DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. JP2021-156817, filed on 09/27/2021.
Status of Claims
Claims 1-10 are currently pending and examined on the merits.
Information Disclosure Statement
The information disclosure statements filed 5/26/2022, 1/23/2023, 7/03/2025 and 11/26/2025 are acknowledged. A signed copy of the corresponding 1449 form has been included with this Office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4-6 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 4 recites “rearranging a conformation after the adding”, on line 4, which lacks antecedent basis. Claim 1 recites generating a model by adding both “main chains and side chains”. It is unclear if the limitation refers to adding main chains, side chains, or both. Using the broadest reasonable interpretation of the claims (see MPEP 2111), the limitation “the adding” is interpreted as adding both main chains and side chains of the plurality of amino acid residues. Claim 5, line 3, recites the same limitation and is similarly indefinite.
Claim 6 recites “acquire a dihedral angle distribution based on backbone dihedral angles acquired in the causing”, on line 3, which lacks antecedent basis. Claim 1 does not recite an active step of “the causing”. The only active steps in claim 1 are generating a model by arranging atoms on a circumference and adding main chains and side chains, and searching for a stable molecule conformation. It is unclear if the limitation “the causing” is referring to one or more of these active steps or an additional undefined active step. The specification is silent regarding a clear and precise definition of “the causing” and one skilled in the art would be unclear in its meaning. Using the BRI of the claims, “the causing” is interpreted as “searching for the stable conformation from the server apparatus”, such that the claim reads “…acquire a dihedral angle distribution based on backbone dihedral angles acquired in the process of searching for the stable conformation from the server apparatus.” More broadly, this is interpreted as the ability to acquire and utilize dihedral angles for the purposes of modeling peptides.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental steps, mathematic concepts, organizing human activity, or a natural law without significantly more.
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea/law of nature/natural phenomenon:
Claims 1, 9, and 10 recite
“…generating a model by identifying alpha carbon atoms of a plurality of amino acid residues,” which is a mental step, i.e. can be performed with pen and paper.
“…arranging the identified alpha carbon atoms on a circumference,” mental step.
“…adding main chains and side chains of the amino acid residues,” mental step.
“…search for a stable molecule conformation,” mental step.
Claims 2-8 recites processor configurations to:
“…arrange the Ca atoms at equal intervals on the circumference.” (Claim 2); mental step,
“…arrange each of n Ca atoms at a position of coordinates…” (Claim 3); mental step,
“…generate the model…” (Claim 4); mental step,
“…rearrange the conformation…” (Claim 5); mental step,
“…acquire a dihedral angle…” (Claim 6); mental step,
“…output the dihedral angle distribution…” (Claim 7); mental step; and,
“…search for the stable conformation by a generalized-ensemble method…” (Claim 8); mental step.
The claims recite an abstract idea of positioning Ca atoms set distances apart from each other so the atoms lie on coordinates of a circle (See MPEP 2106.07(a)).
These recitations are similar to the concepts of collecting information, analyzing it and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas.
While claims 1-10 recite performing some aspects of the analysis with a “model”, there are no additional limitations that indicate that this model requires anything other than carrying out the recited mental process or mathematical concept in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components, then if falls within the “Mental processes” grouping of abstract ideas. As such, claim(s) 1-10 recite(s) an abstract idea/law of nature/natural phenomenon (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception to affect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic computing environment or mere instructions to apply the recited judicial exception via a generic treatment. Specifically, the claims recite the following additional elements:
Claim 1 recites “one or more memories” (Claim 1, line 2) and “one or more processors” (Claim 1, line 3)
Claim 9 recites “An initial conformation generation method for a computer…” (Claim 9, line 1)
Claim 10 recites “A non-transitory computer-readable storage medium…” (Claim 10, line 1)
There are no limitations that indicate that the claimed analysis engine or the formats of the provided data require anything other than generic computing systems. As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. As such, claims 1-10 is/are directed to an abstract idea/law of nature/natural phenomenon (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment. The instant claims recite the following additional elements:
Claim 7 recites “…output the dihedral angle distribution…” (line 3)
The step of outputting an angle distribution does not integrate the abstract idea into a practical application and constitutes an insignificant extra-solution activity (i.e., data gathering and presentation), which does not impose a meaningful limit on the abstract idea. As discussed above, there are no additional limitations to indicate that the claimed analysis engine requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-10 is/are not patent eligible under 35 U.S.C. §101.
