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 .
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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/23/2025 has been entered.
Withdrawn Rejections
The rejection of the claims under 112a is withdrawn in response to the amendments.
Priority
Claims 1, 4-6 and 8 fail to receive foreign priority benefit to application KR10-2019-0025702 filed on 3/6/2019 and to application No. KR10-2020-0027910 filed on 3/5/2020 because the limitation of “a silica particle as a base particle” is not disclosed. Claims 1, 4-6 and 8 have an effective filing date of 03/06/2020, which is the filing date of PCT/KR2020/003145.
Status of the Claims
Claims 1, 4-6 and 8 are pending; claim 1 is amended, claims 2-3, 7 and 9 are canceled; no claims are withdrawn. Claims 1, 4-6 and 8 are examined below.
Claim Interpretation
The term “gaps disposed on the outer surface” as recited in claim 1, is interpreted as the nanogaps illustrated in Figure 1 a) and 2 b) of Yang et al. Small 08 April 2019 https://doi.org/10.1002/smll.201900613 (Cite No. 7 of IDS 9/7/2021). Note that the declaration of inventor, Jong Ho Kim, filed under 37 C.F.R. 1.130(a) (3/4/2025) establishes that the Yang et al. reference originates from the inventors of the instant case. As per Figure 1 a) and 2 b) of Yang et al., the “gaps disposed on the outer surface” are the space between protrusions of silver formed in the surface of the particle.
New Rejections
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 5 and 8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
Independent claim 5 recites “[a] method for diagnosing Alzheimer's disease, comprising:…biological sample…(5) a step of diagnosing as Alzheimer's disease when the ratio of Aβ40 and Aβ42 is from 2.5 to 999”.
The natural relationship to which the claims are directed (i.e., the relation between Aβ40 and Aβ42 levels and Alzheimer's disease) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of Aβ40 and Aβ42 in a biological sample and the presence of Alzheimer's disease.
The correlation between Aβ40 and Aβ42 levels and disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that Aβ40 and Aβ42 levels are elevated to different extents in Alzheimer's disease compared with other disorders.
Additionally, the claims also recite “(4) a step of calculating the ratio of Aβ40 and Aβ42 by measuring a Raman signal of the complex in the sample”. The claimed step of “calculating the ratio” may also be categorized as abstract ideas, namely mathematical calculations. The claims, under their broadest reasonable interpretation, cover performance of calculating the ratio solely within the human mind, or by a human using pen and paper.
Furthermore, claim 8 merely narrows the biological sample used in the judicial exceptions. Therefore, claim 8 is also directed to at least one judicial exception.
Step 2A, Prong 2
The claims also recite “(1) a step of preparing AgNGS-Aβ40 by conjugating an antibody specific for amyloid beta (Aβ) 40 on the surface of the silver nanogap shell (AgNGS) of claim 1; (2) a step of preparing AgNGS-Aβ42 by conjugating an antibody specific for Aβ42 on the surface of AgNGS; (3) a step of inducing the formation of a silver nanogap shell (AgNGS)-based sandwich complex by mixing the AgNGS-Aβ40 and the AgNGS-Aβ42 with a biological sample in vitro”. However, such steps of preparing and mixing the reagents are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015).
Similarly, the claims recite the additional element of the “silver nanogap shell (AgNGS) of claim 1”. However, the purpose of the silver nanogap shell of claim 1 is merely to gather data in order to make the calculation and diagnosis. Therefore, the additional elements of the claims fail to integrate the judicial exceptions into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Although the claims recite antibodies that specifically bind to Aβ40 and Aβ42, no particular or specific antibody is set forth. Furthermore, in this case, it was well-understood, routine and conventional to use the AgNGS of claim 1 for detection.
For example, Kim et al. (KR 101944346 B1)-Cite No. e of IDS 9/7/2021(“Kim”) teaches a composition comprising a silver nanogap shell, wherein the silver nanogap shell comprises: a silica particle as a base particle; and a silver (Ag)-containing metal layer (Abstract, page 7 para. 4) comprising: an inner surface completely surrounding and in contact with the silica particle; and an outer surface with a plurality of gaps disposed on the outer surface, and wherein a Raman label is inserted into the plurality of gaps (page 9 last paragraph and page 10 paragraph 1) to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml (page 7 para. 2).
