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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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Withdrawn Rejections
The rejection of the claims under 102/103 and 103 are withdrawn in response to the amendments.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2020/032010, filed 05/08/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/846,565, filed 05/10/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims 1-2, 4-5, 7, 10, 12-13, 30-31, 33, 41-42, 44, 46, 48-49 and 51-52 are pending; claims 1, 7, 10 and 12-13 are amended, claims 3, 6, 8-9, 11, 14-29, 32, 34-40, 43, 45, 47 and 50 are canceled; no claims are withdrawn. Claims 1-2, 4-5, 7, 10, 12-13, 30-31, 33, 41-42, 44, 46, 48-49 and 51-52 are examined below.
Information Disclosure Statement
The information disclosure statement filed 1/15/2026 is being considered by the examiner.
Claim Interpretation
The claims recite “dose (D) of Aβ42” and “dose (D) of Aβ40”.
The specification paragraph 71 discloses that “"Dose" or "uncorrected dose," as used herein, refers to the calculated concentration of Aβ42 and/or Aβ40 within a body fluid sample. In a preferred embodiment, the dose may be determined using the Quanterix SIMOA® HD-1 Analyzer, using the SIMOA® software's 4PL (4- parameter logistic) regression via the following equation:
Y
=
E
+
A
-
E
1
+
(
D
C
)
B
, (Equation 4) where: A= the minimum value that can be obtained (i.e., detectable signal at 0 dose); E = the maximum value that can be obtained (i.e., detectable signal at infinite dose); C = the point of inflection (i.e., the point on the curve halfway between A and E); B = Hill's slope of the curve (related to the steepness of the curve at point C); Y = detectable signal from individual specimens; D = dose (pg/ml)”. Also, paragraph 105 of the specification discloses “calculating a dose (D) (concentration of analyte), for Aβ42 and Aβ40 based on the relationship between the first, second, and third detectable signals…dose (D) may be calculated using a 4-parameter logistic ("4PL") fitted calibration curve”, and paragraph 114 of the specification discloses that [i]nitial concentrations are calculated using a four parameter logistic calibration curve, according to…Equation 4”. Therefore, the specification suggests that dose (D) is the x-axis component (concentration of Aβ42 and Aβ40) of the fitted 4-parameter logistic calibration curve obtained with the Quanterix SIMOA® HD-1 Analyzer (see Example 1, paras. 111-115) used for determining the concentration of Aβ42 and Aβ40. Therefore, the recited “dose (D) of Aβ42” and “dose (D) of Aβ40” are hereby interpreted as the concentration of Aβ42 and Aβ40 from the fitted 4-parameter logistic calibration curve obtained with the Quanterix SIMOA® HD-1 Analyzer.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-5, 7, 10, 12-13 and 52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 1 and its dependent claims require the new limitation “measuring a dose (D)”.
However, the specification does not disclose or suggest “measuring a dose (D)”. While the specification does disclose “calculating a dose (D)” (paras. 11, 17-18, 33-34, 37, 105), “correcting the doses (D)” (para. 11, 17-18, 33-34, 37, 106), and “dose may be determined” (para. 71), the specification does not disclose the measuring of the dose. It appears that Applicant is not in possession of “measuring a dose”.
For this reason claims 1-2, 4-5, 7, 10, 12-13 and 52 are rejected under 112a new matter.
Claims 1-2, 4-5, 7, 10, 12-13, 30-31, 33, 41-42, 44, 46, 48-49 and 51-52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an enablement rejection.
Independent claim 1 recites “…simultaneously assaying the disassociated Aβ42 and Aβ40 body fluid sample to detect a first detectable signal for measuring a dose (D) of Aβ42 and a second detectable signal for measuring a dose (D) of Aβ40, thereby determining the concentrations of Aβ42 and Aβ40”. Independent claim 30 recites “…determining concentrations of free peptide Aβ42 and Aβ40 in the body fluid sample simultaneously from a single multiplex assay comprising determining the dose (D) of Aβ42 and the dose (D) of Aβ40, thereby determining the amount of Aβ42 and Aβ40 in the body fluid sample”.
