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 .
Withdrawal of Rejections
The response and amendments filed on 06/08/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous claim rejections under 35 U.S.C. 112(b) for indefiniteness, 112(a) for enablement, and 101 for ineligible subject matter have been withdrawn necessitated by Applicant’s amendments. The previous claim rejections under 35 U.S.C. 102 for anticipation and 103 for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Applicant’s Amendments
Claim Rejections - 35 USC § 102, Anticipation
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 7-8, 14, and 40-42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Honkanen (US 2020/0179452; Date of Publication: June 11, 2020 – previously cited).
Honkanen’s general disclosure relates to methods of administering to subjects “one or more mammalian cells modified to express at least one sterol degrading enzyme derived from a bacterium” (see, e.g., Honkanen, abstract). Moreover, Honkanen discloses that the composition containing the sterol degrading enzyme is useful in lowering cholesterol levels in a subject in need thereof” (see, e.g., Honkanen, abstract). Honkanen discloses “methods for modifying a mammalian cell with nucleic acid compositions that enable and/or promote expression of one or more proteins useful in degrading a sterol” (see, e.g., Honkanen, [0009), wherein the proteins are enzymes capable of altering a sterol, such as “cholesterol dehydrogenase (CholD), 3-ketosteroid Δ1-dehydrogenase (Δ1-KstD), anoxic cholesterol metabolism B enzyme (acmB), 3-ketosteroid 9α-hydroxylase (KshAB), 3β-hydroxysteroid dehydrogenase 2 (HSD2), and P450-ferredoxin reductase-ferredoxin fusion protein (P450-FdxR-Fdx)” (see, e.g., Honkanen, [0010]). Furthermore, Honkanen discloses the expression of the sterol degrading enzyme(s) in the mitochondria of liver cells (see, e.g., Honkanen, [0083]-[0086]).
Regarding claim 1 pertaining to treating hepatocellular carcinoma in a subject in need thereof, Honkanen teaches “methods for modifying a mammalian cell with nucleic acid compositions that enable and/or promote expression of one or more proteins useful in degrading a sterol. In some embodiments, the composition includes a vector having one or more control sequences for promoting the expression of one or more protein coding sequences. In some embodiments, the vector is a viral vector or a transposable element” (see, e.g., Honkanen, [0009]). Moreover, Honkanen teaches expression of proteins in a cell that does not normally express such proteins, such as P450-ferredoxin reductase-ferredoxin fusion protein (P450-FdxR-Fdx) (see, e.g., Honkanen, [0010]). Furthermore, Honkanen teaches the expression of a P450-FdxR-Fdx within Hep3B cells (see, e.g., Honkanen, [0103]-[0104]), which is inherently a human hepatocellular carcinoma cell line (see, e.g., Accegen – Hep3B Tumor Cell Line). Furthermore, administration of a nucleic acid vector expressing P450-FdxR-Fdx to Hep3B cells (i.e., human hepatocellular carcinoma cell line), as taught by Honkanen, would inherently result in reducing a growth rate or viability of at least one liver cell. Moreover, Honkanen teaches the same method steps of administering P450-FdxR-Fdx to a subject with hepatocellular carcinoma; therefore, the preamble reciting “A method of treating hepatocellular carcinoma” is considered inherent.
Regarding claim 2 pertaining to expression in the mitochondrion of the liver cell, Honkanen teaches that the P450-FdxR-Fdx was constructed with a mitochondrial targeting sequence in order to localize to the mitochondria within Hep3B cells (see, e.g., Honkanen, [0106]).
Regarding claims 7 and 14 pertaining to the liver cell entering an apoptotic pathway after expressing the fusion protein, this is considered inherent. Honkanen teaches administering a nucleic acid vector encoding P450-FdxR-Fdx to Hep3B cells (i.e., liver cancer cells (see, e.g., Honkanen, [0103]-[0104]), which would inherently result in at least one liver cell entering an apoptotic pathway after expression of P450-FdxR-Fdx.
Regarding claim 8 pertaining to administering the composition and a compound that supports expression, Honkanen teaches “methods for modifying a mammalian cell with nucleic acid compositions that enable and/or promote expression of one or more proteins useful in degrading a sterol. In some embodiments, the composition includes a vector having one or more control sequences for promoting the expression of one or more protein coding sequences. In some embodiments, the vector is a viral vector or a transposable element” (see, e.g., Honkanen, [0009]). Moreover, Honkanen teaches expression of proteins in a cell that does not normally express such proteins, such as P450-ferredoxin reductase-ferredoxin fusion protein (P450-FdxR-Fdx) (see, e.g., Honkanen, [0010]). Furthermore, Honkanen teaches the expression of a P450-FdxR-Fdx within Hep3B cells (i.e., liver cancer cells (see, e.g., Honkanen, [0103]-[0104] & Fig. 81). Honkanen teaches treatment of P450-FdxR-Fdx transformed Hep3B cells with antibiotics such as hygromycin, puromycin, or blasticidin in order to select for Hep3B cells that have been positively transformed with the fusion protein (see, e.g., Honkanen, [0344]); thereby promoting selection and expression of cells that have been positively transformed with the fusion protein. Furthermore, Honkanen teaches “the composition includes a vector having one or more control sequences for promoting the expression of one or more protein coding sequence” (see, e.g., Honkanen, [0009]). Additionally, as discussed above, Honkanen teaches inclusion of a mitochondrial targeting sequence in order to localize to the mitochondria within Hep3B cells (see, e.g., Honkanen, [0106]).
