DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Herein, “the previous Office action” refers to the Final Rejection filed 4/23/2025.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/23/2025 has been entered.
Priority
As detailed on the Filing Receipt filed 6/20/2021, the instant application claims priority to as early as 5/31/2018. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Claim Status
Claims 17-20 and 22-23 are cancelled.
Claims 1-16, 21 and 24-30 are pending.
Claims 2, 6-7, 9, 11-13 and 15 stand withdrawn pursuant to 37 CFR 1.142(b) as being directed to a nonelected invention, there being no currently allowable generic or linking claim. Election without traverse was made in the reply filed 8/12/2024.
Claims 1, 3-5, 8, 10, 14, 16, 21 and 24-30 are under examination.
Withdrawn Rejections
The rejection of claims 1, 3-5, 8, 10, 14, 16, 21 and 24-30 under 35 USC § 102, as being anticipated by Fleishman, is hereby withdrawn in view of Applicant’s amendment of the claims, persuasive argument that Fleishman does not disclose performance of structural decomposition using a graphical representation as required by claim 1 (pg. 8, para. 5 - pg. 9, para. 1), and consideration that Fleishman does not anticipate deduction of the ordered hierarchy of energetic contributions as required by amended claim 10. Please note that the hierarchy is nonetheless considered obvious in light of Fleishman, as explained in the new rejection under 35 USC § 103 herein.
Response to Arguments - Claim Rejections Under 35 USC § 101
In the remarks filed 6/23/2025, Applicant traverses the rejection under 35 USC § 101 and presents supportive arguments.
Applicant alleges that neither of the recited steps of “decomposing a target structure into a plurality of structural motifs” and “generating at least one candidate amino acid sequence” are practicably performable in the human mind, and thus are not properly characterized as mental processes (pg. 6, para. 6 – pg. 7, para. 1).
Given a printed visual key to a plurality of characteristic structural motifs, and a corresponding graphical representation of a target protein structure depicting structural motifs as shown in the key, the human mind is capable of identifying motifs within the representation and reproducing them with pen and paper. The human mind is also capable of writing out an amino acid sequence using pen and paper.
The courts have held that “methods which can be performed mentally, or which are the
equivalent of human mental work, are unpatentable abstract ideas… the ‘basic tools of
scientific and technological work’ that are open to all” (CyberSource Corp. v. Retail Decisions,
Inc., 654 F.3d 1366, 1371 (Fed. Cir. 2011)). The cited steps, as written, are considered as computerized implementations of human mental work and the argument against mental performance is found unpersuasive.
Applicant alleges that the pending claims recite additional elements that integrate the alleged judicial exceptions into a practical application, and highlights the recited steps of: decomposing a target structure, generating at least one candidate amino acid, and expressing a foldable protein (pg. 7, paras. 2-3).
The first and second of these steps are considered as equivalents of human mental work, as discussed above. The third referenced step constitutes a post-solutional application of the data output by prior method steps, i.e., insignificant extra-solution activity. As such, the third step does not integrate the abstract idea into a practical application (MPEP 2106.05(g)). Thus, the argument of integration into a practical application is found unpersuasive.
Applicant highlights amendment of the claims to require that an expressed protein is foldable, and alleges that expressing a foldable protein comprising a candidate amino acid generated from previous steps is not well-understood, routine or conventional (pg. 7, para. 4).
Particular prior art references (Mason, Suo and Thomas) were cited in the previous Office action to support the conclusion that expressing a protein, comprising a candidate amino acid, constitutes well-understood, routine and conventional activity. Each of these references describes optimization of a sequence that codes for a particular protein structure, and enhanced production of the protein via expression of an optimized amino acid sequence in plant cells.
Mason et al (Vaccine 16(13): 1336-1343; published 1998; previously cited) describes “enhanced production of LT-B”, the B subunit of heat-labile enterotoxin, “in potato plants using a synthetic LT-B (sLT-B) coding sequence modified to contain plant-preferred codons and to eliminate spurious mRNA processing signals” (pg. 1337, l. column).
