DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on February 16th, 2023, June 6th, 2023, January 17th, 2024, and August 29th, 2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
European reference EP3917838A1 on the IDS filed January 17th, 2024 has been lined through because the documentation provided consists only of a page indicating the corresponding WIPO application. Therefore, this specific reference has not been considered.
Election/Restrictions
Applicant’s election of Group II, claims 34-35, 37, 50, 52, and 65, in the reply filed on February 2nd, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-2, 4, 6, 13-16, 18-19, 21, 25, 27, 29, and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 2nd, 2026.
Claim Summary
Claims 34 and 37 have been amended. Claims 3, 5, 7-12, 17, 20, 22-24, 26, 28, 30, 32-33, 36, 38-49, 51, 53-64, and 66-171 have been canceled. Claims 1-2, 4, 6, 13-16, 18-19, 21, 25, 27, 29, 31, 34-35, 37, 50, 52, and 65 are pending. Claims 1-2, 4, 6, 13-16, 18-19, 21, 25, 27, 29, and 31 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 34-35, 37, 50, 52, and 65 are under examination and discussed in this Office action.
Specification
The use of the terms such as Circligase, HiSeq, MiSeq, Apple, and QIAamp, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
While the claims are broadly directed towards nucleic acid molecules, it is noted that the specification, and even the title, of the instant disclosure focuses on cell-free DNA. Given this focus, cell-free DNA has been applied as the preferred interpretation of nucleic acid molecules.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 34-35, 37, 50, 52, and 65 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 34 recites the limitations “(d) measuring a first size distribution for a subset of said plurality of said individual nucleic acid molecules having the genomic feature” and “(e) measuring a second size distribution for a subset of said plurality of nucleic acid molecules not having said genomic feature”. There is insufficient antecedent basis for these limitations in the claim. In part (c) of the claim, genomic features have been identified in the plurality of sequence reads, not in the plurality of nucleic acid molecules. It is therefore not clear if the Applicant intends to use the sequence reads of the single-stranded DNA library to determine a size distribution or the plurality of nucleic acid molecules separate from the single-stranded DNA library. Claims 35, 37, 50, and 52 are also rejected here given their dependence on claim 34 and not further clarifying the identified issue. For the purpose of compact prosecution, “(d) measuring a first size distribution for a subset of said plurality of said individual nucleic acid molecules having the genomic feature” and “(e) measuring a second size distribution for a subset of said plurality of nucleic acid molecules not having said genomic feature” will be interpreted to use the plurality of sequence reads as opposed to a plurality of nucleic acid molecules.
Claim 65 recites the limitations “(b) identifying an individual nucleic acid molecule of said single-stranded DNA library as having a genomic feature; (c) identifying at least a 5' end or a 3' end for said individual nucleic acid molecule; (d) associating said genomic feature with a disease based on said 5' end or said 3' end of said individual nucleic acid molecule”. It is unclear how these limitations may be widely applicable to all possible genomic features, particularly those that may change the 5’ and 3’ ends of the nucleic acid molecules. For instance, if a deletion occurs at both the 5’ and 3’ end of a nucleic acid molecule, it is unclear how this may then be used to associate the genomic feature with a disease. For the purpose of compact prosecution, the above limitations are given the broadest reasonable interpretation wherein a genomic feature does not affect the 5’ or 3’ ends of the nucleic acid molecules.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 34-35, 37, 50, 52, and 65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for issues related to scope of enablement. With regards to claims 34-35, 37, 50, 52, and 65, the specification, while being enabling for a human subject, does not reasonably provide enablement for any subject as embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 34 as currently drafted encompasses a method for nucleic acid analysis, comprising preparing a single-stranded DNA library from a plurality of nucleic acid molecules from a subject. Claim 65 as currently drafted also encompasses a method for nucleic acid analysis, comprising preparing a single-stranded DNA library from a plurality of nucleic acid molecules from a subject. “A subject” does not limit the subject to a human subject as described in the specification. Consequently, the breadth of the claims is expansive since they encompass any kind of non-human subject. This can include subjects such as dogs, cats, and birds, among many other examples. Claims 35, 37, 50, and 52 encompass the same breadth as claim 34 since they do not limit the subject to a human subject.
