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 .
Drawings
The drawings are objected to because Figure 3B’s list with the smaller font on the vertical axis is illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claim 12 and 13 and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 12 and 13, both of these claims are dependent on claim 7, which is cancelled. Therefore, there is an improper dependency of claims 12 and 13 which causes their breadths to be undefined. In the interest of compact prosecution, Examiner interprets claims 12 and 13 to instead be dependent on claim 5.
Regarding claim 26, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 26 recites the broad recitation “IgG aggregates greater than about 110 kDa,” and the claim also recites “IgG aggregates greater than… about 200 kDa” and “IgG aggregates greater than… about 300 kDa” which are the narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. In the interest of compact prosecution, Examiner interprets claim 26 to recite “IgG aggregates greater than about 110 kDa.”
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 5-6,8-16,18-21 and 24-28 are rejected under 35 USC § 101 for being directed to an abstract idea without significantly more. The claims will be analyzed below according to MPEP 2106.
Inquiry 1: Is the claim directed to a statutory category of invention (process, machine, manufacture, or composition of matter)?
Yes, claims 5-6,8-16,18-21 and 24-28 are directed to processes.
Inquiry 2A Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Claim 5 recites a “diagnosing…” step to diagnose a neurological disorder in a subject based on the IgG levels in the flow-through of one or more serum samples compared to a control sample from a subject that does not have a neurological disorder. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and is therefore an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 6 recites “diagnosing the subject with MS based on the IgG1 level” in the one or more serum samples. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and is therefore an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 8 recites a “comparing…” step to compare measured IgG levels to that of a healthy control. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and is therefore an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 10 recites “distinguishes a subject having MS from a subject having a different… disorder” based on IgG or IgG1 levels. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 12 recites “elevated IgG3 levels compared to…” control samples is indicative of MS. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 13 recites “elevated IgG1 levels compared to…” control samples is indicative of MS. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 14 recites “increased cytotoxicity… in the samples is indicative of” MS or MS progression. This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the measured cytotoxicity of the neuronal cells after they have been exposed to the sample that was processed via Protein A or G; therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 18 recites “comparing the IgG levels in the flow-through of the serum samples to IgG levels in flow- through of control samples” and “diagnosing… based on the IgG levels.” Each of these recitations read as mental processes that can take place in the human mind and/or with pen and paper by simply observing the IgG levels that were measured previously, and therefore the claim recite two abstract ideas. See MPEP 2106.04(a)(2)(III).
Claim 19 recites “diagnosing the subject with Secondary-Progressive MS (SPMS) when the level of IgGI is elevated compared to an IgGI level of a control sample or unprocessed sample.” This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the IgG1 levels that were measured previously, and therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 24 recites “identifying clusters… using data obtained from the mass spectrometry.” This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the mass spectrometry data that was obtained previously, and therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claim 25 recites “assessing the concentration of IgG aggregates… thereby diagnosing a neurological disorder in a subject.” This reads as a mental process that can take place in the human mind and/or with pen and paper by simply observing the cytotoxicity value that was obtained previously, and therefore the claim recites an abstract idea. See MPEP 2106.04(a)(2)(III).
Claims 9, 11-12, 15-16, 20-21, and 26-28 are dependent on claims that positively recite judicial exceptions and therefore are also drawn to judicial exceptions.
Inquiry 2A Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No they do not.
Regarding claim 5, the steps prior to the judicial exception amount to the insignificant extra-solution activity of mere data gathering. Furthermore, nothing occurs after the judicial exception, so there is no practical application within this claim. See MPEP 2106.05(g).
Regarding claims 6, 10, and 24, they only introduce additional judicial exceptions with nothing occurring afterwards, therefore these claims do not amount to a practical application of the judicial exceptions.
Regarding claims 8, 12-14, 19 and 25, nothing occurs after the judicial exception, and the “measuring” step(s) prior to the judicial exception amounts to mere data gathering. See MPEP 2106.05(g). Therefore, there is no practical application of the judicial exceptions within these claims.
Regarding claims 9, 11, 15, 20-21, 26-27, these claims introduce additional measurement/data collection steps or are drawn to steps that amount to the insignificant extra-solution activity of mere data-gathering. Therefore, these claims are interpreted to amount to, at best, the insignificant extra-solution activity of mere data-gathering. See MPEP 2106.05(g).
