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 .
Response to Amendment
The Amendment filed 08/05/2026 has been entered. Claims 1-4, 6-22, and 24-29 remain pending in the application. Claims 1-4, 6-18, and 27-28 are withdrawn. Applicant’s amendments to the specification and claims have overcome each and every objection and 112(b) rejections previously set forth in the Non-Final Office Action mailed 05/14/2026. New grounds of rejections necessitated by amendments are discussed below.
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.
Claims 19-22, 24-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (Yang et al., “Quantitative Approach for Protein Analysis in Small Cell Ensembles by an Integrated Microfluidic Chip with MALDI Mass Spectrometry”, Anal. Chem. April 5, 2021, 93, 15, 6053-6061; cited in the IDS filed 12/27/2023) in view of Liotta et al. (Liotta et al., “Laser Capture Proteomics: Spatial Tissue Molecular Profiling from the Bench to Personalized Medicine.” Dec 14, 2021. Expert Review of Proteomics 18 (10): 845–61), Li et al. (Li et al., “Microfluidics-Based Systems in Diagnosis of Alzheimer’s Disease and Biomimetic Modeling”, Micromachines (Basel). 2020 Aug 19;11(9):787), and Zhang et al. (US 20130156705 A1).
Regarding claim 19, Yang teaches a system (abstract; Fig. 1) for analyzing tissue for the presence of Aβ-M and Aβ-O species (interpreted as an intended use, see MPEP 2114; abstract teaches a microfluidic device for analysis of cells that includes microfluidic channels; therefore, the device is capable of being used for analyzing tissue for the presence of Aβ-M and Aβ-O species as claimed at a later time), the system comprising:
a manifold (abstract; Fig. 1) comprising a plurality of layered wells (abstract; Fig. 1 teaches a plurality of microwells formed by a fluidic layer and control layer) each comprising an upper chamber (abstract and Fig. 1, the bottom well of a pair of top and bottom well; note that “upper” is a relative position depending on the orientation of the manifold, therefore the bottom well of Fig. 1 can be interpreted as an upper chamber) and a lower chamber (abstract and Fig. 1, the top well of a pair of top and bottom well; note that “lower” is a relative position depending on the orientation of the manifold, therefore the top well of Fig. 1 can be interpreted as the lower chamber), each chamber comprising independent fluidic connections (Fig. 1 teaches each of the top and bottom wells having fluidic connections via valves A and C) and an adjustable valve separating the upper chambers and lower chambers (abstract and Fig. 1, teaches valve B separating the top and bottom wells), wherein the manifold is assembled on an indium-tin oxide coated glass slide (Fig. 1 and page 6054, section “Materials” teaches an ITO coated glass slide);
antibodies positioned within the lower chamber of the layered well (abstract and Fig. 1 teach antibodies positioned in the top wells; note that “lower” is a relative position depending on the orientation of the manifold, therefore the top well of Fig. 1 can be interpreted as the lower chamber);
a matrix solution (page 6056, section “Digestion Efficiency” teaches a matrix solution of α-cyano-4- hydroxycinnamic acid in acetonitrile and trifluoroacetic acid); and
a mass spectrometer (page 6056, section “MS analysis” teaches a MALDI-TOF instrument for MS analysis).
Yang fails to teach: an apparatus for microdissection of cells from a sample of tissue; and an Aβ-specific antibody and an amyloid oligomer-specific antibody positioned within the lower chamber of the layered well.
Yang teaches the proposed approach will eventually provide a new means for proteome studies in small cell ensembles with the potential for single-cell analysis and improve our ability in disease diagnosis, drug discovery, and personalized therapy (abstract). Yang teaches the importance and need of investigation of proteins for various diseases such as neurodegenerative disorders (page 6053, section, “Introduction”).
