DETAILED ACTION
Applicant’s response, filed Jun 18 2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 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.
Claim Status
Claims 1-2, 4-6, 10, 18, 20-21, 26-28, 35-36, 40, 51, and 71-73 are pending.
Claims 3, 7-9, 11-17, 19, 22-25, 29-34, 37-39, 41-50, and 52-70 are canceled.
Claims 71-73 are newly added.
Claims 2 and 73 are objected to.
Claims 1-2, 4-6, 10, 18, 20-21, 26-28, 35-36, 40, 51, and 71-73 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 62/965,138, filed Jan 23 2020.
However, 62/965,138 does not provide support for new claims 71-73.
Applicant's claim for the benefit of a prior-filed application, PCT/US2021/014814, filed Jan 23 2021, is acknowledged.
Accordingly, each of claims 1-2, 4-6, 10, 18, 20-21, 26-28, 35-36, 40, and 51 are afforded the effective filing date of Jan 23 2020, and claims 71-73 are afforded the effected filing date of Jan 23 2021.
Drawings
The replacement drawing sheets submitted Jun 18 2026 are accepted and the outstanding objections from the previous Office Action are withdrawn.
Specification
The amendments to the specification submitted Jun 18 2026 are accepted.
Claim Objections
The outstanding objections to the claims are withdrawn in view of the amendments submitted herein.
The claims are objected to because of the following informalities. The instant objection is newly stated and is necessitated by claim amendment, or is based upon further consideration of the claims.
Claim 2 recites “one of more of”, which should be amended to recite “one or more of”.
Claim 73 recites “the presence of absence”, which should be amended to recite “the presence or absence”.
Claim Interpretation
Contingent Claiming
Claim 4 continues to recite a contingent limitation, as set forth in the previous Office Action.
In the interest of compact prosecution, the instant claims are examined to consider all claim limitations. However, the claims contain recitations of intended use and contingent claim language that affect the scope of the claims, as listed below. The courts have stated that claims must be given their broadest reasonable interpretation (BRI) consistent with the specification (see MPEP § 2111).
The instant claims include a recitation of contingent claim language.
With respect to contingent claiming, said contingencies as claimed require that the claims are interpreted as provided for in the MPEP at 2111.04 (II), wherein: “the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met). For example, assume a method claim requires step A, if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A. If the claimed invention requires both the first and second conditions to occur, then the broadest reasonable interpretation of the claim requires both steps A and B”.
In the instant claims, the following is a “contingent” recitation:
Claim 73: “wherein if a sequence match is detected between one partial testing sequence database and one or more sequence fragments of the test biological molecule, the method further comprises detecting the presence of absence of a sequence match using another of the two or more partial testing sequence databases”.
With respect to the interpretations above, it is suggested that the claims be amended to recite alternative language so as to avoid interpretation of contingent claiming.
These claims and the particular intended use and contingent recitations have been examined with respect to the prior art in the interest of compact prosecution.
35 U.S.C. 112(f)
Claim 21 has been amended and no longer invokes interpretation under 35 USC 112(f).
Claim Rejections- 35 USC § 112
The outstanding 35 USC 112(a) and (b) rejections to the claims are withdrawn in view of the amendments submitted herein.
Claim Rejections - 35 USC § 101
The outstanding rejection to claim 64 is withdrawn because claim 64 has been cancelled.
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, 4-6, 10, 18, 20-21, 26-28, 35-36, 40, 51, and 71-73 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portions are necessitated by claim amendment.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to methods, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) are as follows:
Independent claim 1: (a) preselecting a biological molecule capable of a function of interest;
(b) preparing a testing sequence database comprising a plurality of sequence fragments of the preselected biological molecule, wherein the preselected sequence fragments are a predetermined length;
(c) identifying in the testing sequence database one or more sequence fragments of the preselected biological molecule that match one or more sequence fragments, respectively, of a second biological molecule having a biological function unrelated to the biological function of interest of the preselected biological molecule, and removing the identified one or more sequence fragments of the preselected biological molecule from the testing sequence database;
(d) fragmenting a test biological molecule into sequence fragments having the predetermined length;
(e) detecting a presence or absence of a sequence match between the sequence of at least one sequence fragment of the test biological molecule and at least one of the plurality of sequence fragments of the preselected biological molecule; and
(f) performing an action in response to the detecting in (e).
