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 .
DETAILED ACTION
Status of Claims
The present Office Action is pursuant to Applicant’s communication on 12-16-2022; current application filed on 12-16-2022. This application is a CON of 16/225,789 12/19/2018 PAT 11574702 16/225,789 has PRO 62/608,168 12/20/2017.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 11-21-2023, have been acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1-20 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Step 1
Claim(s) 1-20 is/are within the four statutory categories. Claim(s) 1-20 is/are drawn to a method1, system2 and non-transitory computer-readable3 which means that said claims(s) is/are within the four statutory categories (i.e. process). However, as will be shown below, arguendo, Aforementioned claim(s) is/are nonetheless unpatentable under 35 U.S.C. 101.
Prong 1 of Step 2A
Claim(s) 1, which is/are representative of the inventive concept, recite(s):
1. A method comprising:
identifying at least one structure of a wildtype macromolecule;
seeding and executing a plurality of all atom molecular dynamics (MD) simulations using the at least one structure to generate a conformational landscape of the wildtype macromolecule and a plurality of variants of the wildtype macromolecule, wherein generating the conformational landscape comprises generating, via the plurality of all atom MD simulations, a plurality of variant structures corresponding to each of the plurality of variants of the wildtype macromolecule;
generating a first dataset by determining, from the conformational landscape, structural features and energetic features of the at least one structure and the plurality of variant structures;
processing the first dataset via a first clustering algorithm to generate a wildtype cluster of the at least one structure and a plurality of variant clusters, wherein each of the plurality of variant clusters defines a respective conformational population comprising a different subset of the plurality of variant structures;
generating a second dataset by quantifying structural and energetic features of the wildtype cluster and the respective conformational population defined by each of the plurality of variant clusters; and
performing principal component analysis on the second dataset to generate a principal component feature space of the wildtype macromolecule and the plurality of variants of the wildtype macromolecule.
The underlined limitations as shown above, given the broadest reasonable interpretation, cover the abstract ideas of a mental process and/or a certain method of organizing human activity because they recite a process that could be practically performed in the human mind (i.e. observations, evaluations, judgments, and/or opinions – in this case the highlighted claim limitation(s)4 comprising identification and simulation step akin to loading a 3D digital blueprint of a perfectly working watch (a wildtype macromolecule) and several blueprints of watches with slightly misaligned or substituted gears (variants) and wherein the watchmaker engages in virtual simulation test plays on a supercomputer, running a physics engine that simulates the watches ticking millions of times, and wherein the master watchmaker observes every microscopic vibration and gear collision (generating conformational landscapes), and then engages in data extraction wherein spreadsheets of data from these virtual simulation tests are collected – measuring friction, wobble angles of the gears, and energy lost in mainspring of the watches’ components (quantifying structural and energetic features), then employing a sorting machine (a first clustering algorithm) that sorts by defect, grouping broken watches into piles based on how they malfunctioned (for example, “Pile A: the minute hand stutters,” “Pile B: the gears grind other nearby gears”), and then creating a master data 2D map from the 3D blueprint, the map created by taking all piles and running them through a massive mathematical equation (Principal component Analysis or PCA), this equation squashing millions of data points down to the 2D printed map (a principal component feature space) – on this map the perfect watch sits at the map’s center, such that broken watches are plotted in different map territories based mathematically on how badly their gears wobble, claim limitations describing a process of running a virtual simulation, extracting numerical data from the simulation, applying a mathematical sorting algorithms, and generating a statistical map, but wherein the map does not provide a watchmaker with how to go onto a factory floor, pick up wrenches, and fix a broken watch based on the map, the claims not, for example providing a practical implementation of how a treatment for a disease may be implemented, the claims directed to mathematical principles corresponding to generating a principal component feature space (creating a data map, a visual display of results), but not detailing a practical a practical application showing a physical transformation (such as altering a chemical compound, administering a specific drug to a patient, or improving the physical functioning of the computer itself), in other words, information itself, without a practical, physical application woven into the claims, is abstract, or in other words, the claims are akin to using a pen and paper, but for the recitation of generic computer components (i.e. the computer), e.g. see MPEP 2106.04(a)(2). Any limitations not identified above as part of the abstract ideas are deemed “additional elements,” and will be discussed in further detail below.
Dependent claim(s) 2-7, 9-14 and 16-20, include other limitations, for example:
2. The method of claim 1, wherein the structural features and energetic features comprise global structural features and dynamics of structure subdomains.
3. The method of claim 1, wherein the structural features and energetic features comprise energetic interactions and overall statistical characteristics of structures.
