Prosecution Insights
Last updated: April 19, 2026
Application No. 17/766,017

Improved Variant Caller Using Single-Cell Analysis

Non-Final OA §101§103§112
Filed
Apr 01, 2022
Examiner
DHARITHREESAN, NIDHI
Art Unit
1686
Tech Center
1600 — Biotechnology & Organic Chemistry
Assignee
Mission Bio Inc.
OA Round
1 (Non-Final)
40%
Grant Probability
Moderate
1-2
OA Rounds
6y 2m
To Grant
78%
With Interview

Examiner Intelligence

Grants 40% of resolved cases
40%
Career Allow Rate
19 granted / 47 resolved
-19.6% vs TC avg
Strong +38% interview lift
Without
With
+37.6%
Interview Lift
resolved cases with interview
Typical timeline
6y 2m
Avg Prosecution
34 currently pending
Career history
81
Total Applications
across all art units

Statute-Specific Performance

§101
30.2%
-9.8% vs TC avg
§103
18.7%
-21.3% vs TC avg
§102
18.1%
-21.9% vs TC avg
§112
24.5%
-15.5% vs TC avg
Black line = Tech Center average estimate • Based on career data from 47 resolved cases

Office Action

§101 §103 §112
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. Claims Status Claims 21-59 are canceled. Claims 1-20 are pending and under examination herein. Claims 1-20 are rejected. Priority The instant application is a National Stage entry of PCT/ US2020 /053971 , International Filing Date: 10/02/2020, which claims priority to US Provisional Application 62/909670 , filed 10/02/2019. As such, the effective filing date assigned to each of claims 1- 20 is 10/02/2019 . Information Disclosure Statement The Information Disclosure Statements filed 04/20/2022 and 12/19/2024 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. A signed copy of the IDS is included with this Office Action. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered . Drawings The drawings filed 04/01/2022 have been accepted by the examiner. Claim Interpretation As noted in the Applicant’s Remarks filed 09/19/2022, the claim 1 limitation of “for each of one or more cells in the cell population” refers to each cell of one or more cells in a subpopulation of the population of cells, and does not exclusively refer to each and every cell of the whole population (Applicant’s Remarks filed 09/19/2022, p 5, para 2). Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claims 16-17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 16-17 simply expresses the intended result of a process step positively recited , and therefore does not further limit claim scope of the claims on which it depends (See MPEP 2111.04) FILLIN "Insert an explanation of what is in the claim and why it does not constitute a further limitation." . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. 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 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon 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: Claim 1 recites for each of one or more of the cells in the cell population, correcting sequence reads obtained from the cell, the correction comprising: identifying a base of interest of the sequence reads that differs from a reference base; applying an error correction model to analyze single cell features of the base of interest, the error correction model trained to predict a probability for the base of interest; and correcting the base of interest of the sequence reads derived from the cell; generating cell population features by aggregating corrected sequence reads across cells of the cell population, the corrected sequence reads comprising corrected bases; and applying a variant caller model to the cell population features derived from the aggregated sequence reads to identify one or more variants across the cell population. Claim 3 recites wherein identifying a base of interest of the sequence reads comprises applying a transition matrix comprising likelihoods of transition between reference bases and mismatched bases to a probability of observing a proportion of nucleotide bases across the sequence reads for a mismatched base. . Claim 4 recites wherein identifying a base of interest of the sequence reads further comprises: determining the probability of observing a proportion of nucleotide bases across the sequence reads for the mismatched base; and comparing the determined probability to a likelihood of transition from the transition matrix . These recitations equate to steps of collecting information, analyzing data and making observations, evaluations and judgements that can be carried out in the human mind. Specifically, identifying a base of interest of the sequence reads that differs from a reference base by applying a transition basis and determining a probability of observing a proportion of bases across the reads and comparing the probability to a likelihood from the transition matrix, applying error correction and variant caller models, correcting the base of interest, and generating cell population features by aggregation corrected sequence reads, can be practically performing the human mind as claimed, since the mind can read and compare data and make mathematical estimations/comparisons as claimed and are similar to the concepts of collecting and comparing known information in Classen Immunotherapies, Inc. v. Biogen IDEC , 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) and collecting information, analyzing it, and reporting certain results of the collection and analysis in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016) that the courts have identified as concepts that can be practically performed in the human mind. Therefore, each of the above recited limitations fall under the “Mental Processes” grouping of abstract ideas. Furthermore, the steps of applying an error correction model trained to predict a probability, applying a transition matric and determining probabilities equate to organizing information and manipulating information through mathematical correlations and reciting a mathematical equation, similar to the concepts of taking existing information, manipulating the data using mathematical functions, and organizing this information into a new form in Digitech Image Techs., LLC v. Electronics for Imaging, Inc. , 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014). Therefore, these limitations fall under the “mathematical concepts” grouping of abstract ideas. Claims 2 and 5-20 further qualify the judicial exceptions. As such, claims 1-2 0 recite an abstract idea ( 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, applies or uses the recited judicial exception to affect a particular treatment for a