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 .
Claim Status
Claims 1-10 are currently pending and examined on the merits.
Priority
The instant application is a CON of PCT/CN2023/101281 filed on 6/20/2023 and claims foreign priority to Application CN202211026723X filed on 8/25/2022, in China. At this point in examination, the effective filing date of claims 1-10 is 8/25/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/29/2023 are in compliance with the provisions of 37 CFR 1.97. A signed copy of the corresponding 1449 form has been included with this Office Action.
Claim Objections
Claim 4 is objected to because of the following informalities:
In claim 4, line 15, there should be a space between “
R
y
” and “are”.
This is a typographical error. 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 1-10 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.
Claims 1 and 5 recite the limitation "the system" in lines 8 and 3, respectively. There is insufficient antecedent basis for this limitation in the claim. It is unclear what the system is and if the system is referring to the enzymatic reaction process recited in claim 1. The rejection might be overcome by amending the claims to introduce clear antecedent basis for “the system”. Therefore, claims 1 and 5 are rendered indefinite and rejected under 35 U.S.C. 112(b).
Regarding claim 4, lines 16-18, the phrase "i.e. renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); and (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion).
Subject matter eligibility evaluation in accordance with MPEP 2106:
Eligibility Step 1: Claims 1-10 are directed to an implementation method (process) for ultrasensitive Brink control for a delayed enzymatic reaction based on DNA strand displacement. Therefore, these claims are encompassed by the categories of statutory subject matter, and thus satisfy the subject matter eligibility requirements under Step 1.
[Step 1: YES]
Eligibility Step 2A: First, it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A, Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth described in the claim.
Claims 1-10 recite the following steps which fall within the mental processes and/or mathematical concepts groups of abstract ideas, as noted below.
Independent claim 1 further recites:
describing an enzymatic reaction process using single-molecule and bimolecular chemical reactions (i.e., mental processes);
introducing a time delay factor to obtain an enzymatic reaction process model with time delay (i.e., mental processes);
constructing a CRN-based Brink controller (i.e., mental processes);
obtaining a static mapping expression between an output of the Brink controller and an output of the system under a steady state condition so as to obtain an analytical condition ensuring the performance of the controller (i.e., mental processes);
constructing a Brink controller by DNA strand displacement reaction (i.e., mental processes);
obtaining a time delay representation through a DNA strand displacement mechanism based on a delayed substance and a compensation mechanism (i.e., mental processes);
applying the time delay representation to a DNA implementation of the enzymatic reaction process model (i.e., mental processes);
at the same time, combined with the constructed Brink controller, controlling a delayed enzymatic reaction process model (i.e., mental processes).
Dependent claim 2 further recites:
wherein describing the enzymatic reaction process using single-molecule and bimolecular chemical reactions specifically comprises:
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where S and B represent a substrate and an enzyme, respectively, X and P represent an enzyme-substrate complex and an output substance, respectively (i.e., mental processes).
Dependent claim 3 further recites:
wherein constructing the enzymatic reaction process model with time delay specifically comprises:
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95
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where the parameter
τ
represents a cumulative time delay present in the production of the output substance P (i.e., mental processes).
Dependent claim 4 further recites:
wherein the CRN-based controller is represented as:
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where parameters R and Y are inputs to the Brink controller and U represents an output; parameters
k
c
,
θ
c
, and
α
c
represent the catalysis rate;
γ
c
and
β
c
represents the binding rate;
ϕ
c
represents the degradation rate; further, the parameter R produces substance
R
r
, which in turn is reacted with U* to form U; parameter Y produces substance
R
y
, which in turn is reacted with U to form U*; at the same time, signals
R
r
and
R
y
are bound to form a complex
R
r
∙
R
y
that does not interact with any other substance, i.e. there is an inverse functional mechanism between the two different input parameters R and Y of the Brink controller; the Brink controller uses the signals
R
r
and
R
y
as activator and deactivator, respectively (i.e., mental processes; this is further information limiting the judicial exceptions);
combined with the mass action kinetics (MAKs), the corresponding ODEs equations are:
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obtained from the differential equation indicates that the total mass U + U* is conserved during the process of time evolution (i.e., mental processes, mathematical concepts; this is further information limiting the judicial exceptions).