4. The method of claim 1, wherein the plurality of variants of the wildtype macromolecule are variant proteins.
5. The method of claim 4, wherein the variant proteins cause a disease.
6. The method of claim 5, wherein the disease is a genetic disease.
7. The method of claim 6, wherein the genetic disease is Long QT Syndrome or Polymorphic Ventricular Tachycardia.
9. The system of claim 8, wherein the structural features and energetic features comprise global structural features and dynamics of structure subdomains.
10. The system of claim 8, wherein the structural features and energetic features comprise energetic interactions and overall statistical characteristics of structures.
11. The system of claim 8, wherein the plurality of variants of the wildtype macromolecule are variant proteins.
12. The system of claim 11, wherein the variant proteins cause a disease.
13. The system of claim 12, wherein the disease is a genetic disease.
14. The system of claim 13, wherein the genetic disease is Long QT Syndrome or Polymorphic Ventricular Tachycardia.
16. The non-transitory, computer-readable medium of claim 15, wherein the structural features and energetic features comprise global structural features and dynamics of structure subdomains.
17. The non-transitory, computer-readable medium of claim 15, wherein the structural features and energetic features comprise energetic interactions and overall statistical characteristics of structures.
18. The non-transitory, computer-readable medium of claim 15, wherein the plurality of variants of the wildtype macromolecule are variant proteins.
19. The non-transitory, computer-readable medium of claim 18, wherein the variant proteins cause a disease.
20. The non-transitory, computer-readable medium of claim 19, wherein the disease is a genetic disease.
However these dependent claims only serve to further narrow the abstract idea, and a claim may not preempt abstract ideas, even if the judicial exception is narrow, e.g. see MPEP 2106.04. Additionally, any limitations in dependent claim(s) 2-7, 9-14 and 16-20 are deemed additional elements to the abstract idea, and will be further addressed below. Hence dependent claim(s) 2-7, 9-14 and 16-20 are nonetheless directed towards fundamentally the same abstract idea as independent Claim(s) 1, 8, 15.
Prong 2 of Step 2A
Claim(s) 1, 8, 15 is/are not integrated into a practical application because the additional elements (i.e. comprising non-underlined limitations above – in this case a computing device, memory, non-transitory computer-readable medium, a first clustering algorithm, a principal component feature space)
amount to no more than limitations which:
amount to mere instructions to apply an exception – for example, the recitation of a computer, which amounts to merely invoking a computer as a tool to perform the abstract idea, e.g. see ¶¶1-86 of the present Specification, see MPEP 2106.05(f);
generally link the abstract idea to a particular technological environment or field of use, which amounts to limiting the abstract idea to the field of healthcare, see MPEP 2106.05(h); and/or
add insignificant extra-solution activity to the abstract idea, see MPEP 2106.05(g).
Additionally, dependent claim(s) 2-7, 9-14 and 16-20 include other limitations, but these limitations also amount to no more than generally linking the abstract idea to a particular technological environment or field of use, and/or do not include any additional elements beyond those already recited in independent Claim(s) 1, 8, 15, hence also do not integrate the aforementioned abstract idea into a practical application.
Step 2B
Claim(s) 1 do/does not include additional elements that are sufficient to amount to “significantly more” than the judicial exception because the additional elements (i.e. comprising non-underlined limitations above – in this case a computing device, memory, non-transitory computer-readable medium, a first clustering algorithm, a principal component feature space), as stated above, are directed towards no more than limitations that amount to mere instructions to apply the exception, generally link the abstract idea to a particular technological environment or field of use, and/or add insignificant extra-solution activity to the abstract idea, wherein the insignificant extra-solution activity comprises limitations which:
amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields, as demonstrated by:
The Specification expressly disclosing that the additional elements are well-understood, routine, and conventional in nature:
¶¶1-86 of the Specification discloses that the additional elements (i.e. the computer) comprise a plurality of different types of generic computing systems that are configured to perform generic computer functions (i.e. receive and process data) that are well-understood, routine, and conventional activities previously known to the pertinent industry (i.e. healthcare);
Relevant court decisions: The following are examples of court decisions demonstrating well-understood, routine and conventional activities, e.g. see MPEP 2106.05(d)(II):
Storing and retrieving information in memory, e.g. see Versata Dev. Group, Inc. v. SAP Am., Inc. – similarly, the current invention recites storing or uploading media;
Dependent claim(s) 2-7, 9-14 and 16-20 include other limitations, but none of these limitations are deemed significantly more than the abstract idea because, as stated above, the limitations of the aforementioned dependent claims amount to no more than generally linking the abstract idea to a particular technological environment or field of use, and/or do not recite any additional elements not already recited in independent Claim(s) 1 hence does not amount to “significantly more” than the abstract idea.
