DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Claims 1-30 have been cancelled.
Claims 31 and 32 are currently pending and under exam herein.
Claims 31 and 32 are rejected.
Claim 32 is objected to.
Priority
3. This application is a continuation of U.S. Patent Application No. 17/533,091, filed 22 November, 2021, which claims the benefit of U.S. Provisional Patent Application No.: 63/253,122 filed 6 October, 2021. This application claims the benefit of U.S. Provisional Patent Application No.: 63/281,579
filed 19 November 2021 and U.S. Provisional Patent Application No.: 63/281,592 filed 19 November, 2021. In this action, all claims are examined as though they had an effective filing date of 6 October, 2021. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Information Disclosure Statement
4. The information disclosure statements (IDSs) submitted on 02/09/2023 and 08/03/2023 are being considered by the examiner except for one foreign document number WO2016061396A1 on the IDS submitted 02/09/2023 as no corresponding reference was not found in the submission.
Drawings
5. The drawings submitted on 11/15/2022 are objected to as failing to comply with 37 CFR 1.84(p)(4) because multiple reference characters have been used to designate each part listed below. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Voxel grid is represented by both 512 and 522
Voxels is represented by both 3404 and 514
Training data is represented by both 4300 and 5600
PSSM is represented by both 6000 and 6300
Protein is represented by both 200 and 4912
Further, Figures 9-11, 15-18, 20-10, 27, 29, 31, 33-35, 39-41 and 70 are objected to for containing illegible text. Appropriate correction is required.
Regarding Fig. 38-41, which contain amino acid sequences but no sequence listing, the approval on 07/27/2023 of the petition to waive the requirement is acknowledged.
Specification
6. The disclosure is objected to because of the following informalities: The claims are directed to “gapped spatial representations” whereas the specification is directed to “gaped spatial representations”. The same term should be used consistently throughout the claims and the specification.
Appropriate correction is required.
Claim interpretation
7. Regarding claims 31 and 32, a gap amino acid is interpreted to include amino acids that are present in wild-type or common protein variants but not present in protein variants of patients with genetic mutations that are in-frame deletions. An alternate amino acid is interpreted to include amino acids that are substitutions in proteins of patients with genetic nonsynonymous mutations (or missense mutations) that alter the amino acid of the protein variant compared to wild-type or common variants.
Claim Objections
8. Claim 32 is objected to because of the following informality:
Claim 32, line 6 recites ‘ a gaped spatial representation’, whereas claim 31, lines 5 and 11 recite ‘a gapped spatial representation’. The same term should be used consistently throughout the claims and the specification.
Appropriate correction is required.
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.
9. Claims 31 and 32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 2A, Prong 1
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:
Claim 31 recites: generate a score for the nucleotide variant as benign or pathogenic based at least in part on the gapped spatial representation and the alternative representation.
The limitation directed to ‘generate a score for the nucleotide variant as benign or pathogenic’ is a verbal equivalent for a mathematical calculation that is performed as the limitation and thus falls under the ‘Mathematical concepts’ grouping of abstract ideas.
Although the limitation recites using a neural network to generate the score, there is no structure described for the neural network-based predictor, therefore using the neural network is akin to performing the abstract idea in a generic computing environment.
As such, claims 31 and 32 recite an abstract idea (Step 2A, Prong 1: YES).
Step 2A Prong 2
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 and do not apply or uses the recited judicial exception in some other meaningful way. Rather, the instant claims recite additional elements that amount to activity to provide analytical inputs to the abstract idea, mere instructions to implement the abstract idea in a generic computing environment, or insignificant extra-solution activity.
Specifically, the claims recite the following additional elements:
Claim 31 recites: at least one processor
Claim 31 recites: a non-transitory computer readable medium comprising instructions
Claim 31 recites: access a gapped spatial representation of a protein comprising spatial configurations of non-gap amino acids at positions in the protein and excluding a spatial configuration of a gap amino acid at a particular position in the protein
Claim 31 recites: access an alternative representation of an alternate amino acid created by a nucleotide variant at the particular position corresponding to the gap amino acid
Claim 31 recites: utilizing a neural network-based pathogenicity predictor
Claim 32 recites: access a spatial representation of a protein specifying respective spatial configurations of respective amino acids at respective positions in the protein
Claim 32 recites: remove, from the spatial representation of the protein, a particular spatial configuration of a particular amino acid at a particular position, thereby generating a gapped spatial representation of the protein.
The limitations directed to accessing spatial representations of proteins merely serve to gather data that is used an input for the judicial exception. Therefore, these limitations are mere data gathering activities. As set forth in MPEP 2106.05(g), mere data gathering activity has been identified by the courts as insignificant extra-solution activity that does not provide a practical application.
