DETAILED ACTION
The amendment filed on 06/03/2026 has been entered and fully considered. Claim 2-3, 22, 46 and 85 are canceled. Claims 1, 5-8, 17-18, 20-21, 23-24, 27, 38, 78, 81-82 and 99-102 are pending, of which claim 1, 8, 20-21, 23-24 and 27-28 are amended, and Claims 99-102 are newly added.
Response to Amendment
In response to amendment, the examiner modifies rejection over the prior art established in the previous Office action.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 5-6, 8, 17-18, 20-21, 23-24, 27, 38, 78, 81-82 and 99-102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Giraudon (WO 2011/007209) in view of Gammon (Neuroscience News, 2021).
Regarding claim 1, Giraudon teaches a method for determining an increased risk for a cognitive disorder in a human subject (abstract), comprising:
obtaining a biological sample from the human subject, wherein the biological sample is blood, saliva, urine, serum, tears, skin, tissue, or hair (page 10, line 28-33);
determining a level of collapsing response mediator protein-2 (CRMP2) in the biological sample and a level of phosphorylated CRMP2 (p-CRMP2) in the biological sample by a proteomic assay (page 2, lines 22-29) comprising:
(a) detecting the level of CRMP2 by
i. contacting the biological sample with an agent that recognizes CRMP2 (page 14, lines 25-29), and
ii. measuring the level of bound CRMP2 thereby determining the level of CRMP2 present in the biological sample (page 14, line 25-29);
(b) detecting the level of p-CRMP2 by:
i. contacting the biological sample with an agent that recognizes
phosphorylated CRMP2 (p-CRMP2) (page 15, lines 2-7),
ii. measuring a level of bound p-CRMP2 and thereby determining the level
of p-CRMP2 present in the biological sample (page 15, lines 2-7).
Giraudon does not specifically teach
computing a ratio of the level of the p-CRMP2 to the level of the CRMP2 (pCRMP2:CRMP2 ratio);
detecting a reduction of at least 40% in the p-CRMP2:CRMP2 ratio of the subject compared to a reference p-CRMP2:CRMP2 ratio of a subject lacking the cognitive disorder; and
identifying the subject with the increased risk of having the cognitive disorder based on the reduced p-CRMP2:CRMP2 ratio of the subject.
However, Gammon teaches
computing a ratio of the level of the p-CRMP2 to the level of the CRMP2 (pCRMP2:CRMP2 ratio) (page 2);
detecting a reduction of the p-CRMP2:CRMP2 ratio of the subject compared to a reference p-CRMP2:CRMP2 ratio of a subject lacking the cognitive disorder (page 2); and
identifying the subject with the increased risk of having the cognitive disorder based on the reduced p-CRMP2:CRMP2 ratio of the subject (page 2).
Gammon teaches that “Previous research has shown that most people maintain an even balance between the two forms of CRMP2: its active, non-phosphorylated form and its inactive, phosphorylated form. …The findings indicated that the amount of active CRMP2 was too high in people with schizophrenia and, at least in young people with schizophrenia, was not balanced by an appropriate amount of increased inactive CRMP2. That imbalance between active and inactive CRMP2 could account for some dysfunctions in neural connections. Measuring an abundance of active CRMP2, particularly if its ratio with inactive CRMP2 is too low, could become a format for a rapid, minimally invasive blood test to support the diagnosis of schizophrenia” (page 2). Thus, it would have been obvious to one of ordinary skill in the art to
computing a ratio of the level of the p-CRMP2 to the level of the CRMP2 (pCRMP2:CRMP2 ratio) (page 2);
detecting a reduction of the p-CRMP2:CRMP2 ratio of the subject compared to a reference p-CRMP2:CRMP2 ratio of a subject lacking the cognitive disorder (page 2); and
identifying the subject with the increased risk of having the cognitive disorder based on the reduced p-CRMP2:CRMP2 ratio of the subject (page 2).
It would have been obvious to one of ordinary skill in the art to optimize the cutoff value of the range of the ratio by routine experimentation, because once the prior art teaches that a reduced p-CRMP2:CRMP2 ratio is diagnostically relevant, determining the degree of reduction or threshold value that distinguishes affected subjects from control subjects would have been a matter of routine optimization using ordinary clinical validation. The claimed numerical thresholds merely define the cutoff used to interpret a known biomarker relationship and do not require a new assay, new reagent, new biomarker, or new measurement technique.
Regarding claim 101, Giraudon teaches a method for determining an increased risk of a human subject having a cognitive disorder (abstract), comprising:
(a) obtaining a blood sample from the subject (page 10, line 28-31);
(b) measuring in the sample a level of collapsing response mediator protein-2 (CRMP2) and a level of phosphorylated CRMP2 (p-CRMP2), wherein the measuring comprises contacting the sample with an antigen-binding agent which specifically binds CRMP2 and with an antigen-binding agent which specifically binds p-CRMP2 (page 14, line 25-29, page 15, line 2-7);
Giraudon does not specifically teach
(c) determining a ratio of the level of the p-CRMP2 to the level of the CRMP2 (pCRMP2:CRMP2 ratio) in the sample; and
(d) identifying the subject having the increased risk based on a p-CRMP2:CRMP2ratio of less than 0.2, and wherein the subject is 30 years or less.
However, Gammon teaches
(c) determining a ratio of the level of the p-CRMP2 to the level of the CRMP2 (pCRMP2:CRMP2 ratio) in the sample (page 2); and
(d) identifying the subject having the increased risk based on a p-CRMP2:CRMP2 ratio is very low (page 2), and wherein the subject is 30 years or less (page 3).