Regarding claim 16, the claim is drawn to treating a subject to reduce IgG levels, but this does not amount to a particular treatment or prophylaxis. As worded, this reads as a generic treatment or general strategy in the treatment of a neurological disorder, not a particular treatment regimen. See MPEP 2106.04(d)(2).
Regarding claim 18, the steps prior to the judicial exceptions (obtaining…, exposing…, measuring…) amount to the insignificant extra-solution activity of mere data gathering, and the step that occurs after the judicial exceptions (adjusting…) does not amount to a particular treatment or prophylaxis. Therefore, claim 18 does not apply the judicial exception into a practical application. See MPEP 2106.05(g) and 2106.04(d)(2).
Regarding claim 28, the claim is drawn to the “neurological disorder” of the “diagnosing” step in claim 25. In this case, despite narrowing the ‘list’ of neurological subjects to select from for the diagnosis, the claim still amounts to mere instructions to apply the judicial exception; nothing occurs after the “diagnosing” judicial exception. See MPEP 2106.05(f).
Inquiry 2B: Does the claim recite additional limitations that amount to significantly more than the judicial exception?
No they do not.
Regarding claim 5, the steps prior to the judicial exception amount to the insignificant extra-solution activity of mere data gathering, which is insufficient for amounting to significantly more than the judicial exception(s). See MPEP 2106.05(g).
Regarding claims 8,12-14, 19 and 25, the “measuring” step(s) prior to the judicial exception amounts to mere data gathering, which is insufficient for amounting to significantly more than the judicial exception(s). See MPEP 2106.05(g).
Claims 6, 10, and 24 only introduce additional judicial exceptions with nothing occurring afterwards, therefore these claims do not amount to significantly more than the judicial exception(s).
Regarding claim 18, the steps prior to the judicial exceptions (obtaining…, exposing…, measuring…) amount to the insignificant extra-solution activity of mere data gathering, and the step that occurs after the judicial exceptions (adjusting…) does not amount to a particular treatment or prophylaxis (it merely recites “adjusting a treatment” which is highly generic wording). Therefore, claim 18 does not amount to significantly more than the judicial exception(s). See MPEP 2106.05(g) and 2106.04(d)(2).
Regarding claims 9, 11, 15, 20-21, 26-27, these claims introduce additional measurement/data collection steps or are drawn to steps that amount to the insignificant extra-solution activity of mere data-gathering. Therefore, these claims are interpreted to amount to, at best, the insignificant extra-solution activity of mere data-gathering, rather than significantly more than the judicial exception. See MPEP 2106.05(g).
Regarding claim 16, the claim is drawn to treating a subject to reduce IgG levels, but this does not amount to a particular treatment or prophylaxis. As worded, this reads as a generic treatment or general strategy in the treatment of a neurological disorder, not a particular treatment regimen. Therefore, claim 16 does not amount to significantly more than the judicial exception. See MPEP 2106.04(d)(2).
Regarding claim 28, the claim is drawn to the “neurological disorder” of the “diagnosing” step in claim 25. In this case, despite narrowing the ‘list’ of neurological subjects to select from for the diagnosis, the claim still amounts to mere instructions to apply the judicial exception, which is insufficient for amounting to significantly more than the judicial exception(s). See MPEP 2106.05(f).
Furthermore, the concepts and methodologies of claims 5-6,8-16,18-21 and 24-28 are well-understood, routine, and conventional (WURC) in the arts: Xiaoli (US 20170299589 A1) teaches a method of obtaining samples from patients, exposing those samples to Protein A and/or Protein G, measuring IgG in various forms (IgG1, IgG4, IgG(H+L), etc.) from the flow-through of Protein A and/or Protein G utilizing ELISA and various other immunoassays, and then diagnosing multiple sclerosis (MS) and/or differentiating between healthy individuals and individuals with Relapsing-Remitting MS (RRMS), Secondary-Progressive MS (SPMS), or Primary-Progressive MS (PPMS) based on those measurements and comparisons thereof, and Xiaoli describes the cytotoxic effects of IgG proteins and aggregates on neuronal cells derived from mice; O’Niell et al. (US 20190256546 A1) describes the methodology and value of filtering protein-containing samples (that contain analytes pertinent to MS and other neurological disorders) by using a filter that retains proteins with a molecular weight above about 110 kDa and analyzing the retentate; Avasarala et al. (Journal of Molecular Neuroscience, Vol. 25, January 2025, pgs. 119-125, as cited in the IDS filed on 07/29/2025) teaches of analyzing serum samples from healthy individuals and individuals with MS using mass spectrometry in order to identify clusters of proteins that correlate with having MS or Relapsing-Remitting MS (RRMS); Mosleth et al. (Scientific Reports, Vol. 11, 18 February 2021, pgs. 4087-4105) teaches of analyzing samples from patients with MS for the expression of proteins such as CF1 (complement factor 1). See MPEP 2106.05(d).
