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 .
Claim status
Currently, claims 1-9 are pending in the instant application. Claim 10-11 have been canceled. Claims 1-3, 5, and 7 has been amended and claim 2 is withdrawn. Claim 4 and 6-9 have been rejoined as claim 1 has been amended to include the subject matter of claims 4, 6-9. This action is written in response to applicant' s correspondence submitted 12/1/2025. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant' s amendments to the claims. 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 Final.
Claims 1, 3-9 are under examination with regard to DPT and CLU. Claims 4, 6-8 have been rejoined and are now under examination due to the amendment to claim 1 to include the specific combination of DPT and CLU.
Withdrawn Rejections
The rejection of claims 1, 3, and 5 under 35 USC 101 has been withdrawn due to the amendment to the claims to integrate the judicial exception by including a positive treatment step of performing liver transplantation on the patient determined to have a good HCC prognosis.
The rejection of claims 1, 3, and 5 under 35 USC 103 as unpatentable in view of Coulouarn in view of Mas is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-9 are rejected 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.
Claim 1 recites dermatopontin (Gene Id GC01M168664) and clusterin (gene ID GC08M027596). Parentheticals make the claim indefinite because it is unclear whether the information in the parentheses has the same, less, or more weight as the rest of the claim language. It is not clear if information in the parenthesis is equivalent to the information that it defines, for example it is not clear what Gene Id GC01M168664 represents and if this information includes additional information beyond the gene DPT. This rejection may be overcome by deleting the information in parentheses - i.e. (Gene Id GC01M168664) and (Gene ID GC01M168664).
Response to Arguments
The response traverses the rejection on pages and asserts the use of parentheses have been adjusted (see pg. 4 of the remarks mailed 12/1/2025). It is noted that the claims have been amended but recite Gene ID GC01M168664 and Gene ID GC01M168664 which are not proper or clear names for the recited genes DPT and CLU and this reference should be deleted from the claims for the reasons of record.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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.
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.
Claims 1, 3, 4-5, are rejected under 35 U.S.C. 103 as being unpatentable over Coulouarn et al. (WO2017207545A1) in view of Zheng (Oncotarget, 2017, vol 8, pp 52321-52332) and Mas (Mol Med 2006 12(4-6) 97-104). This rejection is newly presented necessitated by the amendment to the claims.
Coulouarn teaches a molecular signature of hepatocellular carcinoma. Coulouarn teaches methods of prognosis of HCC in a subject by determining the level of expression in a sample. Coulouarn teaches determining expression of DPT (see pg. 2). Coulouarn teaches method of predicting efficacy of therapy (See pg. 50, pg. 52, lines 29-35). Coulouarn teaches an increase in expression of DPT indicates efficacy of therapy (good prognosis).
Coulouarn teaches a reference value (see pg. 57, lines 8-10). Coulouarn teaches increase in expression is an increase of the marker in comparison to a reference or predetermined threshold value (see pg. 57, lines 25-28) (claim 3). Coulouarn teaches expression levels are determined by RT-PCR and quantitative PCR (see pg. 59) (claim 5). Coulouarn teaches HCC signature using algorithms (sese analysis of microarray datasets) (claim 7) Coulouarn teaches monitoring efficiency of an HCC therapy by change in expression. Coulouarn teaches therapy includes surgery. Coulouarn does not teach expression of clusterin or expression in liver samples. Coulouarn does not teach liver transplantation.
Zheng teaches expression of CLU in liver samples. Zheng teaches overexpression of CLU in samples and teaches there was no difference in survival time in patients with stage I and stage II with elevated sCLU expression (see pg. 52324, 1st para). Zheng teaches qRT-PCR of RNA isolated from liver tissue and cells (see pg. 52329). Zheng teaches tumor size <5cm (see table 1). Zheng teaches no association was found between sCLU and tumor size, lymph node metastasis and gross classification (see pg. 52322). While Zheng teaches increased expression of CLU is associated with higher TNM, Zheng also teaches increased expression of CLU in stage I and II, which includes good prognosis of HCC. It is noted the claims do not determine a specific expression level nor do the claims require what type of “good prognosis”.
Treating and identifying patients for liver transplants by gene expression of liver samples was known in the art. Mas teaches obtaining liver tumor samples from patients with HCC (see patients). Mas teaches liver transplant is the best treatment option for HCC and organ transplant can only be offered to patients whose survival is predicted to be similar to that in non-HCC transplant patients. Mas teaches molecular based methods for classification of HCC pretransplantation will permit the detection of patients with different prognoses allowing greater accuracy in selection of patients for treatment cure with transplantation (see pg. 101-102).
