Detailed Action
► The applicant's response (filed 03 DEC 2025) to the Office Action has been entered. Following the entry of the claim amendment(s), Claim(s) 1-27 is/are pending. Rejections and/or objections not reiterated from the previous office action are hereby withdrawn. The following rejections and/or objections are either newly applied or reiterated. They constitute the complete set presently being applied to the instant application.
► The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejection(s) under 35 U.S.C. 103
► Claim(s) 1-4 and 9-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Diehn et al. [US 2016/0032396 — hereinafter “Diehn”] in view of Lee et al. [Nucleic Acids Research 39(19) :e127 (2011) — hereinafter “Lee”].; Wen et al.[Cancer Research 25:1250-1264 (2015) — hereinafter “Wen“] Vaca-Paniagua et al. [Epigenomics 7(3) :353 -362 (2015) - hereinafter “Vaca”] and Snyder et al. [Cell 164:57-68 (2016) -hereinafter “:Snyder”] for the reason(s) of record.
► Claim(s) 5-7 rejected under 35 U.S.C. 103 as being unpatentable over Diehn in view of Lee and/or Wen and/or Vaca as applied above against Claim1 and further in view Sparks et al. [US 2009/0239764 - hereinafter "Sparks"] and Takai et al. [Scientific Reports 5:18425: 10 pgs (2015) - hereinafter "Takai"] and/or Fodor et al. [US 2001/0053519 - hereinafter "Fodor"] for the reason(s) of record.
► Claim(s) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Diehn in view of Lee and/or Wen and/or Vaca as applied above against Claim 1 and further in view de Vooght et al. [Clinical Chemistry 55(4) :698-708 (2009) - hereinafter "de Vooght"] and Sheng.| BBRC 292:422-426 (2002) - hereinafter "Sheng"] for the reason(s) of record.
Response to Applicant’s Amendment / Arguments
► As regards Claim 1 , the only independent Claim recited, the applicant begins their traversal arguing that there is no motivation to make the combination proposed by the examiner. The applicant argues that the prior art is directed to “standalone” methods which focus on a single -type of biomarker (e.g. SNV profiles – Diehn and/or methylation profiles - Lee, Wen and/or Vaca) and emphasize the advantages of their focused approaches. Also, the applicant asserts that the prior art fails to teach the combined approach advocated by the applicant’s claimed invention. Finally the applicant argues that there is no teaching in the prior art that would have motivated the POSA to make the modification proposed by the examiner In response the examiner agrees, in part, that each of the prior art references tend to focus on the standalone approaches disclosed thereby, In addition, the examiner concedes there is no expressed teaching present in the prior art that would have directly motivated the POSA to make the modification proposed. However, the examiner notes that the standard for obviousness as reiterated in KSR v. Teleflex does not preclude the propriety of the rejection(s) outlined in the Non-Final Office Action mailed 04 SEP 2025.
Obviousness standard
The Supreme Court decision in KSR International. Co. v. Teleflex, Inc., et al., 550 U.S.398 (2007) modified the established test for obviousness under 35 U.S.C. § 103. Before KSR, jurisprudence generally required a teaching, suggestion, or motivation to support a combination or modification of cited art (i.e. the TSM test) in an obviousness determination. After KSR, the TSM test is still insightful, but because it is too rigid, a broader, more flexible standard is proper. KSR did not alter the fundamental principles of obviousness.
The Supreme Court in the KSR decision identified four specific errors in applying the TSM test. Extrapolating from these errors, KSR provides the following guidance:
1. In searching for a reason to combine/modify elements of cited art, it is permissible for an Examiner to look not only to the problem to be solved by the inventor, but also at any known problem or need for the combination/modification.
2. One of ordinary skill in the art may be led by art other than that which solves the problem at hand.
3. A claim can be obvious merely because the combination/modification was obvious to try.
4. Common sense, whether guided by hindsight or not, properly plays a role in an obviousness analysis. In the KSR decision, common sense is mentioned five times.
The Supreme Court in its KSR decision, also made clear that “the combination of familiar elements according to known methods was likely to be obvious when it did no more than yield predictable results.
The Patent and Trademark Office (PTO), through the Examiner, has the burden ofestablishing a prima facie case of obviousness. In re Fine, 837 F.2d 1071, 5 U.S.P.Q.2d1596, 1598 (Fed. Cir. 1998). To satisfy this burden, the PTO must set forth a prima faciecase of obviousness under any one of the rationales identified by the Supreme Court inKSR International Co, v. Teleflex, Inc. (550 U.S. 398) (2007). Such rationales can befound in MPEP § 2143, and include:
1) Combining prior art elements according to known methods to yield predictableresults;
2) Simple substitution of one known element for another to obtain predictable results;
3) Use of known technique to improve similar devices (methods, or products) in the same way;
4) Applying known technique to a known device (method, or product) ready for improvement to yield predictable results;
5) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
6) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if variations are predictable to one of ordinary skill in the art;
7) Some teaching, suggestion, or motivation in the prior art [including the references themselves and/or the knowledge generally available to one of ordinary skill in the art] that would have led one of ordinary skill in the art to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. (TSM Test)
In addition, to the rationales set forth above, the obviousness analysis must comply with the statutory scheme as explained by the Supreme Court in Graham v. John Deere Co., 383 U.S. 1, 17 (1966), namely, consideration must be given to: (1) the scope and content of the prior art, (2) the differences between the prior art and the claimed invention, (3) the level of ordinary skill in the pertinent art, and (4) additional evidence, which may serve as indicia of non-obviousness. An excellent summary of how the prior art must be considered to make a case ofprima facie obviousness is contained in In re Ehrreich et al., 220 U.S.P.Q. 504, 509-511(CCPA 1979). There the court states that a reference must not be considered in avacuum, but against the background of the other references of record. It is stated that thequestion of a §103 case is what the reference(s) would "collectively suggest" to one ofordinary skill in the art. However, the court specifically cautioned that the Examiner mustconsider the entirety of the disclosure made by the reference and avoid combining themindiscriminately.