Also, Kim et al. (US 11287385 B2) (“Lee”) teaches the composition comprising a silver nanogap shell, wherein the silver nanogap shell comprises: a silica particle as a base particle; and a silver (Ag)-containing metal layer (claims 1 and 4) comprising: an inner surface completely surrounding and in contact with the silica particle; and an outer surface with a plurality of gaps disposed on the outer surface, and wherein a Raman label is inserted into the plurality of gaps (claims 1 and 3) to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml.
See also Long et al. (CN 105562714 A) (“Long”). Long also teaches a AgNGS for sensitive SERS detection of analytes (“The invention claims a nanometre material for SERS detection and preparation method thereof, wherein the nano-material outside the shell of core composed of an inner core and a coating, the kernel whose grain diameter is 300 ~ 450 nanometer porous silicon dioxide particles. the shell is composed of particle diameter is 5 ~ 80 nanometer silver nanoparticle aggregate is formed; the preparation method comprises the following steps: preparing porous silicon dioxide particles and preparing porous silicon dioxide-silver shell nano-material, it is obtained by preparing kernel of the nanometer material whose grain diameter is 300 ~ 450 nanometer porous silicon dioxide particles. the abundant micro-micro-hole silicon dioxide particle surface can load more Raman label molecules, so under the action of the external laser, the Raman marker molecules in the outer layer of the silver nanoparticles produced by the local surface electromagnetic field for generating a very high intensity of the SERS signal is output such that the nanometre material has higher SERS activity, so as to greatly improve the SERS detection capability” Abstract).
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017).
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in steps (1)-(3) of claim 5 that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
New Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 4-6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (KR 101944346 B1)-Cite No. e of IDS 9/7/2021 in view of Hu et al. Sensors and Actuators B 234 (2016) 63–69 http://dx.doi.org/10.1016/j.snb.2016.04.159 and Chiu et al. Current Alzheimer Research Volume 9, Issue 10, pages 1142-1148, Published 2012 (Cite No. U of PTO 892 9/6/2024) as evidenced by Yang et al. Small 08 April 2019 https://doi.org/10.1002/smll.201900613 (Cite No. 7 of IDS 9/7/2021).
The Kim reference is also being cited on a PTO 892 form and a copy is being provided because the copy provided by Applicant is in a foreign language.
Regrading claims 1 and 6, Kim suggests a composition for diagnosing Alzheimer's disease and for differentially diagnosing Alzheimer’s disease and mild cognitive impairment, comprising a silver nanogap shell, wherein the silver nanogap shell comprises: a silica particle as a base particle; and a silver (Ag)-containing metal layer (“[a] composite particle is provided. The composite particle comprises: a base particle; a metal layer surrounding the base particle and having a surface on which a plurality of gaps are formed; and a marker provided on the metal layer, and provided in the gaps of the metal layer” Abstract, “composite particle was prepared by the method according to Example 1 described above, in which a silver layer was formed on silica particles, and then a Raman label was formed on the silver layer” page 7 para. 4). Note that “for diagnosing Alzheimer's disease” and “for differentially diagnosing Alzheimer’s disease and mild cognitive impairment” are drawn to the intended use of the claimed composition. Therefore, these are not considered limiting the composition. Kim further suggests comprising: an inner surface completely surrounding and in contact with the silica particle; and an outer surface with a plurality of gaps disposed on the outer surface, and wherein a Raman label is inserted into the plurality of gaps (“according to Example 1, the Raman markers are provided in a plurality of gaps formed on the surface of the silver layer so that the Raman markers are stably bonded to the silver layer” page 9 last paragraph and page 10 