DETAILED 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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/17/2025 has been entered.
Priority
The present application was filed on 07/29/2021. Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT/KR2019/016777, filed on 11/09/2019.
Status of the Claims
Claims 1, 5, 9 and 12 have been amended. Claims 10-11 are cancelled. Claims 13-16 have been added. Claims 1-9 and 12-16 are pending and examining herein.
Withdrawn Objections/Rejections
The rejections of claims 1-4 under 35 USC 101 and 35 USC 103 are withdrawn in view of the amendment of the claims.
The rejections of claims 1-9 and 12-16 under 35 USC 103 are updated.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6-8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 6-8 further limit the biological samples and the vesicles recited in claim 5. It is noted that the subject matter of claim 5 is a composition comprising an agent for measuring the expression levels of biomarkers. However, the biological samples and the vesicles are not a part of the claimed composition. Thus, these claims do not further limit the composition of claim 5 then fails to particularly point out and distinctly claim the subject matter.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5-9 and 12, 14-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is written description rejection.
Claims 5, 12, 14 and 16 recite “an agent” for measuring the expression level of the target markers. Claims 9 and 15 recite the agent is an antibody or antigen-binding fragment thereof specifically binding to one of the target markers.
These claims lack written description because the specification does not disclose any specific agent for measuring an expression level of at least one selected from the group consisting of CADM2, APLP1 EPHA7, CRLF1, and SLC6A3 other than anti-LI CAM antibody (ab20148, anti-APLP1 antibody (ab192,481) and anti-CADM2 antibody (bs-8246R) while the claims are generally directed to any and all agents that may be able to measure the expression level of the biomarkers as above.
The claimed agents or antibodies may be any of a genus of agents or antibodies where the agents are defined only in terms of their function, that is for measuring an expression level of the claimed markers or for specifically binding to the claimed markers. The claim scope is potentially enormous depending on how many of the products meet the functional requirements.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of an application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount to support a prima facie case are discussed below.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing and identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. Amgen v. Sanofi describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself; not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
Office guidance has been updated to reflect that adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. See the Memorandum dated February 22, 2018 entitled “Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials” available at https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)) (emphasis added).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number* of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The instant specification does not disclose any partial structure or other identifying characteristics of the agents which are responsible for the desired function. A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that would exhibit this functional property. Since the structural features common to the members of the agent genus are unknown, any agent contributing to the process of measuring an expression level of a marker is potentially considered the claimed agent, e.g., a protein tag, an assay solution, or an enzyme to generate the signal of the assay etc.
In the present case, there is insufficient evidence of which agent meets the functionally required as claimed. Additionally, the three antibodies discloses are not sufficient to established structure-function correlation to enable the entire genus of agents as claimed. The specification does not make clear that Applicant was in possession of all the possible claimed agents. The disclosure is insufficient to represent the claimed genus of agents, which is of enormous size and high variability.
In addition, there is insufficient evidence of which antibody or antigen-binding fragment thereof meets the functionally required as claimed. These antibodies are not sufficient to established a structure-function correlation to enable the entire genus of the antibodies and antigen-binding fragments as claimed because correlation between structure and function is less likely for antibodies than for other molecules. Therefore, the claims draw to a genus of antibody or antigen-binding fragment thereof which is enormous size and high variability.
Antibody structure cannot be easily predicted. Antibody structure is highly variable. The complementary determining regions (CDRs) of antibodies are generally considered to be the region of contact between the antibody and the antigen. See Janeway et al. (Immunobiology: the Immune System in Health and Disease (2001), Elsevier Science Ltd/Garland Publishing, New York, NY, Fifth Edition, see sections 3-6 and 3-7) and Almagro et al. (“Humanization of Antibodies”, Frontiers in Bioscience 13, 1619-1633, 2008) at introduction and section 4. While antibody CDRs are necessary for binding, they are highly diverse in structure, and their sequence does not correlate to binding in a predictable fashion.
For example, Goel et al. (“Plasticity within the Antigen Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response”, The Journal of Immunology 173(12):7358-7367, 2004) made three antibodies that bind to the same 12-mer but have very different CDRs (see Figures 2-3 in particular).