Therefore, the claims require the measuring/determining of the dose (D) of Aβ42 and the dose (D) of Aβ40, thereby determining the concentrations of Aβ42 and Aβ40.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification does not reasonably provide enablement for determining the concentrations of Aβ42 and Aβ40 using the claimed “dose (D)” (response curve).
The specification does not provide sufficient evidence that the claimed method of measuring/determining a dose (D) of Aβ42 and a dose (D) of Aβ40 is effective for determining the concentrations of Aβ42 and Aβ40. The evidence provided is a disclosure statement on the use of a Quanterix SIMOA® HD-1 Analyzer and calibrators of Aβ42 and Aβ40 from Invitrogen and Sigma Aldrich, respectively, to generate a dose response curve and obtain the dose (D) of Aβ42 and the dose (D) of Aβ40 (“Beta amyloid peptide controls… Invitrogen # 03-112… Sigma Aldrich# Al075-1MG” para. 111, “Each calibrator, control, and patient sample (i.e., body fluid sample) is prepared and run in duplicate” para. 113). But the specification fails to disclose any data showing the results, details about the instrument (e.g. data acquisition parameters), or details about the curve fitting to the data (e.g. percent recoveries, goodness of fit, relative error, etc.). Therefore, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied.
In re Wands, 858F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The nature of the invention is a biological/chemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the claimed method(s), with a reasonable expectation of success, because it would not have been predictable from the disclosure that the broadly claimed “dose (D)” would function as claimed with respect to determining the concentrations of Aβ42 and Aβ40 (see MPEP § 2164.03).
In regard to Wands factors (C), (D) and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a).
Accordingly, Kleinschmidt et al. (US 20110091910 A1)-Cite No. A1 of IDS 11/9/2021 (“Kleinschmidt”) teaches that the recovery rate is a necessary validation parameter in multiplex assays of amyloid beta peptides to enable the accurate determinations of the concentration of amyloid beta (“ELISA or ELISA-type systems (Multiplex) are used conventionally for the quantification of Aβ in plasma. The validation parameters of such studies are usually only unsatisfactorily analysed or are completely disregarded. For example, a critical item like the recovery rate is not analysed or is not mentioned in respective publications. The recovery rate is however a decisive parameter for the correct determination of the level of those Aβ peptides, which occur in plasma. Differences in the levels of Aβ peptides in plasma, which occur in different studies, may thus result from the incorrect determination of the recovery rates” para. 20). Kleinschmidt further suggests that dilutions of amyloid beta can also yield errors in the concentration determination (“ because the Aβ peptides are very hydrophobic” para. 19, “in Hansson et al., 2008, the level of the calculated plasma Aβ(1-42) concentration for a 1:20 dilution was three times higher than in the 1:2 dilution of the same sample (Hansson et al., 2008)” para. 20).
Also, Song et al. Alzheimer's Research & Therapy (2016) 8:58 DOI 10.1186/s13195-016-0225-7-Cite No. B7 of IDS 2/7/2023 (“Song”) teaches that “the choice of calibration regression models is essential to achieve accurate quantification for sample measurement. Although a 4PL fit is the most widely used regression model for immunoassays, a cubic fit was found to yield an overall better calibration accuracy for the prototype Simoa assay… Conversely, the relative errors were generally >20% across the calibration range with r2 <0.5 using a 4PL regression model. Consequently, a cubic calibration fit was chosen for sample quantification using the prototype Simoa assay” (page 10 col. 2 para. 1). Note that Song teaches that even using the cubic fit (instead of the 4PL), the calibration performance was only “acceptable over the range of 0.206–50 pg/ml” (page 5 col. 1 para. 2 and col. 2 para. 1), that is it was not acceptable for certain calibrator stock dilutions. Song further teaches that the choice of calibrator standard impacts the concentration determination given that these may be different depending on the source of the standard (“The results showed that the Quanterix standard contained threefold more Aβ1–42 peptide than the Fujirebio standard at the same assigned concentration. These disparate Aβ1– 42 peptide standard contents immediately explain the apparent difference in measured Aβ1–42 concentrations in clinical samples, depending on the selected calibrator, as well as the difference in calibrator response observed during prototype assay development” page 12 col. 2 para. 1).
