an active treatment step, a specific therapeutic intervention, or a technological improvement that changes the eligibility analysis.
Accordingly, the rejection under 35 U.S.C. § 101 is maintained.
Rejection Under 35 U.S.C. § 102 Over Steinacker as Evidenced by MBL ELISA
Applicant argues that Steinacker does not anticipate claim 1 because Steinacker allegedly does not disclose the claimed method as arranged, does not expressly disclose confirming a subject as a treatment candidate, and does not itself disclose the claimed limit of detection. Applicant also argues that MBL ELISA documentation supplies limitations not shown in Steinacker and that commercial Chit-1 assays may not perform equivalently in CSF. Applicant’s arguments are not persuasive. The rejection is based on Steinacker as the anticipatory reference, with MBL ELISA cited as evidentiary support for the known properties of the specific MBL CHIT1 ELISA kit used in Steinacker. The rejection is not a combination of Steinacker “in view of” MBL ELISA under § 102. Steinacker expressly discloses measuring CHIT1 in CSF samples from ALS subjects using an MBL ELISA kit and correlating CSF CHIT1 with ALS severity and progression. MBL ELISA documentation is properly relied upon to establish the characteristics of the specific commercial kit used by Steinacker, including that the kit is a quantitative sandwich ELISA and has a limit of detection below 0.08 ng/mL.
Applicant’s argument that Steinacker does not disclose “confirming the subject is a candidate for neurological treatment” is not persuasive. Steinacker expressly teaches that CSF Chit-1 concentrations may be useful for “prediction of disease progression in ALS” (Abstract, page 239), and that Chit-1 “seems suitable as a supplemental marker for patient stratification in therapeutic trials” (Abstract, page 239). Thus, Steinacker does not merely disclose measuring Chit-1 concentrations in ALS patients; rather, Steinacker teaches using the biomarker information to stratify ALS patients for therapeutic purposes and clinical decision making. Moreover, claim 1 does not require administering a specific treatment, selecting a particular therapeutic agent, or modifying a treatment regimen based on the biomarker result. Rather, the claim merely requires confirming that the subject is a candidate for neurological treatment. Steinacker’s disclosure that Chit-1 is useful for predicting disease progression and stratifying ALS patients for therapeutic trials reasonably satisfies this limitation.
Applicant’s argument that the MBL documentation is limited to serum does not overcome the rejection because Steinacker itself uses the MBL ELISA in CSF samples. Therefore, the relevant disclosure is not merely that the kit could be used in serum, but that Steinacker actually used the kit in CSF in the ALS biomarker context. Applicant also argues that the specification reports that Applicant’s in-house Chit-1 ELISA outperformed the MBL ELISA in CSF spike-in recovery. This argument is not persuasive for claim 1 because claim 1 does not recite a recovery limitation. The reported recovery comparison does not negate Steinacker’s disclosure of using the MBL kit to measure CSF CHIT1 in ALS patients, nor does it negate the MBL kit’s documented limit of detection.
Applicant further argues that the dependent claims are patentable over Steinacker and MBL ELISA because claims 4-6 recite recovery, inter-assay variability, and intra-assay variability and claims 29 and 30 recite antibody and buffer features. The § 102 rejection is maintained to the extent set forth in the present Final Office Action. To the extent additional dependent-claim limitations are not expressly disclosed by Steinacker as evidenced by MBL ELISA, those limitations remain rejected under 35 U.S.C. § 103 for the reasons discussed below.
Accordingly, the rejection under 35 U.S.C. § 102 is maintained.
Rejection Under 35 U.S.C. § 103
Applicant argues that the rejection under 35 U.S.C. § 103 is based on impermissible hindsight, that the cited references do not teach or suggest the claimed method as a whole, that the references are from disparate contexts, and that a PHOSITA would not have had a reasonable expectation of success. Applicant further argues that Thompson, Steinacker, Varghese, Filippou, MBL ELISA, Andreasson, Novus CHIT1 ELISA, Crowther, R&D Systems AF3559, Craig-Schapiro, and Sanfilippo fail to render the pending claims obvious.