See also Edwards et al. ("The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS" J. Mol. Biol. (2003) 334, 103–118, DOI: 10.1016/j.jmb.2003.09.054), which shows the immense combinatorial flexibility and capacity of the human antibody repertoire to generate binding sites to an individual protein antigen, the B-lymphocyte growth factor known as “BLyS” (see entire document). Edwards describes in detail how the breadth of antibody structures against a given immunogen can be influenced by the immunization and/or selection methods (see Discussion Section). Edwards et al. found that a library contained over 1000 antibodies bound to a single 51 kDa protein, including 1098 unique VH and 705 VL sequences. There were 568 different CDR3 regions, indicating high diversity.
Like Edwards, Lloyd et al. ("Modelling the human immune response: performance of a 10e11 human antibody repertoire against a broad panel of therapeutically relevant antigens", Protein Engineering, Design and Selection, Volume 22, Issue 3, 1 March 2009, Pages 159–168, https://doi.org/10.1093/protein/gzn058) shows a repertoire of 1x1011 human antibody variable regions can generate large numbers of unique, biologically active scFvs against a variety of polypeptide targets (see e.g., at page 161-62 bridging paragraph and in Table 1, cited herewith). Lloyd et al. found that on average, about 120 different antibodies in a library can bind to a given antigen.
As further illustration of the unpredictability in the art, Brown et al. (“Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?”, J Immunol. 1996 May;156(9):3285-91), describes how a one amino acid change in the VHCDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region (at 3290 and Tables 1 and 2).
Vajdos et al. (“Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis” J Mol Biol. 2002 Jul 5;320(2):415-28, DOI: 10.1016/S0022-2836(02)00264-4) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (see especially at 416). Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen.
In view of the above, one cannot visualize or recognize the identities of the members of the genus that exhibit the claimed functional properties. A claimed invention may not be adequately described where an invention is described solely in terms of its function. Also, there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule defined solely by its ability to perform a function without a known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. See MPEP 2163.
The level of skill in the art is high. In particular, methods for making and/or screening antibodies with desired binding properties were well known in the art at the time of the invention. At the same time, however, it was not within the skill of the art to predict whether a given antibody would bind specifically to the claimed markers.
In summary, the specification fails to provide adequate written description for the genus of claimed agents or antibodies, as the agents or antibodies are described only in terms of desired functional properties and not in terms of common structure or other relevant identifying characteristics to define the genus. The specification does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 6-8 are rejected because they depend on the rejected claim 5.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 5, 6, 9 and 12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wasco (US 5891991, PTO-892 07/25/24).
Regarding claim 5, Wasco discloses:
A composition for isolating brain-derived vesicles, the composition comprising an agent for measuring an expression level of at least one selected from the group consisting of CADM2 and APLP1 in a biological sample comprising vesicles. (Examiner interprets “for isolating brain-derived vesicles” and “for measuring an expression level of at least one selected from the group consisting of CADM2 and APLP1 in a biological sample comprising vesicles” as intended use. Therefore the claim only require the composition comprising an agent. Wasco in Abstract, teaches antibodies (an agent) used to detect an APLP in biological specimens, including, for example, fluid, serum or tissue samples. Wasco in col. 18 lines 13-15, teaches the APLPs comprise APLP1 or APLP2. Wasco in col.3 lines 41-43, teaches that APLP1 presents in the brain.)
Regarding claim 6, Wasco discloses:
The composition of claim 5, wherein the biological sample is a cell culture supernatant, whole blood, serum, plasma, ascites fluid, cerebrospinal fluid, bone marrow aspirate, bronchoalveolar lavage fluid, urine, semen, vaginal fluid, mucus, saliva, sputum, or purified lysates from a biological tissue sample. (Wasco in Abstract, teaches that the biological sample is fluid, serum, or tissue sample.)
Regarding claim 9, Wasco discloses:
The composition of claim 5, wherein the agent is an antibody or antigen-binding fragment thereof specifically binding to at least one selected from the group consisting of CADM2 and APLP1 or a fragment thereof. (Wasco in Abstract, teaches antibodies used to detect an APLP in biological specimens, including, for example, fluid, serum or tissue samples. Wasco in col. 18 lines 13-15, teaches the APLPs comprise APLP1 or APLP2.)