Dependent claim 5 further recites:
wherein obtaining the static mapping expression between the output of the Brink controller and the output of the system under the steady state, specifically comprises: assuming the Brink controller has achieved steady-state output, the following results are obtained:
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(i.e., mental processes, mathematical concepts);
assuming that the Brink controller reference input R is constant, the following constraints are obtained:
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where the signal
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is indicative of the concentration of the substance
∙
at a steady state (i.e., mental processes, mathematical concepts);
Dependent claim 6 further recites:
wherein constructing the Brink controller by DNA strand displacement reaction, specifically comprises: set
i
,
x
,
y
,
z
as variables, where
i
∈
1,2
,
…
,
12
,
x
∈
1,2
,
…
,
8
,
y
∈
1,2
,
3,4
,
z
∈
1,2
,
…
,
9
(i.e., mental processes);
for reactions
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, there is a common DSD implementation mechanism between the two; these two reactions are converted into:
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at the same time, there is also an identical realization mechanism between the reactions
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, and the transformation is represented as:
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(i.e., mental processes);
for the reactions
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, the corresponding DNA implementations are represented as:
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where
G
x
,
T
x
and
L
y
represent auxiliary substances involved in the reaction;
O
z
and
H
y
represent intermediate products;
B
y
represents inert wastes produced by the reaction which do not interact with other substances; further,
C
m
a
x
represents the initial concentration of the auxiliary substance;
q
m
a
x
represents the reaction rate of maximum strand displacement;
q
i
represents the reaction rate of the corresponding DNA implementation (i.e., mental processes).
Dependent claim 7 further recites:
wherein obtaining the time delay representation through the DNA strand displacement mechanism and based on the delayed substance and a compensation mechanism, specifically comprises: the time delay is represented by a circuit consisting of two abstract chemical reactions taking place simultaneously, the implementation of which is based on the participation of a delaying substance D, and described by the following reactions:
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where parameters
k
p
r
o
d
and
k
d
e
l
a
y
are rate constants; in a first stage, substance O is produced at a constant rate; in the second stage, when the substance O is bound to the delayed substance D, it is rapidly converted into waste
∅
w
a
s
t
e
; the time taken for the substance O to consume substance D is taken as the delay time, and the delay effect thereof depends on the initial concentration of the delay substance D (i.e., mental processes).
Dependent claim 8 further recites:
wherein by applying the time delay representation to the DNA implementation of the enzymatic reaction process model, the enzymatic reaction model is rewritten as:
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where
k
d
e
l
a
y
1
represents a delayed reaction rate (i.e., mental processes);
combined with the mass action kinetics (MAKs), the following results are obtained:
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(i.e., mental processes, mathematical concepts).
Dependent claim 9 further recites:
wherein combined with the constructed Brink controller, controlling the delayed enzymatic reaction process model, specifically comprises:
converting reaction
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to:
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converting degradation reaction
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to:
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further, converting reaction
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to:
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for reversible reaction
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, the original reaction form is maintained when designing the DNA implementation (i.e., mental processes).
Dependent claim 10 further recites:
wherein the enzymatic reaction process model of the Brink-based controller is adjusted by using DSD mechanism; the proposed expression of DNA strand displacement with respect to time delay is improved, specifically as follows: the consumption of substance P in stage
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in the enzymatic reaction is compensated by the following reaction mechanism to achieve the desired yield of output substance P:
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where
k
p
r
o
1
and
k
p
r
o
2
are both reaction rate constants and F is an additionally added reaction substance (i.e., mental processes);
combined with the mass action kinetics (MAKs), the corresponding ordinary differential equations (ODEs) are obtained:
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further, reaction
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is converted to:
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reaction
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is converted to:
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(i.e., mental processes, mathematical concepts).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As the claims are currently recited, the implementation method could be performed by writing down the chemical reactions and equations with pen and paper, and making conversion or transformation decisions with those written reactions and equations. Writing out the reactions and equations and making decisions on them can be practically performed in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Therefore, claims 1-10 recite an abstract idea.
