DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 1-20 is/are currently pending and under exam herein.
Claims 1-20 is/are rejected.
Priority
Priority is acknowledged to Application No. 15958376 filed on 04/20/2018, Application No. 14089720 filed on 11/25/2013, Application No. 12940992 filed on 11/05/2010, Provisional Application No. 61360399 filed on 06/30/2010, and Provisional Application No. 61259076 filed on 11/06/2009. The effective filling date for the instant application is therefore considered to be 11/06/2009.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/27/2024, 10/29/2025 are in compliance with the provisions of 37 CFR 1.97. One NPL reference (CHRISTINA et al. 2010) on the IDS filed on 06/01/2023 was not found to be submitted and therefore was lined through on the IDS. The missing reference (CHRISTINA et al. 2010) had a title identical to another reference (FAN et al. 2010), which was included on the same IDS (06/01/2023) and was submitted two times. Accordingly, all the information disclosure statements are being considered by the examiner.
Drawings
The drawings received on May 12, 2022 are accepted.
Claim Rejections - 35 USC § 112
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 1-20 are rejected under 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.
Claim 1 is indefinite due to the limitation - performing single-molecule sequencing of the DNA molecule to obtain a complete read of the molecule. “Complete” is not defined in the claims or specification. It is unclear if “complete” refers to the sequence quality (all nucleotides identified with no unknowns), sequence coverage (every nucleotide of the molecule was sequenced), or the state of the DNA molecule (no fragmentation).
Claim 5 is indefinite due to the limitation - wherein the threshold value is determined using a reference haplotype. “Reference haplotype” is not defined in the claims or specification. It is unclear if the reference haplotype has to be part of the biological sample or if it can be from some other source.
Claim 6 is indefinite due to the limitation - wherein the threshold value is determined using a euploid sample. “Euploid sample” is not defined in the claims or specification. It is unclear if the euploid sample was part of the biological sample collected or if it can be from some other source.
Claim 7 is indefinite due to the limitation - wherein comparing the first statistical value to the threshold value comprises: calculating, by the computer system, a second statistical value from the sizes of DNA molecules from one or more reference sequences. “Reference sequence” is not defined in the claims or specification. It is unclear if the reference sequence has to be part of the biological sample or if it can come from some other source. Claims 10-11 and 18-20 also refer to reference sequences and are indefinite for the same reason.
Claim 16 is indefinite due to the limitation - determining a second amount of sequences identified as aligning to one or more second sequences. It is unclear if the “second amount of sequences” is the same or different than the “one or more second sequences” it is being aligned to.
Claims 2-4, 8-9, 12-15, and 17 are dependent on indefinite claims and are therefore rejected under 35 U.S.C. 112 (pre-AIA ), second paragraph.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1 recites the limitation - calculating, by the computer system, a first statistical value from the sizes of DNA molecules from a first sequence. Based on the broadest reasonable interpretation, calculating a statistical value could include an equation that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea. Claim 1 also recites the limitations - comparing the first statistical value to a threshold value; determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the first statistical value to the threshold value. Based on the broadest reasonable interpretation, comparing and determining could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitations as abstract ideas. Additionally, using the classification to identify the existence of a sequence imbalance draws the limitation to a natural phenomenon, which classifies the limitation as a law of nature.
Claim 5 recites the limitation - wherein the threshold value is determined using a reference haplotype. Based on the broadest reasonable interpretation, determining a threshold value could include an equation that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 6 recites the limitation - wherein the threshold value is determined using a euploid sample. Based on the broadest reasonable interpretation, determining a threshold value could include an equation that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 7 recites the limitations - wherein comparing the first statistical value to the threshold value comprises calculating, by the computer system, a second statistical value from the sizes of DNA molecules from one or more reference sequences; determining the threshold value using the second statistical value. Based on the broadest reasonable interpretation, calculating a statistical value and determining a threshold value could include equations that could practically be done by the human mind. This draws the limitations to mathematical concepts and mental processes, which classify the limitations as abstract ideas.
Claim 8 recites the limitation - wherein the first statistical value includes the median or average size of the measured sizes for the DNA molecules from the first sequence. Based on the broadest reasonable interpretation, determining a median or average as the statistical value could include equations that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 9 recites the limitation - wherein the first sequence is a chromosome and the sequence imbalance is a fetal chromosomal aneuploidy. Specifying these parameters does not change the judicial exceptions reported for claim 1. Calculating the first statistical value from a chromosome could include equations that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classify the limitation as an abstract idea. Determining a classification of whether a fetal chromosomal aneuploidy exists based on comparison to threshold value could practically be done by the human mind. This draws the limitation to a mental process, which classify the limitation as an abstract idea. Additionally, using the classification to identify the existence of a fetal chromosomal aneuploidy draws the limitation to a natural phenomenon, which classifies the limitation as a law of nature.