Suo et al (Plant Cell Reports 25: 689-697; published 2/21/2006; previously cited) discusses “the effects of codon optimization on the expression of human BMP2”, bone morphogenetic protein 2, “in tobacco plants” (pg. 689, Abstract), and presents findings of increased expression of BMP2 after introduction of certain optimized sequences (pg. 696, r. column).
Thomas et al (Plant Cell Reports 33: 1801-1814; published 2014; previously cited) presents a “study, [wherein] hEGF”, human epidermal growth factor, “was transiently expressed in Nicotiana benthamiana plants… Using a codon optimized sequence was found to increase the yield” (pg. 1801, Abstract).
Successful (e.g., enhanced) production of a particular protein via a biological expression system, as each of these references describe, necessarily requires that an expressed amino acid sequence is foldable into the structure of the particular protein. Mason describes expression of a candidate amino acid sequence that is foldable into the structure of LT-B, Suo describes expression of a candidate amino acid sequence that is foldable into the structure of BMP2, and Thomas describes expression of a candidate amino acid sequence that is foldable into the structure of hEGF.
In this way, review of the prior art of record indicates that the recited step of expressing a foldable protein, comprising a candidate amino acid sequence, is well-understood, routine and conventional activity. Thus, the argument of unconventional nature is found unpersuasive.
For the above reasons, the arguments are found unpersuasive and the rejection is maintained.
Claim Rejections - 35 USC § 101
35 USC § 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-5, 8, 10, 14, 16, 21 and 24-30 are rejected under 35 USC § 101 because the claimed invention is directed to non-statutory subject matter. This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 6/23/2025).
"Claims directed to nothing more than abstract ideas, natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts (including formulas, equations and calculations), and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than an abstract idea.
Step 1: The Four Categories of Statutory Subject Matter (MPEP 2106.03)
The claims are directed to methods (claims 1, 3-5, 8, 10, 14 and 26-30), non-transitory computer-readable storage media (claims 16 and 21) and systems (claims 24-25), which fall under categories of statutory subject matter.
Step 2A, Prong One: Whether the Claims Set Forth or Describe a Judicial Exception (MPEP 2106.04 § II.A.1)
‘Mathematical concepts’ are relationships between variables and numbers, numerical formulas or equations, or acts of calculation, which need not be expressed in mathematical symbols (MPEP 2106.04(a)(2) § I). The claims recite elements which encompass mathematical concepts, at least under their broadest reasonable interpretation, including:
“deducing a value for at least one non-local energetic contribution to a sequence-structure relationship using each of the plurality of structural matches” (claim 1);
“acquiring a value for at least one local energetic contribution to a sequence-structure relationship using each of the plurality of structural matches” (claim 5); and
“sequentially deducing a set of values for energetic contributions to a sequence-structure relationship using each of the plurality of structural matches” (claim 10).
The above elements encompass acts of calculating energetic contribution values, using a mathematical formula, for each member of a data set of structural matches. The recited acts of calculation constitute mathematical concepts.
‘Mental processes’ are processes that can be performed in the human mind at least with use of a physical aid, e.g., a slide rule or pen and paper (MPEP 2106.04(a)(2) § III). The recited acts of calculation comprise steps of evaluating information that are practicably performable in the human mind, in at least simple embodiments under the broadest reasonable interpretation of the claims, rendering them as mental processes. Additionally, the claims recite elements that encompass further processes that are practicably performable in the human mind, at least under their broadest reasonable interpretation, including:
“decomposing a target structure into a plurality of structural motifs using a graphical representation of coupled residues of the target structure and/or residue-backbone influences of the target structure” (claim 1), i.e., subsetting information based on a graphical key;
“decomposing a target structure into a plurality of structural motifs” (claim 10), i.e., subsetting information;
“identifying… a plurality of structural matches for each of the plurality of structural motifs” (claims 1 and 10), i.e., matching information; and
“generating at least one candidate amino acid sequence” (claims 1 and 10), i.e., generating information; and
“organizing the set of values for energetic contributions into a table” (claim 30), i.e., arranging information.