Regarding claim 12, Wasco discloses:
A composition for diagnosing a degenerative brain disease, the composition comprising an agent for measuring an expression level of at least one selected from the group consisting of CADM2 and APLP1 in a biological sample including comprising vesicles.(Examiner interprets “for diagnosing a degenerative brain disease” and “for measuring an expression level of at least one selected from the group consisting of CADM2 and APLP1 in a biological sample comprising vesicles” as intended use. Therefore, the claim only require the composition comprising an agent. Wasco in Abstract, antibodies (an agent) used to detect an APLP in biological specimens, including, for example, fluid, serum or tissue samples. Wasco in col. 18 lines 13-15, teaches the APLPs comprise APLP1 or APLP2. Wasco in col 4 lines 60-61, teaches that APLPl is a candidate gene for the gene defect for late-onset familial Alzheimer’s disease, an example of a degenerative brain disease. Wasco in col.3 lines 41-43, teaches that APLP1 presents in the brain.)
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 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Wasco (US 5891991, PTO-892 07/25/24), as applied in claim 5, in view of Ter-Ovanesyan (US 20180066307, PTO-892 07/25/24).
Regarding claims 7-8, Wasco teaches the invention in claim 5 as discussed above. Wasco does not teach the brain-derived vesicles or neuron-derived vesicles and the vesicle is exosome.
Ter-Ovanesyan teaches that amyloid beta precursor like protein 1 (APLP1) is found in neuron exosome (see Table D page23 col G).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the antibody agent to APLP1 of Wasco for isolating brain-derived vesicle and diagnosing a degenerative brain disease by measuring an expression levels of APLP1 in a biological sample comprising neuron exosomes because the neuron exosome expresses APLP1 as taught by Ter-Ovanesyan. Measuring APLP1 in the brain can diagnose a degenerative disease as taught by Wasco.
One having an ordinary skill in the art would have had a reasonable expectation of success in combining Wasco and Ter-Ovanesyan because Wasco is directed to an agent to detect APLP1 and Ter-Ovanesyan teaches that APLP1 is in neuron exosome. Therefore, using antibody to APLP1 for isolating a biological sample comprising vesicle results in a predictable outcome.
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Wasco as applied to claims 5 and 12 above, further in view of Goetzl (WO 2017/120436, hereinafter Goetzl-436, PTO-892 04/18/25) and Xu et al. (Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy, BMC Medical Research Methodology (2015) 15:94).
Regarding claims 14-16, Wasco teach the invention as discussed above.
Wasco does not teach an agent for measuring an expression level of at least one selected from the group consisting of EPHA7, CRLF1, and SLC6A3 as in claims 14 and 16, wherein the agent is an antibody as in claim 15.
Goetzl-436 teaches an antibody agent for measuring DAT (also called SLC6A3) in neuron-derived exosome (see page 10 lines 6-22, page 23 lines 4-11, DAT (also called SLC6A3) is a marker of neuron-derived exosome; see page 10 lines 6-22, detecting DAT using anti-human antibody to DAT).
Goetzl-436 uses the anti-human antibody to DAT for identification of fetal neural exosomal (FNE) biomarkers isolated from maternal plasma (see Abstract). This teaching encompasses the antibody agent to detect an expression levels of DAT or SLC6A3 in the vesicle sample.
Xu teaches that it has been widely accepted by medical researchers that diagnosis based on one single biomarker may not provide sufficient accuracy. Consequently, it is becoming more and more common that multiple biomarker tests are performed on each individual, and the corresponding measurements are combined into one single score to help clinicians make better diagnostic judgment. See page 1 column 2 paragraph 2.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition taught by Wasco to further comprising the antibody agent that can specifically measure an expression level of SLC6A3 to isolate the brain derived vesicle or diagnose a degenerative brain disease because Xu teaches using multiple biomarkers would help improve the accuracy of the test, e.g., isolating brain-derived vesicles (see Xu page 1 col.2 par.2) and Goetzl-436 teaches that analyzing these markers would be helpful for diagnose or prognose a fetal neurodevelopmental disease or disorder (see Goetzl-436 page 20 lines 13-15).
One having an ordinary skill in the art would have had a reasonable expectation of success in combining Wasco and Goetzl-463 because they both use an immunoassay and an antibody specific to detect a marker in the vesicle sample.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Goetzl (US 9958460, PTO-892 07/25/24) in view of Shu et al. (US20130330718), Frederikse et al. (Synapsin and synaptic vesicle protein expression during embryonic and post-natal lens fiber cell differentiation, Molecular Vision 2004; 10:794-804) and Xu et al. (Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy, BMC Medical Research Methodology (2015) 15:94).