The limitation to ‘generate a gapped spatial representation of a protein’ equates to an analytical processing step for generating inputs for the downstream judicial exception. It is recited at a high level of generality, does not appear to improve spatial representation technology and does not effect a particular treatment or physical transformation. Furthermore, the limitation does not apply the exception in a meaningful technological implementation; this is further supported by the fact that the gapped representation used to generate the score does not need to be the generated gapped representation as the gapped representation can also be simply accessed in the claimed invention.
There are no limitations that indicate that the processor requires anything other than a generic computing system. 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. See also 573 U.S. at 224, 110 USPQ2d at 1984.
Similarly, the claim directed to ‘utilizing neural network-based pathogenicity predictor’ is recited at a high level of generality without any structure. As such, this limitation equates to using a generic computing function, which is akin to instructions to implement the abstract idea in a generic computing environment, which as stated above does not render an abstract idea eligible.
The above recited additional elements do not integrate the judicial exception into a practical application. As such, claims 31 and 32 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B
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 computing environment or well-understood, and conventional activity.
Limitations that merely add an insignificant extra-solution activity, do not amount to an inventive concept, particularly when the activities are well-understood and conventional. Parker v. Flook, 437 U.S. 584, 588-89, 198 USPQ 193, 196 (1978). The steps to access spatial representations equate to storing medical data and retrieve information in memory, which are well-understood, routine, conventional computer functions as recognized by Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93.
The limitation directed to ‘generating a gapped spatial representation of the proteins’ was well understood, routine and conventional at the time of the effective filing date of the invention as evidenced by Glusman et al. (Genome Medicine, 2017, Vol. 9, p. 1-10). Glusman et al. discloses that there are many publicly available databases of 3D protein structures, including experimentally derived structures in the Protein Data Bank (PDB), and structural models in the Protein Model Portal, and interactively generated models on request at I-TASSER, ModWeb, Phyre2, HHpred and SWISSMODEL (p. 2, col. 2, para. 2). Glusman et al. further discloses several other tools that specifically generate protein structures from genetic variants (i.e. gapped representations) including cBioPortal, COSMIC-3D, CRAVAT, Jalview, MuPIT, MutDB, STRUM, Cancer3D and I-TASSER (p. 2, col. 2, para. 3).
As discussed above, there are no additional limitations to indicate that the claimed processor 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.
Generic neural network implementation does not provide an inventive concept. The claim recites a neural network at a high level of generality, without specifying architecture, training procedure, feature construction, loss function or technological improvement. As evidenced by Gao et al. (Patterns, 2020, p. 1-23), neural network/deep learning approaches were broadly used in bioinformatics/protein prediction contexts at the effective filing date of the invention. Gao et al. discloses numerous studies using deep learning in protein structural modeling and design including 19 studies for proteins structure prediction (Table 3), 16 studies for sequence-function relationships (Table 4), 5 studies for protein structure design (Table 5) and 13 studies for sequence-structure relationships (Table 6).
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 31 and 32 are not patent eligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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.
10. Claims 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Won et al. (Bioinformatics, Vol. 37, July 2021, p. 4626-4634, IDS 08/03/2023). The italicized text corresponds to the instant claim limitations.
Regarding claim 31, Won et al. discloses 3Cnet, a platform for pathogenicity prediction of human variants that runs on Python code (which uses a processor). Won et al. further discloses that the code used to execute the study are available at GitHub including the codes to build the sequence data from variant data to train neural networks (featurize) and the codes used to build and test the prediction network (model). Won et al. further discloses that all input data used to train the model including variant data, sequence data and SNVBox features and MSAs for protein sequences are available in a shared zendo repository (p. 4632, col. 1, para. 2; a system comprising: at least one processor; and a non-transitory computer readable medium comprising instructions that, when executed by the at least one processor, cause the system to perform the method).
Regarding claim 31, Won et al. discloses making predictions for multiple types of non-synonymous variants including missense variants (corresponding to an alternate amino acids) and deletions (corresponding to gap amino acids). Won et al. further discloses that spatial configurations of each type of variant are used to make the predictions including: 1) two-dimensional data for each variant wherein a string of the 200 amino acids surrounding the mutation are input into the model to give local structural context and 2) 85 3D-structure-based features from spatial models including active sites, known motifs and protein interactions from SNVBox database. Won et al. further discloses that before modeling, protein sequences were featurized using amino acid embedding to preserve spatial representation; p. 4627, col. 2, para. 1; p. 4628, col. 2, para. 3; p. 4630, col. 2, para. 3; Supplementary Fig. 1; access a gapped spatial representation of a protein comprising spatial configurations of non-gap amino acids at positions in the protein and excluding a spatial configuration of a gap amino acid at a particular position in the protein; access an alternative representation of an alternate amino acid created by a nucleotide variant at the particular position corresponding to the gap amino acid).