Therefore, it would have been prima facie obvious to include liver samples from patients with HCC, as taught by Zheng in the method of Coulouarn and include additional biomarkers, including clusterin for identifying patients for liver transplants based on the method of Coulouarn and Zheng and include patients with overexpression of DPT and CLU because Mas teaches molecular based methods for classification of HCC pretransplantation allows for greater accuracy in selection of patients. It would be obvious to use the method of Coulouarn for identifying and treating patients with liver transplants by gene expression analysis and include additional genes that are associated with HCC including a gene that is associated with differentiation and TNM stage with a reasonable expectation of success because Mas teaches molecular based methods allow for greater accuracy in selection of patients for treatment cure with transplantation and Coulourn teaches methods that identify patients with good prognosis and treatment efficacy by determining increased expression levels of DPT and Zheng teaches analysis of CLU in HCC patients, teaching there is no different in stage I HCC patients, indicating a good prognosis.
The claims do not require the type of prognosis only good prognosis associated with overexpression. Because Coulourn teaches increased expression of DPT for response to therapy, this encompasses a good prognosis and teaching of Coulourn in view of Zheng and Mas anticipate the claimed invention.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Coulouarn et al. (WO2017207545A1) in view of Mas (Mol Med 2006 12(4-6) 97-104) as applied to claims 1, 3, 4-5, above, and further in view of Lee (Gastroenterology, 2004, 127:S51-S55). This rejection is necessitated by the amendment to the claims.
Coulouarn et al. in view of Zheng and Mas is set forth above. Coulouarn in view of Zheng and Mas does not teach a machine learning algorithm, including a linear kernel support vector algorithm to provide a value of likelihood of disease recurrence.
However, Lee teaches gene expression in HCC and survival prediction. Lee teaches 5 different statistical methods used to determine gene expression patterns and predicting survival including LDA, SVM, CCP (see S52). Lee teaches that all 5 models successfully separated poorer survival patients from longer survival patients (see S52 and fig 2).
Therefore, it would be prima facie obvious to include analysis using SVM or linear kernel SVM to identify longer survival patients from poorer survival patients in the method of Coulouarn in view of Zheng and Mas. The ordinary artisan would have been motivated with an expectation of success that analysis of the method of Coulouarn in view of Zheng and Mas could be determined using a SVM or linear kernel SVM with the expected benefit of identifying longer survival patients to allow for systematic analysis of expression for pathogenesis of HCC.
Response to Arguments
The response traverses the previous 103 rejection on pages 6-7 of the remarks mailed 12/1/2025. While the rejection has been withdrawn the new rejection is applicable to some of the traversal and will be addressed.
The response asserts that the combination of DPT and CLU to identify a patient with good HCC prognosis and good candidate for liver transplantation is not taught by Coulouarn in view of Mas. The claims do not require identifying a subject as a good candidate for liver transplantation. The claims require detecting overexpression of DPT and CLU, Coulouarn teaches expression analysis of genes in HCC, while Coulouarn does not teach expression analysis of CLU, it would have been obvious to an ordinary artisan to include known associated genes with HCC in the method of Coulouarn includes CLU as taught by Zheng, as such the teaching of Coulouarn in view of Zheng and Mas teaches detecting overexpression of CLU and DPT and Coulouarn teaches good prognosis in response to therapy by increased expression of DPT. The response further asserts detecting DPT and CLU together provides a synergistic predictive effect in comparison to use of a single marker and points to fig 2, fig 7 and para 100. The pre-grant publication at para 100 relates to the synergistic effect of the combination of DPT and CLU for DFS and a good prognosis following liver transplantation not for any good prognosis. Good prognosis of HCC is broad and encompasses any type of prognosis from therapy, recurrence, to metastasis, a good prognosis could encompass no metastasis to lymph nodes, as taught by Zheng. While the specification asserts good prognosis refers to no recurrence of HHC disease in five years following liver transplantation (see para 35), this is not a specific definition and good prognosis has been given its broadest reasonable interpretation to include any prognosis of HCC that is “better” than a previous prognosis. As such the teaching of both Coulouarn in view of Zheng and Mas render obvious the claimed invention as it would have been obvious to include additional genes in the analysis of Coulouarn to determined overexpression to determine a good HCC prognosis. It is noted if the claims were amended to be commensurate in scope with the teaching of the specification with regard to synergy of CLU and DPT to include, for example DFS or increased prognosis following liver transplantation (para 100) this may overcome the rejection of record.
Conclusion
No claims are allowable.
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 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.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699
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