paragraph 1, see Figure 3 and showing that the “120: Marker” (page 10) is disposed in the gaps) to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml (“In SERS, the presence or absence of gaps can enhance the Raman signal, and in particular, when the width of the gap is 2 nm, the SERS enhancement effect can be remarkably improved” page 7 para. 2). Note that although Kim fails to use the language “to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml”, the teaching of an outer surface with a plurality of gaps disposed on the outer surface, and wherein a Raman label is inserted into the plurality of gaps inherently provides the detection with a sensitivity of below 1 pg/ml as evidenced by Yang et al. Small 08 April 2019 https://doi.org/10.1002/smll.201900613 (Cite No. 7 of IDS 9/7/2021). Yang teaches the “Ag nanogap shells (AgNGSs)” for “surface-enhanced Raman scattering (SERS)” (Abstract). Yang further teaches that “[t]he AgNGSs embedded with the Raman label chemicals emit their unique SERS signals with a huge intensity enhancement of up to 107 and long-term stability… Detection is possible for amounts as low as 0.25 pg mL−1” (Abstract). Although Yang does rely on antibodies (“[t]he AgNGS nanoprobes, conjugated with an antibody specific to Aβ40 or Aβ42, are able to detect these AD biomarkers in a multiplexed manner inhuman serum based on the AgNGS SERS signals” Abstract), these appear to be used for the capturing of the analyte only and fail to provide the detection sensitivity claimed. Yang suggests that the detection with a sensitivity of below 1 pg/ml is enabled by the Ag nanogap shells (“The LOD of the AgNGS nanoprobes for Aβ40 and Aβ42 was calculated to be 0.25 and 0.33 pg mL−1, respectively (Figure S9, Supporting Information), which is one order of magnitude lower than that of ELISA (Table S3, Sup-porting Information). Besides, the AgNGS nanoprobes-based assay has a dynamic range for Aβ detection two orders of magnitude wider than ELISA. As compared with previous SERS-based methods for Aβ detection,[36–38] the AgNGS nanoprobes also show superior sensing performance in terms of LOD, a dynamic range, and multiplex detection capability” (page 9 col. 1 para. 1). Given that Yang specifically teaches that “[t]he AgNGSs embedded with the Raman label chemicals emit their unique SERS signals with a huge intensity enhancement of up to 107 and long-term stability… Detection is possible for amounts as low as 0.25 pg mL−1” (Abstract), and that the limit of detection was “one order of magnitude lower than that of ELISA” suggests that the sensitivity of below 1 pg/ml is enabled by the Ag nanogap shells, not the antibodies. Therefore Kim teaches “to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml” by inherency as evidenced by Yang. Kim further teaches that “[t]hese new materials are now expanding into high technology areas such as…Biotechnology” (page 2 para. 3).
Kim fails to teach comprising one or more antibody selected from the group consisting of an antibody specific for amyloid beta (Aβ)40 and antibody specific for Aβ42 introduced as an active ingredient, and the one or more antibody is introduced on the surface of the metal layer.
Hu teaches “a colorimetric immunosensor using antibody modified-silver nanoparticles (AgNPs) for the specific detection of Aβ(1–40/1–42), which is now can be viewed as a predictor for preclinical diagnosis of Alzheimer’s disease” (Abstract). Hu teaches a composition for diagnosing Alzheimer's disease with an antibody specific for amyloid beta as an active ingredient, comprising a particle and a silver (Ag)-containing metal surface and the antibody introduced on the surface of the metal (see Scheme 1 showing the antibodies introduced on the surface of the silver nanoparticle, page 64). Hu further teaches that “Alzheimer’s disease (AD) is the most common cause of dementia, associated with progressive loss of cognitive function and behavioral abilities in the elderly population. β-Amyloid (Aβ), which mainly composes of Aβ1–40 and A β1–42 species…is prone to assembling into soluble oligomers that have been proposed to be the culprit of cognitive decline in AD…years or decades before the onset of AD” (page 63 col. 1 para. 1).
