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 .
Claim Status
Claims 1-3, 5, 7, 11, 16-19, 22-23, 26, 32, 34, 36, 39, 42-43, 47-48, 53, and 63 are pending and examined. Claims 4, 6, 8-10, 12-15, 20-21, 24-25, 27-31, 33, 35, 37-38, 40-41, 44-46, 49-52, 54-62, and 64-68 are canceled.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) received on 7/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 3, 16, and 36 are objected to because of the following informalities:
Regarding claim 3, Lns. 2-3 recite, “and step (c) comprises detecting aggregation via said reagent”. However, in claim 1, step (d) is the step for determining the presence or absence of aggregation within the droplets. Therefore, the above limitation should recite, “and step (d) comprises detecting aggregation via said reagent”.
Regarding claim 16, Ln. 3 recites, “light sheet fluorescence microscopy of confocal microscopy”. However, “of” is a typo of “or”, and should be appropriately corrected.
Regarding claim 36, Ln. 8 recites, “thiovlain”, which is a typo of “thioflavin”.
Further regarding claim 36, Ln. 13 recites, “µM”. However, as this unit refers to droplet diameter, this is a typo of “µm”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-3, 5, 7, 11, 16-19, 22-23, 26, 32, 34, 36, 39, 42-43, 47-48, 53, and 63 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.
Regarding claim 1, 2nd to Last Ln. – Last Ln. recite, “wherein the concentration of protein aggregate seed in the mixture of step (a) is such that the overwhelming majority of microdroplets of step (b) will each contain either one or zero seeds”. However, the scope of the limitation “the overwhelming majority” is unclear, as it is a relative term which renders the claim indefinite. The term “the overwhelming majority” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what prevalence of the microdroplets having either one or zero seeds would constitute an overwhelming majority.
Claims 2-3, 5, 7, 11, 16-19, 22-23, 26, 32, 34, 36, 39, and 63 are rejected at least for depending on a rejected claim.
Regarding claim 42, the claim similarly recites, “the overwhelming majority of microdroplets…”, and is similarly rejected.
Claims 43, 47-48, and 53 are rejected at least for depending on a rejected claim.
Further regarding claim 1, clause (a) recites, “providing a preparation that (i) comprises, or is suspected of comprising, protein aggregate seeds of said protein…”, and step (c) recites “increasing the monomer chemical potential within the droplets to a point where secondary aggregation processes take place, but not primary aggregation processes”. However, step (c) is constructed as if secondary aggregation processes will always take place, but step (a) is constructed as if the preparation may or may not contain protein aggregate seeds, i.e. protein aggregation will not necessarily always occur. Therefore, it is unclear how, if the preparation recited in step (a) does not contain protein aggregate seeds, how secondary aggregation process will take place in step (c). Further clarification is needed.
Examiner’s Note: in order to overcome the above 112(b) rejection, the Examiner suggests amending the claim to recite in step (c) that secondary aggregation processes would take place if the preparation comprises protein aggregate seeds.
Claim 17 recites the limitation "the sample" in Ln. 2. There is insufficient antecedent basis for this limitation in the claim. For purposes of compact prosecution, the above limitation has been examined as, “a sample”.
Regarding claim 32, the claim recites, “further increasing the monomer chemical potential to a point where primary processes take place and determining again the presence or absence of aggregation within the droplets”. However, as this is a step that is characterized by underlying mechanistic parameters or considerations, rather than by any actual positively recited step, it is unclear how the monomer chemical potential is increased to this point. Further clarification is needed.
Claim 39 recites the limitation "the original sample" in Ln. 3. There is insufficient antecedent basis for this limitation in the claim. For purposes of compact prosecution, the above limitation has been examined as, “an original sample”.
Claim 53 recites the limitation "the sample" in Ln. 2. There is insufficient antecedent basis for this limitation in the claim. For purposes of compact prosecution, the above limitation has been examined as, “a sample”.
