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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/20/2026 has been entered.
Status of the Claims
Claims 1, 3-4, 6-12, and 14-17 are pending.
Claims 10-12 and 14-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was considered to have been made without traverse in the reply filed on 05/10/2023.
Claims 1, 3-4, and 6-9 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn. Prior objections have been addressed by amendment.
In view of Applicant’s persuasive declaration (filed 06/18/2026), the rejection of claims 1, 3-4, and 6-9 under 35 USC 112(a) for failing to comply with the enablement requirement is withdrawn. However, upon further consideration, a new ground of rejection is made under 35 USC 103 in order to address the teachings of Gonzalez-Velasquez et al. (Journal of Neurochemistry, 2008, volume 107, previously cited) in view of Kim et al. (Science Advances, published April 2019) as discussed below. Additionally, a new ground of rejection under 35 USC 101 is made as discussed below.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-4, and 6-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Applicant is directed to the subject matter eligibility test for products processes (MPEP 2106; specifically, MPEP 2106(III) flowchart).
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory category of invention (Step 1), if so, then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, Prong One), if so, then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, Prong Two), and if not, then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, claims 1, 3-4, and 6-9 are drawn to a process, “a method”, which is a statutory category (thus, Step 1, YES).
In regard to Step 2A, Prong One, this part of the eligibility analysis evaluates whether the claim recites a judicial exception.
Claim 1 recites, “A method for an early detection method of Alzheimer’s disease comprising: employing a cell-based biosensor sensing device . . . measuring transendothelial electrical resistance . . introducing at least one cerebral fluid or blood sample . . . determining if introduction of the at least one cerebral fluid or blood samples to the cell-based biosensor causes a change in the transendothelial electrical resistance, wherein a decrease in transendothelial electrical resistance is indicative of Alzheimer’s disease.”
Claim 7 recites, “The method of claim 1 further comprising measuring transendothelial transfer rate of the monolayer of brain microvascular endothelial cells.”
Steps of measuring and determining “can be performed in the human mind, or by a human using a pen and paper” (CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011)) and is therefore a mental process (a judicial exception). As discussed in MPEP 2106.04(a)(2)(III), “[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work” (Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012), quoting Benson, 409 U.S. at 67, 175 USPQ at 675)) (thus, Step 2A, Prong One, YES).
In regards to Step 2A, Prong Two, this part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception.
With respect to Step 2A, prong two, limitations that may be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Improvements to another technology or technical field.
Improvements to the functioning of the computer itself.
Applying the judicial exception with, or by use of, a particular machine.
Effecting a transformation or reduction of a particular article to a different state or thing
Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application.
Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
With respect to Step 2A, prong two, limitations that were found not to be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Adding the words ‘‘apply it’’ (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well understood, routine and conventional activities previously known to the industry
Adding insignificant extra-solution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea
Generally linking the use of the judicial exception to a particular technological environment or field of use.
In the instant claim 1, although the claims recite steps of employing a cell-based biosensor sensing device and introducing at least one cerebral fluid or blood sample from a subject to the cell-based biosensor comprising the monolayer of brain microvascular endothelial cells, these steps all built up to the final step of determining or measuring, and therefore, are all insignificant extra-solution activity and amount to mere gathering for the mental process (the judicial exception). See MPEP 2106.05(g), determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)). Therefore, the claim does not additional elements that integrate the judicial exception as a whole into a practical application (thus, Step 2A, Prong Two, NO).
In regard to Step 2B, this part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the judicial exception.
As discussed above, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception, but rather, are all mere data gathering steps for a final step of the mental process of determining or measuring.
Furthermore, the additional elements of employing a cell-based biosensor sensing device and introducing at least one cerebral fluid or blood sample from a subject to the cell-based biosensor comprising the monolayer of brain microvascular endothelial cells were all routine in the art in the art before the effective filing date.
Indeed, Applicant explicitly admits that the claimed invention of “a cell-based TEER assay employing a standard endothelial monolayer” is “A well-established, widely practiced platform in biomedical engineering and blood brain barrier research” (Remarks, 06/18/2026, p17).
