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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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 23, 2026 has been entered.
This action is in response to the papers filed January 23, 2026. Currently, claims 1-7, 9-12, 14-15, 18-21, 23-25, 27-30, 32-34 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
Priority
This application claims priority to
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Applicant should contact the filing receipt branch for guidance on the inconsistent data.
Drawings
The drawings are acceptable.
Claim Interpretation
The claims have been interpreted to require a determination of APOE4 alleles, and hippocampal volume or cortical thickness. The claims do not encompass an inherent property of a subject to have a hippocampal volume or cortical thickness below a threshold. Some sort of determination is required to have been performed.
Claim Objections
Claim 1 and the claims dependent thereon are objected to because the claim contains more than one period (see 609.01(m)). Periods may not be used elsewhere in the claims except for abbreviations. For example, a. b. i. ii. Iii. Iv. contains a period and the end of the claim contains a period. This objection may be overcome by amending a. to read a) (see MPEP 608.01(m)).
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.
Claims 1-7, 9-12, 14-15, 18-21, 23-25, 27-30, 32-34 is/are rejected under 35 U.S.C. 103 as being obvious over Hey et al. (US 12,083,082, provisional August 1, 2018) in view of Shuff et al. (Brain – A journal of Neurology, Vol. 132, pages 1067-1077, 2009) or KR20180078032 (July 9, 2018) and Jia et al (WO 2018/157014, August 30, 2018).
The applied reference has a common Inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Hey teaches methods for selecting and treating Alzheimer’s disease. Hey teaches a method of treating and preventing Alzheimer’s in a subject that has an MMSE score of 30 (29 or greater), is APOE 4/4 homozygous with ALZ-801 (valyl-3-amino-1-propanesulfonic acid), a small molecule prodrug of tramiprosate.
Hey does not teach the subject has a hippocampal volume below a threshold or cortical thickness below a threshold.
However, Schuff et al teaches MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype. Schuff teaches hippocampal volume change over time has huge potential as a maker for Alzheimer’s disease. Schuff teaches studying the hippocampal loss over 6-12 months (abstract). Table 2 illustrates hippocampal baseline volumes and rates of volume loss by group for different time frames (page 1071). Schuff teaches increased rates of hippocampal loss were associated with presence of the ApoE allele E4 gene in Alzheimer’s disease (abstract). Figure 3 illustrates rates of hippocampal volume loss in carriers and non-carriers of APpoE4 (page 1072). Figure 2 illustrates the rate of volume loss over different time periods of 1-6 and 6-12 months (page 1072). Each of Figure 2 and 3 illustrates the normal baseline that the comparison may be made to, i.e. 5% and 10% below normal. Schuff teaches amyloid AB1-42 are a major component of amyloid plaques that are directly related to Alzheimer’s disease pathology. Schuff teaches that amyloid burden and high rates of hippocampal loss implies the two measures provide complementary information about the presence of Alzheimer’s disease pathology. Schuff teaches the higher hippocampal loss in presence of ApoE4 and reduced amyloid protein supports the concept that increased hippocampal loss is an indicator of Alzheimer’s disease pathology and a potential marker to assess therapeutic interventions in Alzheimer’s disease (page 1076).
Additionally, Gauthier teaches tramiprosate administered to patients with mild-to-moderate Alzheimer’s disease was effective in slowing hippocampal atrophy and has a beneficial effect on cognition. Gauthier teaches analyzing patients using MRI assessments (page 552, col. 2). APOE-4 allele status was also analyzed (page 552, col. 2, para 2). Table 1 illustrates baseline characteristics including APOE4 allele statue and total hippocampus volume (page 553). Gauthier teaches performing analysis over 78 weeks. Gauthier teaches a 120% difference between tramiprosate and placebo in the mean reduction of hippocampus volume during the 18 months of treatment in the study (page 556, col. 1).