Regarding claim 31, Won et al. discloses using a recurrent neural network to train a variant pathogenicity model based on protein sequence. Won et al. further discloses that benign and pathogenic variants were used to train the predictor. Won et al. further discloses that predictions of whether variants were pathogenic or benign were made using the neural network by cross validation and by external validation with held-out samples (4628, col. 1, para. 3-col. 2, para. 3; Fig. 1; p. 4627, para. 4; Fig. 3-4; p. 4628, col. 2, para. 4 – p. 4632, col. 1, para. 1, Supplementary note 3; generate, utilizing a neural network-based pathogenicity predictor, a score for the nucleotide variant as benign or pathogenic based at least in part on the gapped spatial representation and the alternative representation).
Pertaining to claim 32, Won et al. discloses that a total of 147 034 pathogenic variants and 3995 benign variants were found and transformed into sequence data (a two-dimensional spatial representation). Won et al. further discloses that for variants other than missense variants, including start lost, stop gain, deletion and frameshift variants, the center of the sequence was set to the residue where the truncation started or ended. Won et al. further discloses that the truncated region of the mutated sequences was filled with zeroes (zero padding) and that in the case of a stop gain variant, the new termination site was used as the center and the region beyond the site was filled with zeros for the mutated sequence. Won et al. further discloses that frameshift variants were treated the same with stop gain variants and the sites where insertion/deletion occurred were considered the termination sites. Won et al. further discloses that for other deletion variants, the site where the deletion started was used as the center (p. 4627, col. 2, para. 3; the system of claim 31, further comprising instructions that, when executed by the at least one processor, cause the system to: access a spatial representation of a protein specifying respective spatial configurations of respective amino acids at respective positions in the protein; and remove, from the spatial representation of the protein, a particular spatial configuration of a particular amino acid at a particular position, thereby generating a gaped spatial representation of the protein).
Double Patenting
The nonstatutory 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 nonstatutory 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 nonstatutory 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
11 . Claims 31 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 30 of U.S. Patent No. 11,538,555 to Hamp et al. The italicized text corresponds to the instant claim limitations.
Regarding claim 31, although it is not identical to claim 30 of Hamp et al., they are not patentably distinct from each other because they recite the same limitations except claim 31 of the instant application is narrower, thus it is anticipated by claim 30 of the conflicting application. The limitations of both claims are directed to:
a processor and memory/non transitory computer readable medium comprising instructions (lines 1-2 of claim 30 and lines 2-3 of claim 31)
generating or acquiring a gapped spatial representation of the protein comprising spatial configurations of non-gap amino acids and excluding a spatial configuration of a gap amino acid (lines 5-7 of claim 31 (acquiring) and lines 5-12 of claim 30 (generating)
using a neural network to generate a score to predict a variant as benign or pathogenic based on the the gapped spatial representation and an alternative representation (lines 10-12 of claim 31; lines 13-16 of claim 30).
The difference is that the conflicting claim 30 is narrower and requires the generation of rather than just accessing of the gapped spatial representation. Note that claim 31 of the instant application also different as it requires accessing an ‘alternative representation of an alternate acid’, which is not required by the conflicting claim 30; however, this accessing is inherent to claim 30 of the reference patent as the ‘alternative representation’ is used in the scoring step.
Regarding claim 32, which is dependent on claim 31, although it is not identical to claim 30 of Hamp et al., they are not patentably distinct from each other because they recite the same limitations, thus it is anticipated by claim 30 of the conflicting application. The comparison of conflicting claim 30 to claim 31 of the instant application is made above. Claim 32 adds the limitation below, which is also a limitation of the conflicting claim 30:
generating a gapped spatial representation of the protein comprising spatial configurations of non-gap amino acids and excluding a spatial configuration of a gap amino acid (lines 3-7 of claim 32 and lines 5-12 of claim 30)
See MPEP §804 (II)(B)(2).
Conclusion
12. No claims are allowed.
E-mail Communications Authorization
13. Per updated USPTO Internet usage policies, Applicant and/or applicant's representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300): "Recognizing that Internet communications are not secure, / hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. / understand that a copy of these communications will be made of record in the application file."
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273- 8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Inquiries
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER J SMITH whose telephone number is (571)272-7801. The examiner can normally be reached Monday-Friday 7:00 AM - 3:00 PM.
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/J.J.S./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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