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 .
This action is in response to applicants correspondence mailed 07/31/2025. The amendment to the claims mailed 07/31/2025 has been entered.
Claim Status
Currently, claims 1, 7-11, 17-28 are pending in the instant application. Claims 2-6, 12-16 have been canceled. Claims 1, 7-11 has been amended while claims 21-28 have been added and claims 7-11, 18, and 21-28 are withdrawn. This action is written in response to applicant’s correspondence submitted 11/24/2025. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant’s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. This action is Final.
Election/Restrictions
Applicant elected the single position, cg23229261 in the response filed 07/31/2025. The claims have been amended to require both cg23229261 and cg10122865. While the claims do not require on the elected species, in the interest of compact prosecution and because the combination requires the previously elected species the claims are being examined for requiring both cg23229231 and cg10122865 only.
Newly submitted claims 21-28 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: claims 21-28 require detection reagents for PAK1. PPFIA1, and ZNF397OS gene. These genes do not share a special technical feature over the prior art of Wu, Wu teaches DNA methylation markers and reagents on 450K Illumina array, which comprises genes and methylation sites. Each of the species are known in the art and does not contribute a special technical feature. None of these genes were elected in the restriction requirement mailed 06/05/2025
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 21-28 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Currently claims 1, 17, and 19-20 are under examination with respect to OTX1 and cg23229261 and cg10122865.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 for CN20211288235.7
Withdrawn Rejections
The improper Markush grouping of claim 1 has been withdrawn in view of the amendment to the claim to require the combination of cg23229261 and cg10122865.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 17, and 19-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a law of nature. This judicial exception is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. This rejection was previously presented and has been rewritten to address the amendment to the claims.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? Yes, all of the claims are directed to a composition of matter.
Step 2. Is the claim directed to a law of nature, a natural phenomenon or an abstract idea (judicially recognized exception) and does the claim recite additional elements that integrate the judicial exception into a practical application?
The claims are drawn to a composition of matter, which is a law of nature. Claim 1 recites reagent combination for detecting liver cancer comprising a detection reagent for detecting methylation level at methylation site of OTX1 and cg23229261 and cg10122865. Claim 17 requires a reagent for extracting plasma cell-free DNA. Claim 19 requires a kit comprising the reagent combination and claim 20 requires the kit comprising reagent for extracting nucleic acid, purifying nucleic acid, bisulfite, T4 polymerase kinase and T4 ligase. The recitation of any reagent, primer or probe includes naturally occurring sequence. The recitation of an enzyme and reagents include naturally occurring sequences.
The specification does not specifically define detection reaction. The specification states that detection reagent refers to a reagent for detecting methylation level of a gene in a sample wherein methylation level is detected by amplification sequencing, chip, and methylation fluorescence quantitative PCR (see pg. 9 continued to pg. 10). The specification and claims further include that detection reagents include nucleic acid primer and probe. There is no recitation within the claims that indicate that the reagents claimed have any structural or functional characteristics that differ from naturally occurring nucleic acids because the broadest reasonable interpretation of a reagent includes a probe or primer that comprises nucleotide sequences. Additionally the recitation of methylation chip does not structurally change the naturally occurring sequence because there is no definition requiring how a primer or probe is immobilized. The primer or probe can be transiently immobilized without changing any structural characteristics. Thus the claims encompasses naturally occurring nucleic acids. There is no indication in the specification that the nucleic acids claimed here have any structural or functional characteristics that differ from the naturally occurring nucleic acids. Additionally the claims reciting a kit comprise naturally occurring nucleic acids and the recitation of kit, does not result in a structure that is markedly different than the naturally occurring nucleic acid sequence because the kit convey the same nucleic acid sequence. The claimed kit comprising reagents include nucleic acids and enzymes that do not display markedly different characteristic compared to the naturally occurring counterpart.
The claimed reagents include nucleic acids that do not display markedly different characteristic compared to the naturally occurring counterpart and there is no indication that the reagent combination or kit comprising reagents, primers or probes results in changing the structure, function or other properties of the naturally occurring nucleic acid. According the reagent combination and kit encompasses nucleic acids and enzymes are a product of nature exception and the claim is directed to at least one exception. This judicial exception is not integrated into a practical application because the claims encompass nucleic acid sequences as reagents including probes or primers that are naturally occurring and the probes and primers detect naturally occurring sequences. The recitation of probe or primer is nothing more than an attempt to generally link the product of nature to a technological environment and is a nominal extra solution component of the claim and does not structurally change the nucleic acid sequence. Many cited prior art references in this record demonstrate the probes and primers are naturally occurring sequences. Feber (US2018/0305765 A1) and Zhang (WO2019/071161 A1) teaches reagents including probes for cg23229261.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? No.