condition, implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, effects a transformation or reduction of a particular article to a different state or thing or applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. Rather, the instant claims recite additional elements that amount to mere data gathering , mere indicat ing a field of use or technological environment , and mere instructions to implement the abstract idea in a generic computing environment. Specifically, the claims recite the following additional elements : Claims 1 recites obtaining a plurality of sequence reads from cells of the cell population . Claims 8 recites wherein the error correction model is a neural network. Claim 9 recites wherein the error correction model is a deep learning neural network comprising one or more layers that learn motifs and local sequence contexts around a base of interest. Claims 2 -7 and 10 -20 do not recite elements in addition to the recited judicial exceptions. Claim 1 recites further limitations for gathering . These limitations equate to mere data gathering activity to obtain the data necessary for the mental evaluations and judgements (see MPEP 2106.05(g)). Claims 8-9 merely indicates a field of use or technological environment in which the judicial exception is performed and confines the use of the abstract idea to a particular technological environment (neural networks). See MPEP 2106.05(h) . Furthermore, claims 8-9 provide nothing more than mere instructions to implement an abstract idea on a generic computer. See MPEP 2106.05(f) . the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). There is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself. As such, claims 1- 20 are directed to an abstract idea ( 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 ). Further analyzing the additional elements under step 2B , the additional elements as described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s) ; a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s) . With respect to the instant claims under the 2B analysis, the instant specification discloses obtaining sequence reads from cells is well-understood, routine and conventional in the art and there are many commonly used techniques and commercially available technology to obtain such data (para 0047-0048; para 00109-00115) . As such, activities such as data gathering do not provide a non-conventional or unconventional step. Rather, the data gathering and outputting steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception ( MPEP2106.05 (g)&(h)). Claims 8-9 merely are at best mere instructions to “apply” the abstract ideas, which cannot provide an inventive concept. See MPEP 2106.05(f). Furthermore, the use of a computer or other machinery in its ordinary capacity for economic or other tasks ( e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea ( e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). Therefore, 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, and the claims do not amount to significantly more than the judicial exception itself ( Step 2B : NO ). As such, claims 1-2 0 are not patent eligible under 35 U.S.C. 101. 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 ( i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness . This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claim s 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ashutosh et al. ( US20150073724A1 ; 04/20/2022 IDS, US Patent Publication #7; hereafter referred to as Ashutosh), further in view of Azab et al. ( WO2018136888A ; 04/20/2022 IDS, Foreign Patent document #1; hereafter referred to as Azab). With respect to claim 1, Ashutosh discloses a method for identifying a sequence variant in an enriched sample and calling one or more variants of a cell population, by obtaining a plurality of sequence reads from a sample that has been enriched for a genomic region and a reference sequence for the genomic region (abstract; para 0068-007 2 ) . Ashutosh further discloses e ach potential variant is defined by a sequence variation that is found in the sequence reads. As such, all of the candidate sequences in a discrete assembly have the same variation and once the true potential variants have been identified, the mutations defined by the potential variants can be optionally compared to the known mutations for a reference sequence, where the reference sequence is a sequence from a public or in-house database. In certain embodiments the comparing involves determining whether each of the true potential variants contains a mutation that is known to be associated with the reference sequence ( para 0052; para 00541). Ashutosh further teaches examining the quality of a sequence, the number of reads, the quality of base calls and their match to the reference sequence, to provide a score for each of the potential variants and identifying a base of interest of the sequence reads that differs from a reference base (para 0053-0055). However, with respect to claim 1, Ashutosh does not appear to discloses correcting sequence reads obtained from the cell by identifying a base of interest of the sequence reads that differs from a reference base , applying an error correction model to analyze single cell features of the base of interest, the error correction model trained to predict a probability for the base of interest; and correcting the base of interest of the sequence reads derived from the cell; generating cell population features by aggregating corrected sequence reads across cells of the cell population, the corrected sequence reads comprising corrected base. However, Azab , in the same field of endeavor , discloses read group correction comprises correction of a nucleotide in a read assigned to a read group that does not match the nucleotide at that position for other reads in the read group and i n certain instances, read group correction comprises designating a nucleotide as an unreadable or low quality base ("N") in a read assigned to a read group that does not match the nucleotide at that position for other reads in the read group and identifying a base of interest of the sequence reads that differs from a reference base ( p 30, In 22 - p 3 3 , In 2 ) . Azab further discloses applying an error correction model to analyze single cell features of the base of interest, the error correction model trained to predict a probability for the base of interest and correcting the base of interest of the sequence reads derived from the cell (p 21 , In 