DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicants filed response on 2/11/2026 has been received.
Claims 1-20 have been canceled.
Claims 21-41 are pending and under examination.
The rejection on claims 21-41 under 35 USC 101 (judicial exception) is withdrawn because a specific chemotherapeutic treatment to the hepatocellular carcinoma (HCC) patients is included.
The rejection on claims 21-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, on bilirubin is withdrawn because applicants admit that the level of bilirubin alone is not for diagnosis of HCC, rather it is in combination with other HCC biomarker for diagnosis (see Remarks, page 9, middle portion). Note, this also shows that bilirubin along with other CDT, ALT, SGPT, AST, SGOT, GGT, albumin, LDH are aiding marker for liver heath and further requires one of CA125, CA 19-9, E-cadherin or erB2 for diagnosis of HCC.
The rejection on Claim 21, 32-38 and 40-41 uder pre-AIA 35 U.S.C. 103(a) as being unpatentable over Glezer in view of Chen (US 20100203644), Bersohn (S. A. Medical Journal 1969 October 1219), Murawaki (Clinica Chim Acta 1997 259:97) and Borlak is withdrawn because Murawaki teaches that about 46% false positive HCC for CDT (abstract). Thus this would not motivate one clinician in the field to use CDT for aiding HCC diagnosis. As to Borlak reference, Borlak does not teach the listed biomarkers. Nevertheless the same claims can still be rejected under 35 USC 103 in combination of the same referenes Glezer in view of Chen and Bersohn (see below).
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Claim 21, 32-38 and 40-41 are rejected uder pre-AIA 35 U.S.C. 103(a) as being unpatentable over Glezer in view of Chen (US 20100203644) and Bersohn (S. A. Medical Journal 1969 October 1219).
The current invention directs to a method of treating hepatocellular carcinoma (HCC) patient by measuring a variety of biomarkers followed by computer processes, storage and comparison in identifying HCC subjects for treatment. The specification is based on collected known liver health and HCC biomarkers from the known literatures and patents. It is noted that applicant submits NO clinical experiments and no clinical data (emphasis added). It can be considered that the disclosure is “a mere wish or plan for obtaining the claimed invention” (see Ariad Pharmaceuticals 94 USPQ 2d 1161 at page 1176 (2010)). Again, the liver health and HCC biomarkers are KNOWN in the field. Ultimately the similar results would be reasonably achieved if one ordinary skilled person in the field to use the same biomarkers, i.e. identification of HCC followed by treatment.
As to claim 21, in view of the whole Glezer reference, several biomarkers for hepatic cellular carcinoma (HCC) are disclosed, namely CEA, OPN, MMP-9, CA125, CA19-9, E-cadherin and erbB2 (See section 0011, 0022-0024, 0050-0051; Table 3). Glezer teaches using these biomarkers to assess the risk HCC in a subject by comparing the levels of the biomarkers to those of a control at different time points followed by treatment (See section 008-0016 and 0029-0032). Moreover, Glezer also teaches using computer software to collect the measurements, calculate and compare the data for diagnosis purpose. “The specific methods/algorithms for using biomarker levels to make these determinations, as described herein, may optionally be implemented by software running on a computer that accepts the biomarker levels as input and returns a report with the determinations to the user” (section 0032). This statement provides prima facie obviousness to one ordinary skilled person that a non-transitory computer readable medium would have been used to save data from the input and report. Using the disc or hardware to save measurements and comparing data requires merely routine practice in the field. Moreover, Glezer also teaches using chemotherapeutic regimen for the HCC patients (see abstract). However, Gleazer does not explicitly teach combine some of the liver health biomarkers.
Chen teaches that the levels of albumin, total bilirubin, total plasma proteins, AFP, GGT, AST and ALT and the data are shown in Table 1 (section 0052). Chen also teaches followed by treatment (section 0022).
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The bilirubin, total serum protein, albumin, AST, GGT are higher in HCC. More specifically, Chen also observed an increase of GGT levels with tumor stages in Figure 4. Note, even the ratio of AST/ALT is NOT used for the claim as applicants argue, the GGT can still read the claim together with bilirubin and total serum protein as shown in Table 1.
Also, Bersohn teaches that levels of SGOT, SGPT ratio, LDH were elevated in HCC patients (see Results tables VA-VD; page 1221 right column, 1224, right column). Note Bersohn also reviews the study of Spatt and Grayzel (cited #5 reference) in observing an elevated level of alkaline phosphatase (ALP) in HCC patients (read on claim 40).
