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 and Formal Matters
This action is in response to papers filed 11/26/2025.
Claims 8, 10 have been amended.
Claims 8, 10-15 are pending and being examined.
Priority
The instant application was filed 05/28/2021 and is a continuation of 12727824 , filed 03/19/2010, which is a continuation in part of 12709057 , filed 02/19/2010, which is a continuation in part of 11067102 , filed 02/25/2005, which claims priority from provisional application 60548704 , filed 02/27/2004.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 12709057 , filed 02/19/2010, which is a continuation in part of 11067102 , filed 02/25/2005, which claims priority from provisional application 60548704, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claim 8 filed 11/26/2025 requires, “method for detection of the presence or absence of a fetal chromosome aneuploidy comprising:a) providing a human reference genome, wherein the reference genome is partitioned into bins; and wherein the subset of the bins represents about 25% of the reference genome; c) sequencing a sample to obtain nucleic acid sequence reads, wherein the sample comprises cell-free circulating human fetal nucleic acid; d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy.” Review and searching of the provisional application did not reveal support for 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome or 2X normal ratio. Further the parent applications teach on the last paragraph of page 32 is:
Methods of the invention reduce or eliminate the effects of GC bias in sequence information. Numerous protocols may be used to reduce or eliminate the effects of GC bias in sequence information. In certain embodiments, a subset of genomic bins is selected within a given range such that the average GC content per chromosome is equalized (or less skewed). Chromosomal counting is then performed on the selected subset. Figure 8 provides an example of this protocol. In Figure 8, analysis was limited to only genomic bins with a given GC content of 0.42 to 0.48, approximately 25% of the genome (Figure 8 panel A)
Thus the cited portion of the specification provides support for selection during the analysis of the sample data ( thus not step a or b), which is different in scope than “providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome;” prior to the analysis. .Thus the instant claims are being given in the instant filing date.
Response to Arguments
The response on page 5 repeats the previous priority issue. It is noted in view of the amendment neither the provisional application or the prior filed applications provide support for the amendment as filed.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claim 8 has been amended to recite, “cell- free circulating human fetal nucleic acid.”
Response to Arguments
This is a new ground of objection necessitated by amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8, 10-15 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The response of 11/26/2025 amends claim 8 to recite, “ a method for detection of the presence or absence of a fetal chromosome aneuploidy comprising:a) providing a human reference genome, wherein the reference genome is partitioned into bins; and wherein the subset of the bins represents about 25% of the reference genome; c) sequencing a sample to obtain nucleic acid sequence reads, wherein the sample comprises cell-free circulating human fetal nucleic acid; d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy.” Review and searching of the parent applications teach on the last paragraph of page 32 is:
Methods of the invention reduce or eliminate the effects of GC bias in sequence information. Numerous protocols may be used to reduce or eliminate the effects of GC bias in sequence information. In certain embodiments, a subset of genomic bins is selected within a given range such that the average GC content per chromosome is equalized (or less skewed). Chromosomal counting is then performed on the selected subset. Figure 8 provides an example of this protocol. In Figure 8, analysis was limited to only genomic bins with a given GC content of 0.42 to 0.48, approximately 25% of the genome (Figure 8 panel A)
Thus the cited portion of the specification provides support for selection during the analysis of the sample data (not step a or b as claimed), which is different in scope than “providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome” prior to analysis. Thus the instant claims are being given in the instant filing date. Further, while the specification provides antecedent basis for 0.42 to 0.48 with respect to figure 8, which is a specific embodiment, but this does not provide support for the amendment in view of the breadth of the claims as amended. Thus the amendment has introduced new matter.
Response to Arguments
The response traverses the rejection asserting, “Specifically, the Office alleges "[f]urther searching and review of the specification filed June 22, 2021 recites report according 7 times and none of the citations are with respect to "performing chromosomal counting according to counts of the sequence reads mapped to the subset of the bins; and detecting the presence or absence of a fetal chromosome aneuploidy according to the chromosomal counting."" Applicant respectfully submits none of the amended claims as filed on April 15, 2025, or as amended herein, recite "report." “ The examiner apologizes for this error.
The response continues by asserting, “Further, claim 8 as amended herein does not recite "performing chromosomal counting according to counts of the sequence reads mapped to the subset of the bins." As such, Applicant respectfully asserts the rejection has been rendered moot. The Office also states "[f]urther the claim recites, "wherein the subset has been selected to include bins that in the subset of bins have a range of guanine and cytosine (G) content of about 42% to 48%." While the specification provides antecedent basis for 0.42 to 0.48 with respect to figure 8, which is a specific embodiment, but this does not provide support for the amendment in view of the breadth of the claims as amended." Applicant disagrees with the Office and respectfully submits the application was filed on May 28, 2021, provides support for GC content of 0.42 to 0.48 in the context of reducing GC bias for aneuploidy detection, for example at page 32, last paragraph. The term "0.42 to 0.48" was previously amended to "42% to 48%" in response to an indefiniteness rejection and as suggested by Examiner Pohnert during an interview on April 14, 2025.” This argument has been thoroughly reviewed but is not considered persuasive as the interview summary of April 14, 2025 merely indicates there was a discussion. If term "0.42 to 0.48" corresponds to "42% to 48%," applicant should provide either a declaration or a reasoned explanation of how they are the same. Review of the file wrapper does not appear to include such a declaration or reasoned explanation. Further the response has provide no arguments with respect to limitation of a single working example to support the breadth of the claim. Further the amendment has raised new issued.
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 8, 10-15 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.