Chiu teaches a composition for diagnosing Alzheimer’s disease and for differentially diagnosing Alzheimer's disease and mild cognitive impairment (“New Assay for Old Markers-Plasma Beta Amyloid of Mild Cognitive Impairment and Alzheimer's Disease” Title, see Table 1 and Figure 1, “immunomagnetic reduction assay (IMR) to determine the plasma levels of Aβ… plasma Aβ1-42 is a useful biomarker for AD. The Aβ1-42/Aβ1-40 ratio improves the diagnostic power of the plasma Aβ biomarkers” Abstract, “Our study showed that the Aβ1-42/Aβ1-40 ratio can be used to differentiate between control, MCI, and AD subjects” page 1146 col. 2 para. 1) comprising a particle with one or more antibody selected from the group consisting of an antibody specific for amyloid beta (Aβ) 40 and antibody specific for Aβ42 introduced as an active ingredient (“bind the antibodies (anti-Aβ1-40 (sc53822, Santa Cruz Biotech) and anti-Aβl-42 (437900, Invitrogen)) to the dextran of the magnetic nanoparticles” page 1144 col. 2 para. 2). Chiu further suggests that differentially diagnosing AD and mild cognitive decline enables clinical staging of the disease (“Furthermore, the Aβ1-42/Aβ1-40 ratio can improve the diagnosis because we can formulate useful cut-off values to differentiate between control, MCI and AD subjects. This ratio is significant in clinical staging and APOE ɛ4 load. Higher Aβ1-42/Aβ1-40 ratios were found in patients with higher clinical staging and in those carrying the APOE ɛ4 allele” page 1147 col. 1 last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Kim to include an antibody specific for amyloid beta as an active ingredient introduced on the surface of the silver taught by Hu because Hu teaches that amyloid beta is "the culprit of cognitive decline in AD…years or decades before the onset of AD" (Abstract) and teaches that "Alzheimer’s disease (AD) is the most common cause of dementia…in the elderly" (Abstract). Therefore, one would have been motivated to make such a modification in order to diagnose AD early in the elderly population, which as suggested by Hu, is a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because Kim and Hu are both drawn to particles comprising a surface made of silver for biotechnology applications.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Kim in view of Hu to rely on the antibody being one or more antibody selected from the group consisting of an antibody specific for amyloid beta (Aβ) 40 and antibody specific for Aβ42 taught by Chiu because Chiu teaches that Aβ1-42 is a useful biomarker of AD and Aβ1-42/Aβ1-40 ratio improves the diagnostic power, and Kim in view of Hu is concerned with diagnosing AD, which is a current need in the field. Also, Chiu suggests that differentiating between AD and MCI is useful for clinical staging of the disease. Therefore, a person having ordinary skill in the art would have found it obvious to use antibodies specific for Aβ40 and Aβ42 and differentially diagnose AD and MCI, namely because relying on these specific antibodies improves the diagnostic power and differentially diagnosing is useful in staging the disease, a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success given that both Kim in view of Hu and Chiu are drawn to compositions comprising particles for diagnosing Alzheimer’s disease.
Regarding claim 4, Kim in view of Hu and Chiu teach the composition for diagnosing Alzheimer's disease according to claim 1 as discussed above.
Hu further suggest wherein the one or more antibody forms a silver nanogap shell (AgNGS)-based sandwich complex by mixing with one or more noninvasive biological sample selected from the group consisting of blood and serum (see Scheme 1 showing the sandwich complex page 64, “serum samples” page 65 col. 2 para. 2, “to quantitatively detect Aβ(1–40/1–42) in real blood samples” page 67 col. 2 para. 3 of Hu).
Chiu further teaches that “[a] lumbar puncture to collect CSF is an invasive treatment
with potential side effects… a blood sample is considered the gold standard and is easily obtained in clinical settings” (page 1142 col. 2 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Kim in view of Hu and Chiu to rely on the wherein the one or more antibody forms a silver nanogap shell (AgNGS)-based sandwich complex by mixing with one or more noninvasive biological sample selected from the group consisting of blood and serum taught by Hu because Chiu teaches that blood is the gold standard sample type in the context of diagnostic assays, and is safer and easier to get than CSF. A person having ordinary skill in the art would have had a reasonable expectation of success given that Kim, Hu and Chiu all teach particles for biotechnological applications.
Regarding claims 5 and 8, Kim in view of Hu and Chiu teach the composition for diagnosing Alzheimer's disease according to claim 1 as discussed above.