The above liver health biomarkers, GGT, AST and ALT, albumin, SGOT, SGPT, and LDH also reflect pathological status of a HCC patient. It is noted that the markers albumin, GGT, SGOT, SGPT or LDH, are well-known and are often considered as a preliminary evaluation for subsequent more serious potential hepatic diseases.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to motivate one as Gleazer to incorporate the liver health biomarkers, such as GGT, SGOT, albumin, total serum protein, bilirubin and LDH as taught by Chen and Bersohn for liver health evaluation and further using CEA, OPN, MMP-9, CA125, CA19-9, or E-cadherin in subsequent diagnosis of HCC in a subject. Adding more liver health/HCC related biomarkers for aiding diagnosis would provide more thorough and accurate assessment, especially to ensure the liver condition in the preliminary evaluation which provides more accurate subsequent analysis on HCC. As to the two time points, it would have been prima facie obvious to one clinician in the field to compare the two time points, e.g. annual physical checks with family history of HCC, for an early detection of potential HCC patients.
As to claim 32-33, various liver diseases patients are used for detection, including fibrosis, alcoholic liver disease, cirrhosis or fatty liver (see Gleazer Example 1; section 0050-051).
As to claim 34-35, blood, urine, mucosa, serum, plasma samples can be used for detection (See Gleazer section 0034).
As to claim 36-38, multiplexed assays are used for measurements (see Gleazer section 0047).
Claim 39 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Glezer, Chen and Bersohn as applied to claim 21, 32-38 and 40-41 above, and further in view of Debad (US20060205012).
Claim 39 directs to a statistical analysis of using statistically weighted difference greater than “1” on the data to evaluate HCC. Glezer, Chen, and Bersohn do not explicitly teach using a statistically weighted difference more than “1” as a threshold for determining HCC presence. However, using statistic analysis is well-known and commonly practiced in the field.
For example, Debad teaches using a statistically weighed difference more than “1” as a threshold for comparing biomarkers in a subject in diagnosing an immune disease, such as Crohn’s disease (section 0057-0059).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the statistically weighted difference model “greater than 1” as taught by Debad for analysis of the results of the biomarkers for diagnosis of HCC. One ordinary skilled person in the field would have been adapted a known and acceptable statistical model in analyzing the data for identifying potential HCC subjects with reasonable expectation of success. Under KSR case law, it is now apparent "obvious to try" may be an appropriate test in more situations. “When there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense”. In that instance the fact that a combination was obvious to try might show that it was obvious under 35 USC 103. See KSR Int'l Co v. Teleflex Inc., 127 S. Ct. 1727; 82 USPQ 1385, 1397 (2007). The problem facing those in the art was the statistical analysis, and there were a number of methods and models available to do so. The skilled artisan would have reason to try these methodologies with reasonable expectation that at least one would be successful. Thus, this statistically weighted difference model was “the product not of innovation but of ordinary skill and common sense.”
Claim 22-31 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Glezner, Chen and Bersohn as applied to claim 21, 32-38 and 40-41 above, and further in view of Bisceglie (Hepathology 2009 48:S56-S60; IDS reference), Drucker (Biomedicine 1979 Vol. 31, page 23-25) and El-Serag (Hepatology 2002 36:S74-S-83).
Glezer, Chen, and Bersohn references have been discussed above. However none explicitly teaches identifying markers for hepatitis A, B or C.
Hepatitis A, B and C (HBV and HCV) infection have been studied for decades and both the research as well as epidemiological data have shown an association of the HCC with hepatitis A, B or C.
For instance, Drucker found out about 62.5% of HCC patients also suffered hepatitis A infection (See Summary). Drucker teaches using anti-hepatitis A antibody and anti-hepatitis B for identifications (see Materials and Methods).
In addition, Bisceglie have reported a high correlation of hepatitis B patients with the incidence of HCC (see Abstract). Bisceglie also teaches detecting antibody to hepatitis B for identification (S57, right column).
Furthermore, El-Serag have shown that HCC develops only after 2 or more decades of HCV. El-Serag further estimates that the incidence and mortality rates of HCC among 30-50 years of age would be double given the prevalence of HCV infection this group (Abstract). The detection of HAV, HBV and HCB are based on immunoassay antigen/antibody or polymerase chain reaction (page S74, left column; S75 left column).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further screen HAV, HBV or HCV in the subjects for a more thorough evaluation and diagnosis because evidence of medical studies have shown a higher risk of developing HCC from HAV, HBV and/or HCV infection patients. One ordinary skilled person in the field would have been motivated to simultaneously identify HAV, HBV or HCV to ensure the diagnosis or assessment of the risk of HCC followed by appropriate medical care.