Claim 10 recites the limitation - wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences comprise one chromosome. Based on the broadest reasonable interpretation, determining the threshold value could include an equation that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 11 recites the limitation - wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences are a plurality of chromosomes. Based on the broadest reasonable interpretation, determining the threshold value could include an equation that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 16 recites the limitations - determining a first amount of sequences identified as aligning to the first sequence of the human genome; determining a second amount of sequences identified as aligning to one or more second sequences; using the first amount and the second amount to determine another parameter. Based on the broadest reasonable interpretation, determining amounts and a parameter could include equations that could practically be done by the human mind. This draws the limitations to mathematical concepts and mental processes, which classify the limitations as abstract ideas. Claim 16 also recites the limitation - comparing the other parameter to one or more second cutoff values to determine another classification of whether the sequence imbalance exists for the first sequence. Based on the broadest reasonable interpretation, comparing a parameter to a cutoff value could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea.
Claim 17 recites the limitation - comparing the classification determined using the first statistical value and the threshold value to the other classification determined using the first amount and the second amount. Based on the broadest reasonable interpretation, comparing classifications could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea.
Claim 18 recites the limitation - wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences have a GC content that is similar to a GC content of the first sequence. Based on the broadest reasonable interpretation, determining the threshold value could include an equation that could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 19 recites the limitations - calculating the GC content of the one or more reference sequences; and calculating the GC content of the first sequence. Based on the broadest reasonable interpretation, calculating GC contents could include an equation that could practically be done by the human mind. This draws the limitations to mathematical concepts and mental processes, which classify the limitations as abstract ideas.
Claims 2-4, 12-15, and 20 are dependent on claims that exhibit judicial exceptions and are therefore rejected under 35 U.S.C. 101.
These limitations recite concepts of analyzing, organizing and identifying information that are so generically recited that they can be practically performed in the human mind as claimed, which falls under the “Mental processes” and “Mathematical concepts” grouping of abstract ideas. These recitations are similar to the concepts of collecting information, analyzing it and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. These limitations also recite natural correlations which fall under laws of nature. This is similar to detecting a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk (Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017)) that the courts have identified as a law of nature. Therefore, these limitations fall under laws of nature judicial exception. As such claims 1-20 recite an abstract idea or law of nature (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). These judicial exceptions are not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology (MPEP § 2106.04(d)(1)). Rather, the claims provide insignificant extra-solution activity (MPEP § 2106.05(g)) and provide mere instructions to apply a judicial exception (MPEP § 2106.05(f)). Specifically, the claims recite the following additional elements:
Claim 1 recites measuring a size of the DNA molecule, wherein measuring the size of the DNA molecule comprises performing single-molecule sequencing of the DNA molecule to obtain a complete read of the molecule; identifying which nucleic acid sequence in the human genome the DNA molecule is derived from, wherein identifying which DNA sequence the DNA molecule is derived from includes aligning, by a computer system, a portion of the complete read to the human genome.
Claim 2 recites wherein the single-molecule sequencing comprises nanopore sequencing.
Claim 3 recites wherein the single-molecule sequencing comprises single-molecule, real time sequencing.
Claim 4 recites extracting the mixture of cell-free DNA to obtain the biological sample.
Claim 12 recites wherein the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid.
Claim 13 recites wherein the plurality of the DNA molecules includes at least one million DNA molecules.
Claim 14 recites collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample.
Claim 15 recites displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence.
Claim 20 recites wherein the GC content of the one or more reference sequences and the GC content of the first sequence are obtained for a particular sequencing platform.
There are no limitations that indicate that the claimed calculations, comparisons, and determinations require anything other than generic computing systems. As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. There is no indication that these steps are affected by the judicial exceptions in any way and thus do not integrate the recited judicial exceptions into a practical application. As such, claims 1-20 are directed to an abstract idea or natural law (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment. The claims also recite additional elements that represent insignificant extra-solution activities. The instant claims recite the following additional elements:
Claim 1 recites measuring a size of the DNA molecule, wherein measuring the size of the DNA molecule comprises performing single-molecule sequencing of the DNA molecule to obtain a complete read of the molecule; identifying which nucleic acid sequence in the human genome the DNA molecule is derived from, wherein identifying which DNA sequence the DNA molecule is derived from includes aligning, by a computer system, a portion of the complete read to the human genome.
Claim 2 recites wherein the single-molecule sequencing comprises nanopore sequencing.
Claim 3 recites wherein the single-molecule sequencing comprises single-molecule, real time sequencing.
Claim 4 recites extracting the mixture of cell-free DNA to obtain the biological sample.
Claim 12 recites wherein the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid.
Claim 13 recites wherein the plurality of the DNA molecules includes at least one million DNA molecules.
Claim 14 recites collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample.