[Step 2A, Prong One: YES]
Eligibility Step 2A, Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that, when examined as a whole, integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
Claims 1-10 do not recite any additional elements in addition to the judicial exception and therefore fail to integrate the abstract ideas into a practical application. See MPEP 2106.04.II.A.2.
[Step 2A, Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
Claims 1-10 are drawn to a judicial exception and do not recite any additional elements that amount to significantly more than the judicial exception. Furthermore, an inventive concept cannot be furnished by a judicial exception. See MPEP 2106.05.I.
[Step 2B: NO]
Therefore, claims 1-10 are patent ineligible under 35 U.S.C. § 101.
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.
Claims 1, 4-5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Samaniego et al. (Cell Systems, 2021, 12(3), 272-288), in view of Fern et al. (ACS Synthetic Biology, 2016, 6(2), 190-193).
With respect to claim 1:
Regarding the recited constructing a CRN-based Brink controller, Samaniego et al. discloses an ultrasensitive synthetic molecular network named “brink” controller (BC) (pg. 274, col. 1, para. 3, lines 1-6; pg. 276, Figure 3). This teaches a Brink controller based on chemical reaction networks (CRNs).
Regarding the recited obtaining a static mapping expression between an output of the Brink controller and an output of the system under a steady state condition so as to obtain an analytical condition ensuring the performance of the controller, Samaniego et al. discloses deriving expressions for the input-output static map of the Brink controller and obtaining analytical conditions which guarantee ultra sensitivity of the map at steady state (pg. 276, col. 1, para. 1; pg. 277, col. 2, para. 2, lines 7-10). This teaches obtaining static map expressions under a steady state condition to obtain an analytical condition, ensuring ultra sensitivity of the Brink controller.
Regarding the recited constructing a Brink controller by DNA strand displacement reaction, Samaniego et al. discloses an ultrasensitive synthetic molecular network named “brink” controller (BC) (pg. 274, col. 1, para. 3, lines 1-6; pg. 276, Figure 3). This teaches constructing a Brink controller.
Samaniego et al. does not disclose a DNA strand displacement reaction.
However, Fern et al. discloses constructing a timer circuit that controls the release of a DNA strand by building a set of DNA strand-displacement reactions that emulate the abstract production and delay reactions (pg. 190, col. 2, para. 2; pg. 191, col. 1, para. 2, lines 1-4; pg. 191, Figure 2). This teaches DNA strand displacement reactions.
Samaniego et al. does not disclose describing an enzymatic reaction process using single-molecule and bimolecular chemical reactions, and introducing a time delay factor to obtain an enzymatic reaction process model with time delay.
However, Fern et al. discloses a chemical timer circuit consisting of the following two simultaneous abstract chemical processes that releases a target sequence of DNA at a constant rate from DNA complexes after a tunable delay period:
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(pg. 190, col. 1, para. 2, lines 1-3; pg. 190, col. 1-2, para. 3-5). Also, further discloses a time delay, which is the time needed to produce enough O to consume all of the D that is initially present (pg. 190, col. 2, para. 6). This teaches an enzymatic reaction process model using single-molecule and bimolecular chemical reactions and a time delay factor.
Samaniego et al. does not disclose obtaining a time delay representation through a DNA strand displacement mechanism based on a delayed substance and a compensation mechanism, and applying the time delay representation to a DNA implementation of the enzymatic reaction process model; at the same time, combined with the constructed Brink controller, controlling a delayed enzymatic reaction process model.