Indeed, Lue et al. Neurol Ther 6 (Suppl 1), 25–36 (2017). https://doi.org/10.1007/s40120-017-0074-8 (Cite No. B5 of IDS 2/7/2023) (“Lue”) teaches that “freeze–thaw cycles, type of calibration proteins, batch-to-batch reagent variability, and site-to-site operations” (page S27 col. 1 para. 2) affect the determination of Aβ42 and Aβ40 levels.
Furthermore, Duffy et al. (WO 2016115256 A1)-Cite No. B3 of IDS 2/7/2023 (“Duffy”) teaches that “different portions of the array may produce different background signals. Such variations may lead to changes in calibration signals (e.g., differences in the determined average bead signal) between arrays, portions of and array or at multiple times, which can lead to inaccurate determinations in some cases. Non-limiting examples of parameters that may cause variation include labeling agent concentration, temperature, focus, intensity of detection light, depth and/or size of the locations in an array, reduction in activity of reagents (e.g., enzyme label), etc.” (page 29 lines 18-23).
Given the cited teachings of the prior art that the dose (D) of Aβ42 and the dose (D) of Aβ40, i.e. calibration curves using a 4PL fit, yield inaccurate results, the cited references demonstrate that the use of the claimed “dose (D)” for determining the concentration of Aβ42 and Aβ40 is unpredictable.
While the level of skill in the art is high, the amount of guidance provided regarding how to use the claimed dose (D) of Aβ42 and dose (D) of Aβ40 in the claimed methods is scant. Accordingly, the amount of experimentation required to determine how to use the recited dose (D) of Aβ42 and dose (D) of Aβ40 is quite extensive.
Due to the large quantity of experimentation necessary to determine how to use the recited dose (D) of Aβ42 and dose (D) of Aβ40 to determine the concentrations of Aβ42 and Aβ40, the lack of direction/guidance presented in the specification regarding the same, the complex nature of the invention, the limited state of the prior art, the unpredictability of the effects of complex biological molecules, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. §112 first paragraph.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 30-31, 33, 41-42, 44, 46, 48-49 and 51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 30 recites the limitation "the dose (" in lines 8-9. There is insufficient antecedent basis for this limitation in the claim. It is not clear what the dose (D) of Aβ42 and the dose (D) of Aβ40 refers to because a dose (D) of Aβ42 and a dose (D) of Aβ40 are not recited in the claim.
Claims 31, 33, 41-42, 44, 46, 48-49 and 51 are included in the rejection because they depend from rejected claim 30 but fail to clarify the scope of patent protection sought.
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 1-2, 4-5, 7, 10, 12-13, 30-31, 33, 41-42, 44, 46, 48-49 and 51-52 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).
Claim 1 recites “…simultaneously assaying the disassociated Aβ42 and Aβ40 body fluid sample to detect a first detectable signal for measuring a dose (D) of Aβ42 and a second detectable signal for measuring a dose (D) of Aβ40, thereby determining the concentrations of Aβ42 and Aβ40”. The limitation of using the “signal for measuring a dose” reads on an abstract idea, i.e. a judicial exception. Note that “dose” is interpreted as the x-axis component (i.e. concentration of Aβ42 or Aβ40) of the calibration curve/dose response curve of Aβ42 or the calibration curve/dose response curve of Aβ40 (see claim interpretation section above). Therefore, the limitation above suggests that the determining of the concentrations of Aβ42 and Aβ40 comprises simply comparing the signal measured to the corresponding concentration of Aβ42 and Aβ40 from the calibration curve. Therefore, these steps are considered to be directed to an abstract idea, i.e. steps that can be performed solely by the human mind or using a pen and paper.
