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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Nov. 17, 2025 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 17, 2025. Claims 1, 3-8, 10 and 12-17 are pending. Claims 10 and 12-17 are withdrawn. Claims 1 and 3-8 are currently examined.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
(Previous Rejection – Maintained) Claim 8 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because it is directed to a judiciary exception (JE).
A claim directed to a judicial exception must be analyzed to determine whether the elements of the claim, considered both individually and as an ordered combination, are sufficient to ensure that the claim as a whole amounts to significantly more than the exception itself. To be patent-eligible, a claim that is directed to a judicial exception must include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception.
Claim 8 is directed to an isolated nucleotide molecule encoding a truncated form of a host factor specific for hepatitis B virus (HBV) infection or the truncated form of the host factor specific for hepatitis B virus (HBV) infection, wherein the truncated form comprises an N-terminus domain of the host factor, and wherein the truncated form of the host factor comprises an amino acid sequence as shown in SEQ ID NO: 9 or 10, or an amino acid sequence that has at least 90% identity to the amino acid sequence as shown in SEQ ID NO: 9 or 10. SEQ ID NO: 9 or 10 is comprised in the human scavenger receptor class F, member 2 (SCARF2). See GenBank: BC172421.1 (Synthetic construct Homo sapiens clone IMAGE:100069115, MGC:199126 scavenger receptor class F, member 2 (SCARF2) mRNA, encodes complete protein; dated Mar. 16, 2009). A fragment of this human protein as well as the genomic nucleic acid sequence encoding it are naturally occurring products, and, therefore a JE. Merely reciting “isolated” does not amount to significantly more than the exception itself.
Accordingly, claim 8 is directed to a naturally existing product.
Claim Rejections - 35 USC § 103
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 of this title, 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.
(Previous Rejection – Maintained) Claims 1 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii et al. (THE JOURNAL OF BIOLOGICAL CHEMISTRY. Vol. 277, No. 42, Issue of October 18, pp. 39696–39702, 2002), in view of GenBank: BC172421.1 (Synthetic construct Homo sapiens clone IMAGE:100069115, MGC:199126 scavenger receptor class F, member 2 (SCARF2) mRNA, encodes complete protein. Dated Mar. 16, 2009).
Claim 1 is directed to a cell expressing a truncated form of a first exogenous host factor specific for hepatitis B virus (HBV) infection, wherein the truncated form comprises an N-terminus domain of the first exogenous host factor, and wherein the truncated form of the first exogenous host factor comprises an amino acid sequence as shown in SEQ ID NO: 9 or 10, or an amino acid sequence that has at least 90% identity to the amino acid sequence as shown in SEQ ID NO: 9 or 10.
Claim 8 is directed to an isolated nucleotide molecule encoding a truncated form of a first host factor specific for hepatitis B virus (HBV) infection or the truncated form of the first host factor specific for hepatitis B virus (HBV) infection, wherein the truncated form comprises an N-terminus domain of the first host factor, and wherein the truncated form of the first host factor comprises an amino acid sequence as shown in SEQ ID NO: 9 or 10, or an amino acid sequence that has at least 90% identity to the amino acid sequence as shown in SEQ ID NO: 9 or 10.
SEQ ID NOs: 9 and 10 are contained in SEQ ID NO: 8, which is 100% identical to the amino acid sequence of a human scavenger receptor class F, member 2 (SCARF2) protein, also called scavenger receptor expressed by endothelial cells 2 (SREC-II) protein. (SEQ ID NO: 8 contains SEQ ID NO: 9, and SEQ ID NO: 9 contains SEQ ID NO: 10.)
Ishii teaches a study on interactions between SREC-I and SREC-II through extracellular domains. It teaches that the cDNA for murine SREC-II encodes an 834-amino acid protein with 35% homology to SREC-I. Similar to SREC-I, SREC-II contains multiple epidermal growth factor-like repeats in its extracellular domain. However, in contrast to SREC-I, SREC-II had little activity to internalize modified low density lipoproteins (LDL). A Northern blot analysis revealed a tissue expression pattern of SREC-II similar to that of SREC-I with predominant expression in human heart, lung, ovary, and placenta. Mouse fibroblast L cells with no tendency to associate showed noticeable aggregation when SREC-I was overexpressed in these cells, whereas overexpression of SREC-II caused only slight aggregation. Remarkably, intense aggregation was observed when SREC-I-expressing cells were mixed with those expressing SREC-II. Deletion of almost all of the cytoplasmic receptor domain had no effect on the receptor expression and cell aggregation, indicating that solely the extracellular domain is involved in cell aggregation. The association of SREC-I and -II was effectively suppressed by the presence of scavenger receptor ligands such as acetylated LDL and oxidized LDL. These findings suggest that SREC-I and -II show weak cell-cell interaction by their extracellular domains (termed homophilic trans-interaction) but display strong heterophilic trans-interaction through the extracellular epidermal growth factor-like repeat domains. See Abstract.
