DETAILED ACTION
Status of the Claims
Claims 84-85, 87, 94, 97, 104, 106-110, and 112-120 are currently pending and are the subject of this Office Action.
The following Office Action is in response to Applicant’s communication dated 10/23/2025. Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/23/2025 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Please note that the new examiner of record is Jeremy C. Flinders.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as "means" and "said," should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The abstract of the disclosure is objected to because it is too short and does not provide enough information to reasonably inform the reader of the substance of the invention. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 84-85, 87, 94, 97, 104, 106-110, and 112-120 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
Independent claim 84 recites collections of polynucleotides sized 125-200 base pairs in length and comprising sequences with variations that are within 30 bases of one another. Similarly, independent claim 112 recites collections of polynucleotides (of any size) comprising variants that are present in the collection at a ratio of less than 1:9. Both claims encompass embodiments that are either naturally occurring, or are non-naturally occurring but lacking markedly different characteristics as compared to their naturally occurring counterparts, and therefore are “product of nature” judicial exceptions as per MPEP 2106.04(c). Specifically, such pluralities of variants (e.g., insertions, deletions, fusions, duplications, frameshifts, repeat expansions, and/or substitutions) are present together in, for example, tumor environments where genetic instability leads to such heterogeneity.
Regarding the length limitations of claims 84 and 118 of 125-200 base pairs, it is noted that this is the primary size distribution in circulating tumor DNA (ctDNA), a subset of cfDNA. In addition, it is noted that as per MPEP 2106.04(c), isolated portions of a genome are addressed as differing from their naturally occurring counterpart by being merely being isolated from flanking chromosomal DNA regions, and such isolation does not render them patent eligible. See, e.g., Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 591-94, 106 USPQ2d 1972, 1979-81 (2013) (comparing isolated BRCA1 genes and BRCA1 cDNA molecules to naturally occurring BRCA1 gene), Roche Molecular System, Inc. v. CEPHEID, 905 F.3d 1363, 1371, 128 USPQ2d 1221, 1227 (Fed. Cir. 2018) (comparing claimed primers to "their corresponding nucleotide sequences on the naturally occurring DNA"), and/or University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 760, 113 USPQ2d 1241, 1241 (Fed. Cir. 2014) (comparing single-stranded nucleic acid to the same strand found in nature, even though "single-stranded DNA cannot be found in the human body").
Claims 85, 87, 94, 104, 106-110, and 113-120 depend from claims 84 and 112, respectively, and further recite limitations as to the number, ratios, origins, and nature of variations in the pluralities of polynucleotides, but since these are all found in nature, they do not represent markedly different characteristics.
Regarding claim 97, the inclusion of the instructions and packaging, while not being naturally occurring, do not make the claim patent eligible. See MPEP 2106.04(c)(I)(A), which states:
Where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to "a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt"), the markedly different characteristics analysis should be applied only to the nature-based product limitation. For instance, for the yogurt starter kit example, the Lactobacillus would be analyzed for markedly different characteristics. The container and instructions would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B if needed) if it is determined that the Lactobacillus does not have markedly different characteristics from any naturally occurring counterpart and thus is a product of nature exception.
The present instructions and packaging correspond to the instructions and container of this example, and therefore only need be considered as potential “additional elements”, as below.
Therefore, it can be reasonably concluded that the analysis for patent eligibility fails Prong One of Step 2A, and the claim must be further analyzed in the Step 2A Prong Two and Step 2B to determine whether the claim as a whole integrates the exception into a practical application or there are additional elements that amount to significantly more than the judicial exception. Relevant considerations for evaluating whether additional elements integrate a judicial exception into a practical application, based on the Supreme Court and Federal Circuit, are discussed at length in MPEP 2106.04(d) and in the Federal Register (Vol. 84, No. 4, from January 7, 2019). In the present case, the only “additional elements” are the instructions and/or packaging in claim 97, and are recited at a high level of generality and constitute routine, conventional, and well-understood elements such that they cannot transform the claim into something patent eligible. See MPEP 2106.04(d).
For further information, please see the latest revision of MPEP § 2104-2106 {Patent Subject Matter Eligibility Under 35 U.S.C. 101}, including MPEP § 2106.04 {Eligibility Step 2A: Whether a Claim is Directed to a Judicial Exception} and 2106.05 {Eligibility Step 2B: Whether a Claim Amounts to Significantly More}, as well as any additional guidance on Subject Matter Eligibility, provided on the USPTO website at
https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter-eligibility.
Claim Rejection(s) – 35 USC § 112 – New Matter
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 84-85, 87, 94, 97, 104, and 106-110 are 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(s), at the time the application was filed, had possession of the claimed invention. This rejection concerns “new matter.”