However, Fern et al. discloses constructing a timer circuit that controls the release of a DNA strand by building a set of DNA strand-displacement reactions that emulate the abstract production and delay reactions (pg. 190, col. 2, para. 2; pg. 191, col. 1, para. 2, lines 1-4; pg. 191, Figure 2). This teaches building a time delay representation using DNA strand displacement reactions, which emulate the abstract enzymatic reactions.
Fern et al. does not disclose the constructed Brink controller.
However, Samaniego et al. discloses an ultrasensitive synthetic molecular network named “brink” controller (BC) (pg. 274, col. 1, para. 3, lines 1-6; pg. 276, Figure 3). This teaches a constructed Brink controller.
It would have been prima facie obvious to one of ordinary skill in the art to combine the Brink controller disclosed by Samaniego et al. with the DNA strand displacement mechanism disclosed by Fern et al. One would be motivated to combine DNA strand displacement and a Brink controller because Fern et al. discloses that the synthetic DNA strand-displacement timer circuit can facilitate precise coordination of chemical events in vitro without external stimulation (pg. 190, Abstract, lines 9-10). Therefore, one of ordinary skill in the art would be able to use DNA strand displacement with the Brink controller to control delayed enzymatic reactions. There is a likelihood of success, since the Brink controller and DNA strand displacement mechanism are well known techniques in the field of computational chemistry.
With respect to claim 4:
Fern et al. does not disclose wherein the CRN-based controller is represented as:
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where parameters R and Y are inputs to the Brink controller and U represents an output; parameters
k
c
,
θ
c
, and
α
c
represent the catalysis rate;
γ
c
and
β
c
represents the binding rate;
ϕ
c
represents the degradation rate; further, the parameter R produces substance
R
r
, which in turn is reacted with U* to form U; parameter Y produces substance
R
y
, which in turn is reacted with U to form U*; at the same time, signals
R
r
and
R
y
are bound to form a complex
R
r
∙
R
y
that does not interact with any other substance, i.e. there is an inverse functional mechanism between the two different input parameters R and Y of the Brink controller; the Brink controller uses the signals
R
r
and
R
y
as activator and deactivator, respectively.
However, Samaniego et al. discloses the following list of Brink controller model reactions:
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268
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(pg. 274, col. 1-2, para. 3). While reactant and product parameter representations in the Brink controller model reactions are different from those recited in the claim, they are still equivalent and not patentably distinct. One of ordinary skill in the art would be able to adjust the parameter representations to achieve the desired CRN-based controller reactions as this is merely aesthetic design choice.
Fern et al. does not disclose combined with the mass action kinetics (MAKs), the corresponding ODEs equations are:
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obtained from the differential equation indicates that the total mass U + U* is conserved during the process of time evolution.
However, Samaniego et al. discloses the following ordinary differential equations (ODEs) for the Brink controller using the law of mass action:
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(pg. 274, col. 2, para. 2). Also, further discloses assuming the total concentration of output U remains constant, while it can either be in active (U) or inactive state (U*) (pg. 274, col. 1, para. 3, lines 6-8). Because the Brink controller is observed under steady state and total concentration of the output is constant, total mass of the output is conserved. While the parameter representations in the ODEs are different from those recited in the claim, they are still equivalent and not patentably distinct. One of ordinary skill in the art would be able to adjust the parameter representations to achieve the desired ODEs as this is merely aesthetic design choice.
With respect to claim 5:
Fern et al. does not disclose wherein obtaining the static mapping expression between the output of the Brink controller and the output of the system under the steady state, specifically comprises: assuming the Brink controller has achieved steady-state output, the following results are obtained:
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.
However, Samaniego et al. discloses deriving expressions for the input-output static map of the Brink controller under steady state conditions including a first step of deriving equilibrium conditions by setting the ODEs equal to zero (pg. 274, col. 2, para. 2; pg. 276, col. 1, para. 1-2). This teaches ODEs of the Brink controller under steady state conditions. While the parameter representations in the equations are different from those recited in the claim, they are still equivalent and not patentably distinct. One of ordinary skill in the art would be able to adjust the parameter representations to achieve the desired equations as this is merely aesthetic design choice.