Claim 15 recites displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence.
Claim 20 recites wherein the GC content of the one or more reference sequences and the GC content of the first sequence are obtained for a particular sequencing platform.
As discussed above, there are no additional limitations to indicate that the claimed calculations, comparisons, and determinations require anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. As specified in MPEP 2106.05(g), extra-solution activities can be understood as incidental to the primary process or product that are merely a nominal or tangential addition to the claim. Insignificant extra-solution activities include mere data gathering, selecting a particular data source or type of data to be manipulated. Some examples include performing clinical tests on individuals to obtain input for an equation (In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989)) and determining the level of a biomarker in blood (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012)). 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 1-20 are not patent eligible.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 4, 6-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Fan et al. (PNAS, Vol. 105, No. 42, Pgs. 16266–16271, DOI: 10.1073_pnas.0808319105. Published October 21, 2008), hereafter referred to as Fan et al., in view of Lapaire et al. (Clinical Chemistry, Vol. 53, No. 3, Pgs. 405–411, DOI: 10.1373/clinchem.2006.076083, Published March 1, 2007), hereafter referred to as Lapaire et al.
Claim 1. A method for performing prenatal diagnosis of a sequence imbalance in a biological sample obtained from a female subject pregnant with a fetus, wherein the biological sample includes a mixture of cell-free DNA molecules that are part of DNA sequences of a human genome, the biological sample including DNA molecules from the fetus and the female subject, the method comprising:
for each of a plurality of the DNA molecules in the biological sample:
i. measuring a size of the DNA molecule, wherein measuring the size of the DNA molecule comprises: performing single-molecule sequencing of the DNA molecule to obtain a complete read of the molecule;
ii. identifying which nucleic acid sequence in the human genome the DNA molecule is derived from, wherein identifying which DNA sequence the DNA molecule is derived from includes: aligning, by a computer system, a portion of the complete read to the human genome;
iii. calculating, by the computer system, a first statistical value from the sizes of DNA molecules from a first sequence;
vi. comparing the first statistical value to a threshold value; and
v. determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the first statistical value to the threshold value.
Claim 4. The method of claim 1, further comprising extracting the mixture of cell-free DNA to obtain the biological sample.
Claim 6. The method of claim 1, wherein the threshold value is determined using a euploid sample.
Claim 7. The method of claim 1, wherein comparing the first statistical value to the threshold value comprises: calculating, by the computer system, a second statistical value from the sizes of DNA molecules from one or more reference sequences; and determining the threshold value using the second statistical value.
Claim 8. The method of claim 1, wherein the first statistical value includes the median or average size of the measured sizes for the DNA molecules from the first sequence.
Claim 9. The method of claim 1, wherein the first sequence is a chromosome and the sequence imbalance is a fetal chromosomal aneuploidy.
Claim 10. The method of claim 9, wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences comprise one chromosome.
Claim 11. The method of claim 9, wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences are a plurality of chromosomes.
Claim 12. The method of claim 1, wherein the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid.
Claim 13. The method of claim 1, wherein the plurality of the DNA molecules includes at least one million DNA molecules.
Claim 14. The method of claim 1, further comprising: collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample.
Claim 15. The method of claim 1, further comprising displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence.
Claim 16. The method of claim 1, further comprising:
i. determining a first amount of sequences identified as aligning to the first sequence of the human genome;
ii. determining a second amount of sequences identified as aligning to one or more second sequences;
iii. using the first amount and the second amount to determine another parameter;
iv. comparing the other parameter to one or more second cutoff values to determine another classification of whether the sequence imbalance exists for the first sequence.
Claim 17. The method of claim 16, further comprising: comparing the classification determined using the first statistical value and the threshold value to the other classification determined using the first amount and the second amount.
Claim 18. The method of claim 1, wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences have a GC content that is similar to a GC content of the first sequence.
Claim 19. The method of claim 18, further comprising: calculating the GC content of the one or more reference sequences; and calculating the GC content of the first sequence.
Claim 20. The method of claim 18, wherein the GC content of the one or more reference sequences and the GC content of the first sequence are obtained for a particular sequencing platform.