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, 5, 7, 11, 16-19, 22-23, 26, 32, 34, 36, 39, 42-43, 47-48, 53, and 63 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The subject matter eligibility test for the claims is shown below:
Step 1: Independent claim 1 and independent claim 42 are each directed toward a method.
Step 2A, Prong One: Identify the law of nature/natural phenomenon/abstract idea.
Claim 1 recites the abstract idea, “determining the presence or absence of aggregation within the droplets”, which is a determination/evaluation-type mental process abstract idea that could be performed by a human person.
Claim 42 similarly recites the abstract idea, “determining the presence or absence of aggregation within the droplets”, which is a determination/evaluation-type mental process abstract idea that could be performed by a human person.
Step 2A, Prong Two: Has the abstract idea been integrated into a particular practical application?
No. After the determination is made, no further action is taken, and therefore there is not a particular practical application.
Independent claim 1 additionally recites, “providing a preparation that comprises…protein aggregate seeds…and…monomers of said protein…generating microdroplets…increasing the monomer chemical potential within the droplets…wherein the concentration of protein aggregate seed in the mixture of step (a) is such that the overwhelming majority of microdroplets of step (b) will each contain either one or zero seeds”. However, these steps are necessary preparation steps to prepare the protein aggregate seeds within the microdroplets for potential aggregation, and amount to insignificant extra-solution activity. See MPEP 2106.05(g).
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claims 1 and 42 each recite the additional elements of a preparation that (i) comprises, or is suspected of comprising, protein aggregate seeds of a protein and (ii) comprises monomers of said protein, and microdroplets. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Crowther et al. (US Pub. No. 2016/0011208; hereinafter Crowther; already of record on the IDS received 7/12/2024) teaching a preparation that (i) comprises, or is suspected of comprising, protein aggregate seeds of a protein and (ii) comprises monomers of said protein ([0016]-[0021], see Fig. 1), and microdroplets ([0016]-[0021], see Fig. 1). Further, Concha et al. (US Pub. No. 2021/0311077; hereinafter Concha) teaches a preparation that (i) comprises, or is suspected of comprising, protein aggregate seeds of a protein and (ii) comprises monomers of said protein ([0006]). Arosio et al. (WO Pub. No. 2020/094827; hereinafter Arosio) teaches microdroplets (Pg. 4 Ln. 19-Pg. 5 Ln. 2, Pg. 6 Ln. 18-Pg. 7 Ln. 1).
Claims 2-3, 5, 7, 11, 16-19, 22-23, 26, 32, 34, 36, 39, 43, 47-48, 53, and 63 each either further define the data-gathering steps previously recited in the independent claims, and are therefore insignificant extra-solution activity, or further define the detecting step, which has already been established as an abstract idea. These dependent claims therefore do not amount to significantly more than the judicial exception, and do not incorporate the judicial exception into a practical application.
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 1-3, 5, 7, 11, 16-19, 22-23, 34, 36, 39, 42-43, 47-48, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Crowther in view of Knowles et al., “Observation of spatial propagation of amyloid assembly from single nuclei”, 06 September 2011, PNAS, Vol. 8, No. 36, Pgs. 14746-14751 (hereinafter Knowles; already of record on the IDS received 7/12/2024).
Regarding claim 1, Crowther discloses a method of detecting aggregates of a protein that are capable of seeding further protein aggregation ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1). The method comprises:
(a) providing a preparation that (i) comprises, or is suspected of comprising, protein aggregate seeds of said protein and (ii) comprises monomers of said protein ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1).
(b) generating microdroplets of the preparation of (a) ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1).
(d) determining the presence or absence of aggregation within the droplets ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1).
The concentration of protein aggregate seed in the mixture of step (a) is such that the overwhelming majority of microdroplets of step (b) will each contain either one or zero seeds (see Fig. 1, which clearly shows that the positive droplets, i.e. droplets containing aggregate seeds, are “rare”. Therefore, the overwhelming majority of droplets formed contain either one or zero seeds).