KR20180078032 teaches shrinking cerebral cortex for Alzheimer’s disease. KR20180078032teaches cortical thickness is a risk factor for Alzheimer’s disease. Figure 2 teaches the cortical thickness from brain imaging of Alzheimer’s disease and normal patients. KR20180078032 teaches cortical atrophy refers to a value obtained by converting cortical thickness of Alzheimer’s disease patients based on a standard score calculated from cortical thickness values from a normal population. The cortical thickness maybe calculated from the normal group based on the image of the normal group.
Additionally, Jia teaches measuring cortical thickness and hippocampal volume using MRI measurements. Mean values of volume, cortical thickness in 11 Alzheimer’s related brain regions were used as phenotypes (para 83). Jia teaches performing linear regression using APOE e4 status as a covariate. Jia teaches determining a baseline total cerebral cortex for use in analysis (para 85). Jia teaches hippocampal volume and cortical thickness are markers for Alzheimer’s disease.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have analyzed a human subject with a MMSE score of 30 for APOE4 alleles, hippocampal volume, cortical thickness and amyloid status to select a patient at risk of Alzheimer’s disease. Hey teaches selecting patients at risk for Alzheimer’s disease and treating with tramiprosate prodrugs and metabolites allows for prevention of Alzheimer’s disease. The instant invention provides a set of markers, namely APOE4 alleles, hippocampal volume, cortical thickness and amyloid deposits that were previously known to be associated with Alzheimer’s disease. It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the methods claimed so as to have surveyed additional markers known to be associated with Alzheimer’s disease, in order to provide a more complete picture of the potential of Alzheimer’s disease in a patient for known markers. It is prima facie obvious to combine elements, each of which is taught by the prior art to be useful for the same purpose. See MPEP 2144.06. Hey selects patients at risk for Alzheimer’s disease, namely APOE4 positive patients with MMSE scores of 30 may be treated with ALZ-801 (valyl-3-amino-1-propanesulfonic acid), a small molecule prodrug of tramiprosate to prevent Alzheimer’s disease. Gauthier also teaches tramiprosate is effective in slowing reduction of hippocampus volume. Jia teaches hippocampal volume and cortical thickness are also markers for Alzheimer’s diseases. Here all of the recited markers were known in the prior art to be associated with Alzheimer’s disease and ALZ-801 (valyl-3-amino-1-propanesulfonic acid), a small molecule prodrug of tramiprosate slows the progression of Alzheimer’s. The ordinary artisan would have been motivated to combine this method with other known markers associated with Alzheimer’s disease like hippocampal volume and amyloid deposits to select and treat adults and prevent Alzheimer’s disease.
The claims do not require any particular volume below any particular threshold. The claims only require the hippocampal volume and cortical thickness were analyzed and are below a random unspecified threshold. All volumes and thicknesses are below some threshold. Applicant may wish adding a limitation to require determining the hippocampal volume or cortical thickness and selecting a patient with a particular volume or thickness.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-7, 9-12, 14-15, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10,471,029 in view of Shuff et al. (Brain – A journal of Neurology, Vol. 132, pages 1067-1077, 2009) or KR20180078032 (July 9, 2018) and Jia et al (WO 2018/157014, August 30, 2018).
Claims 1-7, 9-12, 14-15, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12083,082 in view of Shuff et al. (Brain – A journal of Neurology, Vol. 132, pages 1067-1077, 2009) or KR20180078032 (July 9, 2018) and Jia et al (WO 2018/157014, August 30, 2018).
Claims 1-7, 9-12, 14-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,053,192 in view of Shuff et al. (Brain – A journal of Neurology, Vol. 132, pages 1067-1077, 2009) or KR20180078032 (July 9, 2018) and Jia et al (WO 2018/157014, August 30, 2018).
Claims 1-7, 9-12, 14-15, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,187,668 in view of Shuff et al. (Brain – A journal of Neurology, Vol. 132, pages 1067-1077, 2009) or KR20180078032 (July 9, 2018) and Jia et al (WO 2018/157014, August 30, 2018).