(B) The nature of the invention: The invention is in the field of a nucleic acid analysis.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Juppner (Functional properties of the PTH/PTHrP receptor, Bone, August 1995, S39-S42) teaches that despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics (Abstract; Pages 39S-40S). This art indicates that there is known functional differences between homologs in different organisms, and therefore inter-species extrapolation would be unpredictable.
The art supports use of specific subjects. However, methods comprising any subject are highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: While the Applicant has provided description of a subject including any animal, preferably a mammal (paragraph [00100]), the working examples provided by the Applicant are directed to only human subjects. As noted in Example 1, starting at paragraph [00107], the samples used in the working examples are clinical samples from humans. The Applicant has not provided working examples directed towards any other type of subject.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that a subject very broadly refers to any number of different species and thus applicability of the claimed methods to a subject as embraced by the claims remains unpredictable, requiring undue experimentation. For example, an artisan would need to test the methods on an expansive number of different organisms to determine if it is applicable to genomic features, size distributions, and 5’ and 3’ ends in said organisms. This reasonably represents undue experimentation.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 34-35, 37, 50, 52, and 65, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 34-35, 37, 50, 52, and 65 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to it the full scope embraced by the claims.
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 34-35, 37, 50, 52, and 65 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and abstract ideas without significantly more. While the claims are directed to processes, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), claims 34-35, 37, 50, and 52 recite the natural correlation between nucleic acid size distribution, genomic features, and disease. Such correlation is a natural phenomenon because it describes a consequence of the human body. Claims 34-35, 37, 50, and 52 further recite the abstract ideas of determining a difference in size and associating a genomic feature with a disease based on size. Such recitations are mental process abstract ideas because both determining a difference in size and associating a genomic feature can reasonably be performed in the human mind after simply looking at data. Claim 65 recites the natural correlation between ends of nucleic acid molecules, genomic features, and disease. Such correlation is a natural phenomenon because it describes a consequence of the human body. Claim 65 also recites the abstract ideas of identifying a 5’ or 3’ end of a nucleic acid molecule and associating a genomic feature with a disease based on these ends. Such recitations are mental process abstract ideas because both identifying ends of nucleic acid molecules and associating a genomic feature with a disease based on those ends can reasonably be performed in the human mind after simply looking at data.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe natural phenomena and abstract ideas: the natural correlation between nucleic acid size distribution, genomic features, and disease; the abstract ideas of determining a difference in size and associating a genomic feature with a disease based on size; the natural correlation between ends of nucleic acid molecules, genomic features, and disease; and the abstract ideas of identifying a 5’ or 3’ end of a nucleic acid molecule and associating a genomic feature with a disease based on these ends.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of preparing single-stranded DNA libraries from nucleic acid molecules (further including denaturing the molecules, and/or ligating adapters to 5’, 3’, or both ends of the molecules with a DNA ligase specific for single-stranded DNA, and circularizing the single stranded DNA molecules and further amplifying the circularized molecules with relation to claims 34-35, 37, 50 and 52), obtaining sequencing reads, preparing a single-stranded DNA library from a plurality of nucleic acid molecules; obtaining sequencing reads; identifying a genomic feature (wherein a genomic feature can comprise those seen in claim 50 or claim 52 with relation to claims 34-35, 37, 50 and 52); and either measuring a first size distribution for molecules having the genomic feature, measuring a second size distribution for molecules not having the genomic feature, determining a size difference between the distributions, and associating the genomic feature with a disease based on difference in size (claims 34-35, 37, 50, and 52); or identifying a 5’ end or 3’ end of an individual nucleic acid molecule and associating the genomic feature with a disease based on an end (claim 65), the claims do not improve upon DNA extraction technologies, sequencing technologies, genomic feature detection technologies, or size distribution measurement technologies. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of preparing single-stranded DNA libraries from nucleic acid molecules (further including denaturing the molecules, and/or ligating adapters to 5’, 3’, or both ends of the molecules with a DNA ligase specific for single-stranded DNA, and circularizing the single stranded DNA molecules and further amplifying the circularized molecules with relation to claims 34-35, 37, 50 and 52), obtaining sequencing reads, preparing a single-stranded DNA library from a plurality of nucleic acid molecules; obtaining sequencing reads; identifying a genomic feature (wherein a genomic feature can comprise those seen in claim 50 or claim 52 with relation to claims 34-35, 37, 50 and 52); and either measuring a first size distribution for molecules having the genomic feature, measuring a second size distribution for molecules not having the genomic feature, determining a size difference between the distributions, and associating the genomic feature with a disease based on difference in size (claims 34-35, 37, 50, and 52); or identifying a 5’ end or 3’ end of an individual nucleic acid molecule and associating the genomic feature with a disease based on an end (claim 65), no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a sequencing apparatus, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. Preparing sequencing libraries and subsequently sequencing DNA molecules does not transform that DNA into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between nucleic acid size distribution, genomic features, and disease; the abstract ideas of determining a difference in size and associating a genomic feature with a disease based on size; the natural correlation between ends of nucleic acid molecules, genomic features, and disease; and the abstract ideas of identifying a 5’ or 3’ end of a nucleic acid molecule and associating a genomic feature with a disease based on these ends in the instant case have to do with preparing single-stranded DNA libraries from nucleic acid molecules (further including denaturing the molecules, and/or ligating adapters to 5’, 3’, or both ends of the molecules with a DNA ligase specific for single-stranded DNA, and circularizing the single stranded DNA molecules and further amplifying the circularized molecules with relation to claims 34-35, 37, 50 and 52), obtaining sequencing reads, preparing a single-stranded DNA library from a plurality of nucleic acid molecules; obtaining sequencing reads; and identifying a genomic feature (wherein a genomic feature can comprise those seen in claim 50 or claim 52 with relation to claims 34-35, 37, 50 and 52). These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exceptions are the natural correlation between nucleic acid size distribution, genomic features, and disease; the abstract ideas of determining a difference in size and associating a genomic feature with a disease based on size; the natural correlation between ends of nucleic acid molecules, genomic features, and disease; and the abstract ideas of identifying a 5’ or 3’ end of a nucleic acid molecule and associating a genomic feature with a disease based on these ends. The additional elements recited in the claims (i.e. preparing single-stranded DNA libraries from nucleic acid molecules (further including denaturing the molecules, and/or ligating adapters to 5’, 3’, or both ends of the molecules with a DNA ligase specific for single-stranded DNA, and circularizing the single stranded DNA molecules and further amplifying the circularized molecules with relation to claims 34-35, 37, 50 and 52), obtaining sequencing reads, preparing a single-stranded DNA library from a plurality of nucleic acid molecules; obtaining sequencing reads; and identifying a genomic feature (wherein a genomic feature can comprise those seen in claim 50 or claim 52 with relation to claims 34-35, 37, 50 and 52)) does amount to mere instructions to apply the judicial exceptions, since the preparing sequencing libraries, sequencing, and identifying genomic features serve as mere conventional steps taken for the purpose of gathering data about the nucleic acid molecules, which any practical use of the judicial exceptions would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to preparing sequencing libraries, sequencing, and identifying genomic features.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of “[a] method for nucleic acid analysis”, is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was routine and conventional in the prior art to sequence DNA from a single-stranded library, identify a genomic feature, measure size distributions, and associate genomic features with a disease based on size distributions. It was further routine and conventional in the prior art to sequence DNA, identify a genomic feature, identify 5’ or 3’ ends of sequenced DNA molecules, and associate a genomic feature with a 5’ or 3’ end.
