DETAILED ACTION
This Office action is responsive to communications filed on 01/21/2026. Claims 1-14 have been amended. Presently, Claim(s) 1-14 remain pending and are hereinafter examined on the merits.
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 .
Response to Arguments
Previous objections to the Abstract are withdrawn in view of the amendments filed on 01/21/2026.
Previous rejections under 35 USC § 112(a) are withdrawn in view of the amendments filed on 01/21/2026.
Previous rejections under 35 USC § 112(b) are withdrawn in view of the amendments filed on 01/21/2026.
Previous claim objections are withdrawn in view of the amendments filed on 01/21/2026.
The Applicant’s arguments with respect to rejections under 35 USC § 101 have been fully, considered, but are not persuasive. The Examiner directs the Applicant’s attention provided in the Office Action regarding the grounds for rejection of the claims under 35 U.S.C. 101 in view of the amendments filed on 01/21/2026. Specifically, the Examiner response is set forth in the rejection under 35 U.S.C. 101 below.
Applicant’s arguments with respect to claim(s) have been considered but are moot because the new ground of rejection does not rely strictly on the specified references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The new grounds of rejection now rely on:
Claims 1, 6-7, & 9 are rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.), as applied to claim 1, in further view of Thompson et al. (2017. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 February; 17(2):162-173. Epub 2017 Dec. 21).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.), as applied to claim 1, in further view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016), as applied to claim 3, in further view of Thompson et al. (2017. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 February; 17(2):162-173. Epub 2017 Dec. 21).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.), as applied to claim 9, in further view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016),
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016), as applied to claim 12, in further view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)) in view of Schwenkenbecher et al (Impact of the McDonald Criteria 2017 on Early Diagnosis of Relapsing-Remitting Multiple Sclerosis. Front Neurol. 2019 Mar 15).
Abstract
The abstract of the disclosure is objected to and should recite:
“The present invention refers to an in vitro method for the diagnosis and/or prognosis of multiple sclerosis (MS). The method includes assessing [[the]]a concentration level of sIFNAR2 in a biological sample obtained from [[the]]a subject in combination with [[the]]an obtention of a magnetic resonance imaging (MRI) to assess [[the]]a presence or absence of dissemination in space (MRI-DS) and/or dissemination in time (MRI-DT), wherein [[the]]an identification of a lower level of sIFNAR2 as compared with a pre-established threshold level, and the presence of MRI-DS and/or MRI-DT, are indications that the subject is suffering from MS.”
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
The following claims are objected to because of the following informalities and should recite:
Line numbers refer to the amendments to the claim (i.e., the non-clean version filed).
Claim 2: line 5, “determined by the MRI”
Claim 3: line 4, “[[an]]the indication”.
Claim 4: line 4, “[[an]]the indication”.
Claim 5: line 3, “[[the]]a concentration level”
Claims 6-8: “[[An]]The in vitro method”. Claims 2-4 already recite the proposed amendment.
Claim 9:
“In vitro use of sIFNAR2 in a biological sample obtained from a subject, in combination with magnetic resonance imaging (MRI) measured variables to determine a presence of dissemination in space (MRI-DS) and/or dissemination in time (MRI-DT), for a diagnosis and/or prognosis of multiple sclerosis (MS),
wherein an identification of a lower concentration level of sIFNAR2 using an immunoassay as compared with a pre-established threshold level, in combination with [[a]] the presence of MRI-DS and/or MRI-DT is an indication that the subject is suffering from MS.”
Claims 10-11: “The [[In]]in vitro use”.
Appropriate correction is needed.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 5 & 8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 5 recites: “wherein the risk score is calculated using logistic regression analysis”
The claim is rejected under 35 USC § 112(a) for a lack of written description. Proper written description cannot be identified in the specification, claims, and drawings directed the full scope of the steps defining a risk score using logistic regression analysis. The specification lacks a step-by-step description or any algorithmic or flowchart-based disclosure of how these steps are implemented using a computing device.
An algorithm is defined, for example, as "a finite sequence of steps for solving a logical or mathematical problem or performing a task." Microsoft Computer Dictionary (5th ed., 2002). Applicant may "express that algorithm in any understandable terms including as a mathematical formula, in prose, or as a flow chart, or in any other manner that provides sufficient structure." Finisar Corp. v. DirecTV Grp., Inc., 523 F.3d 1323, 1340 (Fed. Cir. 2008) (internal citation omitted). This can occur when the algorithm or steps/procedure for performing the computer function are not explained at all or are not explained in sufficient detail (simply restating the function recited in the claim is not necessarily sufficient). In other words, the algorithm or steps/procedure taken to perform the function must be described with sufficient detail so that one of ordinary skill in the art would understand how the inventor intended the function to be performed. It is not enough that one skilled in the art could write a program to achieve the claimed function because the specification must explain how the inventor intends to achieve the claimed function to satisfy the written description requirement. See, e.g., Vasudevan Software, Inc. v. MicroStrategy, Inc., 782 F.3d 671, 681-683, 114 USPQ2d 1349, 1356, 1357 (Fed. Cir. 2015), see MPEP § 2161(I).
These limitations are computer/processor-implemented functional claim limitation as it is directed to a processor-controlled algorithm configured to determine measurements based on signals. Yet the specification does not disclose the computer and the algorithm (e.g., the necessary steps and/or flowcharts) that perform the claimed functions, i.e., “wherein the risk score is calculated using logistic regression analysis” in sufficient detail such that one of ordinary skill in the art can reasonably conclude that the inventor possessed the claimed subject matter at the time of filing. It is not enough to disclose that one skilled in the art could write a program to achieve the claimed function because the specification must explain how the inventor intends to achieve the claimed function to satisfy the written description requirement. See, e.g., Vasudevan Software, Inc. v. MicroStrategy, Inc., 782 F.3d 671, 681-683, 114 USPQ2d 1349, 1356, 1357 (Fed. Cir. 2015). As the specification does not provide a disclosure of the computer and algorithm in sufficient detail to demonstrate to one of ordinary skill in the art that the inventor possessed the invention, these claims are rejected for lack of written description. For more information regarding the written description requirement, see MPEP §§ 2161, 2162-2163.07(b).
The specification provides a high-level of generality tantamount to a conceptual framework rather the providing specific equations, numerical weights, and the software implementation for how the risk score is calculated using logistic regression. Indeed the specification provides general statements about calculating the risk score using logistic regression analysis, ¶0010-0011, ¶0017, ¶0019, ¶0029-0030 ¶0049, Table 2 (the results). There are no mathematical formulas disclosed for the logistic regression models. The specific coefficients or weights assigned to each variable (i.e., how much weight the sIFNAR2 has compared to the MRI findings) in the final risk score calculation). The specification does use a computer program, but with no specific code or algorithms included. Lastly, the specification provided general steps of receiving, processing, and providing the results, but lacks any detailed technical flowchart of the internal logic used to generate the risk score. Stating the use of logistic regression analysis is not sufficient.
Consequently, one of ordinary skill in the art would not deem the instant specification having sufficient detail so that they could understand how the inventor intended to achieve the aforementioned feature. Since the instant specification fails to provide a finite sequence of steps for how the risk score is calculated using logistic regression analysis, the aforementioned claim fails to meet the written description requirement under 35 U.S.C. 112(a). In addition, the assertion that it could be derived using simulations or test (i.e., the prophetic example provide) does not demonstrate that the inventors actual did so or had possession of the specific functional relationships and constraints to obviate the lack of written description requirement.
Dependent claims are rejected by virtue of their dependency to abovementioned claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-5, 8, & 12-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth the subject matter which the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the applicant regards as the invention.
