DETAILED ACTION
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 .
Response to Amendments
This Office Action is in reply to Applicant’s response of 1 May 2026. Applicant’s remarks
and amendments have been fully and carefully considered but are not found to be sufficient to
put the application in condition for allowance.
Note: 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 made FINAL.
Withdrawn Objections and Rejections
The objection to the specification in the Office Action mailed 7 April 2026 is withdrawn in view of Applicant’s amendment to the specification filed 15 June 2026.
The objection to the claims in the Office Action mailed 7 April 2026 is withdrawn in view of Applicant’s amendment to the claims filed 15 June 2026.
All rejections of claim 5 in the Office Action mailed 7 April 2026 are withdrawn in view of the cancelation of claim 5 in Applicant’s amendment to the claims filed 15 June 2026 rendering the rejections moot.
Claim Status
Claims 1-8 are pending.
Claims 1-3 and 7-8 are withdrawn.
Claim 5 is canceled.
Claims 4 and 6 are under examination.
Claim Interpretation
Maintained
The recitation “necessary for diagnosing hepatocellular carcinoma” in claim 4, lines 1-2 is an intended use of the invention recited in the preamble. MPEP §2111.02 II. states: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. As the body of the claim sets forth clear and full steps describing the claimed process, the recitation “necessary for diagnosing hepatocellular carcinoma” does not carry patentable weight.
New
The recitation in claim 4 “determining as hepatocellular carcinoma when the measured expression level of SF3B4 is higher than that of the control sample” is a contingent limitation, reciting that the action of “determining as hepatocellular carcinoma” is contingent on the condition of the measured expression level of SF3B4 being higher than that of the control sample. MPEP §2111.04(II) states: “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. The method of claim 4 encompasses samples from patients where the measured expression level of SF3B4 is not higher than that of the control sample, so the method of claim 4 encompasses embodiments where the step of determining as hepatocellular carcinoma is not performed due to the condition not being met. The further limitations of the step of determining as hepatocellular presented in lines 8-14 of claim 4 as amended on 15 June 2026 only restricts this contingent limitation, so they do not further limit the claim, and prior art is not required to teach these limitations in order to read on the claim.
Claim Rejections - 35 USC § 101
Maintained - Modified as Necessitated by Amendment
Claims 4 and 6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature (natural correlation) and an abstract idea without significantly more. The claims recite “comparing the measured expression level”, “determining as hepatocellular carcinoma when the measured expression level of SF3B4 is higher than that of the control sample”, “converting a relative expression ratio […] to log 10”, and “determining the patient as having hepatocellular carcinoma when the cut-off value is at or above 0.85”. The following inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes, the claims are directed to processes.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes, where the claims recite the acts of comparing the measured expression level, determining as hepatocellular cancer (both recitations), and converting a relative expression ratio to log 10, these concepts are abstract ideas as they can be performed in one’s head or by hand by a skilled person looking at data. Where the claims recite the correlation of hepatocellular carcinoma with the measured expression of SF3B4 in the blood-derived serum exosome sample being higher than that of a control sample, this concept is a recitation of a law of nature (natural correlation).
Step 2A, prong 2. Does the claim recite additional elements that integrate the exception into a practical application? No, the judicial exceptions to which the claims are directed are not integrated into a practical application because the rejected claims do not require any particular practical steps that are not considered extra-solution activity due to being mere data gathering, such as measuring an expression level from a sample (MPEP §2106.05(g), an example of mere data gathering includes “Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968)”).
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No, the claims include the practical step of measuring an expression level of SF3B4, but the broadly recited step is properly considered routine and conventional and is mere data gathering, so the claims are not significantly more than the judicial exceptions to which they are directed.
For these reasons, claims 4 and 6 are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant's arguments, see pages 7-11 of the remarks filed 15 June 2026, with respect to the rejection of claims 4 and 6 under 35 U.S.C. 101 have been fully considered but they are not persuasive. On page 7 and the top of page 8 Applicant begins by reciting guidance from the 2019 Revised Patent Subject Matter Eligibility Guidance and a portion of the rejection.
On pages 8-9 of the remarks, Applicant presents arguments in a section titled “Prong 1: The claims do not recite an abstract idea”, but beyond quoting relevant guidance and the office action does not dispute whether the claims recite judicial exceptions but rather provide arguments that the claim is directed to a judicial exception. As no arguments are presented for why the claims do not recite a judicial exception, Step 2A Prong 1 is satisfied and these arguments are treated as arguments pertaining to Step 2A Prong 2 and Step 2B along with those present on pages 10-11 of the remarks.