Regarding claims 40-41 pertaining to SEQ ID NO: 1, Honkanen teaches SEQ ID NO:5, which has 100% sequence identity to instant SEQ ID NO: 1 (see, e.g., Honkanen, [0106] & Office Action Appendix).
Regarding claim 42 pertaining to the nucleic acid vector, Honkanen teaches “methods for modifying a mammalian cell with nucleic acid compositions that enable and/or promote expression of one or more proteins useful in degrading a sterol. In some embodiments, the composition includes a vector having one or more control sequences for promoting the expression of one or more protein coding sequences.” (see, e.g., Honkanen, [0009] & claims 1-3). Since Honkanen teaches expression of one protein useful in degrading a sterol and one control sequence for promoting expression of the protein coding sequence, this would read upon the instantly claimed invention that the vector does not encode any additional cholesterol metabolizing proteins since the vector can expression one protein useful in degrading a sterol and one control sequence. Furthermore, Honkanen teaches that P450-FdxR-Fdx was humanized and expressed in E. coli, wherein lentiviral expression constructs were developed to produce stable Hep3B and U-937 cell lines that independently expressed each enzyme (see, e.g., Honkanen, [0166]). Therefore, independent expression of P450-FdxR-Fdx reads upon the instantly claimed invention since P450-FdxR-Fdx is expressed without any additional cholesterol metabolizing proteins.
Examiner’s Response to Arguments
Applicant's arguments filed 06/08/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that Honkanen does not teach administration of claimed P450-FdxR-Fdx protein to a subject with hepatocellular carcinoma (remarks, pages 9-10), this argument is not persuasive. Honkanen teaches administration of nucleic acid vectors expressing P450-FdxR-Fdx (see, e.g., Honkanen, abstract & [0009]-[0010]), wherein the vectors can be administered to express P450-FdxR-Fdx within Hep3B cells (see, e.g., Honkanen, [0103]-[0104]), which is inherently a human hepatocellular carcinoma cell line (see, e.g., Accegen – Hep3B Tumor Cell Line). Therefore, Honkanen teaches administering a nucleic acid vector expressing P450-FdxR-Fdx to human hepatocellular carcinoma cells (i.e., subject in need thereof). Since Honkanen teaches the same method steps and same population being treated, the preamble of “A method of treating hepatocellular carcinoma” is considered inherent. Therefore, Honkanen inherently teaches treatment of hepatocellular carcinoma and anticipated the instantly claimed invention.
Regarding Applicant’s argument that Honkanen does not anticipate affecting the growth of liver cells (remarks, pages 9-10), this argument is not persuasive because this is considered inherent. As discussed above, Honkanen teaches administering a nucleic acid vector expressing P450-FdxR-Fdx to human hepatocellular carcinoma cells (i.e., subject in need thereof), which would inherently result in reducing the growth rate or viability of at least one liver cell.
New Grounds of Rejection Necessitated by Applicant’s Amendments
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 3, 5-6, 9-10, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Honkanen (US 2020/0179452; Date of Publication: June 11, 2020 – previously cited) as applied to claims 1-2, 7-8, 14, and 40-42 above, and further in view of Grazie (Chemotherapy for hepatocellular carcinoma: The present and future; 2017 – previously cited)..
Honkanen’s general disclosure is discussed above as it pertains to administering P450-FdxR-Fdx to treat hepatocellular carcinoma in a subject in need thereof.
However, Honkanen does not teach: wherein the at least one liver cell is contacted with at least one chemotherapeutic compound, and the chemotherapeutic compound is administered to the subject before, after, or while the cell is expressing the fusion protein (claims 3, 9, and 10); or wherein the chemotherapeutic compound is selected from sorafenib and levatinib (claim 5 and 12).
Grazie’s general disclosure relates to a review of chemotherapeutic therapies for hepatocellular carcinoma (see, e.g., Grazie, abstract). Moreover, Grazie teaches that “sorafenib is the only standard treatment available for advanced HCC” (see, e.g., Grazie, abstract). Additionally, Grazie teaches “To develop novel systemic therapies for HCC, sorafenib was also evaluated as second-line therapy after fluoropyrimidine plus platinum-based chemotherapy[33]: The resulting disease control rate of 58.3%, with overall survival and progression-free survival of 7.1 and 2.3 mo, respectively, without increased incidence of adverse events, suggests a modest efficacy of sorafenib as second-line treatment after other systemic therapies” (see, e.g., Grazie, “Sorafenib”, pg. 909).