Applicants’ Remarks are summarize below:
First, the paragraph of Chen which the Office cites states that correlation of tumor
stage was analyzed with respect to levels of AFP, GGT, and the ratio AST/ALT ratio. However, that same paragraph of Chen states that the AST/ALT ratio was compared to HCC patients and cirrhosis patients and that while the AST/ALT ratio is significantly lower in HCC patients than cirrhosis patients, Chen teaches that the AST/ALT ratio had no significant correlation to tumor stage. As such, Chen does not teach or suggest that AST or ALT can be used as biomarkers in the detection of HCC. In fact, not only does Chen not teach or suggest such a theory, Chen dismisses it by stating that there is no correlation of the AST/ALT ratio to tumor stage. Consequently, Chen does not teach or suggest that AST and ALT can be used as biomarkers in the detection of HCC as the Office alleges.
Additionally, Bersohn does not rectify the deficiencies of Gezer and Chen. The
Office alleges that Bersohn teaches that the difference between primary liver cancer patients and non-cancer patients was the elevation in enzyme levels of SGOT, SGOT/SGPT ratio, and LDH, along with a lower level of albumin in HCC patients.
However, Bersohn states that while there were marked deviations from the normal range in the proved cancer group, the marked deviations from the normal range were also seen in the non-cancer groups (page 1221, 2"d column). Additionally, both groups showed a "very wide scatter in most results which was reflected in the high standard deviations" (id.). Perhaps more telling, the teaching that "[i]t appears that there are no biochemical tests that can be considered specific enough to be diagnostic of primary cancer of the liver" (id. at 1225, 1St column). Bersohn continues that while a combination of tests may be used as possible presumptive evidence of primary liver cancer, "the only test that affords a specific diagnosis of primary cancer of the liver...is the AFP test"
Applicant’s arguments have been considered but are not persuasive.
The current invention directs to use two sets of markers (1st set for liver health in general, and 2nd for HCC specific) for diagnosis of HCC followed by administering chemotherapy to the identified subject. First, applicants have NOT presented any clinical data for the instant invention. No discussion or teaching on each of the first set biomarkers (not the HCC specific biomarker, CA125, CA19-9, E-cadherin or erbB2) in relation to HCC. Both the general liver health biomarkers and the HCC specific markers are known in the field. It would have been prima facie obvious to one clinician in the field combine the two sets markers together for an evaluation on the potential HCC because the biomarkers involving a preliminary assessment on the health of the liver followed by a specific analysis on a particular liver disease HCC.
As admitted by applicants, the liver heath biomarkers alone (first set biomarkers) are not sufficient for diagnosis of HCC (see “Applicants respectfully submits that the claim is not directed to diagnosis of HCC on the levels of bilirubin alone, but in combination with other biomarkers which are included in the claims”, page 9 of Remarks, middle portion). It is known in the field that one clinician often measures these biomarkers to evaluate liver health as a preliminary evaluation (i.e. using the first set biomarker panel as a preliminary evaluation for annual physical examination on the health condition of the liver) and followed by more specific characterization of a particular HCC.
As to the Chen reference, Table 1 list the clinical data which indicate higher levels of bilirubin, total serum protein, albumin, GGT are higher in HCC (middle column).
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The data in Table 1 would have motivated one ordinary skilled person like Gleazer to have run the preliminary testing, such as GGT (also Figure 4), albumin, or total serum protein in subsequent combining the HCC specific biomarker (e.g. CA125, CA19-9, E-cadherin or erbB2) assay for diagnosis of HCC.
As to Bersohn reference which provides additional biomarkers. Bersohn states at the beginning of Discussion (page 1221, right column) “..the striking feature was the marked elevation in the enzyme levels in the cancer group. The SGOT, SGOT/SGPT ratio, LDH, alpha-hydroxybutyric dehydrogenase, LDH isoenzyme fraction V, aldolase,….were all significantly higher in cancer cases. Bersohn then discusses each biomarker. At least significantly higher SGOT level in HCC is observed (page 1222, right column, last 2nd paragraph). Also significantly higher LDH is confirmed (page 1224, right column, last third paragraph). Bersohn concludes that while a combination of tests may be used as possible presumptive evidence of primary liver cancer, "the only test that affords a specific diagnosis of primary cancer of the liver...is the AFP test" (page 1225, left column, last paragraph). Yet Bersohn continues comments that “AFP test has not been found in the sera of several thousand healthy individuals tested, nor in patients with a wide variety of cancers other than hepatocellular carcinoma (exceptive for positive results in a few cases of neoplasm of embryonal character) even when liver continued metastases” (Id).
Although data from some of the biomarkers may scatter and deviate, nevertheless Bersohn does not teach away applying these biomarkers in evaluating HCC. Rather Bersohn suggests a combination of biomarkers for evaluation. It would have been prima facie obvious to motivate Gleazer to measure more additional significantly higher levels of biomarkers as taught by Gleazer and Chen in combing SGOT and LDH as taught by Bersohn for a more thorough and complete evaluation of HCC.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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CHANGHWA J. CHEU
Primary Examiner
Art Unit 1678
/CHANGHWA J CHEU/ Primary Examiner, Art Unit 1678