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
Instant application eligible to benefit from the domestic application as claimed by applicant on 12/17/2021 and effective filling date was considered as 12/17/2021.
Information Disclosure Statement
IDS has been submitted on 05/22/2025 and considered by the examiner.
Claim Status
Claims 1-18 are pending and examined on the merits.
Claim 1-18 are rejected.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Under 35 U.S.C. 112(a), claims 1-18 are rejected for lacking an adequate written description. The claims recite a sequencing step without reciting the required device to perform it. It is unclear if sequencing is physical or analytical, so it is treated as physical. System and computer-readable medium (CRM) claims must include this device. Additionally, the method claim improperly recites a processor that sequences, which is not technically feasible.
System and CRM claims omit the necessary device to execute the physical sequencing step. The specification fails to clarify whether sequencing is a physical manipulation or an analysis step. (paragraph 0068) Additionally, the method claim incorrectly attributes physical sequencing capability directly to a processor.
Claim Rejections - 35 USC § 112(b)
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 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 17, and 18 are rejected as indefinite because they fail to distinctly claim the physical and cooperative elements necessary to perform the recited "sequencing step," and improperly attribute physical sequencing actions to a processor
Claims 1, 17, and 18 are indefinite for omitting essential structural elements. Under MPEP 2172.01 and 2173.05, a claim fails to point out the invention when it recites a physical transformation or procedural step (such as a physical biological sequencing step) without claiming the necessary structural device or apparatus required to execute that step.
The term "sequencing step" is ambiguous and lacks clarity regarding its metes and bounds. It is unclear whether the term denotes a physical laboratory assay or a purely logical data-analysis operation.
Under the broadest reasonable interpretation, the step is construed as a physical action. Consequently, system and computer-readable medium (CRM) claims omitting the structural sequencing hardware fail to set forth the complete cooperative relationship of the invention.
The claims recite a "processor that sequences," which renders the limitation indefinite or impossible under standard physical principles, as a processor performs computational and analytical operations on data rather than executing the physical steps of material sample sequencing.
Claims 2-9 are rejected under 35 U.S.C. 112(b) as being indefinite because the "wherein" clauses fail to clearly distinguish between positive active steps and statements of intended use or capability. This ambiguity leaves the metes and bounds of the claimed scope unclear to a person of ordinary skill in the art.
Claims 2-7 and 9 recite the relative terms “desirable gene” and “undesirable gene,” which constitute subjective terms of degree without providing an objective baseline or standard in the claims. Per MPEP 2173.05(b), relative terminology is permitted only if the specification provides examples or an objective standard enabling one of ordinary skill in the art to determine the metes and bounds with reasonable certainty. The written description in specification is completely silent regarding a clear, precise, or objective definition for what constitutes a “desirable” versus an “undesirable” gene. Without guidance in the specification or claim text, one skilled in the art cannot ascertain the boundaries of the claimed genetic elements with a reasonable degree of certainty, rendering the claim language vague and ambiguous
Claim 10 is rejected under 35 U.S.C. 112(b) as being indefinite because the relative term “about” fails to provide an objective boundary or standard for measuring the scope, leaving the metes and bounds of the claimed range unclear to one of ordinary skill in the art.
Relative terms like “about” are not per se indefinite, but the specification must provide a standard or guide to apprise a person of ordinary skill in the art of the true boundaries. The disclosure fails to define the numerical limits or the degree of approximation intended by “about” in claim 10. Without guidance in the specification or claim, the exact coverage cannot be ascertained, lacks a defined objective boundary and failing to particularly point out and distinctly claim the exact coverage ranges, rendering the metes and bounds of the invention unclear (MPEP 2173.05(b)).
Regarding claim 11, The claim recites “a first phased region... that corresponds to a second phased region.” However, it fails to specify what exact characteristic is being compared to establishing the correspondence. (Lack of Antecedent) Does it correspond by genomic location? By base-pair position? By the alleles present? Because the basis of comparison is missing, one ordinary skill in the art cannot determine the boundaries of the claim or how correspondence is measured.
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 therefore, subject to the conditions and requirements of this title.
Claims 1-18 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, the instant claims 1-16, are drawn to a process (method), claims 17 and 18 are drawn to a system and CRM respectively, and therefore are found to recite statutory subject matter (Step 1: YES). The instant claims 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). The instant claims recite the following limitations that equate to an abstract idea:
Claims 1, 17 and 18 recite
Identifying, …. one or more informative variants ….. genetic sequence information. (Mental process and Mathematical concept)
Identifying, … one or more informative reads in …. more informative variants. (Mathematical concept and mental process)
Constructing, … in the first and second genetic sequence information. (Mental process)
The above active steps describe intellectual tasks (identifying, constructing) that could theoretically be performed entirely in the human mind with a pen and paper.
Claim 11 recites “identifying the one or more informative variants further comprises identifying a first phased region … corresponding a second region is a mental comparison.
Claim 12 recites “searching, by the one or more processors, the sequence of the progeny to identify matches with the one or more informative variants.” (Mental process)
Claim 13 recites “constructing the genotype …. constructing, by the …. second genetic sequence information. (Mental process)
Claim 16 recites “performing a phase cleaning technique … comprises correcting phase flipping by executing a median filter to correct incorrect phasing. “Correcting phase” is an evaluative step and is a mental process because it requires human interpretation and judgment.
Claim 2-9, 14 and 15 have no active steps.
As such claims 1-18 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 integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Specifically, the claims recite the following additional elements:
Claims 1, 17 and 18 recite
“A method for computational …. by one or more processors coupled to memory of a computing system ….
Maintain…information of a sire and information for a dam… indicating SNPs.