Herein the claims as a whole are not considered to recite any additional elements that amount to significantly more than the naturally occurring nucleotide sequences. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Besides the nucleic acids, the claims recite reagents for extracting or purifying DNA and include a kit in the preamble. At the time the invention was made, a kit or combination of reagents was well-established, routine and conventional. Additionally reagents for extracting or purifying DNA broadly encompass water, salt, buffer, or nucleic acid probes all of which are naturally occurring and there is no recitation within the claim that results in markedly different structure that the naturally occurring components. Additionally where a composition such as a kit is recited at such a high level of generality it does not meaningfully limit the claim. The recitation of chip does not structurally change the nucleic acid sequence is not significantly more than the naturally occurring sequence. Thus the claims as a whole does not amount to significantly more than each “product of nature” by itself and the claims do not qualify as eligible subject matter.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection on pages 2-4 of the remarks mailed 11/24/2025. The response asserts that the detection target is an artificially defined functional fragment not a naturally existing undifferentiated genetic region. The response asserts the claims require a liver cancer specific region and fragment boundaries and detection scope covering cg23229261 and cg10122865 with artificially delineated requiring capture by specific primers for detection. The response asserts that this complies with patent eligible subject matter under MPEP 2106.04 natural law + technical application. This response has been reviewed but not found persuasive. The claims are to a product not a method and there are not limitations recited within the claim that are result in a structurally different sequences than naturally occurring sequence. MPEP 2106.02 (II), product of nature are considered to be exception because they tie up the use of naturally occurring things sequence. The instant claims recite a nature based product that does not have markedly different characteristics from its naturally occurring counterpart and is a product of nature. The technical application recited in the preamble is an intended use and does not result in a markedly different characteristic from the primer and probes of the reagent and the recitation further encompasses a field of use limitation and does not result in patent eligible subject matter.
The response asserts the detection reagents are artificially modified non-natural products excluding natural nucleic acids. The response asserts the nucleic acid primer must be adapted to bisulfite converted sequence, the sequence tag comprises P5/P7 adapters, methylation chip comprises probes to bind methylated sequences, and the nucleic acid probes must carry fluorescence labels to distinguish methylated and unmethylated sequences. The response asserts the limitation of “Adapting to the fragment set forth in SEQ ID NO 2” the amended claims exclude natural nucleic acids and asserts the reagent combination constitutes a complete clinical detection workflow rather than isolated natural products. The response asserts the reagent combination is a complete technical workflow servicing cfDNA liver cancer detection. This response has been reviewed but not found persuasive. The claims are not directed to methods but are directed to products. The claims do not recite any of the asserted limitations of the primer, probe, sequence tag, or methylation chip. The broadest reasonably interpretation of primer, probe, and sequence tag is a sequence that is capable of detection a methylation level of cg23229261 and cg10122865. The primer, probe or sequence tag is not required to comprise any specific sequence but merely be capable of detection of positions cg23229261 and cg10122865. Additionally the claim does not limit the number of nucleotides required for the reagent and any probe or primer sequence of any length can be included. As such there are many naturally occurring sequences that fall within the limitation of a probe or a primer that is capable of detecting methylation of cg23229261 and cg10122865. The claims do not require a specific sequence nor do the claims require a specific sequencing tag sequence or require any label on the reagent. As such the broadest, reasonable interpretation of the claimed reagent encompass naturally occurring sequences. For these reasons and reasons of record this rejection is maintained.
Claim Rejections - 35 USC § 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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 17, and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (WO2019/071161 A1). This rejection was previously presented and has been rewritten to address the amendment to the claims.
With regard to claim 1 and 16, Zhang teaches cg23229261 (see pg. 288). Zhang teaches the Illumina 450k methylation array. The 450K array comprising probes for both cg23229261 and cg10122865. This bead chip comprises probes for methylation detection including cg23229261 (see para 287 and 365). The 450k methylation array comprises detection reagents for detection cg23229261 and cg10122865. Thus the Illumina 450k is a methylation chip is a reagent that will detect both cg23229261 and cg10122865. The methylation array comprises probes and is a methylation chip. Zhang teaches cfDNA methylation and liver disease including cancer (see para 132).
With regard to claim 17 and 19-20, Zhang teaches kit comprises primers or probes to detect methylation status. Zhang teaches the kit comprises reagents including sodium bisulfite, probes, primers (see para 180). Zhang teaches the kit includes a buffering agent, nucleic acid stabilizing agent(See para 185) (reagent for extracting plasma cell free DNA).
Claims 1, 17, and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feber (US20180305765A1). This rejection was previously presented and has been rewritten to address the amendment to the claims.
With regard to claim 1, Feber teaches cg23229261 and probe for detecting (see table 1, para 267). Feber teaches the Illumina 450k methylation array. This bead chip comprises probes for methylation detection including cg23229261 and cg10122865 (see para 126). The 450k methylation array comprises detection reagents for detection cg23229261 and cg10122865. Thus the Illumina 450k is a methylation chip is a reagent that will detect both cg23229261 and cg10122865. The methylation array comprises probes and is a methylation chip.
With regard to claim 17 and 19-20, Feber teaches kit comprises arrays that comprise probes to detect methylation status. Feber teaches the kit comprises reagents including sodium bisulfite and probes (see para 203-205). Zhang teaches the kit includes reagents for amplifying DNA (See para 185). The claim does not indicate a specific reagent for extracting plasma cfDNA and a reagent for amplifying DNA can be used for extracting plasma cell free DNA, including buffers and primers.