Independent claim 35: (a) preselecting a biological molecule capable of a function of interest;
(b) preparing a testing sequence database comprising a plurality of sequence fragments of the preselected biological molecule, wherein the preselected sequence fragments are a predetermined length, and preparing the testing sequence data comprises:
(i) screening the plurality of sequence fragments of the preselected biological molecule against a control sequence database, wherein the control sequence database comprises a plurality of control sequence fragments of at least one molecule capable of a function of interest unrelated to the function of interest of the preselected biological molecule;
(ii) identifying the presence of a match between a sequence fragment in the plurality of sequence fragments of the preselected biological molecule and a control sequence fragment in the control sequence database; and
(iii) removing from the testing sequence database the sequence fragment of the preselected biological molecule identified as matching the control sequence fragment;
(c) fragmenting a test biological molecule into sequence fragments having the predetermined length; and
(d) detecting a presence or absence of a sequence match between the sequence of at least one sequence fragment of the test biological molecule and at least one of the plurality of sequence fragments of the preselected biological molecule.
Dependent claim 5: wherein a means of preparing the testing sequence database comprises:
(i) screening the plurality of sequence fragments of the preselected biological molecule against a control sequence database, wherein the control sequence database comprises a plurality of control sequence fragments of at least one molecule capable of a function of interest unrelated to the function of interest of the preselected biological molecule;
(ii) identifying the presence of a match between a sequence fragment in the plurality of sequence fragments of the preselected biological molecule and a control sequence fragment in the control sequence database; and
(iii) removing from the testing sequence database the sequence fragment of the preselected biological molecule identified as matching the control sequence fragment.
Dependent claim 21: identifying the functional equivalents….
Dependent claim 72: dividing the testing sequence database into two or more partial testing sequence databases.
Dependent claim 73: wherein if a sequence match is detected between one partial testing sequence database and one or more sequence fragments of the test biological molecule, the method further comprises detecting the presence of absence of a sequence match using another of the two or more partial testing sequence databases.
Dependent claims 2, 6, 10, 18, 20, 26-28, 36, 40, 51, and 71 recite further steps that limit the judicial exceptions in independent claims 1 and 35 and, as such, also are directed to those abstract ideas. For example, claim 2 further limits the action of claim 1(f) to one or more of DNA molecule design and further sequence identification steps; claims 6 and 36 further limit the preselected biological molecule to a polynucleotide; claims 10 and 40 further limit the preselected biological molecule to a polypeptide; claims 18 and 20 further limit the testing sequence database composition; and claims 26-28, 51, and 71 further limit the identities of all sequence fragments of one or both of the testing sequence database and the test biological molecule to being protected using a cryptographic hash function.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually detect a sequence match between fragments of a preselected biological molecule and one or more test biological molecules, and then performing an action in response to the detection. Without further detail as to the methodology involved in “preselecting”, “preparing”, “fragmenting”, “detecting”, “performing an action”, “identifying”, and “dividing”, under the BRI, one may simply, for example, use pen and paper to preselect a biological molecule with a function of interest, fragment the sequence of the preselected biological molecule into predetermined lengths to prepare a testing sequence database, screen those fragments against control sequences associated with an unrelated function of interest and remove any matches from the testing sequence database, identify functional equivalents using a computational means and adding the functionally equivalent sequences to the testing sequence database, divide the testing sequence database into two or more partial testing sequence databases, fragment the sequence of one or more test biological molecules into predetermined lengths, detect whether or not there is match between the testing sequence database or one partial testing sequence database and the fragments of the test biological molecules, detecting the presence or absence of a sequence match using another of the two or more partial testing sequence databases if a sequence match is detected using the one partial testing sequence database, and perform an action in response to detecting step, where the action could be to design a DNA molecule or perform a further sequence identification step which could comprise a computational step able to be performed mentally.
Therefore, claims 1 and 35 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Dependent claim 2: wherein the action comprises one of more of: preventing synthesis of the test biological molecule, permitting synthesis of the test biological molecule, performing sequencing one or more polynucleotide molecules, performing DNA sequencing, and making polypeptide sequence determination.
Dependent claim 4: wherein if the presence of a sequence match is detected in (e) the action comprises preventing synthesis of the test biological molecule.
Dependent claim 21: … using a computational means.
