DETAILED ACTION
Status of the Claims
Claims 1, 4-9, and 12-16 are currently pending.
Claims 2-3 and 10-11 have been canceled by Applicant.
Claims 1, 5-7, 9, 12-13, and 15 are amended.
Claims 1, 4-9, and 12-16 are the subject of the Office Action.
The following Office Action is in response to Applicant’s communication dated 01/05/2026. Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Allowable Subject Matter
Claims 1, 4-5, 9, and 12-16 are allowed.
Priority
Filing of a certified English translation of the foreign application on 01/05/2026 is acknowledged.
Claim Interpretation
As per MPEP § 2111 and § 2111.01, “[d]uring patent examination, the pending claims must be ‘given their broadest reasonable interpretation consistent with the specification’" and the words of a claim must be given their ‘plain meaning’ unless such meaning is inconsistent with the specification, wherein ‘plain meaning’ of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the relevant time. The ordinary and customary meaning of a term may be evidenced by a variety of sources, including the words of the claims themselves, the specification, drawings, and prior art. Because applicant has the opportunity to amend the claims during prosecution, giving a claim its broadest reasonable interpretation will reduce the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Yamamoto, 740 F.2d 1569, 1571 (Fed. Cir. 1984)
Below are notes made by the examiner regarding claim interpretation of the most recent set of claims.
Claim 1 requires the primer pair used to amplify the library is two single-stranded DNA molecules consisting of the full-length sequences of SEQ ID NO: 25 and 26. Sequences comprising SEQ ID NO: 25 or 26 are known in the prior art but there is no suggestion of how to or why one would truncate these oligonucleotides to arrive at primers consisting of the nucleotide sequences of SEQ ID NO: 25 and SEQ ID NO: 26. Claim 9 similarly requires the presence of single-stranded DNA molecules of SEQ ID NO: 28-402, and it is noted that not all of these sequenced were found in the prior art.
Modified Claim Rejections – 35 U.S.C. 103(a)
Necessitated by Amendments
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.
Gnerre et al. and Bonora et al.
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Gnerre et al. (U.S. PGPub 2016/0319345 A1, of record) in view of Bonora et al. (PLoS ONE, 2019, 14(4):e0214368, of record).
Note that Applicant has amended the preamble of claim 6 to include “which is used for detecting tumor mutation and/or methylation”, which is a recitation of intended use of the instantly claimed kit and a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2111.02, citing In re Sinex, 309 F.2d 488, 492, 135 USPQ 302, 305 (CCPA 1962) (statement of intended use in an apparatus claim did not distinguish over the prior art apparatus), and MPEP 2112.01 citing In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) stating that “discovery of an unobvious property and use does not overcome the statutory restraint of section 102 when the claimed composition is known”. It is also noted that the limitations regarding detection of malignant liver tumor detection in claims 7-8 are similarly recitations of intended use.
Gnerre discloses partially double-stranded adapters for ligating to DNA that has been fragmented, end-repaired, and A-tailed in making sequencing libraries (e.g., as per Fig. 2A). Gnerre discloses several variations of said adapters, all of which include an upstream primer A and a downstream primer A, wherein the upstream primer A includes an anchor sequence A at least partially base-paired with the anchor sequence B of the downstream primer A (to form a Y-shaped adapter), and wherein the upstream primer ends with a T residue for subsequent TA ligation to the fragmented DNA. Gnerre further discloses that in several of the adapters, the upstream primer A has a 5’ sequencing adapter A and the downstream primer A has a sequencing adapter B, wherein they differ for different sequencing platforms (e.g., P5 and P7 sequencing adapters as per Fig. 2A). Further, Gnerre discloses a random tag in at least one primer (e.g., a UMI as per Fig. 2A, which “includes fewer than 12 amino acids” as per para 0008) and a pair of index sequences (e.g., i5 and i7 in Fig. 2A) which vary between the different groups of n adapters. Additionally, Gnerre discloses that different adaptors may have different indexing sequences, including that “[i]n some implementations, each sequence differs from every other sequence in the set by a particular number of (e.g., 2, 3, or 4) nucleotides” (e.g., as per para 0076). Gnerre also acknowledges the difficulties with repeats of nucleotides, or so-called homopolymeric regions (e.g., as per para 0173-0175) in sequencing and aligning them.
However, it is noted that despite the several permutations presented by Gnerre, that none exactly match the ordering of parts as required by the claims. The closest adaptor is shown in Fig. 2A(iii), which differs from the claimed adaptors by the inclusion of a second random tag (e.g., UMI), however, it is noted that the claim uses the term “includes” (e.g., the upstream primer A includes a sequencing adapter A, a random tag, an anchor sequence A and a base T sequentially from the 5’ end” as per claim 1), which is inclusive or open-ended and does not exclude additional, unrecited elements or method steps, as stated in MPEP 2111.03.
Furthermore, note that as per MPEP § 2144.04(VI) the mere rearrangement of parts is prima facie obvious in the absence of new or unexpected results. Therefore, it would have been obvious to one of ordinary skill in the art to rearrange the parts of Gnerre to arrive at the presently claimed adaptors absence evidence to the contrary. In the present case, either version of the adapters would be expected to give the same results when used to create a sequencing library, since either ordering could be subsequently sequenced with no loss of information, that is, the random tag and the anchor index sequence(s) would still be sequenced and associated with their corresponding DNA fragment(s).