Fan et al. teaches measuring a size of the DNA molecule (Page 16269, Figure 3: see X axes - size of sequenced fragments and length of sequenced DNA fragments) and includes performing single-molecule sequencing of the DNA molecule to obtain a complete read of the molecule (Page 16271, Column 1, Paragraph 2: 454/Roche platform was used) (Claim 1.i). Fan et al. also teaches identifying which nucleic acid sequence in the human genome the DNA molecule is derived from by aligning the DNA to the reference genome (Page 16271, Column 1, Paragraph 3: reads were uniquely mapped to the human genome) (Claim 1.ii). Fan et al. also teaches also extracting the mixture of cell-free DNA to obtain the biological sample (Page 16270, Column 2, Paragraph 4: DNA was extracted from cell-free plasma) (Claim 4). Fan et al. also teaches the use of a chromosome as a first sequence and the sequence imbalance is a fetal chromosomal aneuploidy (Page 16267, Column 2, Paragraph 1: Detection of Fetal Aneuploidy - The distribution of chromosome 21 sequence tag density for all nine T21 pregnancies is clearly separated from that of pregnancies bearing disomy 21 fetuses) (Claim 9). Fan et al. also teaches determining a threshold value using one or more reference sequences, which comprise one chromosome (Page 16267, Column 2, Paragraph 1: The coverage of chromosome 21 for T21 cases is 4–18% higher than that of the disomy 21 cases) (Claim 10). Fan et al. also teaches determining a threshold value using one or more reference sequences, which comprise multiple chromosome (Page 16271, Column 2, Paragraph 1: Chromosomes X and Y are considered) (Claim 11). Fan et al. also teaches the biological sample includes blood (Page 16270, Column 2, Paragraph 4: peripheral blood drawn from each subject and donor was collected) (Claim 12). Fan et al. also teaches the plurality of the DNA molecules includes at least one million DNA molecules (Page 16266, Column 2, Paragraph 2: Approximately 50% (i.e., 5 million) of the reads mapped uniquely to the human genome) (Claim 13). Fan et al. also teaches collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample (Page 16270, Column 2, Paragraph 4: Peripheral blood drawn from each subject and donor was collected. Blood was centrifuged. Plasma was transferred and centrifuged to remove residual cells.) (Claim 14). Fan et al. also teaches displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence (Claim 15). Fan et al. teaches all analyses were done with Matlab, which would have been executed on a computer and would have displayed the results of the analyses (Page 16271, Column 2, Paragraph 1). Fan et al. also teaches determining an amount of sequences aligning to a sequence of the human genome (Claim 16.i); determining another amount of sequences aligning to other sequences (Claim 16.ii); and using the first amount and the second amount to determine another parameter (Claim 16.iii) (Page 16266, Column 2, Paragraph 3: The median count for each chromosome was selected. The median of the autosomal values was used as a normalization constant). Fan et al. also teaches comparing the other parameter to one or more second cutoff values to determine another classification of whether the sequence imbalance exists for the first sequence (Page 1626, Columns 1 and 2: normalized values were used for comparing different samples and for subsequent analysis including detection of fetal aneuploidy) (Claim 16.iv). Fan et al. also teaches comparing the classification determined using a statistical value and the threshold value to the other classification determined using the first amount and the second amount (Page 16267, Column 2, Paragraph 1 and Page 16268, Column 2, Paragraph 3: tag density and size frequency are each used for exploring differences between samples) (Claim 17). Fan et al. also teaches the threshold value is determined using one or more reference sequences, and the one or more reference sequences have a GC content that is similar to a GC content of the first sequence (Page 16270, Column 1, Paragraph 2: The results were influenced by a GC bias indicating that utilizing a refence with a similar GC would remove the bias) (Claim 18). Fan et al. also teaches calculating the GC content of the one or more reference sequences; and calculating the GC content of the first sequence (Page 16271, Column 2, Paragraph 2: information regarding GC content were obtained) (Claim 19). Fan et al. also teaches wherein the GC content of the reference sequences and the GC content of the first sequence are obtained for a particular sequencing platform (Page 16271, Column 2, Paragraph 2: information regarding GC content were obtained) (Claim 20).
Fan et al. does not teach calculating a first statistical value from the sizes of DNA molecules (Claim 1.iii). Fan et al. also does not teach comparing the first statistical value to a threshold value (Claim 1.vi). Fan et al. also does not teach determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the first statistical value to the threshold value (Claim 1.v). Fan et al. also does not teach the threshold value is determined using a euploid sample (Claim 6). Fan et al. also does not teach calculating another statistical value from the sizes of DNA molecules from reference sequences; and determining the threshold value using the other statistical value (Claim 7). Fan et al. also does not teach the first statistical value includes the median or average size of the measured sizes for the DNA molecules (Claim 8).
Lapaire et al. teaches calculating a first statistical value from the sizes of DNA molecules (Page 407, Column 2, Paragraph 2: Descriptive statistics, including medians, were generated for all study variables, fragment size was a variable) (Claim 1.iii). Lapaire et al. also teaches comparing the first statistical value to a threshold value (Page 408, Column 2, Paragraph 2: size distributions were statistically compared between euploid and aneuploid samples) (Claim 1.iv). Lapaire et al. also teaches determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the first statistical value to the threshold value (Page 408, Column 2, Paragraph 2: size distributions were statistically different between euploid and aneuploid samples) (Claim 1.v). Lapaire et al. also teaches the threshold value is determined using a euploid sample (Page 406, Paragraph 3: amniotic fluid was studied from women carrying euploid fetuses) (Claim 6). Lapaire et al. also teaches calculating another statistical value from the sizes of DNA molecules from reference sequences; and determining the threshold value using the other statistical value (Page 408, Column 2, Paragraph 2: The median AUCs for DNA fragments of different lengths were determined for fresh and frozen euploid samples, as well as for aneuploid samples) (Claim 7). Lapaire et al. also teaches the first statistical value includes the median of the measured sizes for the DNA molecules (Page 408, Column 2, Paragraph 2: The median AUCs for DNA fragments of different lengths was determined) (Claim 8).