The recited elements encompass steps that are practicably performable in the human mind, because the human mind is capable of, e.g., comparing sequences and identifying matches between those sequences. The recited steps of manipulating and generating information therefore constitute mental processes.
The following claim element delimits embodiments of the above abstract ideas, but does not alter their characterization as abstract ideas:
“the candidate amino acid is foldable into the target structure or a binding partner of the target structure” (claims 1 and 10);
“the at least one non-local energetic contribution is from a backbone in spatial but not sequence proximity to a single design position within one of the plurality of structural motifs” (claim 3);
“the at least one non-local energetic contribution is from a pair of coupled residues within one of the plurality of structural motifs” (claim 4);
“the target structure is a tertiary structure of a protein” (claims 8, 14, 26 and 28);
“according to a hierarchy of energetic contributions… comprising: first, at least one local energetic contribution for a single design position within one of the plurality of structural motifs for backbone ϕ (phi) and ψ (psi) dihedral angles, second, at least one local energetic contribution for a single design position within one of the plurality of structural motifs for backbone (omega) dihedral angles… [and] one or more of… at least one non-local energetic contribution from a backbone in spatial but not sequence proximity to the single design position, [and] at least one non-local energetic contribution from a pair of coupled residues comprising the single design position” (claim 10);
“for… design of an amino acid sequence that can fold into a target structure” (claims 16 and 21); and
“the candidate amino acid is foldable into the target structure” (claims 27 and 29).
Hence, the claims recite elements that, individually and in combination, constitute an abstract idea. The claims must therefore be examined further to determine whether they integrate this abstract idea into a practical application (MPEP 2106.04(d)).
Step 2A, Prong Two: Whether the Claims Contain Additional Elements that Integrate the Judicial Exception(s) into a Practical Application (MPEP 2106.04 § II.A.2)
The claims recite additional elements which require performance of claimed functions on a computer and/or constitute computer structures that perform claimed functions, including:
“in silico” (claims 1, 10 , 16, 21, and 24-25);
“in a structural database” (claims 1 and 10) i.e., a digital data structure;
“A non-transitory computer-readable storage medium encoded with instructions… executable by a processor and comprising the method” (claims 16 and 21); and
“A system … comprising a processor and computer-executable instructions that cause the processor to perform the method” (claims 24-25).
The claims do not describe any specific computational steps by which a computer performs or carries out functions drawn to the abstract idea , nor do they provide any details of how specific structures of a computer are used to implement these functions. The claims state nothing more than that a generic computer performs functions drawn to the abstract idea, and are therefore mere instructions to apply the abstract idea using a computer. As such, the claims do not integrate the abstract idea into a practical application (see MPEP 2106.04(d) § I and 2106.05(f)).
The claims further recite the following additional element which applies the result of claimed method steps:
“expressing a foldable protein comprising the candidate amino acid sequence in an expression system” (claims 1 and 10).
This element constitutes a post-solutional application of the data output by claimed method steps, i.e., insignificant extra-solution activity. As such, this step does not integrate the abstract idea into a practical application (MPEP 2106.05(g)).
No further additional elements are recited.
When the claims are considered as a whole: they do not improve the functioning of a computer, other technology, or technical field (MPEP 2106.04(d)(1) and 2106.05(a)); they do not apply the abstract idea to effect a particular treatment or prophylaxis for a disease or medical condition (MPEP 2106.04(d)(2)); they do not implement the abstract idea with, or in conjunction with, a particular machine (MPEP 2106.05(b)); they do not effect a transformation or reduction of a particular article to a different state or thing (MPEP 2106.05(c)); and they do not apply or use the abstract idea in some other meaningful way beyond linking the use of the abstract idea to a particular technological environment and/or field of use (e.g., structure-based protein design; MPEP 2106.05(e) and 2106.05(h)).