On pages 8-9 and on page 11 in the last substantive paragraph before section VI., Applicant argues that the claimed method is directed to a noninvasive liquid biopsy using serum-derived exosomes requiring concrete steps of isolating exosomes, measuring SF3B4 expression via qRT-PCR, and applying a cut-off value to determine HCC status, rather than being directed to an abstract idea, and that these steps integrate the exception into a practical application and amount to significantly more. This argument is not persuasive.
Firstly, claim 4 does not require an active step of isolating exosomes and, though it requires measuring SF3B4 expression, it does not claim doing so via qRT-PCR. As these are not limitations of the claim, they do not factor into the subject matter eligibility analysis. The claimed limitations identified in this argument are therefore (a) that it uses an exosome sample isolated from a patient by a noninvasive liquid biopsy, (b) measuring SF3B4 expression, and (c) applying the cut-off value.
The use of a specific type of sample and the measurement step fail to integrate the judicial exception into a practical application because, though concrete steps, they are mere data gathering and therefore represent insignificant extra-solution activity (step 2A Prong 2). See MPEP §2106.05(g), reciting as examples of mere data gathering “Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989)” and “Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)”. Regarding Step 2B, in addition to being mere data gathering, it is further noted that using exosome samples for cancer diagnosis isolated from blood samples (a type of noninvasive liquid biopsy) is well-understood, routine, conventional activity in the art as exemplified by the teachings of Soung (see 35 U.S.C. 103 rejection below regarding the teachings of Soung).
The application of the specific cut-off cannot integrate a judicial exception into a practical application because it itself is part of a judicial exception, the abstract idea (mental process) that can be accomplished in one’s head of determining the patient as having hepatocellular carcinoma when the cut-off value is at or above 0.85. This is simply done by one of ordinary skill in the art looking at the cut-off value and determining, in their head, whether it is greater than or equal to 0.85. MPEP §2106.04(d)(III) instructs that a judicial exception cannot be integrated into a practical application by the recitation of another judicial exception: “Because a judicial exception alone is not eligible subject matter, if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application”. Furthermore, even were this limitation not part of a judicial exception, it merely defines the claimed judicial exception by delineating the claimed natural correlation more precisely and therefore does not integrate it into a practical application. Therefore, this argument is not persuasive.
On page 10, Applicant argues that the specific cut-off value is critical and not merely a generic application of a natural correlation. Firstly, as discussed in the preceding paragraph, a judicial exception cannot be integrated into a practical application by reciting another judicial exception. Additionally, the assertions regarding the criticality of 0.85 as an optimal point are not arguments relevant to subject matter eligibility analysis (see MPEP §2106). Therefore, this argument is not persuasive.
On page 11, Applicant argues that the claimed method provides superior performance over comparable methods and that its results are unexpected and solve a long-standing problem in the art. None of these arguments are relevant to subject matter eligibility analysis (see MPEP §2106). Therefore, these arguments are not persuasive.
Therefore, this rejection is maintained.
Claim Rejections - 35 USC § 103
Modified - Necessitated by Amendment
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Nam et al. (WO 2019/146841, published 8 January 2019), herein Nam, in view of Soung et al. ("Exosomes in Cancer Diagnostics" Cancers, 9(1): 8 (2017)), herein Soung.
Regarding claim 4, Nam teaches a method of providing information for diagnosing hepatocellular carcinoma, comprising: (1) measuring an expression level of SF3B4 from a blood serum sample isolated from a patient (“The method of measuring the expression level or protein level of […] SF3B4 […] in the above can be performed by a known process for detecting or isolating mRNA or protein from a biological sample […] the “biological sample” refers to […] blood, serum” FIT Translation page 15); (2) comparing the measured expression level of SF3B4 with a control sample (“comparing the measured expression levels of […] SF3B4 with the expression levels of the corresponding genes of the control sample” FIT Translation page 15); and (3) determining as hepatocellular carcinoma when the measured expression level of SF3B4 is higher than that of the control sample (“the expression level of […] SF3B4 is determined to be higher than the expression level of the control sample to determine that the liver cancer has occurred” FIT Translation page 6; see also Figure 6b, eHCC indicates early hepatocellular carcinoma, NL indicates normal liver tissue, DN indicates dysplastic nodule, this shows higher SF3B4 expression in hepatocellular carcinoma than controls). Though Nam teaches determining hepatocellular carcinoma when SF3B4 is higher in the patient sample than the control sample, this limitation is not required for prior art to read on the claim, as discussed in the Claim Interpretation section above, and the further limitations on the step of determining as hepatocellular carcinoma are not required for prior art to read on the claim.
