DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Arguments
2. Claims 1-7, 9 and 10 are pending.
Claims 1-6, drawn to a non-elected invention is withdrawn from examination.
Claim 8 has been cancelled.
Claims 7, 9 and 10 are examined on the merits with species (molecule detected): d. gene encoding interleukin 29 (IL-29).
3. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 112
4. The rejection of claim 8 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of the cancellation of the claim, see Amendments to the Claims submitted February 3, 2026.
5. Claim 8 no longer recite limitations, whereby there were insufficient antecedent basis for the former limitations in the claim, see Amendments to the Claims submitted February 3, 2026.
Claim Rejections - 35 USC § 101
6. Cancelled claim 8 is no longer directed to non-statutory subject matter, see Amendments to the Claims submitted February 3, 2026.
Claim Rejections - 35 USC § 102
7. The rejection of claim(s) 7 under 35 U.S.C. 102(a)(2) as being anticipated by Lee et al., US 2019/0317098 A1 (effective filing date November 24, 2017/ IDS reference #2 submitted September 26, 2024) is withdrawn in light of arguments submitted February 3, 2026, paragraph (para.) bridging pages 5 and 6. Claim 8 has been cancelled.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
8. 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.
9. The rejection of claim(s) 7, 9 and 10 under 35 U.S.C. 103 as being unpatentable over Lee et al., US 2019/0317098 A1 (effective filing date November 24, 2017/ IDS reference #2 submitted September 26, 2024), and further in view of Delmonica et al., (Int. J. Mol. Sci. 4894: 1-21, published 2 October 2019) and Macherey-Nagel. RNA from blood User manual: NucleoSpin® RNA Blood NucleoSpin® RNA Blood Midi, (pages 1-30, Rev. 05, September 2017) is maintained. Claim 8 has been cancelled.
Applicant states the limitations of claim 7 and emphasize the wherein clause, “wherein the blood sample is a blood-derived buffy coat.”, see the Remarks submitted February 3, 2026, paragraph (para.) bridging pages 5 and 6.
Applicant argues primary reference, “Lee… does not describe using a "blood-derived buffy coat" as the blood sample for detection as required by Claim 7, and Lee et al. does not describe the buffy coat as the "whole white blood cell layer formed between the upper plasma layer and the lower red blood cell layer following centrifugation," which is the buffy coat expressly
defined in the instant specification. The Office's statement that “mononuclear cells are art known to be derived from the buffy coat" does not cure the deficiency because Claim 7 requires that the blood sample itself is a blood-derived buffy coat, not that a mononuclear cell fraction is isolated from blood and then analyzed. In addition, the instant disclosure distinguishes buffy coat from PBMC of Lee et al[.], explaining that buffy
coat is a distinct, whole white blood cell layer and is not synonymous with PBMC. When the claims are read in light of the specification, Lee et al. fails to disclose the claimed sample type and thus fails to disclose an essential limitation of Claim 7.
Applicant also respectfully traverses the rejection of Claims 7-10 under 35 U.S.C. § 103 over Lee et al. in view of Delmonica et al. and the Macherey-Nagel RNA from blood user manual. Lee et al. allegedly teaches diagnosing pancreatic diseases by measuring IL-29 (and related markers) in mononuclear cells or exosomes isolated from blood, serum, or plasma. Lee et al. therefore directs the skilled person toward isolating a particular subpopulation (mononuclear cells) or isolating exosomes, rather than analyzing a whole buffy coat layer. In contrast, Claim 7 requires the detection step be performed in a blood-derived buffy coat.
On the other hand, Delmonico et al. describes an 80-gene expression workflow in a circulating tumor cell (CTC) detection context and characterizes blood, including buffy coat, primarily as a background/control matrix rather than as a diagnostic specimen from which disease-specific leukocyte biomarkers are read out. In particular, Delmonico et al. reports buffy-coat measurements from non-cancer cases ("blood sample (buffy coat)" from "cases with conditions other than cancer") in its experimental validation (Delmonico et al., Fig. 2(d); §2.4), and explains that its spiking experiments dilute RNA from breast cancer cell lines (e.g., MDA-MB-231 and BT-474) into pooled RNA derived from buffy coats obtained from individuals with conditions other than cancer to test a hypothetical ability to detect CTCs "among the global blood cells" (Delmonico et al., §2.5; §4.7.3; §4.7.5; Fig. 3)”, see pages 6 and 7.