Therefore, the claims do not integrate the abstract idea into a practical application. See MPEP 2106.04(d) § I.
Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are directed to the abstract idea. Claims that are directed to an abstract idea must be examined further to determine whether the additional elements besides the abstract idea render the claims significantly more than the abstract idea. Additional elements besides the abstract idea may constitute inventive concepts that are sufficient to render the claims significantly more (MPEP 2106.05).
Step 2B: Whether the Claims Contain Additional Elements that Amount to an Inventive Concept (MPEP 2106.05)
Insignificant extra-solution activity and mere instructions to implement the abstract idea using computer hardware are, when considered individually, insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (MPEP 2106.05(g); MPEP 2106.05(f)).
Additionally, review of the following prior art indicates that the recited step of expressing a foldable protein comprising the candidate amino acid sequence is well-understood, routine and conventional activity:
Mason et al (Vaccine 16(13): 1336-1343; published 1998; previously cited) describes “enhanced production of LT-B”, the B subunit of heat-labile enterotoxin, “in potato plants using a synthetic LT-B (sLT-B) coding sequence modified to contain plant-preferred codons and to eliminate spurious mRNA processing signals” (pg. 1337, l. column). In this way, Mason describes expression of a candidate amino acid sequence that is foldable into the structure of LT-B.
Suo et al (Plant Cell Reports 25: 689-697; published 2/21/2006; previously cited) discusses “the effects of codon optimization on the expression of human BMP2”, bone morphogenetic protein 2, “in tobacco plants” (pg. 689, Abstract), and presents findings of increased expression of BMP2 after introduction of certain optimized sequences (pg. 696, r. column). In this way, Suo describes expression of a candidate amino acid sequence that is foldable into the structure of BMP2.
Thomas et al (Plant Cell Reports 33: 1801-1814; published 2014; previously cited) presents a “study, [wherein] hEGF”, human epidermal growth factor, “was transiently expressed in Nicotiana benthamiana plants… Using a codon optimized sequence was found to increase the yield” (pg. 1801, Abstract). In this way, Thomas describes expression of a candidate amino acid sequence that is foldable into the structure of hEGF.
Well-understood, routine and conventional activities, such as expressing a foldable protein comprising an optimized amino acid sequence, are likewise insufficient to constitute an inventive concept that would render the claims significantly more than an abstract idea (MPEP 2106.05(d)).
When the claims are considered as a whole, they do not integrate the abstract idea into a practical application; they do not confine the use of the abstract idea to a particular technology; they do not solve a problem rooted in or arising from the use of a
particular technology; they do not improve a technology by allowing the technology to
perform a function that it previously was not capable of performing; and they do not
provide any limitations beyond generally linking the use of the abstract idea to a particular technological environment and/or field of use (i.e., structure-based protein design; MPEP 2106.05(e) and 2106.05(h)).
Therefore, the claims do not provide an inventive concept and/or significantly more than the abstract idea itself. See MPEP 2106.05.
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole, are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Response to Arguments - Claim Rejections Under 35 USC § 102
In the remarks filed 6/23/2025, Applicant traverses the rejection under 35 USC § 102 and presents supportive arguments.
Applicant alleges distinction between the claimed process of segmenting of target structures into structural motifs and teachings of Fleishman regarding segmenting of non-target structures (pg. 8, para. 4).
Fleishman discloses a library construction process involving steps of providing a plurality of source structures having a common structural fold, replacing the amino-acid sequence of each source structure with the amino-acid sequence of a target protein, and segmenting the source structures into structurally homologous segments, i.e., common structural motifs (para. 0068). The referenced claim features are considered patentably indistinct from the teachings of Fleishman.
