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 .
Election/Restrictions
2. Applicant’s election of species (i) of "methods that require enriching a cfDNA fraction from a sample of a pregnant woman for fetal nucleic acids" in the reply filed on 12/22/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
It is noted that the response states
“As the Office Action notes, the methodologies of (i), (ii), and (iii), are not mutually exclusive and can be used together. See Office Action at p. 3.“
However, the Office action did not make such a statement.
The response further states:
“Accordingly, the foregoing election of (i) should include (i) and any combination of (ii) and/or (iii) so long as they are not expressly excluded. This election thus reads on claims 1-27 and 28-33.”
However, as set forth in the ejection each of species (i)-(iii) are distinct. Applicant was given the opportunity to elect (i) in combination with (ii) or with (iii) or any other combination of species (i)-(iii). Yet, Applicant elected species (i) alone. Claims which require (i) in combination with (ii) and/or (iii) constitute non-elected species and are withdrawn from consideration.
Claim Status
3. Claims 1-33 are pending.
Claims 1-10, 13, 16-20, 28, 30, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 11, 12, 14, 15, 21-27, 29, 31 and 33 read on the elected invention and have been examined herein to the extent that the claims read on the elected species of (i). It is noted that claims 11, 12, 14, 15, 21-26, 29, 31 and 33 encompass non-elected species. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Objection to Drawings
4. The drawings are objected to under 37 CFR 1.83(a). A set of drawings filed on 01/10/2023 includes figures presented in color. See figures 1-5 and 7-8.
MPEP 608.02, part VIII states:
Color drawings and color photographs are not accepted in utility applications filed under 35 U.S.C. 111 unless a petition filed under 37 CFR 1.84(a)(2) or (b)(2) is granted. Color drawings and color photographs are not permitted in international applications (see PCT Rule 11.13 ).
Unless a petition is filed and granted, color drawings or color photographs will not be accepted in a utility patent application filed under 35 U.S.C. 111. The examiner must object to the color drawings or color photographs as being improper and require applicant either to cancel the drawings or to provide substitute black and white drawings.
Herein, a petition for color drawings or color photographs has not been filed and the conditions for color drawings have not been met. Note that color drawings are only accepted on rare occasions when they are the only practical medium by which to disclose the subject matter to be patented. See MPEP 608.02(VIII).
If the drawings are intended to be in color, a petition for color drawings must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Alternatively, corrected drawing sheets in black and white in compliance with 37 CFR 1.121(d) are required.
Appropriate correction is required.
Specification
5. The use of the term “Myriad PREQUEL™ Prenatal Screen”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
This is one example of a trademark that is used in the specification. The specification should be reviewed for any additional trademarks or trade names and the terms should be accompanied by their generic terminology and capitalized or where appropriate accompanied by a proper symbol.
Claim Rejections - 35 USC § 101
6. 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 11, 12, 14, 15, 21-26 and 33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of
an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
Claims 11, 12, 14, 15, 21-26 require performing the step of “iv) detecting the presence or absence of aneuploidy and the presence or absence of at least one genetic variant in the single, maternal sample.” The claims do not set forth how the detecting step is performed and there is no limiting definition in the specification for the detecting step. As broadly recited, the claims encompass reading information regarding the sequencing results or any other information regarding the maternal sample and mentally drawing the conclusion that the maternal sample is one in which aneuploidy and a genetic variation is present or absent in the fetal cfDNA or in the maternal DNA. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
Claims 24 and 33 also recite steps of normalizing sequence depth. In the absence of a limiting definition in the specification or the claims, the normalizing step can also be performed mentally and is thereby an abstract idea / process. Alternatively, the normalizing step can be performed using pen and paper or using a generic computer.
Similarly, the analyzing step in claims 21-23 and the step of fitting sequencing depth to a model can be performed using pen or paper or with a generic computer / generic software.
As stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Herein, the use of a generic computer to normalize sequence depth, to analyze sequence depth or to fit sequence depth to a model does not constitute something more than an abstract idea.