Fern et al. does not disclose assuming that the Brink controller reference input R is constant, the following constraints are obtained:
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where the signal
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is indicative of the concentration of the substance
∙
at a steady state.
However, Samaniego et al. discloses considering the case in which the inhibitor species I is kept constant and acts as a reference input, and subtraction of the first and second ODEs with the third ODE at equilibrium yields the following steady state constraint:
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(pg. 274, col. 2, para. 2; pg. 276, col. 1, para. 1-2). Also, further discloses following similar steps to find the input-output mapping when the inhibitor I is varied, while the activator a is constant (pg. 277, col. 1-2, para. 4, lines 14-17; pg. 9, Supplementary Information, Section “3.3 Equilibrium maps and conditions for ultrasensitive behavior”). This teaches the obtained constraint. While the parameter representations in the equation may be different from those recited in the claim, they are still equivalent and not patentably distinct. One of ordinary skill in the art would be able to adjust the parameter representations to achieve the desired equation as this is merely aesthetic design choice.
With respect to claim 7:
Samaniego et al. does not disclose wherein obtaining the time delay representation through the DNA strand displacement mechanism and based on the delayed substance and a compensation mechanism, specifically comprises: the time delay is represented by a circuit consisting of two abstract chemical reactions taking place simultaneously, the implementation of which is based on the participation of a delaying substance D, and described by the following reactions:
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where parameters
k
p
r
o
d
and
k
d
e
l
a
y
are rate constants; in a first stage, substance O is produced at a constant rate; in the second stage, when the substance O is bound to the delayed substance D, it is rapidly converted into waste
∅
w
a
s
t
e
; the time taken for the substance O to consume substance D is taken as the delay time, and the delay effect thereof depends on the initial concentration of the delay substance D.
However, Fern et al. discloses a chemical timer circuit consisting of the following two simultaneous abstract chemical processes that releases a target sequence of DNA at a constant rate from DNA complexes after a tunable delay period:
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(pg. 190, col. 1, para. 2, lines 1-3; pg. 190, col. 1-2, para. 3-5). Also, further discloses a time delay, which is the time needed to produce enough O to consume all of the D that is initially present (pg. 190, col. 2, para. 6). This teaches time delay represented as a circuit consisting of two abstract chemical reactions taking place simultaneously.
Claims 2-3, 6, and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Samaniego et al. (Cell Systems, 2021, 12(3), 272-288) and Fern et al. (ACS Synthetic Biology, 2016, 6(2), 190-193) as applied to claims 1, 4-5, and 7 above, in view of Sawlekar et al. (IEEE Transactions on NanoBioscience, 2016, 15(5), 443-454).
Samaniego et al. and Fern et al. are applied to claims 1, 4-5, and 7 above.
With respect to claim 2:
Samaniego et al. and Fern et al. do not disclose wherein describing the enzymatic reaction process using single-molecule and bimolecular chemical reactions specifically comprises:
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where S and B represent a substrate and an enzyme, respectively, X and P represent an enzyme-substrate complex and an output substance, respectively.
However, Sawlekar et al. discloses the following reversible, bimolecular chemical reaction:
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27
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, and that unimolecular reactions feature only one reactant (pg. 444, col. 1, para. 2). Also, further discloses that degradation of a chemical species X at rate k into a waste product or an inert form is denoted as
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23
48
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(pg. 444, col. 1, para. 2, lines 10-11). It would be obvious for one of ordinary skill in the art to adjust the reactant and product parameters in the reactions disclosed by Sawlekar et al. to achieve the desired enzymatic reaction process model, which amounts to routine optimization.