Claims 84 and 106 each has been amended to include limitations that the positions of the variations in the polynucleotides are “1 to 30 bases” from the other positions, however, the specification as originally filed does not provide adequate written description support for such proximity limitations. A thorough analysis of the disclosure as originally filed did not reveal any indication that Applicant was in possession of an invention limited to variations that must reside within 30 bases of one another in the different primary polynucleotides.
Claims 85, 87, 94, 97, 104, and 107-110 depend from claim 84 and are therefore similarly rejected.
Applicants are reminded, as per 37 C.F.R. 1.121, that no amendment may introduce new matter into the disclosure of an application, and that in accordance with MPEP § 2163(II)(A)(3)(b), when filing an amendment an applicant should show support in the original disclosure for new or amended claims.
MPEP §2163(I) states that to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. MPEP §2163(I)(B) explains the written description matter as it relates to new and amended claims, stating that the written description requirement prevents an applicant from claiming subject matter that was not adequately described in the specification as filed.
MPEP 2163.06(I) notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).”
Claim Rejections - 35 USC § 112 -- Indefiniteness
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 110 and 120 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 pre-AIA the applicant regards as the invention.
Claims 110 and 120 each recites the polynucleotide library of claim 84 and 112, respectively, wherein the plurality of primary polynucleotides is substantially free of cellular components and biomolecules derived from plasma. However, since it is noted that DNA is a cellular component and a biomolecule that can be derived from plasma, this limitation appears to be a contradiction and therefore the metes and bounds of the claim are unascertainable.
As per MPEP 2173: It is of utmost importance that patents issue with definite claims that clearly and precisely inform persons skilled in the art of the boundaries of protected subject matter. Therefore, claims that do not meet this standard must be rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph as indefinite. Further, as per MPEP 2173.02: If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. As currently written, the metes and bounds of the rejected claims are unascertainable for the reasons set forth above, thus the above claim(s) and all dependent claims are rejected under 35 USC 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Claim Rejections – 35 U.S.C. 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Keup et al.
Claims 84-85, 87, 94, 106-107, 112-114, and 117-119 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Keup et al (Cellular and Molecular Life Sciences, 2020, 77:497–509, of record) as evidenced by Underhill et al. (PLOS Genetics, 2016, 12(7): e1006162).
Regarding claims 84 and 106, Keup discloses a polynucleotide library comprising:
a plurality of primary polynucleotides, wherein each primary polynucleotide has a length of 125 to 200 base pairs (e.g., cfDNA and specifically the circulating tumor DNA, known to be in this size range as per Underhill in the abstract and/or Fig. 1);
a plurality of background polynucleotides, wherein each background polynucleotide corresponds to a primary polynucleotide of the plurality of primary polynucleotides (e.g., background polynucleotides corresponding to the wild-type and primary polynucleotides being the mutations in Keup);
wherein each primary polynucleotide comprises a variation compared to a corresponding background polynucleotide, wherein the variation comprises an insertion, a deletion, a fusion, a duplication, a frameshift, a repeat expansion, or a substitution (e.g., indels, substitutions, etc. as per Fig. 2 and/or the Supplementary Materials); and
wherein the plurality of primary polynucleotides comprises a variation in a first, second, third, and fourth primary polynucleotide at a first, second, third, and fourth position in the respective primary polynucleotide, wherein the variations are identical (e.g., mutations) and are all 1 to 30 bases from each other (e.g., in several cases, including the ESR1 gene, showing mutations 1607 A>C, 1610 A>C and A>G, 1613 A>G, 1616 A>C, and 1617 A>G as per the Supplementary Materials #5 spreadsheet).
Regarding claim 85, Keup discloses the above, wherein the variation is derived from genomic sequences (e.g., as per the Abstract).
Regarding claim 87, Keup discloses the above, wherein 0.001% to 0.1% of a total amount of polynucleotides in the library include the variation included in the first and second primary polynucleotides (e.g., as per Fig. 2).
Regarding claim 94, Keup discloses the above, wherein the variation of each primary polynucleotide includes a modification to a tumor suppressor gene or an oncogene (e.g., as per the Abstract and Fig. 3).
Regarding claim 107, Keup discloses the above, having a ratio of primary polynucleotides to background polynucleotides is 1:1 to 1:9 (e.g., as per Fig. 2).
Regarding claim 112, Keup discloses a polynucleotide library comprising:
a plurality of primary polynucleotides (e.g., cfDNA as per the Abstract and throughout);
a plurality of background polynucleotides, wherein each background polynucleotide corresponds to a primary polynucleotide of the plurality of primary polynucleotides, wherein each primary polynucleotide comprises a variation compared to a corresponding background polynucleotide (e.g., background polynucleotides corresponding to the wild-type and primary polynucleotides being the mutations in Keup); and
wherein the variation of a first primary polynucleotide is identical to a variation of a second primary polynucleotide, and the variation of the first primary polynucleotide is at a different position in the first primary polynucleotide than a position of the variation in the second primary polynucleotide (e.g., indels, substitutions, etc. as per Fig. 2 and/or the Supplementary Materials);
wherein a ratio of primary polynucleotides to background polynucleotides in the polynucleotide library is less than 1:9 (e.g., as per the mutational frequencies shown in Fig. 2 and/or the Supplementary Materials).