Claim 8 recites, “b) providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome” The claim later recites, “d) mapping the nucleic acid sequence reads to the subset of the bins.” The claim is confusing and unclear how to map all the sequence reads which are nucleic acid sequence and can broadly encompass RNA and DNA and the whole genome to a subset of bins which is limited to about 25% of the refence genome. It is thus unclear how mapping is done for sequences not in the 25% of the reference genome in the subset of bins. This makes it unclear how the mapping and quantifying provide a presence or absence of fetal chromosome aneuploidy. As sequences that are not identical or complementary to the bins of 25% of the reference genome are required to be mapped to the subset of bins which are about 25% of the reference genome in the subset of bins. This issue may be addressed by making the claim more consistent with the teachings of the specification.
Claim 8 recites, “wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy.” The recitation of normal ratio suggests there is abnormal ratio. The specification and claims provide no standard or definition to differentiate normal ratio from an abnormal ratio. Further it unclear what a 2x normal ratio is. Further it is unclear if a 2x ratio of the X chromosome in a male fetus provides for fetal aneuploidy in view of the amendments.
. Response to Arguments
The response traverses the rejection in view of the amendment. While the amendment addressed some issues it has raised new issues as addressed in the rejection above.
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 8, 9-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step without significantly. The claim(s) recite(s) the abstract idea or mental step of determining, correcting and analyzing. This judicial exception is not integrated into a practical application because there are no additional steps which depend from or otherwise integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional steps which depend from or otherwise integrate the judicial exception.
Claim analysis
The instant claim 8 is directed towards a method for detection of the presence or absence of a fetal chromosome aneuploidy comprising:;a) providing a human reference genome, wherein the reference genome is partitioned into bins;;b) providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome; c) sequencing a sample to obtain nucleic acid sequence reads, wherein the sample comprises cell-free circulating human fetal nucleic acid; d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; and f) detecting the presence or absence of a fetal chromosome aneuploidy by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy. The steps of providing, providing, mapping, quantifying, and detecting are mental steps or abstract ideas.
The claim requires a step of sequencing a sample. The claim further provides steps of providing, providing, mapping, quantifying, and detecting are abstract ideas/steps.
The recited “sequencing” step, however, is a step required to gather the data for the mental processes of claim 8. The “sequencing” data-gathering step is therefore merely insignificant extra-solution activity, and is not an indication that the recited judicial exception has been integrated into a practical application. The Specification makes clear that the sequencing step recited in claim 8 does not represent an improvement in technology, because the specification states that “[t]he sequencing reaction may be any sequencing reaction.” Spec. 2.
Dependent claims set forth further limitations to bins, sample and methods of sequencing.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea/mental step and law of nature or natural phenomena.
With regards to claim 8, the claim recites, providing a human reference genome, wherein the reference genome is partitioned into bins;;b) providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome;” and “d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; and f) detecting the presence or absence of a fetal chromosome aneuploidy by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy.” These are abstract idea or mental step and/or natural correlation.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no the claim provide no active step depend from or otherwise integrate the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the claims provide no active step which require specific reagents that can be considered significantly more.
With regards to claim 8 the claim requires a single active step of sequencing a sample. The specification teaches:
The specification teaches,
“The sequencing reaction may be any sequencing reaction. In particular embodiments, the sequencing reaction is a single molecule sequencing reaction. Single-molecule sequencing is shown for example in Lapidus et al. (U.S. Pat. No. 7,169,560), Lapidus et al. (U.S. patent application number 2009/0191565), Quake et al. (U.S. Pat. No. 6,818,395), Harris (U.S. Pat. No. 7,282,337), Quake et al. (U.S. patent application number 2002/0164629), and Braslaysky, et al., PNAS (USA), 100: 3960-3964 (2003), the contents of each of these references is incorporated by reference herein in its entirety.” (page 2-3)
Further Fan et al (Proceedings National Academy of Sciences (2008) volume 105, pages 16266-16271 and supplemental information), Hinds et al (Sciences (2005) volume 307, pages 1072-10-79), Porreca (Multiplex Polony Sequencing for Analysis of Genomes, Transcriptomes, and Exonomes.(2007)teaches sequencing of maternal blood was routine and conventional. The claims and specification provide no evidence the method improves the operation of the sequencing.
Without additional limitations, a process that employs conventional methods of obtaining sequencing data in addition providing, providing, mapping, quantifying, and detecting are not patent eligible. An example of a case identifying a concept relating to a data comparison that can be performed mentally as abstract is CyberSource Corp. v. Retail Decisions, 654 F.3d 1366, 99 USPQ2d 1690 (Fed. Cir. 2011). The law of nature and natural phenomenon exceptions reflect the Supreme Court's view that the basic tools of scientific and technological work are not patentable, because the “manifestations of laws of nature” are “part of the storehouse of knowledge,” “free to all men and reserved exclusively to none.” Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948). Thus, “a new mineral discovered in the earth or a new plant found in the wild is not patentable subject matter” under Section 101. Diamond v. Chakrabarty, 447 U.S. 303, 309, 206 USPQ 193, 197 (1980). “Likewise, Einstein could not patent his celebrated law that E=mc2; nor could Newton have patented the law of gravity.” Id. Nor can one patent “a novel and useful mathematical formula,” Parker v. Flook, 437 U.S. 584, 585, 198 USPQ 193, 195 (1978); electromagnetism or steam power, O' Reilly v. Morse, 56 U.S. (15 How.) 62, 113-114 (1853); or “[t]he qualities of ... bacteria, ... the heat of the sun, electricity, or the qualities of metals,” Funk, 333 U.S. at 130, 76 USPQ at 281; see also Le Roy v. Tatham, 55 U.S. (14 How.) 156, 175 (1853).