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.
Claim(s) 1-7, 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Tomonaga et al. (J.P. 2019-179,304) in view of Olender et al. (Journal of Chemical Information and Computer Sciences 2001 41 (3), 731-738)
The claims are directed to a computer configured to generate a three-dimensional model representing a cyclic peptide molecule by: 1) identifying alpha carbon atoms from amino acid residues, 2) arranging the alpha carbon atoms on a circumference, 3) adding main and side chains of a plurality of amino acid residues, and 4) searching for a stable conformation of the cyclic peptide molecule by using the generated model as an initial conformation of the cyclic peptide molecule.
Tomonaga et al. is drawn to a computer configured to calculate a three-dimensional model representing a stable steric structure of a cyclic peptide.
Olender et al. is drawn to an algorithm capable of identifying molecules that display a pharmacophore, or in general a structural motif, by efficiently constructing and screening virtual combinatorial libraries of diverse compounds, including the ability to build and screen libraries of alpha carbons and 3D molecular representations of cyclic peptides.
With respect to claim 1, Tomonaga, et al. discloses a stable three-dimensional (hereby interchangeably referred to as “3D”) structure calculation method, calculation device and a calculation program for the stable stereostructure of a cyclic peptide using a computer with CPU, memory, storage and display (Clm. 1). Tomonaga, et al. further discloses “a program for causing a computer to calculate a stable 3D structure of a cyclic peptide…causing the computer to execute…a first 3D structure acquisition step of, with respect to 3D structure data of a stable 3D structure of a substituted cyclic peptide which is a stable 3D structure…” (Clm. 11, ln 1-4). Tomonaga et al. further discloses “an apparatus…” to perform these calculations and “an apparatus…” to acquire “3D structure data” (Clm. 12, ln. 1; clm. 13, ln. 1-2). Tomonaga et al. further discloses in the specification that “The disclosed technology can be used, for example, for searching for lead compounds that are expected to have high pharmacological activity,” and that “The disclosed technology can also be used for investigating the physical properties of cyclic peptides regardless of drug discovery. It does not matter whether the cyclic peptide here is a known peptide or an unknown compound.” (Spec; Mode for carrying out the invention, para. 0018, ln. 1-2). This is interpreted as the ability to search for peptide conformations. Finally, Tomonaga et al. discloses in the specification that “The step of obtaining the 3D structure data of the cyclic peptide may include a process of calculating the stable 3D structure of the substituted cyclic peptide…the process of calculating the stable three-dimensional structure of the substituted cyclic peptide may include a process of creating the three-dimensional structure data of the substituted cyclic peptide.” (Spec; Para 0031, ln. 1-4). Using the broadest reasonable interpretation (BRI) in light of the specification, this is interpreted as using the/a generated model as an initial conformation of the cyclic peptide molecule.
Tomonaga et al. does not explicitly disclose a structure calculation method that is used for searching and modeling peptides (Tomonaga et al. discloses the method could be used for searching), while in claim 1 the applicant discloses an apparatus that is used for searching and modeling peptides.
With respect to claim 1, Olender et al. teaches an “algorithm for identifying molecules that display a pharmacophore, or in general a structural motif, by efficiently constructing and screening huge virtual combinatorial libraries of diverse compounds,” noting that “The uniqueness of this algorithm is its ability to build and screen libraries of ca” (Abstract). Olender et al. further discloses that “virtually screened libraries may be truly virtual, existing solely on the computer or corporately/commercially/publicly available databases of existing compounds.” (Introduction). Olender further discloses on page 732 that “The algorithm requires as input a library of chemical scaffolds and a library of substituents, which are combined to form a “virtual combinatorial library” (VCL), and a pharmacophore, against which the virtual combinatorial library is searched (Figure 1). The scaffolds and substituents are each represented by a set of discrete 3D conformations (Figure 1a,b)…” Using the BRI in light of the specification, this is interpreted of an algorithm capable of generating 3D conformations of molecules derived from user-input and capable of searching databases of structural compounds both on the computer and crowdsourced.