Applicant further asserts “Delmonica et al. therefore does not teach, suggest, or motivate using buffy coat as a diagnostic specimen from a pancreatic cancer subject for measuring IL-28 and/or IL-29 as claimed, and instead uses buffy coat as a non-cancer reference background or as a matrix for spiking experiments. Put differently, Delmonica et al. does not provide a reason to modify Lee et al.'s specifically taught mononuclear-cell/exosome approach by substituting in a buffy coat sample for the diagnostic measurement step in a pancreatic cancer assay.
Moreover, even if one were to assume that buffy coat preparation techniques were generally known, the present disclosure provides evidence that the claimed selection of buffy coat as the diagnostic sample yields unexpected and advantageous results compared with the PBMC approach reflected in Lee et al. The instant examples and figures demonstrate that, when IL-29 and IL-28 are analyzed in PBMC samples, there is no significant difference between pancreatic cancer patients and normal controls, whereas a remarkable expression difference is observed in buffy coat samples. The disclosure further explains that, taken together, more reliable diagnostic information can be obtained from buffy coat than from PBMC. These results are not suggested by Lee et al. or Delmonica et al., and they rebut any asserted reasonable expectation of success for replacing Lee et al.'s mononuclear cell sample with a buffy coat sample. The claims therefore are not a predictable use of prior art elements according to their established functions, but instead reflect a nonobvious selection of sample type that provides a demonstrably superior diagnostic signal.”, see pages 7 and 8 of the Remarks.
Applicant’s arguments and points of view have been carefully considered, but fail to persuade.
As Applicant is fully aware, “[t]he key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "‘[R]ejections on obviousness cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.’" KSR, 550 U.S. at 418, 82 USPQ2d at 1396. See also Adapt Pharma Operations Ltd. v. Teva Pharms. USA, Inc., 25 F.4th 1354, 1365, 2022 USPQ2d 144 (Fed. Cir. 2022) (stating that a determination of obviousness "requires ‘identify[ing] a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does’" (quoting KSR, 550 U.S. at 418, 82 USPQ2d at 1395).”, see MPEP 2141, III.
Lee teaches one of ordinary skill in the art can simply and rapidly diagnose pancreatic cancer “…through a non-invasive method by using monocytes obtained from blood,” with the assessment of interleukin 29, see abstract; page 2, sections 0010 and 0011; and entire document. Blood samples from pancreatic cancer patients were collected for measurement of expression levels of IL-29, see pages 3, 4, 7 and entire document.
While Applicant attempts to dissuade one of the importance of Delmonico, as well as the alleged lack of impetus to arrive at a whole blood-derived buffy coat as taught by Delmonico. It is art known that circulating tumor cells (CTCs) are present in the bloodstream. One of ordinary skill in the art would be motivated to utilize the blood samples of Lee with the NucleoSpin® RNA Blood method taught in Delmonico to arrive at the buffy coat containing the main source of candidate biomarkers in whole blood, teeming with an increased concentration of rare and distinguishing CTCs, see all references.
“Obviousness does not require absolute predictability of success…all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988)). Applicant has no evidence to rebut the reasonable expectation of success suggested by the combination of prior art.
This modification of the primary reference in light of the secondary reference is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981).
It would not have been unexpected for the claimed invention to achieve the advantages argued by Applicant. Furthermore, Applicant has not presented evidence establishing the properties/functions/characteristics of the claimed invention and the combination of the prior art references differ to such an extent that any differences are unexpected.
The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.
Lee teaches “…a method of providing information for diagnosing… diseases such as pancreatic diseases,”…by measuring the mRNA of genes that encode interleukin 29 (IL-29), see page 1, section 0008; page 5, section 0051; and page 10, section 0122. “As used herein, the term “interleukin 29 (IL-29)”, which is also called “interferon lambda-1”, refers to a protein encoded by interleukin 29 gene located on chromosome 19, belongs to the helical cytokine family, and corresponds to type III interferon.”, see page 3, section 0027.
“[T] mRNA of the gene encoding the protein may be present in a biopsy specimen, preferably blood, serum or plasma isolated from a target subject, and more preferably a mononuclear cell or exosome isolated from the blood, serum or plasma.”, see page 3, sections 0029 and 0031; and page 12, Example 3. Mononuclear cells are art known to be derived from the buffy coat.