Crowther fails to explicitly disclose (c) increasing the monomer chemical potential within the droplets to a point where secondary aggregation processes take place, but not primary aggregation processes, wherein the monomer chemical potential is increased by reducing the droplet diameter by 40-90%.
However, Knowles, in the analogous field of observing protein aggregation (Knowles Pg. 14746 Col. 1 1st Para.), teaches that reducing droplet diameter will result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.). It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the method of Crowther with the teaching of Knowles to include a step of increasing the monomer chemical potential within the droplets to a point where secondary aggregation processes take place, but not primary aggregation processes, wherein the monomer chemical potential is increased by reducing the droplet diameter by 40-90%, in order to isolate secondary aggregation processes independently of primary aggregation, increasing the monomer chemical potential within the droplets to a point where secondary aggregation processes take place, but not primary aggregation processes (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.), particularly for the purposes of Crowther, which is to identify a subject at risk of a disease involving protein aggregation (Crowther [0016]-[0021]).
Further, although Knowles does not specifically teach reducing the droplet diameter by 40-90%, It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to reduce the droplet diameter by 40-90%, since, absent a statement of criticality or a showing of unexpected results, it would have been obvious to determine, through routine experimentation, the optimum reduction of the droplet diameter. The motivation would have been to optimize the droplet diameter to emphasize secondary aggregation, such that previously aggregated proteins, which are indicative of disease in a subject, can be readily observed.
Regarding claim 2, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the method further comprises a step of mixing a sample that comprises, or is suspected of comprising, the protein aggregate seeds with the monomers to form the preparation of step (a) (Crowther [0016]-[0021]).
Regarding claim 3, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the preparation of (a) further comprises a reagent which is capable of detecting the formation of aggregates, and step (d) comprises detecting aggregation via said reagent (Crowther [0052]).
Regarding claim 5, modified Crowther discloses the method of claim 1.
Modified Crowther fails to explicitly disclose that (i) the concentration of seeds in the preparation of (a) is between 20 fM and 2 nM monomer equivalent; and/or (ii) the concentration of monomers in the preparation of (a) is 1-100 µM.
However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to have the concentration of seeds in the preparation of (a) be between 20 fM and 2 nM monomer equivalent; and/or (ii) the concentration of monomers in the preparation of (a) be 1-100 µM, since, absent a statement of criticality or a showing of unexpected results, it would have been obvious to determine, through routine experimentation, the optimum concentrations of seeds and/or monomers. The motivation would have been to provide the seeds and/or monomers at a concentration where aggregation can be readily observed while reducing the potential for noise if the concentration is undesirably high.
Regarding claim 7, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the protein is an aggregation-prone protein, amyloidogenic, or one of the proteins listed in group (c) (Crowther [0048]-[0049]).
Regarding claim 11, modified Crowther discloses the method of claim 3. Modified Crowther further discloses that the reagent which is capable of detecting the formation of aggregates is thioflavin T (Crowther [0061]).
Regarding claim 16, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the presence or absence of aggregates within the droplets is determined by brightfield microscopy (Crowther [0122]), or confocal microscopy (Crowther [0130]).
Regarding claim 17, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that dilution of the sample comprising or suspected of comprising the seeds is used to prepare the mixture of step (a) (Crowther [0065]).
Regarding claim 18, modified Crowther discloses the method of claim 1.
Modified Crowther further discloses that the protein is α-synuclein (Crowther; [0048], [0073]).
Modified Crowther fails to explicitly disclose that the monomer chemical potential is increased 5 to 20 fold.
However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to increase the monomer chemical potential 5 to 20 fold, since, absent a statement of criticality or a showing of unexpected results, it would have been obvious to determine, through routine experimentation, the optimum increase in monomer chemical potential. The motivation would have been to increase the monomer chemical potential to a point where aggregation can be readily observed.
Regarding claim 19, modified Crowther discloses the method of claim 1.
Modified Crowther fails to explicitly disclose that the monomer chemical potential is increased by evaporation of the droplets, or the monomer chemical potential is increased by flowing a high-salt buffer in proximity to the droplets.