Applying the KSR standard to Tomonaga et al. and Olender et al., the examiner concludes that the combination of Tomonaga et al. and Olender et al. represents use of known techniques to improve similar methods. Both Tomonaga et al. and Olender et al. represent peptides as 3D stable structures. Tomonaga et al. only disclosed an apparatus and calculation program capable of representing 3D, stable cyclic peptides with added side chains; and the possibility of searching for stable structures with said program, without the explicit or clear processes to do so. In the same field of research, Olender et al. provided an algorithm capable of rendering 3D representations of molecules, inclusive of cyclic peptides (as noted on page 733; “In the following we present a conceptual description of the algorithm as applied to a cyclic peptide library.”)
One of ordinary skill in the art of computational chemistry and chemical modeling would have been motivated to combine the three-dimensional structure calculation apparatus of Tomonaga et al. with the algorithm of Olender et al. because Olender et al teaches an algorithm that can search user-populated databases, a reference teaching that, when combined with Tomonaga et al.’s structure calculation of similar context in silico, would provide an avenue for one or ordinary skill in the art to produce an algorithm capable of both searching user-defined databases for stable residues to be added to a peptide structure and generating stable stereostructures. Furthermore, As Tomonaga, et al. discloses an apparatus which computationally generates a model representing a cyclic peptide molecule with stable additions of main and side chain amino acid residues (Abstract, ln. 1-13, pg. 1, “…calculating a stable three-dimensional structure of a cyclic peptide…obtaining three-dimensional structure data…replacing a replacement residue with an amino acid…”); and, in doing so: 1) identifies alpha carbon atoms from a plurality of amino acid resides, 2) identifies via search cyclic peptides for substitution (clm. 1, ln. 1-19, “…by substituting the substituted residue for an amino acid residue having a predetermined stable three-dimensional structure…”; Spec, para. 0018, ln. 1-2, “The disclosed technique can be used, for example, to search for a lead compound…”), and, 3) arranges the amino acid such that the residue substitutions are stable (Spec, para. 0071, ln. 1-4, “The a atoms of the atom group to be inserted may be arranged on a straight line…or may be arranged at a position other than the straight line.”), combining these features with Olender, et al’s art would provide a robust, user-influenced data structure search algorithm.
One of skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success at combining the programs of Tomonaga et al. and Olender et al., as Tomonaga et al. explicitly states that their program could be used for searching. As the program of Olender et al. also accepts data, one of ordinary skill in the art could, for example, combine Olender, et al.’s search algorithm with stable structural data calculated with Tomonaga et al.’s art. This or other potential combinations would have been expected to result in a program capable of generating a stable 3D cyclic peptide generation and search tool used to identify stable additions to a cyclic peptide. Therefore, the invention would have been prima facie obvious to one of skill in the art at the time of filing of the application, absent evidence to the contrary.
With respect to dependent claim 2, which teaches arranging alpha carbons at equal intervals on a circumference, Tomonaga, et al. discloses a method of arranging atomic information data along a computationally-based three-dimensional structure of atoms (“Step of converting into three-dimensional structure data of n-membered cyclic compound”, para. 64, ln. 1-12). In the specification, Tomonaga, et al. discloses that “The number of atoms in the atomic group is not particularly limited…” (Spec; para. 0070, ln. 1); and “A atoms of the atomic group to be inserted may be arranged…” (Spec; para. 0071, ln. 1-5). This is interpreted as the ability to arrange alpha carbons along a cyclic peptide, for example, at equal intervals, as is stated in the specification (Spec, para. 0064, ln. 15-18, “The distance at which a bond can be formed varies depending on the type of the bond to be formed and the environment around the atoms to be bonded, and is not particularly limited and may be appropriately selected depending on the intended purpose.”).
With respect to dependent claim 3, which teaches coordinate calculation, Tomonaga, et al. discloses in the specification that 3D structure includes coordinate information data, the coordinate information data as data related to coordinates (positions) of atoms (Spec; para. 0031, ln. 1-9). The apparatus of Tomonaga et al. allows for arranging alpha carbon atoms at various positions or coordinates along a cyclic compound. This is interpreted as the ability to arrange alpha carbons along coordinates. Tomonaga, et al. also states the coordinate system is involved in calculating initial structures (Spec, para. 0048, ln. 1-3, “…Potential energies and forces are calculated… atoms are moved… along the axial direction of the coordinate system, and the energy and force are recalculated…”). The specific equations/models are symbolic of the parameters considered above and provided in a more accessible format for analysis. Therefore, in regards to the equation stated on lines 2-3 of claim 3 of the instant claims, all the claimed elements were known in the prior art, and a person of ordinary skill in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art at the time of the invention.