Applicant also explicitly admits that “TEER measurement of endothelial monolayers is a standard, highly reproducible technique (Remarks 06/18/2026, p17, citing declaration filed 06/18/2026, paragraphs 17, 20).
Turning to the art, Gonzalez-Velasquez et al. (Journal of Neurochemistry, 2008, volume 107, previously cited), evidences a blood-brain barrier model comprising endothelial monolayers for measuring TEER when contacted with AB aggregates (Abstract, p466; Fig. 1, p469).
This model is confirmed by Qosa et al. (Biochimica et Biophysica Acta, 2014, previously cited), who evidences contacting a blood-brain barrier model comprising endothelial monolayers with AB aggregates and measuring TEER (Title, Abstract, p1806; Effects of synthetic amyloid-β mixtures on hCMEC/D3 cells monolayer integrity, p1808).
Additionally, as evidenced by Kim et al. (Science Advances, published April 2019), it was known in the art that blood samples could be taken from patients and subjected to assays for the detection of AB aggregates and diagnosis of Alzheimer’s disease (Title, Abstract, p1; Fig. 1, p2).
As further evidenced by Kaneko et al. (Proc Jpm Acad, Ser B, 2014), it was known in the art that concentrations of AB aggregates in the blood could be compared to distinguish Alzheimer’s disease patients (Abstract, p353).
As evidenced by Sierks et al. (Integr Biol (Camb), 2011), it was known in the art that CSF samples could be taken from patients and subjected to assays for the detection of AB aggregates and distinction of Alzheimer’s disease compared to normal samples (Title, Abstract, p1).
Furthermore, as evidenced by Shui et al. (Biochemie, 2018), AB in blood or CSF is a routine diagnostic marker for Alzheimer’s disease (Introduction, p14).
See also MPEP 2106.05(d), Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 67, 101 USPQ2d 1961, 1964 (2010) provides an example of additional elements that were not an inventive concept because they were merely well-understood, routine, conventional activity previously known to the industry, which were not by themselves sufficient to transform a judicial exception into a patent eligible invention. Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 79-80, 101 USPQ2d 1969 (2012) (citing Parker v. Flook, 437 U.S. 584, 590, 198 USPQ 193, 199 (1978) (the additional elements were "well known" and, thus, did not amount to a patentable application of the mathematical formula)). In Mayo, the claims at issue recited naturally occurring correlations (the relationships between the concentration in the blood of certain thiopurine metabolites and the likelihood that a drug dosage will be ineffective or induce harmful side effects) along with additional elements including telling a doctor to measure thiopurine metabolite levels in the blood using any known process. 566 U.S. at 77-79, 101 USPQ2d at 1967-68. The Court found this additional step of measuring metabolite levels to be well-understood, routine, conventional activity already engaged in by the scientific community because scientists "routinely measured metabolites as part of their investigations into the relationships between metabolite levels and efficacy and toxicity of thiopurine compounds." 566 U.S. at 79, 101 USPQ2d at 1968. Even when considered in combination with the other additional elements, the step of measuring metabolite levels did not amount to an inventive concept, and thus the claims in Mayo were not eligible. 566 U.S. at 79-80, 101 USPQ2d at 1968-69.
As a result, the additional elements individually or in combination with the judicial exception were routine in the art, and therefore, do not provide an inventive concept, and therefore, the claim as a whole does not amount to significantly more than the judicial exception (thus, Step 2B: NO).
Regarding dependent claims 3-4 and 6-9, the claims neither add additional elements that are sufficient to amount to significantly more than the judicial exception (e.g., the claims are directed to routine or conventional methods for modifying AB (claim 3); embodiments of the endothelial cells (claim 8); or describe outcomes (claim 4, “wherein no amplification . . .signifies . . .; claim 6, wherein AB aggregation . . . is detected); claim 9, wherein no change in resistance occurs) . As above, claim 7 itself is a step of measuring, which is a mental exercise.