It is noted that “a computational means” is interpreted as requiring a computer to perform the action.
Dependent claim 71: wherein the plurality of independent sources comprise independent computer servers.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to preventing synthesis of the test biological molecule, permitting synthesis of the test biological molecule, sequencing one or more polynucleotide molecules, DNA sequencing, and polypeptide sequence determination in response to (d), as in claim 2, are mere instructions to apply the judicial exception to a technical field (MPEP 2106.05(f)). Claim 2 recites the idea of a solution or outcome but fails to recite details of how a solution to a problem is accomplished in a general manner. Further, claim 2 also recites actions which are judicial exceptions, as explained above, and requires only one of the recited actions. Therefore, the additional elements recited in claim 2 are not required to be performed. Further, the action in is only performed in response to the performance of step (e), but does not link the actions to the outcome of step (d), i.e, whether a sequence match is detected or not. Claim 4 recites a contingent limitation which is not required to be performed and therefore cannot provide a practical application at Step 2A, Prong 2. It is noted that even if “preventing synthesis” were not recited contingently, such an action does not actually perform an action in the real world that would provide a practical application to the recited judicial exceptions.
Further additional non-abstract steps directed to additional non-abstract elements of “a computational means” and “the plurality of independent sources comprise independent computer servers” do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exception of perform identifying the functional equivalents and the cryptographic hash function, nor do they provide any details of how specific structures of the computer are used to implement these functions beyond performing actions in a parallel manner. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc.… are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (MPEP 2106.05(f)).
The specification as published discloses applications of the method in general at [0003], but does not provide a clear explanation for how the additional elements provide these improvements. Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly affect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represent other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the specification as published discloses that “Various means of assessing DNA molecule design, sequencing of DNA and/or protein sequences are known in the art and can be applied as part of an action” at [0044], indicating that synthesis of biological molecules, sequencing one or more polynucleotide/DNA molecules, and polypeptide sequence determination are “apply it” additional elements that are routine, well-understood and conventional in the art. Further, the prior art review to Yang et al. (IEEE Access, 2019, 7:159426-159465; newly cited) discloses that requiring a plurality of independent computer servers to compute a cryptographic has function is well-understood, routine, and conventional (see at least p. 159444, col. 1, par. 3 to col. 2, par. 1; p. 159450, col. 2, par. 1). As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to claims 21 and 73 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (see MPEP 2106.06(A)). Further, the specification provides no disclosure of a specialized computer. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (see MPEP 2106.05(b)I-III).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Response to Applicant Arguments
At p. 11-12, section V, Applicant submits that independent claims 1 and 35 include limitations that cannot be practically performed in the human mind, because, while a human is capable of comparing two things to identify a match, a human cannot practically compare a multitude of sequence fragments in a database.
It is respectfully submitted that this is not persuasive. Applicant has offered no reasoning that or specific arguments why a human mind cannot perform the limitations “identifying in the testing sequence database one or more sequence fragments of the preselected biological molecule that match one or more sequence fragments, respectively, of a second biological molecule having a biological function unrelated to the biological function of interest of the preselected biological molecule, and removing the identified one or more sequence fragments of the preselected biological molecule from the testing sequence database” in claim 1 and those directed to screening, identifying, and removing in claim 35. There are no limitations in the instant claim to preclude a human mind from performing these actions, as described in the above rejection. The claims merely require a human mind to fragment a sequence and compare those fragments to fragments from another sequence. The claims do not limit the number or the size of fragments being compared, and thus read on the comparison of even two small fragments from the preselected biological molecule to two small fragments of the second biological molecule. Therefore, the claims encompass an embodiment which a human mind is capable of being performed.
Even if the claims were limited to require more extensive comparisons of sequences, it is considered that such actions would also be capable of being performed in a human mind. If a claim recites a limitation that can practically be performed in the human mind, with or without the use of a physical aid such as pen and paper, the limitation falls within the mental processes grouping, and the claim recites an abstract idea. See, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674 (noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, 839 F.3d at 1139, 120 USPQ2d at 1474 (holding that claims to the mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper").