Claim 23 also recites the judicial exception of a mathematical concept of the formula that is used to correct for cellular heterogeneity. See MPEP 2106.04(a)(2):
“A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of obtaining a sample from a pregnant woman; extracting cfDNA from the sample; preparing a cfDNA library and sequencing the cfDNA library, as well as the step of enriching the cfDNA by size separation are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the additionally recited steps of obtaining a sample from a pregnant woman; extracting cfDNA from the sample; preparing a cfDNA library and sequencing the cfDNA library, as well as the step of enriching the cfDNA by size separation were well-known, routine and conventional in the prior art. See, for example, the teachings of Welker et al (High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening. Genetics in Medicine. 15 Nov. 2020. 23: 443-450, and Supplementary Information, p. 1-7) and Osteras et al (U.S. 20150275290), each discussed in detail below. See also Hu et al (J Trends Med. 2019. 17:124, p. 1-9) which teaches methods of obtaining a plasma sample from a pregnant woman; extracting cfDNA from the sample; using end-repair, adapter ligation and PCR amplification to generate a NIPS library; using magnetic beads to separate DNA fragments with a cut-off size of 160 bp and then sequencing the enriched fraction of fetal cfDNA (p. 2, col. 2). Liang et al (Scientific Reports. 2018. 8: 17675, p. 1-8) also teaches methods comprising obtaining a plasma sample from a pregnant woman; extracting cfDNA from the plasma sample; generating a cfDNA library; selecting cfDNA that is a size ranging from 100 to 150 bp (i.e., having a cutoff of 150 bp) and then sequencing the size-selected / enriched cfDNA (e.g., p. 6 “”cfDNA extraction and library construction”, “Library size selection” and “Sequencing and data analysis”).
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Further, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
7. 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 11, 12, 14, 15, 21-26, 31 and 33 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 11, 12, 14, 15, and 21-26 are indefinite and vague over the recitation of “detecting the presence or absence of aneuploidy and the presence or absence of at least one genetic variant in the single, maternal sample” because the claims do not set forth the criteria for detecting / determining the presence or absence of aneuploidy and the presence or absence of at least one genetic variant and/or how this step relates back to steps (i)-(iii) of the claims. For instance, the claims do not require using the results of sequencing the cfDNA library or using the sequence library to detect the presence or absence of aneuploidy and the presence or absence of at least one genetic variant.
Claim 23 is indefinite over the recitation of “pregnancy depth” because this phrase is not clearly defined in the specification or the claims and there is no art recognized definition for this phrase. It is acknowledged that the specification (para [0150]; para numbering herein is with respect to the published application states “For the purposes of this disclosure, “depth” is defined as the ratio of the number of reads obtained by sequencing that overlap with a site of interest to the size of the library or the average number of times each base is measured in the library.” However, this definition does make clear what is encompassed by “pregnancy depth.” Similarly it is not clear as to what constitutes the “background depth” because it is unclear as to what background is being referred to. This phrase is not defined in the specification or the claims and there is no specific definition for this phrase in the prior art as it pertains to “sequence depth.” Additionally, claim 23 is indefinite because it is unclear as to how this claim further depends from claim 21. While claim 21 recites a step of analyzing a sequence depth, claim 21 does not recite a nexus between analyzing and calculating and it is unclear as to whether the claim requires analyzing / evaluating a sequence depth that can be calculated using the formula in claim 23 or if claim 23 intends for the analyzing step to comprise calculating a sequence depth using the formula recited in claim 23.
Claims 24 and 33 are indefinite over the recitation of normalized to control for hybridization probe capture because the claim does not require performing a step of hybridization probe capture and thereby it is unclear as to how this recitation is intended to further limit the claimed method.