Line numbers refer to the amendments to the claim (i.e., the non-clean version filed).
Claim 2:
line 7, “already predefined locations”, is unclear. If the locations are predefined locations, then they’re already prefunded locations. It is unclear what is meant by already predefined locations means in the context of the claim. For examination purposes, the Examiner assumes predefined locations. Clarity is needed.
line 8, “that have developed during the course of the MS”. There is insufficient antecedent basis for this limitation “the course of the MS” in the claim, as required by MPEP 2173.05(e). It is unclear what is meant by during the course of MS in the context of the claim. For examination purposes, the Examiner assumes during a course of the subject suffering from the MS. Accordingly, proper antecedent basis is required.
Claim 3:
lines 5-6, claim positively imports (“area under the curve (AUC)”). The scope of the claim is indeterminate with respect to if the limitation within parenthesis is required. Thus, the claim is indefinite as the metes and bounds of the claimed invention are unclear. Specifically, it unclear if accuracy is abbreviated as area under the curve (AUC) or if the phrase is intended to recite the accuracy or area under the curve is 0.90. For examination purposes, the Examiner assumes the method predicts that the subject is suffering from MS with an area under the curve (AUC) of at least 0.90. One of ordinary skill in the art would denote an AUC of at least 0.90 to mean the accuracy of the diagnosis is 0.90. Appropriate correction is required.
The above rejections to claim 3 applies to Claim 5 lines 28-29 and Claim 12 line 12 for substantially identical claim limitations recited in the claim. Appropriate correction is required.
The dependent claims of the above rejected claims are rejected due to their dependency.
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.
Claims 1-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1 of the subject matter eligibility test (see MPEP 2106.03).
Claims 1-4, 6-7 are directed to a “method” which describes one of the four statutory categories of patentable subject matter, i.e., a process.
Claims 5 & 8 are directed to a “method” which describes one of the four statutory categories of patentable subject matter, i.e., a process.
Claims 9-11 are directed to a “method” which describes one of the four statutory categories of patentable subject matter, i.e., a process.
Claims 12-14 are directed to an “apparatus” which describes one of the four statutory categories of patentable subject matter, i.e., a machine.
Step 2A of the subject matter eligibility test (see MPEP 2106.04).
Prong One:
Claim 1 recite (“sets forth” or “describes”) the abstract idea of “a mental process” (MPEP 2106.04(a)(2).III.), substantially as follows:
“wherein a lower concentration level of sIFNAR2 in the biological sample as compared with a pre-established threshold level, in combination with the presence of MRI-DS and/or MRI-DT in the subject is an indication that the subject is suffering from multiple sclerosis (MS).”
Claim 5 recite (“sets forth” or “describes”) the abstract idea of “a mental process” (MPEP 2106.04(a)(2).III.), & the abstract idea of “mathematical concepts” (MPEP 2106.04(a)(2).I.), substantially as follows:
“(5) determining if the subject is suffering from MS, wherein the following are indications that the subject is suffering from MS:
(i) an identification of a lower concentration level of the sIFNAR2 as compared with a pre- established threshold level, in combination with the presence of the MRI-DS and/or the MRI- DT;
(ii) a delayed VEP latency value as compared with a pre-established VEP latency value; and
(iii) the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum; and
(6) using information obtained in (1)-(5) to define a risk score, wherein the risk score is calculated using logistic regression analysis; and wherein a deviation or variation of the risk score as compared with a reference value is indicative that the subject is suffering from MS;
wherein the method predicts that the subject is suffering from MS with an accuracy (area under the curve (AUC)) of at least 0.90.”
Claim 9 recite (“sets forth” or “describes”) the abstract idea of “a mental process” (MPEP 2106.04(a)(2).III.), substantially as follows:
“wherein an identification of a lower concentration level of sIFNAR2 using an immunoassay as compared with a pre-established threshold level, in combination with a presence of MRI-DS and/or MRI-DT is an indication that the subject is suffering from MS.”
Claim 12 recite (“sets forth” or “describes”) the abstract idea of “a mental process” (MPEP 2106.04(a)(2).III.), substantially as follows:
“wherein an identification of a lower concentration level of sIFNAR2 as compared with a pre-established threshold level, in combination with the presence of MRI-DS and/or MRI-DT is an indication that the subject is suffering from MS;”
For each claim (1, 5, 9, 12), the above recited steps can be practically performed in the human mind because each involve observation, comparison and/or diagnostic judgement.
For claim 1, the steps recite a mental process because the claim limitations evaluate observed test data results against pre-established criteria and reach a diagnostic conclusion that the subject is suffering from MS. Specifically, the claim compares the measured sIFNAR2 concentration level and the presence of MRI-DS and/or MRI-DT with a threshold to determine whether those finding indicate MS. which is an observation, evaluation, and judgement that can be practically performed in the mind. There is nothing recited in the claim to suggest an undue level of complexity in this comparison assessment.
For claim 5, recites a mental process because the claim limitations amount to merely interpreting multiple diagnostic findings, including sIFNAR2 levels, MRI findings, VEP latency values, and oligoclonal IgG bands, and evaluate those findings against pre-established criteria to determine whether the subject is suffering from MS. The claim further recites using resulting information (without specifics of the information used, just information) to identify a deviation from a reference value indicates MS, which amounts to analyzing information and making a diagnostic determination that can be practically performed mentally. The claim does not preclude this. Claim 5 also recites a mathematical concept because the claim expressively requires calculating a risk score using logistic regression analysis, and evaluating deviations of that score from a reference value, which is a mathematical relationships and calculation used to derived a diagnostic result.
For claim 9, recites a mental process because the claim limitations compare the identified concentration level of sIFNAR2 with a pre-established threshold level and evaluate that information together with the presence of MRI-DS and/or MRI-DT to determine whether the subject is suffering from MS. This recited evaluation and diagnostic conclusion constitutes an observation and judgement that can be practically performed din the human mind.
For claim 12, recites a mental process because the claimed limitations require evaluating whether the identified sIFNAR2 concentration level is lower than a pre-established threshold and considering that information together with the MRI-DS and/or MRI-DT finding to determine whether the subject is suffering from MS. The claim therefore recites analyzing collected information and reaching a diagnostic conclusion based on that information, which is a mental evaluation.
There is nothing recited in the claim to suggest an undue level of complexity in how any of the steps of assessing are processed. Therefore, a person would be able to perform the identified steps above mentally and/or mathematically.
Prong Two: Claims (1, 5, 9, 12) do not include additional elements that integrate the mental process into a practical application.
This judicial exception is not integrated into a practical application. In particular, the claims recites:
(1) additional steps of “(1) using an immunoassay to determine a concentration level of sIFNAR2 in a biological sample obtained from a subject; and (2) using magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI- DT) in the subject;”- (claim 1), “(1) using an immunoassay to determine the concentration level of sIFNAR2 in a biological sample obtained from the subject; (2) using magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI- DT) in the subject; (3) using recorded visual evoked potential (VEP) values to determine a VEP latency value in the subject; (4) using cerebrospinal fluid (CSF) data to determine a presence or absence of oligoclonal IgG bands (BOC-IgG) in CSF of the subject;" (claim 5), “magnetic resonance imaging (MRI) measured variables dissemination in space (MRI-DS) and/or dissemination in time (MRI-DT), for a diagnosis and/or prognosis of multiple sclerosis (MS),” (claim 9), “an immunoassay comprising reagents for assessing the concentration level of sIFNAR2 in a biological sample; wherein the immunoassay is performed in combination with magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI-DT) in the subject;” (claim 12); and
(2) further an additional step of “wherein the kit has an accuracy (area under the curve (AUC)) of at least 0.90.” (claim 12). Claims 1, 5, & 9 do not provide any additional post-solution activity. These claims (1, 5, & 9) including claim 12 as claimed amount to nothing more than using data and producing a desired result. Upon review of the specification, it appears the specification provides no asserted solution to solve a technological solution in a meaningful way in order to provide a practical application. The results of the methods disclosed merely amount to desired results rather than solving a technological solution in a meaningful way such that a practical application is realized. The mere assertion of the generalized steps to achieve desired results or the results of a diagnosis does not provide a practical application.