An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Both references share the same goal – the detection of fetal aneuploidy using cell free DNA from a biological sample provided by a pregnant female. Fan et al. uses a next-generation sequencing approach and several analytical methods to detect fetal aneuploidy. Lapaire et al. uses a PCR based approach to assess the distribution of DNA molecule sizes. Fan et al. explains that the clinical use of PCR based methods for the detection of fetal aneuploidy using cell free DNA has been challenging due to the low fraction of fetal DNA (Page 16266, Column 1, Paragraph 2) and proposes to use next-generation sequencing to overcome this issue (Page 16266, Column 1, Paragraph 3). Combining the sequencing approach from Fan et al. with the focus on DNA molecule size from Lapaire et al. would therefore give greater speed and efficiency to accomplish the joint goal for detecting fetal aneuploidy. Therefore, it would have been obvious to someone of ordinary skill in the art the time of the effective filling date to combine the methods from both of the references indicated above.
Furthermore, one of ordinary skill in the art would predict that the method taught by Fan et al. could be readily added to the method of Lapaire et al. with a reasonable expectation of success because the techniques discussed were previously established and individually shown to be effective at accomplishing a noninvasive means of detecting fetal aneuploidy. Accordingly, claims 1, 4, and 6-20 taken as a whole would have been prima facie obvious before the effective filing date.
Claims 2-3 and 5 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Fan et al. (PNAS, Vol. 105, No. 42, Pgs. 16266–16271, DOI: 10.1073_pnas.0808319105. Published October 21, 2008), hereafter referred to as Fan et al., in view of Lapaire et al. (Clinical Chemistry, Vol. 53, No. 3, Pgs. 405–411, DOI: 10.1373/clinchem.2006.076083, Published March 1, 2007), hereafter referred to as Lapaire et al., and in further view of Clarke et al. (Nature Nanotechnology, Vol.4: 265-270, DOI: 10.1038/NNANO.2009.12, Published February 22, 2009), hereafter referred to as Clarke et al.
Claim 2. The method of claim 1, wherein the single-molecule sequencing comprises nanopore sequencing.
Claim 3. The method of claim 1, wherein the single-molecule sequencing comprises single-molecule, real time sequencing.
Claim 5. The method of claim 1, wherein the threshold value is determined using a reference haplotype.
Fan et al. and Lapaire et al. teach claim 1. Fan et al. and Lapaire et al. do not teach single-molecule sequencing using nanopore (Claim 2) or real time (Claim 3) sequencing. The also do not teach the use of a reference haplotype (Claim 5).
Benner et al. teaches sequencing single molecules using nanopore (Page 265, Column 1, Paragraph 2: Nanopore DNA sequencing offers the possibility of a label-free, single-molecule approach) (Claim 2). Benner also et al. teaches real time single molecule sequencing (Page 265, Column 2, Paragraph 3: key technical problems were solved required for real-time, high-resolution nucleoside monophosphate detection.) (Claim 3). Benner also et al. teaches the utilization of a reference haplotype (Page 269, Column 2, Paragraph 1: the techniques offer additional benefits such as direct information on haplotypes) (Claim 5).
An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Both Fan et al. and Lapaire et al. have the same fundamental goal – the detection of fetal aneuploidy using cell free DNA from a biological sample provided by a pregnant female. Combing the sequencing approach from Fan et al. with the focus on DNA molecule size from Lapaire et al. would give an enhanced ability to detect fetal aneuploidy over prior methods. Clarke et al. introduces further advancements in sequencing technologies, such as real time sequencing and the use of nanopores. Combing Clarke et al. advancements with the works Fan et al. and Lapaire et al. would therefore further improve the efficiency and efficacy of sequencing technologies to provide size information on DNA modules and the detection of fetal aneuploidy. Therefore, it would have been obvious to someone of ordinary skill in the art the time of the effective filling date to combine the methods from both of the references indicated above.