With respect to dependent claim 4, which teaches rearranging a conformation, as mentioned earlier, “the adding” is interpreted as adding both main chains and side chains of the plurality of amino acid residues. Tomonaga, et al. discloses a method of arranging atomic information data along a computationally-based three-dimensional structure of atoms (Spec; “Step of converting into three-dimensional structure data of n-membered cyclic compound”, para. 64, ln. 1-12). This is interpreted as the ability to rearrange the conformation of the structure. Tomonaga, et al. also discloses in the specification a stability calculation using a model stable three-dimensional peptide compared against the same model with a substitution residue (Spec; para. 0061, ln. 1-10; Spec; Para. 0062, ln. 8-11). This is interpreted as the ability to generate 3D peptides with substitutions of, amino acid residues. Therefore, Tomonaga can calculate a stable three-dimensional peptide that can be rearranged.
With respect to dependent claim 5, which teaches fixed alpha carbons during arrangement, as mentioned earlier, “the adding” is interpreted as adding both main chains and side chains of the plurality of amino acid residues. Tomonaga, et al. discloses a method of arranging atomic information data along a computationally-based three-dimensional structure of atoms in the context of cyclic peptides which, include alpha carbons. The specification states the arrangements can, for example, come from inserting an atomic group onto a cyclic compound while keeping the main arrangement fixed (“conversion is performed by inserting an atomic group including at least a atoms in the vicinity of the ring of the (n-a) - membered cyclic compound…”) (Spec; para. 0064, ln. 1-8). This is interpreted as the ability to rearrange the conformation after adding both main chains and side chains of the plurality of amino acid residues while keeping arrangement of the alpha atoms fixed. Furthermore, as computationally-based steps necessarily require processors, and as the aforementioned steps necessitate adding atoms to a fixed cyclic peptide with alpha carbons, Tomonaga et al. addresses the limitation of claim 5.
Therefore, as previously stated, combining Olender, et al.’s searching algorithm teaching with Tomonaga, et al.’s rearrangement teaching component would have a reasonable expectation of success, and a person of ordinary skill in the art would have been motivated to combine prior art to achieve claim 5 of the applicant’s invention, and, as there would have been a reasonable expectation of success, and it would have been obvious for one of ordinary skill in the art to do so in address of claim 5 of the applicant’s invention.
With respect to dependent claim 6, which teaches dihedral angle distribution acquisition, as mentioned earlier, “the causing” is interpreted as the ability to acquire and utilize dihedral angles for the purposes of modeling peptides. Tomonaga, et al. also discloses in the specification a stability calculation using dihedral angles to model stable three-dimensional peptide compared against the same model with a substitution residue (“Step of obtaining three-dimensional structure data of cyclic peptide [step (1)]”, Spec; para. 0039, ln. 1-10). This is interpreted as the ability to acquire and utilize dihedral angles for the purposes of modeling peptides; Tomonaga, et al. addresses the limitations of claim 6.
With respect to dependent claim 7, which teaches color output correlated to the number of searches per dihedral angle, Tomonaga, et al. also discloses in the specification a stability calculation using dihedral angles to model stable three-dimensional peptide compared against the same model with a substitution residue (“Step of obtaining three-dimensional structure data of cyclic peptide [step (1)]”, Spec; para. 0039, ln. 1-10). Tomonaga, et al. does not explicitly disclose output the dihedral angle distribution in colors each corresponding to the number of searches for the stable conformation performed. However, in In re Seid, 161 F.2d 229, 73 USPQ 431 (CCPA 1947), the court found that matters relating to ornamentation only which have no mechanical function cannot be relied upon to patentably distinguish the claimed invention from the prior art. Therefore, although Tomonaga, et al. does not explicitly disclose coloring dihedral angle distribution output in relation to number of searches, this meets the statutory burden for aesthetic design change of the output and does not distinguish the claimed invention from the prior art.