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 5-6, 8-10, 12-14, 16, 18-19, 25, 28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xiaoli (US 20170299589 A1).
Regarding claim 5, Xiaoli teaches a method for diagnosing a neurological disorder in a subject (abstract) (The methods disclosed herein include diagnosing a patient with MS), comprising:
obtaining one or more serum or plasma samples from a subject suspected of having or developing a neurological disorder ([0059]) (To analyze the unique features of IgG antibodies in sera of MS patients, we performed native PAGE followed by Coomassie staining and immunoblotting in sera of MS); (Note that “sera” is the plural form of “serum”)
exposing the one or more serum samples or plasma to one or more of a Protein A matrix, a Protein G matrix, or a Protein A/Protein G matrix ([0059]) (blots of various preparations of sera from MS and controls, including total sera, Protein A and Protein G flow-through (FT));
collecting a flow-through or unbound portion of the one or more serum or plasma samples after exposing the samples to the one or more of the Protein A matrix, the Protein G matrix, or the Protein A/Protein G matrix ([0059]) (blots of various preparations of sera from MS and controls, including total sera, Protein A and Protein G flow-through (FT));
measuring IgG levels in the flow-through or unbound portion of the one or more serum or plasma samples ([0059]) (probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies. We showed that the significantly elevated levels of IgG1 and IgG3 are present); and
diagnosing a neurological disorder in the subject based on at least one of a total IgG (H+L)/Fc level, an IgGI level, or an IgG3 level, kappa light chain level, or lambda light chain level in the flow-through or unbound portion of the one or more serum or plasma samples compared to one or more samples from a control subject not having a neurological disorder ([0072] and [0094]) (lab procedures to… differentiate MS from other inflammatory CNS diseases. PPMS, secondary progressive MS (SPMS), and RRMS can be differentiated by SDS-PAGE Western blots of CSF and sera samples of total, Protein G, and Protein A purified IgG, and Protein A and G flow through probed with anti-human IgG (H+L), anti-human IgG1 and anti-human IgG3 antibodies and to determine whether the amount of IgG is elevated, the amount of IgG is compared to an appropriate control… MS patient will contain, on average, approximately 2.5-fold higher amounts of IgG than inflammatory control patients, and 4-fold more IgG than healthy controls).
Regarding claim 6, Xiaoli teaches the method according to claim 5 as rejected above, comprising diagnosing the subject with MS based on the IgGI level in the flow-through of the one or more serum samples ([0059] and [0094]) (significantly elevated levels of IgG1 and IgG3 are present in both Protein A FT (A-FT) and Protein G-FT (G-FT)… in MS and to determine whether the amount of IgG is elevated, the amount of IgG is compared to an appropriate control… MS patient will contain, on average, approximately 2.5-fold higher amounts of IgG than inflammatory control patients, and 4-fold more IgG than healthy controls). Note that “FT” in “Protein A FT” and “Protein G FT” means “flow-through.”
Regarding claim 8, Xiaoli teaches the method according to claim 5 as rejected above. Xiaoli teaches wherein measuring IgG (H+L)/Fc levels comprises measuring total IgG (H+L)/Fc and comparing total IgG (H+L)/Fc to healthy control subject samples, and wherein elevated total IgG (H+L)/Fc levels compared to the healthy control subject samples is indicative of having a neurological disorder in the subject ([0062]) (Point (b), high molecular weight IgG (150-250 kD) are only detected in native PAGE WB with anti IgG (H+L) antibody (not by anti-Fc antibody) in total sera, suggesting that the immune complexes contain blocked Fc region, and further support the presence of immune complexes). Examiner interprets “/Fc” to mean “blocked Fc region”.