Claim 10 recites “wherein the concentration of Aβ42 in the dissociated Aβ42 and Aβ40 body fluid is determined from the dose (D) according to the relationship: [Aβ42 (pg/ml)] = (C1D)C2; and the concentration of Aβ40 in the dissociated Aβ42 and Aβ40 body fluid is determined from the dose (D) according to the relationship: [Aβ40 (pg/ml)] = (C3) (D) + D, wherein C1, C2, and C3 are correction factors, wherein C1 is approximately 2.4271, C2 is approximately 0.9196, and C3 is approximately 0.35”. This limitation is drawn to a mathematical calculation in order to determine the concentration of Aβ, i.e., the abstract idea. See MPEP §2106.04(a)(2).
Claim 30 recites “determining the dose (D) of Aβ42 and the dose (D) of Aβ40, thereby determining the amount of Aβ42 and Aβ40 in the body fluid sample”. However, “determining the dose” reads on an abstract idea as above. Note that the dose is interpreted to be drawn to the calibration curve, i.e. a dose response curve (see claim interpretation above). Therefore, “determining the dose” from a calibration curve can be performed solely within the human mind. For example, by simply comparing numerical values.
Further, claim 31 recites “determining the dose (D) of Aβ42 from at least the first detectable signal; determining the dose (D) of Aβ40 from at least the second detectable signal; and correcting the doses (D) of Aβ42 and Aβ40 to determine the concentrations of Aβ42 and Aβ40 in the body fluid; or (b)… determining the dose (D) of Aβ42 from at least the first detectable signal and the third detectable signal; determining the dose (D) of Aβ40 from at least the second detectable signal and the third detectable signal; and correcting the doses (D) of Aβ42 and Aβ40 to determine the concentrations of Aβ42 and Aβ40 in the body fluid”. The limitation “correcting” is drawn to either a mathematical calculation or a mental step, which are abstract ideas, i.e., a judicial exception. Claim 31 also recites “determining the dose” as in claim 30, which is reasonably interpreted as drawn to a judicial exception, an abstract idea.
Furthermore, claim 48 recites “[a] method of detecting, monitoring the progression of, assessing the efficacy of a treatment for, or assessing risk for development of a neurodegenerative disorder in a subject, comprising the method of claim 46”. Claim 48 is directed to a natural correlation, i.e. a judicial exception. Claim 48 relies on the natural occurring correlation between the amount of Aβ42 and Aβ40 in the body fluid and neurodegenerative disorder. The correlation between the amount of Aβ42 and Aβ40 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.
Claim 49 merely limits the disease used in the natural correlation. Therefore claim 49 is also directed to a judicial exception.
Step 2A, Prong 2
This judicial exception(s) (listed above) are not integrated into a practical application (none of the additionally recited elements/steps apply on, rely on or use the judicial exception such to amount to a practical application thereof).
Claim 1 recites the additional elements of obtaining a body fluid sample, dissociating at least one of Aβ42 and Aβ40 within the body fluid sample, and simultaneously assaying the dissociated Aβ42 and Aβ40. However, all these limitations are considered insignificant presolution activity because it amounts to steps/elements performed as part of the assay to collect the data. The step of disassociating fails to further apply, rely on or use the judicial exception in a way that amounts to a practical application of the judicial exception(s).
Claims 2, 4 and 52 merely limit the buffer or dissociation step. Therefore, these claims are also drawn to insignificant data gathering steps, i.e. insignificant presolution activity.
Claims 5 and 13 limit the sample used for the data gathering. Therefore, these elements are also drawn to insignificant presolution activity.
Claims 7 and 12 limit the assay step used for data gathering. Therefore, these elements are also drawn to insignificant presolution activity.