Therefore, the claims are not considered to recite something significantly different than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez-Velasquez et al. (Journal of Neurochemistry, 2008, volume 107, previously cited) in view of Kim et al. (Science Advances, published April 2019).
In regards to claims 1 and 8, Gonzalez-Velasquez (who is noted is the same inventive entity as the Applicant) teaches methods comprising employing a blood-brain barrier model ex vivo comprising human brain microvascular endothelial monolayers for measuring transendothelial electrical resistance (TEER) in response to amyloid-β (AB) aggregates (Abstract, p466; Cell culture and treatment, p468; Permeability assay, p468-469).
Gonzalez-Velasquez teaches steps of measuring TEER in a monolayer of brain microvascular endothelial cells in response to introduction of AB aggregates (Fig. 2, p470; Fig. 4, p472).
Additionally, Gonzalez-Velasquez teaches that AB aggregate-stimulated increases in endothelial monolayer permeability occurred in a dose-dependent manner as the concentration of the unpurified AB reaction mixture was increased from 0.1 to 10 µmol/L (p470, left column; Fig. 2, p470). This is a concentration range of 0.1 µM to 10 µM which overlaps with the claimed range as being indicated as suitable for inducing an effect (it is noted that the claims do not require a sample with AB aggregate at any concentration and only describe an effect when a sample has AB aggregate at this concentration).
The difference between the method of Gonzalez-Velasquez and the instant claimed invention, is that Gonzalez-Velasquez tests prepared AB aggregates, not samples of blood or CSF, and Gonzalez-Velasquez does not detect or determine Alzheimer’s (AD) disease per se.
However, Gonzalez-Velasquez also teaches that cerebral amyloid angiopathy associated with Alzheimer’s disease, is characterized by cerebrovascular deposition of the AB, and biochemical alterations in the cerebral microvasculature, which culminate in hemorrhagic stroke, and that AB aggregates are primarily responsible for endothelial activation, suggesting that these same species may elicit other changes in the cerebrovasculature associated with cerebral amyloid angiopathy and Alzheimer’s disease (Abstract, p466). Therefore, a person of ordinary skill in the art would have recognized that the method of Gonzalez-Velasquez was at least in the context of Alzheimer’s disease.
Furthermore, methods for testing blood samples comprising AB aggregates against assays was known in the art before the effective filing date.
Specifically, Kim teaches a method of diagnosing (detecting) Alzheimer’s disease comprising taking blood samples from a patient, introducing that sample to an assay, and analyzing the results to determine the detection of AB aggregates (Title, Abstract, p1; Fig. 1, p2).
Therefore, a person of ordinary skill in the art would have been motivated to adopt the method of Gonzalez-Velasquez to detect Alzheimer’s disease specifically because cerebrovascular deposition of the AB is a known phenomenon in this disease and doing so would provide insight on reducing the risk of hemorrhagic stroke.
They would have been motivated to use a blood sample because it is a known source of AB aggregates and specifically because Kim teaches that it is less invasive and more accessible (Abstract, p1).
Furthermore, because Kim teaches that fluid samples such as blood samples can be utilized for the detection of AB in bioassays and the subsequent diagnosis of Alzheimer’s disease, and because, as above, the method of Gonzalez-Velasquez is in the context of Alzheimer’s disease, a person of ordinary skill in the art could have adapted the method of Gonzalez-Velasquez to detect and determine Alzheimer’s disease with a patient blood sample with predictable results and a reasonable expectation of success.
In regards to whether a decrease in TEER is indicative of Alzheimer’s disease, this is an inherent property of the blood-brain barrier model when contacted with a fluid sample (blood or CSF, which contains pathologic AB) from a patient with Alzheimer’s disease. It is also noted that the claim does not require that the fluid sample come from a patient with Alzheimer’s disease but only state that this is the effect when the same does come from a patient with Alzheimer’s disease.