Regarding claim 9, Xiaoli teaches the method according to claim 5 as rejected above. Xiaoli teaches wherein measuring IgG levels comprises using an ELISA assay, flow cytometry, Nephelometry or other immunoassay for detecting IgG antibodies in the flow-through of the one or more serum samples ([0059]) (SDS-PAGE Western blots of various preparations of sera from MS and controls… and probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies… Elevated levels of total IgG was further demonstrated by ELISA of MS sera).
Regarding claim 10, Xiaoli teaches the method according to claim 5 as rejected above. Xiaoli teaches wherein the method distinguishes a subject having MS from a subject having a different inflammatory CNS disorder based on the level of IgG or the level of IgGI ([0072]) (lab procedures to… differentiate MS from other inflammatory CNS diseases. PPMS, secondary progressive MS (SPMS), and RRMS can be differentiated by SDS-PAGE Western blots of CSF and sera samples of total, Protein G, and Protein A purified IgG, and Protein A and G flow through probed with anti-human IgG (H+L), anti-human IgG1 and anti-human IgG3 antibodies).
Regarding claim 12, Xiaoli teaches the method according to claim 5 as rejected above (recall that Examiner is interpreting claim 12 to be dependent on claim 5 rather than the cancelled claim 7). Xiaoli teaches wherein the one or more serum samples are exposed to a Protein A matrix and further comprising measuring IgG3 levels in the flow-through ([0059]) (probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies. We showed that the significantly elevated levels of IgG1 and IgG3 are present), wherein elevated IgG3 levels compared to healthy control samples and samples from a subject having a neurological disorder other than MS is indicative that the subject has MS ([0072] and [0094]) (lab procedures to… differentiate MS from other inflammatory CNS diseases. PPMS, secondary progressive MS (SPMS), and RRMS can be differentiated by SDS-PAGE Western blots of CSF and sera samples of total, Protein G, and Protein A purified IgG, and Protein A and G flow through probed with anti-human IgG (H+L), anti-human IgG1 and anti-human IgG3 antibodies and to determine whether the amount of IgG is elevated, the amount of IgG is compared to an appropriate control… MS patient will contain, on average, approximately 2.5-fold higher amounts of IgG than inflammatory control patients, and 4-fold more IgG than healthy controls).
Regarding claim 13, Xiaoli teaches the method according to claim 5 as rejected above (recall that Examiner is interpreting claim 13 to be dependent on claim 5 rather than the cancelled claim 7). Xiaoli teaches wherein the one or more serum samples are exposed to a Protein G matrix and further comprising measuring IgGI levels in the flow-through of the one or more serum samples ([0059]) (probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies. We showed that the significantly elevated levels of IgG1 and IgG3 are present), wherein elevated IgGI levels compared to healthy control samples and samples from a subject having a neurological disorder other than MS is indicative that the subject has MS ([0072] and [0094]) (lab procedures to… differentiate MS from other inflammatory CNS diseases. PPMS, secondary progressive MS (SPMS), and RRMS can be differentiated by SDS-PAGE Western blots of CSF and sera samples of total, Protein G, and Protein A purified IgG, and Protein A and G flow through probed with anti-human IgG (H+L), anti-human IgG1 and anti-human IgG3 antibodies and to determine whether the amount of IgG is elevated, the amount of IgG is compared to an appropriate control… MS patient will contain, on average, approximately 2.5-fold higher amounts of IgG than inflammatory control patients, and 4-fold more IgG than healthy controls).
Regarding claim 14, Xiaoli teaches the method of claim 5 as rejected above. Xiaoli teaches further comprising performing a neuronal cytotoxic analysis of one or more serum samples exposed to at least one of a Protein A or Protein G matrix and measuring cytotoxicity, wherein increased cytotoxicity, as demonstrated by increased apoptosis, necrosis, or necroptosis in primary neuronal cells or cell lines selected from neurons, astrocytes, oligodendrocytes, microglia, or mouse brain tissues in the samples is indicative of at least one of MS or MS progression ([138]) (FIG. 19 shows the complement independent cytotoxicity of MS sera G-FT on mouse CNS cells. IgG3-IgG1 complexes from Protein G flow-through was found to display cytotoxicity on murine neuronal cells… Significantly higher levels of cytotoxicity was observed in MS G-FT).