Claim 26 is indefinite over the recitations of “at least one genetic variant is associated with a disease selected from…Angiotensin II Receptor, Type I, Apolipoprotein E Genotyping…Plasminogen Activator Inhibitor I, Polycystic Kidney Disease, Autosomal Recessive” because it is not clear as to what is encompassed by these diseases. In particular, Angiotensin II Receptor, Type I and Plasminogen Activator Inhibitor I are proteins, and are not themselves diseases. Apolipoprotein E Genotyping is an assay and not itself a disease. Additionally, claim 26 is indefinite over the recitation of “Infantile Myopathy and Lactic Acidosis (Fatal and Non-Fatal Forms).” Parentheticals make the claims indefinite because it is unclear whether the information in the parentheses has the same, less, or more weight as the rest of the claim language. Accordingly, it is not clear as to whether the information in parenthesis is intended to be required by the claims or is optional.
Claim 31 recites “The method of claim 29, wherein the enriching the biological sample for cell-free fetal DNA (cffDNA) comprises the method of claim 27. Claim 29 recites obtaining a biological sample from a pregnant women and processing the cfDNA in the biological sample by enriching the biological sample for cffDNA. However, claim 27 also recites a step of obtaining a biological sample from a pregnant women. It is thereby unclear as to whether claim 31 intends to require performing two steps of obtaining a biological sample and if so it is unclear as to the relevance of obtaining the first biological sample from the pregnant women. If claim 31 intends to recite only the method of claim 27 of enriching a biological sample for cell-free DNA, it is unclear as to how claim 31 further limits the method of claim 27.
Claim 33 is further indefinite over the recitation of “further comprising normalization to control” because the claim does not set forth what is being normalized. It is unclear as to what parameter is being normalized since the claim recites only steps of obtaining a sample from a pregnant women and enriching the sample for cfDNA. In contrast, note that claim 24 recites a step of sequencing the cfDNA library and recites “wherein the sequence depth is normalized to control for GC-bias…”.
Priority
8. Claims 27, 29, 30 and 31 are entitled to priority to U.S. provisional application 63/298,593.01/11/2022.
Claims 11, 12, 14, 15, 21-26 and 33 are entitled to priority to U.S. provisional application 63/357,915, filed on 07/01/2022. It is noted that a claim as a whole is assigned an effective filing date rather than the subject matter within a claim being assigned individual effective filing dates. U.S. Application 63/298,593 does not provide support for each of the embodiments in independent claim 11 and each of the embodiments in the dependent claims or each of the embodiments in claim 33.
If Applicant asserts that the present claims are entitled to priority to the provisional applications, Applicant should point to specific teachings (e.g., by page and line number) in the priority applications to establish priority for each of the recitations set forth in the claims.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” states “To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
Claim Rejections - 35 USC § 102
9. 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.
Claim(s) 11, 12, 14, 15, 21-22, 25-27, 29 and 31 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Welker et al (High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening. Genetics in Medicine. 15 Nov. 2020. 23: 443-450, and Supplementary Information, p. 1-7).
Regarding claim 11, Welker teaches a method for simultaneously / parallel detecting the presence or absence of aneuploidy and the presence or absence of at least one genetic variant (i.e., a microdeletion) in a single, maternal sample, comprising (i) obtaining a biological sample from a pregnant woman, wherein the biological sample comprises cell-free DNA (cfDNA); (ii) preparing a cfDNA library; (iii) sequencing the cfDNA library to produce a sequence library; and (iv) detecting the presence or absence of aneuploidy and the presence or absence of at least one genetic variant (a microdeletion) in the single, maternal sample; wherein the cfDNA library is enriched to increase a fetal fraction by performing size separation of the cfDNA library (see e.g.,, p. 444 “FFA methodology,” Tables 1, S1 and S4; and Figure S4). In particular, Welker (p. 444, col. 2) states:
“cfDNA libraries were size selected via gel electrophoresis on 2% agarose cassettes (BluePippin, Sage Science) following the manufacturer’s instructions for “range” mode (a FFA workflow could include one of many different gel electrophoresis strategies, e.g., 2% E Gel EX from Invitrogen as in Qiao et al.28 and Liang et al.29). Short fragments were eluted from the gel until the average length of the eluted cfDNA was 140nt, which preferentially retains fetal cfDNA and depletes maternal cfDNA (schematic in Fig. S1). The size-selected libraries had higher FF because fetal-derived fragments comprise a higher fraction of the total size-selected cfDNA.”