Kim in view of Hu and Chiu further suggest a method for diagnosing Alzheimer's disease (Abstract of Chiu), comprising: (1) a step of preparing AgNGS-Aβ40 by conjugating an antibody specific for amyloid beta (Aβ) 40 on the surface of the silver nanogap shell (AgNGS) of claim 1 (page 1144 col. 2 para. 2 of Chiu); (2) a step of preparing AgNGS-Aβ42 by conjugating an antibody specific for Aβ42 on the surface of AgNGS (page 1144 col. 2 para. 2 of Chiu); (3) a step of inducing the formation of a silver nanogap shell (AgNGS)-based sandwich complex by mixing the AgNGS-Aβ40 and the AgNGS-Aβ42 with a biological sample in vitro (Scheme 1 and page 67 col. 2 para. 3 of Hu), wherein the biological sample is one or more noninvasive sample selected from the group consisting of blood and serum (“serum samples” page 65 col. 2 para. 2 of Hu, “to quantitatively detect Aβ(1–40/1–42) in real blood samples” page 67 col. 2 para. 3 of Hu).
Hu further suggests (4) a step of calculating the ratio of Aβ40 and Aβ42 by measuring a signal of the complex in the sample (“an increasing number of investigators suggest that both the ratio of Aβ1–40 to Aβ1–42 and the total amount of the two types can be regarded as better predictors than single indicator” page 63 col. 2 para. 1).
Chiu further teaches (5) a step of diagnosing as Alzheimer's disease when the ratio of Aβ40 and Aβ42 is from 2.5 to 999 (“We also obtained a cut-off value of 0.303 for Aβ1-42/Aβl-40 ratios with 85.3% sensitivity and 96.2% specificity” Abstract see Table 1 last row and Fig. 1C). Although Chiu fails to explicitly teach the ratio of Aβ40 to Aβ42, a person having ordinary skill in the art would have recognized that the ratios presented by Chiu are equivalent and within the range of the ratios claimed in the instant application. Chiu teaches in the Abstract a cutoff ratio of 0.303. Therefore, the equivalent Aβ40 to Aβ42 ratio of 0.303 is 0.303-1 = 3.3, which is from 2.5 to 999. Chiu further teaches that “[t]he Aβ1-42/Aβ1-40 ratio improves the diagnostic
power of the plasma Aβ biomarkers” (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Kim in view of Hu and Chiu to rely on the calculating the ratio of Aβ40 and Aβ42 taught by Hu using a Raman signal of the complex in the sample because Hu suggests that the ratio is a useful parameter in the diagnosis of AD, which is the most common cause of dementia in the elderly population. A person having ordinary skill in the art would have had a reasonable expectation of success because Hu suggests that the ratio of Aβ40 and Aβ42 is well known in the field.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Kim in view of Hu and Chiu to rely on the a step of diagnosing as Alzheimer's disease when the ratio of Aβ40 and Aβ42 is from 2.5 to 999 taught by Chiu because Chiu suggests that this is an effective way of diagnosing AD and the ratio improves the diagnostic power. A person having ordinary skill in the art would have had a reasonable expectation of success because Hu suggests that the ratio of Aβ40 and Aβ42 is well known in the field.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 4-6 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. US 11287385 B2 in view of Hu and Chiu as evidenced by Yang.