Response to Arguments
It is noted the claims are to using bins to map sequencing reads and determine aneuploidy. The only active step requiring analysis of a sample is sequencing a sample to provide sequence reads, which encompass 2 sequencing reads. The claim recites, “ a) providing a human reference genome, wherein the reference genome is partitioned into bins; and wherein the subset of the bins represents about 25% of the reference genome” This is merely instructions. The claim continues after the sequencing step to recite,” d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts;by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy.” These are instructions or mental steps describing how to analyze the data obtained. The claims provide no limitations with respect to how the sample is obtain or how the sequencing is done. The specification states:
“The sequencing reaction may be any sequencing reaction. In particular embodiments, the sequencing reaction is a single molecule sequencing reaction. Single-molecule sequencing is shown for example in Lapidus et al. (U.S. Pat. No. 7,169,560), Lapidus et al. (U.S. patent application number 2009/0191565), Quake et al. (U.S. Pat. No. 6,818,395), Harris (U.S. Pat. No. 7,282,337), Quake et al. (U.S. patent application number 2002/0164629), and Braslaysky, et al., PNAS (USA), 100: 3960-3964 (2003), the contents of each of these references is incorporated by reference herein in its entirety.” (page 2-3)
Thus the claim clearly encompasses Sanger sequencing which provides a very limited number of reads.
The response begins traversing the rejection by asserting, “The Office asserts that the claims are directed to an abstract idea, and specifically are directed to a mental process. Applicant disagrees and respectfully submits the claims are patent eligible under Step 2A, prong (2), of the patent subject matter eligibility analysis as set forth in MPEP § 2106 (hereafter "eligibility analysis"), as the claims recite additional elements that integrate the alleged judicial exception into a practical application claimed,8.”. This argument been thoroughly reviewed but is not considered persuasive as claim 8 provide no additional steps which depend from or otherwise integrate the judicial exceptions.
The response continues by asserting, “Applicant disagrees and respectfully submits the elements of "mapping" and "providing" are not mental steps or abstract ideas, and thus are additional elements outside the judicial exception, as explained below. Independent claim 8 specifies in part (d) mapping the nucleic acid sequence reads to the subset of the bins. Claim 8 also specifies the subset of bins represents about 25% of the human reference genome. The human reference genome is about 3 billion base pairs in length and a quarter of that is about 750 million base pairs. To put this massive amount of data in context, the human genome if written out fills more 262,000 densely printed pages (see e.g., https://www.kqed.org/futureofyou/154916/how-many-pages-does-it-take- to-print-someones-genetic-code-video). In view of the massive amount of reference genome data, Applicant respectfully submits mapping even one sequence read to a quarter of the human reference genome cannot practically be performed in the mind, let alone mapping the multiple sequence reads that would be required to provide a meaningful amount of data for an aneuploidy analysis.” This argument has been thoroughly reviewed but is not considered persuasive as mapping and providing are mental steps, instructions, or abstract ideas. Applicants asserts these are not mental steps, this is confusing as these steps are clearly instructions and do not require any physical activity. Further the claims provide no limitations requiring a computer. While the analysis encompassed by the claim may be faster with a computer than by hand with pencil and paper the courts have held:
It is acknowledged that such computations performed mentally, or with paper and pencil, would take considerable time and effort, but that is, of course, the singular purpose of computers and computer networks, to perform large numbers of calculations, via algorithms, rapidly, and without error (assuming no error in user input). Although a general-purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.), 687 F.3d 1266,1278 (Fed. Cir. 2012) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also See SiRF Tech., Inc. v. Int’l Trade Comm ’n, 601 F.3d 1319,1333 (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations)."
Further, the argument about of amount of data has been thoroughly reviewed but is not considered persuasive as this is not specifically required of the claim. The claim encompass sequence reads which encompasses 2 sequence. Further the providing a human genome and providing subset of bins can be done from a database or print out of human genome and can be done by hand or pencil and paper. The specification states, “Generally, the obtained sequences are aligned to a reference genome ( e.g., a maternal genome, a paternal genome, or an external standard representing the numerical range considered to be indicative of a normal).” Further the specification teaches, “comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality. In certain embodiments, the reference genome may be the maternal genome, the paternal genome, or a combination thereof. In other embodiments, the reference genome may be an external standard representing the numerical range considered to be indicative of a normal, intact karyotype, such as the currently existing HG 18 human reference genome.” (page 20) Thus the specification demonstrates the claims do not require a full human genome. Further the claim does not provide a number of sequence reads. Thus the broadest reasonable interpretation is two sequence. While aligning two sequence reads to a reference sequence or genome can be time consuming, these can be done by pencil and paper.
It is noted the sequencing read data it is dependent on the sample used and the method of sequencing. Thus the claims do not require an enormous amount of sequencing data, as implied by the response, but it encompasses 2 reads of any length.
Further the claims are being evaluated for what is being performed and instructed. The artisan could go to a database to obtain reference genome data. The artisan could determine GC content of any sequence or read and determine bins based on the sequence or sequencing reads by pencil and paper. The artisan can map any sequence to any sequence, portion of a sequence, or printout. The detecting step is dependent on the data provided by the sequencing which encompasses Sanger sequencing.
The response continues by asserting the method integrates the judicial exception. This argument has been thoroughly reviewed but is not considered persuasive as the claim provide limitations which depend from or otherwise integrate the judicial exception. Further the method encompasses Sanger sequencing and thus does not require a “system.”
The response continues by providing arguments with respect to PTAB decision, PTAB decision, Exparte SUNG K. KIM, GREGORY HANNUM, JENNIFER GEIS, and COSMIN DECIU (hereafter Kim), Appeal No. 2019-003792 (PTAB September 26, 2019). This argument has been thoroughly reviewed but is not considered persuasive as it is not precedential and appears to have a different fact pattern than the instant application.