Claim 30 requires “incubating a body fluid sample from a subject in a buffer solution comprising a protein-compatible surfactant for at least 30 minutes to produce free peptides in the body fluid sample; and performing an immunoassay on the body fluid sample”; and claim 31 recites the additional limitation of “wherein the step of performing an immunoassay further comprises: (a) measuring a first detectable signal from Aβ42 immunocomplexes; measuring a second detectable signal from Aβ40 immunocomplexes;… or (b) measuring a first detectable signal from Aβ42 immunocomplexes; measuring a second detectable signal from Aβ40 immunocomplexes; measuring a third detectable signal from product molecules”. These additional limitations are all also insignificant extra-solution activity that do not integrate the judicial exception into a practical application because none of these recited steps/elements apply on, rely on or use the judicial exception in way that amounts to a practical application.
Claims 33, 41-42, 44, 46 and 51 are further drawn to data gathering steps, i.e. insignificant presolution activity in order to make the determination or correction of the dose (claims 30-31 abstract ideas) and/or in order to correlate the amount of Aβ42 and Aβ40 in the body fluid sample to the neurodegenerative disorder (claims 48-49 natural correlation, i.e. a natural law). Therefore, these additional elements fail to integrate the judicial exception(s) into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the sample preparation method of claims 1 and 30, including the buffer solution, body fluid, and immunoassay, as well as measuring and determining the concentration of Aβ and calculating the ratio of Aβ42 to Aβ40, are all well understood, routine and conventional in the art and does not amount to significantly more than the judicial exception. The steps of measuring Aβ42 and Aβ40 are recited at a high level of generality and is not limited, for example, to any specific testing technique.
Furthermore, dissociating a body fluid sample using a buffer solution comprising a buffer; and a protein-compatible surfactant, wherein the body fluid is incubated in the buffer solution for at least 30 minutes, thereby producing a dissociated body fluid sample is well-understood routine and conventional in the art.
For example, Sarasa (EP 2511296 A1)-Cite No. B1 of IDS, now referred as S1, teaches the sample preparation method of claim 1, including the buffer solution, body fluid, and immunoassay as well as measuring and determining the concentration of Aβ from a body fluid sample (Abstract, page 21, line 1; paragraphs 64, 138, 171, and 177, Example 4, and claim 11). S1 teaches disassociating a body fluid sample from endogenous proteins by incubating the body fluid sample in a buffer solution comprising: a buffer ; and a protein-compatible surfactant (“50 mM Tris-HCI pH 8, 0.5M NaCl; 0.05 %; BSA, 0.05 % Triton X-100” page 21, line 1; “Antibody Diluent: 50mM tris, 0.05% BSA, 0.5M NaCl, 0.05% Tween20, pH 8.0” paragraph 171), wherein the body fluid sample is incubated in the buffer solution for at least 30 minutes (“incubated overnight at 4⁰C (or for 2h at 37°C)” paragraph 177), thereby producing a dissociated body fluid sample (“[t]he contacting step is carried out under conditions adequate for achieving partial or, preferably, full dissociation of the amyloid beta peptide from the protein and lipids present in the biological sample” paragraph 138).
Furthermore, Sarasa (WO 2011070174)-Cite No. N of PTO 892 10/09/2024-now referred as S2, teaches calculating the ratio of Aβ42 to Aβ40 using an immunoassay (pages 34-35, lines 29-31 and 1-14; Table 8, page 58, line 12).
The specification admits that protein-compatible surfactants are known in the art (“[p]rotein-compatible surfactants known in the art include, but are not limited to, polysorbate 20 (i.e., Tween-20) and Triton X-100” paragraph 52).