However, as previously stated in claim 1, Knowles teaches that reducing droplet diameter will result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.). It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to select evaporation as the method to reduce droplet diameter from a finite number of identified, predictable ways to reduce droplet diameter, i.e. it would have been obvious to try evaporation of the droplets in order to optimize the monomer chemical potential of the droplets. The motivation would have been that evaporation, which is known to reduce droplet diameter, can be used to result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.).
Regarding claim 22, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the initial average droplet diameter is 75 to 200 µm (Crowther [0041]).
Regarding claim 23, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the method further comprises modifying the shape of the microdroplets (see Claim 1 above at Knowles teaching reducing droplet diameter in Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para. Reducing droplet diameter will intrinsically modify the shape of the microdroplets).
Regarding claim 34, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the droplets are flowed past a detector (Crowther [0185]).
Regarding claim 36, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the protein is α-synuclein (Crowther; [0048], [0073]), the preparation of (a) comprises thioflavin T (Crowther [0061]), the buffer for the preparation of (a) is PBS or MES (Crowther [0195]), and the initial average droplet diameter is 75 to 200 µm (Crowther [0041]).
Modified Crowther fails to explicitly disclose that the concentration of seed in the preparation of (a) is between 200 fM and 2 nM monomer equivalent, optionally between 2pM and 2 nM monomer equivalent, or between 2 pM and 1 nM monomer equivalent; the concentration of protein monomer in the preparation of (a) is about 25 µM; the preparation of (a) comprises about 2 µM thioflavin T, and the monomer chemical potential is increased by evaporation of the droplets.
However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to have the concentration of seed in the preparation of (a) be between 200 fM and 2 nM monomer equivalent, the concentration of protein monomer in the preparation of (a) be about 25 µM, and the preparation of (a) comprises about 2 µM thioflavin T, since, absent a statement of criticality or a showing of unexpected results, it would have been obvious to determine, through routine experimentation, the optimum concentrations of components in the preparation of (a). The motivation would have been to ensure that the components are present in a sufficient concentration to initiate secondary aggregation as desired, and be able to detect the secondary aggregation when it occurs.
Further, as previously stated in claim 1, Knowles teaches that reducing droplet diameter will result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.). It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to select evaporation as the method to reduce droplet diameter from a finite number of identified, predictable ways to reduce droplet diameter, i.e. it would have been obvious to try evaporation of the droplets in order to optimize the monomer chemical potential of the droplets. The motivation would have been that evaporation, which is known to reduce droplet diameter, can be used to result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.).
Regarding claim 39, modified Crowther discloses the method of claim 1. Modified Crowther further discloses that the method further comprises quantifying the number of protein aggregates capable of seeding further protein aggregation in the original sample by determining the number of droplets positive and negative for aggregation (Crowther; [0006]-[0011], [0016]-[0021], [0048], see Fig. 1. See also [0182]).
Regarding claim 42, Crowther discloses a method of detecting aggregates of a protein that are capable of seeding further protein aggregation ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1). The method comprises:
(a) providing a preparation that (i) comprises, or is suspected of comprising, protein
aggregate seeds of said protein and (ii) comprises monomers of said protein ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1).
(b) generating microdroplets of the preparation of (a) ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1).
(d) determining the presence or absence of aggregation within the droplets ([0006]-[0011], [0016]-[0021], [0048], see Fig. 1).
The concentration of protein aggregate seed in the mixture of step (a) is such that the overwhelming majority of microdroplets of step (b) will each contain either one or zero seeds (see Fig. 1, which clearly shows that the positive droplets, i.e. droplets containing aggregate seeds, are “rare”. Therefore, the overwhelming majority of droplets formed contain either one or zero seeds).
Crowther fails to explicitly disclose (c) modifying the shape of the droplets.