Furthermore, one of ordinary skill in the art would predict that the methods taught by Clarke et al. could be readily added to the methods of Fan et al. and Lapaire et al. with a reasonable expectation of success because the sequencing advancements were previously established techniques that were shown to have benefits over other forms of sequencing. Accordingly, claims 2-3, and 5 taken as a whole would have been prima facie obvious before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1, 5-9, and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 7, 12, 14, and 22 of U.S. Patent No. 8620593 (reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant Claim 1. A method for performing prenatal diagnosis of a sequence imbalance in a biological sample obtained from a female subject pregnant with a fetus, wherein the biological sample includes a mixture of cell-free DNA molecules that are part of DNA sequences of a human genome, the biological sample including DNA molecules from the fetus and the female subject, the method comprising: for each of a plurality of the DNA molecules in the biological sample:
i. measuring a size of the DNA molecule, wherein measuring the size of the DNA molecule comprises: performing single-molecule sequencing of the DNA molecule to obtain a complete read of the molecule;
ii. identifying which nucleic acid sequence in the human genome the DNA molecule is derived from, wherein identifying which DNA sequence the DNA molecule is derived from includes: aligning, by a computer system, a portion of the complete read to the human genome;
iii. calculating, by the computer system, a first statistical value from the sizes of DNA molecules from a first sequence;
vi. comparing the first statistical value to a threshold value; and
v. determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the first statistical value to the threshold value.
Instant Claim 2. The method of claim 1, wherein the single-molecule sequencing comprises nanopore sequencing.
Instant Claim 3. The method of claim 1, wherein the single-molecule sequencing comprises single-molecule, real time sequencing.
Instant Claim 4. The method of claim 1, further comprising extracting the mixture of cell-free DNA to obtain the biological sample.
Instant Claim 5. The method of claim 1, wherein the threshold value is determined using a reference haplotype.
Instant Claim 6. The method of claim 1, wherein the threshold value is determined using a euploid sample.
Instant Claim 7. The method of claim 1, wherein comparing the first statistical value to the threshold value comprises:
i. calculating, by the computer system, a second statistical value from the sizes of DNA molecules from one or more reference sequences; and
ii. determining the threshold value using the second statistical value.
Instant Claim 8. The method of claim 1, wherein the first statistical value includes the median or average size of the measured sizes for the DNA molecules from the first sequence.
Instant Claim 9. The method of claim 1, wherein the first sequence is a chromosome and the sequence imbalance is a fetal chromosomal aneuploidy.
Instant Claim 10. The method of claim 9, wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences comprise one chromosome.
Instant Claim 11. The method of claim 9, wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences are a plurality of chromosomes.
Instant Claim 12. The method of claim 1, wherein the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid.
Instant Claim 13. The method of claim 1, wherein the plurality of the DNA molecules includes at least one million DNA molecules.
Instant Claim 14. The method of claim 1, further comprising: collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample.
Instant Claim 15. The method of claim 1, further comprising displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence.
Instant Claim 16. The method of claim 1, further comprising: determining a first amount of sequences identified as aligning to the first sequence of the human genome; determining a second amount of sequences identified as aligning to one or more second sequences; using the first amount and the second amount to determine another parameter; comparing the other parameter to one or more second cutoff values to determine another classification of whether the sequence imbalance exists for the first sequence.
Instant Claim 17. The method of claim 16, further comprising: comparing the classification determined using the first statistical value and the threshold value to the other classification determined using the first amount and the second amount.
Instant Claim 18. The method of claim 1, wherein the threshold value is determined using one or more reference sequences, and the one or more reference sequences have a GC content that is similar to a GC content of the first sequence.
Instant Claim 19. The method of claim 18, further comprising: calculating the GC content of the one or more reference sequences; and calculating the GC content of the first sequence.
Instant Claim 20. The method of claim 18, wherein the GC content of the one or more reference sequences and the GC content of the first sequence are obtained for a particular sequencing platform.
The reference patent (No. 18036122) contains the following claims that anticipate the instant application claims:
Reference Claim 1. A method for performing prenatal diagnosis of a sequence imbalance in a biological sample obtained from a female subject pregnant with a fetus, wherein the biological sample includes nucleic acid molecules that are part of nucleic acid sequences, the biological sample including nucleic acid molecules from the fetus and the female subject, the method comprising: for each of a plurality of the nucleic acid molecules in the biological sample: measuring a size of the nucleic acid molecule (Instant Claim 1.i); identifying which nucleic acid sequence the nucleic acid molecule is derived from (Instant Claim 1.ii);
Reference Claim 2. The method of claim 1, further comprising: determining a maternal genotype of the pregnant female subject, wherein the first sequence contains at least part of the maternal genotype; and based on the maternal genotype of the pregnant female subject and the determined size distribution, determining a classification of whether a sequence imbalance exists for the first sequence in the biological sample relative to the maternal genotype (Instant Claim 6).