4-21 ; p 30 , In 22 - p 33 , In 2) . Azab also discloses that for a base pair in an overlap position (e.g., A and its complementary base T), when a non­complementary base is read (e.g., A and a non-complementary base C or G), the base at the complementary position is corrected to T (e.g., when the corresponding A has a higher base quality than the non-complementary C or G) , and in certain instances, read mates from paired-end sequencing are presented as sequences corresponding to the first strand (i.e., + strand, leading strand) of the corresponding fragment , and when performing a sequence error correction in an overlap region, mismatched bases are identified and corrected such that the base having the higher quality is kept ( p 30, In 22 – p 31, In 4). With respect to claim 2, Azab discloses the single cell features comprise contextual sequences around the base of interest, sequencing depth of the base of interest, allele frequency of the base of interest, and allele frequency of bases in a window around the base of interest (p 32, In 15 - p 33, In 2; p 192, In 19-23). With respect to claim 3, Ashutosh discloses applying a transition matrix (para 0050 ; para [0067-0070). Azab also discloses identifying a base of interest of the sequence reads comprises applying comprising likelihoods of transition be tween reference bases and mismatched bases to a probability of observing a proportion of nucleotide bases across the sequence reads for a mismatched base (p 30, In 22 – p 31, In 4) . With respect to claim 4, Ashutosh discloses comparing the determined probability to a likelihood of transition from the transition matrix (para 0050­0055; para 0067-0070). Azab teaches determining the probability of observing a proportion of nucleotide bases across the sequence reads for the mismatched base (p 30, In 22 – p 31, In 4 ). With respect to claims 9 and 10, Azab discloses the data set can be analyzed by a neural networks and multiple statistical algorithms and manipulations comprising one or more layers that learn motifs and local sequence contexts around a base of interest (p 97, ln 21 - p 98, ln 22; p 119, ln 13- p 122, ln 13; p 150, ln 3-27) With respect to claim 11, Azab suggest performing correction for all bases that differ from reference bases (p 30, ln 19 - p 33, ln 13). With respect to claims 15-16, Azab discloses t he sensitivity, specificity or confidence level was above 99% and for some , demonstrated sensitivity was >78% for variant allele frequencies >0.5% and s pecificity was >99% for all variant levels at clinically actionable genomic loci (p 134, ln 11-31; p 196, ln 20-21) It would have been prima facie obvious to one of ordinary skill in the art , at the effective filing data of the instant application, to have modified the system of Ashutosh by including or a plurality of cells in the cell population, correcting sequence reads obtained from the cell, the correction comprising identifying a base of interest of the sequence reads that differs from a reference base , applying an error correction model to analyze single cell features of the base of interest, the error correction model trained to predict a probability for the base of interest , and correcting the base of interest of the sequence reads derived from the cell and generating cell population features by aggregating corrected sequence reads across cells of the cell population, the corrected sequence reads comprising corrected base as taught by Azab because the modification identifies and correct mismatched bases such that the base having the higher quality is kept as disclosed by Azab. There would be a reasonable expectation of success because applying the error correction model disclosed by Azab would not impede the method of Ashutosh. With respect to claim 5, Ashutosh discloses identifying the mismatched base as a base of interest in respons e to the determined probability being greater than the likelihood of transition (para 0050-0055 ; para 0067-0070 ). With respect to claim 6, Ashutosh discloses the transition matrix is generated using training data comprising sequence reads derived from one or more sample populations of cells (para 0050-0055 ; para 0067-0070). With respect to claim 7, Ashutosh discloses t he transition matrix is generated using the plurality of sequence reads from cells of the cell population (para 0050-0055, 0067-0070 ). With respect to claim 8, Ashutosh discloses the likelihoods of transition in the transition matrix are dynamically updated as sequence reeds of the one or more cells of the cell population are corrected (para 0050-0055, 0067-0070 ). With respect to claim s 1 2 and 15 , Ashutosh suggests the sequence information from the cell population contains percentage of homozygous or heterozygous calls (para 0052). With respect to claim s 12 -13 , Ashutosh discloses examining various alleles present in the candidate solutions when c alling a variant at a locus , suggesting that the variant caller model can predict heterozygous , homozygous or indeterminate variants (para 0068-0072). With respect to claim 18, Ashutosh discloses the DNA being analyzed may be derived from a single source (e.g., a single organism, virus, tissue, cell, subject, etc.) (para 0043). With respect to claims 19-20, Ashutosh discloses “reference sequence” refers to a known sequence, e.g., a sequence from a public or in-house database, to which a candidate sequence can be compared , and could be a reference genome or control cel ( para 0026; para 0047; para 0054 ). Therefore, the invention is prima facie obvious. Conclusion No claims allowed. Inquiries Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT NIDHI DHARITHREESAN whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-5486 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday 9:00 - 5:00 . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Larry D Riggs II can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT (571) 270-3062 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center ( EBC ) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /N.D./ Examiner, Art Unit 1686 /Karlheinz R. Skowronek/ Supervisory Patent Examiner, Art Unit 1687
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Prosecution Timeline

Apr 01, 2022
Application Filed
Mar 24, 2026
Non-Final Rejection — §101, §103, §112 (current)

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Expected OA Rounds
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6y 2m
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