With respect to claims 9 and 10, which teaches using a computer equipped with a conformation generation apparatus with stable cyclic peptide conformation search capabilities, Tomonaga, et al. discloses a stable three-dimensional structure calculation method, calculation device and a calculation program for the stable stereostructure of a cyclic peptide using a computer with CPU, memory, storage and display, (Abstract, pg. 1.; clm. 1; reference list 10-11). As Tomonaga, et al. applies alpha carbon modeling and arrangement of said alpha carbons on a cyclic peptide, Tomonaga et al. addresses all limitations of claim 9. Furthermore, as a computer is considered an apparatus with a non-transitory computer-readable storage medium such as storage, Tomonaga et al. addresses all limitations of claim 10.
Therefore, as previously stated in regards to claim 1, combining Olender, et al.’s searching algorithm teaching with Tomonaga, et al.’s stability calculation method would have would have been prima facie obvious to one of skill in the art at the time of filing of the application, absent evidence to the contrary.
Claim 8 is rejected under 35 U.S.C. 103(a) as being unpatentable over Tomonaga et al. (J.P. 2019-179,304), in view of Olender et al., as applied to claims 1-7, 9 and 10 above, and in view Mitsutake et al., (Enhanced Sampling Algorithms. In: Monticelli, L., Salonen, E. (eds) Biomolecular Simulations. Methods in Molecular Biology, vol 924. Chapter 7, pp 153-195; Humana Press, Totowa, NJ.).
The claims are directed to a computer configured to generate a three-dimensional model representing a cyclic peptide molecule in which one or more processors are further configured to search for the stable conformation by a generalized-ensemble method using the generated model as the initial conformation of the cyclic peptide molecule.
Tomonaga et al., in view of Olender et al., is applied to claims 1-7, 9 and 10 above.
Mitsutake et al. is drawn to several generalized-ensemble algorithms capable of being applied to search databases and identify configurations of algorithms.
With respect to dependent claim 8, the applicant defines “generalized-ensemble method” in the specification, as “a multi-canonical method” (Spec, para. 0036, ln. 3-4). Tomonaga et al. states that “The step of obtaining the 3D structure data of the cyclic peptide may include a process of calculating the stable 3D structure of the substituted cyclic peptide…the process of calculating the stable three-dimensional structure of the substituted cyclic peptide may include a process of creating the three-dimensional structure data of the substituted cyclic peptide.” (Spec; Para 0031, ln. 1-4). This is interpreted as using the/a generated model as an initial conformation of the cyclic peptide molecule. Additionally, the specification of Tomonaga et al. discloses that “The disclosed technology can be used, for example, for searching for lead compounds that are expected to have high pharmacological activity,” and that “The disclosed technology can also be used for investigating the physical properties of cyclic peptides regardless of drug discovery. It does not matter whether the cyclic peptide here is a known peptide or an unknown compound.” (Spec; Mode for carrying out the invention, para. 0018, ln. 1-2). This is interpreted as the ability to search for peptide conformations. Furtherore, Olender et al. teaches an algorithm capable of searching databases both on the computer and crowdsourced, leading to user-generated data input.
Neither Tomonaga et al. nor Olender et al. explicitly disclose a generalized-ensemble method used for searching.
With respect to dependent claim 8, Mitsutake et al. discloses generalized-ensemble algorithms capable of sampling “configurational space” using a “random walk” (Sec. 2.3, pg. 167, ln. 1-11), with “one of the most well-known” being the multicanonical algorithm (MUCA) (pg. 154, para. 3, ln 1-2). This is interpreted as using a search method to identify configurations of atoms (as mentioned as an example in Sec 3.4, pg. 178, ln. 4-8).
Applying the KSR standard to Tomonaga et al., Olender et al., and Mitsutake et al., the examiner concludes that the combination of Tomonaga et al., Olender et al., and Mitsutake et al. represents use of known techniques to improve similar methods.