The response continues by providing arguments with respect to improvement in technology. The response traverses the rejection asserting, “Applicant respectfully submits the claims herein are patent eligible under Step 2A, prong (2), of the eligibility analysis, by way of demonstrating an improvement to a technology. For example, the claimed method provides specific benefits over conventional nucleic acid analysis technology, including an effective method to address GC bias. “ This argument has been thoroughly reviewed but is not considered persuasive as the only technology required of the claim is sequencing. The claims provide no specific step which improve sequencing, to the contrary the specification specifically states,
The sequencing reaction may be any sequencing reaction. In particular embodiments, the sequencing reaction is a single molecule sequencing reaction. Single-molecule sequencing is shown for example in Lapidus et al. (U.S. Pat. No. 7,169,560), Lapidus et al. (U.S. patent application number 2009/0191565), Quake et al. (U.S. Pat. No. 6,818,395), Harris (U.S. Pat. No. 7,282,337), Quake et al. (U.S. patent application number 2002/0164629), and Braslaysky, et al., PNAS (USA), 100: 3960-3964 (2003), the contents of each of these references is incorporated by reference herein in its entirety.” (page 2-3)
The claim at best may improve the analysis of data obtained from sequences reads of a sample, but provides no steps which improve GC bias associated with sequencing.
The response continues by arguing, “The 101 memo states on page 4 "an additional limitation (or combination) that meaningfully limits the judicial exception can render it eligible." As noted above, the claim features of "mapping" and "providing" are not mental processes and thus are additional elements outside the judicial exception that meaningfully limit the judicial exception. In particular, providing a subset of bins and mapping to the subset are integral to the improved method of addressing GC bias. Accordingly, independent claim 8 recites additional elements that integrate any alleged judicial exceptions into a practical application by way of an improvement to a technology (i.e., an improvement to nucleic acid analysis technology).” This argument has been thoroughly reviewed but is not considered persuasive as the mapping and providing steps are nothing more than instructions or mental steps. Thus the mapping and providing are judicial exceptions and are not additional elements, but mental steps or instructions required of the claim.
The response continues by arguing, “The 101 memo states on page 5 "[c]laims that are determined to improve computer capabilities or improve technology or a technical field support a finding that the claim integrates the judicial exception into a practical application or amounts to significantly more than the judicial exception itself." The claimed method improves nucleic acid analysis technology and therefore improves technology or a technical field.” This argument has been thoroughly reviewed but is not considered persuasive as the only technology required of the claim is sequencing. The specification states:.
The sequencing reaction may be any sequencing reaction. In particular embodiments, the sequencing reaction is a single molecule sequencing reaction. Single-molecule sequencing is shown for example in Lapidus et al. (U.S. Pat. No. 7,169,560), Lapidus et al. (U.S. patent application number 2009/0191565), Quake et al. (U.S. Pat. No. 6,818,395), Harris (U.S. Pat. No. 7,282,337), Quake et al. (U.S. patent application number 2002/0164629), and Braslaysky, et al., PNAS (USA), 100: 3960-3964 (2003), the contents of each of these references is incorporated by reference herein in its entirety.” (page 2-3)
The response continues by asserting, “As explained in the previous responses, correcting for GC bias using a mathematical formula or algorithm is a manipulation of the raw sequencing data that attempts to artificially match sequencing data with the actual copy number of chromosomes or chromosome segments in a sample. Using a mathematical formula or algorithm can, in some instances, result in changing the original counts of sequence reads produced by sequencing DNA of a sample and introduce errors that may manifest as inaccurate chromosomal counts. In addition, retaining the number of counts of sequence reads originally generated is important to the sensitivity of the method. Alteration of sequencing data by applying the same mathematical correction for sequence reads, obtained from across the genome, may, in some instances, not faithfully preserve the relative amounts of reads from sections of different chromosomes. This may preclude, or make more difficult, the detection of slight differences in counts of sequence reads between parts of different chromosomes that is necessary to detect a chromosome abnormality (e.g., a chromosome aneuploidy).” This argument is consistent with the use of conventional sequencing with the claimed method of analysis. The response is arguing the analysis has improved which does not improve the only technology required of the claim which is sequencing.
The response continues by asserting, “he 101 memo states on page 4 "an additional limitation (or combination) that meaningfully limits the judicial exception can render it eligible." As noted above, the claim features of "mapping" and "providing" are not mental processes and thus are additional elements outside the judicial exception that meaningfully limit the judicial exception. In particular, providing a subset of bins and mapping to the subset are integral to the improved method of addressing GC bias. Accordingly, independent claim 8 recites additional elements that integrate any alleged judicial exceptions into a practical application by way of an improvement to a technology (i.e., an improvement to nucleic acid analysis technology).” This argument has been thoroughly reviewed but is not considered persuasive as the claim provides a single active step c) and 5 mental steps, abstract ideas or instructions a)-b), d), e) and f).
The response continues by arguing, “ The 101 memo states on page 5 "[c]laims that are determined to improve computer capabilities or improve technology or a technical field support a finding that the claim integrates the judicial exception into a practical application or amounts to significantly more than the judicial exception itself." The claimed method improves nucleic acid analysis technology and therefore improves technology or a technical field.” This argument is confusing as the claims do not require a computer. Thus it is unclear how it improves anything to do with a computer. The only technology recited in the claim is sequencing, which the specification on pages 2-3 indicates can be any sequencing reaction. Thus as the claims provide no limitations which improve sequencing this is not persuasive.
The response continues by arguing, “Applicant's assertion that the claimed method improves a technology, and specifically improves nucleic acid analysis technology, is supported by the PTAB decision, Exparte Gregory Porreca and Uri Laserson (hereafter Porreca), Appeal No. 2022-002597 (PTAB September 6, 2023), attached hereto as APPENDIX B. The claims in Porreca are directed to a method of correcting for errors or bias introduced during a nucleic acid analysis.” This argument has been thoroughly reviewed but is not considered persuasive a Porecca is not a precedential decision and is thus not binding on the Corp. Further Porecca has a different fact pattern the instant claims. Thus this argument is not persuasive.