Also, Navarrete Santos and Boehm (WO 2008/012101 Al) Cite No. N of PTO 892 2/6/2025-(hereinafter Navarrete) teach “a method for the detection of marker of the Alzheimer's disease, namely the amyloid-β oligomers in human CSF, using a combination of steps including demasking the epitopes responsible for antibody binding on the Aβ peptide oligomers” (Abstract). Navarrete further teaches that “it has been found to be crucial to remove any proteins being attached to the amyloid-β peptides oligomers from the peptides before contacting them with antibodies. The removal of proteins attached to the Aβ is called "demasking"” (page 5 last paragraph). Navarrete further teaches “Preferred demasking solutions:… 10-50, pref. 25 mM Tris-HCI pH 80.4-0.6, pref. 0.5 wt.-% Triton X-100” (page 7 paragraph 2). Navarrete further teaches that “[t]he buffer solution containing the detergents and the body fluid is incubated for about 15 min to 3 h, preferably 30-90 min at a temperature of about 10-40°C” (page 7 last paragraph). Therefore, Navarrete teaches dissociating a body fluid sample using a buffer solution comprising a buffer; and a protein-compatible surfactant, wherein the body fluid is incubated in the buffer solution for at least 30 minutes, thereby producing a dissociated body fluid sample.
There is also evidence that performing a multiplex assay for Aβ42 and Aβ40 on a dissociated body fluid sample is well-understood, routine and conventional.
For example, Hansson et al. Neurobiology of Aging 31 (2010) 357–367 doi:10.1016/j.neurobiolaging.2008.03.027 (“Hansson”) “analyzed plasma samples using a new multiplex immunoassay for simultaneous analysis of Aβ1–40, Aβn–40, Aβ1–42, and Aβn–42” (Abstract). Hansson teaches that “[a]ll plasma samples were diluted 1/3 with a buffer containing detergent before analysis” (page 359 col. 2 para. 2).
Also, Kleinschmidt et al. (US 20110091910 A1)-Cite No. A1 of IDS 11/9/2021 (“Kleinschmidt”) teaches that “Multiplex Assay Systems are available from several manufacturers and are well known and broadly used in the field. A suitable example for use in the methods of the present invention is the INNO-BIA plasma Aβ forms assay (Innogenetics). This assay is a well standardized multiparameter bead-based immunoassay for the simultaneous quantification of human β-amyloid forms Aβ(1-42) and Aβ(1-40) or Aβ(X-42) and Aβ(X-40) in plasma using xMAP.RTM. technology (xMAβ is a registered trademark of Luminex Corp.)” para. 183).
Also, the use of a dose (D) response curve to determine the concentration of Aβ42 and Aβ40 is well-understood, routine and conventional in the art.
For example, Song et al. Alzheimer's Research & Therapy (2016) 8:58 DOI 10.1186/s13195-016-0225-7-Cite No. B7 of IDS 2/7/2023 (“Song”) teaches that “the Aβ1–42 concentrations in each sample were quantified using calibration curves generated with Quanterix and Fujirebio Aβ1–42 standard peptides” (page 8 col. 2 para. 2).
Also, Hansson teaches that “[s]ynthetic Aβ peptides, purified by reverse-phase high performance liquid chromatography, were obtained from Bachem (Heidelberg, Germany) and used as calibrators. The standard curve was constructed by plotting the median fluorescence values for each of the standards against its corresponding concentration using the sigmoidal curve fitting method, and the mean MFI values for the duplicate plasma samples were used to determine the concentration of the Aβ isoforms” (page 359 col. 2 para. 3 and page 360 col. 1 para. 1).
Also, using an assay disc appears to be well-understood, routine and conventional in the art.
For example, Janelidze et al., Scientific Reports, May 31, 2016, 6(1):26801, 1-11-Cite No. B4 on IDS teach immobilizing the labeled immunocomplexes onto an assay disc in the presence of substrate molecules, wherein the substrate molecules react with the labeled Aβ42 immunocomplexes or labeled Aβ40 immunocomplexes to produce product molecules, and wherein the product molecules emit a third detectable signal (Abstract, page 3, paragraphs 1-2).