Thus, taken alone, the additional elements do not amount to significantly more than the abstract idea identified above. Furthermore, looking at the limitations as an ordered combination adds nothing that is not already present when looking at the elements taken individually, and there is no indication that the combination of elements improves the functioning of a computer or improves any other technology, and their collective functions merely provide conventional computer implementation.
Therefore, whether taken individually or as an ordered combination, claim(s) 1-20 is/are nonetheless rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Double Patenting
The non-statutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A non-statutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on non-statutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are rejected on grounds of non-statutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,574,702. Although the claims at issue are not identical, they are not patentably distinct from each other because all the elements of the application claims 1-20 are to be found in patent claims 1-20. The difference between the application claims and the patent claims lies in the fact that the patent claim includes more elements and is thus more specific. Thus the invention of claims 1-20 of the patent is in effect a “species” of the “generic” invention of the application claims 1-20. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). Since application claims 1-20 are anticipated by claims 1-20 of the patent, it is not patentably distinct from the claims of the patent.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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 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.
Claim(s) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over De Vivo5 in view of Panopoulos6.
Regarding claim(s) 1, 8, 15, De Vivo discloses: A method, A system comprising memory, A non-transitory, computer-readable medium embodying a program that, when executed by at least one computing device, causes the at least one computing device to comprising:
identifying at least one structure of a wildtype macromolecule; [directed to “classical MD simulations in studying biological systems”7, seeding of [b] associated with obtaining or identifying “different conformations of proteins and nucleic acids” 8]
seeding and executing a plurality of all atom molecular dynamics (MD) simulations using the at least one structure to generate a conformational landscape of the wildtype macromolecule and a plurality of variants of the wildtype macromolecule, wherein generating the conformational landscape comprises generating, via the plurality of all atom MD simulations, a plurality of variant structures corresponding to each of the plurality of variants of the wildtype macromolecule (i.e., processing a primary structural dataset through a conformational clustering algorithm to partition wildtype and variant macromolecular states – accomplished by computing pairwise structural distances such as root-mean-square deviations or dihedral angle differences); [“A limited conformational ensemble can improve both the final enrichment and the chemical diversity of the resulting hits. In fact, if the set of target conformations for MRC is too large and diverse, this often generates an overwhelming noise that deteriorates the virtual screening performance.115 For these reasons, a limited (yet hopefully significant) number of conformations is advisible for efficient MRC virtual screening. This can be selected by means of cluster analysis, as one example.116 Ideally, the selected snapshots should capture the entire structural diversity of the target, sampled along the trajectory, with the minimum number of significant conformers (Figure 4C). For instance, a nonredundant set of conformations could be obtained using rmsd-based hierarchical-agglomerative cluster analysis protocols and clusterization methods based on QR-factorization.117 In a comparative study, Nichols et al.116 demonstrated how MD generated receptor variants can match and possibly outperform crystal structures in retrospective virtual screening experiments. Each variant is used in an independent run to generate an individual set of results (Figure 4D). These separate rankings are eventually joined together (Figure 4E).118,119 Importantly, the relaxed complex method was successfully used to prospectively identify several modulators of relevant pharma ceutical targets, as reviewed in detail by Ivetac and McCammon”9 associated with “dihedral angles(θ)”10]
generating a first dataset by determining, from the conformational landscape, structural features and energetic features of the at least one structure and the plurality of variant structures; [Extensive molecular dynamics allow for a “thorough sampling of the conformational space”11, a capability that facilitates a description of pathways such as ligand binding to a target protein, which parallels a goal of generating variant structures corresponding to a wildtype macromolecule12]
processing the first dataset via a first clustering algorithm to generate a wildtype cluster of the at least one structure and a plurality of variant clusters, wherein each of the plurality of variant clusters defines a respective conformational population comprising a different subset of the plurality of variant structures; [Following extraction of features, clustering techniques are recommended to reduce redundancy and manage conformational complexity, such that “A limited conformational ensemble can improve both the final enrichment and the chemical diversity of the resulting hits. In fact, if the set of target conformations for MRC is too large and diverse, this often generates an overwhelming noise that deteriorates the virtual screening performance.115 For these reasons, a limited (yet hopefully significant) number of conformations is advisible for efficient MRC virtual screening. This can be selected by means of cluster analysis, as one example.116 Ideally, the selected snapshots should capture the entire structural diversity of the target, sampled along the trajectory, with the minimum number of significant conformers (Figure 4C). For instance, a nonredundant set of conformations could be obtained using rmsd-based hierarchical-agglomerative cluster analysis protocols and clusterization methods based on QR-factorization”13]