Regarding claim 16, Xiaoli teaches the method of claim 5 as rejected above. Xiaoli teaches treating the subject to reduce IgG levels, wherein reducing IgGI in the subject treats MS in the subject ([0095]) (The method may further include the step of administering a pharmaceutical compound effective for treating MS to the patient having an elevated level of IgG).
Regarding claim 18, Xiaoli teaches a method for identifying MS (Multiple Sclerosis) subtypes in a subject comprising:
obtaining one or more serum samples from a subject suspected of having or developing MS ([0059]) (To analyze the unique features of IgG antibodies in sera of MS patients, we performed native PAGE followed by Coomassie staining and immunoblotting in sera of MS); (Note that “sera” is the plural form of “serum”);
exposing the one or more serum samples to a Protein A matrix ([0059]) (blots of various preparations of sera from MS and controls, including total sera, Protein A and Protein G flow-through (FT));
collecting flow-through of the one or more serum samples after exposing the samples to the Protein A matrix ([0059]) (blots of various preparations of sera from MS and controls, including total sera, Protein A and Protein G flow-through (FT));
measuring IgG levels in the flow-through of the one or more serum samples; comparing the IgG levels in the flow-through of the serum samples to IgG levels in flow- through of control samples ([0059]) (SDS-PAGE Western blots of various preparations of sera from MS and controls… and probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies… Elevated levels of total IgG was further demonstrated by ELISA of MS sera));
diagnosing Relapsing-Remitting MS (RRMS), Secondary-Progressive MS (SPMS), or Primary-Progressive MS (PPMS) in the subject based on the IgG levels in the flow-through of the one or more serum samples ([107]) (for Protein A and G purified IgG: RRMS>SPMS>PPMS; for IgG3-IgG1 complexes: PPMS>SPMS>RRMS); and
adjusting a treatment of the subject based on the diagnosis ([104]) (therapies/treatments may be adjusted in accordance with the clinical presentation of MS in the patient).
Regarding claim 19, Xiaoli teaches the method of claim 18 as rejected above. Xiaoli teaches wherein measuring IgG levels comprises measuring IgGI levels, and further comprising diagnosing the subject with Secondary-Progressive MS (SPMS) when the level of IgGI is elevated compared to an IgGI level of a control sample or unprocessed sample ([106] and [107]) (comparing the amount of IgG… in the sample with an appropriate control and The appropriate control can vary. In one embodiment, where the method is directed to determining whether a patient has PPMS, an appropriate control can include a patient or patient pool having relapsing-remitting MS (RRMS)… for Protein A and G purified IgG: RRMS>SPMS>PPMS; for IgG3-IgG1 complexes: PPMS>SPMS>RRMS).
Regarding claim 25, Xiaoli teaches a method for diagnosing a neurological disorder in a subject, comprising:
obtaining one or more serum samples from a subject suffering from, suspected of having, or suspected of developing a neurological disorder ([0059]) (To analyze the unique features of IgG antibodies in sera of MS patients, we performed native PAGE followed by Coomassie staining and immunoblotting in sera of MS); (Note that “sera” is the plural form of “serum”)
processing the one or more serum samples to create an enriched sample having a greater concentration of IgG aggregates than an unprocessed serum sample ([0025] and [0059]) (there were significantly elevated amounts of IgG antibodies present in the flow-through after Protein G purification of MS sera and significantly elevated levels of IgG1 and IgG3 are present in both Protein A FT (A-FT) and Protein G-FT (G-FT));
combining the enriched sample with a population of live neuronal cells ([0044]) (FIG. 19 shows the results of the complement dependent cytotoxicity of MS sera and healthy sera from Protein G flow-through on mouse CNS cells);
quantifying the number of neuronal cells that die in the presence of the enriched sample to create a cytotoxicity value; See Figure 19, which shows a cytotoxicity value (y-axis, “% kiling”):
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assessing the concentration of IgG aggregates in the enriched sample from the cytotoxicity value([138]) (IgG3-IgG1 complexes from Protein G flow-through was found to display cytotoxicity on murine neuronal cells) (note “IgG3-IgG1 complexes” are interpreted to be “IgG aggregates”), and thereby diagnosing a neurological disorder in a subject ([73]) (diagnosing a patient with MS or with a likelihood of having MS, or selecting a patient for further testing for MS should the patient show elevated level of human IgG relative to an appropriate control).