Claim Rejections - 35 USC § 102
The outstanding rejections from the previous Office Action are withdrawn in view of the amendments submitted herein. Claim 1 does not teach limitation (c) “removing the identified one or more sequence fragments of the preselected biological molecule from the testing sequence database”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
A. Claims 1-2, 4-6, 10, 18, 20-21, 26-27, 35-36, 40, 51, and 71-73 are rejected under 35 U.S.C. 103 as being unpatentable over Esvelt (PLOS Pathogens, 2018, 14(1):e1007286, p. 1-7; cited on the Feb 2 2023 IDS) in view of Diggans (US 2017/0357,752; newly cited). The instant rejection is newly stated and is necessitated by claim amendment.
Claim 1 discloses a method of assessing a biological sequence capable of a preselected function.
The method of claim 1 comprises:
(a) preselecting a biological molecule capable of a function of interest;
(b) preparing a testing sequence database comprising a plurality of sequence fragments of the preselected biological molecule, wherein the preselected sequence fragments are a predetermined length;
(c) identifying in the testing sequence database one or more sequence fragments of the preselected biological molecule that match one or more sequence fragments, respectively, of a second biological molecule having a biological function unrelated to the biological function of interest of the preselected biological molecule, and removing the identified one or more sequence fragments of the preselected biological molecule from the testing sequence database;
(d) fragmenting a test biological molecule into sequence fragments having the predetermined length; and
(e) detecting a presence or absence of a sequence match between the sequence of at least one sequence fragment of the test biological molecule and at least one of the plurality of sequence fragments of the preselected biological molecule; and
(f) performing an action in response to the detecting in (e).
The prior art to Esvelt discloses a description of an upgrade the current system for screening synthesized DNA for hazardous sequences (abstract). Esvelt teaches that order fragments of approximately 40 bp (i.e., fragments of one or more test biological molecules in steps (b) and (d)) could be screened for exact matches (i.e., detecting a match in step (d); to provide an assessment as in step (e)) against a hashed database of hazardous sequences (i.e., testing sequence database of sequence fragments of a preselected biological molecule of interest capable of a function of interest in steps (a)-(b)) by a cooperative international network of servers (Fig. 1; p. 2, par. 3). Esvelt teaches cleared sequences can be synthesized (i.e., acting in response in step (e)) (Fig. 1). Esvelt teaches that the database contains hazardous sequences curated by experts (Fig. 1), which indicates that non-hazardous sequences are not present in the database. However, Esvelt does not explicitly teach limitation (c).
However, the prior art to Diggans discloses software tools for effective biosecurity based on community knowledge and participation (abstract). Diggans teaches database comprising a list of harmful biological sequences, receiving one or more design instructions for a plurality of biological sequences, and automatically determining whether the plurality of biological sequences corresponds to a threshold of the harmful biological sequences in the database [0003]. Diggans teaches that the database pathogenic proteins to the database in an attempt to include most potentially regulated sequences or other sequences known to be harmful, and that the system may curate an “unrestricted” list of NCBI GI identifiers corresponding to genes that may be considered harmless [0036]. Diggans teaches that sequences found to be on the restrictive list are further evaluated against an unrestricted list that comprises known false positives (i.e., steps (i)-(ii) of claim 5) [0041].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Esvelt and Diggans because both references disclose methods for screening biological sequences before sequencing. Although Diggans does not explicitly teach removing sequences found on both the restricted and unrestricted list, it would have been obvious to one of ordinary skill in the art to remove those sequences, because Diggans teaches that they are known to be false positives for identifying harmful sequences [0041].
Regarding claim 2, Esvelt in view of Diggans teaches claim 1 as described above. Claim 2 further adds that action comprises one of more of preventing synthesis of the test biological molecule, permitting synthesis of the test biological molecule, sequencing one or more polynucleotide molecules, performing DNA sequencing, performing DNA molecule design, making polypeptide sequence determination, and further sequence identification steps.
Esvelt teaches clearing orders for DNA synthesis after screening (i.e., permitting synthesis of the test biological molecule) (Fig. 1) and universal DNA synthesis screening for hazardous prior to DNA synthesis (i.e., preventing synthesis of the test biological molecule).
Regarding claim 4, Esvelt in view of Diggans teaches claim 1 as described above. Claim 4 further adds that if the presence of a sequence match is detected in (e) the action comprises preventing synthesis of the test biological molecule.