In response to applicant’s argument that the examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the motivation to combine is found in the prior art’s recognition that CHIT1, CHI3L1, and CHI3L2 are ALS-related CSF biomarkers associated with disease progression, neuroinflammation, pNFH, and survival/progression measures, together with the routine skill in the art to implement and optimize known sandwich ELISA assays for low-abundance CSF biomarkers using known validation parameters such as sensitivity, recovery, precision, antibody selection, buffer selection, and assay reproducibility.
In response to applicant’s arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claim 1
Applicant argues that the combination of Thompson, Steinacker, Varghese, Filippou, and MBL ELISA fails to teach or suggest the claimed method as a whole because Thompson allegedly does not disclose the specific immunoassay format, explicit fast-progressor cutoff values, or LoD thresholds; Steinacker allegedly does not disclose measuring CHI3L1; Varghese allegedly does not classify patients by progression rate or performance thresholds; and Filippou allegedly concerns a different analyte and is not related to ALS biology.
These arguments are not persuasive because the rejection does not require any single reference to disclose all limitations. Thompson provides the central ALS biomarker rationale by teaching that CSF CHIT1, CHI3L1, and CHI3L2 are elevated in ALS and correlate with disease progression rate and pNFH. Varghese further supports CHIT1 as an ALS CSF biomarker and validates CHIT1 elevation by ELISA. Steinacker supports measuring CSF CHIT1 in ALS subjects and correlating CSF CHIT1 with disease severity and progression using the MBL ELISA kit. MBL ELISA establishes the known properties of that kit, including sandwich ELISA format and a LoD below the claimed threshold. Filippou supports that low-LoD sandwich ELISA design and optimization were within ordinary skill.
Applicant’s assertion that the references do not teach the claimed “specific improved immunoassay context” is not persuasive. The claims recite a sandwich ELISA having a limit of detection less than 0.08 ng/mL, but they do not require a new ELISA architecture or a newly discovered antibody pair. The art already provided a reason to quantify ALS-associated CSF chitinase biomarkers, and the assay art provided predictable tools for doing so using sensitive sandwich ELISA methods.
Applicant also argues that commercial MBL assay performance in CSF was worse than Applicant’s in-house assay. This argument is not commensurate with claim 1, which does not recite a recovery limitation. Even if Applicant’s assay produced improved recovery values in CSF, the claim as a whole remains obvious because selecting and optimizing an ELISA for sensitivity and matrix performance would have been a routine task once the ALS-CSF chitinase biomarker target was known.
Accordingly, claim 1 remains unpatentable under 35 U.S.C. § 103.
Claim 4
Applicant argues that claim 4 is patentable because Andreasson merely teaches general recovery-validation principles and Novus CHIT1 ELISA provides recovery values only in serum and EDTA plasma, not CSF.
This argument is not persuasive. Claim 4 recites that recovery by the immunoassay is at least 70%, 80%, 90%, or 95%. Recovery is a routine assay-validation parameter for immunoassays. Andreasson establishes that recovery is a standard validation consideration for immunoassays. Novus CHIT1 ELISA provides concrete CHIT1 recovery data in biological matrices, thereby confirming that recovery values within the claimed ranges were achievable using CHIT1 ELISA systems.
The fact that Novus reports recovery in serum, EDTA plasma, and cell culture media does not defeat obviousness. The rejection does not rely on Novus to show that the identical CSF recovery value was expressly achieved before Applicant’s filing. Rather, Novus and Andreasson show that recovery testing and optimization were routine and predictable in CHIT1 ELISA development. A PHOSITA developing a CSF CHIT1 immunoassay for ALS categorization would have been motivated to evaluate and optimize recovery in CSF to ensure reliable quantification in the selected matrix.
Accordingly, claim 4 remains unpatentable under 35 U.S.C. § 103.
Claims 5 and 6
Applicant argues that claims 5 and 6 are patentable because Crowther is a general ELISA guide and Novus concerns commercial CHIT1 ELISA rather than the claimed ALS CSF assay.