Regarding claims 1-2, Goetzl-460 teaches a method of isolating vesicles from a biological sample and diagnosing a neurodegenerative disease (see col 2 lines 54-60). The method comprises obtaining the biological sample including vesicles from a subject (see col 2 lines 59-60) and analyzing an expression level of at least one biomarker (see col 2 lines 60-61).
Goetzl-460 teaches that the vesicle can be brain-derived (see col 2 lines 18-21: teaching that the biological sample is brain tissue or cerebrospinal fluid). This teaching encompasses claim 2.
Nevertheless, Goetzl-460 does not specifically analyzing expression levels of CADM2 and APLP1 for isolating brain-derived vesicle.
Shu teaches a method that can be used to image the ultrastructural localization of proteins in cells and tissues (see par.9). The method comprises obtaining the biological sample including vesicles from a subject (see par.195: teaching that sample includes a cell, tissue, or organism, fixing the cell, tissue, or section of the organism; see par.69, discloses that sample comprises vesicles).
The method also comprises analyzing an expression level of CADM2 (see par.69: teaching that SynCAM2 is shown in tissue section of mouse brain, see par.251: teaching that SynCAM2 localized to postsynaptic sites in cultured cortical neurons, identified by postsynaptic densities and by the opposition of these terminals to presynaptic boutons bearing synaptic vesicles).
It is noted that SynCAM2 is an alternative name of CADM2. Thus, Shu shows that SynCAM2/CADM2 is expressed in a brain vesicle.
Frederikse discloses a method of detecting and analyzing protein expression during embryonic and post-natal lens fiber cell differentiation, wherein a sample comprises lens and brain tissues (see page 4 last paragraph) and the sample comprises vesicle (see page 5 last paragraph). The method also comprises analyzing an expression level of APLP1 (see page 5 last paragraph: stating that expression of Alzheimer precursor-like proteins APLPI and APLPII is in lens fiber cell; see page 9 par.3). Thus, Frederikse shows that APLPI is expressed in a brain vesicle.
Xu teaches that it has been widely accepted by medical researchers that diagnosis based on one single biomarker may not provide sufficient accuracy. Consequently, it is becoming more and more common that multiple biomarker tests are performed on each individual, and the corresponding measurements are combined into one single score to help clinicians make better diagnostic judgment. See page 1 column 2 paragraph 2.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Goetzl-460, analyzing the expression of markers, e.g., CADM2 and APLP1, for isolating brain-derived vesicle because: Shu and Frederikse teach that CADM2 and APLP1 are expressed in brain-derived vesicles.
One would have motivation to analyze multiple markers, e.g., CADM2 and APLP1, in a biological sample comprising vesicles because Xu teaches using multiple biomarkers would help improve the accuracy of the test, e.g., isolating brain-derived vesicles (see Xu page 1 col.2 par.2). Moreover, isolating brain vesicle also helps to diagnose a neurological disease in a subject, so analysis of multiple biomarkers also help to improve the neurological disease diagnosis as taught by Goetzl (see Goetzl col 2 lines 60-65)
Moreover, a skilled artisan would have had a reasonable expectation of success in combining Goetzl-460, Shu, and Frederikse because they are directed to a similar method comprising obtaining the sample comprising vesicle and analyzing the expression levels of markers. These are the two active steps of the claimed method, so the combined teachings of the cited references thus render obvious the instant invention of claims.
Regarding claims 3-4, Goetzl-460, Shu, Frederikse and Xu teach the invention as discussed above.
Goetzl-460 teaches the vesicles are from neuron derived exosomes (see col.2 lines 47-51). Shu teaches the vesicles are from neuron synapses, means they are neuron-derived vesicles (see par.12, par.69 and par.79). Frederikse teaches the sample comprising vesicle is from brain tissue (see page 4 last paragraph).
Goetzl-460 further teaches the vesicles are selected from the group of exosomes, microparticles microvesicles, nanosomes, extra-cellular vesicles, and ectosomes (see col 2 lines 42-45).
Shu and Frederikse do not teach the vesicle are selected from the group consisting of exosomes, microparticles, microvesicles, nanosomes, extracellular vesicles and ectosomes.