Liotta teaches a review of laser capture microdissection (LCM) for isolating or capturing specific cells of interest in a tissue section and the emerging frontier for LCM single cell molecular analysis combining proteomics with genomic and transcriptomic analysis (abstract). Liotta teaches LCM has been used to generate data for disease and neurobiology research (page 845, left column). Liotta teaches advantages of LCM includes sampling and extracting molecules within the full thickness of tissue cells targeted for analysis, resulting in high sensitivity and yield for precise microscopic regions, which is useful for analysis (page 846, left column, section “Article highlights”, second bullet). Liotta teaches LCM guided mass spectrometry methods are rapidly advancing and are beginning to realize the dream of robust high-yield LCM single cell tissue proteomics from the same thin-tissue section, high yield single cell transfer to nanochip, subcellular precision, and high throughput with high sensitivity (page 852, left column, first paragraph). Liotta teaches LCM guided mass spectrometry methods are rapidly advancing for discovery applications from region of interest to single-cell resolution (page 846, left column, section “Article highlights”, third bullet). Liotta teaches hybrid imaging LCM systems have the potential to enable state-of-the-art co-evolving downstream molecular and cellular analytical discovery platforms, including microfluidics and mass spectrometry (page 854, left column, section 4.1). Liotta teaches using microdissection tissue special profiling combined with mass spectrometry, such as MALDI, (page 853; table 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of Yang to incorporate Yang’s teachings of analysis of cells for diseases and neurobiological research (abstract; page 6053, section, “Introduction”) and Liotta’s teachings of emerging technologies of LCM combined with mass spectrometry and microfluidics for cell analysis for disease and neurobiology research (abstract; page 845, left column; page 846, left column, section “Article highlights”; page 852, left column, first paragraph; page 853; table 1) to provide: an apparatus for microdissection of cells from a sample of tissue (i.e. LCM). Doing so would have a reasonable expectation of successfully improving isolating or capturing specific cells of interest in sample such as a tissue section prior for cell processing and analysis for improved investigation of disease or neurobiology. Additionally, doing so would have a reasonable expectation of successfully improving high-yield of a sample for analysis, high yield single cell transfer to the system, subcellular precision, and high throughput with high sensitivity (Liotta, page 852, left column, first paragraph).
Modified Yang fails to teach: an Aβ-specific antibody and an amyloid oligomer-specific antibody positioned within the lower chamber of the layered well.
Yang teaches the proposed approach will eventually provide a new means for proteome studies in small cell ensembles with the potential for single-cell analysis and improve our ability in disease diagnosis, drug discovery, and personalized therapy (abstract). Yang teaches the importance and need of investigation of proteins for various diseases such as neurodegenerative disorders (page 6053, section, “Introduction”).
Li teaches early detection and accurate diagnosis of Alzheimer’s disease (AD) is essential for patient care and disease treatment (abstract); and microfluidic chips integrated with other technologies for AD diagnostic biomarker detection and profiling for disease detection and diagnosis (abstract). Li teaches a need for diagnosis and modeling of AD (section 1.1) and advantages of microfluidic technology in AD biomarker detection (section 1.2). Li teaches amyloid-beta (Aβ) protein is one of the most characteristic AD histopathological biomarkers and is one of the most studied biomarkers in AD detection and diagnosis (sections 2.1-2.2). Li teaches it is known for PDMS microfluidic devices to immobilize Aβ antibody to detect Aβ peptides in a sample (page 3, paragraphs 1-3). Li teaches an Aβ-specific antibody (Fig. 1B, 6E10 antibody) for immunoassay of Aβ (Fig. 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of modified Yang to incorporate Yang’s teachings of improving disease diagnosis and a need for investigation of proteins for various diseases such as neurodegenerative disorders (abstract; page 6053, section, “Introduction”) and Li’s teachings of the need for diagnosis and modeling of AD, fluidic devices to immobilize Aβ antibody to detect Aβ peptides in a sample, and an anti-Aβ antibody (i.e. 6E10 antibody) for Aβ immunoassay (Fig. 1; abstract; sections 1.1-1.2, 2.1-2.2; page 3, paragraphs 1-3) to provide: an Aβ-specific antibody (i.e. 6E10 antibody) positioned within the lower chamber of the layered well. Doing so would have a reasonable expectation of successfully improving disease diagnosis of known disease, such as AD.
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. one or more antibodies positioned within the lower chamber of the layered well and anti-Aβ antibodies for analysis of AD) by known methods with no change in their respective functions (i.e. analysis of biomarkers for diseases), and the combinations yielded nothing more than predictable results (i.e. providing one or more anti-Aβ antibodies positioned within the lower chamber of the layered well would yield nothing more than the obvious and predictable result of enabling improved analysis of various diseases, such as AD). See MPEP 2143(A).
Modified Yang fails to teach: an amyloid oligomer-specific antibody positioned within the lower chamber of the layered well.