Sequencing, …. based on a skim sequencing technique
Claim 10 recites “the sample of genetic information of the progeny at a low coverage corresponding to about 0.004x-2x coverage.”
For claim 1, 17 and 18, claims merely states that the steps are performed by a processor, which is merely a conventional “generic computer components.”
With respect to claim 1, 17 and 18, the additional elements merely recite a conventional computer processor and a memory used to execute the claimed instructions. Under Alice Corp. v. CLS Bank Int'l, simply implementing or analyzing data using a generic, general-purpose computer does not transform an unpatentable abstract idea into a patent-eligible application.
Under the MPEP 2106.05(g) The recited limitations serve solely as data-gathering or analyzing activities. Because these additional elements do not reflect any specific improvement to computer functioning or physical technology, the claim fails to integrate the judicial exception into a practical application.
There are no limitations that indicate that the genotype imputation process requires anything other than a conventional computer to execute the instructions (a series of steps). 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 in 1983. See also 573 U.S. at 224, 110 USPQ2d in 1984.
The steps of maintaining information (refers to storing, updating, or holding data in a memory or database structure) Generic data storage or simply “maintaining information” is typically treated as insignificant extra-solution activity. It does not integrate an abstract idea into a practical application unless the claim specifies a technical improvement to how a computer system or specific data structure functions internally.
and sequencing (refers to the arrangement, order, or-step-by-step processing of data, tasks, or events) “Sequencing” steps usually fall under methods of organizing human activity or mental processes. If the sequencing merely orders abstract business or cognitive tasks without changing technical performance, it fails Prong Two integration and pushes the analysis forward to Step 2B.
So, maintaining information and sequencing typically reflects generic data that fail to integrate the exception unless they effect a specific technological improvement.
The above recited additional elements do not provide a practical application of the recited judicial exception. As such, claims 1-18 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 are routine and conventional as evidenced by the review articles
As discussed above, there are no additional limitations other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than 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 in 1983. See also 573 U.S. at 224, 110 USPQ2d in 1984.
The skim sequencing technique (low-coverage or shallow whole-genome sequencing) fails to provide an inventive concept under Step 2B of a 35 U.S.C. 101 rejections when the additional claim elements rely entirely on generic, routine, and well-understood biochemical or computational steps. Under the Alice/Mayo framework, simply applying standard sequencing hardware at a lower depth to observe genetic material does not amount to “significantly more” than the underlying natural correlation or abstract data manipulation. Executing the sequence on standard processors or memory layers does not transform the abstract nature of the routine.
A “maintaining information” step such as storing, updating, or keeping records of data is typically characterized as an abstract idea (e.g., a method of organizing human activity or a mental process). When evaluated under Step 2B (the search for an inventive concept or “significantly more”), a generic limitation of “maintaining information” fails to transform the claim because data storage and record-keeping are considered well-understood, routine, and conventional activities in society and computer technology.
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 1-18 are not patent eligible.
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 way 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 1, 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. (Genetic Select Evolution 2012, 44:9) in view of Rubinacci et al. (Nature Genetics VOL 53 | January 2021|120-126).
Hikey et al. discloses use of sire and dam genotype information from SNP’s for genotype imputation (pg. 2, c2, top; pg. 4, c2, top; Figure 2), inferring progeny genotypes from parental information (pg. 9, c1, bottom), use of pedigree information for imputation of genotype.(pg. 9, c1, bottom) and livestock genotype imputation suggesting the limitations of “maintaining, ……first genetic sequence …… single nucleotide polymorphisms(SNPs) of interest” and “constructing , ……, a genotype of the progeny …… second genetic sequence information.”
The above cited reference above covers 1. Maintaining parental genotypes, 2. Pedigree based imputation, and 3. Reconstruction of offspring genotype from sire and dam data
Hikey et al. does not teach explicitly the skim sequencing of technique, low coverage sequencing and imputation from sparse sequencing reads.
Rubinacci et al. teaches phasing and imputation of low coverage sequencing dataset using method called GLIMSE by them (Abstract) suggesting the limitation of “sequencing ……. on a skim sequencing technique”.
It would have been obvious to one of the ordinary skill in the art at the time of the effective filing date to substitute the SNP-array or partially observed offspring data of Hikey et al. with the low pass/skim sequencing observations taught by Rubinacci et al. to reduce sequencing cost while retaining genotype inference accuracy. Hikey et al. already discloses maintaining sire and dam SNP genotype information and using that parental information, together with pedigree information, to construct or infer the progeny genotype (pg. 2, c2, top; pg. 4, c2, top; pg. 9, c1, bottom; Figure 2), but Hikey et al. relies on SNP-array or otherwise directly observed offspring genotype data rather than low-coverage sequencing reads, and does not teach identifying informative variants or informative reads from sparse sequencing data. Rubinacci et al.’s GLIMPSE method fills this gap, teaching phasing and imputation of a low-coverage sequencing dataset (Abstract) by leveraging the sites at which reference/parental haplotypes are informative – i.e., variants at which the parental genotypes differ or are otherwise diagnostic and using the sequencing reads that overlap those informative sites to compute genotype likelihoods for the sampled individual, which is the same type of informative-variant/informative-read analysis recited in claim 1’s identifying steps. Because Rubinacci et al.’s skim-sequencing and informative-site analysis operates on the identical type of parental/offspring SNP data already maintained and used by Hikey et al., a PHOSITA would have recognized that substituting Rubinacci et al.’s low-coverage sequencing-based informative-variant and informative-read identification for Hikey et al.’s directly-observed SNP data is the predictable substitution of one known genotyping input (low-pass sequencing reads) for another (SNP-array calls) within the same pedigree-based imputation framework.