Regarding claims 1 and 6, U.S. Patent No. US 11287385 B2 recites a composition for diagnosing Alzheimer's disease and for differentially diagnosing Alzheimer’s disease and mild cognitive impairment, comprising a silver nanogap shell, wherein the silver nanogap shell comprises: a silica particle as a base particle; and a silver (Ag)-containing metal layer (“ A composite particle comprising: a base particle; a metal layer enclosing the base particle and having a surface on which a plurality of gaps are formed” claim 1, “ wherein the base particle comprises a silica particle” claim 4). Note that “for diagnosing Alzheimer's disease” and “for differentially diagnosing Alzheimer’s disease and mild cognitive impairment” are drawn to the intended use of the claimed composition. Therefore, these are not considered limiting the composition. U.S. Patent No. US 11287385 B2 further recites comprising: an inner surface completely surrounding and in contact with the silica particle; and an outer surface with a plurality of gaps disposed on the outer surface, and wherein a Raman label is inserted into the plurality of gaps (“wherein the surface of the metal layer has a plurality of convex portions, wherein the gaps are located between the convex portions of the metal layer, and wherein the gaps have sidewall surfaces and a bottom surface; and a marker provided on the metal layer and provided within the plurality of gaps of the metal layer, wherein the marker is provided on the bottom surface of the gaps; wherein the metal layer and the marker are formed from a Ag thiolate polymer provided on a surface of the base particle” claim 1, “wherein the marker comprises a Raman marker” claim 3) to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml. Note that although U.S. Patent No. US 11287385 B2 fails to use the language “to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml”, the teaching of the silver nanogap shell with Raman labels inserted into the gaps inherently provides the detection with a sensitivity of below 1 pg/ml as evidenced by Yang et al. Small 08 April 2019 https://doi.org/10.1002/smll.201900613 (Cite No. 7 of IDS 9/7/2021). Yang teaches the “Ag nanogap shells (AgNGSs)” for “surface-enhanced Raman scattering (SERS)” (Abstract). Yang further teaches that “[t]he AgNGSs embedded with the Raman label chemicals emit their unique SERS signals with a huge intensity enhancement of up to 107 and long-term stability… Detection is possible for amounts as low as 0.25 pg mL−1” (Abstract). Although Yang does rely on antibodies (Abstract), these appear to be used for the capturing of the analyte only and fail to provide the detection sensitivity claimed. Yang suggests that the detection with a sensitivity of below 1 pg/ml is enabled by the Ag nanogap shells (page 9 col. 1 para. 1). Therefore U.S. Patent No. US 11287385 B2 teaches “to enable surface-enhanced Raman scattering (SERS) detection with a sensitivity of below 1 pg/ml” by inherency as evidenced by Yang.
U.S. Patent No. US 11287385 B2 fails to recite comprising one or more antibody selected from the group consisting of an antibody specific for amyloid beta (Aβ)40 and antibody specific for Aβ42 introduced as an active ingredient, and the one or more antibody is introduced on the surface of the metal layer.
Hu teaches “a colorimetric immunosensor using antibody modified-silver nanoparticles (AgNPs) for the specific detection of Aβ(1–40/1–42), which is now can be viewed as a predictor for preclinical diagnosis of Alzheimer’s disease” (Abstract). Hu teaches a composition for diagnosing Alzheimer's disease with an antibody specific for amyloid beta as an active ingredient, comprising a particle and a silver (Ag)-containing metal surface and the antibody introduced on the surface of the metal (page 64). Hu further teaches that “Alzheimer’s disease (AD) is the most common cause of dementia, associated with progressive loss of cognitive function and behavioral abilities in the elderly population. β-Amyloid (Aβ), which mainly composes of Aβ1–40 and A β1–42 species…is prone to assembling into soluble oligomers that have been proposed to be the culprit of cognitive decline in AD…years or decades before the onset of AD” (page 63 col. 1 para. 1).
Chiu teaches a composition for diagnosing Alzheimer’s disease and for differentially diagnosing Alzheimer's disease and mild cognitive impairment (Title, Table 1 and Figure 1, Abstract, page 1146 col. 2 para. 1) comprising a particle with one or more antibody selected from the group consisting of an antibody specific for amyloid beta (Aβ) 40 and antibody specific for Aβ42 introduced as an active ingredient (page 1144 col. 2 para. 2). Chiu further suggests that differentially diagnosing AD and mild cognitive decline enables clinical staging of the disease (page 1147 col. 1 last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 11287385 B2 to include an antibody specific for amyloid beta as an active ingredient introduced on the surface of the silver taught by Hu because Hu teaches that amyloid beta is "the culprit of cognitive decline in AD…years or decades before the onset of AD" (Abstract) and teaches that "Alzheimer’s disease (AD) is the most common cause of dementia…in the elderly" (Abstract). Therefore, one would have been motivated to make such a modification in order to diagnose AD early in the elderly population, which as suggested by Hu, is a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because U.S. Patent No. US 11287385 B2 and Hu are both drawn to particles comprising a surface made of silver.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 11287385 B2 in view of Hu to rely on the antibody being one or more antibody selected from the group consisting of an antibody specific for amyloid beta (Aβ) 40 and antibody specific for Aβ42 taught by Chiu because Chiu teaches that Aβ1-42 is a useful biomarker of AD and Aβ1-42/Aβ1-40 ratio improves the diagnostic power, and U.S. Patent No. US 11287385 B2 in view of Hu is concerned with diagnosing AD, which is a current need in the field. Also, Chiu suggests that differentiating between AD and MCI is useful for clinical staging of the disease. Therefore, a person having ordinary skill in the art would have found it obvious to use antibodies specific for Aβ40 and Aβ42 and differentially diagnose AD and MCI, namely because relying on these specific antibodies improves the diagnostic power and differentially diagnosing is useful in staging the disease, a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success given that both U.S. Patent No. US 11287385 B2 in view of Hu and Chiu are drawn to compositions comprising particles for diagnosing Alzheimer’s disease.