It would have been prima facie obvious to one of ordinary skill in the art to modify the Brink controller implementation method disclosed by Samaniego et al. and Fern et al. to incorporate unimolecular and bimolecular chemical reactions disclosed by Sawlekar et al. One would be motivated to modify the implementation method to incorporate these chemical reactions because Sawlekar et al. discloses that a set of unimolecular and bimolecular reactions can be used to design nonlinear feedback controllers and implemented with DNA strand displacement (DSD) reactions (pg. 443, Abstract, lines 1-9). Therefore, unimolecular and bimolecular reactions can be used with DSD reactions to design the Brink controller implementation. There is a likelihood of success, since unimolecular and bimolecular reactions, Brink controllers, and DSD time delay circuits are well known elements in the field of computational chemistry.
With respect to claim 3:
Samaniego et al. and Fern et al. do not disclose wherein constructing the enzymatic reaction process model with time delay specifically comprises:
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63
95
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67
98
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where the parameter
τ
represents a cumulative time delay present in the production of the output substance P.
However, Sawlekar et al. discloses the following reversible, bimolecular chemical reaction:
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1
27
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, and that unimolecular reactions feature only one reactant (pg. 444, col. 1, para. 2). Also, further discloses that degradation of a chemical species X at rate k into a waste product or an inert form is denoted as
PNG
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23
48
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(pg. 444, col. 1, para. 2, lines 10-11). This teaches the enzymatic reaction process model.
Sawlekar et al. does not disclose a time delay parameter.
However, Fern et al. discloses a chemical timer circuit consisting of the following two simultaneous abstract chemical processes that releases a target sequence of DNA at a constant rate from DNA complexes after a tunable delay period:
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89
135
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(pg. 190, col. 1, para. 2, lines 1-3; pg. 190, col. 1-2, para. 3-5). Also, further discloses a time delay
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56
92
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, which is the time needed to produce enough O to consume all of the D that is initially present (pg. 190, col. 2, para. 6). It would be obvious for one of ordinary skill in the art to modify the unimolecular and bimolecular chemical reactions disclosed by Sawlekar et al. to incorporate time delay disclosed by Fern et al. in order to achieve an enzymatic reaction process model where the conversion of the output substance into inert waste depends on time delay of the output substance, which amounts to routine optimization.
With respect to claim 6:
Samaniego et al. and Fern et al. do not disclose wherein constructing the Brink controller by DNA strand displacement reaction, specifically comprises: set
i
,
x
,
y
,
z
as variables, where
i
∈
1,2
,
…
,
12
,
x
∈
1,2
,
…
,
8
,
y
∈
1,2
,
3,4
,
z
∈
1,2
,
…
,
9
.
However, Sawlekar et al. discloses DNA strand displacement reaction implementations for catalysis, bimolecular, and degradation reactions (pg. 447, Fig. 5 and 6; pg. 448, Fig. 8). It would be obvious to one of ordinary skill in the art to routinely optimize the sets of variables i, x, y, and z for reaction indices, auxiliary substances, intermediate products, and inert wastes in order to generate the counts of the species necessary for constructing the desired DNA strand displacement implementations.
Fern et al. and Sawlekar et al. do not disclose for reactions
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241
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, there is a common DSD implementation mechanism between the two; these two reactions are converted into:
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228
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at the same time, there is also an identical realization mechanism between the reactions
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32
172
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, and the transformation is represented as:
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58
224
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for the reactions
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28
410
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31
73
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, the corresponding DNA implementations are represented as:
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278
239
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where
G
x
,
T
x
and
L
y
represent auxiliary substances involved in the reaction;
O
z
and
H
y
represent intermediate products;
B
y
represents inert wastes produced by the reaction which do not interact with other substances; further,
C
m
a
x
represents the initial concentration of the auxiliary substance;
q
m
a
x
represents the reaction rate of maximum strand displacement;
q
i
represents the reaction rate of the corresponding DNA implementation.