Regarding claims 3, 5, 9-10, and 12 pertaining to administration of chemotherapy and treatment of hepatocellular carcinoma in a subject in need thereof, Grazie teaches that Sorafenib is the only standard treatment administered to patients with hepatocellular carcinoma (see, e.g., Grazie, abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer Honkanen’s cholesterol catabolizing protein in combination with a chemotherapeutic, such as Sorafenib, for hepatocellular carcinoma, as taught by Grazie. One would have been motivated to do so because Grazie teaches “The action of sorafenib is expressed on various molecular targets involved in the mechanism of tumor growth and angiogenesis, leading to their inhibition” (see, e.g., Grazie, “Sorafenib”, pg. 908). Moreover, Grazie teaches “The SHARP trial compared Sorafenib treatment (400 mg twice a day) to placebo among 602 patients, showing a significant difference in overall survival (10.7 mo vs 7.9 mo, P < 0.001), time to radiologic progression (5.5 mo vs 2.8 mo, P < 0.001) and disease control rate (43% vs 32%, P = 0.002)” (see, e.g., Grazie, “Sorafenib”, pg. 909). Additionally, Grazie teaches “To develop novel systemic therapies for HCC, sorafenib was also evaluated as second-line therapy after fluoropyrimidine plus platinum-based chemotherapy[33]: The resulting disease control rate of 58.3%, with overall survival and progression-free survival of 7.1 and 2.3 mo, respectively, without increased incidence of adverse events, suggests a modest efficacy of sorafenib as second-line treatment after other systemic therapies” (see, e.g., Grazie, “Sorafenib”, pg. 909). Moreover, Honkanen teaches the expression of a cholesterol catabolizing protein, P450-FdxR-Fdx, within Hep3B cells (i.e., hepatocellular carcinoma cell line) (see, e.g., Honkanen, [0084], [103]-[104]); therefore, since Honkanen teaches the same claimed method steps of expressing P450-FdxR-Fdx within the same claimed subject then the cholesterol catabolizing protein can inherently treat hepatocellular carcinoma. Based on the teachings of Honkanen and Grazie, it would have been obvious to add Sorafenib to the administered composition due to the additive treatment of hepatocellular carcinoma (see, e.g., In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One of ordinary skill in the art would have expected success because Honkanen and Grazie both teach treatment of diseases.
Regarding claims 6 and 13 pertaining to preventing or reducing the liver cell resistance to chemotherapy, this is considered inherent. Honkanen and Grazie teach the instantly claimed invention of administering a nucleic acid vector encoding P450-FdxR-Fdx (see, e.g., Honkanen, [0009]-[0010]) and a chemotherapeutic compound (see, e.g., Grazie, abstract) to a subject in need thereof (see, e.g., Honkanen, [0103]-[0104]), which would inherently result in preventing or reducing liver cell resistance to chemotherapy.
Examiner’s Response to Arguments
Applicant's arguments filed 06/08/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that Honkanen and Grazie are combined using improper hindsight (remarks, page 10), this argument is not persuasive because, as discussed above, Honkanen teaches administering a nucleic acid vector expressing P450-FdxR-Fdx to human hepatocellular carcinoma cells (i.e., subject in need thereof). Since Honkanen teaches the same method steps and same population being treated, the preamble of “A method of treating hepatocellular carcinoma” is considered inherent. Therefore, Honkanen inherently teaches treatment of hepatocellular carcinoma. Moreover, Grazie teaches treatment of hepatocellular carcinoma by administering Sorafenib, which is a chemotherapy (see, e.g., Grazie, abstract). Therefore, both Honkanen and Grazie both teach treatment of hepatocellular carcinoma by administering compositions capable of treating hepatocellular carcinoma. Therefore, one of ordinary skill in the art would be motivated to combine administration of a nucleic acid vector encoding P450-FdxR-Fdx, as taught by Honkanen, and Sorafenib, as taught by Grazie, because both are art recognized equivalents known for the same purpose and due to the additive treatment of hepatocellular carcinoma (see, e.g., In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Furthermore, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As stated above and reiterated here, Honkanen teaches administration of the same composition (i.e., nucleic acid vector expressing P450-FdxR-Fdx), to the same population (i.e., Hep3B – human hepatocellular carcinoma cells), which would inherently result in treatment of hepatocellular carcinoma. Furthermore, Grazie teaches treatment of hepatocellular carcinoma by administering Sorafenib, which is a chemotherapy (see, e.g., Grazie, abstract). Therefore, P450-FdxR-Fdx and Sorafenib are art recognized equivalents for the treatment of hepatocellular carcinoma and one would be motivated to combine the two in order to treat hepatocellular carcinoma. Honkanen and Grazie teach the instantly claimed invention and there is motivation to combine the art recognized equivalents; therefore, there is no hindsight bias based on Applicant’s disclosure.
Art of Record
Accegen, Hep3B Tumor Cell Lines. Hep 3B https://www.accegen.com/product/hep-3b-abc-tc5585/ - AcceGen
Conclusion
Claims 1-3, 5-10, 12-14, and 40-42 are rejected.
No claims are allowed.
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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