A PHOSITA would have had a reasonable expectation of success in this substitution because Hikey et al. already teaches every step of the claimed pedigree-based reconstruction – maintaining first and second genetic sequence information for the sire and dam indicating SNPs of interest (pg. 2, c2, top; pg. 4, c2, top; Figure 2) and constructing the progeny genotype from that parental information (pg. 9, c1, bottom), so substituting Rubinacci et al.’s skim-sequencing input leaves the underlying pedigree-based construction logic of Hikey et al. unchanged; it only changes how the progeny’s own sequence information is obtained and processed before being compared against the parental SNPs of interest. Because Rubinacci et al. was specifically developed to solve the well-known problem of imputing accurate genotypes from sparse, low-coverage sequencing reads (Abstract), a PHOSITA would have had every reason to expect that applying Rubinacci et al.’s method to identify informative variants and informative reads in the progeny’s skim-sequenced data, and then using those informative reads together with Hikey et al.’s parental SNPs of interest, would successfully and predictably yield the progeny genotype, as each reference already discloses in its own field.
Under KSR rationale, a PHOSITA would have been motivated to replace the known offspring genotype observations in Hikey et al. with the known low-pass sequencing observations from Rubinacci et al., and it would result in predictable genotype imputation of the pedigree with high accuracy (MPEP 2143(I)(B)). Due to market needs for lower sequencing cost and larger throughput, a PHOSITA would have been motivated to combine Hikey et al.’s pedigree-based genotype imputation with Rubinacci et al.’s skim sequencing technique to yield this predictable result.
Regarding claim 10:
In addition to claim limitations of 1, claim 10 add limitation “sequencing of progeny at low coverage corresponding to about 0.004x -2x coverage.”
Rubinacci et al. discusses of using of low coverage sequencing (1x, 1.7x) genome to identify loci that are important for several diseases (pg. 1, c1, middle) which suggesting the limitation of “using low coverage sequencing of progeny”. The use of this low coverage sequencing for imputation can be applied to progeny as well without any difficulties, since the sequencing only relies on genetic material such as RNA or DNA of a biological sample.
Regarding claim 12:
In addition to claim limitations of 1, claim 12 add limitation “the sequence of the progeny to identify …… one or more informative variants.”
Under the BRI, this limitation recites a conventional bioinformatic operation such as identify variant loci of interest followed by searching sequencing reads to find reads containing those loci and finally use the matching reads for downstream genotype inference.
As described in claim 1 rejection, Hikey et al teaches identifying informative parental markers for genotype inference. (pg. 9, c1, bottom), Rubinacci et al. teach low coverage sequencing based genotype imputation using sequence reads corresponding to variant loci. (Abstract)
GATK/Samtools (Conventional sequence analysis tools in the bioinformatic pipelines) variant analysis tool teaches searching sequence reads for known variant positions and identifying reads supporting alleles. It would have been obvious to one ordinary skill in the art at the time of the effective filing date to search the progeny sequence (genotype) inferred from parental information taught by Hikey et al. with low coverage sequencing technology taught by Rubinacci et al. to identify reads matching informative variants using GATK/Samtools to obtain the predictable results of identifying reads useful for genotype reconstruction.
Claim 2, 3, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., as applied to claims 1, 10 and 12 above, and further in view of Humblot et al. (Veterinary Medicine International | Volume 2010|Article IS 192787) and Youngs et al. (Journals of visualized experiments| August 2011|54|e2764)
Hikey et al. in view of Rubinacci et al., as applied to claims 1, 10 and 12.
For claim 2, the additional limitation is: “the progeny is an embryo” and “the embryo is frozen …… desirable genes or variants”.
Hikey et al. and Rubinacci et al. dose not explicitly teach about whether the progeny is embryos, and they are selected and frozen based on their genotype.
Humblot et al. teaches embryo biopsy (pg. 4, c1, bottom), embryo genotyping (pg. 4, c1, middle), genomic evaluation of embryos (pg. 5, c2, top) and selecting embryos breeding value (pg. 5, c2, bottom; pg. 6, c1, middle) suggesting the limitations of “progeny is an embryo”, and “embryo having …… desirable genes or variants.”
However, Humblot et al. does not teach the preservation (how it is stored) method of embryos.
Youngs et al. teaches cryopreservation of preimplantation embryos of cattle (Abstract) suggesting the limitation of “the embryo is frozen based on the genotype”.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to apply the genotype determination method of claim 1 taught by Hikey et al. and Rubinacci et al. to an embryo taught by Humblot et al., because Humblot et al. teaches that the progeny genotyped for genomic selection may itself be an embryo, disclosing embryo biopsy (pg. 4, c1, bottom), embryo genotyping (pg. 4, c1, middle), genomic evaluation of embryos (pg. 5, c2, top), and selecting embryos based on breeding value (pg. 5, c2, bottom; pg. 6, c1, middle). Because Hikey et al.’s and Rubinacci et al.’s pedigree-based genotype-imputation method operates on genetic sequence information of a progeny regardless of the progeny’s developmental stage, and because embryo genotyping for genomic selection was well known in livestock breeding, as confirmed by Humblot et al.’s own disclosure, a PHOSITA would have recognized that applying the combined Hikey/Rubinacci genotype-imputation technique to embryo-derived biopsy samples of the type Humblot et al. discloses is the predictable application of a known genotyping method to a known sample source.