Also see Figure 19 above, which shows that the “PPMS1” sample shows a higher “% kiling”, therefore it is interpreted to have been assessed as having a higher concentration of IgG aggregates.
Regarding claim 28, Xiaoli teaches the method of 25 as rejected above. Xiaoli teaches wherein the neurological disorder is selected from Relapsing-Remitting MS (RRMS), Secondary-Progressive MS (SPMS), or Primary-Progressive MS (PPMS) ([0072] of Xiaoli) (lab procedures to… differentiate MS from other inflammatory CNS diseases. PPMS, secondary progressive MS (SPMS), and RRMS).
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 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.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xiaoli (US 20170299589 A1).
Regarding claim 11, Xiaoli teaches the method according to claim 5 as rejected above. Xiaoli teaches of exposing serum samples to Protein A and Protein G ([0059]) (blots of various preparations of sera from MS and controls, including total sera, Protein A and Protein G flow-through (FT)). Xiaoli teaches that exposing the serum samples to Protein A and Protein G only partially purifies the serum samples, and produces less IgG, due to the poor binding of the present IgG1-IgG3 complexes with Protein A or Protein G ([107]) (IgG3-IgG1 complexes compared to RRMS and do not bind well to Protein A or G, therefore produce less IgG when purified, but leave most in the flow through).
Xiaoli is silent to wherein the one or more serum samples are exposed to one or more of the Protein A matrix, the Protein G matrix, or the Protein A/Protein G matrix at least two times by collecting the flow-through and reapplying the flow-through to at least a second Protein A matrix, Protein G matrix, or Protein A/Protein G matrix.
It would have been obvious for a person having ordinary skill in the art before the effective filing date of the invention to duplicate the step of exposing the one or more serum samples to Protein A or Protein G because doing so would further purify the serum samples to produce additional IgG with a reasonable expectation of success (see [59] and [107] of Xiaoli). See also MPEP 2144.04. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960).
Claim 15, 26-27 rejected under 35 U.S.C. 103 as being unpatentable over Xiaoli (US 20170299589 A1) as applied to claim 5 and 25 above, further in view of O’Niell et al. (US 20190256546 A1).
Regarding claim 15, Xiaoli teaches the method of claim 5 as rejected above. Xiaoli teaches measuring IgG1 levels from the Protein A and Protein G flow-through ([0059]) (We showed that the significantly elevated levels of IgG1 and IgG3 are present in both Protein A FT (A-FT) and Protein G-FT (G-FT)). Xiaoli teaches that the serum of MS patients contains large amounts of high molecular weight IgG ([0059]) (demonstrated the presence of large amounts of high molecular weight (MW) IgG (greater than 230 kD) in MS sera).
Xiaoli is silent to further comprising exposing the flow-through to a filter having a molecular weight cut-off of about 110 kDa, about 200 kDa or about 300 kDa or size cut-off of about 100 nm and further comprising measuring at least one of IgGI or IgG4 levels in a retentate.
In the analogous art of diagnostic and treatment protocols for neurological disorders that include MS ([0035]) (the disease or disorder may be…neurological disease or disorder… multiple sclerosis), O’Niell teaches exposing a sample to a filter having a molecular weight cut-off of about 110 kDa and measuring analyte levels in a retentate ([0237]) (filtering a biological sample from a subject through… a filter that retains molecules greater than about 100 kiloDaltons; collecting from the filtration module a retentate… and determining a biosignature for at least a subset of the captured vesicles) (note that: “a filter that retains molecules greater than about 100 kiloDaltons” is interpreted as “a filter having a molecular weight cut-off of about 110 kDa”; “captured vesicles” is interpreted as an analyte). O’Niell teaches that implementing a size exclusion step can separate highly abundant proteins and other non-desired entities, effectively purifying the analyte by separating high and low molecular weight proteins ([0226] of O’Niell) (Removal of highly abundant proteins and other non-desired entities can further be facilitated with a non-stringent size exclusion step. For example, the sample can be processed using a high molecular weight cutoff size exclusion step to preferentially enrich high molecular weight vesicles apart from lower molecular weight proteins and other entities).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to modify the flow-through measurement of IgG1 as taught by Xiaoli by first passing the flow-through through a filter having a molecular cut-off value of about 110 kDa and then measuring IgG1 levels in a retentate as suggested by O’Niell because it would lead to separating highly abundant proteins and other non-desired entities from the analyte, effectively purifying the analyte, with a reasonable expectation of success ([56], [58] of Xiaoli; [0035], [0237], [0226] of O’Niell).