For example, Mouliere (Enhanced detection of circulating tumor DNA by fragment size analysis, Science Translational Medicine, November 2018, 10, 1-13; cited on the IDS filed January 17th, 2024, copy with supplement is provided) teaches a method for nucleic acid analysis, comprising: (a) preparing a deoxyribonucleic acid (DNA) library from a plurality of nucleic acid molecules (Supplementary Materials, Page 3), said plurality comprising single-stranded DNA and double-stranded DNA derived from a subject (Page 10, column 2, paragraph 2; Supplementary Materials, Page 3). Mouliere’s methods use cfDNA and ctDNA (which is a fraction of total cfDNA, see Mouliere’s introduction) from plasma (Page 2, column 1, paragraph 4 to column 2, paragraph 1). As evidenced by Yang (Cell-Free DNA Comprises the Strand-Specific Characteristic Associated with Transcription and Methylation, Clinical Chemistry, September 2025, 71, 980-992), cfDNA in blood contains both single-stranded and double-stranded DNA (Page 980, column 2, Introduction). Mouliere further teaches (b) obtaining a plurality of sequence reads of said DNA library (Supplementary Materials, Page 3); (c) identifying a genomic feature in said plurality of sequence reads (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2C); (d) measuring a first size distribution for a subset of said plurality of nucleic acid molecules having the genomic feature (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2D); (e) measuring a second size distribution for a subset of said plurality of nucleic acid molecules not having said genomic feature (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2D); (f) using said first size distribution and said second size distribution to determine a difference in size between said first size distribution and said second size distribution (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2D); and (g) associating said genomic feature with a disease based on said difference in size (Page 2, column 1, paragraph 4 to column 2, paragraph 1).
In a further example, Wang (CLAmp-seq: A Novel Amplicon-Based NGS Assay with Concatemer Error Correction for Improved Detection of Actionable Mutations in Plasma cfDNA from Patients with NSCLC, Small Methods, August 2019, 4, 1-10) teaches preparing a single-stranded deoxynucleic acid (DNA) library from a plurality of nucleic acid molecules (Page 2, column 2, paragraph 2; Figure 1) and obtaining a plurality of sequence reads specifically from a single-stranded DNA library (Page 2, column 2, paragraph 2; Figure 1). As evidenced by Cheng (A review on the impact of single-stranded library preparation on plasma cell-free diversity for cancer detection, Frontiers in Oncology, March 2024, 14, 1-11), CLAmp-seq is considered a single-stranded DNA library preparation technique (Page 4, column 2, paragraphs 2-3).
In a final example, Lo (US 20170024513 A1; cited on the IDS filed February 16th, 2023) teaches a method for nucleic acid analysis, comprising: (a) preparing plasma DNA sequencing data (Pages 24-25, paragraphs [0307]-[0309]); (b) identifying an individual nucleic acid molecule of said plasma DNA sequencing data as having a genomic feature (Pages 24-25, paragraphs [0307]-[0309]); (c) identifying at least an ending position for said individual nucleic acid molecule (Pages 24-25, paragraphs [0307]-[0309]); (d) associating said genomic feature with a disease based on said ending position of said individual nucleic acid molecule (Pages 24-25, paragraphs [0307]-[0309]). As earlier defined by Lo, an “ending position” is the genomic coordinate of the outermost base (i.e. extremities) of a cell-free DNA molecule or plasma DNA molecule, and further that an end position can refer to either end of a DNA molecule (Page 3, paragraph [0057]). As evidenced by MGI, 5’ and 3’ ends are also identifiers of one particular end of a single-stranded nucleic acid molecule (whole document). Therefore, Lo can reasonably be considered to be discussing 5’ and 3’ ends as claimed. This particular embodiment of Lo does not specifically recite preparing a single-stranded DNA library from a plurality of nucleic acid molecules, said plurality comprising single-stranded DNA and double-stranded DNA derived from a subject. However, Lo does teach on plasma DNA as a nucleic acid of interest in the above embodiment (Page 24-25, paragraphs [0307]-[0309]). Lo further teaches that plasma DNA can comprise single-stranded and double-stranded DNA (Page 26, paragraph [0328]). Lo also teaches using single-stranded DNA sequencing library preparation protocols to determine ends of plasma DNA (Page 3, paragraph [0057]).
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), as well as the well-understood, routine, and conventional nature of what is claimed given the examples of Mouliere, Wang, and Lo, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. Therefore, claims 34-35, 37, 50, 52, and 65 are rejected here under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 34-35, 37, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Mouliere (Enhanced detection of circulating tumor DNA by fragment size analysis, Science Translational Medicine, November 2018, 10, 1-13; cited on the IDS filed January 17th, 2024, copy with supplement is provided), in view of Wang (CLAmp-seq: A Novel Amplicon-Based NGS Assay with Concatemer Error Correction for Improved Detection of Actionable Mutations in Plasma cfDNA from Patients with NSCLC, Small Methods, August 2019, 4, 1-10), as evidenced by Yang (Cell-Free DNA Comprises the Strand-Specific Characteristic Associated with Transcription and Methylation, Clinical Chemistry, September 2025, 71, 980-992) and Cheng (A review on the impact of single-stranded library preparation on plasma cell-free diversity for cancer detection, Frontiers in Oncology, March 2024, 14, 1-11).