The steps in (1) represent merely data gathering or pre-solution activities that are necessary for use of the recited judicial exception and are recited at a high level of generality with conventionally used tools (see below Step IIB for further details). Data gathering and mere instructions to implement an abstract idea on a computer do not integrate a judicial exception into a practical application (MPEP 2106.05 (f and g)).
As a whole, the additional elements merely serve to gather and feed information to the abstract idea and to output a desired result based on the abstract idea, while generically implementing it on conventionally used tools. There is no practical application because the abstract idea is not applied, relied on, or used in a meaningful way. No improvement to the technology is evident, and the estimated bio-information is not outputted in any way such that a practical benefit is realized. Therefore, the additional elements, alone or in combination, do not integrate the abstract idea into a practical application.
Accordingly, these additional elements do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract idea. Further, there is no evidence of record that would support the assertion that this step is an improvement to a computer or technological solution to a technological problem. Ultimately, the Applicant’s describe improvement in the process of using McDonald techniques, but this is not an improvement in the function of a computer or other technology (See MPEP 2106.05(a)(ii); “the court determined that the claimed user interface simply provided a trader with more information to facilitate market trades, which improved the business process of market trading but did not improve computers or technology”; See MPEP 2106.04(d)(1); 2106.05(a); and 2106.05(f)). The claims are directed to the abstract idea. Also, there does not appear to be any particular structure or machine, treatment or prophylaxis, transformation, or any other meaningful application that would render the claim eligible at step 2A, prong 2.
Step 2B of the subject matter eligibility test (see MPEP 2106.05).
Claims (1, 5, 9, 12) do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As discussed above, the claims recite additional steps using an immunoassay to determine the concentration level of sIFNAR2 in a biological sample obtained from the subject, using MRI to determine a presence or absence of dissemination in space and time, & using recorded visual evoked potentials to determine a VEP latency value in the subject. These steps represents mere data gathering, data outputting or pre/post/extra-solution activities that are necessary for use of the recited judicial exception and are recited at a high level of generality. Furthermore, as discussed above, limitations with respect to the processor languages/terms, respectively, amount to mere instructions to implement the abstract idea on a computer. As discussed with respect to Step 2A Prong Two, the additional elements in the claims amount to no more than insignificant extra solution activity and mere instructions to apply the exception using a generic computer component. The same analysis applies here in 2B and does not provide an inventive concept. The data gathering steps that were considered insignificant extra-solution activity in Step 2A Prong Two, have been re-evaluated in Step 2B and determined to be well-understood, routine, conventional activity in the field.
As an evidence, Hageman et al (US 2015/0211065 A1) discloses:
¶0100, ‘It is understood and herein contemplated that tissue samples obtained directly from the subject can be obtained by any means known in the art including invasive and non-invasive techniques. It is also understood that methods of measurement can be direct or indirect. Examples of methods of obtaining or measuring a tissue sample can include but are not limited to venipuncture, tissue biopsy, tissue lavage, aspiration, tissue swab, spinal tap, magnetic resonance imaging (MRI),’
As an evidence, Fernández Fernández et al (US 20160011212 A1) discloses:
¶0057, ‘Although the protein of the invention (soluble IFNAR2, sIFNAR2 or IFNAR2.3) is preferably a recombinant protein, and even more preferably a recombinant protein obtained by the method described in the present invention, since the described methods for obtaining and purifying same are advantageous, it can be obtained by any method known in the state of the art for obtaining proteins.’
As an evidence, Gallily (US 20190321426 A1) discloses:
¶0182, ‘at least one parameter may refer to any criteria known in the art for diagnosis or prognosis of MS such as Poser criteria or McDonald criteria.’
As an evidence, Mitsuhashi et al (US 5382880 A) discloses:
[Col 1 l.52-56], ‘We studied the relationship between eyestrain and illumination particularly utilizing the visual evoked potential (abbreviated hereinafter as "VEP") which has been known as clinical test for troubles and diseases in ophthalmology, and discovered the phenomenon that when a visual task causes eyestrain, the latency of P100 wave significantly delays.”
As an evidence, Hemmer et al (US 20140080156 A1) discloses:
¶0034, ‘Typically, such lesions occur in the periventricular, juxtacortical and/or infratentorial region of the brain. Inflammation markers indicative of MS are well-known in the art and are preferably to be selected from pleocytosis (abnormally increased number of cells in the CSF, wherein typical values of increased cell numbers are between 5 and 50 cells/.mu.l or above), intrathecal IgG synthesis and the occurrence of oligoclonal IgG bends in the CSF.’
For these reasons, there is no inventive concept. The claim is not patent eligible. Even when viewed as a whole, nothing in the claim adds significantly more to the abstract idea.
Dependent Claims
The following dependent claims merely further define the abstract idea and are, therefore, recite an abstract idea for similar reasons:
(Claim 2) defining wherein the subject shows clinical and/or radiologic features suggestive of the MS and is characterized by the presence of the MRI-DS and/or the MRI-DT identified by the MRI; wherein the presence of the MRI-DS is assessed by a presence of inflammatory lesions in more than one already predefined locations in a central nervous system, and the presence of the MRI-DT is assessed by new lesions that have developed during the course of the MS.
(Claim 3) defining further comprising using recorded visual evoked potential (VEP) values to determine a VEP latency value in the subject, wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS; and wherein the method predicts that the subject is suffering from MS with an accuracy (area under the curve (AUC)) of at least 0.90.
(Claim 4) defining further comprising using cerebrospinal fluid (CSF) data to determine a presence or absence of oligoclonal IgG bands (BOC-IgG) in CSF, wherein the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum is an indication that the subject is suffering from MS.
(Claim 14) defining for a diagnosis and/or prognosis of multiple sclerosis (MS).
The following dependent claims merely further describe the extra-solution activities and therefore, do not amount to significantly more than the judicial exception or integrate the abstract idea into a practical application for similar reasons:
(Claim 6) defining wherein the biological sample is a biological fluid selected from blood, plasma, serum, cerebrospinal fluid, urine or tears.
(Claim 7) defining wherein the immunoassay is selected from at least one of: immunoblot, enzyme-linked immunosorbent assay (ELISA), linear immunoassay (LIA), radioimmunoassay (RIA), immunofluorescence, x-map, protein chips, aptamer-based ELISA, or any combination thereof.
(Claim 8) (Currently Amended) An in vitro method, according to claim 5, further comprising: a) receiving by a computer program the concentration level of the sIFNAR2, the presence or absence of dissemination in space (MRI-DS) and/or the presence or absence of dissemination in time (MRI-DT), visual evoked potential (VEP) values, and the presence or absence of oligoclonal IgG bands (BOC-IgG) in cerebrospinal fluid (CSF) of the subject; b) processing information received according to the step a) for finding a variation or deviation with respect to equivalent information obtained from a healthy subject, and c) providing an output through a terminal display when the variation or deviation is found which indicates that the subject is suffering from MS.
(Claim 10) defining the sIFNAR2 in combination with the MRI measured variables MRI-DS and/or MRI-DT; and in further combination with visual evoked potential (VEP) values to determine a VEP latency value in the subject, wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS.
