Patent Application 16099188 - SYNAPTIC PROTEIN BIOMARKERS AND DIFFERENTIAL

Title: SYNAPTIC PROTEIN BIOMARKERS AND DIFFERENTIAL DIAGNOSIS OF ALZHEIMER'S DISEASE AND OTHER NEURODEGENERATIVE DISORDERS

Application Information

Invention Title: SYNAPTIC PROTEIN BIOMARKERS AND DIFFERENTIAL DIAGNOSIS OF ALZHEIMER'S DISEASE AND OTHER NEURODEGENERATIVE DISORDERS
Application Number: 16099188
Submission Date: 2025-04-07T00:00:00.000Z
Effective Filing Date: 2018-11-05T00:00:00.000Z
Filing Date: 2018-11-05T00:00:00.000Z
National Class: 435
National Sub-Class: 007100
Examiner Employee Number: 89126
Art Unit: 1675
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 1

Cited Patents

The following patents were cited in the rejection:

US 0119278🔗

Office Action Text

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 .

Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/2/2024 has been entered.

Claims 26- 30, 32 and 35 are under consideration in the instant Office Action.

Withdrawn Rejections
The rejection of claims 26 and 31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot since claim 31 has been cancelled.
The rejection of claims 26 and 31 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 is moot since claim 31 has been cancelled.
The rejection of claims 26-30, 32 and 35 rejected 35 U.S.C. 102(a)(2) as being anticipated by Joyce et al., WO2015/130956 is withdrawn in view of the newly amended claim 26 which no longer requires synaptophysin and Joyce does not teach the other claimed biomarkers.
The rejection of claims 26-32 and 34-35 under 35 U.S.C. 103 as being unpatentable over Goetzl US2015/0119278 (3/13/2024 PTO-892) in view of Joyce et al., WO2015/130956 is withdrawn in view of the newly amended claim 26 which no longer requires synaptophysin and Joyce does not teach the other claimed biomarkers.

New Rejection Necessitated by Amendment
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.
Claims 26-30, 32 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Goetzl US2015/0119278 (3/13/2024 PTO-892) in view of Joyce et al., WO2015/130956 (7/31/2024, PTO-892) and Marquez-Sterling et al., 1997 (instant PTO-892).
Goetzl teaches methods of diagnosing or prognosing neurodegenerative disorders in a subject by obtaining biological samples from the subject and measuring the levels of biomarkers wherein the method comprising isolating vesicles from the biological sample (see paragraph 5) as in instant claim 26. Goetzl teaches that vesicles are selected from the group of exosomes, microparticles, macrovesicles, nanosomes, extracellular vesicles, and ectosomes (see paragraph 5) as in instant claim 27. Goetzl teaches that the isolated exosomes are selected from the group consisting of neuron derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia-derived exosomes (see paragraph 5) as in instant claim 28. Goetzl teaches that the level of one or more biomarkers is the protein, phosphorylated protein, mRNA, or miRNA level of the one or more biomarker (see paragraph 5) as in instant claim 29. Goetzl teaches that the samples are selected from whole blood, serum, plasma, urine and cerebrospinal fluid (see paragraph 5) as in instant claim 30. Goetzl teaches that the isolating vesicles from a biological sample comprises: contacting the biological sample with an agent under conditions wherein a vesicle present in said biological sample binds to said agent to form a vesicle-agent complex; and isolating said vesicle from said vesicle-agent complex to obtain a sample containing said vesicle, wherein the vesicles present in said sample is greater than the vesicles present in said biological sample (see paragraph 6) as in instant claim 26. Goetzl teaches that at least one of the one or more biomarkers are selected from the group consisting of Tau, phosphorylated Tau, Ab1-42, TDP-43,a-synuclein, SOD-1, FUS, FKBP51, IRS-1, phosphorylated IRS-1, cathepsin D (CTSD), type 1 lysosome-associated membrane protein (LAMP1), ubiquitinylated proteins (UBP), heat-shock protein 70 (HSP70), neuron-specific enolase (NSE), neurofilament light chain (NFL), CD9, CD63, CD81, and CD171 (see paragraph 6) as in instant claim 32.
Goetzl teaches that the agent is an antibody and that the antibody is a monoclonal anti human NCAM antibody; a monoclonal CD171 antibody; a monoclonal anti-human CD171 antibody; a monoclonal CD9 antibody; a monoclonal CD63 antibody; and a monoclonal CD81 antibody (see paragraph 6) as in instant claim 26. Goetzl teaches that the biomarker is measured by a method selected from the group consisting of immunohistochemistry, immunocytochemistry, immunofluorescence, immunoprecipitation, western blotting, and ELISA (see paragraphs 39 and 45) as in instant claim 35. Goetzl does not specifically teach the required biomarkers of claim 26, like synaptotagmin.
Joyce teaches methods for isolating, measuring, detecting and analyzing extracellular vesicles, such as exosomes, which contain biomarkers including peptides, protein and or nucleic acids that indicate brain diseases like Alzheimer’s disease (see paragraphs 2, 10, 14, 17, 41, 253, 277) as in instant claims 26-27 and 29. Joyce teaches that the exosomes are derived specifically from brain cells (see paragraph 2, 277) and reads on the exosomes of claim 28 since neurons, astrocytes, oligodendrocytes and microglia are all brain derived cells. Joyce also teaches that the antigens on the exosomes include tau, beta amyloid, neurons specific enolase, NFL and synaptophysin (see paragraph 2, 17, 41, 236, 277, 286) as in instant claims 26 and 32. Joyce teaches that the biological samples include whole blood, plasma and serum (see paragraphs 40, 207, 253, 277, 286 ) as in instant claim 30. Joyce teaches using enzyme linked assay like and ELISA for quantitative analysis of the amount of a biomarker (see paragraphs 159, 189-190, 198) as in instant claim 35. Joyce teaches that biomarker synaptophysin is found in exosomes isolated from biological samples that include blood, serum or plasma and are biomarkers for diseases like Alzheimer’s diseases as in instant claims 26-28 and 30 but fail to specifically teach the biomarker synaptotagmin.
Marquez-Sterling teaches that vesicles purified from brains have the recycling synaptic vesicle integral membrane proteins synaptophysin, synaptotagmin and SV2 (see abstract) as in instant claim 26. Marquez-Sterling teaches that the APP protein that is a precursor to amyloid beta in internalized with recycling synaptic vesicle integral membrane proteins (see page 140, 2nd column, 2nd paragraph). Marquez-Sterling teaches immunoisolation of synaptic vesicle using synaptophysin beads and immunocytochemistry to detect synaptophysin, synaptotagmin and SV2 proteins (see page 143, 2nd column and page 144, 2nd column, 1st paragraph) as in instant claims 26 and 35. Marquez-Sterling does not teach the instantly claimed method.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Goetzl, Joyce and Marquez-Sterling. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because both Goetzl and Joyce teach methods of measuring biomarker levels to determine the status of an Alzheimer’s patient and Marquez-Sterling teaches that synaptophysin, synaptotagmin and SV2 are biomarkers used to identify synaptic vesicles. Therefore, it would be obvious to use the synaptophysin, synaptotagmin and SV2 biomarker taught by Joyce and Marquez-Sterling since Joyce teaches that this biomarker is linked to AD diagnosis as are the methods and biomarkers taught by Goetzl. One of ordinary skill would be motivated to combine biomarkers known to be effective in diagnosing AD and identify synaptic vesicles and would have expected the combination of biomarkers be at least as good as biomarkers alone. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.

Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.

Claims 26-30, 32 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 9,958,460 in view of Joyce et al., WO2015/130956 (instant PTO-892) and Marquez-Sterling et al., 1997 (instant PTO-892). ‘460 claims a method of analyzing a sample from a subject by obtaining a biological sample comprising vesicles from a subject, (ii) isolating vesicles from the biological sample, and (iii) detecting one or more biomarkers from the isolated vesicles, wherein at least one of the one or more biomarkers is selected from the group consisting of Tau, phosphorylated Tau, beta-amyloid 1-42 (Aβ1-42), transactive response DNA binding protein 43 (TDP-43), α-synuclein, superoxide dismutase 1 (SOD-1), FUS RNA binding protein (FUS), FK506 binding protein 51 (FKBP51), insulin receptor substrate 1 (IRS-1), phosphorylated IRS-1, cathepsin D (CTSD), lysosomal-associated membrane protein 1 (LAMP1), ubiquitinylated proteins (UBP), heat-shock protein 70 (HSP70), neuron specific enolase (NSE), and neurofilament light chain (NFL), wherein the biological sample is whole blood, serum, or plasma, and wherein the vesicles are selected from the group consisting of neuron-derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia-derived exosomes; wherein the isolating vesicles from a biological sample comprises: contacting the biological sample with an agent under conditions wherein a vesicle present in said biological sample binds to said agent to form a vesicle-agent complex; and isolating said vesicle from said vesicle-agent complex to obtain a sample containing said vesicle and wherein the detection of one or more biomarkers is the detection of protein, phosphorylated protein, mRNA, or miRNA of the one or more biomarkers. These limitations read on the instant claims except that they do not claim the biomarker like synaptophysin or synaptotagmin found in exosomes as required in instant claim 26. Joyce and Marquez-Sterling make up for that deficiency. Joyce teaches biofluid markers for Alzheimer’s disease, a neurodegenerative disease (see abstract and paragraphs 14, 18) and Marquez-Sterling teaches that synaptic vesicles have synaptotagmin and synaptophysin as synaptic markers. ‘460 and Joyce teach methods of measuring biomarker levels to determine the status of an Alzheimer’s patient. Therefore, it would be obvious to use the synaptotagmin and synaptophysin biomarkers taught by Joyce and Marquez-Sterling since the references teach that these biomarkers are linked to identifying synaptic vesicles and are linked to AD diagnosis as are the methods and biomarkers taught by ‘460. One of ordinary skill would be motivated to combine biomarkers known to be effective in diagnosing AD and would have expected the combination of biomarkers be at least as good as biomarkers alone.

Claims 26-30, 32 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 12-13, and 22-25 of copending Application No. 17/945,058. Although the claims at issue are not identical, they are not patentably distinct from each other because ‘058 claims a method of obtaining a biological sample comprising vesicles, isolating the vesicles and detecting biomarkers; claim vesicles and exosomes, the biomarkers include Tau, phosphorylated Tau, Ab1-42, a-synuclein, type 1 lysosome-associated membrane protein (LAMP1), ubiquitinylated proteins (UBP), CD9, CD63, CD81, and CD171 and SYT( aka synaptotagmin) and using antibodies to detect the vesicle biomarkers vi an immunoassay like an ELISA.
This is a provisional nonstatutory double patenting rejection.

Response to Arguments
Applicant's arguments filed 12/2/2024 have been fully considered but they are not persuasive. Applicant argues that the removal of the limitation of synaptophysin from the instant claims makes them allowable because the Joyce reference fails to teach the other biomarkers. This is not found persuasive because the new reference, Marquez-Sterling et al., teaches one of the other biomarkers, synaptotagmin and synaptophysin, and therefore, the instant claims are anticipated or obvious over the prior art of record.
Finally, applicant fails to argues against the double patenting rejections and they are maintained over the reasons set forth above.

Conclusion
No claims are allowed.
Advisory Information
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675