Claims 1-7, 9-12, 14-15, 18-21, 23-25, 27-30, 32-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19, 24-35 of copending Application No. 17/877,380 in view of Shuff et al. (Brain – A journal of Neurology, Vol. 132, pages 1067-1077, 2009) or KR20180078032 (July 9, 2018) and Jia et al (WO 2018/157014, August 30, 2018).
‘029 claims a method of selecting and treating patients based on the presence of two ApoE4 alleles and administering ALZ-801 (valyl-3-amino-1-propanesulfonic acid), a small molecule prodrug of tramiprosate. ‘082 claims methods of preventing and treating using ALZ-801 (valyl-3-amino-1-propanesulfonic acid), a small molecule prodrug of tramiprosate in patients with MMSE score of 30, with APOE4/4 homozygous. ‘192 and ‘668 teach treating Alzheimer’s disease with tramiprostate derivatives/prodrugs when the patient is homozygous for ApoE4. ‘380 is a method of selecting and treating a patient with ApoE4 positive ALZ-801 (valyl-3-amino-1-propanesulfonic acid), a small molecule prodrug of tramiprosate.
The patent claims and the pending claims do not teach determining a hippocampal volume or cortical thickness and selecting a subject with hippocampal volume or cortical thickness below a threshold.
However, Schuff et al teaches MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype. Schuff teaches hippocampal volume change over time has huge potential as a maker for Alzheimer’s disease. Schuff teaches studying the hippocampal loss over 6-12 months (abstract). Table 2 illustrates hippocampal baseline volumes and rates of volume loss by group for different time frames (page 1071). Schuff teaches increased rates of hippocampal loss were associated with presence of the ApoE allele E4 gene in Alzheimer’s disease (abstract). Figure 3 illustrates rates of hippocampal volume loss in carriers and non-carriers of APpoE4 (page 1072). Figure 2 illustrates the rate of volume loss over different time periods of 1-6 and 6-12 months (page 1072). Each of Figure 2 and 3 illustrates the normal baseline that the comparison may be made to, i.e. 5% and 10% below normal. Schuff teaches amyloid AB1-42 are a major component of amyloid plaques that are directly related to Alzheimer’s disease pathology. Schuff teaches that amyloid burden and high rates of hippocampal loss implies the two measures provide complementary information about the presence of Alzheimer’s disease pathology. Schuff teaches the higher hippocampal loss in presence of ApoE4 and reduced amyloid protein supports the concept that increased hippocampal loss is an indicator of Alzheimer’s disease pathology and a potential marker to assess therapeutic interventions in Alzheimer’s disease (page 1076).
Additionally, Gauthier teaches tramiprosate administered to patients with mild-to-moderate Alzheimer’s disease was effective in slowing hippocampal atrophy and has a beneficial effect on cognition. Gauthier teaches analyzing patients using MRI assessments (page 552, col. 2). APOE-4 allele status was also analyzed (page 552, col. 2, para 2). Table 1 illustrates baseline characteristics including APOE4 allele statue and total hippocampus volume (page 553). Gauthier teaches performing analysis over 78 weeks. Gauthier teaches a 120% difference between tramiprosate and placebo in the mean reduction of hippocampus volume during the 18 months of treatment in the study (page 556, col. 1).
However, KR20180078032 teaches shrinking cerebral cortex for Alzheimer’s disease. KR20180078032teaches cortical thickness is a risk factor for Alzheimer’s disease. Figure 2 teaches the cortical thickness from brain imaging of Alzheimer’s disease and normal patients. KR20180078032 teaches cortical atrophy refers to a value obtained by converting cortical thickness of Alzheimer’s disease patients based on a standard score calculated from cortical thickness values from a normal population. The cortical thickness maybe calculated from the normal group based on the image of the normal group.