However, Samaniego et al. discloses the following list of Brink controller model reactions:
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40
268
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189
329
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(pg. 274, col. 1-2, para. 3). While reactant and product parameter representations in the Brink controller model reactions are different from those recited in the claim, they are still equivalent and not patentably distinct. One of ordinary skill in the art would be able to adjust the parameter representations to achieve the desired Brink controller reactions as this is merely aesthetic design choice. This teaches the reactions to be converted into DNA strand displacement implementations.
Samaniego et al. does not disclose the DNA strand displacement implementations of chemical reactions.
However, Sawlekar et al. discloses the following DNA strand displacement reaction implementations for catalysis, bimolecular, and degradation reactions, respectively:
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182
478
media_image42.png
Greyscale
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191
490
media_image43.png
Greyscale
PNG
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149
488
media_image44.png
Greyscale
(pg. 447, Fig. 5; pg. 448, Fig. 8). It would be obvious for one of ordinary skill in the art to modify the DNA implementations disclosed by Sawlekar et al. to incorporate the relevant Brink controller reactions disclosed by Samaniego et al. in order to achieve the desired DNA strand displacement implementations, which amounts to routine optimization.
With respect to claim 8:
Samaniego et al. and Fern et al. do not disclose wherein by applying the time delay representation to the DNA implementation of the enzymatic reaction process model, the enzymatic reaction model is rewritten as:
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156
127
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where
k
d
e
l
a
y
1
represents a delayed reaction rate.
However, Sawlekar et al. discloses the following reversible, bimolecular chemical reaction:
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1
27
media_image39.png
Greyscale
, and that unimolecular reactions feature only one reactant (pg. 444, col. 1, para. 2). Also, further discloses that degradation of a chemical species X at rate k into a waste product or an inert form is denoted as
PNG
media_image40.png
23
48
media_image40.png
Greyscale
(pg. 444, col. 1, para. 2, lines 10-11). This teaches the enzymatic reaction process model.
Sawlekar et al. does not disclose a time delay representation.
However, Fern et al. discloses a chemical timer circuit consisting of the following two simultaneous abstract chemical processes that releases a target sequence of DNA at a constant rate from DNA complexes after a tunable delay period:
PNG
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89
135
media_image34.png
Greyscale
(pg. 190, col. 1, para. 2, lines 1-3; pg. 190, col. 1-2, para. 3-5). Also, further discloses a time delay
PNG
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56
92
media_image41.png
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, which is the time needed to produce enough O to consume all of the D that is initially present (pg. 190, col. 2, para. 6). It would be obvious for one of ordinary skill in the art to modify the unimolecular and bimolecular chemical reactions disclosed by Sawlekar et al. to incorporate the time delay representation disclosed by Fern et al. to achieve a delayed enzymatic reaction for Brink control, which amounts to routine optimization.
Samaniego et al. and Fern et al. do not disclose combined with the mass action kinetics (MAKs), the following results are obtained:
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211
281
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.
However, Sawlekar et al. discloses applying Michaelis-Mentens kinetics to generate the following set of ordinary differential equations for an enzymatic reaction process model composed of both unimolecular and bimolecular reactions:
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166
267
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(pg. 446-447, col. 2, para. 5-6). This teaches obtaining ODEs combined with mass action kinetics. It would be obvious for one of ordinary skill in the art to adjust the ordinary differential equations to incorporate the relevant substrate and enzyme parameters representative of the enzymatic reaction process model for Brink control, which amounts to routine optimization.
Sawlekar et al. does not disclose applying the time delay representation.
However, Fern et al. discloses a chemical timer circuit consisting of the following two simultaneous abstract chemical processes that releases a target sequence of DNA at a constant rate from DNA complexes after a tunable delay period:
PNG
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89
135
media_image34.png
Greyscale
(pg. 190, col. 1, para. 2, lines 1-3; pg. 190, col. 1-2, para. 3-5). Also, further discloses a time delay
PNG
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56
92
media_image41.png
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, which is the time needed to produce enough O to consume all of the D that is initially present (pg. 190, col. 2, para. 6). It would be obvious for one of ordinary skill in the art to modify the ODEs disclosed by Sawlekar et al. to incorporate time delay disclosed by Fern et al. in order to achieve ODEs representative of the delayed enzymatic reaction process model for Brink control, which amounts to routine optimization.