A PHOSITA would further have been motivated to freeze the embryos identified by the combined Hikey/Rubinacci/Humblot method as possessing desirable genetic variants, using the cryopreservation method taught by Youngs et al., because embryo cryopreservation of selected embryos was a routine and well-known breeding practice. Humblot et al. teaches selecting embryos according to breeding value (pg. 5, c2, bottom; pg. 6, c1, middle) but does not teach how the selected embryos are preserved or stored. Youngs et al. fills this gap, teaching cryopreservation of preimplantation embryos of cattle (Abstract). Because Youngs et al.’s cryopreservation technique is performed on the same type of preimplantation cattle embryo that Humblot et al. genotypes and selects, a PHOSITA would have had a reasonable expectation that applying Youngs et al.’s known freezing technique to the embryos selected by Humblot et al.’s genotype-based selection would successfully preserve those embryos pending later implantation, exactly as Youngs et al. already discloses for embryos generally. The combination merely uses known techniques, each according to its own established function, to achieve the predictable result of preserving genetically desirable embryos identified using the genotype-imputation method of claim 1.
Humblot and Youngs’s prior art references teach, respectively, embryo genotyping and genotype-based selection (pg. 4, c1, middle-bottom; pg. 5, c2; pg. 6, c1, middle), and embryo freezing (Abstract). Applying this known practice, genotyping and selecting an embryo, then cryopreserving it based on that genotype to the pedigree-based genotype-imputation technique for offspring taught by Hikey et al. and Rubinacci et al. would have produced predictable results, because each reference performs its own discrete, known function (genotype imputation, embryo genotyping/selection, and embryo cryopreservation) as it already discloses (MPEP 2143 (I)(A)).
For the reasons of earlier selection (efficient timing), reduced cost, and avoiding implantation of genetically inferior embryos – benefits that Humblot et al.’s teaching of genomic evaluation and selection of embryos based on breeding value (pg. 5, c2, top-bottom; pg. 6, c1, middle) and Youngs et al.’s teaching of routine cryopreservation of preimplantation embryos (Abstract) were each already understood to provide in the field – there was substantial motivation for a PHOSITA to genotype embryos before implantation, using the genotype-imputation method of claim 1, and to preserve the embryos identified as possessing desirable genes or variants.
Regarding claim 3:
For claim 3, the additional limitation is: “the progeny is an embryo” and “the embryo is terminated …… undesirable genes or variants”.
In addition to limitations taught by Humbolt et al. for claims 2 rejection, Humblot et al. further teaches embryo biopsy (pg. 4, c1, bottom), embryo genotyping (pg. 4, c1, middle), genomic evaluation of embryos based on desirable and undesirable genetic footprints (pg. 2, c1) and selecting embryos breeding value (pg. 5, c2, bottom; pg. 6, c1, middle) suggesting the limitations of “progeny is an embryo”, and “terminated based ….. embryo having …… undesirable genes or variants.”
Regarding claim 8:
Claim 8 add limitation “the embryo is vitrified based on the genotype of the progeny.”
Youngs et al. teaches cryopreservation of preimplantation embryos of cattle (Abstract). He discloses that embryos are placed into a hypertonic solution (1.4-1.5 M) of a cryoprotective agent (CPA) such as ethylene glycol (EG) or glycerol (GLYC) to create an osmotic gradient that facilitate cellular dehydration (Abstract) and to avoid intracellular ice crystal formation during the CPA, which map the limitation of “the embryo is vitrified based on the genotype of the progeny”.
Regarding claim 9:
Claim 9 add limitation “the embryo is selected as a future sire or a future dam ….. desirable genes or variants.”
From above cited prior arts taught by Hikey et al., Rubinacci et al., Humbolt et al. and Youngs et al. for claim 1 and 2 rejections, it would have obvious to one ordinary skill in the art at the time of the effective filing date to select an embryo identified as possessing desirable genes or variants as a future dam or sire because doing so merely applies known genomic selection principles to embryos to obtain predictable results of accelerating genetic improvement.
For earlier selection decisions, to reduce generation intervals, and for the need of identification of desirable breeding stock before birth would motivate a PHOSITA for embryo -level selection of future sire and dams.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. as applied to claims 1-4, 8-10, and 12 above and further in view of Mebratu et al. (Int. J Phar, & Biomedi. Rese. (2020) 7(1), 40-54).
Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. are applied to claims 1, 2, ,3 4, 8, 9, 10, and 12.
Claim 4 adds limitations to claim 1 are following: 1. “the embryo is a progeny” and “the embryo is implanted …. a more desirable genes or variants.
Hikey et al., Rubinacci et al., Humbolt et al. and Youngs et al. does not explicitly teach implantation of selected embryos.
Mebratu et al. teaches implantation/transfer of selected embryos (pg. 2-4) suggesting the limitation of “implanted based on the …. desirable genes or variants.”
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to implant an embryo identified by the genotype-determination method of claim 1 taught by Hikey et al. as possessing desirable genes or variants, because Humblot et al. teaches selecting embryos according to favorable genetic characteristics – specifically, genomic evaluation of embryos (pg. 5, c2, top) and selecting embryos based on breeding value (pg. 5, c2, bottom; pg. 6, c1, middle) but Hikey et al., Rubinacci et al., Humblot et al., and Youngs et al. do not explicitly teach implantation of the selected embryo. Mebratu et al. supplies this missing teaching, disclosing implantation/transfer of selected embryos (pg. 2-4). Because Mebratu et al.’s implantation/transfer technique is performed on the same type of genotype-selected embryo that Humblot et al. identifies as having a favorable breeding value, a PHOSITA would have recognized that applying Mebratu et al.’s known implantation procedure to the embryo selected by the combined Hikey/Humblot genotype-selection method is the predictable use of a known technique for its known, intended purpose.
A PHOSITA would have had a reasonable expectation of success in this combination because each reference performs its own discrete, known role exactly as already disclosed: Hikey et al. and Rubinacci et al. determine the progeny/embryo genotype from parental and skim-sequencing data, Humblot et al. evaluates and selects the embryo based on that genotype and its breeding value (pg. 5, c2, top-bottom; pg. 6, c1, middle), and Mebratu et al. transfers the selected embryo into a recipient (pg. 2-4). Combining these known elements therefore yields nothing more than the predictable result of transferring a genetically desirable embryo for development, without requiring any of the references to function in a new or unexpected way.