Additionally, Jia teaches measuring cortical thickness and hippocampal volume using MRI measurements. Mean values of volume, cortical thickness in 11 Alzheimer’s related brain regions were used as phenotypes (para 83). Jia teaches performing linear regression using APOE e4 status as a covariate. Jia teaches determining a baseline total cerebral cortex for use in analysis (para 85). Jia teaches hippocampal volume and cortical thickness are markers for Alzheimer’s disease.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have analyzed a human subject for APOE4 alleles, hippocampal volume, cortical thickness and amyloid status to select a patient at risk of Alzheimer’s disease. The patents and patent applications teach selecting patients at risk for Alzheimer’s disease and treating with tramiprosate prodrugs and metabolites allows for prevention of Alzheimer’s disease. The instant invention provides a set of markers, namely APOE4 alleles, hippocampal volume, cortical thickness and amyloid deposits that were previously known to be associated with Alzheimer’s disease. It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the methods claimed so as to have surveyed additional markers known to be associated with Alzheimer’s disease, in order to provide a more complete picture of the potential of Alzheimer’s disease in a patient for known markers. It is prima facie obvious to combine elements, each of which is taught by the prior art to be useful for the same purpose. See MPEP 2144.06. The claims of the patent and applications select patients at risk for Alzheimer’s disease, namely APOE4 positive patients may be treated with tramiprosate to prevent Alzheimer’s disease. Gauthier also teaches tramiprosate is effective in slowing reduction of hippocampus volume. Jia teaches hippocampal volume and cortical thickness are also markers for Alzheimer’s diseases. Here all of the recited markers were known in the prior art to be associated with Alzheimer’s disease and tramiprosate slows the progression of Alzheimer’s. The ordinary artisan would have been motivated to combine this method with other known markers associated with Alzheimer’s disease like hippocampal volume and amyloid deposits to select and treat adults and prevent Alzheimer’s disease.
Response to Arguments
The response traverses the rejection. The response asserts Applicant identified for the first time that hippocampal volume loss below a threshold and/or cortical thickness below a threshold are leading indicators of Alzheimer’s disease. This argument has been reviewed but is not persuasive. The claims do not require any particular hippocampal volume or cortical thickness below any particular threshold. The claims only require the hippocampal volume and cortical thickness were analyzed and are below a random unspecified threshold. All volumes and thicknesses are below some threshold. Applicant may wish adding a limitation to require determining the hippocampal volume or cortical thickness and selecting a patient with a particular volume or thickness.
If Applicant is arguing unexpected results of the hippocampal volume loss or cortical thickness below a threshold, the arguments are not commensurate in scope with the claims because the claims are not drawn to these thresholds. Additionally, Tables 2 and 3 in the specification is directed to a difference in ApoE 3/3 and 4/4 subjects and hippocampus volume for mild AD and mild cognitive impairment. The specification does not study and provide analysis of patients with MMSE score of 29 or greater and CDR-global score of less than 0.5. The specification does not consider heterozygotes, as encompassed by the claims (pages 30 and 32 of the specification).
The cited prior art provides hippocampal volume and cortical thickness are each associated with Alzheimer’s and thus, analyzing the hippocampal volume and cortical thickness were a marker for Alzheimer’s disease and would provide a clear picture of Alzheimer’s status for a patient. The prior art, including Shuff, teaches normal patients are MMSE above 29, thus, determining a patient is normal or asymptomatic for Alzheimer’s disease by determining MMSE is 29 or 30 was known in the art.
Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Abushakra et al. J. of Prevention of Alzheimer’s Disease “Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential”. Vol. 4, No. 3, pages 149-156, 2017.
Abushakra et al. J. Prevention of Alzheimer’s Disease, Vol. 3, No. 4, pages 219-228, 2016. Abushakra 2016 teaches clinical benefits of tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 alleles.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
February 27, 2026