The response continues by asserting, “The 101 memo states on page 3, "[t]he analysis in Step 2A Prong Two considers the claim as a whole. The way in which the additional elements use or interact with the exception may integrate the judicial exception into a practical application. Accordingly, the additional limitations should not be evaluated in a vacuum, completely separate from the recited judicial exception. Applicant respectfully submits the claimed method, when viewed as a whole, includes additional elements that integrate the alleged judicial exception into a practical application, as evidenced by an improvement to a technology (i.e., an improvement to nucleic acid analysis technology), as discussed above.” This argument has been thoroughly reviewed but is not considered persuasive as the only technology recited in the claim is sequencing, which the specification on pages 2-3 indicates can be any sequencing reaction. Thus as the claims provide no limitations which improve sequencing this is not persuasive.
Thus the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 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 of this title, 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 negatived by the manner in which the invention was made.
Claims 8, 10-15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Fan et al (Proceedings National Academy of Sciences (2008) volume 105, pages 16266-16271 and supplemental information), Hinds et al (Sciences (2005) volume 307, pages 1072-10-79), Porreca (Multiplex Polony Sequencing for Analysis of Genomes, Transcriptomes, and Exonomes.(2007)
This rejection is set forth with respect to the interpretation of the claims in view of 112-2nd or 112(b) rejections demonstrating the lack of clarity of claims 8, 10-15. This rejection is set forth as in view of these issues.
The claims has been amended to recite, “and wherein the subset of the bins represents about 25% of the reference genome.” While this may provide a size limitation on the genome, it appears to a property of selecting sequences with about 42% to 48% GC content as it is not specifically a positive active step.
While the claims provide steps a)-f) MPEP 2111.01 II states:
The problem is to interpret claims ‘in view of the specification’ without unnecessarily importing limitations from the specification into the claims."); Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order).
Thus the broadest reasonable interpretation of the claims is steps a)- f) can be done in any order.
With regards to claim 8 Fan teaches a method of shotgun sequencings of cell free plasma (16266). Fan teaches the GC content of the sequence tag was correlated with the GC content of the chromosome (162667). Fan teaches, “We plotted in Fig. 1A the sequence tag density for each chromosome (ordered by increasing GC content) relative to the corresponding value of the genomic DNA control to remove such bias” (16267). Fan teaches the sequence tags were used to detect fetal aneuploidy (16267). Fan teaches we applied a sliding scale of 50 kb window for each chromosome and looked at variations across chromosomes of the genome. Thus Fan teaches a method of sequencing a sample to obtain sequence information, determining the amount of GC bias (or content) in the sequences, correcting for the bias and analyzing the corrected information. Fan teaches detection of trisomy 13, 18 and 21.
The specification fails to provide a limiting definition of “bins.” Thus a “bin” is being given the broadest reasonable interpretation of any partitioning.
Fan teaches, “The mean sequence tag density of each chromosome correlates with the GC content of the chromosome (P<10-9) (Fig. S1 A and B). The standard deviation of sequence tag density for each chromosome also correlates with the absolute degree of deviation in chromosomal GC content from the genome wide GC content (P<10-12) (Fig. S1 A and C). The GC content of sequenced tags of all samples (including the genomic DNA control) was, on average, 10% higher than the value of the sequenced human genome (41%) (21) (Table S1), suggesting that there is a strong GC bias stemming from the sequencing process.” (16267). Thus Fan teaches partitioning of each chromosome and sequence bias based on the partitioning.
Fan does not explicitly teach analysis based on bin or as range of GC content about 0.42 to 0.48.
However, Hinds teaches bins of <500kb, 500 to 100kb, and ≥1000kb (table 3). Hinds teaches, “We identified five bins of more than 200 SNPs each and 17 genomic intervals containing bins that span more than 1000 kb in one or more populations.”
Porreca teaches, “Target abundances binned by fraction GC content for the eMIP reaction are shown in Figure 8. Not surprisingly, we observe a one hundred-fold mean bias in favor of moderate GC content (40-50%) over extreme (10-20% and 70-80%). Examination of bias for each arm individually did not indicate that either exerted a significantly stronger effect (data not shown), even though the selective events occurring at each end are much different. Quite unexpectedly, the SeleCirc reaction did not exhibit any appreciable GC content bias (data not shown).”(116)
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Porreca teaches, “However, we also observe variation in target abundances over more than four orders of magnitude, an unacceptable range for targeted resequencing of exons. While specificity will affect overall sequencing error rate to the extent read length limits the uniqueness of a read in the full genome, non-uniformity will affect cost by decreasing the fraction of the target set coverable per dollar of sequencing. It is this tradeoff between non-uniform amplification and the requirement for additional sequencing that guides the choice of how much variation is acceptable. The de facto ceiling on acceptable variation, of course, is defined by the amount of sequencing required to cover the full genome. For example, if one wishes to sequence 1% of the genome for the purpose of reducing sequencing cost, a variation of 100-fold is unacceptable since the necessary additional coverage could instead be applied to sequencing the full genome.” (117, top)
MPEP 2144.05 III states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the bins described by Hinds and Porreca in the method of Fan as Fan suggests analysis of chromosome aneuploidy which could be considered a bin to determine chromosome counts. The artisan would be motivated determine if bin size provide a different chromosomal count as Hinds demonstrated that bin analysis was a known method for the analysis of nucleic acid sequence information including 1000kb bins. The artisan would be motivated to use GC content of about 40% to 50% as Porreca suggest moderate GC content provides best uniformity of sequencing. The artisan would have a reasonable expectation of success as the artisan is merely combining a further method of analyzing nucleic acid sequences with the more specific teachings of Hinds and Porreca..
With regards to claim 9, Fan teaches, “approximately 50% (i.e., 5million) of the reads mapped uniquely to the human genome with at most, one mismatch against the human genome, covering 4%of the entire genome. An average of 154,000, 135,000, and 65,700 sequence tags mapped to chromosomes 13, 18, and 21,respectively.” Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made if 50% of reads mapped to human genome, then about 25% of the reads would map to a subset of bins. The artisan would be motivated as Fan suggest providing 50 kb windows, while Hinds and Porreca specifically teaches bins. The artisan would have a reasonable expectation of success as the artisan merely following the teachings of the prior art.