Applicant alleges distinction between the claimed process of identifying structural matches in a structural database and teachings of Fleishman regarding matching segmented structures onto a molecular surface of interest (pg. 8, para. 4).
Structural motif libraries, constructed according to the teachings of Fleishman, are considered equivalent to the claimed "structural databases". Fleishman discloses a protein design process comprising matching segments to structural motifs within a constructed library (paras. 0036 and 0043-44), which is considered equivalent to the claimed process of identifying structural matches in a structural database. Furthermore, Fleishman explicitly discloses matching segmented template structures to a pre-computed database of homologous segments extracted from source structures within the Protein Data Bank (paras. 0257 and 0324). The referenced claim features are considered patentably indistinct from the teachings of Fleishman.
Applicant alleges distinction between the claimed graphical representation, used to decompose a target structure into structural motifs, and that depicted in Figure 2 of Fleishman (pg. 8, para. 5 - pg. 9, para. 1).
The instant specification exemplifies the claimed graphical representation as a graph of nodes and edges representing structural motifs (para. 0080; Fig. 4, Graph G). Fleishman discloses that homologous segments are defined by locations of highest structural conservation as conceptualized in a depicted graphic representation of cross-protein structural similarity on a three-dimensional, superimposed protein structure (para. 0113; Fig. 2). The referenced node-and-edge representation is considered distinct from the cited three-dimensional representation of Fleishman, and the argument is found persuasive with respect to the rejection of claim 1 and dependents thereof. Unlike claim 1, independent claim 10 does not require “using a graphical representation”. Consequently, the argument is not found persuasive with respect to the rejection of claim 10 and dependents thereof.
For these reasons, at least one argument is found persuasive regarding claim 1 and dependents thereof. The arguments are found unpersuasive with respect to claim 10 and dependents thereof. However, Fleishman is not considered to anticipate the ordered hierarchy of energetic contributions as recited by amended claim 10. Hence, the rejection of the pending claims (i.e., claims 1, 10 and dependents thereof) under 35 USC § 102 has been withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 USC §§ 102 and 103 is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-5, 8, 16, 24 and 27 are rejected under 35 USC § 103 as being unpatentable over Fleishman et al (US 2017/0206308; published 7/20/2017; previously cited), in view of Xu et al (Proc 2005 IEEE Comp Syst Bioinf Conf, pp. 247-256, IEEE Xplore; published 9/6/2005; previously cited).
Claim 1 recites a method for in silico design and expression of an amino acid sequence, comprising steps of: decomposing a target structure into structural motifs using a graphical representation of coupled residues and/or residue-backbone influences of the structure; identifying structural matches for each motif in a database; calculating at least one non-local energetic contribution to a sequence-structure relationship; generating at least one candidate amino acid sequence that is foldable into the target structure or a binding partner of the target structure; and expressing a foldable protein, comprising the candidate amino acid sequence, in an expression system.
With respect to claim 1, Fleishman discloses a method of constructing a library of amino acid sequences having a common structural fold, and designing an amino acid sequence having a desired affinity to a molecular surface of interest therefrom, comprising steps of: decomposing a source structure into a plurality of structurally homologous segments, i.e., structural motifs (paras. 0026-27); designing libraries of segments with common structural motifs, i.e., structural databases (paras. 0036 and 0043); matching segments to a molecular surface of interest to design a plurality of structure-surface complexes each having an assigned matching score (paras. 0044, 0168 and 0180); and selecting amino-acid sequences that exhibit desired affinity to the molecular surface of interest based on a combined matching score (paras. 0046 and 0189).
Fleishman further discloses optimizing energy criteria by minimizing polynomial functions, based on weights and constraints pertaining to, e.g., backbone dihedral angles and atomic coordinates, via structural refinement operations including amino acid side-chain packing (para. 0136). Fleishman also discloses weighting energy functions according to a position-specific scoring matrix (para. 0140) that encodes sequence-structure rules (para. 0475), and describes evaluation of side-chain packing efficiency by iteratively calculating an energy score, using the Rosetta all-atom energy function, for each rotational state of each residue that makes an appreciable contribution to binding (para. 0300). In this way, Fleishman discloses deducing values for non-local energetic contributions to a sequence-structure relationship.