Furthermore, as taught by Gonzalez-Velasquez TEER decreases with increased concentration of AB aggregates (Fig. 2, p470) and therefore, the blood-brain barrier model of Gonzalez-Velasquez has this same effect.
Additionally, in regards to increased permeability of the monolayer of brain endothelial cells and movement of at least one tight junction protein away from at least cell border contained in the monolayer, these too are inherent properties of the blood-brain barrier model when contacted with a fluid sample (blood or CSF, which contain pathologic AB) from a patient with Alzheimer’s disease. Again, it is also noted that the claim does not require that the fluid sample come from a patient with Alzheimer’s disease but only state that this is the effect when the same does come from a patient with Alzheimer’s disease.
Furthermore, as taught by Gonzalez-Velasquez increased permeability and changes in tight junctions are known properties of the blood-brain barrier model when exposed to AB aggregates (Abstract, p466; Fig. 2, p470; Fig. 3, p471).
In regards to claim 6, in regards to wherein AB aggregation including AB oligomerization is detected is an inherent result of AB aggregates from a fluid sample from a patient with Alzheimer’s disease. Indeed, Gonzalez-Velasquez explicitly teaches that soluble Ab aggregation intermediates, including AB-derived diffusible ligands, oligomers, and protofibrils, play a significant role in the pathology of Alzheimer’s disease (p467, left column).
In regards to claim 7, Gonzalez-Velasquez teaches that the transendothelial transfer rate (which is noted is a different measurement from transendothelial electrical resistance, or TEER as discussed above) of the monolayer of brain microvascular endothelial cells can be measured and indicates that it can be used to determine the effect of Aβ aggregation on brain microvascular endothelial cells permeability (Fig 1., p469).
In regards to claim 9, in regards to whether no change in resistance occurs when at least one AB monomer or at least one mature AB fibril is present without presence of at least one pathogenic AB aggregates is an inherent result of testing a fluid sample on the blood-brain barrier model that does not contains AB monomers or mature AB fibrils but not pathogenic AB aggregates. Additionally, as above, the claims do not require testing any specific patient fluid sample. Moreover, as taught by Gonzalez-Velasquez, subjecting the blood-brain barrier model to AB monomers does not result in a reduction of TEER (Fig. 4, p472).
Therefore, the combined teachings of Gonzalez-Velasquez and Kim renders the invention unpatentable as claimed.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez-Velasquez et al. (Journal of Neurochemistry, 2008, volume 107, previously cited) in view of Kim et al. (Science Advances, published April 2019) as applied to claim 1 above, and further in view of An et al. (Alzheimer’s Research and Therapy, 2017, previously cited).
In regards to claim 3, Gonzalez-Velasquez does not explicitly teach a step of using a synthetic monomer to amplify a concentration of at least one physiologically active AB aggregate. However, a person of ordinary skill in the art would have been motivated to do so because An teaches that fluid samples of patients with Alzheimer’s disease can be spiked with synthetic Aβ (which comprises synthetic Aβ monomers) and that this causes dynamic change in the formation of Aβ oligomers over time, and that this is useful for assays with high sensitivity and specificity for Alzheimer’s disease (Abstract, p1; Abstract, p1; Measurement of Aβ monomers (Aβ40 and Aβ42), p4). Furthermore, because An indicates that patient samples can be spiked with synthetic Aβ monomers and because Son and An are in the same technical field of developing assays for the detection of Alzheimer’s disease, it could have been done with predictable results and a reasonable expectation of success.
Additionally, in regards to whether the synthetic monomer is used to increase compromise of the monolayer of brain microvascular endothelial cells by inducing oligomer formation of active Aβ between at least one physiologically active Aβ oligomer ranging from 0.1 µM to 1 µM and the synthetic monomer present in the cerebral fluid or blood sample, is an intended use of the claim (see MPEP 2111.02) or an inherent property of the effect of using a synthetic monomer on a fluid sample comprising AB aggregates. Indeed, as above, An teaches that spiking fluid samples with synthetic AB monomers causes dynamic change in the formation of Aβ oligomers over time. Therefore, the method of Gonzalez-Velasquez as modified would also exhibit this property when synthetic AB monomers are added, absent evidence to the contrary.