Welker teaches that this enrichment procedure (i.e., fetal fraction amplification (FFA)) increases the fetal fraction 2.3 fold on average for each sample (p. 445, col. 2 “Results).
Regarding claim 12, Welker (e.g., p. 444 “FFA methodology”) teaches that the sample is a plasma sample.
Regarding claim 14, as discussed above, Welker(p. 444, col. 2) teaches “(s)hort fragments were eluted from the gel until the average length of the eluted cfDNA was 140nt.” Thereby, Welker teaches that the method comprises removing from the cfDNA library any fragments greater than about 150 nucleotides.
Regarding claim 15, Welker(p. 444, col. 2) teaches removing the DNA fragments from the cfDNA library comprises electrophoresis (i.e., “cfDNA libraries were size selected via gel electrophoresis on 2% agarose cassettes”).
Regarding claim 21, Welker (p. 444, col. 2; p. 446, col. 1 and Figure 3) teaches that the method further comprises analyzing a sequence depth of at least one sequence corresponding to a chromosome of interest in the sequence library.
Regarding claim 22, Welker teaches that the sequence depth of the sequence suspected of being aneuploid is fit to a model of expected depth for this sequence (p. 445, “Sensitivity and specificity assessment”).
Regarding claim 25, Welker (Table 1) teaches that the aneuploidy is trisomy (i.e., trisomy 21 (T21), trisomy 18 (T18) or trisomy 13 (T13).
Regarding claim 26, Welker (Table 1) teaches that the genetic variation is a microdeletion at 22q11.2 that is associated with DiGeorge syndrome, which is a “neurological phenotype” since it is associated with neurological disorders, such as epilepsy and movement disorders.
Regarding claim 27, the method of Welker comprises obtaining a biological sample comprising cfDNA from a pregnant woman, wherein it is a property of the cfDNA comprises cffDNA and cell-free maternal DNA (cfmDNA); extracting the cfDNA from the biological sample; and subjecting the extracted cfDNA to a size exclusion process (p. 144). Welker teaches isolating fragments of about 140bp and thereby teaches that the size exclusion process has a cutoff size of “about” 150 nucleotides. Note that specification (para [0074]) states that “about” encompasses a range of +/- 10% of the stated value and thereby the present claims encompass methods in which the cutoff size is 140bp. Further note that the claim 27 recites the open claim language of comprising and thereby may include additional processing steps of the extracted cfDNA prior to the size exclusion process.
Regarding claims 29 and 31, Welker teaches that the methods disclosed therein are for preparing cfDNA from the plasma sample of the pregnant woman for noninvasive prenatal screening (NIPS). Further, since the method steps of Welker are the same as those in the claimed method, the method of Welker also reduce background noise from superfluous genetic material. Additionally, the recitation in claims 29 and 31 of “of reducing background noise from superfluous genetic material” constitutes an intended use limitation and does not materially distinguish the claimed method over that of Welker.
Claim Rejections - 35 USC § 103
10. 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.
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) 24 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Welker et al (High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening. Genetics in Medicine. 15 Nov. 2020. 23: 443-450, and Supplementary Information, p. 1-7) in view of Muzzy et al (U.S. 20180089364).
The teachings of Welker are presented above.
Welker (p. 444, col. 2) teaches that fetal fraction “is measured either via a regression on autosomal bin depth or from the normalized depth of NGS data for a particular region (e.g., chrY, chr21).” However, Welker does not teach normalizing the sequence depth to control GC-bias.
However, Muzzy teaches methods of noninvasive prenatal screening (NIPS) in which fetal-derived cell-free DNA present in a plasma sample from a pregnant woman is sequenced to detect the presence of a chromosomal abnormality (e.g., para [0007] and [0058]).