It would have been obvious to one of ordinary skill in the art to optimize the cutoff value of the range of the ratio by routine experimentation, because once the prior art teaches that a reduced p-CRMP2:CRMP2 ratio is diagnostically relevant, determining the degree of reduction or threshold value that distinguishes affected subjects from control subjects would have been a matter of routine optimization using ordinary clinical validation. The claimed numerical thresholds merely define the cutoff used to interpret a known biomarker relationship and do not require a new assay, new reagent, new biomarker, or new measurement technique.
Regarding claim 5, Gammon teaches that wherein the cognitive disorder is Schizophrenia (SCZ) (page 2).
Regarding claim 6, Gammon teaches that wherein the SCZ is an early stage of SCZ (title, page 3).
Regarding claim 8, Giraudon teaches that wherein the biological sample is a blood sample comprising peripheral blood mononuclear cells (PBMC) (e.g. lymphocytes) (page 10, lines 28-32).
Gammon also teaches that wherein the biological sample is a blood sample comprising peripheral blood mononuclear cells (PBMC) (e.g. lymphocytes) (page 2, par 1).
Regarding claim 17, Giraudon teaches that wherein the proteomic assay is immunoassay, mass spectrometry, or intracellular flow cytometry (page 14, lines 25-29).
Regarding claim 18, Giraudon teaches that wherein the immunoassay is selected from western blotting, dot blotting, quantitative enzyme-linked immunosorbent assays (ELISA), immunocytochemistry (ICC), immunohistochemistry (IHC), protein multiplex assay, or lateral flow test (page 14, lines 25-29).
Regarding claim 20, Giraudon teaches that wherein the antigen-binding agent that recognizes CRMP2 is an anti-CRMP2 antibody; and the antigen-binding agent that recognizes p-CRMP2 is an anti-p-CRMP2 antibody (page 5, lines 14-15).
Regarding claim 21, Giraudon teaches that wherein the anti-CRMP2 antibody is a monoclonal antibody (page 5, line 14-20); and
the anti-p-CRMP2 antibody is a monoclonal antibody (page 5, line 14-20).
Regarding claim 23-24, 100, and 102, Gammon teaches identifying the human subject with added risk of having the cognitive disorder if the p-CRMP2:CRMP2 ratio of the subject is very lower than the reference (page 2). It would have been obvious to one of ordinary skill in the art to optimize the range of the ratio by routine experimentation, because once the prior art teaches that a reduced p-CRMP2:CRMP2 ratio is diagnostically relevant, determining the degree of reduction or threshold value that distinguishes affected subjects from control subjects would have been a matter of routine optimization using ordinary clinical validation. The claimed numerical thresholds merely define the cutoff used to interpret a known biomarker relationship and do not require a new assay, new reagent, new biomarker, or new measurement technique.
Regarding claim 27, Giraudon teaches that wherein the CRMP2 is phosphorylated at Serine 522 (p-S522-CRMP2) (page 2, par 1), wherein measuring the level of p-CRMP2 comprises measuring a phosphorylation of CRMP2 at Serine 522 (page 15, par 2).
Regarding claim 38, it is conventional to treat schizophrenia human subject with one or more antipsychotic drugs.
Regarding claim 78, Giraudon in view of Gammon teaches a method of treating a cognitive disorder in a human subject, comprising:
performing the method as in claim 1; and
Giraudon further teaches administering a therapeutic agent or clinical investigational product to the human subject (page 1, line 21-27).
Regarding claim 81, Gammon teaches that wherein the cognitive disorder is Schizophrenia (SCZ). Gammon teaches that “Measuring an abundance of active CRMP2, particularly if its ratio with inactive CRMP2 is too low, could become a format for a rapid, minimally invasive blood test to support the diagnosis of schizophrenia.” (page 2). Vesicular monoamine transporter 2 (VMAT2) inhibitor are known therapeutic agent or clinical investigational product for treating Schizophrenia.
Regarding claim 82, the VMAT2 inhibitor Valbenazine, or Tetrabenazine are known therapeutic agent or clinical investigational product for treating Schizophrenia.
Regarding claim 99, Gammon teaches that wherein the subject is 30 years old or less (page 3).
Response to Arguments
Applicant's arguments filed 06/03/2026 have been fully considered but they are not persuasive.
Applicant argues that neither Giraudon nor Gammon teaches a specific magnitude of reduction in the p-CRMP2:CRMP2 ratio, such as “at least 40%,” “less than 0.2,” or “0.1 or less.” However, the rejection is not based on an express disclosure of the exact numerical threshold. Rather, Giraudon teaches measuring CRMP2 and p-CRMP2 as CNS disease biomarkers, and Gammon teaches that schizophrenia is associated with an imbalance in active versus inactive CRMP2 and that a ratio between active and inactive CRMP2 that is “too low” may support diagnosis of schizophrenia.
Once the prior art teaches that a reduced p-CRMP2:CRMP2 ratio is diagnostically relevant, determining the degree of reduction or threshold value that distinguishes affected subjects from control subjects would have been a matter of routine optimization using ordinary clinical validation. The claimed numerical thresholds merely define the cutoff used to interpret a known biomarker relationship and do not require a new assay, new reagent, new biomarker, or new measurement technique.
Applicant’s assertion of unexpected results is also not persuasive because the relied-upon data appear to confirm the same directional relationship taught by Gammon—namely, that schizophrenia subjects have a lower p-CRMP2:CRMP2 ratio than controls. The claims broadly cover determining increased risk for a cognitive disorder based on reduced ratio values, but do not recite a particular statistical method, sensitivity, specificity, or clinical improvement tied to the selected cutoff. Therefore, the alleged magnitude of reduction is insufficient to overcome the prima facie case of obviousness.
Accordingly, the rejection under 35 U.S.C. §103 over Giraudon in view of Gammon is maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
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