(Claim 11) defining of the sIFNAR2 in combination with the MRI measured variables MRI-DS and/or MRI-DT, VEP values and a presence or absence of oligoclonal IgG bands (BOC-IgG) in cerebrospinal fluid (CSF), wherein the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum is an indication that the subject is suffering from MS.
(Claim 13) defining further comprising:(i) surface recording electrodes for recording visual evoked potential (VEP) values to determine a VEP latency value in the subject; and(ii) reagents for isoelectric focusing followed by staining for detecting oligoclonal IgG bands (BOC-IgG) values in cerebrospinal fluid (CSF) of the subject.
Taken alone and in combination, the additional elements do not integrate the judicial exception into a practical application at least because the abstract idea is not applied, relied on, or used in a meaningful way. They also do not add anything significantly more than the abstract idea. Their collective functions merely provide computer/electronic implementation and processing, and no additional elements beyond those of the abstract idea. Looking at the limitations as an ordered combination adds nothing that is not already present when looking at the elements individually. There is no indication that the combination of elements improves the functioning of a computer, output device, improves technology other than the technical field of the claimed invention, etc. Therefore, the claims are rejected as being directed to non-statutory subject matter.
Examiners Notes
Claim 5 & 8 are not rejected under prior art, but is rejected under 35 USC §. 101, 35 USC 112(a), 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action. Note; a change in scope in view of the requested corrections will require further search and consideration.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-7, & 9 are rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1).
Claim 1: Órpez-Zafra discloses, An in vitro method comprising:
(1) using an immunoassay to determine a concentration level of sIFNAR2 in a biological sample obtained from a subject; and
-Órpez-Zafra discloses an in vitro method for the diagnosis of MS that comprises assessing the concentration levels of soluble interferon-β (IFN-β) receptor (sIFNAR2) in a biological sample obtained from the subject in combination with the obtention of a magnetic resonance imaging (MRI) using a ELISA.
[Abstract, pg. 937], [Introduction, pg. 938, left col ¶3], [Quantification of soluble IFNAR2 in serum by ELISA, pg. 939, left col ¶3], [Sample Analysis, pg. 939], [Evaluation of sIFNAR2 in CSF, pg. 940], [Discussion, pg.942, left col ¶2 to ¶1 right col]. [Introduction / p. 939], “we developed and validated an ELISA for its quantification in human serum. The validated ELISA was used to determine sIFNAR2 concentration in serum samples from untreated MS patients and healthy controls (HCs), showing that sIFNAR2 levels in MS patients were significantly lower than those in HCs”
Note; [Materials and Methods Section] / pg. 938 ], The McDonald criteria implicitly involves the concepts of dissemination in space and dissemination in time verified through clinical assessment with the obtention of MRI.
wherein a lower concentration level of sIFNAR2 in the biological sample as compared with a pre-established threshold level, is an indication that the subject is suffering from multiple sclerosis (MS).
-Órpez-Zafra core finding in patients with MS and CIS exhibit lower circulating sIFNAR2 levels compared to healthy controls and patients with other inflammatory neurological disorders, , [Abstract, pg. 937], [Results-Evaluation of sIFNAR2 in serum, ¶2 left col], [Discussion, pg.942, left col ¶2 to ¶1 right col]. For instance, in the second cohort study, the median sIFNAR2 concentration for naïve MS patients was 70.43 ng/mL, while HC has a median of 153.64 ng/mL, and OIND patients had a median of 150.70 ng/ML, Table 2 pg. 939. This indicates observation of lower levels of sIFNAR2.
-Órpez-Zafra uses receiver operating characteristics (ROS) curve analysis to define the optimal cutoff values of sIFNAR2 to discriminate between groups, [Statistical Analysis, pg. 939-940]. These cutoff values represent pre-established threshold levels used to diagnose MS based on sIFNAR2 concentration, ‘receiver operating characteristic (ROC) curve analysis was performed to define the optimal cutoff values of sIFNAR2.’-[Statistical Analysis, pg. 939-940], see also [Evaluation of soluble IFNAR2 as a diagnostic biomarker for MS, pg. 940-941], [Discussion, pg.943, left col, ¶2]-, ‘The differences observed between naïve MS patients and HC or patients with other neurological diseases suggest that sIFNAR2 could be a potential diagnostic biomarker for MS, so we evaluated the relevance of our results in the clinical context using the ROC analysis. Our results suggest that serum sIFNAR2 measurement may be a useful and easy-performing biomarker contributing to MS diagnosis since it has a sensitivity of 72.6% and a specificity of 77.0%, with the established cutoff, to discriminate from HC. Regarding the ability to discriminate from OIND patients, sIFNAR2 showed very similar values with a sensitivity of 70.11% and a specificity of 79.4%. Taking into account that we are analyzing one univariate indicator, sIFNAR2 levels show a significant discriminatory ability to distinguish between MS patients and HCs or OIND patients; this ability might improve by combining with additional markers that should be investigated further, as has been described with other soluble receptors addressed as potential biomarkers.’. See [Table 2 / pg. 939], for the comparison of levels found. MS patients had lower median levels of sIFNAR2 compared to the healthy group. [Evaluation of sIFNAR2 in CSF / pg 940], ‘The differences observed between naïve MS patients suggested that serum levels of sIFNAR2 could be a potential diagnostic biomarker for MS.”
Orpez-Zafra fails to explicitly disclose: (2) using magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI- DT) in the subject; [...] and wherein a lower concentration of the biomarker in the biological sample as compared with a pre-established threshold is in combination with the McDonald Criteria in the subject is an indication that the subject is suffering from multiple sclerosis (MS).
However, Mirzaii-Dizgah in the context of diagnosing multiple sclerosis in patients discloses, (2) using magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI- DT) in the subject; ([Introduction/ pg. 310], [Methods / pg. 310], [Discussion / pg. 312], The MS diagnostic criteria evaluates clinical features including the use of MRI to show lesions in the brain and spinal cord. The MBP is checked in combination with these clinical features to allow for early diagnosis. The McDonald Criteria is a diagnostic framework that looks for evidence of dissemination in space and time.)
a lower concentration of the biomarker in the biological sample as compared with a pre-established threshold ([Abstract / pg. 309], [Methods / pg. 311], [Results / pg. 311] The biomarker MBP is present at significantly lower levels in serum and simulated saliva of MS patients. The cut-off to indicate MS is 1000 ng/L for serum and 457 for simulated saliva. The level of MBP was determining using an ELISA kit.), in combination with the presence of MRI-DS and/or MRI-DT in the subject is an indication that the subject is suffering from multiple sclerosis (MS). ([Introduction/ pg. 310], [Methods / pg. 310], [Discussion / pg. 312], The MS diagnostic criteria evaluates clinical features including the use of MRI to show lesions in the brain and spinal cord. The MBP is checked in combination with these clinical features to allow for early diagnosis. The McDonald Criteria is a diagnostic framework that looks for evidence of dissemination in space and time).
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Órpez-Zafra to include the teachings of Mirzaii-Dizgah. The motivation to do this yield predictable results such as enabling prognosis prediction, illness management, and determining the effectiveness of an intervention, as suggested by Mirzaii-Dizgah, [Introduction / pg. 310]. The modified combination would disclose using magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI- DT) in the subject; wherein the lower concentration level of sIFNAR2 in the biological sample as compared with a pre-established threshold level in combination with the presence of MRI-DS and/or MRI-DT in the subject is an indication that the subject is suffering from multiple sclerosis (MS).