Regarding claim 4, U.S. Patent No. US 11287385 B2 in view of Hu and Chiu address the composition for diagnosing Alzheimer's disease according to claim 1 as discussed above.
Hu further suggest wherein the one or more antibody forms a silver nanogap shell (AgNGS)-based sandwich complex by mixing with one or more noninvasive biological sample selected from the group consisting of blood and serum (Scheme 1 page 64, page 65 col. 2 para. 2, page 67 col. 2 para. 3).
Chiu further teaches that “[a] lumbar puncture to collect CSF is an invasive treatment
with potential side effects… a blood sample is considered the gold standard and is easily obtained in clinical settings” (page 1142 col. 2 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 11287385 B2 in view of Hu and Chiu to rely on the wherein the one or more antibody forms a silver nanogap shell (AgNGS)-based sandwich complex by mixing with one or more noninvasive biological sample selected from the group consisting of blood and serum taught by Hu because Chiu teaches that blood is the gold standard sample type in the context of diagnostic assays, and is safer and easier to get than CSF. A person having ordinary skill in the art would have had a reasonable expectation of success given that U.S. Patent No. US 11287385 B2, Hu and Chiu all teach particles.
Regarding claims 5 and 8, U.S. Patent No. US 11287385 B2 in view of Hu and Chiu teach the composition for diagnosing Alzheimer's disease according to claim 1 as discussed above.
U.S. Patent No. US 11287385 B2 in view of Hu and Chiu further suggest a method for diagnosing Alzheimer's disease (Abstract of Chiu), comprising: (1) a step of preparing AgNGS-Aβ40 by conjugating an antibody specific for amyloid beta (Aβ) 40 on the surface of the silver nanogap shell (AgNGS) of claim 1 (page 1144 col. 2 para. 2 of Chiu); (2) a step of preparing AgNGS-Aβ42 by conjugating an antibody specific for Aβ42 on the surface of AgNGS (page 1144 col. 2 para. 2 of Chiu); (3) a step of inducing the formation of a silver nanogap shell (AgNGS)-based sandwich complex by mixing the AgNGS-Aβ40 and the AgNGS-Aβ42 with a biological sample in vitro (Scheme 1 and page 67 col. 2 para. 3 of Hu), wherein the biological sample is one or more noninvasive sample selected from the group consisting of blood and serum (page 65 col. 2 para. 2 of Hu, page 67 col. 2 para. 3 of Hu).
Hu further suggests (4) a step of calculating the ratio of Aβ40 and Aβ42 by measuring a signal of the complex in the sample (page 63 col. 2 para. 1).
Chiu further teaches (5) a step of diagnosing as Alzheimer's disease when the ratio of Aβ40 and Aβ42 is from 2.5 to 999 (Abstract see Table 1 last row and Fig. 1C). Although Chiu fails to explicitly teach the ratio of Aβ40 to Aβ42, a person having ordinary skill in the art would have recognized that the ratios presented by Chiu are equivalent and within the range of the ratios claimed in the instant application. Chiu teaches in the Abstract a cutoff ratio of 0.303. Therefore, the equivalent Aβ40 to Aβ42 ratio of 0.303 is 0.303-1 = 3.3, which is from 2.5 to 999. Chiu further teaches that “[t]he Aβ1-42/Aβ1-40 ratio improves the diagnostic
power of the plasma Aβ biomarkers” (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 11287385 B2 in view of Hu and Chiu to rely on the calculating the ratio of Aβ40 and Aβ42 taught by Hu using a Raman signal of the complex in the sample because Hu suggests that the ratio is a useful parameter in the diagnosis of AD, which is the most common cause of dementia in the elderly population. A person having ordinary skill in the art would have had a reasonable expectation of success because Hu suggests that the ratio of Aβ40 and Aβ42 is well known in the field.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 11287385 B2 in view of Hu and Chiu to rely on the a step of diagnosing as Alzheimer's disease when the ratio of Aβ40 and Aβ42 is from 2.5 to 999 taught by Chiu because Chiu teaches that this is an effective way of diagnosing AD and that the ratio improves the diagnostic power. A person having ordinary skill in the art would have had a reasonable expectation of success because Hu suggests that the ratio of Aβ40 and Aβ42 is well known in the field.