With regards to claim 10, Hinds teaches bins of ≥1000kb (table 3).
With regards to claims 11-12 Fan teaches the use of maternal blood, serum or plasma sample.
With regards to claim 13, Fan teaches Solexa/Illumina platform, which is sequencing by synthesis.
With regards to claim 14, Fan teaches, “We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus.”(abstract).
With regards to claim 15, Fan teaches, “ Plasma was transferred to microcentrifuge tubes and centrifuged at 16,000 g for 10 min to remove residual cells. The two centrifugation steps were performed within 24 h after blood collection. Cell-free plasma was stored at 80°C until further processing and was frozen and thawed only once before DNA extraction. DNA was extracted from cell-free plasma by using the QIAamp DNA Micro kit (Qiagen) or the NucleoSpin Plasma kit (Mach-erey–Nagel) according to the manufacturers’ instructions. Genomic DNA was extracted from 200l of whole blood of the donors by using the QIAamp DNA Blood Mini kit (Qiagen)” (16270, 2nd column sample and processing). Thus Fan teaches enriching fetal DNA from whole blood.
Response to Arguments
The response traverses the rejection in view of the amendments . This argument has been thoroughly reviewed but is not considered persuasive as the rejection has been amended in view of the amendment. The claims has been amended to recite, “and wherein the subset of the bins represents about 25% of the reference genome.” While this may provide a size limitation on the genome, it appears to a property of selecting sequences with about 42% to 48% GC content as it is not specifically a positive active step.
The response alleges none or the prior art teaches 42 to 48% GC content. This argument has been thoroughly reviewed but is not considered persuasive as Porreca teaches, “Target abundances binned by fraction GC content for the eMIP reaction are shown in Figure 8. Not surprisingly, we observe a one hundred-fold mean bias in favor of moderate GC content (40-50%) over extreme (10-20% and 70-80%). Examination of bias for each arm individually did not indicate that either exerted a significantly stronger effect (data not shown), even though the selective events occurring at each end are much different. Quite unexpectedly, the SeleCirc reaction did not exhibit any appreciable GC content bias (data not shown).”(116) Thus Porecca suggest bins of about 42 to 48% GC content
The response continues by arguing, “the claimed method specifies the subset of bins represents about 25% of the reference genome. Accordingly, the claimed method discards about 75% of the reference genome for the sequence analysis. None of the cited references teach or suggest discarding about 75% of the reference genome. Thus the rejection is maintained.” This argument has been thoroughly reviewed but is not considered persuasive as the claims do not require discarding over 75% of the referencing genome. The claims recite, “and wherein the subset of the bins represents about 25% of the reference genome.” This appears can be interpreted as a result of selecting bins with about 42% to 48% of GC content. Thus this argument is not persuasive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 8, 10-16 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,497,462 and Porreca (Multiplex Polony Sequencing for Analysis of Genomes, Transcriptomes, and Exonomes.(2007). Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
This rejection is set forth with respect to the interpretation of the claims in view of 112-2nd or 112(b) rejections demonstrating the lack of clarity of claims 8, 10-15. This rejection is set forth as in view of these issues.
The claims has been amended to recite, “and wherein the subset of the bins represents about 25% of the reference genome.” While this may provide a size limitation on the genome, it appears to a property of selecting sequences with about 42% to 48% GC content as it is not specifically a positive active step.
While the claims provide steps a)-f) MPEP 2111.01 II states:
The problem is to interpret claims ‘in view of the specification’ without unnecessarily importing limitations from the specification into the claims."); Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order).
Thus the broadest reasonable interpretation of the claims is steps a)- f) can be done in any order.
The instant claims are drawn to “ a method for detection of the presence or absence of a fetal chromosome aneuploidy comprising:;a) providing a human reference genome, wherein the reference genome is partitioned into bins;;b) providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome; c) sequencing a sample to obtain nucleic acid sequence reads, wherein the sample comprises cell-free circulating human fetal nucleic acid; d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; and f) detecting the presence or absence of a fetal chromosome aneuploidy by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy
The claims of 462 are drawn to A computer-implemented method for outputting a classification of presence or absence of a chromosome aneuploidy for sequenced test sample nucleic acid from a pregnant female, comprising: (a) sequencing test sample nucleic acid by a massively parallel sequencer that generates sequence reads, which test sample nucleic acid comprises circulating cell-free nucleic acid from blood of a pregnant female bearing a fetus, wherein the sequencing is at about 1-fold coverage or less; (b) mapping, using a microprocessor, the sequence reads to portions of a reference genome; (c) counting, using a microprocessor, the sequence reads mapped to the portions, which counting generates counts of sequence reads mapped to the portions; (d) normalizing, using a microprocessor, the counts of sequence reads mapped to chromosomes 13, 18, and 21, or segments thereof, according to guanine-cytosine (GC) content, which normalizing generates normalized counts; (e) calculating, using a microprocessor, three ratios from the normalized counts, wherein the three ratios consist of: (i) a ratio between counts mapped to chromosome 13, or segment thereof, to counts mapped to chromosome 21, or segment thereof, (ii) a ratio between counts mapped to chromosome 13, or segment thereof, to counts mapped to chromosome 18, or segment thereof, and (iii) a ratio between counts mapped to chromosome 18, or segment thereof, to counts mapped to chromosome 21, or segment thereof; (f) computationally comparing, using a microprocessor, the three ratios to corresponding ratios of one or more euploid samples, which comparing generates a comparison; and (g) outputting, using a microprocessor, a classification of the presence of absence of a chromosome aneuploidy for the test sample according to the comparison generated in (f).
The claims of 462 do not specifically teach the use of bins with about 0.42 to about 0.48 GC content.