Regarding claim 26, Xiaoli teaches the method of claim 25 as rejected above. Xiaoli teaches that the processing step increases the amount of IgG aggregates in a sample ([0025] and [0059]) (there were significantly elevated amounts of IgG antibodies present in the flow-through after Protein G purification of MS sera and significantly elevated levels of IgG1 and IgG3 are present in both Protein A FT (A-FT) and Protein G-FT (G-FT)).
Xiaoli does not clearly teach wherein processing step includes enriching for IgG aggregates greater than about 110 kDa, about 200 kDa, or about 300 kDa.
In the analogous art of diagnostic and treatment protocols for neurological diseases and disorders that include MS ([0035] of O’Niell) (the disease or disorder may be…neurological disease or disorder… multiple sclerosis), O’Niell teaches of enriching a sample for analytes having a molecular weight above 110 kDa by passing the sample through a filter with a molecular weight cut-off of about 110 kDa that causes the higher molecular weight proteins to be with the retentate ([0237] of O’Niell) (filtering a biological sample from a subject through… a filter that retains molecules greater than about 100 kiloDaltons; collecting from the filtration module a retentate). O’Niell teaches that implementing this sort of size exclusion step can separate highly abundant proteins and other non-desired entities from the sample and separates high-molecular weight and low molecular weight proteins ([0226] of O’Niell) (Removal of highly abundant proteins and other non-desired entities can further be facilitated with a non-stringent size exclusion step. For example, the sample can be processed using a high molecular weight cutoff size exclusion step to preferentially enrich high molecular weight vesicles apart from lower molecular weight proteins and other entities).
It would have been obvious to a person having ordinary skill in the art to modify the processing step (contacting with Protein A and/or Protein G) of Xiaoli to process the sample by passing it through a filter with a molecular weight cut-off of about 110 kDa that causes the higher molecular weight proteins to be with the retentate as taught by O’Niell because it would lead to separating/removing highly abundant proteins and other non-desired entities from the sample and separating high-molecular weight and low molecular weight proteins with a reasonable expectation of success (see [0025], [0059] of Xiaolil; [0035], [0237], [0226] of O’Niell).
Regarding claim 27, modified Xiaoli teaches the method of claim 26 as rejected above. Modified Xiaoli teaches wherein the processing step includes passing the serum sample through a filter ([0237] of O’Niell) (filtering a biological sample from a subject through… a filter that retains molecules greater than about 100 kiloDaltons; collecting from the filtration module a retentate).
Claims 20 and 24 are rejected under 35 USC 103 as being unpatentable over Xiaoli (US 20170299589 A1) as applied to claim 18 above, further in view of Avasarala et al. (Journal of Molecular Neuroscience, Vol. 25, January 2025, pgs. 119-125, as cited in the IDS filed on 07/29/2025).
Regarding claim 20, Xiaoli teaches the method of claim 18 as rejected above. Xiaoli analyzes the flow-through of the one or more serum samples using immunoassays, including ELISA ([0059]) (SDS-PAGE Western blots of various preparations of sera from MS and controls… and probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies… Elevated levels of total IgG was further demonstrated by ELISA of MS sera).
Xiaoli is silent to wherein the flow-through of the one or more serum samples is further subjected to mass spectrometry.