See also, Rissin et. al. nature biotechnology Volume 28, Number 6. Published online 23 May, 2010-Cite No. U of PTO 892 10/9/2024. Rissin et. al. teach wherein the assay disc comprises wells; immobilizing labeled immunocomplexes onto an assay disc comprises immobilizing the labeled immunocomplexes or bare capture agents within the wells; and each well is configured to contain no more than one labeled immunocomplex or one bare capture agent therein, wherein immobilizing labeled immunocomplexes onto an assay disc further comprises enclosing the labeled immunocomplexes in the presence of the substrate molecules, within the wells, under an oil layer (page 596, column 1, paragraph 1 “confinement”).
Finally, a digital ELISA seems to be well-understood, routine and conventional in the art.
For example, Song et al. Alzheimer's Research & Therapy (2016) 8:58 DOI 10.1186/s13195-016-0225-7-Cite No. B7 of IDS 2/7/2023 (“Song”) teaches “A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1–42 peptide in human plasma with utility for studies of Alzheimer’s disease therapeutics” (Title).
Also, Janelidze et. al. teach “an ultrasensitive digital ELISA to measure plasma Aβ 42 and Aβ 40” (page 8, paragraph 1 of Janelidze et al.).
Looking to the claims as a whole, none of the steps considered individually or in combination include additional elements that are sufficient to amount to significantly more than the judicial exception because the claimed steps are routine, conventional and must necessarily be performed in order to prepare a body fluid sample for detection of at least one of β-amyloid 42 ("Aβ42") and β-amyloid 40 ("Aβ40"), or for determining the concentration of Aβ42 to Aβ40 in a body fluid. Therefore, claims 1-2, 4-5, 7, 10, 12-13, 30-31, 33, 41-42, 44, 46, 48-49 and 51-52 are directed to patent ineligible subject matter.
Response to Arguments
Applicant's arguments filed 9/23/2025 have been fully considered but they are not persuasive.
Regarding the 101 rejections, Applicant argues that “the claims are directed to a laboratory method, not a judicial exception… Claim 10 incorporates the limitations of the claims from which it depends, and further recites transforming the measured dose (D) of each of Aβ42 and Aβ40 using the empirically-derived signal-dose relationship that integrates specific correction factors which were empirically determined by performing the recited laboratory method… Applicants submit that claim 10 as a whole… is not directed to a judicial exception” (page 9 last paragraph and all page 10). However, contrary to Applicant’s remark, claim 10 is directed to mathematical calculations, i.e. a judicial exception (see rejection above). Applicant further argues that “even if claim 10 recites a judicial exception (which Applicant submits it does not), it also recites additional elements that integrate the judicial exception into a practical application of the exception - an improved, highly sensitive test for Aβ42 and Aβ40… The claims are a practical application because they sufficiently limit the use of the alleged abstract idea to prepare and assay the enriched sample to determine, using the recited, specific correction factors, to determine the concentrations of Aβ42 and Aβ40, as specifically claimed, thereby increasing the sensitivity for detecting Aβ42 and Aβ40” (page 11 paras. 1-2). However, the additional elements are considered insignificant data gathering steps for performing the mathematical calculation, i.e. the abstract idea (see rejection above for a full analysis). Applicant further argues that “[e]ven if for the sake of argument, claim 10 is directed to a mathematical concept (which, for the reasons stated above, Applicant submits it is not directed to a judicial exception), the additional steps in claim 10 …ensure that the claim as a whole amounts to significantly more than the judicial exception itself…As discussed above, claim 10 depends directly from claim 7, and indirectly depends from claims 1, 2, 4, and 5, from which the following additional elements are incorporated…” (page 11 para. 3 and page 12 para 1). However, claim 10 only incorporates elements from the claims from which it depends, that is claims 1 and 7. And claims 1 and 7 fail to add significantly more than the judicial exception (see rejection above). Nevertheless, claims 2, 4, and 5 also recite insignificant data gathering steps (see rejection above). Applicant further argues that “claim 1 presently recites a simultaneous assay of Aβ42 and Aβ40, which was not previously