Claim 6: Orpez-Zafra as modified discloses all the elements above in claim 1, Orpez-Zafra discloses, wherein the biological sample is a biological fluid selected from blood, plasma, serum, cerebrospinal fluid, urine or tears. (Órpez-Zafra discloses, that the biological sample for assessing the concentration level of sIFNAR2 is a biological fluid, and it specifically identifies blood, serum, and CSF, [Sample Collection, pg 938], [Results/Evaluation of sIFNAR2 in serum, pg. 940], [Results/Evaluation of sIFNAR2 in CSF, pg. 940].)
Claim 7: Orpez-Zafra as modified discloses all the elements above in claim 1, Orpez-Zafra discloses, wherein the immunoassay is selected from at least one of: immunoblot, enzyme-linked immunosorbent assay (ELISA), linear immunoassay (LIA), radioimmunoassay (RIA), immunofluorescence, x-map, protein chips, aptamer-based ELISA, or any combination thereof. (Órpez-Zafra discloses, [Quantification of soluble IFNAR2 in serum by ELISA, pg. 939] ‘Quantification of sIFNAR2 was performed with an ELISA developed and validated in our laboratory, [...] whose parameters of validation, accuracy, and precision met the acceptance criteria for immunoassays of protein biomarkers.’, see also the Abstract.)
Claim 9: Orpez-Zafra discloses: In vitro use of sIFNAR2 in a biological sample obtained from a subject,
-Órpez-Zafra discloses an in vitro method for the diagnosis of MS that comprises assessing the concentration levels of soluble interferon-β (IFN-β) receptor (sIFNAR2) in a biological sample obtained from the subject in combination with the obtention of a magnetic resonance imaging (MRI) using a ELISA.
[Abstract, pg. 937], [Introduction, pg. 938, left col ¶3], [Quantification of soluble IFNAR2 in serum by ELISA, pg. 939, left col ¶3], [Sample Analysis, pg. 939], [Evaluation of sIFNAR2 in CSF, pg. 940], [Discussion, pg.942, left col ¶2 to ¶1 right col]. [Introduction / p. 939], “we developed and validated an ELISA for its quantification in human serum. The validated ELISA was used to determine sIFNAR2 concentration in serum samples from untreated MS patients and healthy controls (HCs), showing that sIFNAR2 levels in MS patients were significantly lower than those in HCs”
Note; [Materials and Methods Section] / pg. 938 ], The McDonald criteria implicitly involves the concepts of dissemination in space and dissemination in time verified through clinical assessment with the obtention of MRI.
wherein an identification of a lower concentration level of sIFNAR2 using an immunoassay as compared with a pre-established threshold level, is an indication that the subject is suffering from MS.
-Órpez-Zafra core finding in patients with MS and CIS exhibit lower circulating sIFNAR2 levels compared to healthy controls and patients with other inflammatory neurological disorders, , [Abstract, pg. 937], [Results-Evaluation of sIFNAR2 in serum, ¶2 left col], [Discussion, pg.942, left col ¶2 to ¶1 right col]. For instance, in the second cohort study, the median sIFNAR2 concentration for naïve MS patients was 70.43 ng/mL, while HC has a median of 153.64 ng/mL, and OIND patients had a median of 150.70 ng/ML, Table 2 pg. 939. This indicates observation of lower levels of sIFNAR2.
-Órpez-Zafra uses receiver operating characteristics (ROS) curve analysis to define the optimal cutoff values of sIFNAR2 to discriminate between groups, [Statistical Analysis, pg. 939-940]. These cutoff values represent pre-established threshold levels used to diagnose MS based on sIFNAR2 concentration, ‘receiver operating characteristic (ROC) curve analysis was performed to define the optimal cutoff values of sIFNAR2.’-[Statistical Analysis, pg. 939-940], see also [Evaluation of soluble IFNAR2 as a diagnostic biomarker for MS, pg. 940-941], [Discussion, pg.943, left col, ¶2]-, ‘The differences observed between naïve MS patients and HC or patients with other neurological diseases suggest that sIFNAR2 could be a potential diagnostic biomarker for MS, so we evaluated the relevance of our results in the clinical context using the ROC analysis. Our results suggest that serum sIFNAR2 measurement may be a useful and easy-performing biomarker contributing to MS diagnosis since it has a sensitivity of 72.6% and a specificity of 77.0%, with the established cutoff, to discriminate from HC. Regarding the ability to discriminate from OIND patients, sIFNAR2 showed very similar values with a sensitivity of 70.11% and a specificity of 79.4%. Taking into account that we are analyzing one univariate indicator, sIFNAR2 levels show a significant discriminatory ability to distinguish between MS patients and HCs or OIND patients; this ability might improve by combining with additional markers that should be investigated further, as has been described with other soluble receptors addressed as potential biomarkers.’. See [Table 2 / pg. 939], for the comparison of levels found. MS patients had lower median levels of sIFNAR2 compared to the healthy group. [Evaluation of sIFNAR2 in CSF / pg 940], ‘The differences observed between naïve MS patients suggested that serum levels of sIFNAR2 could be a potential diagnostic biomarker for MS.”
Orpez-Zafra fails to disclose that the in vitro method of the biomarker in the biological sample obtained from a subject is in combination with magnetic resonance imaging (MRI) measured variables dissemination in space (MRI-DS) and/or dissemination in time (MRI-DT), for a diagnosis and/or prognosis of multiple sclerosis (MS), [...] in combination with a presence of MRI-DS and/or MRI-DT
However, Mirzaii-Dizgah in the context of diagnosing multiple sclerosis in patients discloses, a method for evaluating a biomarker performed outside of the patient body on samples s in combination with magnetic resonance imaging (MRI) measured variables dissemination in space (MRI-DS) and/or dissemination in time (MRI-DT), ([Introduction/ pg. 310], [Methods / pg. 310], [Discussion / pg. 312], The MS diagnostic criteria evaluates clinical features including the use of MRI to show lesions in the brain and spinal cord. The MBP is checked in combination with these clinical features to allow for early diagnosis. The McDonald Criteria is a diagnostic framework that looks for evidence of dissemination in space and time.)
wherein an identification of a lower concentration of the biomarker using an immunoassay as compared with a pre-established threshold ([Abstract / pg. 309], [Methods / pg. 311], [Results / pg. 311] The biomarker MBP is present at significantly lower levels in serum and simulated saliva of MS patients. The cut-off to indicate MS is 1000 ng/L for serum and 457 for simulated saliva. The level of MBP was determining using an ELISA kit.), in combination with the presence of MRI-DS and/or MRI-DT in the subject is an indication that the subject is suffering from multiple sclerosis (MS). ([Introduction/ pg. 310], [Methods / pg. 310], [Discussion / pg. 312], The MS diagnostic criteria evaluates clinical features including the use of MRI to show lesions in the brain and spinal cord. The MBP is checked in combination with these clinical features to allow for early diagnosis. The McDonald Criteria is a diagnostic framework that looks for evidence of dissemination in space and time).
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Órpez-Zafra to include the teachings of Mirzaii-Dizgah. The motivation to do this yield predictable results such as enabling prognosis prediction, illness management, and determining the effectiveness of an intervention, as suggested by Mirzaii-Dizgah, [Introduction / pg. 310]. The modified combination would disclose using in vitro method of the sIFNAR2 in the biological sample obtained from a subject is in combination with magnetic resonance imaging (MRI) measured variables dissemination in space (MRI-DS) and/or dissemination in time (MRI-DT), for a diagnosis and/or prognosis of multiple sclerosis (MS), wherein an identification of a lower concentration of the biomarker using an immunoassay as compared with a pre-established threshold in combination with a presence of MRI-DS and/or MRI-DT
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.), as applied to claim 1, in further view of Thompson et al. (2017. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 February; 17(2):162-173. Epub 2017 Dec. 21).