Esvelt teaches clearing orders for DNA synthesis after screening (i.e., permitting synthesis of the test biological molecule) (Fig. 1) and universal DNA synthesis screening for hazardous sequences prior to DNA synthesis (i.e., preventing synthesis of the test biological molecule).
Regarding claim 5, Esvelt in view of Diggnas teaches claim 1 as described above. Claim 5 further adds a means of preparing the testing sequence database that comprises: (i) screening the plurality of sequence fragments of the preselected biological molecule against a control sequence database, wherein the control sequence database comprises a plurality of control sequence fragments of at least one molecule capable of a function of interest unrelated to the function of interest of the preselected biological molecule; (ii) identifying the presence of a match between a sequence fragment in the plurality of sequence fragments of the preselected biological molecule and a control sequence fragment in the control sequence database; and (iii) removing from the testing sequence database the sequence fragment of the preselected biological molecule identified as matching the control sequence fragment.
Esvelt teaches that the database contains hazardous sequences curated by experts (Fig. 1), which indicates that non-hazardous sequences (i.e., control sequences) are not present in the database, but does not explicitly teach the limitations of steps (i)-(iii).
However, the prior art to Diggans discloses software tools for effective biosecurity based on community knowledge and participation (abstract). Diggans teaches database comprising a list of harmful biological sequences, receiving one or more design instructions for a plurality of biological sequences, and automatically determining whether the plurality of biological sequences corresponds to a threshold of the harmful biological sequences in the database [0003]. Diggans teaches that the database pathogenic proteins to the database in an attempt to include most potentially regulated sequences or other sequences known to be harmful, and that the system may curate an “unrestricted” list of NCBI GI identifiers corresponding to genes that may be considered harmless [0036]. Diggans teaches that sequences found to be on the restrictive list are further evaluated against an unrestricted list that comprises known false positives (i.e., steps (a)-(b) of claim 5) [0041].
Regarding claim 6, Esvelt in view of Diggans teaches claim 1 as described above. Claim 6 further adds that the preselected biological molecule is a polynucleotide.
Esvelt teaches screening DNA (i.e., a polynucleotide) synthesis orders (Fig. 1).
Regarding claim 10, Esvelt in view of Diggnas teaches claim 1 as described above. Claim 10 further adds that the preselected biological molecule comprises a polypeptide molecule, which Esvelt does not teach.
However, Diggans teaches examining protein sequences of pathogens [0022].
Regarding claim 18, Esvelt in view of Diggnas teaches claim 1 as described above. Claim 18 further adds that the testing sequence database comprises one or more sequence fragments randomly or pseudorandomly selected from sequences of molecules known to be capable of a function different from the function of interest of the preselected biological molecule, which Esvelt does not teach.
However, Diggans teaches an “unrestricted” list of NCBI GI identifiers corresponding to genes that may be considered harmless [0036], which reads on random or pseudorandom selected from sequences of molecules known to be capable of a function different from the preselected molecule's function of interest as instantly claimed.
Regarding claim 20-21, Esvelt in view of Diggnas teaches claim 1 as described above. Claim 20 further adds that the testing sequence database further comprises sequences that are functional equivalents of the plurality of sequence fragments of the preselected biological molecule. Claim 21 further adds identifying the functional equivalents using a computational means.
Esvelt teaches that hazardous sequences could be filtered (i.e., a computational means) from crowdsourced suggestions (i.e., functional equivalents) by an international team of experts (Fig. 1).
Regarding claim 26-27, Esvelt in view of Diggans teaches claim 1 as described above. Claim 26 further adds that the identities of all sequence fragments of one or both of the testing sequence database and the test biological molecule are protected. Claim 27 further adds a means of the protecting comprises application of a cryptographic hash function, wherein the cryptographic hash function deterministically maps the sequence data to a bit string of fixed size using a one-way function.
Esvelt teaches performing local one-way encryption (i.e., protection) to produce hashed DNA synthesis orders which are screened against a hashed database (Fig. 1).
Claim 35 discloses a method of identifying a biological sequence capable of a preselected function.