This argument is not persuasive. Claims 5 and 6 recite inter-assay variability less than 11% and intra-assay variability less than 6%, respectively. Assay precision, repeatability, inter-assay variability, and intra-assay variability are routine validation parameters for ELISA assays. Crowther teaches that repeatability is evaluated using intra-assay and inter-assay CV values and that CV values are used to assess acceptable repeatability during assay development. Novus CHIT1 ELISA provides actual CHIT1 ELISA intra-assay and inter-assay CV values demonstrating that such precision values were achievable using CHIT1 ELISA systems.
Applicant’s argument that these are “assay-performance limitations” does not render them patentable. Once a PHOSITA was motivated by Thompson, Varghese, and Steinacker to measure ALS-associated CSF chitinase biomarkers, the PHOSITA would have had reason to select or optimize an ELISA having acceptable precision and variability to reliably quantify the biomarker. Achieving inter-assay and intra-assay variability within known acceptable ranges would have been routine assay optimization, not an inventive departure.
Accordingly, claims 5 and 6 remain unpatentable under 35 U.S.C. § 103.
Claims 29 and 30
Applicant argues that claims 29 and 30 are patentable because Crowther merely provides general ELISA-development guidance, R&D Systems AF3559 is a goat anti-human CHIT1 antibody without teaching the claimed ordered combination, and Crowther does not specifically teach the buffer recited in claim 30.
These arguments are not persuasive. Claim 29 recites specific assay components including a goat anti-human Chit-1 antibody, a mouse anti-human Chit-1 antibody, and a goat anti-mouse IgG-HRP conjugate. R&D Systems AF3559 provides a known goat anti-human CHIT1 antibody. The use of capture antibodies, detection antibodies, and HRP-conjugated secondary antibodies in sandwich ELISA systems was conventional and is supported by the cited ELISA references. A PHOSITA seeking to construct or optimize a sandwich ELISA for human CHIT1 would have had reason to select known anti-human CHIT1 antibodies and standard HRP-based detection reagents.
Claim 30 recites a Tris-based buffer comprising sodium chloride, ProClin 300, and BSA at pH 7.6. Crowther supports that coating buffers, buffer pH, preservatives, stabilizers, blocking proteins, and reagent conditions are routine variables in ELISA development. The recited buffer components are conventional immunoassay buffer ingredients: Tris provides buffering capacity, sodium chloride provides ionic strength, ProClin 300 functions as a preservative, and BSA functions as a protein stabilizer/blocking component. Selecting such a buffer for antibody-antigen binding and reagent stability would have been routine optimization.
Applicant’s argument that the specification identifies these features as part of an improved assay does not overcome the rejection. The relevant question is whether the claimed features would have been obvious to a PHOSITA in view of the prior art, not whether the specification describes them as preferred or improved. The cited references show that the components and optimization considerations were known and predictable.
Accordingly, claims 29 and 30 remain unpatentable under 35 U.S.C. § 103.
Claims 32 and 38
Applicant argues that Craig-Schapiro does not concern ALS fast progression and therefore does not provide a teaching, suggestion, or reasonable expectation of success for selecting a 390 ng/mL CHI3L1 threshold to categorize fast-progressing ALS.
This argument is not persuasive. Craig-Schapiro is not relied upon as the primary ALS reference. Thompson provides the ALS-specific CHI3L1 teaching by showing that CSF CHI3L1 is elevated in ALS and correlates with disease progression rate and pNFH. Craig-Schapiro is relied upon to show known CSF CHI3L1/YKL-40 concentration levels and the use of CHI3L1/YKL-40 as a CSF biomarker in neurodegenerative disease. In view of Thompson’s ALS-specific disclosure, a PHOSITA would have had reason to evaluate clinically useful CHI3L1 threshold concentrations in CSF for ALS progression categorization.
The claimed threshold does not render the claim nonobvious where the art already taught the biomarker, the relevant biological sample, and the relationship to ALS progression, and where optimization of diagnostic cutoff values was a routine part of biomarker assay development. Selecting or confirming a threshold value for categorization would have been a predictable optimization of a known biomarker measurement.