Claim 2: Orpez-Zafra as modified discloses all the elements above in claim 1, Orpez-Zafra fails to disclose: wherein the subject shows clinical and/or radiologic features suggestive of the MS and is characterized by the presence of the MRI-DS and/or the MRI-DT identified by the MRI; wherein the presence of the MRI-DS is assessed by a presence of inflammatory lesions in more than one already predefined locations in a central nervous system, and the presence of the MRI-DT is assessed by new lesions that have developed during the course of the MS.
However, Thompson in the context of diagnosing MS using the McDonald Criteria, discloses: wherein the subject shows clinical and/or radiologic features suggestive of the MS and is characterized by the presence of the MRI-DS and/or the MRI-DT identified by the MRI; ([Summary / pg. 162], [Panel 1 / pg. 163], diagnostic criteria is intended for patients experiencing clinically isolated syndrome which is defined as a clinical feature with objective findings reflecting focal and multifocal inflammatory demyelinating events in the CNS suggested of MS in the presence of MRI-DS and MRI-DT identified by the MRI)
wherein the presence of the MRI-DS is assessed by a presence of inflammatory lesions in more than one already predefined locations in a central nervous system, and ([Panel 1 / pg. 163], ‘Cortical MRI lesions Lesions within the cerebral cortex. Typically, special MRI techniques such as double inversion recovery, phase-sensitive inversion recovery, and magnetisation-prepared rapid acquisition with gradient echo sequences are required to visualise these lesions.7, 11, 12 The lesions detected by these techniques are primarily of the leukocortical type; subpial lesions are rarely detected. Care is needed to distinguish potential cortical lesions from neuroimaging artefacts.7 Dissemination in space The development of lesions in distinct anatomical locations within the CNS—ie, indicating a multifocal CNS process. Dissemination in time The development or appearance of new CNS lesions over time.’; [Panel 5/ pg. 168], “2017 McDonald criteria for demonstration of dissemination in space and time by MRI in a patient with a clinically isolated syndrome • Dissemination in space can be demonstrated by one or more T2-hyperintense lesions* that are characteristic of multiple sclerosis in two or more of four areas of the CNS: periventricular†, cortical or juxtacortical, and infratentorial brain regions, and the spinal cord • Dissemination in time can be demonstrated by the simultaneous presence of gadolinium-enhancing and non-enhancing lesions* at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI”)
the presence of the MRI-DT is assessed by new lesions that have developed during the course of the MS. ([Panel 1 / pg. 163] & [Panel 5/ pg. 168])
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify method of modified Orpez-Zafra to include the teachings of Thompson. The motivation to do this yield predictable results such as achieving an earlier, more sensitive, and more specific diagnosis of multiple sclerosis (MS), as suggested by Thompson, [Introduction / pg. 162].
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.), as applied to claim 1, in further view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016).
Claim 3: Orpez-Zafra as modified discloses all the elements above in claim 1, Orpez-Zafra fails to disclose: further comprising using recorded visual evoked potential (VEP) values ( to determine a VEP latency value in the subject, wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS; and
However, Thabit in the context of visual evoked potentials discloses, further comprising using recorded visual evoked potential (VEP) values ([Visual evoked potential / pg. 3)]) to determine a VEP latency value in the subject (¶Abstract / pg.1] [Table 2 / pg. 4]),
wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS; (¶Abstract / pg.1], [Introduction pg. 2], [Table 2 / pg. 4], [Discussion / pg 7])
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of modified Opez-Zafra to further comprise, using recorded visual evoked potential (VEP) values to determine a VEP latency value in the subject, wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS as taught by Thabit. The motivation to do this yields predictable results such as to provide a safe, non-invasive, and relatively inexpensive tools for assessment of the degree of axonal loss and hence the disability, as suggested by Thabit [Conclusion, pg. 7].
Orpez-Zafra fails to disclose: wherein the method predicts that the subject is suffering from MS with an accuracy (area under the curve (AUC)) of at least 0.90.
However, De Santiago in the context of visual evoked potentials discloses, wherein the method predicts that the subject is suffering from MS with an accuracy (area under the curve (AUC)) of at least 0.90. ([3.2. AUC values / pg 1577], [Table 3 / pg. 1578], The mean discrimination capacity value for the various sectors revealed that the highest values were found in rings 5 AUC = 0.89)
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of modified Opez-Zafra such that the method predicts that the subject is suffering from MS with an accuracy (area under the curve (AUC)) of at least 0.90 as taught by De Santiago. The motivation to do this yield predictable results such as to improve the assessment and prediction of MS progression in patients who are at risk, as suggested by De Santiago, ¶Abstract.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016), as applied to claim 3, in further view of Thompson et al. (2017. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 February; 17(2):162-173. Epub 2017 Dec. 21).
Claim 4: Orpez-Zafra as modified discloses all the elements above in claim 3, Orpez-Zafra fails to disclose: further comprising using cerebrospinal fluid (CSF) data to determine a presence or absence of oligoclonal IgG bands (BOC-IgG) in CSF, wherein the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum is an indication that the subject is suffering from MS.
However, Thompson in the context of diagnosing MS using the McDonald Criteria, discloses: further comprising using cerebrospinal fluid (CSF) data to determine a presence or absence of oligoclonal IgG bands (BOC-IgG) in CSF, wherein the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum is an indication that the subject is suffering from MS. ([Role of CSF examination in diagnosis of multiple sclerosis / pg. 166], The qualitative demonstration of two or more CSF specific oligoclonal bands is the most reliable indicator. The methods for IFG are the most sensitive for this. The paired CSG and serum samples essential to confirm that the oligoclonal band are unique demonstrates the brands must not be present in serum.)
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify method of modified Orpez-Zafra to further include the teachings of Thompson. The motivation to do this yield predictable results such as achieving an earlier, more sensitive, and more specific diagnosis of multiple sclerosis (MS), as suggested by Thompson, [Introduction / pg. 162].
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.), as applied to claim 9, in further view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)).
Claim 10: Orpez-Zafra as modified discloses all the elements above in claim 9, Orpez-Zafra fails to disclose: that the method is in further combination with visual evoked potential (VEP) values to determine a VEP latency value in the subject, wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS.
However, Thabit in the context of visual evoked potentials discloses,
a combination with visual evoked potential (VEP) values ([Visual evoked potential / pg. 3)]) to determine a VEP latency value in the subject (¶Abstract / pg.1] [Table 2 / pg. 4]),
wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS. (¶Abstract / pg.1], [Introduction pg. 2], [Table 2 / pg. 4], [Discussion / pg 7])
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of modified Opez-Zafra to combine combination with visual evoked potential (VEP) values to determine a VEP latency value in the subject, wherein a delayed VEP latency value as compared with a pre-established VEP latency value, is an indication that the subject is suffering from MS as taught by Thabit. The motivation to do this yields predictable results such as to provide a safe, non-invasive, and relatively inexpensive tools for assessment of the degree of axonal loss and hence the disability, as suggested by Thabit [Conclusion, pg. 7].
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)), as applied to claim 11, in further view of Thompson et al. (2017. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 February; 17(2):162-173. Epub 2017 Dec. 21).
Claim 11: Orpez-Zafra as modified discloses all the elements above in claim 10, Orpez-Zafra fails to disclose: the combination with VEP values
However, Thabit is relied upon above discloses, VEP values ([Visual evoked potential / pg. 3)]) (¶Abstract / pg.1], [Introduction pg. 2], [Table 2 / pg. 4], [Discussion / pg 7])
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method the combination of modified Opez-Zafra to combine with the VEP values as taught by Thabit. The motivation to do this yields predictable results such as to provide a safe, non-invasive, and relatively inexpensive tools for assessment of the degree of axonal loss and hence the disability, as suggested by Thabit [Conclusion, pg. 7].