Muzzy teaches normalizing sequence reads for variations in GC content (para [0032], [0094], [0101] and [0110]. For instance, Muzzy (para [0101]) states:
“some bins within the interrogated region may have a higher GC content than other bins within the interrogation region. The higher GC content may increase or decrease the sequencing efficiency within that bin, inflating the relative number of sequencing reads for reasons other than fetal fraction. Methods to normalize GC content are known in the art, for example as described in Fan & Quake, PLoS ONE, vol. 5, e10439 (2010).”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Welker so as to have normalized the sequence depth in order to control for variations in GC content / GC bias, as taught by Muzzy. One would have been motivated to have done so because Muzzy teaches that different regions of the genome having variations in GC content may show higher or lower sequencing efficiency. Thereby, the ordinary artisan would have recognized that modification of the method of Welker so as to have included a step of normalizing sequence to control for GC content / bias would have provided a more accurate means for determining the presence or absence of a chromosomal aneuploidy or a microdeletion (genetic variation).
11. Claim(s) 27, 29 and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Osteras et al (U.S. 20150275290).
Regarding claim 27, Osteras (para [0067-0071] and claims 1 and 4) teaches a method for detecting fetal aneuploidy comprising comprises obtaining a blood sample comprising cell-free DNA(cfDNA) from a pregnant woman, wherein it is a property of the cfDNA comprises cffDNA and cell-free maternal DNA (cfmDNA); extracting cfDNA from the blood sample; performing size selection on the extracted cfDNA in order to remove DNA molecules having a size greater than 200 bp; and processing the size-selected extracted cell-free DNA for the preparation of a sequencing library, Note that specification (para [0074]) states that “about” encompasses a range of +/- 10% of the stated value. Thereby, the present claims encompass methods wherein the cutoff is 200 bp.
Regarding claims 29 and 31, Osteras teaches that the methods disclosed therein are for “non-invasive prenatal diagnosis of fetal aneuploidy using cell-free DNA, particularly size-selected cell-free DNA” (para [0001]). Further, since the method steps of Osteras are the same as those in the claimed method, the method of Osteras also reduce background noise from superfluous genetic material. Additionally, the recitation in claims 29 and 31 of “of reducing background noise from superfluous genetic material” constitutes an intended use limitation and does not materially distinguish the claimed method over that of Osteras.
12. Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Osteras et al (U.S. 20150275290) in view of Muzzy et al (U.S. 20180089364).
The teachings of Osteras are presented above.
Osteras (para [0009]) states that “(t)he sensitivity of non-invasive prenatal diagnosis to detect fetal aneuploidy with whole genome next generation sequencing (WG-NGS) depends on the fetal DNA fraction in the maternal plasma, and on the sequencing depth.”
Osteras does not teach normalizing the sequence depth to control GC-bias.
However, Muzzy teaches methods of noninvasive prenatal screening (NIPS) in which fetal-derived cell-free DNA present in a plasma sample from a pregnant woman is sequenced to detect the presence of a chromosomal abnormality (e.g., para [0007] and [0058]).
Muzzy teaches normalizing sequence reads for variations in GC content (para [0032], [0094], [0101] and [0110]. For instance, Muzzy (para [0101]) states:
“some bins within the interrogated region may have a higher GC content than other bins within the interrogation region. The higher GC content may increase or decrease the sequencing efficiency within that bin, inflating the relative number of sequencing reads for reasons other than fetal fraction. Methods to normalize GC content are known in the art, for example as described in Fan & Quake, PLoS ONE, vol. 5, e10439 (2010).”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Osteras so as to have normalized the sequence depth in order to control for variations in GC content / GC bias, as taught by Muzzy. One would have been motivated to have done so because Muzzy teaches that different regions of the genome having variations in GC content may show higher or lower sequencing efficiency. Thereby, the ordinary artisan would have recognized that modification of the method of Osteras so as to have included a step of normalizing sequence to control for GC content / bias would have provided a more accurate means for determining the presence or absence of a chromosomal aneuploidy or a microdeletion (genetic variation).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682