In finding that the "subject matter as a whole" would not have been obvious inEhrreich the court concluded: The test is whether the claimed invention as a whole, in light ofall the teachings of the references in their entireties, would have been obvious to one of ordinary skill in the art at the time the invention was made."
Claim Interpretation - Attention is directed to MPEP 904.01.
The breadth of the claims in the application should always be carefully noted; that is, the examiner should be fully aware of what the claims do not call for, as well as what they do require. During patent examination, the claims are given the broadest reasonable interpretation consistent with the specification. See In re Morris, 127 F.3d 1048, 44 USPQ2d 1023 (Fed. Cir. 1997). See MPEP § 2111 - § 2116.01 for case law pertinent to claim analysis.
Narrowing limitations found in the specification cannot be inferred in the claims where the elements not set forth in the claims are linchpin of patentability. In re Philips Industries v. State Stove & Mfg. Co, Inc.., 186 USPQ 458 (CA6 1975). While the claims are to be interpreted in light of the specification, it does not follow that limitations from the specification may be read into the claims. On the contrary, claims must be interpreted as broadly as their terms reasonably allow. See Ex parte Oetiker, 23 USPQ2d 1641 (BPAI, 1992).
The applicant argues, in part, because Diehn focuses entirely on identifying somatic mutations associated with cancer (i.e, residual disease detection) while Lee, Wen and Vaca focus on methylation profiling there would have been no motivation to combine these two approaches into a single standalone method . The examiner respectfully disagrees, to the contrary, the POSA would have been motivated to combine these two assays into a single assay to expand the universe of potential biomarkers capable of identifying residual disease - common sense.
The applicant then points to “fundamental technical incompatibilities”, that is - Diehn’s focuses on a patient personalized approach(es) while Lee, Wen and Vaca use a more general methylation profiling approach. The applicant argues that combination of the two would not have been be obvious because there was no problem taught by the prior art that would have required this specific combination. As noted above the TSM test in an obviousness determination, after KSR is still insightful, but because it is too rigid, a broader, more flexible standard is proper. the combination of familiar elements according to known methods was likely to be obvious when it did no more than yield predictable results.
The applicant further argues that one of the “fundamental technical incompatibilities” inherent to the methylation profiling taught by Lee, for example, comprises a harsh chemical treatment (i.e. bisulfite treatment) that fragments and degrades DNA causing significant loss of precious input cfDNA. In response the examiner notes that while the methods of Lee, and Wen require bisulfite treatment, methods of sequencing DNA omitting this harsh chemical step were known, consider Vaca and/or Timp et al. [US 2011/0226623 – hereinafter Timp], see at least para 74 and Claims 1 and 8-9.
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Finally, the applicant argues that designing a multi-functional panel as claimed, is not a trivial task and that a PHOSITA would have understood that optimizing a panel for capturing mutational hotspots as taught by Diehn is a different task from targeting genes or genomic regions which are both CpG islands and differentially methylated regions.. A PHOSITA would not have had any motivation to modify the personalized panel from Diehn in such a way as to achieve the distinct features required by the sequencing panel of claim 1. The examiner concedes this point, in part, and agrees with the applicant that designing a multi-functional panel as claimed is not a trivial task. However, the examiner assert that the prior art, when considered as a whole, would have reasonably suggested the claimed invention. Lee clearly teach a panel of capture probes capable of enriching differentially methylated CpG island sequence and sequencing the enriched population of cfDNAs while Diehn clearly teach enriching and sequence analysis of enriched cfDNA which analysis reports the presence or absence of residual disease. The examiner finds the combination of these two assays into a single standalone assay would have been obvious to the POSA in order to screen for as many residual disease biomarkers as possible in a single assay. (i.e. preferably all known biomarkers indicative of residual disease at the time of the invention)..
Conclusion
C1. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. § 1.136(a).
A SHORTENED STATUTORY PERIOD FOR RESPONSE TO THIS FINAL ACTION IS SET TO EXPIRE THREE MONTHS FROM THE DATE OF THIS ACTION. IN THE EVENT A FIRST RESPONSE 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 C.F.R. § 1.136(a) WILL BE CALCULATED FROM THE MAILING DATE OF THE ADVISORY ACTION. IN NO EVENT WILL THE STATUTORY PERIOD FOR RESPONSE EXPIRE LATER THAN SIX MONTHS FROM THE DATE OF THIS FINAL ACTION.
C2. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ethan Whisenant whose telephone number is (571) 272-0754. The examiner can normally be reached Monday-Friday from 8:30 am -5:30 pm EST or any time via voice mail. If repeated attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Anne Gussow, can be reached at (571) 272-6047.
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/ETHAN C WHISENANT/Primary Examiner, Art Unit 1683 ethan.whisenant@uspto.gov