In regards to claim 4, in regards to wherein no amplification or increase in the number of active AB aggregates signifies an absence of the at least one pathogenic AB aggregate, similar to as above, this is an inherent property of subjecting the blood-brain barrier model to a fluid sample lacking a pathogenic AB aggregate. It is also noted that the claims do not require testing any specific fluid sample (either containing or not containing a pathogenic AB aggregate). Moreover, as above, as taught by Gonzalez-Velasquez the blood-brain barrier model retains TEER when there is no concentration of AB aggregates in the sample (Fig. 2, p470).
Additionally, it is noted that in the Declaration under 37 CFR 1.132 filed 06/18/2026, Applicant admits that the use of synthetic AB monomers for amplification of AB aggregation is well known in the art (see paragraphs 17-20).
Therefore, the combined teachings of Gonzalez-Velasquez, Kim, and An renders the invention unpatentable as claimed.
Declaration under 37 CFR 1.132
Applicant declares that the invention is enabled for determining Alzheimer’s disease when AB aggregates are present in the claimed concentrations citing specifically Applicant’s own work, the post-filing reference Watson et al. (Tissue Barriers, 2026) (paragraphs 3-5, 7-9, citing Fig. 4, p4 of Watson).
As argued by Applicant, and as evidenced by Watson, increasing concentration of AB oligomers results in reduction in TEER (see Fig. 4, p4).
This confirms with what was previously known in the art.
As taught by Gonzalez-Velasquez as discussed above, prepared AB aggregates stimulate reductions in TEER in a dose-dependent manner as the concentration of unpurified AB reaction mixture is increased from 0.1 to 10 µmol/L (p470, left column; Fig. 2, p470). This is a concentration range of 0.1 µM to 10 µM which overlaps with the claimed range as being indicated as suitable for inducing an effect when AB aggregate is in a sample.
However, like Gonzalez-Velasquez, Watson tests prepared AB aggregates (i.e., reagent grade manufactured AB aggregates) to induce changes in TEER on blood-brain barrier models comprising monolayers of endothelial cells (see Watson, p2, “Aβ1–40 was purchased from Peptide 2.0 (Chantilly, VA). Aβ1–42 was purchased from AnaSpec (Fremont, CA)”) not samples of blood or CSF as required by the claims.
It is also specifically noted that the instant disclosure does not provide working examples for testing blood or CSF samples, but like Gonzalez-Velasquez and Watson, only tests AB aggregates (paragraph [0052], referring to Fig. 3, which is noted appears to be identical to Figs. 1a and 2b, p469-470 of Gonzalez-Velasquez).
Additionally, paragraph [0064] of the specification explicitly states, “Current work involves confirming these responses with biological samples and implementing amplification to bolster measurements of biological samples” and therefore, admits that working examples do not blood or CSF samples specifically. Therefore, the claimed embodiment of using blood or CSF samples is prophetic (see MPEP 2164.02).
However, the mount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification (see MPEP 2164.03).
Thus, if Applicant’s declaration that Watson is sufficient to demonstrate enablement of the claims, since Watson does not test blood or CSF samples, and since the instant disclosure does not test blood or CSF samples, it suggests that this feature was known in the prior art.
Indeed, as discussed above, as taught by Kim et al. (Science Advances, published April 2019) methods for diagnosing (detecting) Alzheimer’s disease comprising taking blood samples from a patient, introducing that sample to an assay, and analyzing the results to determine the detection of AB aggregates (Title, Abstract, p1; Fig. 1, p2) was known in the art.
Therefore, taken together, while Applicant’s declaration is persuasive to overcome the previous rejections under 35 USC 112(a). However, upon reconsideration, in view of Kim, a new ground of rejection under 35 USC 103 is made as discussed above.