Fleishman additionally discloses selection of amino acid sequences based on assessment of fold stability (paras. 0063-64), providing for design of an amino acid sequence that is able to fold into a stable 3D structure exhibiting a desired affinity to the molecular surface of interest (para. 0241). Fleishman also discloses expressing a selected amino acid in an expression system (paras. 0049 and 0208).
Fleishman does not disclose decomposing a target structure into a plurality of structural motifs using a graphical representation as claimed.
Xu discusses a tree decomposition-based algorithmic approach that models a protein structure as a geometric neighborhood graph, with vertices representing structural units and edges representing inter-residue interactions, and teaches formulation and efficient solution of structural prediction problems in terms of assigning optimal labels to graph vertices and thus minimizing an associated energy function (pg. 247, Abstract; pg. 248, r. column).
Xu discusses embodiment as a ‘template contact graph’ for predicting backbone structure, wherein the vertices represent a linear series of ‘cores’ (most-conserved segments, i.e., structural motifs) into which the primary structure of a template is parsed, the labels represent all possible sequence alignment positions for each core, and the energy function parameterizes sequence-template alignment (pg. 248, r. column).
Xu also discusses embodiment as a ‘residue interaction graph’ for predicting sidechain conformation, wherein vertices represent a linear series of residues into which a backbone structure is parsed, the labels represent all possible side-chain conformations for each residue, and the energy function parameterizes side-chain packing (pg. 249, l. column).
Xu further teaches that their graph-based approaches exhibit equal predictive accuracy to, and are generally more computationally efficient than, analogous linear programming approaches to predicting protein structure (pg. 247, Abstract; pg. 253, l. column).
With respect to claim 3, Fleishman discloses optimizing spatial and/or energy criteria by minimizing functions pertaining to backbone atomic positions (para. 0136), and exemplifies calculating the root mean squared deviation of aligned backbone positions (paras. 0084, 0116, and 0158). In other words, optimizing non-local energetic contributions of backbones in spatial but not sequence proximity.
With respect to claim 4, Fleishman discloses that conformations are characterized by key conserved residue identities that maintain the backbone (para. 0014). Fleishman exemplifies a conserved motif including two cysteine residues that form an intra-chain disulfide bond (para. 0126), i.e., a non-local energetic contribution from a pair of coupled residues within a structural motif.
With respect to claim 5, Fleishman discloses evaluating rotameric states of contributive residues in each match and excluding rotamers that are predicted to form steric clashes (para. 0300). Steric hindrance is a local energetic contribution.
With respect to claim 8, Fleishman discloses sampling backbone conformations and sequence information from natural protein folds for which a set of three dimensional atomic coordinates, i.e., tertiary structure, is available (para. 0098).
With respect to claim 16, Fleishman discloses software implementation of numerous method functions (e.g., paras. 0275, 0279, 0283, 0289-90, 0314) and saving data files to a disk, i.e., a non-transitory computer-readable storage medium (para. 0312). The limitations of the method of claim 1 are made obvious by the combined teachings of Fleishman and Xu as described above.
With respect to claim 24, Fleishman exemplifies execution of method functions on a standard CPU, i.e., a processor (paras. 0310 and 0433). The limitations of the method of claim 1 are made obvious by the combined teachings of Fleishman and Xu as described above.