“As used herein, the term “measurement of expression levels of mRNA” refers to a process of detecting the presence of mRNA of genes encoding the … interleukin 29, … and the expression level thereof in biological samples in order to diagnose diseases including pancreatic cancer of the present invention, and means measurement of the amount of mRNA. The analysis methods for measurement of expression levels of mRNA include, but are not limited to, reverse transcription polymerase chain reaction (RT-PCR), competitive reverse transcription polymerase chain reaction (competitive RT-PCR), real-time RT-PCR, RNase protection assay (RPA), northern blotting, DNA chips and the like.”, see page 4, section 0039.
Lee teaches “when the expression level of the interleukin 29 or mRNA of the gene encoding the interleukin 29 measured from the biopsy specimen isolated from a target subject is higher than that of the normal control group, the likelihood of the onset of a disease, particularly, a pancreatic disease, is determined to be high. More preferably, when the expression level measured from the biopsy specimen isolated from a target subject is at least 2 times, at least 3 times, at least 4 times, at least 5 times or at least 6 times the expression level in the normal control group, the likelihood of the onset of a pancreatic disease is determined to be high.”, see page 7, section 0076; and section 0110 and corresponding Figure 7.
“In addition, [Lee teaches], when the expression level of the mRNA of the gene encoding the interleukin 29 measured from the biopsy specimen isolated from the target subject is 2 to 15 times, 2.5 to 15 times, 3 to 13 times, 3.5 to 13 times, 4 to 13 times, or 4 to 10 times that in the normal control group, the likelihood of onset of a pancreatic disease, particularly pancreatic cancer, is determined to be high.”, see page 8, section 0078.
Lee does not explicitly teach the claimed method, wherein the blood-buffy coat is a whole white blood cell layer formed between the upper plasma layer and the lower red blood cell layer following centrifugation and is obtained by forming an upper plasma layer, a medium buffy coat layer, and a lower red blood cell layer upon centrifugation under at least one selected from the following conditions (1) to (3) and isolating the medium buffy coat layer:
(1) temperature: 2 to 30°C;
(2) speed: 300g to 2000g; and
(3) duration time: 5 to 20 minutes.
Furthermore, Lee does not explicitly teach the claimed method, wherein the buffy coat is obtained by forming an upper plasma layer, a medium buffy coat layer, and a lower red blood cell layer upon centrifugation under at least one selected from the following conditions (1) to (3) and isolating the medium buffy coat layer:
(1) temperature: 4 to 25°C;
(2) speed: 500g to 1800g; and
(3) duration time: 7 to 20 minutes.
However, Delmonico teaches “…[identifying] genes with higher expression in solid tumor cells by comparing human tumor biopsies with healthy blood samples…”, as well as matched samples from patients with a range of solid cancers including pancreatic cancer, see Abstract on page 1; segment 4.7.6 on page 16; and the entire document. Buffy coats were derived and isolated from the blood samples and “RNA… was extracted was extracted using the NucleoSpin® RNA Blood Kit (Macherey-Nagel, Düren, Germany), according to the manufacturer’s protocol.”, see Figure 2 caption and segment 2.5 on page 7; Table 1 caption on page 15; and segments 4.7.3. and 4.7.6 on page 16.
The Macherey-Nagel User manual teaches the manufacturer’s protocol, isolating RNA from blood utilizing centrifugation at room temperature (18 – 25 °C), at speeds ranging from of approximately 2,000g-11,000g with duration times ranging from seconds up to 10 min., see entire manual.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references to follow one of the NucleoSpin® RNA blood isolation protocols with referenced in Delmonico and set forth in the user manual to arrive at the different and distinct layers with centrifugation and isolate the buffy coat layer to identify and sample the mRNA encoding IL-29 from a subject’s blood sample, see all documents in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all the references and in particular, Delmonico, “[b]lood sampling has advantages over solid biopsy, as it is widely accepted, readily repeated, convenient, minimally invasive and of low cost. Furthermore, liquid biopsy could speed up the diagnostic process and potentially reduce health care costs by providing a reliable screening tool. Biomarkers in blood have the potential to detect a wide variety of primary tumors and metastases located throughout the body.”, see I. Introduction spanning pages 1-3, as well as entire document.
Conclusion
10. THIS ACTION IS MADE FINAL. 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.
11. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
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, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
23 February 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643