Reference Claim 4. The method of claim 1, further comprising: determining a maternal haplotype of the pregnant female subject, wherein the first sequence contains at least part of the maternal haplotype; and based on the maternal haplotype of the pregnant female subject and the determined size distribution, determining a classification of whether a sequence imbalance exists for the first sequence in the biological sample relative to the maternal haplotype (Instant Claim 5).
Reference Claim 7. The method of claim 1, wherein the first sequence is a chromosome and the sequence imbalance is a fetal chromosomal aneuploidy (Instant Claim 9).
Reference Claim 12. The method of claim 7, wherein determining a size distribution of the nucleic acid molecules corresponding to a first chromosome includes: calculating a first statistical value from the sizes of nucleic acid molecules corresponding to the first chromosome (Instant Claim 1.iii); calculating a second statistical value from the sizes of nucleic acid molecules corresponding to one or more second chromosomes, (Instant Claim 7.i) and wherein based on the determined size distribution, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome includes: determining a separation value between the first statistical value and the second statistical value (Instant Claim 7.ii); comparing the separation value to one or more cutoff values (Instant Claim 1.iv); and based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome (Instant Claim 1.v).
Reference Claim 14. The method of claim 12, wherein the first statistical value and the second statistical value include an average size of the measured sizes for the nucleic acid molecules corresponding to a respective chromosome (Instant Claim 8).
Reference Claim 22. The method according to claim 7, where the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid (Instant Claim 12).
All limitations of instant claims 1, 5-9, and 12 are therefore anticipated by reference claims 1-2, 4, 7, 12, 14, and 22.
Claims 1, 4, and 7-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 11-15 of U.S. Patent No. 9982300 (reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other. See double patenting over of U.S. Patent No. 8620593 for a list of the instant claims.
The reference patent (No. 9982300) contains the following claims that anticipate the instant application claims:
Reference Claim 1. A method for performing prenatal diagnosis of a sequence imbalance in a biological sample obtained from a female subject pregnant with a fetus, wherein the biological sample includes a mixture of cell-free DNA molecules that are part of DNA sequences of a human genome, the biological sample including DNA molecules from the fetus and the female subject, the method comprising: extracting the mixture of cell-free DNA to obtain the biological sample (Instant Claim 4); for each of a plurality of the DNA molecules in the biological sample: measuring a size of the DNA molecule, wherein measuring the size of the DNA molecule comprises: paired-end sequencing of the DNA molecule to obtain two sequence reads, wherein the paired-end sequencing is part of performing a random sequencing of the plurality of DNA molecules in the biological sample (Instant Claim 1.i), and identifying which nucleic acid sequence in the human genome the DNA molecule is derived from, wherein identifying which DNA sequence the DNA molecule is derived from includes: aligning, by a computer system, the two sequence reads to the human genome (Instant Claim 1.ii); calculating, by the computer system, a first statistical value from the sizes of DNA molecules from a first sequence (Instant Claim 1.iii); identifying one or more reference sequences (Instant Claim 10); calculating, by the computer system, a second statistical value from the sizes of DNA molecules from the one or more reference sequences (Instant Claim 7.i); determining a parameter using the first statistical value and the second statistical value, the parameter being a difference or a ratio of the first statistical value and the second statistical value (Instant Claim 7.ii); and determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the parameter to a cutoff value (Instant Claim 1.iv and 1.v).
Reference Claim 2. The method of claim 1, wherein the first statistical value includes the median or average size of the measured sizes for the DNA molecules from the first sequence (Instant Claim 8).
Reference Claim 3. The method of claim 1, wherein the first sequence is a chromosome and the sequence imbalance is a fetal chromosomal aneuploidy (Instant Claim 9).
Reference Claim 4. The method of claim 3, wherein the one or more reference sequences comprise one chromosome (Instant Claim 10).
Reference Claim 5. The method of claim 3, wherein the one or more reference sequences are a plurality of chromosomes (Instant Claim 11).
Reference Claim 6. The method of claim 1, wherein the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid (Instant Claim 12).
Reference Claim 7. The method of claim 1, wherein the plurality of the DNA molecules includes at least one million DNA molecules (Instant Claim 13).
Reference Claim 8. The method of claim 1, further comprising: collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample (Instant Claim 14).
Reference Claim 9. The method of claim 1, further comprising displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence (Instant Claim 15).
Reference Claim 11. The method of claim 1, further comprising: determining a first amount of sequences identified as aligning to the first sequence of the human genome; determining a second amount of sequences identified as aligning to one or more second sequences; using the first amount and the second amount to determine another parameter; comparing the other parameter to one or more second cutoff values to determine another classification of whether the sequence imbalance exists for the first sequence (Instant Claim 16).
Reference Claim 12. The method of claim 11, further comprising: comparing the classification determined using the first statistical value and the second statistical value to the other classification determined using the first amount and the second amount (Instant Claim 17).
Reference Claim 13. The method of claim 1, wherein the one or more reference sequences have a GC content that is similar to a GC content of the first sequence (Instant Claim 18).