Regarding instant claim 34, Mouliere teaches a method for nucleic acid analysis, comprising: (a) preparing a deoxyribonucleic acid (DNA) library from a plurality of nucleic acid molecules (Page 10, column 2, paragraph 2; Supplementary Materials, Page 3), said plurality comprising single-stranded DNA and double-stranded DNA derived from a subject (Page 10, column 2, paragraph 2; Supplementary Materials, Page 3). Mouliere’s methods use cfDNA and ctDNA (which is a fraction of total cell-free DNA, see Mouliere’s introduction) from plasma (Page 2, column 1, paragraph 4 to column 2, paragraph 1). As evidenced by Yang, cfDNA in blood contains both single-stranded and double-stranded DNA (Page 980, column 2, Introduction). Mouliere further teaches (b) obtaining a plurality of sequence reads of said DNA library (Supplementary Materials, Page 3); (c) identifying a genomic feature in said plurality of sequence reads (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2C; Supplementary Materials, Page 3); (d) measuring a first size distribution for a subset of said plurality of nucleic acid molecules having the genomic feature (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2D); (e) measuring a second size distribution for a subset of said plurality of nucleic acid molecules not having said genomic feature (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2D); (f) using said first size distribution and said second size distribution to determine a difference in size between said first size distribution and said second size distribution (Page 2, column 1, paragraph 4 to column 2, paragraph 1; Figure 2D); and (g) associating said genomic feature with a disease based on said difference in size (Page 2, column 1, paragraph 4 to column 2, paragraph 1).
Mouliere does not teach preparing a single-stranded deoxynucleic acid (DNA) library from a plurality of nucleic acid molecules and obtaining a plurality of sequence reads specifically from a single-stranded DNA library.
Wang, in a reasonably pertinent field, teaches preparing a single-stranded deoxynucleic acid (DNA) library from a plurality of nucleic acid molecules (Page 2, column 2, paragraph 2; Figure 1) and obtaining a plurality of sequence reads specifically from a single-stranded DNA library (Page 2, column 2, paragraph 2; Figure 1). As evidenced by Cheng, CLAmp-seq is considered a single-stranded DNA library preparation technique (Page 4, column 2, paragraphs 2-3).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Mouliere with the library preparation of Wang. Since Wang teaches on library preparation for sequencing of cell-free DNA, which is reasonably pertinent to Mouliere, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because the preparation technique of Wang utilizes concatemer error correction to suppress sequencing errors as well as polymerase errors introduced during PCR amplification (Page 2, column 1, paragraph 2).
It is noted by the Examiner that the recitation of “identifying a genomic feature in said plurality of sequence reads” and “associating said genomic feature with a disease based on said difference in size” has been interpreted such that the genomic feature is previously known to be associated with a disease. This interpretation is based on descriptions from the instant specification at paragraphs [0066], [0074], and [0075]. Given this interpretation, the difference in size distribution serves as confirmation that the genomic feature is associated with the disease given that it appears in a different nucleic acid size distribution than nucleic acid molecules that lack the genomic feature.
Regarding instant claim 35, Mouliere, in view of Wang, teaches the method of claim 34. Wang further teaches wherein (a) comprises denaturing said plurality of nucleic acid molecules (Page 2, column 2, paragraph 2).
Regarding instant claim 37, Mouliere, in view of Wang, teaches the method of claim 34. Wang further teaches wherein (a) comprises (i) circularizing individual single stranded DNA molecules of said plurality of nucleic acid molecules to form a plurality of circular nucleic acid molecules (Page 2, column 2, paragraph 2; Figure 1); and (ii) amplifying said plurality of circular nucleic acid molecules to yield a plurality of amplified nucleic acid molecules (Page 2, column 2, paragraph 2; Figure 1).