The method of claim 35 comprises:
(a) preselecting a biological molecule capable of a function of interest;
(b) preparing a testing sequence database comprising a plurality of sequence fragments of the preselected biological molecule, wherein the preselected sequence fragments are a predetermined length, and preparing the testing sequence data comprises:
(i) screening the plurality of sequence fragments of the preselected biological molecule against a control sequence database, wherein the control sequence database comprises a plurality of control sequence fragments of at least one molecule capable of a function of interest unrelated to the function of interest of the preselected biological molecule;
(ii) identifying the presence of a match between a sequence fragment in the plurality of sequence fragments of the preselected biological molecule and a control sequence fragment in the control sequence database; and
(iii) removing from the testing sequence database the sequence fragment of the
preselected biological molecule identified as matching the control sequence fragment;
(c) fragmenting a test biological molecule into sequence fragments having the predetermined length; and
(d) detecting a presence or absence of a sequence match between the sequence of at least one sequence fragment of the test biological molecule and at least one of the plurality of sequence fragments of the preselected biological molecule.
The prior art to Esvelt discloses a description of an upgrade the current system for screening synthesized DNA for hazardous sequences (abstract). Esvelt teaches that order fragments of approximately 40 bp (i.e., fragments of one or more test biological molecules in step (c)) could be screened for exact matches (i.e., equivalent length to predetermined length of sequence fragments of preselected biological molecule in step (c); detecting a match in step (d)) against a hashed database of hazardous sequences (i.e., testing sequence database of sequence fragments of a preselected biological molecule of interest capable of a function of interest in steps (a)-(b)) by a cooperative international network of servers (Fig. 1; p. 2, par. 3). Esvelt teaches that the database contains hazardous sequences curated by experts (Fig. 1), which indicates that non-hazardous sequences (i.e., control sequences) are not present in the database, but does not explicitly teach the limitations of steps (i)-(iii).
However, the prior art to Diggans discloses software tools for effective biosecurity based on community knowledge and participation (abstract). Diggans teaches database comprising a list of harmful biological sequences, receiving one or more design instructions for a plurality of biological sequences, and automatically determining whether the plurality of biological sequences corresponds to a threshold of the harmful biological sequences in the database [0003]. Diggans teaches that the database pathogenic proteins to the database in an attempt to include most potentially regulated sequences or other sequences known to be harmful, and that the system may curate an “unrestricted” list of NCBI GI identifiers corresponding to genes that may be considered harmless [0036]. Diggans teaches that sequences found to be on the restrictive list are further evaluated against an unrestricted list that comprises known false positives (i.e., steps (i)-(ii)) [0041].
Regarding claims 35, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Esvelt and Diggans because both references disclose methods for screening biological sequences before sequencing. Although Diggans does not explicitly teach removing sequences found on both the restricted and unrestricted list, it would have been obvious to one or ordinary skill in the art to remove those sequences, because Diggans teaches that they are known to be false positives for identifying harmful sequences [0041].
Regarding claim 36, Esvelt in view of Diggans teaches claim 35 as described above. Claim 36 further adds that the preselected biological molecule is a polynucleotide.
Esvelt teaches screening DNA (i.e., a polynucleotide) synthesis orders (Fig. 1).
Regarding claim 40, Esvelt in view of Diggans teaches claim 35 as described above. Claim 36 further adds that the preselected biological molecule comprises a polypeptide molecule, which Esvelt does not teach.
However, Diggans teaches examining protein sequences of pathogens [0022].
Regarding claim 51, Esvelt in view of Diggans teaches claim 35 as described above. Claim 36 further adds that the identities of all sequence fragments of one or both of the testing sequence database and the test biological molecule are protected.
Esvelt teaches performing local one-way encryption (i.e., protection) to produce hashed DNA synthesis orders which are screened against a hashed database (Fig. 1).
Regarding claim 71, Esvelt in view of Diggans teaches claims 1 and 26-27 as described above. Claim 71 further adds that the cryptographic hash function requires keys from a plurality of independent sources, thereby requiring the plurality of independent sources to cooperate to compute the hash without any one independent source gaining access to the sequence fragments, wherein the plurality of independent sources comprise independent computer servers.
Esvelt teaches that orders and database could be kept private using uniquely salted local hashes plus a multiparty ball-and-chain (i.e., keys from a plurality of independent sources), using a cooperative network of servers (i.e., independent computer servers) (Fig. 1).
Regarding claim 72-73, Esvelt in view of Diggans teaches claim 1 as described above. Claim 72 further adds dividing the testing sequence database into two or more partial testing sequence databases. Claim 73 further adds that if a sequence match is detected between one partial testing sequence database and one or more sequence fragments of the test biological molecule, the method further comprises detecting the presence of absence of a sequence match using another of the two or more partial testing sequence databases. Esvelt does not teach these claims.