For livestock breeding, there is an increased need for genetic gain, higher productivity, improved health traits, and reduced breeding costs, benefits that Humblot et al.’s genomic evaluation and selection of embryos for favorable breeding value (pg. 5, c2, top-bottom; pg. 6, c1, middle) and Mebratu et al.’s embryo implantation/transfer technique (pg. 2-4) were each already understood in the art to help achieve. This incentive would have motivated a PHOSITA to implant embryos identified as genetically desirable, consistent with the KSR rationale that combining known elements according to known methods to yield predictable results was obvious to a PHOSITA
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. as applied to claims 1, 2, ,3 4, 8, 9, 10, and 12 above and further in view of Eenennaam et al. (Clones, January 2008)
Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. are applied to claims 1, 2, ,3 4, 8, 9, 10, and 12.
Claim 5 add limitation “the embryo is cloned ….. desirable genes or variants.”
Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. does not explicitly teach how embryo is cloned.
Eenennaam et al. teaches the process of cloning (pg. 2) suggesting the limitation “the embryo is cloned ….. desirable genes or variants.”
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to clone an embryo identified through the genotype-determination method taught by Hikey et al. as possessing desirable genes or variants, because the embryo genomic-selection teaching of Humblot et al. identifies genetically desirable embryos through genomic evaluation and selection by breeding value (pg. 5, c2, top-bottom; pg. 6, c1, middle), and Eenennaam et al. teaches the process of cloning as a means of reproducing and preserving genetically valuable livestock (pg. 2). Because Eenennaam et al.’s cloning process is performed on livestock or livestock embryos already identified as genetically valuable, and Humblot et al.’s genomic selection already identifies embryos of exactly that type, a PHOSITA would have recognized that applying Eenennaam et al.’s known cloning technique to the genetically selected embryo identified by Hikey et al. and Humblot et al. merely applies a known technique to a known, compatible input to achieve the predictable result of propagating desirable genetics.
A PHOSITA would have had a reasonable expectation of success in this combination because Eenennaam et al.’s cloning process (pg. 2) does not depend on how the source embryo’s genetic merit was determined; it operates on any embryo or cell line already identified as genetically desirable. Because the combined Hikey/Rubinacci/Humblot method already supplies exactly that type of genotype-selected embryo (pg. 5, c2, top-bottom; pg. 6, c1, middle), substituting or applying Eenennaam et al.’s cloning technique to that embryo would predictably succeed in propagating the identified desirable genetics without altering the function of either the genotype-determination method or the cloning process.
After obtaining a favorable genotype selection, there are only a few recognized management options for propagating and preserving the identified genetics, including (a) implantation, as taught by Mebratu et al., (b) freezing, as taught by Youngs et al. (Abstract), (c) breeding, or (d) cloning, as taught by Eenennaam et al. (pg. 2). Selecting cloning as a means of propagating desirable genetics would therefore have been one of a finite number of recognized, predictable alternatives available to a PHOSITA seeking to propagate a genetically desirable embryo, such that choosing Eenennaam et al.’s cloning technique from among this finite set of known options would have had a reasonable expectation of success, consistent with MPEP 2143(I)(E) and the KSR rationale that choosing from a finite number of identified, predictable solutions is likely obvious to a person in the ordinary skill in the art.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. as applied to claims 1, 2, ,3 4, 8, 9, 10, and 12 above and further in view of Eguizabal et al. (Human Reproduction Open, pp-1-17, 2019).
Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. are applied to claims 1, 2, ,3 4, 8, 9, 10, and 12
Claim 6 adds limitation “a cell line is created ….. desirable genes or variant.”
Hikey et al. in view of Rubinacci et al., and Humblot et al. does not explicitly teach creation of cell lines using the embryo based on the genotype of the embryo having one or more desirable genes or variants.
Eguizabal et al. disclose in his review the generation of stem cell from human embryo and states that these cells can be maintained in the so-called pluripotent state (pg. 2, middle; Figure 2) suggesting the limitation of “a cell line is created …… having one or more desirable genes or variant.” His teaching discloses deriving cell lines from embryos, establishing embryonic stem cell culture and preservation of genetically valuable biological material through cultured cell lines.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to create a cell line, as taught by Eguizabal et al., from an embryo identified through the genotype-determination method of claim 1 as possessing desirable genes or variants, because Humblot et al. teaches identifying genetically desirable embryos through genomic evaluation and selection by breeding value (pg. 5, c2, top-bottom; pg. 6, c1, middle), and Eguizabal et al. teaches, in its review of stem cell derivation, generating a stem cell line from a human embryo and maintaining those cells in the pluripotent state (pg. 2, middle; Figure 2), thereby establishing embryonic stem cell culture and preservation of genetically valuable biological material through cultured cell lines. Because Eguizabal et al.’s cell-line derivation technique is performed on an embryo without regard to how that embryo’s genetic merit was determined, and Humblot et al. already identifies embryos of exactly that type as genetically desirable, a PHOSITA would have recognized that applying Eguizabal et al.’s known cell-line creation technique to the genotype-selected embryo of Hikey et al. and Humblot et al. merely applies a known technique to a known, compatible starting material to achieve the predictable result of preserving the identified desirable genetics in cultured cell-line form.