Accordingly, claims 32 and 38 remain unpatentable under 35 U.S.C. § 103.
Claim 36
Applicant argues that Sanfilippo does not render claim 36 obvious because Sanfilippo does not teach the claimed CSF immunoassay method, ALS fast-progression categorization, or treatment-candidacy confirmation.
This argument is not persuasive. Sanfilippo is not relied upon as the sole reference for the claimed method. Rather, Sanfilippo is relied upon for the additional limitation that increased CHI3L2 concentration is connected to microglial activation. Thompson already teaches CSF CHI3L2 elevation in ALS and correlation with disease progression rate and pNFH. Sanfilippo further teaches that CHI3L1 and CHI3L2 are overexpressed in motor cortex and spinal cord of sporadic ALS patients and are associated with neuroinflammation and microglial/astrocytic activation.
Therefore, when Sanfilippo is considered with Thompson and the other base references, it supports the obviousness of using increased CHI3L2 as an indicator related to microglial activation in the ALS biomarker context.
Accordingly, claim 36 remains unpatentable under 35 U.S.C. § 103.
Applicant’s arguments do not overcome the prima facie case of obviousness. The cited references are not a hindsight-driven collection of unrelated disclosures. Rather, the references establish: (1) ALS relevance of CSF CHIT1, CHI3L1, and CHI3L2; (2) correlation of these markers with ALS progression and neurodegeneration; (3) known use of ELISA to measure CHIT1 in CSF; and (4) routine sandwich ELISA development and validation parameters, including sensitivity, recovery, precision, antibody selection, buffer selection, and HRP-based detection.
Accordingly, the rejections under 35 U.S.C. § 103 are maintained.
Nonstatutory Obviousness-Type Double Patenting
Applicant argues that the pending claims are patentably distinct from claims 1-3 of U.S. Patent No. 12,050,217 because the pending claims recite additional limitations directed to sandwich ELISA format, CSF sample, analytical sensitivity, assay performance, recovery, variability, antibody components, and buffer components. Applicant further requests that the terminal-disclaimer requirement be held in abeyance until otherwise allowable subject matter is indicated.
Applicant’s arguments are not persuasive. The claims of U.S. Patent No. 12,050,217 are directed to categorizing a human subject for treatment based on CHI3L1 and Chit-1 protein concentrations measured in CSF, including comparing the concentrations to cutoff values, categorizing the subject as having ALS, and administering an anti-inflammatory agent when the biomarker concentrations meet the recited cutoff criteria. The pending claims are directed to obvious assay implementations and refinements of that same CSF CHI3L1/Chit-1 ALS biomarker categorization concept. The additional limitations in the pending claims do not render the claims patentably distinct. Sandwich ELISA format, CSF biomarker measurement, LoD optimization, recovery assessment, inter-assay variability, intra-assay variability, antibody selection, HRP-based detection, and buffer selection are routine assay-development and validation features. A PHOSITA seeking to practice the patented CSF CHI3L1/Chit-1 ALS categorization method would have found it obvious to implement and optimize a sandwich ELISA with known antibody, buffer, and performance features to reliably measure the same biomarkers in CSF.
Applicant’s request to hold the rejection in abeyance is also not persuasive. The present nonstatutory obviousness-type double patenting rejection is based on issued U.S. Patent No. 12,050,217, not merely a co-pending application. Therefore, the rejection is properly maintained unless Applicant establishes patentable distinctness or files a proper terminal disclaimer, if appropriate.
Accordingly, the nonstatutory obviousness-type double patenting rejection over claims 1-3 of U.S. Patent No. 12,050,217 is maintained.
Ultimately, the objection to the specification and Abstract are withdrawn. The rejection under 35 U.S.C. § 112(b) is withdrawn. The rejections under 35 U.S.C. § 101, 102, and 103, and the nonstatutory obviousness-type double patenting rejection are maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 25, 2026
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