Orpez-Zafra fails to disclose: the combination with a presence or absence of oligoclonal IgG bands (BOC-IgG) in cerebrospinal fluid (CSF), wherein the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum is an indication that the subject is suffering from MS.
However, Thompson in the context of diagnosing MS using the McDonald Criteria, discloses: a presence or absence of oligoclonal IgG bands (BOC-IgG) in cerebrospinal fluid (CSF), wherein the presence of at least two oligoclonal IgG bands (BOC-IgG) in CSF not present in serum is an indication that the subject is suffering from MS. ([Role of CSF examination in diagnosis of multiple sclerosis / pg. 166], The qualitative demonstration of two or more CSF specific oligoclonal bands is the most reliable indicator. The methods for IFG are the most sensitive for this. The paired CSG and serum samples essential to confirm that the oligoclonal band are unique demonstrates the brands must not be present in serum.)
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify method combination of modified Orpez-Zafra to further include the teachings of Thompson. The motivation to do this yield predictable results such as achieving an earlier, more sensitive, and more specific diagnosis of multiple sclerosis (MS), as suggested by Thompson, [Introduction / pg. 162].
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016),
A kit-of-parts for determining if a subject is suffering from multiple sclerosis (MS), comprising: an immunoassay comprising reagents for assessing the concentration level of sIFNAR2 in a biological sample;
-Órpez-Zafra discloses an in vitro method for the diagnosis of MS that comprises assessing the concentration levels of soluble interferon-β (IFN-β) receptor (sIFNAR2) in a biological sample obtained from the subject in combination with the obtention of a magnetic resonance imaging (MRI) using a ELISA.
[Abstract, pg. 937], [Introduction, pg. 938, left col ¶3], [Quantification of soluble IFNAR2 in serum by ELISA, pg. 939, left col ¶3], [Sample Analysis, pg. 939], [Evaluation of sIFNAR2 in CSF, pg. 940], [Discussion, pg.942, left col ¶2 to ¶1 right col]. [Introduction / p. 939], “we developed and validated an ELISA for its quantification in human serum. The validated ELISA was used to determine sIFNAR2 concentration in serum samples from untreated MS patients and healthy controls (HCs), showing that sIFNAR2 levels in MS patients were significantly lower than those in HCs”
Órpez-Zafra discloses, that the biological sample for assessing the concentration level of sIFNAR2 is a biological fluid, and it specifically identifies blood, serum, and CSF, [Sample Collection, pg 938], [Results/Evaluation of sIFNAR2 in serum, pg. 940], [Results/Evaluation of sIFNAR2 in CSF, pg. 940].
Note; [Materials and Methods Section] / pg. 938 ], The McDonald criteria implicitly involves the concepts of dissemination in space and dissemination in time verified through clinical assessment with the obtention of MRI.
wherein an identification of a lower concentration level of sIFNAR2 as compared with a pre-established threshold level is an indication that the subject is suffering from MS;
-Órpez-Zafra core finding in patients with MS and CIS exhibit lower circulating sIFNAR2 levels compared to healthy controls and patients with other inflammatory neurological disorders, , [Abstract, pg. 937], [Results-Evaluation of sIFNAR2 in serum, ¶2 left col], [Discussion, pg.942, left col ¶2 to ¶1 right col]. For instance, in the second cohort study, the median sIFNAR2 concentration for naïve MS patients was 70.43 ng/mL, while HC has a median of 153.64 ng/mL, and OIND patients had a median of 150.70 ng/ML, Table 2 pg. 939. This indicates observation of lower levels of sIFNAR2.
-Órpez-Zafra uses receiver operating characteristics (ROS) curve analysis to define the optimal cutoff values of sIFNAR2 to discriminate between groups, [Statistical Analysis, pg. 939-940]. These cutoff values represent pre-established threshold levels used to diagnose MS based on sIFNAR2 concentration, ‘receiver operating characteristic (ROC) curve analysis was performed to define the optimal cutoff values of sIFNAR2.’-[Statistical Analysis, pg. 939-940], see also [Evaluation of soluble IFNAR2 as a diagnostic biomarker for MS, pg. 940-941], [Discussion, pg.943, left col, ¶2]-, ‘The differences observed between naïve MS patients and HC or patients with other neurological diseases suggest that sIFNAR2 could be a potential diagnostic biomarker for MS, so we evaluated the relevance of our results in the clinical context using the ROC analysis. Our results suggest that serum sIFNAR2 measurement may be a useful and easy-performing biomarker contributing to MS diagnosis since it has a sensitivity of 72.6% and a specificity of 77.0%, with the established cutoff, to discriminate from HC. Regarding the ability to discriminate from OIND patients, sIFNAR2 showed very similar values with a sensitivity of 70.11% and a specificity of 79.4%. Taking into account that we are analyzing one univariate indicator, sIFNAR2 levels show a significant discriminatory ability to distinguish between MS patients and HCs or OIND patients; this ability might improve by combining with additional markers that should be investigated further, as has been described with other soluble receptors addressed as potential biomarkers.’. See [Table 2 / pg. 939], for the comparison of levels found. MS patients had lower median levels of sIFNAR2 compared to the healthy group. [Evaluation of sIFNAR2 in CSF / pg 940], ‘The differences observed between naïve MS patients suggested that serum levels of sIFNAR2 could be a potential diagnostic biomarker for MS.”
Órpez-Zafra fails to disclose:
wherein the immunoassay is performed in combination with magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI-DT) in the subject; and wherein an identification of a lower concentration level of the biomarker as compared with a pre-established threshold level, in combination with the presence of MRI-DS and/or MRI-DT is an indication that the subject is suffering from MS;
However, Mirzaii-Dizgah in the context of diagnosing multiple sclerosis in patients discloses, wherein the immunoassay is performed in combination with magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI-DT) in the subject; and wherein an identification of a lower concentration level of the biomarker as compared with a pre-established threshold level, in combination with the presence of MRI-DS and/or MRI-DT is an indication that the subject is suffering from MS; ([Introduction/ pg. 310], [Methods / pg. 310], [Discussion / pg. 312], The MS diagnostic criteria evaluates clinical features including the use of MRI to show lesions in the brain and spinal cord. The MBP is checked in combination with these clinical features to allow for early diagnosis. The McDonald Criteria is a diagnostic framework that looks for evidence of dissemination in space and time.) ([Abstract / pg. 309], [Methods / pg. 311], [Results / pg. 311] The biomarker MBP is present at significantly lower levels in serum and simulated saliva of MS patients. The cut-off to indicate MS is 1000 ng/L for serum and 457 for simulated saliva. The level of MBP was determining using an ELISA kit.) ([Introduction/ pg. 310], [Methods / pg. 310], [Discussion / pg. 312], The MS diagnostic criteria evaluates clinical features including the use of MRI to show lesions in the brain and spinal cord. The MBP is checked in combination with these clinical features to allow for early diagnosis. The McDonald Criteria is a diagnostic framework that looks for evidence of dissemination in space and time).
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the kit-of-parts of Órpez-Zafra to include the teachings of Mirzaii-Dizgah. The motivation to do this yield predictable results such as enabling prognosis prediction, illness management, and determining the effectiveness of an intervention, as suggested by Mirzaii-Dizgah, [Introduction / pg. 310]. The modified combination would disclose wherein the immunoassay is performed in combination with magnetic resonance imaging (MRI) to determine a presence or absence of dissemination in space (MRI-DS) and/or a presence or absence of dissemination in time (MRI-DT) in the subject; and wherein an identification of a lower concentration level of the sIFNAR2 as compared with a pre-established threshold level, in combination with the presence of MRI-DS and/or MRI-DT is an indication that the subject is suffering from MS.