However, Knowles, in the analogous field of observing protein aggregation (Knowles Pg. 14746 Col. 1 1st Para.), teaches that reducing droplet diameter will result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.). Further, reducing droplet diameter will intrinsically modify the shape of the droplets. It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the method of Crowther with the teaching of Knowles to include a step of reducing droplet diameter, thereby intrinsically modifying the shape of the droplets, in order to isolate secondary aggregation processes independently of primary aggregation, increasing the monomer chemical potential within the droplets to a point where secondary aggregation processes take place, but not primary aggregation processes (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.), particularly for the purposes of Crowther, which is to identify a subject at risk of a disease involving protein aggregation (Crowther [0016]-[0021]).
Regarding claim 43, modified Crowther discloses the method of claim 42.
Modified Crowther fails to explicitly disclose that step (c) comprises flowing the droplets from a wider channel into a narrower channel in order to compress the droplets.
However, as previously stated in claim 42, Knowles teaches that reducing droplet diameter will result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.). It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to select compressing the droplets by flowing them from a wider channel to a narrower channel as the method to reduce droplet diameter from a finite number of identified, predictable ways to reduce droplet diameter, i.e. it would have been obvious to try compressing the droplets by flowing them from a wider channel in order to optimize the monomer chemical potential of the droplets. The motivation would have been that evaporation, which is known to reduce droplet diameter, can be used to result in droplets where secondary aggregation can be observed independently of primary aggregation, thereby allowing for a more fundamental understanding of amyloid growth and its potential consequences in vitro and in vivo (Knowles; Pg. 14746 Col. 2 2nd Para., Pg. 14750 Col. 1 3rd Para.).
Regarding claim 47, modified Crowther discloses the method of claim 42. Modified Crowther further discloses that the preparation of (a) further comprises a reagent which is capable of detecting the formation of aggregates, and step (d) comprises detecting aggregation via said reagent (Crowther [0052]).
Regarding claim 48, modified Crowther discloses the method of claim 42.
Modified Crowther fails to explicitly disclose that (i) the concentration of seeds in the preparation of (a) is between 20 fM and 2 nM monomer equivalent; and/or (ii) the concentration of monomers in the preparation of (a) is 1-100 µM.
However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to have the concentration of seeds in the preparation of (a) be between 20 fM and 2 nM monomer equivalent; and/or (ii) the concentration of monomers in the preparation of (a) be 1-100 µM, since, absent a statement of criticality or a showing of unexpected results, it would have been obvious to determine, through routine experimentation, the optimum concentrations of seeds and/or monomers. The motivation would have been to provide the seeds and/or monomers at a concentration where aggregation can be readily observed while reducing the potential for noise if the concentration is undesirably high.
Regarding claim 53, modified Crowther discloses the method of claim 42. Modified Crowther further discloses that dilution of the sample comprising or suspected of comprising the seeds is used to prepare the mixture of step (a) (Crowther [0065]).
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Crowther in view of Knowles as applied to claims 1-3, 5, 7, 11, 16-19, 22-23, 34, 36, 39, 42-43, 47-48, and 53 above, and further in view of Eisenberg et al. (US Pub. No. 2020/0010507; hereinafter Eisenberg).
Regarding claim 63, modified Crowther discloses the method of claim 1.
Modified Crowther fails to explicitly disclose that the presence of aggregates is determined using a digital imaging method.
Eisenberg is in the analogous field of detecting amyloid fibrils in a biological sample (Eisenberg [0045]). Eisenberg teaches determining the presence of aggregates using a digital imaging method (Eisenberg [0111]). It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the method of modified Crowther with the teachings of Eisenberg so that the presence of aggregates is determined using a digital imaging method, as Eisenberg teaches that digital imaging methods can be used to determine protein aggregation (Eisenberg [0111]), and would therefore be similarly suitable for the method of modified Crowther.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to John McGuirk whose telephone number is (571)272-1949. The examiner can normally be reached M-F 8am-530pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Charles Capozzi can be reached at (571) 270-3638. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOHN MCGUIRK/Primary Examiner, Art Unit 1798
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