With respect to claim 26, Fleishman discloses sampling backbone conformations and sequence information from natural protein folds for which a set of three dimensional atomic coordinates, i.e., tertiary structure, is available (para. 0098). Fleishman further describes design according to natural antibody-protein complexes, i.e., quaternary structures (para. 0459). The limitations of the method of claim 1 are made obvious by the combined teachings of Fleishman and Xu as described above.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented decomposition of the protein structure using a graphical representation, as taught by Xu, to enhance the protein design method of Fleishman, because Xu teaches that computational approaches to protein structural prediction using a graphical representation achieve equal predictive accuracy and generally greater computationally efficiency than analogous linear programming approaches (pg. 247, Abstract; pg. 253, l. column). Said practitioner would have had a reasonable expectation of success because Fleishman and Xu both discuss algorithmic methods of protein structural prediction.
In this way the disclosure of Fleishman, in view of Xu, makes obvious the limitations of claims 1, 3-5, 8, 16, 24 and 27. Thus, the claimed invention is prima facie obvious.
Claims 10, 14, 21, 25 and 28-30 are rejected under 35 USC § 103 as being unpatentable over Fleishman et al (US 2017/0206308; published 7/20/2017; previously cited). The new grounds of rejection presented herein were necessitated by Applicant’s amendment of the claims (filed 6/23/2025) to incorporate new limitations.
Claim 10 recites a method for in silico design of an amino acid sequence, comprising steps of: decomposing a target structure into structural motifs; identifying matches for each motif in a database; sequentially calculating energetic contributions, for single design positions within the plurality of motifs, according to a hierarchy; generating at least one candidate amino acid sequence that is foldable into the target structure or a binding partner of the target structure; and expressing a foldable protein, comprising the candidate amino acid sequence, in an expression system.
The claim further requires that the hierarchy comprises: first, at least one local energetic contribution for backbone ϕ (phi) and ψ (psi) dihedral angles; second, at least one local energetic contribution for backbone ω (omega) dihedral angles; and subsequently, one or more of: at least one non-local energetic contribution from a backbone in spatial but not sequence proximity, and at least one non-local energetic contribution from a pair of coupled residues.
With respect to claim 10, Fleishman discloses a method of constructing a library of amino acid sequences having a common structural fold, and designing an amino acid sequence having a desired affinity to a molecular surface of interest therefrom, comprising steps of: decomposing a source structure into a plurality of structurally homologous segments, i.e., structural motifs (paras. 0026-27); designing libraries of segments with common structural motifs, i.e., structural databases (paras. 0036 and 0043); matching segments to a molecular surface of interest to design a plurality of structure-surface complexes each having an assigned matching score (paras. 0044, 0168 and 0180); and selecting amino-acid sequences that exhibit desired affinity to the molecular surface of interest based on a combined matching score (paras. 0046 and 0189).
Fleishman further discloses iteratively optimizing portions (‘split segments’) of the structural motifs according to geometrical, spatial and/or energy criteria by minimizing polynomial functions, based on weights and constraints pertaining to, e.g., backbone dihedral angles and/or atomic positions, and describes particular weight fitting procedures including rigid body orientation, modulation of dihedral angles, amino acid side-chain packing and change of amino acids (para. 0136). Fleishman exemplifies performance of optimization via cyclic coordinated descent using the default all-atom energy function from the Rosetta software suite (para. 0136).
Fleishman further discloses weighting energy functions according to a position-specific scoring matrix (para. 0140), and iteratively calculating an energy score, using the Rosetta all-atom energy function, for each rotational state of each residue that makes an appreciable contribution to binding (para. 0300). In this way, Fleishman discloses deducing energetic contributions for each design position.
Fleishman further discloses that dihedral angles can be modulated based on structural constraints and include ϕ, ψ and ω dihedral angle values for each of the residues (paras. 0324 and 0351). Fleishman thus discloses evaluation of local energetic contributions for backbone ϕ, ψ and ω dihedral angles.
Fleishman further discloses calculating the root mean squared deviation (RMSD) between aligned backbone positions (paras. 0084 and 0158), and notes that antibody stability is influenced by contributions of the entire backbone (para. 0095). Fleishman thus discloses evaluating non-local energetic contributions of backbones in spatial but not sequence proximity.