Specifically, as discussed above, Gonzalez-Velasquez teaches the same blood-brain barrier model comprising monolayers of human endothelial cells for testing AB aggregates as claimed.
While Gonzalez-Velasquez does not specifically test blood samples for diagnosing Alzheimer’s disease, as discussed above, Kim teaches a method of diagnosing (detecting) Alzheimer’s disease comprising taking blood samples from a patient, introducing that sample to a bioassay, and analyzing the results to determine the detection of AB aggregates (Title, Abstract, p1; Fig. 1, p2).
Therefore, a person of ordinary skill in the art would have been motivated to adopt the method of Gonzalez-Velasquez to detect Alzheimer’s disease specifically because cerebrovascular deposition of the AB is a known phenomenon in this disease and doing so would provide insight on reducing the risk of hemorrhagic stroke.
They would have been motivated to use a blood sample because it is a known source of AB aggregates and specifically because Kim teaches that it is less invasive and more accessible (Abstract, p1).
Furthermore, because Kim teaches that fluid samples such as blood samples can be utilized for the detection of AB in bioassays and the subsequent diagnosis of Alzheimer’s disease, and because, as above, the method of Gonzalez-Velasquez is in the context of Alzheimer’s disease, a person of ordinary skill in the art could have adapted the method of Gonzalez-Velasquez to detect and determine Alzheimer’s disease with a patient blood sample with predictable results and a reasonable expectation of success.
Applicant declares that Fig. 7 of the specification demonstrates that AB oligomers activate the transcription factor NF-kB at concentrations as low as 50 pM and that this demonstrates that the biosensor is responsive to AB oligomers at concentrations well within the physiological range (paragraph 6).
Applicant also declares that the term physiologically active AB oligomers as used in the specification refers to oligomeric AB species that exhibit biological activity, specifically, the ability to disrupt cellular function, including reduction in TEER in endothelial monolayers (paragraphs 10-16).
Applicant declares that the use of synthetic AB monomers for amplification of AB aggregation is well known in the art (paragraphs 17-20).
Applicant’s declaration under 37 CFR 1.132 filed 06/18/2026 has been fully considered but is moot because the previous grounds of rejection under 35 USC 112(a) have been withdrawn in reconsideration of the claims.
Response to Arguments
Applicant traverses the rejection under 35 USC 112(a) citing Applicant’s declaration under 37 CFR 1.132 filed 06/18/2026 and citing Watson et al. (Tissue Barriers, 2026; Fig. 4) (Remarks, p6-19).
Applicant argues that Fig. 7 of the instant specification independently demonstrates picomolar sensitivity (Remarks, p10).
Applicant’s arguments filed 06/18/2026 have been fully considered and are persuasive. However, a new grounds of rejection is made under 35 USC 103 in order to address the teachings Kim et al. (Science Advances, published April 2019) as discussed above.
Applicant argues that citation of paragraph [0064] of the specification which states, “Current work involves confirming these responses with biological samples and implementing amplification to bolster measurements of biological samples” as an admission that the invention was not fully enabled as of the filing date is misplaced (Remarks, p10-11).
Specifically, Applicant argues that statements in a specification describing ongoing or future confirmatory work are not admissions of non-enablement (citing Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (fed. Cir. 1997); MPEP 2164.07; Remarks, p10-11).
Applicant also argues that the relevant inquiry is whether a skilled artisan could practice the claimed invention without undue experimentation as of the filing date, not whether all confirmatory studies had been completed (citing In re Wands, 858 F.2d at 737; Remarks, p10-11).
Finally, Applicant argues that most importantly, paragraph [0064] in context describes extending the TEER-based biosensor platform to direct patient sampling, which is precisely what Watson 2026 now confirms is operable at picomolar concentrations (Remarks, p10-11). Therefore, Applicant concludes that the statement in paragraph [0064] reflects normal scientific diligence, not a concession of non-operability (Remarks, p11).