In the analogous art of analyzing multiple sclerosis (MS) serum proteomic patterns, Avasarala teaches of analyzing serum samples with mass spectrometry to reveal a distinct proteomic pattern (abstract) (we tested sera from 25 newly diagnosed relapsing-remitting MS patients and 25 healthy controls with matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry… revealed a distinct proteomic pattern in the MS group). Avasarala teaches that analyzing serum samples with mass spectrometry to reveal a distinct proteomic pattern is advantageous because it offers rapidity and can achieve sensitivities in the femtomolar range, and can differentiate between healthy controls and relapsing-remitting MS (RRMS) (pg. 120, starting at the last sentence of the left column) (Mass spectrometry offers rapidity (<1min for the entire process)… and can achieve sensitivities in the femtomolar range… and capable of differentiating between patients with relapsing-remitting MS (RRMS) and healthy controls).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to combine the immunoassay analysis method of Xiaoli with the mass spectrometry analysis method of Avasarala to provide: wherein the flow-through of the one or more serum samples is further subjected to mass spectrometry. Doing so would lead to the predictable outcome of rapidly detecting proteins in the femtomolar and differentiating between healthy controls and RRMS with a reasonable expectation of success (see [0059] of Xiaoli; pg. 120, starting at the last sentence of the left column of Avasarala).
Regarding claim 24, Modified Xiaoli teaches the method of claim 20 as rejected above. Modified Xiaoli teaches further comprising identifying clusters of differentially expressed proteins using data obtained from the mass spectrometry (pg. 120 right column first paragraph of Avasarala) (we report our preliminary findings that a combination of MALDITOF/mass spectrometry and serum proteomic pattern recognition analysis of serum) (Note that Examiner interprets “clusters of differentially expressed proteins” to be the same as “proteomic pattern”). Avasarala teaches that identifying clusters of differentially expressed proteins may be useful in the early detection of MS (pg. 119 left column first paragraph) (As serum offers a protein-rich environment that is obtainable, proteomic pattern recognition might be useful in detecting the earliest changes that represent MS).
Claims 21 is rejected under 35 USC 103 as being unpatentable over Xiaoli (US 20170299589 A1) as applied to claim 18 above, further in view of Mosleth et al. (Scientific Reports, Vol. 11, 18 February 2021, pgs. 4087-4105).
Regarding claim 21, Xiaoli teaches the method of claim 18 as rejected above. Xiaoli analyzes the flow-through of the one or more serum samples using immunoassays, including ELISA, to detect IgG ([0059]) (SDS-PAGE Western blots of various preparations of sera from MS and controls… and probed with anti-human IgG (H+L)-HRP, rabbit/mouse anti-human IgG1 and IgG3 antibodies followed by corresponding HRP-secondary antibodies… Elevated levels of total IgG was further demonstrated by ELISA of MS sera).
Xiaoli is silent to analyzing the flow-through of the one or more serum samples for protein expression of one or more of IGKV1-5 (Immunoglobulin Kappa Variable 1-5); IGLV2-18 (Immunoglobulin Lambda Variable 2-18); C5 (Complement component 5); CFI (Complement Factor I); ORM1 (Orosomucoid 1); IGHV1-18 (Immunoglobulin Heavy Variable 1-18); IGHV3-49 (Immunoglobulin Heavy Variable 3-49); IGLV3-21 (Immunoglobulin Lambda Variable 3-21); LGALS3BP (Galectin 3 Binding Protein); PROC (Protein C, Inactivator Of Coagulation Factors Va And VIIIa); and SERPINAS (serine proteinase inhibitor).
In the analogous art of identifying sample proteomes associated with MS, Mosleth teaches analyzing samples for protein expression of CFI (complement factor I) (pg. 4096, third paragraph) (Among the proteins that were significantly decreased in CSF from MS/CIS… compared with controls were… CFI). Mosleth teaches that the analysis of this under-expressed protein can aid in gauging the progression of the disease and the lack of neural development (pg. 4096, third paragraph and pg. 4099 sixth paragraph) (proteins that were decreased in abundance in MS/CIS patients relative to controls reflect an underlying mechanism of disturbed neural development present from the early phases of the disease and analysis of the CSF proteome suggest that failure in neural development… is a common event of MS present from the early stage).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to modify the immunoassay analysis method to detect IgG as taught by Xiaoli to analyze samples for protein expression of CFI (complement factor I) as taught by Mosleth to lead to the predictable outcome of gauging the disease progression of MS and the lack of neural development associated therewith with a reasonable expectation of success (see [0059] of Xiaoli; pg. 4096, third paragraph and pg. 4099 sixth paragraph of Mosleth).
Conclusion
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/H.D.C./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
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