Response to Arguments
The response traverses the rejections under 35 USC 102 on pages 4-5 of the remarks mailed 11/24/2025. The response asserts that Zhang fails to mention the fragment set forth in SEQ ID NO 2 where the site of cg23229261. The response further asserts that single site detection and fragment average methylation detection are completely distinct. This response has been thoroughly reviewed but not found persuasive. The claims recite a product, a detection reagent for detection the methylation level of the fragment set forth in SEQ ID NO 2 wherein methylation level is determined by detecting the methylation levels of cg23229261 and cg10122865. The recitation of for detecting the methylation levels and wherein the methylation is determined by detecting the levels of cg23229261 and cg10122865 is intended use and does not result in any structural requirements of the reagent other than to be capable of detecting methylation level of SEQ ID NO 1. The Illumina 450k methylation array as disclosed by Zhang is capable of detecting levels of cg23229261 and cg10122865 as it comprises probes for these positions and therefore is capable of detecting the methylation level of SEQ ID NO 2. Furthermore the only structural limitation required for the claimed reagent is that it consists of a nucleic acid primer, probe, sequence tag, or methylation chip. The Illumina 450k is a methylation chip and comprises probes for positionscg23229261 and cg10122865.
The response asserts that Feber only discloses a probe for cg23229261 on Illumina 450k chip. The response asserts that the probes of this chip target random genome-wide sites and not associated with fragment set forth in SEQ ID NO 2 of the OTX1 gene. The response further asserts that neither Zhang nor Fever disclose the detection reagent combination adapted to SEQ ID No 2. This response has been reviewed but not found persuasive. As addressed above, the Illumina 450k array comprises probes for both cg23229261 and cg10122865 and therefore has the ability to detect methylation of SEQ ID NO 2. The claims do not require a probe that comprises or consists of SEQ ID NO 2, the claim only requires a reagent capable of detecting methylation of SEQ ID NO 2 using cg23229261 and cg10122865, which is disclosed by both Zhang and Fever.
The response further addresses that the Zhang does not teach sequence tags. The response asserts that Febers kit only includes sodium bisulfite and probe chips, wherein the probe chips are universal and lack tag sequences. The response addressed the amended claim 1 as not being obvious over the cited art. The response continues to argue that the combination of Tag sequences, nucleic acid primers and methylation chips
The claims do not require probes with a sequence tags, the claims recite the detection reagent is any one or more selected from the group consisting of, which requires only one of the recited reagents, Zhang and Feber both teach a primer, probe and methylation chip. Additionally the methylation chip comprises two probes and is a reagent that will detect both methylation sites and therefore detect the level of SEQ ID NO 2.
The response addresses the sample and specificity of the detection reagents pointing to example 6 of the specification, however the claims are directed to a reagent and not a method and the sample and specificity does not result in a structural difference of the product claimed. As such Zhang and Feber anticipate the claimed invention. For these reasons and reasons of record the rejection is maintained.
New Grounds of Rejection, Necessitated by Amendment to the Claims
Claim Rejections - 35 USC § 112
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 1, 17, and 19-20rejected 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 1 recites a reagent combination for detecting a liver cancer comprising the following detection reagents: a detection reagent for detection the methylation level of the fragment set forth in SEQ ID NO 2 in the OTX1 gene wherein the methylation level of the fragment set forth in SEQ ID NO 2 is determined by detecting the methylation level of at least the following methylation sites: cg23229261, cg10122865. This recitation renders the claim indefinite. The limitation "the methylation level" and “the fragment set forth in SEQ ID NO 2” is recited in line 3 of the claim. There is insufficient antecedent basis for these limitations in the claim. It is unclear what methylation level is required for the reagent and what fragment is the fragment set forth in SEQ ID NO 2. Additionally the claim is directed to a product, specifically the preamble recites a reagent combination however the claim only limits a detection reagent and does not recite any reagent combinations. It is further unclear what is structural requirements of the claimed detection reagent. The structural limitations of the reagent recited within the claim requires that the reagent is either a primer, probe, sequencing Tag sequence or a methylation chip. These recitation do not require an additional reagent but further limit the detection reagent recited within the claim and not the reagent combination of the preamble. It is unclear based on the functional language of the claim what other features of the detection reagent are required. For example it is unclear if the detection reagent is capable of detecting methylation of both cg23229261 and cg10122865, if the detection reagent is capable of detection methylation of a fragment of SEQ ID NO 2 or if the detection reagent detects either cg23229261 and cg10122865, the recitation of “for detecting…cg23229261, cg10122865” renders the claim indefinite and one of ordinary skill in the art would not be apprised of the metes and bounds of the claimed detection reagent.
Conclusion
No claims are allowable.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAE L BAUSCH whose telephone number is (571)272-2912. The examiner can normally be reached M-F 9a-4p.
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, Fereydoun Sajjadi can be reached at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAE L BAUSCH/Primary Examiner, Art Unit 1699