However, Diggans teaches that the system may carry out an initial curation process adding many pathogenic proteins to the database (i.e., testing sequence database) in an attempt to include most potentially regulated sequences or other sequences known to be harmful [0036]. Diggans then teaches a workflow where query sequences are queried to databases containing sequence annotations identifying sequences associated with harmful biological sequences (protein or nucleic acids), also referred to as “restricted” lists (i.e., partial testing sequence databases), which are available for a user to select for screening [0040; 0042]. As Diggans teaches an initial database as well as multiple restricted lists, it is considered that Diggans fairly teaches dividing the testing sequence database into two or more partial testing sequence databases as instantly claimed.
Regarding claim 73, it is noted that the claim recites a contingent limitation and is not required to be performed. Therefore, Esvelt in view of Diggans is considered to teach the required scope of the claim. However, it is noted that Diggans also teaches a data input source such as physical nucleic acid or protein material (which can be sequenced), a nucleic acid sequence (which can be translated into a protein sequence), or a protein sequence can be evaluated using an algorithm which searches one or more databases to determine if it is on a restricted list, and sequences found to be on the restrictive list are further evaluated against an unrestricted list that comprises known false positives [0041]. Therefore, Diggans teaches searching another database if a match to a restrictive list, which reads on a partial testing sequence, is found.
While Diggans does not explicitly teach searching another restrictive list in response to finding a match in one restrictive list, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify, in the course of routine experimentation and with a reasonable expectation of success, Esvelt and Diggans to iteratively search different restricted lists based on whether previous matches were found, because Diggans teaches performing iterative searches on successive databases as well as multiple restricted lists.
B. Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Esvelt in view of Diggans, as applied to claims 1 and 26-27 above, and as evidenced by El-Moursy et al. (J. Softw. Eng. Intell. Syst, 2018, 3(1):67-82; previously cited).
Regarding claim 28, Esvelt in view of Diggans teaches claims 1 and 26-27 as described above. Claim 28 further adds that the application of the cryptographic hash function cannot be reversed without a brute-force search of all possible sequence inputs into the testing sequence database, optionally, wherein the application of the cryptographic hash function further comprises use of one or more information keys that must be accessed to attempt the brute-force search.
The claim is interpreted only serving to further limit the cryptographic hash function applied in claim 27 to one that cannot be reversed without a brute-force search, While Esvelt teaches hash functions to protect the DNA synthesis orders and the database (Fig. 1), Esvelt does not explicitly teach that the hash function can be reversed with a brute-force search of all possible sequence inputs into the testing sequence database. However, as evidenced by El-Mousry, the key element of breaking any encryption mechanism, including encryption of DNA sequences, is brute force attacks (p. 74, par. 2). Therefore it is considered that the hash function taught by Esvelt inherently teaches claim 28.
Response to Applicant Arguments
At p. 12-14, Applicant submits that Diggans just leaves harmless, i.e., false positive, genes in the "restricted" database and utilizes a secondary unrestricted list to identify a false positive, claim 1 recites removing a sequence fragment(s) from the testing sequence database. Diggans and claim 1 recite distinct database management techniques that result in two different sequence assessment protocols. By removing a sequence fragment(s) as claimed, one need not separately maintain the unrestricted list of Diggans.
It is respectfully submitted that this is not persuasive. Applicant’s assessment of the art of Diggans is agreed upon and is discussed in the above rejection. However, the rejection goes on to say that it would have been obvious to one of ordinary skill in the art to remove the harmless sequences from the restricted database, motivated by the teaching of Diggans that they are known to be false positives for identifying harmful sequences [0041]. As Esvelt teaches a database with only hazards (Fig 1), it is considered that one of ordinary skill in the art would recognize that removing harmless sequences from a database of hazardous sequences would result in the database taught by Esvelt. As Applicant has provided no arguments to this reasoning, the rejection is maintained.
Regarding Applicant’s assertion that the instant invention allows one to not need to maintain the unrestricted list of Diggans, it is further noted that the claims do not preclude such a list from being maintained. The claims merely recite removing the unrelated sequence fragments from the testing sequence database.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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