Porreca teaches, “Target abundances binned by fraction GC content for the eMIP reaction are shown in Figure 8. Not surprisingly, we observe a one hundred-fold mean bias in favor of moderate GC content (40-50%) over extreme (10-20% and 70-80%). Examination of bias for each arm individually did not indicate that either exerted a significantly stronger effect (data not shown), even though the selective events occurring at each end are much different. Quite unexpectedly, the SeleCirc reaction did not exhibit any appreciable GC content bias (data not shown).”(116)
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Porreca teaches, “However, we also observe variation in target abundances over more than four orders of magnitude, an unacceptable range for targeted resequencing of exons. While specificity will affect overall sequencing error rate to the extent read length limits the uniqueness o f a read in the full genome, non-uniformity will affect cost by decreasing the fraction of the target set coverable per dollar of sequencing. It is this tradeoff between non-uniform amplification and the requirement for additional sequencing that guides the choice of how much variation is acceptable. The de facto ceiling on acceptable variation, of course, is defined by the amount of sequencing required to cover the full genome. For example, if one wishes to sequence 1% of the genome for the purpose of reducing sequencing cost, a variation of 100-fold is unacceptable since the necessary additional coverage could instead be applied to sequencing the full genome.” (117, top)
MPEP 2144.05 III states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the bins described by Porreca in the method of claims which suggests mapping to portions of genome which could be considered a bin to determine chromosome counts. The artisan would be motivated to use GC content of about 0.4 to 0.5 as Porreca suggest moderate GC content provides best uniformity of sequencing. The artisan would have a reasonable expectation of success as the artisan is merely combining a further method of analyzing nucleic acid sequences with the more specific teachings of Hinds and Porreca..
Dependent claims are rejected as they are commensurate in scope.
Response to Arguments
The response traverses the rejection in view of the arguments previously set forth with respect to Porreca. This argument is not persuasive as for the reasons of record as set forth in the art rejection..
Claims 8, 10-16 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,482,994 and Porreca (Multiplex Polony Sequencing for Analysis of Genomes, Transcriptomes, and Exonomes.(2007). Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
This rejection is set forth with respect to the interpretation of the claims in view of 112-2nd or 112(b) rejections demonstrating the lack of clarity of claims 8, 10-15. This rejection is set forth as in view of these issues.
The claims has been amended to recite, “and wherein the subset of the bins represents about 25% of the reference genome.” While this may provide a size limitation on the genome, it appears to a property of selecting sequences with about 42% to 48% GC content as it is not specifically a positive active step.
While the claims provide steps a)-f) MPEP 2111.01 II states:
The problem is to interpret claims ‘in view of the specification’ without unnecessarily importing limitations from the specification into the claims."); Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order).
Thus the broadest reasonable interpretation of the claims is steps a)- f) can be done in any order.
The instant claims are drawn to “ a method for detection of the presence or absence of a fetal chromosome aneuploidy comprising:;a) providing a human reference genome, wherein the reference genome is partitioned into bins;;b) providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome; c) sequencing a sample to obtain nucleic acid sequence reads, wherein the sample comprises cell-free circulating human fetal nucleic acid; d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; and f) detecting the presence or absence of a fetal chromosome aneuploidy by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy
The claims of 994 are drawn to A computer-implemented method for determining fetal fraction based on a copy number variation in a maternal genome, comprising: (a) sequencing a test sample from a pregnant female bearing a fetus by a non-targeted massively parallel sequencing process that generates nucleotide sequence reads, the test sample comprising circulating cell-free nucleic acid from (i) a maternal genome and (ii) a fetal genome; mapping the sequence reads to genomic sections of a reference genome; and counting the sequence reads mapped to the genomic sections of the reference genome, thereby obtaining counts of sequence reads mapped to the genomic sections of the reference genome; (b) normalizing, using a microprocessor, the counts mapped to the genomic sections of the reference genome, thereby providing normalized counts for the genomic sections; (c) identifying a first elevation of the normalized counts for a first set of genomic sections significantly different than a second elevation of the normalized counts for a second set of genomic sections, wherein the first set of genomic sections and the second set of genomic sections are within the same chromosome; (d) determining a copy number variation in the maternal genome for the first set of genomic sections based on the identified first and second elevations; (e) determining a categorization for the copy number variation in the maternal genome by comparing the first elevation to expected elevations for predetermined copy number variation categorizations; and (f) determining, using a microprocessor, a fetal fraction of the circulating cell-free nucleic acid according to the first elevation and a deviation from an expected elevation of normalized counts for the categorization
The claims of 994 do not specifically teach the use of bins with about 0.42 to about 0.48 GC content.
Porreca teaches, “Target abundances binned by fraction GC content for the eMIP reaction are shown in Figure 8. Not surprisingly, we observe a one hundred-fold mean bias in favor of moderate GC content (40-50%) over extreme (10-20% and 70-80%). Examination of bias for each arm individually did not indicate that either exerted a significantly stronger effect (data not shown), even though the selective events occurring at each end are much different. Quite unexpectedly, the SeleCirc reaction did not exhibit any appreciable GC content bias (data not shown).”(116)
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Porreca teaches, “However, we also observe variation in target abundances over more than four orders of magnitude, an unacceptable range for targeted resequencing of exons. While specificity will affect overall sequencing error rate to the extent read length limits the uniqueness o f a read in the full genome, non-uniformity will affect cost by decreasing the fraction of the target set coverable per dollar of sequencing. It is this tradeoff between non-uniform amplification and the requirement for additional sequencing that guides the choice of how much variation is acceptable. The de facto ceiling on acceptable variation, of course, is defined by the amount of sequencing required to cover the full genome. For example, if one wishes to sequence 1% of the genome for the purpose of reducing sequencing cost, a variation of 100-fold is unacceptable since the necessary additional coverage could instead be applied to sequencing the full genome.” (117, top)
MPEP 2144.05 III states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the bins described by Porreca in the method of claims which suggests mapping to portions of genome which could be considered a bin to determine chromosome counts. The artisan would be motivated to use GC content of about 0.4 to 0.5 as Porreca suggest moderate GC content provides best uniformity of sequencing. The artisan would have a reasonable expectation of success as the artisan is merely combining a further method of analyzing nucleic acid sequences with the more specific teachings of Hinds and Porreca..