A PHOSITA would have had a reasonable expectation of success in this combination because Eguizabal et al. further teaches maintaining cell lines derived from genetically valuable animals (pg. 2, middle; Figure 2), confirming that the same pluripotent-cell derivation and maintenance technique used for human embryos was already understood in the art to be applicable to embryos selected for their genetic value more generally. Because the combined Hikey/Rubinacci/Humblot method supplies exactly this type of genetically valuable embryo, and Eguizabal et al.’s cell-line establishment protocol operates on embryos generally, a PHOSITA would have predictably and successfully derived and maintained a cell line from the genotype-selected embryo, exactly as Eguizabal et al. already discloses. The combination therefore merely employs known techniques according to their established functions to preserve desirable genetics and would have been obvious.
Livestock breeding requires preservation of desirable genetics, future cloning capability, genomic resource banking, and germplasm conservation – needs that Eguizabal et al.’s teaching of deriving and maintaining pluripotent cell lines from genetically valuable embryos (pg. 2, middle; Figure 2) was already understood in the art to help satisfy, by providing a self-renewing, indefinitely maintainable source of the embryo’s genetic material beyond what freezing (Youngs et al., Abstract) or a single round of implantation (Mebratu et al.) or cloning (Eenennaam et al.) could provide from the embryo alone. The above-described incentive would have motivated a PHOSITA to create a cell line from an embryo, using the technique taught by Eguizabal et al., once that embryo had been identified as genetically desirable by the combined Hikey/Rubinacci/Humblot method, consistent with the KSR rationale that combining known elements according to known methods to yield predictable results.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. as applied to claims 1, 2, ,3 4, 8, 9, 10, and 12 above and further in view of Illmensee et al. (Middle east Fertility Society journal (2010) 15, 67-63)
Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. are applied to claims 1, 2, ,3 4, 8, 9, 10, and 12.
Claim 7 adds limitation “the embryo is split based on the genotype.”
Hikey et al. in view of Rubinacci et al., Humblot et al. and Youngs et al. does not explicitly teach splitting of desirable embryo.
Illmensee et al. in his review discloses that in nonhuman primate’s embryo splitting has resulted in several pregnancies. He suggested that embryo splitting may be advantageous for providing additional embryos to cryopreserved. He further discusses that in cattle, embryo split into blastomere at the 4-cell stage could further develop to term giving multiple monozygotic healthy calves (Abstract; pg. 2, c1) suggesting the limitation of “the embryo is split based on the genotype.”
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to split an embryo identified through the genotype-determination method of claim 1 as possessing desirable genes or variants, because Humblot et al. teaches identifying genetically superior embryos through genomic evaluation and selection by breeding value (pg. 5, c2, top-bottom; pg. 6, c1, middle), and Illmensee et al., in his review, discloses that embryo splitting in nonhuman primates has resulted in several pregnancies, and suggests that embryo splitting may be advantageous for providing additional embryos for cryopreservation; he further discusses that in cattle, an embryo split into blastomeres at the 4-cell stage can further develop to term, giving multiple monozygotic healthy calves (Abstract; pg. 2, c1). Because Illmensee et al.’s embryo-splitting technique is performed on an embryo without regard to how that embryo’s genetic merit was determined, and Humblot et al. already identifies embryos of exactly that type as genetically desirable, a PHOSITA would have recognized that applying Illmensee et al.’s known embryo-splitting technique to the genotype-selected embryo of Hikey et al. and Humblot et al. merely applies a known reproductive technology to a known, compatible starting material to achieve the predictable result of increasing the number of embryos carrying the desirable genetics.
A PHOSITA would have had a reasonable expectation of success in this combination because Illmensee et al.’s own review confirms that embryo splitting had already been demonstrated to produce viable, healthy offspring in cattle, multiple monozygotic healthy calves developing to term from a single split embryo (Abstract; pg. 2, c1) and had already resulted in several successful pregnancies in nonhuman primates. Because the combined Hikey/Rubinacci/Humblot method supplies exactly the type of genetically desirable embryo to which Illmensee et al.’s splitting technique had already been successfully applied, a PHOSITA would have predictably and successfully replicated that embryo into multiple genetically identical embryos, as Illmensee et al. already discloses. Embryo splitting was thus a known technique used to replicate valuable embryos, and once the desirable embryo was selected from genomic evaluation, applying embryo splitting to that embryo would have been obvious to increase the number of embryos available for propagation.
Combining these teachings merely applies a known reproductive technology, taught by Illmensee et al., to a known genetically desirable embryo, identified using the method of Hikey et al. and Humblot et al., to achieve the predictable result of increasing the number of embryos carrying desirable genetics. Illmensee et al.’s own suggestion that split embryos provide additional embryos for cryopreservation (Abstract) further confirms that splitting a genotype-selected embryo would have been recognized in the art as complementary to, rather than in tension with, the other propagation and preservation options – implantation, freezing, cloning, or cell-line derivation available to a PHOSITA, consistent with the KSR rationale that combining known elements according to known methods to yield predictable results.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., as applied to claims 1, 10, and 12 above and further in view of Che et al. (Genetics in Medicine | Volume 22|Number 5|may 2020)
Hikey et al. in view of Rubinacci et al., are applied to claims 1, 10, and 12
Claim 11 adds limitation “identifying a first phased region ……. homozygous that corresponds to a second phased … is heterozygous.”
In addition to teaching by Hikey et al for claim 1, 10, and 12, for rejections, Hikey et al. further teaches phased parental haplotypes (pg. 2, c2, top), inferring progeny genotypes from parental information (pg. 9, c1, bottom) suggesting the limitation of “maintaining, ……first genetic sequence …… single nucleotide polymorphisms (SNPs) of interest” and “constructing, ……, a genotype of the progeny …… second genetic sequence information.” He also teaches phased parental haplotypes and offspring genotype reconstruction.