Applicant’s arguments filed 06/18/2026 have been fully considered but are moot because the rejection of the clams under 35 USC 112(a) has been withdrawn as discussed above. Instead, a new grounds of rejection is made under 35 USC 103 in order to address the teachings Kim et al. (Science Advances, published April 2019) as discussed above.
However, in regards to Applicant’s arguments in regards to the evidence in Watson specifically, it is noted that Watson does not extent the TEER-based biosensor platform to direct patient sampling as argued by Applicant. Instead, as discussed above, the sample of Watson are specifically manufactured (see Watson, p2, “Aβ1–40 was purchased from Peptide 2.0 (Chantilly, VA). Aβ1–42 was purchased from AnaSpec (Fremont, CA)”), not samples of blood or CSF as required by the claims or as asserted by Applicant.
In regards to the statement in paragraph [0064] of the specification, that “Current work involves confirming these responses with biological samples and implementing amplification to bolster measurements of biological samples”, this is therefore an admission that working examples do not blood or CSF samples specifically. Therefore, the claimed embodiment of using blood or CSF samples is prophetic (see MPEP 2164.02).
However, the mount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification (see MPEP 2164.03).
Thus, because the disclosure does not provide working examples of testing the method with blood or CSF, in order to be enabled, the use of blood or CSF must have been known in the prior art before the effective filing date.
However, as discussed above, as taught by Kim et al. (Science Advances, published April 2019) methods for diagnosing (detecting) Alzheimer’s disease comprising taking blood samples from a patient, introducing that sample to an assay, and analyzing the results to determine the detection of AB aggregates (Title, Abstract, p1; Fig. 1, p2) was known in the art.
Therefore, it is determined that there is predictability in regards to this embodiment, and as a result the rejection under 35 USC 112(a) has been withdrawn as discussed above.
However, upon further consideration, in view of the teachings of Kim et al. (Science Advances, published April 2019) a new ground of rejection is made under 35 USC 103 as discussed above.
Specifically, as discussed above, Gonzalez-Velasquez teaches the same blood-brain barrier model comprising monolayers of human endothelial cells for testing AB aggregates as claimed.
While Gonzalez-Velasquez does not specifically test blood samples for diagnosing Alzheimer’s disease, as discussed above, Kim teaches a method of diagnosing (detecting) Alzheimer’s disease comprising taking blood samples from a patient, introducing that sample to a bioassay, and analyzing the results to determine the detection of AB aggregates (Title, Abstract, p1; Fig. 1, p2).
Therefore, a person of ordinary skill in the art would have been motivated to adopt the method of Gonzalez-Velasquez to detect Alzheimer’s disease specifically because cerebrovascular deposition of the AB is a known phenomenon in this disease and doing so would provide insight on reducing the risk of hemorrhagic stroke.
They would have been motivated to use a blood sample because it is a known source of AB aggregates and specifically because Kim teaches that it is less invasive and more accessible (Abstract, p1).
Furthermore, because Kim teaches that fluid samples such as blood samples can be utilized for the detection of AB in bioassays and the subsequent diagnosis of Alzheimer’s disease, and because, as above, the method of Gonzalez-Velasquez is in the context of Alzheimer’s disease, a person of ordinary skill in the art could have adapted the method of Gonzalez-Velasquez to detect and determine Alzheimer’s disease with a patient blood sample with predictable results and a reasonable expectation of success.
Additionally, Applicant argues that baseline TEER drift does not support an enablement rejection (Remarks, p11-12); that physiologically active AB oligomers and pathogenic AB aggregates are co-extensive (Remarks, p13-14); that synthetic monomer amplification is fully enabled and a well-established principle in the art (Remarks, p14-15); and that a comprehensive Wands factor analysis confirms that there is no undue experimentation (Remarks, p16-17).
Applicant’s arguments filed 06/18/2026 have been fully considered but are moot because the rejection of the clams under 35 USC 112(a) has been withdrawn as discussed above. Instead, a new grounds of rejection is made under 35 USC 103 in order to address the teachings Kim et al. (Science Advances, published April 2019) as discussed above.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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