Dependent claims are rejected as they are commensurate in scope.
Response to Arguments
The response traverses the rejection in view of the arguments previously set forth with respect to Porreca. This argument is not persuasive as for the reasons of record as set forth in the art rejection
Claims 8-16 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,112,832 and Porreca (Multiplex Polony Sequencing for Analysis of Genomes, Transcriptomes, and Exonomes.(2007). Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
This rejection is set forth with respect to the interpretation of the claims in view of 112-2nd or 112(b) rejections demonstrating the lack of clarity of claims 8, 10-15. This rejection is set forth as in view of these issues.
The claims has been amended to recite, “and wherein the subset of the bins represents about 25% of the reference genome.” While this may provide a size limitation on the genome, it appears to a property of selecting sequences with about 42% to 48% GC content as it is not specifically a positive active step.
While the claims provide steps a)-f) MPEP 2111.01 II states:
The problem is to interpret claims ‘in view of the specification’ without unnecessarily importing limitations from the specification into the claims."); Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order).
Thus the broadest reasonable interpretation of the claims is steps a)- f) can be done in any order.
The instant claims are drawn to “ a method for detection of the presence or absence of a fetal chromosome aneuploidy comprising:;a) providing a human reference genome, wherein the reference genome is partitioned into bins;;b) providing a subset of the bins, wherein the subset has been selected to include bins that have a range of guanine and cytosine (GC) content of about 42% to 48%, and wherein the subset of the bins represents about 25% of the reference genome; c) sequencing a sample to obtain nucleic acid sequence reads, wherein the sample comprises cell-free circulating human fetal nucleic acid; d) mapping the nucleic acid sequence reads to the subset of the bins; e) quantifying the nucleic acid sequence reads mapped to the subset of the bins for one or more chromosomes, thereby generating chromosome counts; and f) detecting the presence or absence of a fetal chromosome aneuploidy by assessing the chromosome counts, wherein a deviation from a 2X normal ratio is indicative of the presence of a fetal chromosome aneuploidy.
The claims of 832 are drawn to A system comprising: I. a sequencing module that performs a non-targeted massively parallel sequencing process to generate nucleic acid sequence reads from a test sample from a pregnant subject, wherein the sequence reads are reads of circulating cell-free nucleic acid from (i) a maternal genome and (ii) a fetal genome; and II. one or more microprocessors and memory, which memory comprises instructions executable by the one or more microprocessors, and which instructions executable by the one or more microprocessors are configured to: (a) map the nucleic acid sequence reads to genomic sections of a reference genome, count the nucleic acid sequence reads mapped to the genomic sections of the reference genome, and normalize the counts of the nucleic acid sequence reads mapped to the genomic sections of a reference genome, thereby providing normalized counts for the genomic sections, wherein the sequence reads that are mapped, counted, and normalized comprise reads of the maternal genome and the fetal genome; (b) identify a first elevation of the normalized counts for a first set of genomic sections significantly different than a second elevation of the normalized counts for a second set of genomic sections; (c) determine a copy number variation in the maternal genome for the first set of genomic sections based on the identified first and second elevations; (d) determine a categorization for the copy number variation in the maternal genome by comparing the first elevation to expected elevations for predetermined copy number variation categorizations; and (e) determine a fetal fraction of the circulating cell-free nucleic acid according to the first elevation and a deviation from an expected elevation of normalized counts for the categorization.
The claims of 832 do not specifically teach the use of bins with about 0.42 to about 0.48 GC content.
Porreca teaches, “Target abundances binned by fraction GC content for the eMIP reaction are shown in Figure 8. Not surprisingly, we observe a one hundred-fold mean bias in favor of moderate GC content (40-50%) over extreme (10-20% and 70-80%). Examination of bias for each arm individually did not indicate that either exerted a significantly stronger effect (data not shown), even though the selective events occurring at each end are much different. Quite unexpectedly, the SeleCirc reaction did not exhibit any appreciable GC content bias (data not shown).”(116)
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Porreca teaches, “However, we also observe variation in target abundances over more than four orders of magnitude, an unacceptable range for targeted resequencing of exons. While specificity will affect overall sequencing error rate to the extent read length limits the uniqueness o f a read in the full genome, non-uniformity will affect cost by decreasing the fraction of the target set coverable per dollar of sequencing. It is this tradeoff between non-uniform amplification and the requirement for additional sequencing that guides the choice of how much variation is acceptable. The de facto ceiling on acceptable variation, of course, is defined by the amount of sequencing required to cover the full genome. For example, if one wishes to sequence 1% of the genome for the purpose of reducing sequencing cost, a variation of 100-fold is unacceptable since the necessary additional coverage could instead be applied to sequencing the full genome.” (117, top)
MPEP 2144.05 III states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the bins described by Porreca in the method of claims which suggests mapping to portions of genome which could be considered a bin to determine chromosome counts. The artisan would be motivated to use GC content of about 0.4 to 0.5 as Porreca suggest moderate GC content provides best uniformity of sequencing. The artisan would have a reasonable expectation of success as the artisan is merely combining a further method of analyzing nucleic acid sequences with the more specific teachings of Hinds and Porreca..
Dependent claims are rejected as they are commensurate in scope.
Response to Arguments
The response traverses the rejection in view of the arguments previously set forth with respect to Porreca. This argument is not persuasive as for the reasons of record as set forth in the art rejection.
Summary
No claim is allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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