Regarding instant claim 52, Mouliere, in view of Wang, teaches the method of claim 34. Mouliere further teaches wherein said genomic feature comprises a single nucleotide variant (SNV) (Supplementary Materials, Page 3, Tam-Seq).
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Mouliere (Enhanced detection of circulating tumor DNA by fragment size analysis, Science Translational Medicine, November 2018, 10, 1-13; cited on the IDS filed January 17th, 2024, copy with supplement is provided) and Wang (CLAmp-seq: A Novel Amplicon-Based NGS Assay with Concatemer Error Correction for Improved Detection of Actionable Mutations in Plasma cfDNA from Patients with NSCLC, Small Methods, August 2019, 4, 1-10), as applied to claims 34-35, 37, and 52 above, and further in view of Lo (US 20170024513 A1; cited on the IDS filed February 16th, 2023).
Regarding instant claim 50, Mouliere, in view of Wang, teaches the method of claim 34.
Neither reference teaches wherein said genomic feature comprises an epigenetic modification selected from the group consisting of methylation, phosphorylation, ubiquitination, sumoylation, acetylation, ribosylation, citrullination, and fragmentation.
Lo, in the same field of endeavor, teaches on looking at both fragment size and methylation in cell-free DNA fragments to determine informativeness or specificity to a disease (e.g. cancer) (Page 23, paragraph [0294]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Mouliere, in view of Wang, with the genomic feature of Lo. Since both Mouliere, in view of Wang, and Lo are in the same field of endeavor (e.g. cfDNA fragmentation pattern as it relates to tumors), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because using multiple disease associated parameters increases specificity in identification of informative fragments (Lo, Page 23, paragraph [0294]).
Claim 65 is rejected under 35 U.S.C. 103 as being unpatentable over Lo (US 20170024513 A1; cited on the IDS filed February 16th, 2023), as evidenced by MGI (Glossary Term 5’ and Glossary Term 3’ [online]. MGI, [2026] [retrieved on February 27th, 2026]. Retrieved from: https://www.informatics.jax.org/glossary/_5_prime and https://www.informatics.jax.org/glossary/_3_prime).
Regarding instant claim 65, Lo teaches a method for nucleic acid analysis, comprising: (a) preparing plasma DNA sequencing data (Pages 24-25, paragraphs [0307]-[0309]); (b) identifying an individual nucleic acid molecule of said plasma DNA sequencing data as having a genomic feature (Pages 24-25, paragraphs [0307]-[0309]); (c) identifying at least an ending position for said individual nucleic acid molecule (Pages 24-25, paragraphs [0307]-[0309]); (d) associating said genomic feature with a disease based on said ending position of said individual nucleic acid molecule (Pages 24-25, paragraphs [0307]-[0309]). As earlier defined by Lo, an “ending position” is the genomic coordinate of the outermost base (i.e. extremities) of a cell-free DNA molecule or plasma DNA molecule, and further that an end position can refer to either end of a DNA molecule (Page 3, paragraph [0057]). As evidenced by MGI, 5’ and 3’ ends are also identifiers of one particular end of a single-stranded nucleic acid molecule (whole document). Therefore, Lo can reasonably be considered to be discussing 5’ and 3’ ends as claimed.
The above embodiment of Lo does not specifically recite preparing a single-stranded DNA library from a plurality of nucleic acid molecules, said plurality comprising single-stranded DNA and double-stranded DNA derived from a subject. However, Lo does teach on plasma DNA as a nucleic acid of interest in the above embodiment (Page 24-25, paragraphs [0307]-[0309]). Lo further teaches that plasma DNA can comprise single-stranded and double-stranded DNA (Page 26, paragraph [0328]). Lo also teaches using single-stranded DNA sequencing library preparation protocols to determine ends of plasma DNA (Page 3, paragraph [0057]). It would then be obvious to use single-stranded DNA library preparation to produce sequencing data from a plurality of nucleic acid molecules comprising single-stranded and double-stranded DNA because this would amount to simple substitution of one known method for another to obtain predictable results (see MPEP 2141(III)).
Conclusion
All claims stand rejected.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683