However, Nam does not teach that the blood sample is a blood-derived serum exosome sample and does not specify that the sample is obtained by a non-invasive liquid biopsy. This deficiency is made up for in the teachings of Soung.
Regarding claim 4, Soung teaches obtaining exosome samples by a non-invasive liquid biopsy (“Exosome based liquid biopsy merits consideration over conventional tissue biopsy for following reasons. It provides the convenient and non-invasive way of diagnosis over tissue biopsy that requires surgery” page 1 last paragraph), the isolation of exosomes from blood serum (“exosomes from blood serum were successfully isolated” page 2 para 2), and using isolated exosomes for diagnosis of cancer (“cancer derived exosomes likely serves as biomarker for early detection of cancer as they carry the cargo reflective of genetic or signaling alterations in cancer cells of origin” page 1 last para). Soung also teaches that the use of exosome samples is advantageous over conventional tissue samples because it provides a more convenient and non-invasive way of diagnosis than the surgery required for tissue biopsy (page 1 last para).
Regarding claim 6, Nam teaches a method of providing information for diagnosing hepatocellular carcinoma wherein the hepatocellular carcinoma is early stage hepatocellular carcinoma (“method for providing information for the diagnosis of early liver cancer” FIT Translation page 6; see also Figure 6b, eHCC is early hepatocellular carcinoma).
In view of Soung’s teaching that using an isolated exosome sample for cancer diagnosis is advantageous over tissue samples because it provides a more convenient and non-invasive method of diagnosis, one of ordinary skill in the art would be motivated to combine the method of diagnosing hepatocellular carcinoma taught by Nam with the method of using exosomes taught by Soung. One of ordinary skill in the art would have a reasonable expectation of success in this combination because Nam teaches using blood serum as its sample and Soung teaches isolating exosomes from blood serum, so the combination merely adds an additional step of processing the blood serum sample, and because Soung teaches that cancer derived exosomes carry cargo reflective of the genetic alterations in cancer cells of origin. Therefore, the invention as a whole of claims 4 and 6 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Response to Arguments
Applicant's arguments, see pages 11-12 of the remarks filed 15 June 2026, with respect to the rejection of claims 4 and 6 under 35 U.S.C. 103 have been fully considered but they are not persuasive. On page 11 and the top of page 12 of the remarks, Applicant first states the rejection and relevant case citations establishing the required factual inquiries, explicit analysis, and expectation of success in rejection under 35 U.S.C. 103.
On page 12 of the remarks, Applicant argues that Nam and Soung fail to disclose or suggest every claimed feature and states that claim 4 has been amended to incorporate subject matter of claim 5, identifying in particular the line “determining the patient as having hepatocellular carcinoma when the cut-off value is at or above 0.85”. This argument is not persuasive because this is introduced as a limitation of the step of “determining hepatocellular carcinoma” which, as discussed in the rejection above, is a contingent limitation that is not necessary for the method to be practiced, since the method may be practiced on a patient where the measured level of SF3B4 is not higher than that of the control sample. Therefore, the amended subject matter of the claim is not necessary for the claim to be practiced and does not limit the claim with any features that are not disclosed in Nam or Soung. To clarify, as currently claimed, in order to practice the claimed method, claim 4 only requires the step of measuring on lines 3-4 of claim 4 and the step of comparing on line 5 of claim 4.
Additionally, in the second to last paragraph of page 12 of the remarks, Applicant makes reference to “Hatano and Iwamoto”. As no references with these names were used in the Office Action mailed 7 April 2026, it is unclear to Examiner what Applicant is trying to argue in this paragraph, so this argument is not persuasive.
Examiner notes that though previously filed claim 5 (see claims filed 24 May 2023) was previously indicated as free of the prior art, that indication was specifically because previously filed claim 5 recited a limitation for a Ct value (threshold cycle) of 0.85. This limitation has not been incorporated in any of the claims filed 15 June 2026 that are under examination.
Conclusion
Applicant's amendment necessitated the new ground(s) of and modification(s) of rejections 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 Jeffrey Lawrence Bellah whose telephone number is (571)272-1024. The examiner can normally be reached M-Th, 7:30-5 ET.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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