However, Hikey et al. in view of Rubinacci et al., dos not teach explicitly “identifying a first phased region in the first genetic sequence information that is homozygous that corresponds to a second phased region in the second genetic sequence information that is heterozygous.”
Che et al. teach identifying informative SNP variants after parental phasing (Abstract, pg. 3, c2, top), wherein an informative SNP is one for which one parent is heterozygous and other parent is homozygous (Figure 1; pg. 3 ,c2, top) and further categorizing such informative SNPs according to phased parental genotypes (Figure 1, pg. 3 ,c2, top) suggesting the limitation of “identifying a first phased region …..corresponds to ------ that is heterozygous.”
Che at al. further teach identifying informative loci by evaluating parental zygosity states, including loci one parent is homozygous and the other parent is heterozygous.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to identify informative variants using homozygous/heterozygous phased parental loci, as taught by Che et al., within the pedigree-based genotype-imputation framework of Hikey et al. and Rubinacci et al. Hikey et al. already teaches phased parental haplotypes (pg. 2, c2, top) and inferring progeny genotypes from that parental information (pg. 9, c1, bottom), but does not explicitly teach identifying a first phased region in the first genetic sequence information that is homozygous corresponding to a second phased region in the second genetic sequence information that is heterozygous. Che et al. supplies this missing teaching, disclosing identification of informative SNP variants after parental phasing (Abstract; pg. 3, c2, top), wherein an informative SNP is one for which one parent is heterozygous and the other parent is homozygous (Figure 1; pg. 3, c2, top), and further categorizing such informative SNPs according to phased parental genotypes (Figure 1; pg. 3, c2, top). Che et al. further teaches identifying informative loci by evaluating parental zygosity states generally, including loci at which one parent is homozygous and the other parent is heterozygous. Because Che et al.’s homozygous/heterozygous zygosity-comparison technique operates on the same type of phased parental haplotype data that Hikey et al. already maintains and uses (pg. 2, c2, top), a PHOSITA would have recognized that applying Che et al.’s informative-SNP identification criterion to Hikey et al.’s phased parental data is the predictable application of a known variant-classification technique to a known type of genetic sequence information.
A PHOSITA would have had a reasonable expectation of success in this combination because identifying informative markers based on parental zygosity was a standard technique for determining inheritance, assigning parental haplotypes, and reconstructing offspring genotype, as confirmed by Che et al.’s own disclosure that such loci are used to categorize informative SNPs according to phased parental genotypes (Figure 1; pg. 3, c2, top). Identifying informative variants using such loci is known to facilitate determination of parental haplotype transmission and offspring genotype inference, yielding the predictable result of improved genotype construction when applied within Hikey et al.’s and Rubinacci et al.’s pedigree-based imputation framework, which already performs genotype construction from phased parental haplotype and progeny sequence information (pg. 2, c2, top; pg. 9, c1, bottom).
Applying Che et al.’s homozygous-to-heterozygous informative-variant identification criterion to the claim 1 limitations taught by Hikey et al. and Rubinacci et al. to yield a predictable result would therefore have been obvious to a PHOSITA, consistent with the KSR rationale that combining familiar elements according to known methods to yield predictable results is obvious to a PHOSITA.
Claim 13, 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al., as applied to claims 1, 10, and 12 above and further in view of Browning et al. (The American Journal of Human Genetics 108, 1880-1890. October 7, 2021)
Hikey et al. in view of Rubinacci et al., as applied to claims 1, 10, and 12.
Regarding claim 13:
Claim 13 adds limitation “The genotype of the progeny …. or the second genetic sequence information.”
Hikey et al. in view of Rubinacci et al., does not explicitly teach haplotype block inference in the progeny.
Browning et al. teaches haplotype block inference (Figure 1) and haplotype-based genotype construction. (pg. 2, c1, middle; Figure 1; pg. 4, c1, c2) suggesting the limitation “The genotype of the progeny ……. or the second genetic sequence information.” Browining et al. in his beagle software also teaches genotype imputation and phasing using haplotype blocks.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to construct the genotype of the progeny using one or more haplotype blocks from the sire or dam (parental), as taught by Browning et al., within the pedigree-based genotype-imputation framework of Hikey et al. and Rubinacci et al. Hikey et al. and Rubinacci et al. already construct the progeny genotype from parental SNP and sequencing information, but do not explicitly teach haplotype block inference in the progeny. Browning et al. fills this gap, teaching haplotype block inference (Figure 1) and haplotype-based genotype construction (pg. 2, c1, middle; Figure 1; pg. 4, c1-c2), and, through its Beagle software, teaching genotype imputation and phasing using haplotype blocks. Because Browning et al.’s haplotype-block construction operates on the same type of parental genetic sequence information that Hikey et al. and Rubinacci et al. already maintain and use to construct the progeny genotype, a PHOSITA would have recognized that constructing the progeny genotype to include one or more haplotype blocks of the first or second genetic sequence information, using Browning et al.’s known haplotype-based reconstruction technique, is the predictable application of a known genotype-construction refinement to a known pedigree-imputation method.
A PHOSITA would have had a reasonable expectation of success in this combination because haplotype-based genotype reconstruction, as taught by Browning et al. (pg. 2, c1, middle; Figure 1; pg. 4, c1-c2), was a well-known technique for improving imputation accuracy and represents a predictable use of known pedigree-imputation methods. A PHOSITA working in genotype imputation would naturally use inherited parental haplotypes because (1) haplotype inheritance is the biological mechanism underlying pedigree imputation, which Hikey et al. already exploits by inferring progeny genotypes from parental information, and (2) haplotype blocks provide more information than isolated SNPs, as reflected in Browning et al.’s own teaching of haplotype-based genotype construction and phasing via Beagle software (Figure 1; pg. 4, c1-c2).