With respect to claim 9:
Samaniego et al. and Fern et al. do not disclose wherein combined with the constructed Brink controller, controlling the delayed enzymatic reaction process model, specifically comprises:
converting reaction
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29
93
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to:
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62
228
media_image22.png
Greyscale
converting degradation reaction
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27
63
media_image23.png
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to:
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46
170
media_image24.png
Greyscale
further, converting reaction
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29
121
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to:
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58
242
media_image26.png
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for reversible reaction
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32
87
media_image27.png
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, the original reaction form is maintained when designing the DNA implementation.
However, Sawlekar et al. discloses the following reversible, bimolecular chemical reaction:
PNG
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1
27
media_image39.png
Greyscale
, and that unimolecular reactions feature only one reactant (pg. 444, col. 1, para. 2). Also, further discloses that degradation of a chemical species X at rate k into a waste product or an inert form is denoted as
PNG
media_image40.png
23
48
media_image40.png
Greyscale
(pg. 444, col. 1, para. 2, lines 10-11). This teaches the enzymatic reaction process model. Sawlekar et al. further discloses the following DNA strand displacement reaction implementations for catalysis, bimolecular, and degradation reactions, respectively:
PNG
media_image42.png
182
478
media_image42.png
Greyscale
PNG
media_image43.png
191
490
media_image43.png
Greyscale
PNG
media_image44.png
149
488
media_image44.png
Greyscale
(pg. 447, Fig. 5; pg. 448, Fig. 8). This teaches DNA strand displacement implementations for reactions in an enzymatic reaction process model. Reversible reactions are maintained in the DNA implementation for bimolecular reactions depicted in Figure 6.
Sawlekar et al. does not disclose a time delay representation.
However, Fern et al. discloses a chemical timer circuit consisting of the following two simultaneous abstract chemical processes that releases a target sequence of DNA at a constant rate from DNA complexes after a tunable delay period:
PNG
media_image34.png
89
135
media_image34.png
Greyscale
(pg. 190, col. 1, para. 2, lines 1-3; pg. 190, col. 1-2, para. 3-5). Also, further discloses a time delay
PNG
media_image41.png
56
92
media_image41.png
Greyscale
, which is the time needed to produce enough O to consume all of the D that is initially present (pg. 190, col. 2, para. 6). It would be obvious for one of ordinary skill in the art to modify the DNA implementations disclosed by Sawlekar et al. to incorporate a time delay representation disclosed by Fern et al. in order to achieve DNA implementations representative of a delayed enzymatic reaction for Brink control, which amounts to routine optimization.
Claim 10 which recites wherein the enzymatic reaction process model of the Brink-based controller is adjusted by using DSD mechanism; the proposed expression of DNA strand displacement with respect to time delay is improved, specifically as follows: the consumption of substance P in stage
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121
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in the enzymatic reaction is compensated by the following reaction mechanism to achieve the desired yield of output substance P:
PNG
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59
119
media_image28.png
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where
k
p
r
o
1
and
k
p
r
o
2
are both reaction rate constants and F is an additionally added reaction substance; combined with the mass action kinetics (MAKs), the corresponding ordinary differential equations (ODEs) are obtained:
PNG
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86
233
media_image29.png
Greyscale
further, reaction
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27
113
media_image30.png
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is converted to:
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91
228
media_image31.png
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reaction
PNG
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28
80
media_image32.png
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is converted to:
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60
241
media_image33.png
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Is free of the art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jammy Luo whose telephone number is (571)272-2358. The examiner can normally be reached Monday - Friday, 9:00 AM - 5:00 PM EST.
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/J.N.L./Examiner, Art Unit 1686
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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