disclosed or enabled, and therefore was not routine or conventional” (page 12 para. 1). However, a simultaneous assay of Aβ42 and Aβ40 is well-understood, routine and conventional in the art (see rejection above). Applicant further argues that “claim 7 incorporates performing an immunoassay on the disassociated Aβ42 and Aβ40 body fluid sample after incubating the body fluid sample in the buffer solution” (page 12 para. 1). However, claim 7 is also considered well-understood, routine and conventional in the art (see rejection above). Applicant further argues that “Claim 10 also further incorporates the step of determining the concentrations of Aβ42 and Aβ40 from the [measured] doses of Aβ42 and Aβ40 by using specific correction factors for each analyte's baseline recovery” (page 12 para. 1). However, “determining the concentrations of Aβ42 and Aβ40 from the [measured] doses of Aβ42 and Aβ40 by using specific correction factors for each analyte's baseline recovery” is directed to the judicial exception, and is therefore not an additional element. Applicant further argues that “claim 10 amount to significantly more than the alleged mathematical concept recited in the claim, as evidenced by the improved, increased sensitivity of the assay step, as discussed above (Specification at [0118]). Accordingly, Applicant respectfully submits that claim 10 is patent eligible under step 2B” (page 12 last paragraph and page 13 para. 1). However, claim 10 is patent ineligible because it is directed to a judicial exception without significantly more. Although Applicant argues that the assay step has “improved, increased sensitivity”, the recited additional elements fail to integrate the judicial exception into a practical application and fail to add significantly more than the judicial exception (see rejection above). Applicant further argues that “claim 12 also indirectly depends from claims 1, 2, 4, and 5 and thereby incorporates all of the limitations which are not merely insignificant extrasolution activity, and add significantly more to any alleged judicial exception, for the reasons discussed above for claim 10. Claim 12 provides additional detail for the inventive concept of a method of preparing a body fluid sample…Similarly…Claim 13 do not merely limit the type of sample as the Office asserted, but rather provide additional detail for the inventive concept of claim 1, which is directed to a method of preparing a body fluid sample enriched for Aβ42 and/or Aβ40 by dissociating Aβ42 and Aβ40 from a body fluid sample and performing an improved assay on the dissociated sample” (page 13 paras. 2-3). However, claims 12-13 fail to integrate the judicial exception(s) into a practical application and fail to add significantly more than the judicial exception(s) (see rejection above). Applicant further argues that “Applicant respectfully submits that the additional limitations of claim 31 recite additional details of how one embodiment of the improved immunoassay of claim 30 is performed, and that the limitations of the independent claim from which claim 31 depends cannot be properly interpreted to be mere insignificant data gathering steps for the steps recited in the dependent claim” (page 14 para. 2). However, new grounds of rejection are set forth above. Claim 30 is considered directed to an abstract idea; “determining the dose (D)” is reasonably interpreted as a mathematical calculation (see rejection above). Also, contrary to Applicant’s arguments, the additional elements of claims 30-31 are considered to be insignificant data gathering steps. Applicant further argues that “Claim 31 describes the additional steps of transforming detectable signals from immunocomplexes into the dose (D) of each of Aβ42 and Aβ40, and correcting the doses of Aβ42 and Aβ40 to permit the novel, simultaneous, improved determination of the concentrations of Aβ42 and Aβ40 in the processed sample. MPEP § 2106.05(1). The additional elements of claim 31 therefore adds significantly more to the alleged mathematical concept” (page 15 paras. 4-5). However, “transforming detectable signals from immunocomplexes into the dose (D) of each of Aβ42 and Aβ40, and correcting the doses of Aβ42 and Aβ40” read on an abstract idea, steps that can be performed in the mind or with a pen and paper. Therefore, these are limitations directed to the judicial exception and cannot add significantly more (see rejection above).
Conclusion
No claim is allowed.
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677