Zhang teaches treatment and/or prevention of Alzheimer's disease and diagnostic imaging of Aβ plaque (abstract). Zhang teaches methods of imaging or visualizing Aβ plaque in brain tissue for diagnostic purposes, i.e. to determine whether Aβ plaques are present in the brain of as subject ([0047]). Zhang teaches biological assays using Aβ-specific antibody ([0093], “6E10 antibody”) and an amyloid oligomer-specific antibody ([0093], “A11 oligomer Rabbit polyclonal antibody”). Zhang teaches immunocytochemistry assays of cells using A11 rabbit antibody ([0096]). Zhang teaches in order to further confirm the inhibition of small AβOs by 14 in MC65 cells, an AβO-specific antibody A11 combined with Alexa Fluor 568 conjugated secondary antibodies was employed to detect the expression of AβOs in MC65 cells using immunocytochemistry techniques ([0058]). Zhang teaches A11 antibody is more specific to AβOs ([0058]). Zhang teaches samples were analyzed using 6E10 antibody ([0059]). Zhang teaches recently emerging evidence indicate that small, soluble oligomers (AβOs) are responsible for disruption of neuronal synaptic plasticity and the resulting early cognitive impairment associated with AD ([0004]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the antibodies positioned within the lower chamber of the layered well of modified Yang to incorporate Zhang’s teachings of AβOs as potential biomarkers resulting in AD ([0004]) and performing assays using Aβ-specific antibody ([0093], “6E antibody”) and an amyloid oligomer-specific antibody ([0093], “A11 oligomer Rabbit polyclonal antibody”), wherein A11 antibody is more specific to AβOs ([0058]) to additionally provide: an amyloid oligomer-specific antibody (i.e. A11 antibody) positioned within the lower chamber of the layered well. Doing so would have a reasonable expectation of successfully improving analysis of known biomarkers for AD, such as AβO, using a known biomarker (i.e. A11 oligomer Rabbit polyclonal antibody) that is more specific to AβO.
Regarding claim 20, note that “sample of tissue” (claim 19) and therefore “a sample of human brain tissue comprising human brain cells” (claim 20) are not positively recited structurally and is interpreted as a functional limitation of the claimed system. A claim is only limited by positively recited elements; thus, inclusion of the material or article (“sample of human brain tissue comprising human brain cells”) worked upon by a structure (apparatus) being claimed does not impart patentability to the claims (see MPEP 2115).
Note that a functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the functional limitations, then it meets the claim. See MPEP 2114. The apparatus of modified Yang is identical to the presently claimed structure. Modified Yang discloses the claimed apparatus for microdissection of cells from a sample of tissue as claimed and therefore, would have the ability to perform the use recited in the claim. See MPEP 2112.01 (I). I.e. the apparatus for microdissection of cells from a sample of tissue of modified Yang, which incorporates Liotta’s LCM, is structurally capable of microdissection of cells from a sample of human brain tissue comprising human brain cells.
Regarding claim 21, modified Yang further teaches wherein the apparatus for microdissection comprises a laser capture microdissection (LCM) apparatus (see above claim 19; Yang in combination with Liotta provides the apparatus as a LCM; Liotta, abstract).
Regarding claim 22, Yang further teaches wherein the manifold is comprised of a polymeric material comprising poly(dimethylsiloxane) (PDMS) (page 6054, section “Materials” teaches PDMS; page 6055, left column, first paragraph teaches “PDMS manifold”).
Regarding claim 24, modified Yang further teaches wherein the Aβ-specific antibody comprises an immunoglobulin G (IgG) 6E10 antibody (see above claim 19; Yang in combination with Li provides the Aβ-specific antibody as a 6E10 antibody, i.e. IgG 6E10 antibody).
Regarding claim 25, Yang further teaches wherein the matrix solution comprises either α-cyano-4- hydroxycinnamic acid or sinapinic acid suspended in a solution of acetonitrile and trifluoroacetic acid (page 6056, section “Digestion Efficiency” teaches a matrix solution of α-cyano-4- hydroxycinnamic acid in acetonitrile and trifluoroacetic acid).
Regarding claim 26, Yang further teaches wherein the mass spectrometer comprises a mass spectrometer configured for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (page 6056, section “MS analysis” teaches a MALDI-TOF instrument for MS analysis).