Fig. 1A presents amino acid sequences of human and mouse SREC-I and SREC-II proteins, showing that the SREC-II protein sequence is about identical to SEQ ID NO: 8. Fig. 1B shows the domain structures of SREC-I and SREC-II proteins, indicating that the extracellular domains are located in the N-terminal portion of each protein.
Ishii teaches that the homology between murine and human SREC-II, as revealed by the GENETYX-MAC program, is 81.6%. See page 39697, right column, para 1. Ishii further teaches that to verify the biological functions of SREC-II, the authors first compared the ability of modified LDL uptake between SREC-I and -II. The expression plasmid containing either murine SREC-I or murine SREC-II cDNA (pcDNA3-SREC-I or pcDNA3-SREC-II) was transfected into CHO cells, and the transfectants were incubated with DiI-AcLDL (Fig. 3A). See page 39699, left column, para 2.
Accordingly, Ishii teaches SREC-II proteins of murine and human origins as well as cells expressing exogenous murine SREC-II (which is about 81.6% homology to human SREC-II) produced by transfecting of an expression plasmid containing cDNA encoding the murine SREC-II or an N-terminal truncated form with the C-terminal intracellular domain truncated. However, Ishii is silent on a cell expressing a protein that is at least 90% identical to SEQ ID NO: 9 or 10 (including a human SREC-II protein).
GenBank: BC172421.1 discloses a nucleotide sequence encoding SCARF2 which is 100% identical to SEQ ID NO: 8, which comprises SEQ ID NOs: 9 and 10, indicating that cDNA sequence of human SREC-II is known at the time of invention.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to modify the studies of Ishii by substituting the murine SREC-II (and SREC-I when necessary) gene with the human counterpart, disclosed in GenBank: BC172421.1, and produce a transfected cell expressing exogenous hSREC-II to study the interaction for the human SREC-I and SREC-II proteins, in the same way as that for the murine proteins.
(Previous Rejection – Maintained) Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii et al. (THE JOURNAL OF BIOLOGICAL CHEMISTRY. Vol. 277, No. 42, Issue of October 18, pp. 39696–39702, 2002) in view of GenBank: BC172421.1 (Synthetic construct Homo sapiens clone IMAGE:100069115, MGC:199126 scavenger receptor class F, member 2 (SCARF2) mRNA, encodes complete protein. Dated Mar. 16, 2009), as applied in the rejections above, and further in view of Nakagawa et al. (Endocrinology 155: 4706–4719, 2014) and GenBank: ABZ92411.1 (cAMP responsive element binding protein 3-like 3, partial [synthetic construct]. Dated Jul. 26, 2016).
Claims 3-4 specify that the cell according to claim 1 further comprising a second exogenous host factor specific for HBV infection and/or a truncated form thereof capable of regulating expression or function of the first specific host factor, wherein the second exogenous host factor comprises an amino acid sequence as shown in SEQ ID NO: 1, or has an amino acid sequence having at least 90% identity to the amino acid sequence as shown in SEQ ID NO: 1.
SEQ ID NO: 1 represents the human cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3). See GenBank: ABZ92411.1.
Relevance of Ishii and GenBank: BC172421.1 is set forth in the rejections above. However, they are silent on a second exogenous host factor to be expressed in the cells of claim 1, as claimed.
Nakagawa teaches that transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. The authors show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor (PPAR) a promoter in an autoloop fashion and is crucial for the ligand transactivation of PPARa by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1a. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes. See Abstract.
Accordingly, teachings of Nakagawa indicate that CREB3L3 is a host transcription regulator that is involved in energy and lipid metabolism in liver cells and that its regulation functions have been studied by overexpression of CREB3L3 through an exogenously introduced gene.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Ishii, GenBank: BC172421.1, Nakagawa and GenBank: ABZ92411.1 to arrive at the invention as claimed. One would have been motivated to do so to study the combined effect of SCARF2 and CREB3L3 proteins exogenous expressed (overexpressed) in affecting lipid metabolism pathways, based on the teachings in Ishii and Nakagawa for individually overexpressing SCARF2 and CREB3L3, respectively, and their effect on lipid metabolism. There is a reasonable expectation of success that genes encoding both of the host factors can be exogenously introduced to host cells for overexpression and functional studies according to the teachings of Ishii and Nakagawa.