Regarding claim 113, Keup discloses the above, wherein the variation comprises an insertion, deletion, fusion, duplication, frameshift, repeat expansion, or substitution (e.g., indels, substitutions, etc. as per Fig. 2 and/or the Supplementary Materials).
Regarding claim 114, Keup discloses the above, wherein the variation comprises a copy number variant, microsatellite instability, loss of heterozygosity (LOH), DNA methylation, premature stop codon, trinucleotide repeat, translocation, somatic rearrangement, allelomorph, single nucleotide variant, indel, splice variant, regulator variant, copy number variant, or fusion (e.g., indels, substitutions, etc. as per Fig. 2 and/or the Supplementary Materials).
Regarding claim 117, Keup discloses the above, wherein at least 5 primary polynucleotides contain an identical variation, and the identical variation is at a different location on each of the at least 5 primary polynucleotides (e.g., in several cases, including the ESR1 gene, showing mutations 1607 A>C, 1610 A>C and A>G, 1613 A>G, 1616 A>C, and 1617 A>G as per the Supplementary Materials #5 spreadsheet).
Regarding claim 118, Keup discloses the above, wherein each primary polynucleotide has a length of 125 to 200 base pairs (e.g., cfDNA and specifically the circulating tumor DNA, known to be in this size range as per Underhill in the abstract and/or Fig. 1).
Regarding claim 119, Keup discloses the above, wherein the polynucleotide library is configured such that 0.001% to 10% of a total amount of polynucleotides in the library include the variation included in the first and second primary polynucleotides (e.g., as per the mutational frequencies shown in Fig. 2 and/or the Supplementary Materials).
Claim Rejections – 35 U.S.C. 103(a)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Keup et al.
Claims 84-85, 87, 94, 104, 106-109, and 112-119 are rejected under 35 U.S.C. 103 as being unpatentable over Keup et al (Cellular and Molecular Life Sciences, 2020, 77:497–509, of record).
Keup is relied on as above. However, it is noted that the reference is silent regarding the limitations of the polynucleotide library comprises at least 500 background polynucleotides, as set forth in claim 104, the plurality of primary polynucleotides comprises at least 150 or 400 different variations, as set forth in claims 108 and 115, and the plurality of primary polynucleotides comprises variations located in at least 50 or 75 genes, as set forth in claims 109 and 116.
It would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified Keup to include more genes and more variations at least because Keup concludes the article stating “more comparative research needs to be done, focusing on other [breast cancer] BC subtypes and also on other BC relevant genes to further emphasize the advantages of deep sequencing of cfDNA for BC therapy management”, thus explicitly suggesting to do so.
Keup et al. and Weiner et al.
Claims 84-85, 87, 94, 97, 104, 106-109, and 112-119 are rejected under 35 U.S.C. 103 as being unpatentable over Keup et al (Cellular and Molecular Life Sciences, 2020, 77:497–509, of record) in view of Weiner et al. (BioTechniques, 2008, 44:5, 701-704, of record).
Keup is relied on as above. However, it is noted that the reference is silent regarding the limitation of a kit for detecting a variation in a sample, comprising the polynucleotide library of claim 84, instructions for use of the kit, and packaging configured to hold and describe contents of the kit, as set forth in claim 97.
However, Weiner teaches utilizing kits and includes protocols for use along with packaging material for the kit’s contents (Col. 2, para. 1, pg. 701).
It would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified Keup to incorporate the teachings of Weiner to package libraries taught by Keup as taught by Weiner because “as new techniques and technologies become popular, they drive the market to produce kits to make these methods readily available to researchers” (Col. 1, para. 2, pg. 703). Also, “all in all, kits appear to have provided a selective advantage to the molecular biology field. And this they will continue to do” (Col. 1, para. 1, pg. 704).
Regarding printed instructions included as part of a kit, and in accordance with MPEP § 2111.05, while “a claim must be read as a whole, USPTO personnel may not disregard claim limitations comprised of printed matter ... [h]owever, USPTO personnel need not give patentable weight to printed matter absent a new and unobvious functional relationship between the printed matter and the substrate”, citing In re Lowry, 32 F.3d 1579, 1583-84, 32 USPQ2d 1031, 1035 (Fed. Cir. 1994). In MPEP § 2111.05(I)(B), citing In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864, it is noted that “in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals”. Therefore, in the instant claim, the recited instructions do not distinguish over the prior art as instantly applied.
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since the inclusions of instructions and packaging is extremely common practice.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEREMY FLINDERS whose telephone number is (571)270-1022. The examiner can normally be reached M-F 10-6:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on (571)272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEREMY C FLINDERS/
Primary Examiner, Art Unit 1684