generating a second dataset by quantifying structural and energetic features of the wildtype cluster and the respective conformational population defined by each of the plurality of variant clusters (i.e. calculating binding free energies); [Page(s) 4039, for example, eq 10] and
Regarding De Vivo does not explicitly disclose as disclosed by Panopoulos:
performing principal component analysis on the second dataset to generate a principal component feature space of the wildtype macromolecule and the plurality of variants of the wildtype macromolecule (i.e., employing principal component analysis as a visual tool capable of identifying deviations of variants from wildtypes). [Pages 1087-1091]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified De Vivo, including mechanism(s) [f] as taught by Panopoulos. One of ordinary skill would have been so motivated to employ said mechanism(s) provide a diagnostic map to facilitate correlation of individual response to drugs associated with captured features of principal components analyzed. [Pages 1087-1091]
Regarding claim(s) 2, 9, 16, De Vivo-Panopoulos as a combination discloses: The method of claim 1, The system of claim 8, The non-transitory, computer-readable medium of claim 15, De Vivo disclosing: wherein the structural features and energetic features comprise global structural features and dynamics of structure subdomains (i.e. calculating binding free energies). [Page(s) 4039, for example, eq 10]
Regarding claim(s) 3, 10, 17, De Vivo-Panopoulos as a combination discloses: The method of claim 1, The system of claim 8, The non-transitory, computer-readable medium of claim 15, De Vivo disclosing: wherein the structural features and energetic features comprise energetic interactions and overall statistical characteristics of structures (i.e. calculating binding free energies). [Page(s) 4039, for example, eq 10]
Regarding claim(s) 4, 11, 18, De Vivo-Panopoulos as a combination discloses: The method of claim 1, De Vivo disclosing: The system of claim 8, The non-transitory, computer-readable medium of claim 15, wherein the plurality of variants of the wildtype macromolecule are variant proteins. [Page(s) 4042, 4048]
Regarding claim(s) 5, 12, 19, De Vivo-Panopoulos as a combination discloses: The method of claim 4, The system of claim 11, The non-transitory, computer-readable medium of claim 18, De Vivo disclosing: wherein the variant proteins cause a disease. [Page(s) 4052, 4055]
Regarding claim(s) 6, 13, 20, De Vivo-Panopoulos as a combination discloses: The method of claim 5, The system of claim 12, The non-transitory, computer-readable medium of claim 19, De Vivo disclosing: wherein the disease is a genetic disease. [Page(s) 4052, 4055]
Regarding claim(s) 7, 14, De Vivo-Panopoulos as a combination discloses: The method of claim 6, The system of claim 13, Panopoulos disclosing [a]: wherein the genetic disease is Long QT Syndrome or Polymorphic Ventricular Tachycardia. [Page(s) 1095-1096]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified De Vivo, including mechanism(s) [a] as taught by Panopoulos. One of ordinary skill would have been so motivated to employ said mechanism(s) provide a diagnostic map to facilitate correlation of individual response to drugs associated with captured features of principal components analyzed. [Pages 1087-1091]
Conclusion
The prior art made of record14 and NOT relied upon is considered pertinent to applicant's disclosure:
Kalalakaran15:
Relevance of a study genetic variant observed in diagnostic subject genetic data that is associated by a clinical study with a phenotype characteristic is assessed as follows. A set of polymorphisms functionally related to the study genetic variant are identified. A foreground distribution is computed of variants observed in the diagnostic subject genetic data for the set of polymorphisms. A background distribution is computed of variants observed in genetic data of subjects of the clinical study for the set of polymorphisms. A comparison metric is computed comparing the foreground distribution and the background distribution. Relevance of the study variant to the diagnostic subject is quantified based on the comparison metric, with higher similarity of the foreground and background distributions corresponding to higher relevance
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL EZEWOKO whose telephone number is 571 272 7850. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fonya Long can be reached on 571 270 5096. The fax phone number for the organization where this application or proceeding is assigned is 571-273-7850.
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/MICHAEL I EZEWOKO/Primary Examiner, Art Unit 3682
1 Claim(s) 1-7
2 Claim(s) 8-14
3 Claim(s) 15-20
4 Comprising a framework in which said claims are compared to a process wherein a master watchmaker is trying to understand why certain batches of highly complex, mechanical Swiss watches keep failing – instead of the watchmaker opening up physical watches and looking at them with a magnifying glass, the watchmaker uses a supercomputer
5 See Form 892: Non-Patent Literature
6 See Form 892: Non-Patent Literature
7 page(s) 4035
8 page(s) 4035
9 Page(s) 4042
10 Page(s) 4037
11 Page(s) 4054
12 Page 4054: “This allows a thorough sampling of the conformational space, including that of large biomolecules”
13 Page(s) 4042
14Please see Form 892 for complete listing
15 US 10,679,726
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