However, it would have been obvious to utilize this known potential method of Goetzl-460, Shu and Frederikse for the purpose of isolating brain-derived vesicles selected from the claimed group in claim 4 with a reasonable expectation of success since their method can analyze the expression of CADM2 and APLP1 in a sample comprising vesicles.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Goetzl (US 9958460, PTO-892 07/25/24) in view of Shu et al. (US20130330718), Frederikse et al. (Synapsin and synaptic vesicle protein expression during embryonic and post-natal lens fiber cell differentiation, Molecular Vision 2004; 10:794-804) and Xu et al. (Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy, BMC Medical Research Methodology (2015) 15:94), as applied in claim 1 above, and further in view of Goetzl (WO 2017/120436, hereinafter Goetzl-436, PTO-892 04/18/25) and Routenberg et al. (WO 2019/222708, PTO-892 04/18/25).
Regarding claim 13, Goetzl-460, Shu, Frederikse and Xu teach the invention as discussed above. Goetzl-460 does not teach further analyzing an expression of SLC6A3 in the tissue sample.
Goetzl-436 teaches a method for identification of fetal neural exosomal (FNE) biomarkers isolated from maternal plasma (see Abstract). The method comprises:
obtaining the biological sample including vesicles from a subject (see page 3 lines 10-17, page 10 lines 6-22);
analyzing an expression level of at least one biomarker (see page 3, lines 10-17: disclosing that the level of a biomarker in the vesicle is determined), the at least one biomarker can be Dopamine Transporter (DAT), which is an alternative name of SLC6A3 (see page 10 lines 6-22: disclosing that isolating FNEs from the biological sample is done by using anti-human antibody to DAT).
Goetzl-436 teaches that DAT is a marker which is used to positively enrich vesicle in the sample (see page 22 lines 15-24). Particularly, Goetzl-426 emphasizes that DAT is a marker of neuron-derived exosome (see page 10 lines 6-22, page 23 lines 4-11). This teaching encompasses that the DAT marker expression is higher on the neuron derived exosomes compared to that on the exosomes from other sources, thereby the DAT expression can be used to isolate neuron derived-exosome.
Further, Goetzl-436 teaches the isolation of FNEs is for diagnose or prognose a fetal neurodevelopmental disease or disorder (see page 20 lines 13-15).
Thus, Goetzl-436 shows that DAT/ SLC6A3 is expressed in a brain vesicle.
In addition, Routenberg et al. also taught that the dopamine transporter DAT1 is an extracellular vesicle (EV) surface marker that is specific to a neuron (see par.102, 137, 157, and claim 31).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the modified method of Goetzl-460, further analyzing the expression of markers SLC6A3, for isolating brain-derived vesicle because: Goetzl-436 shows that DAT/ SLC6A3 is expressed in a brain vesicles and Routenberg also recognized DAT1 to be a neuron-specific marker.
One would have motivation to analyze multiple markers, e.g., CADM2 and APLP1 and SLC6A3, in a biological sample comprising vesicles because Xu teaches using multiple biomarkers would help improve the accuracy of the test, e.g., isolating brain-derived vesicles (see Xu page 1 col.2 par.2). Moreover, isolating brain vesicle also helps to diagnose a neurological disease in a subject, so analysis of multiple biomarkers also help to improve the neurological disease diagnosis as taught by Goetzl (see Goetzl-460 col 2 lines 60-65, Goetzl-436 page 20 lines 13-15).
Moreover, a skilled artisan would have had a reasonable expectation of success in combining Goetzl-460, Shu, Frederikse and Goetzl-436 because they are directed to a similar method comprising obtaining the sample comprising vesicle and analyzing the expression levels of markers. These are the two active steps of the claimed method, so the combined teachings of the cited references thus render obvious the instant invention of claims.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-12 under 35 U.S.C. 101 and 103 have been considered. The arguments based on the amended claims.
The arguments are moot in view of the new grounds of rejection. The argued limitations are taught by the combination of Shu, Frederikse, Goetzl-460, Goetzl-436, Wasco, Ter-Ovanesyan, and Routenberg as discussed in detail in the new grounds of rejection set forth above, as necessitated by applicant's amendments.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHAU N.B. TRAN whose telephone number is (571)272-3663. The examiner can normally be reached Mon-Fri 8:30-6:30 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy L Nguyen can be reached on 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHAU N.B. TRAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 October 10, 2025