Also, Gnerre is silent as to the presence of a methylation sensitive restriction endonuclease, as set forth in claim 6.
Bonora discloses preparation of sequencing libraries with similar adapters to Gnerre and including a step of sample digestion using three methylation sensitive restriction endonucleases (e.g., HpaII, Hin6 and AciI as per the Material and Methods section)
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to combine the sequencing library preparation adaptors of Gnerre with the methylation sensitive restriction endonucleases of Bonorra.
In accordance with MPEP 2141 citing KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385,1395 (2007), "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results”, and as per MPEP 2143(I)(A), the rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. In the present case, all of the elements of the methylation-dependent sequencing library preparation were well known in the art, as per Gnerre and Bonorra, the mere combining of the individual elements in one embodiment in the manner of the claimed invention results in no change in the elements respective functions, and the combination yields nothing more than predictable results.
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 such combining would merely require standard molecular biology techniques that are well within reach of the skilled artisan.
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Response to Arguments
The 01/05/2026 remarks argue: not all elements are taught.
Applicant's arguments have been fully considered but they are not persuasive for at least the following reasons.
RE: “Applicant submits that the one of ordinary skill in the art would appreciate that the Gnerre and Bonora references are directed to materially different technical issues.”
In response to applicant's argument that the elements of the Gnerre and Bonora references are for other intended purposes, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
RE: “Applicant also notes that Gnerre never mentions ‘methylation’ or suggests to one of ordinary skill in the art any reason to utilize ‘methylation-sensitive restriction enzymes.’ Similarly, Applicant notes that Bonora references standard commercial adapters but does not provide any disclosure that would teach or suggest to one of ordinary skill in the art that specific modifications to the adapters' internal structure (such as the relative positions of anchor sequences and random tags) would provide any synergy or improvement in Bonora's enzyme digestion method.”
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
RE: “Applicant contends that no one of ordinary skill in the art would have derived from the references any teaching or motivation to modify Gnerre's commercial universal adapter library and specifically incorporate Bonora's enzyme digestion method to solve the ultra-high sensitivity challenge in ctDNA detection.”
In response, it is first noted that as per MPEP 2141(III), “If the search of the prior art and the resolution of the Graham factual inquiries reveal that an obviousness rejection may be made using the familiar teaching-suggestion-motivation (TSM) rationale, then such a rejection is appropriate. Although the Supreme Court in KSR cautioned against an overly rigid application of TSM, it also recognized that TSM was one of a number of valid rationales that could be used to determine obviousness.” Furthermore, in response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., the alleged “ultra-high sensitivity challenge in ctDNA detection”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
RE: “Applicant contends that one of ordinary skill in the art would understand that when Y-shaped adapters are used simultaneously with methylation-sensitive enzymes, issues such as incomplete digestion of partially double-stranded DNA, increased adapter self-ligation, and higher library failure rates are prone to occur" and “Applicant maintains, therefore, that one of ordinary skill in the art simply could not have envisioned or derived the technical solution provided in the pending claims from the teachings provided in the cited references.”
In response, it is noted that the remarks do not give any factual evidence as to why the skilled artisan could not have arrived at the claimed invention in light of these supposed technical challenges. Furthermore, it is noted that (as per claim 1) the restriction endonuclease and the adapters are to be used at differing points in the intended method, noting the presence of an end repair and adenylation step between the restriction digest and introduction of the adaptors.
RE: “Applicant contends that one of ordinary skill in the art will appreciate that one of the most significant challenges in ctDNA detection is addressing the combination of high background noise and extremely faint target signals. The complete methods as recited in the present invention (including adapter design, enzyme digestion, and subsequent nested PCR data analysis) constitute an integrated, interdependent technical solution aimed at minimizing amplification bias and sequencing errors, thereby distinguishing true biological signals from technical noise. Applicant maintains that this integration of a complete solution tailored to a specific application scenario (ultra-high sensitivity liquid biopsy) cannot be understood or derived from the disclosures of Gnerre and Bonora by one of ordinary skill in the art.”
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., the alleged “significant challenges in ctDNA detection”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
RE: “Applicant acknowledges the Office's observation that "there is no suggestion of how to or why one would truncate these oligonucleotides to arrive at primers consisting of the nucleotide sequences of SEQ ID NO: 25 and SEQ ID NO: 26. Applicant notes that these specific sequences are incorporated in claims 1, 5-8 of the present application.”
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., the primers consisting of the nucleotide sequences of SEQ ID NO: 25 and SEQ ID NO: 26) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
RE: “Applicant maintains, therefore, that the pending claims define a complete solution whose components (UMIs at specific positions, anchor sequences, enzyme digestion, nested PCR, duplex analysis) work synergistically and are inseparable” and “Applicant maintains that this solution constitutes an unexpected result that could not be achieved by one of ordinary skill in the art simply by combining the teachings of the applied prior art references.”
This is not found persuasive because the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”) (see MPEP 2145 I.) In the instant case, Applicant’s counsel argues unexpected synergy in the claimed arrangements, however counsel does not provide objective evidence establishing this as a fact.
Conclusion
Claims 1, 4-5, 9, and 12-16 are allowed.
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 extension fee 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 date of this final action.
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.
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/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684