Response to Arguments
Applicant's arguments filed 9/23/2025 have been fully considered but they are not persuasive.
Regarding Priority, Applicant argues that “Applicant has amended claim 1 to recite, in part, "a silica particle as a base particle" and "a silver (Ag)-containing metal layer comprising: an inner surface completely surrounding and in contact with the silica particle; and an outer surface with a plurality of gaps disposed on the outer surface." Applicant respectfully submits that the above amendments are sufficiently supported from the disclosure of KR10-2019-0025702 filed on 3/6/2019 and to application No. KR10-2020-0027910 filed on 3/5/2020” (page 4 last two paragraphs). However, the claims still fail to receive foreign priority benefit to application KR10-2019-0025702 filed on 3/6/2019 and to application No. KR10-2020-0027910 filed on 3/5/2020 because the limitation of “a silica particle as a base particle” is not disclosed (see Priority section above).
Regarding the 103 rejections, Applicant argues that “one of ordinary skill in the art would plainly understand that You is completely silent on "a silica particle as a base particle; and a silver (Ag)-containing metal layer comprising: an inner surface completely surrounding and in contact with the silica particle; and an outer surface with a plurality of gaps disposed on the outer surface," as recited in claim 1, and Chiu, Halas, and Jiang fail to cure the deficiencies of You. Therefore, the suggested combination of You, Chiu, Halas, and Jiang fails to disclose or suggest every claim feature…Applicant respectfully submits that there was no motivation or suggestion in Halas to modify the star-shaped metal core of You into a spherical silica core” (page 8 para 1, page 10 para. 1). However, You, Halas and Jiang are no longer relied upon in the rejection of the claims under 103. New rejection relies on Kim as the primary reference in view of Hu and Chiu. Kim does address the new limitations (see rejection above). Applicant further argues that “the claimed invention enables the detection of Aβ40 and Aβ42 with "very high sensitivity of below 1 pg/ml." This addresses the critical limitations of conventional SERS-based diagnostic methods, which are often "limited to detection of a single target" and exhibit "very low sensitivity". Such a significant technical improvement was not predictable from a mere combination of You, Chiu, Halas, and Jiang. Furthermore, the ability to achieve "non-invasive early diagnosis" through "high-sensitivity multiplexed detection" in the "complex environment of human serum" represents an unexpected benefit that is not taught or suggested by You, Chiu, Halas, and Jiang” (page 11 last paragraph and page 12 para. 1). However, as stated above, new grounds of rejection are set forth above, that rely on Kim in view of Hu and Chiu. Kim in view of Hu and Chiu as evidenced by Yang do suggest the increased SERS sensitivity (see rejection above) and suggest its use in human serum (see rejection above). Therefore, the arguments regarding “unexpected results” are not persuasive. Applicant further argues “You, Chiu, Halas, and Jiang, and Nakamura fails to cure the deficiencies of You, Chiu, Halas, and Jiang…Accordingly, Applicant respectfully submits that claim 1 is allowable over You, and Chiu, Halas, Jiang, and Nakamura fails to cure the deficiencies of You, noted above with regard to claim 1” (page 12 para. 4 and page 13 para. 4). However, as stated above, new grounds of rejection are set forth above over Kim in view of Hu and Chiu (see rejection above). Therefore, Applicant’s arguments are not persuasive.
Conclusion
No claim is allowed.
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/Fernando Ivich/ Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/ Primary Examiner, Art Unit 1677