Órpez-Zafra fails to disclose:
wherein the kit has an accuracy (area under the curve (AUC)) of at least 0.90.
However, De Santiago in the context of visual evoked potentials discloses, wherein the kit has an accuracy (area under the curve (AUC)) of at least 0.90. ([3.2. AUC values / pg 1577], [Table 3 / pg. 1578], The mean discrimination capacity value for the various sectors revealed that the highest values were found in rings 5 AUC = 0.89)
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the kit-of-parts of modifed Opez-Zafra such that the wherein the kit has an accuracy (area under the curve (AUC)) of at least 0.90 as taught by De Santiago. The motivation to do this yield predictable results such as to improve the assessment and prediction of MS progression in patients who are at risk, as suggested by De Santiago, ¶Abstract.
Claim 14: Órpez-Zafra as modified discloses all the elements above in claim 12, further discloses, for a diagnosis and/or prognosis of multiple sclerosis (MS).
-Órpez-Zafra core finding in patients with MS and CIS exhibit lower circulating sIFNAR2 levels compared to healthy controls and patients with other inflammatory neurological disorders, , [Abstract, pg. 937], [Results-Evaluation of sIFNAR2 in serum, ¶2 left col], [Discussion, pg.942, left col ¶2 to ¶1 right col]. For instance, in the second cohort study, the median sIFNAR2 concentration for naïve MS patients was 70.43 ng/mL, while HC has a median of 153.64 ng/mL, and OIND patients had a median of 150.70 ng/ML, Table 2 pg. 939. This indicates observation of lower levels of sIFNAR2.
-Órpez-Zafra uses receiver operating characteristics (ROS) curve analysis to define the optimal cutoff values of sIFNAR2 to discriminate between groups, [Statistical Analysis, pg. 939-940]. These cutoff values represent pre-established threshold levels used to diagnose MS based on sIFNAR2 concentration, ‘receiver operating characteristic (ROC) curve analysis was performed to define the optimal cutoff values of sIFNAR2.’-[Statistical Analysis, pg. 939-940], see also [Evaluation of soluble IFNAR2 as a diagnostic biomarker for MS, pg. 940-941], [Discussion, pg.943, left col, ¶2]-, ‘The differences observed between naïve MS patients and HC or patients with other neurological diseases suggest that sIFNAR2 could be a potential diagnostic biomarker for MS, so we evaluated the relevance of our results in the clinical context using the ROC analysis. Our results suggest that serum sIFNAR2 measurement may be a useful and easy-performing biomarker contributing to MS diagnosis since it has a sensitivity of 72.6% and a specificity of 77.0%, with the established cutoff, to discriminate from HC. Regarding the ability to discriminate from OIND patients, sIFNAR2 showed very similar values with a sensitivity of 70.11% and a specificity of 79.4%. Taking into account that we are analyzing one univariate indicator, sIFNAR2 levels show a significant discriminatory ability to distinguish between MS patients and HCs or OIND patients; this ability might improve by combining with additional markers that should be investigated further, as has been described with other soluble receptors addressed as potential biomarkers.’.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Órpez-Zafra et al (Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Multiple Sclerosis Journal. 2016) in view of Mirzaii-Dizgah et al (Serum and Saliva Myelin Basic Protein as Multiple Sclerosis Biomarker. Basic Clin Neurosci. 2021 Epub 2021 May 1.) in view of De Santiago et al (A signal-to-noise-ratio-based analysis of multifocal visual-evoked potentials in multiple sclerosis risk assessment. Clin Neurophysiol. 2016), as applied to claim 12, in further view of Thabit et al (Early disability in ambulatory patients with multiple sclerosis: optical coherence tomography versus visual evoked potentials, a comparative study. Egypt J Neurol Psychiatry Neurosurg 56, 70 (2020)) in view of Schwenkenbecher et al (Impact of the McDonald Criteria 2017 on Early Diagnosis of Relapsing-Remitting Multiple Sclerosis. Front Neurol. 2019 Mar 15).
Claim 12: Orpez-Zafra discloses, The kit-of-parts according to claim 12, but fails to disclose: further comprising:
(i) surface recording electrodes for recording visual evoked potential (VEP) values to determine a VEP latency value in the subject; and
However, Thabit in the context of visual evoked potentials discloses, (i) surface recording electrodes for recording visual evoked potential (VEP) values ([Visual evoked potential / pg. 3)]) to determine a VEP latency value in the subject; and (¶Abstract / pg.1], [Introduction pg. 2], [Table 2 / pg. 4], [Discussion / pg 7])
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method kit-of-parts of modified Opez-Zafra to further comprise, using surface recording electrodes for recording visual evoked potential (VEP) values to determine a VEP latency value in the subject as taught by Thabit. The motivation to do this yields predictable results such as to provide a safe, non-invasive, and relatively inexpensive tools for assessment of the degree of axonal loss and hence the disability, as suggested by Thabit [Conclusion, pg. 7].
Orpez-Zafra fails to disclose:
(ii) reagents for isoelectric focusing followed by staining for detecting oligoclonal IgG bands (BOC-IgG) values in cerebrospinal fluid (CSF) of the subject.
However, Schwenkenbecher in the context of the McDonald Criteria on early diagnosis of MS, discloses, (ii) reagents for isoelectric focusing followed by staining for detecting oligoclonal IgG bands (BOC-IgG) values in cerebrospinal fluid (CSF) of the subject. ([Oligoclonal Bands in Multiple Sclerosis / pg. 2], “The qualitative demonstration of two or more cerebrospinal fluid specific oligoclonal bands is the most sensitive method to show an intrathecal IgG antibody synthesis (16–18). The highest sensitivity and specificity of oligoclonal band testing can be achieved with the method of isoelectric focusing (16–18). To confirm that oligoclonal bands are exclusive to cerebrospinal fluid, paired cerebrospinal fluid and serum samples have to be analyzed in parallel and equal amounts of IgG have to be applied (2). Visualization of oligoclonal bands is preferentially performed by IgG specific antibody staining or by a general protein staining (16). Five isoelectric focusing patterns of oligoclonal bands are differentiated following the recommendations of the first European consensus on cerebrospinal fluid analysis in multiple sclerosis (16). Isoelectric focusing pattern type 1 are defined as absence of oligoclonal bands in the cerebrospinal fluid. Type 2 represents oligoclonal bands restricted to the cerebrospinal fluid (local synthesis). Type 3 means oligoclonal bands restricted to the cerebrospinal fluid and additional identical oligoclonal bands in cerebrospinal fluid and serum (local and systemic synthesis). Type 4 represents identical oligoclonal bands in cerebrospinal fluid and serum (systemic synthesis, no local synthesis). Type 5 demonstrates monoclonal bands in cerebrospinal fluid and serum (paraproteinemia, no local synthesis).”)
It would have been obvious to one of ordinary skilled in the art before the effective filing date of the claimed invention to modify the method kit-of-parts of modified Opez-Zafra to further comprise reagents for isoelectric focusing followed by staining for detecting oligoclonal IgG bands (BOC-IgG) values in cerebrospinal fluid (CSF) of the subject as taught by Schwenkenbecher. The motivation to do this yields predictable results such as to provide the highest sensitivity and specificity of oligoclonal band testing as suggested by Schwenkenbecher, [Oligoclonal Bands in Multiple Sclerosis / pg. 2].
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.A.R./Examiner, Art Unit 3798
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