Because Browning et al.’s haplotype-block inference and genotype-construction technique performs the identical function it already performs in Beagle – improving the accuracy of pedigree-based genotype imputation – when applied within Hikey et al.’s and Rubinacci et al.’s framework, the combination yields nothing more than the predictable and expected result of constructing the progeny genotype to include one or more haplotype blocks of the first or second genetic sequence information, consistent with the KSR rationale that combining familiar elements according to known methods to yield predictable results.
Regarding claim 14:
Claim 14 add limitation “The genotype of the progeny is constructed based …… on a phased haplotype block.”
Hikey et al., in view of Rubinacci et al., does not explicitly teach construction of progeny genotype based on haplotype block inference from the parental information.
Browning et al. teaches haplotype phasing, haplotype block inference (Figure 1) and haplotype-based genotype construction by imputation (pg. 2, c1, middle; Figure 1; pg. 4, c1, c2) suggesting the limitation of “the genotype of the progeny is constructed … on a phased haplotype block.”
Regarding claim 16:
Claim 16 narrows claim 1 by “performing a phase cleaning … of the progeny wherein the phase cleaning …… executing a median filter to correct phasing.”
Browning et al. teaches about phased haplotypes, (pg. 2, c1, middle; Figure 1; pg. 4, c1, c2; Figure 1) phase errors (pg. 4, c2, top; Figure 2; pg. 5, c2, middle) and phase correction (pg. 7, c2, middle) suggesting the limitation of “correct phasing”
Conventional and routine statistical median filtering process teaches use of median filtering (a non-linear filtering technique) allows to reduce noise in the data.
Browning et al. teaching of phased haplotypes and the occurrence of phasing error along the conventional and routine knowledge of the use of median filtering to reduce noise in any type of data, it would have been obvious to one of ordinary skill in the art to apply a median filter to phased genotype data in order to correct phase-flipping errors because median filters were a well-known technique for eliminating local noise and producing more consistent reliable data, yielding predictable result of improved phase accuracy.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Hikey et al. in view of Rubinacci et al. as applied to claims 1, 10, and 12 above and further I n view of Mullaart et al. (Animal Biotechnology 2) and Hu et al. (Frontiers in Cell and Developmental Biology |October 2016|Volume4|Article 116)
Hikey et al., in view of Rubinacci et al., are applied to claims 1, 10, and 12.
Claim 15 narrows claim 1 by specifying that the progeny sample used for sequencing is obtained from “four or fewer cells”.
Hikey et al., in view of Rubinacci et al., does not teach of fewer cells (four or fewer) from embryo biopsy.
Under the BRI, “four or fewer cells” encompasses either a single or two or three or four cell samples obtained from an embryo or other progeny source for subsequent sequencing or genotyping construction.
Mullaart et al. teaches obtaining DNA from a few embryonic cells from embryo biopsy and performing genetic analysis (Abstract, pg. 81; Table 5.1, pg. 85) and Hu et al. teaches sequencing and genotyping from single or few cells using whole genome amplification. (Figure 1) suggesting the limitation of “sequencing is obtained from “four or fewer cells”.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize a sample consisting of four or fewer cells, as taught by Mullaart et al. and Hu et al., within the pedigree-based genotype-imputation framework of Hikey et al. and Rubinacci et al., because the number of cells obtained from an embryo biopsy is a recognized result-effective variable. Mullaart et al. teaches obtaining DNA from a few embryonic cells via embryo biopsy and performing genetic analysis on that small sample (Abstract; pg. 81; Table 5.1, pg. 85), and Hu et al. teaches sequencing and genotyping from a single cell or a few cells using whole-genome amplification (Figure 1). Because Hikey et al. and Rubinacci et al. already sequence a sample of genetic information from the progeny without specifying the number of cells in that sample, a PHOSITA would have recognized that selecting a small number of cells, specifically four or fewer as taught by Mullaart et al. and Hu et al., to reduce embryo damage while retaining sufficient genetic information for sequencing and genotyping is a matter of routine optimization of a recognized result-effective variable, predictably successful because Mullaart et al. and Hu et al. already demonstrate that useful genetic analysis, sequencing, and genotyping can be obtained from samples of this size.
A PHOSITA would have had a reasonable expectation of success in this optimization because Mullaart et al.’s own data show that DNA obtained from a few embryonic cells via biopsy (Abstract; pg. 81; Table 5.1, pg. 85) is sufficient to perform genetic analysis, and Hu et al.’s whole-genome amplification technique (Figure 1) was specifically developed to enable sequencing and genotyping from single or few cells notwithstanding the limited starting material. The need for minimizing embryo damage and maximizing embryo survival, while still obtaining sufficient genetic information, would have motivated a PHOSITA to reduce biopsy size to four or fewer cells while maintaining genotyping capability, using the combined Mullaart/Hu techniques applied to the sequencing and genotype-construction steps already taught by Hikey et al. and Rubinacci et al.
Selecting a sample size of four or fewer cells therefore represents the routine optimization of a result-effective variable – biopsy sample size – that was already recognized in the art, through Mullaart et al.’s and Hu et al.’s own successful use of comparably small samples, to affect the competing considerations of embryo damage and genetic-information sufficiency, consistent with MPEP 2144.05(II) and the KSR rationale that discovering an optimum value of a known result-effective variable through routine experimentation is likely obvious to a PHOSITA.
.
Regarding claim 17 (A system) and 18 (A CRM) comprise the same limitations as claim 1 regarding the commuter-implemented evaluation of biological sample using various elements, therefore, the teachings of the above prior art for claim 1 rejection.
Conclusion
No claims are allowed.
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/A.H.K./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686
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