Fleishman further discloses that conformations are characterized by key conserved residue identities that maintain the backbone (para. 0014), and discloses calculating the RMSD between interfacing residues (para. 0459). Fleishman exemplifies a conserved structural motif including two cysteine residues that form an intra-chain disulfide bond (para. 0126). Fleishman thus discloses evaluation of energetic contributions from pairs of coupled residues.
Fleishman further discloses selection of amino acid sequences based on assessment of fold stability (paras. 0063-64), providing for design of an amino acid sequence that is able to fold into a stable 3D structure exhibiting a desired affinity to the molecular surface of interest (para. 0241). Fleishman also discloses expressing a selected amino acid in an expression system (paras. 0049 and 0208).
Fleishman thus discloses deduction of each of the recited energetic contributions, but does not describe deduction according to a hierarchy as claimed (i.e., in the claimed order of first, second, and subsequent to said second).
However, predictable variations of known elements are obvious. The deductions of Fleishman are performed in a computing environment, and sequential execution of computational steps is well-understood, routine and conventional in the field of computing. The claimed ordering amounts to mere arrangement of known elements.
Thus, the ordering of energetic contributions is not considered to patentably distinguish the instant claims from the teachings of Fleishman. See In re Burhans, 154 F.2d 690 (CCPA 1946), wherein the court ruled that selection of any particular performance order of known process steps is prima facie obvious in the absence of new or unexpected results.
With respect to claim 14, Fleishman discloses sampling backbone conformations and sequence information from natural protein folds for which a set of three dimensional atomic coordinates, i.e., tertiary structure, is available (para. 0098).
With respect to claim 21, Fleishman discloses software implementation of numerous method functions (e.g., paras. 0275, 0279, 0283, 0289-90, 0314) and saving data files to a disk, i.e., a non-transitory computer-readable storage medium (para. 0312). The limitations of the method of claim 10 are made obvious by the teachings of Fleishman as described above.
With respect to claim 25, Fleishman exemplifies execution of method functions on a standard CPU, i.e., a processor (paras. 0310 and 0433). The limitations of the method of claim 10 are made obvious by the teachings of Fleishman as described above.
With respect to claim 28, Fleishman discloses sampling backbone conformations and sequence information from natural protein folds for which a set of three dimensional atomic coordinates, i.e., tertiary structure, is available (para. 0098). Fleishman further describes design according to natural antibody-protein complexes, i.e., quaternary structures (para. 0459). The limitations of the method of claim 10 are made obvious by the teachings of Fleishman as described above.
With respect to claim 29, Fleishman discloses designing amino acid sequences, based on source structures having a common structural fold and amino-acid sequence length identical to that of a target protein (paras. 0026 and 0068), by performing fold stability scoring and selecting a sequence based on the fold stability scoring (para. 0064). Thus, all designed sequences are foldable into a target structure. The limitations of the method of claim 10 are made obvious by the teachings of Fleishman as described above.
With respect to claim 30, Fleishman discloses weighting energy functions according to generated position-specific scoring matrices (paras. 0140 and 0307), i.e., sets of values for energetic contributions organized into tables.
An invention would have been obvious to one of ordinary skill in the art if the differences between the invention and prior art reference teachings amount to mere rearrangement of elements in a predictable manner. Before the effective filing date of the claimed invention, said practitioner would have implemented deduction of the various energetic contributions, disclosed by Fleishman, as computational operations sequentially ordered as claimed, because the deductions of Fleishman are performed in a computing environment and sequential execution of computational steps is well-understood, routine and conventional in the field of computing.
In this way the disclosure of Fleishman makes obvious the limitations of claims 10, 14, 21, 25 and 28-30. Thus, the claimed invention is prima facie obvious.
Conclusion
At this point in prosecution, no claim is allowed.
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/T.C.S./Examiner, Art Unit 1685
/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 November 15, 2025