One of ordinary skill in the art of computational chemistry and chemical modeling would have been motivated to apply Mitsutake et al.’s known algorithm to Tomonaga et al.’s known method of as using the/a generated model as an initial conformation of the cyclic peptide molecule, and Olender et al.’s search algorithm with user input in silico, because the potential structural results found using Mitsutake et al.’s algorthim would likely be of a higher quality due to the design of Mitsutake et al.’s algorithm and the addition of Tomonaga et al. and Olender et al.’s teaching. One skilled in the art could apply the logic disclosed in Mitsutake et al.’s algorithm in the context of Olender et al.’s search algorithm and Tomonaga et al.’s stable calculations, for example, increasing the number of relevant results discovered from a peptide database. The results (using the combination of Tomonaga et al.’s generated model, the step of obtaining three-dimensional structure data stated in Tomonaga et al.’s Spec. paragraph 0008, line 4-5, Olender et al.’s search with user-input teaching, and the generalized ensemble algorithm of Mitsutake et al. to search for a stable cyclic peptide conformation using the initial structure) would have been predictable to one of ordinary skill in the art. There would be a reasonable expectation of success of combining the modeling of cyclic peptides of Tomonaga et al., the database search of Olender et al., and the algorithm of Mitsutake et al. because:
1) The applicant’s invention discloses in the specification that “the stable conformation search unit…searches for the stable conformation by, for example, a generalized-ensemble method. Examples of the generalized-ensemble method mentioned herein include a multi-canonical method…” (para. 0036),
2) Tomonaga et al. simulates peptides, which are biomolecules. Mitsutake et al. states that Conventional (Monte Carlo (MC) and molecular dynamics (MD)) simulations of biomolecules are greatly hampered by the multiple minima problem, in that fixed-temperature simulations at low temperatures tend to get trapped in a few of a huge number of local-minimum-energy states which are separated by high energy barriers (pg. 153).
3) the “random walk” and MUCA algorithm of Mitsutake et al. “allows the simulation to escape from any energy barrier and to sample much wider conformational space than by conventional methods” (pg. 154)
4) MUCA’s have “been extensively used in many applications in protein and other biomolecular systems…” (pg. 154, para. 3),
5) Tomonaga et al. discloses their art “can be used, for example, for searching for lead compounds that are expected to have high pharmacological activity”, such that Tomonaga et al. establishes that searching is a use-case for the art (Spec),
6) Tomonaga et al. discloses that “it is very difficult to obtain a stable steric structure by a systematic search method…” and that stable three-dimensional structure search “takes time”, and present their art as a solution to “obtaining a stable three-dimensional structure of a cyclic peptide in a short time” (Spec),
7) Mitsutake et al.’s algorithm explicitly allows one to “…sample the configurational space much more widely than…conventional methods” (pg. 167)
8) Mitsutake, et al. discloses generalized-ensemble algorithms as a method of atomic, energy state, and coordinate calculations (Sec 3.4, pg. 178, “Let us consider a physical system that consists of N atoms and that is in a box of a finite volume V…”),
9) Tomonaga et al. discloses a method for calculating a stable three-dimensional structure of a cyclic peptide using a computer, a cyclic peptide contains atoms (alpha carbons are atoms) (clm. 1),
10) Tomonoaga et al. discloses “Performing energy minimization of the cyclic peptide using the three-dimensional structure data” as a component of their stability calculation in claim 7 (“The calculation method of the stable three-dimensional structure of Claim 6 including the process which performs energy minimization of the cyclic peptide…”),
11) Olender et al.’s search method, when combined with Tomonaga et al.’s structure calculation and Mitsutake, et al.’s algoritm of similar context in silico, would provide an avenue for one or ordinary skill in the art to produce a stable structure search with database input from user-defined databases, and
12) As mentioned in Mitsutake, et al. pg. 161, conventional simulations of biomolecules have an energy local minima problem, and simulations of crystal structure data and amino acid additions to, for example, a peptide backbone, include stable energy calculations, and a generalized-ensemble algorithm such as the MUCA from Mitsutake, et al., or an extension of those methods mentioned by Mitsutake, et al., is known to overcome this local minima problem, the art taught by Mitsutake, et al. could be applied to Tomonaga et al.’s art to assist with identifying stable structures by using energy simulations that sample configurations of crystal structures in a range (low and high) of energy states and configurations, escaping “local minima” and reliably discovering energy stable crystal structures.
One skilled in the art could have applied one of Mitsutake et al.’s generalized-ensemble algorithms to the search of stable, energy favorable “three-dimensional structure data” (Abstract) as disclosed by Tomonaga et al., in address of the limitation of a generalized-ensemble method used for searching. This combination could have been expected to have provided faster, more relevant analysis and generation of stable 3D peptide structures. Therefore, the invention would have been prima facie obvious to one of skill in the art at the time of filing of the application, absent evidence to the contrary.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN T STUBBS whose telephone number is (571)272-0340. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry Riggs can be reached at 571-270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.T.S./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686