Reference Claim 14. The method of claim 13, further comprising: calculating the GC content of the one or more reference sequences; and calculating the GC content of the first sequence (Instant Claim 19).
Reference Claim 15. The method of claim 13, wherein the GC content of the one or more reference sequences and the GC content of the first sequence are obtained for a particular sequencing platform (Instant Claim 20).
All limitations of instant claims 1, 4, and 7-20 are therefore anticipated by reference claims 1-9 and 11-15.
Claims 1, 4, and 7-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-10, and 12-17 of U.S. Patent No. 11365448 (reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other. See double patenting over of U.S. Patent No. 8620593 for a list of the instant claims.
The reference patent (No. 11365448) contains the following claims that anticipate the instant application claims:
Reference Claim 1. A method for performing prenatal diagnosis of a sequence imbalance in a biological sample obtained from a female subject pregnant with a fetus, wherein the biological sample includes a mixture of cell-free DNA molecules that are part of DNA sequences of a human genome, the biological sample including DNA molecules from the fetus and the female subject, the method comprising: for each of a plurality of the DNA molecules in the biological sample, the plurality of DNA molecules including at least one million DNA molecules (Instant Claim 13): measuring a size of the DNA molecule, and identifying which nucleic acid sequence in the human genome the DNA molecule is derived from, wherein identifying which DNA sequence the DNA molecule is derived from includes: sequencing at least a portion of the DNA molecule to obtain a sequence as part of performing a random sequencing of the plurality of the DNA molecules in the biological sample (Instant Claim 1.i); and aligning, by a computer system, the sequence to the human genome (Instant Claim 1.ii); calculating, by the computer system, a first statistical value from the sizes of DNA molecules from a first sequence (Instant Claim 1.iii); calculating, by the computer system, a second statistical value from the sizes of DNA molecules from one or more reference sequences (Instant Claim 7.i); determining a parameter using the first statistical value and the second statistical value (Instant Claim 7.ii), the parameter being a difference or a ratio of the first statistical value and the second statistical value; and determining a classification of whether a sequence imbalance exists for the first sequence based on a comparison of the parameter to a cutoff value (Instant Claim 1.iv and 1.v).
Reference Claim 4. The method of claim 1, wherein the first statistical value includes the median or average size of the measured sizes for the DNA molecules from the first sequence (Instant Claim 8).
Reference Claim 5. The method of claim 1, wherein the first sequence is a chromosome and the sequence imbalance is a fetal chromosomal aneuploidy (Instant Claim 9).
Reference Claim 6. The method of claim 5, wherein the one or more reference sequences comprise one chromosome (Instant Claim 10).
Reference Claim 7. The method of claim 5, wherein the one or more reference sequences are a plurality of chromosomes (Instant Claim 11).
Reference Claim 8. The method of claim 1, further comprising: extracting the mixture of cell-free DNA to obtain the biological sample (Instant Claim 4).
Reference Claim 9. The method of claim 1, further comprising: collecting a blood sample from the female subject, and extracting plasma from the blood sample to obtain the biological sample (Instant Claim 14).
Reference Claim 10. The method of claim 1, further comprising displaying, by the computer system, the classification of whether the sequence imbalance exists for the first sequence (Instant Claim 15).
Reference Claim 12. The method of claim 1, further comprising: determining a first amount of sequences identified as aligning to the first sequence of the human genome; determining a second amount of sequences identified as aligning to one or more second sequences; using the first amount and the second amount to determine another parameter, wherein the other parameter is a difference or a ratio of the first amount and the second amount; comparing the other parameter to one or more second cutoff values to determine another classification of whether the sequence imbalance exists for the first sequence (Instant Claim 16).
Reference Claim 13. The method of claim 12, further comprising: comparing the classification determined using the first statistical value and the second statistical value to the other classification determined using the first amount and the second amount (Instant Claim 17).
Reference Claim 14. The method of claim 1, wherein the one or more reference sequences have a GC content that is similar to a GC content of the first sequence (Instant Claim 18).
Reference Claim 15. The method of claim 14, further comprising: calculating the GC content of the one or more reference sequences; and calculating the GC content of the first sequence (Instant Claim 19).
Reference Claim 16. The method of claim 14, wherein the GC content of the one or more reference sequences and the GC content of the first sequence are obtained for the same sequencing platform (Instant Claim 20).
Reference Claim 17. The method of claim 1, wherein the biological sample includes blood, plasma, serum, maternal blood containing fetal cells, fetal cells obtained from maternal blood, urine, saliva, or uterine lavage fluid (Instant Claim 12).
All limitations of instant claims 1, 4, and 7-20 are therefore anticipated by reference claims 1, 4-10 and 12-17.
Conclusion
No claims are allowed.
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/B.H.E./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687