Regarding claim 29, modified Yang further teaches wherein the amyloid oligomer-specific antibody comprises an immunoglobulin G (IgG) A11 antibody (see above claim 19; Yang in combination with Li and Zhang provides the amyloid oligomer-specific antibody as a A11 oligomer Rabbit polyclonal antibody, i.e. IgG A11 antibody; Zhang; [0093], “A11 oligomer Rabbit polyclonal antibody”).
Response to Arguments
Applicant’s arguments, see pages 8-9, filed 08/05/2026, with respect to specification objections, claim objections, and rejections under 35 U.S.C. 112(b) have been fully considered and are persuasive. The specification objections, claim objections, and rejections under 35 U.S.C. 112(b) of 08/05/2026 have been withdrawn.
Applicant’s arguments, see pages 10-11, filed 08/05/2026, with respect to the rejections of claims 19-26 under 35 U.S.C. 103, specifically regarding amended claim 19 requiring an amyloid oligomer-specific antibody, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yang et al. (Yang et al., “Quantitative Approach for Protein Analysis in Small Cell Ensembles by an Integrated Microfluidic Chip with MALDI Mass Spectrometry”, Anal. Chem. April 5, 2021, 93, 15, 6053-6061; cited in the IDS filed 12/27/2023) in view of Liotta et al. (Liotta et al., “Laser Capture Proteomics: Spatial Tissue Molecular Profiling from the Bench to Personalized Medicine.” Dec 14, 2021. Expert Review of Proteomics 18 (10): 845–61), Li et al. (Li et al., “Microfluidics-Based Systems in Diagnosis of Alzheimer’s Disease and Biomimetic Modeling”, Micromachines (Basel). 2020 Aug 19;11(9):787), and Zhang et al. (US 20130156705 A1).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Yuyama et al. (US 20140256793 A1) teaches treatment of Alzheimer’s disease associated with Aβ protein and screening for diseases associated with Aβ ([0001]). Yuyama teaches an incubation mixture was subjected to a dot-blot assay using an anti-oligomer antibody (A11) and an anti-Aβ antibody (6E10) ([0071]). Yuyama teaches in order to investigate the effect of exosomes on the formation of oligomeric Aβ, mixtures of Aβ with or without N2a-derived exosomes were subjected to a dot blot analysis with an anti-oligomer antibody A11 ([0236]).
Buhimschi et al. (US 20110280863 A1) teaches methods and kits that relate to the diagnosis, treatment, and/or prevention of preeclampsia (abstract). Buhimschi teaches a therapeutic approaches have been used to treat Alzheimer's disease, e.g., using antibodies against the beta-amyloid protein; and applicants have found that preeclampsia is a disease associated with the accumulation of abnormal protein oligomers ([0160]). Buhimschi teaches representative clones were selected in comparison to the A11 polyclonal antibody and 6E10, a sequence dependent mouse monoclonal antibody; wherein, A11 polyclonal antibody reacts with all types of prefibrillar oligomers, but not Aβ monomer or fibrils and 6E10 recognizes only samples containing Aβ ([0277]). Buhimschi teaches A11 of the generic monoclonals recognize Aβ oligomers because they were used as the primary screen ([0281]).
Sun et al. (US 20230036181 A1; effectively filed 01/13/2020) teaches antibodies and compositions used to binding to Gal3 and cell surface markers and proteins associated with Alzheimer’s disease (abstract). Sun teaches samples were incubated in the appropriate primary antibody (6E10 and A11) ([1808]).
Wang et al. (Wang et al., “Naturally occurring autoantibodies against Aβ oligomers exhibited more beneficial effects in the treatment of mouse model of Alzheimer's disease than intravenous immunoglobulin”, Neuropharmacology 105 (2016) 561-576) teaches Alzheimer’s disease is characterized by Aβ plaque (abstract). Wang teaches brain tissue processing (section 2.11) and Aβ ELISA of brain tissue (section 2.12). Wang teaches immunohistochemical staining of the brain tissue with primary antibodies, such as 6E10 (section 2.14). Wang teaches dot blots with antibodies 6E10, A11, OC, W20, and IVIG as controls were visualized to determine the specificity of purified NAbs-Aβo (section 3.1, first paragraph). Wang teaches 6E10 recognized the monomers, oligomers, and fibrils of Aβ40 and Aβ42; and A11, an anti-prefibrillar oligomer antibody, only bound to oligomers of Aβ40 and Aβ42 (section 3.1, first paragraph).
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 HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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