(Previous Rejection – Maintained) Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii et al. (THE JOURNAL OF BIOLOGICAL CHEMISTRY. Vol. 277, No. 42, Issue of October 18, pp. 39696–39702, 2002) in view of GenBank: BC172421.1 (Synthetic construct Homo sapiens clone IMAGE:100069115, MGC:199126 scavenger receptor class F, member 2 (SCARF2) mRNA, encodes complete protein. Dated Mar. 16, 2009), as applied in the rejections above, and further in view of Nikolaou et al. (Physiol Rep, 4 (21), 2016, e12944).
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii et al. (THE JOURNAL OF BIOLOGICAL CHEMISTRY. Vol. 277, No. 42, Issue of October 18, pp. 39696–39702, 2002) in view of GenBank: BC172421.1 (Synthetic construct Homo sapiens clone IMAGE:100069115, MGC:199126 scavenger receptor class F, member 2 (SCARF2) mRNA, encodes complete protein. Dated Mar. 16, 2009), as applied in the rejections above, and further in view of Nikolaou et al. (Physiol Rep, 4 (21), 2016, e12944).
Claim 5 specifies that the cell is selected from a group consisting of HepG2 cells, HepG2-NTCP cells, and primary human hepatocytes (PHHs). Claim 6 specifies that the cells are cultured in a medium containing DMSO and/or insulin.
Relevance of Ishii and GenBank: BC172421.1 is set forth in the rejections above. However, they are silent on using the human hepatocyte specified in claim 5, and they are silent on using a cell culture medium containing DMSO and/or insulin.
Nikolaou teaches that primary human hepatocytes are considered to be the “gold standard” cellular model for studying hepatic fatty acid and glucose metabolism; however, they come with limitations. Although the HepG2 cell line retains many of the primary hepatocyte metabolic functions they have a malignant origin and low rates of triglyceride secretion. The aim of this study was to investigate whether dimethyl sulfoxide (DMSO) supplementation in the media of HepG2 cells would enhance metabolic functionality leading to the development of an improved in vitro cell model that closely recapitulates primary human hepatocyte metabolism. HepG2 cells were cultured in media containing 1% dimethyl sulfoxide for 2, 4, 7, 14, and 21 days. Gene expression, protein levels, intracellular triglyceride, and media concentrations of triglyceride, urea, and 3-hydroxybutyrate concentrations were measured. Dimethyl sulfoxide treatment altered the expression of genes involved in lipid (FAS, ACC1, ACC2, DGAT1, DGAT2, SCD) and glucose (PEPCK, G6Pase) metabolism as well as liver functionality (albumin, alpha-1-antitrypsin, AFP). mRNA changes were paralleled by alterations at the protein level. DMSO treatment decreased intracellular triglyceride content and lactate production and increased triglyceride and 3-hydroxybutyrate concentrations in the media in a time-dependent manner. The authors have demonstrated that the addition of 1% dimethyl sulfoxide to culture media changes the metabolic phenotype of HepG2 cells toward a more primary human hepatocyte phenotype. This will enhance the currently available in vitro model systems for the study of hepatocyte biology related to pathological processes that contribute to disease and their response to specific therapeutic interventions. See Abstract.
These teachings indicate that HepG2 is a good in vitro model for the study of lipid metabolism in liver and that addition of DMSO help to improve the cell line functions to more closely resemble primary hepatocytes.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to modify the studies of Ishii by substituting the CHO cells used in the study with the HepG2 cell line (with or without DMSO) to better study the SREC-I/II interactions in hepatocytes. One of skill in the art would have been further motivated to do so based on the teachings of Ishii that a kind of lipid metabolism (i.e., uptake of LDL) is involved in the study. See discussion in the 103 rejection above.
Response to Applicant’s Amendments
Applicant’s amendments filed on Nov. 17, 2025 have been fully considered. Arguments regarding withdrawn rejections are moot. Applicant’s arguments relevant to the current rejections are addressed as follows.
For the 101 rejection of claim 8, the addition of the word "isolated" does not amount to significantly more than the claimed nucleotide or amino acid sequences which are naturally occurring.
For the 103 rejections, Applicant argues that Ishii discloses that SREC-II has a very similar genetic structure to SREC-I and can interact with SREC-I by their extracellular domains. Applicant argues that Ishii fails to disclose or suggest the claimed structural features, i.e., the truncated form. Applicant argues that Ishii also fails to disclose that the functional contributions of individual domains within the 10 EGF-like cysteine-rich motifs of the SREC-II extracellular domain, thus, there would not have been any motivation to use the specifically claimed truncated form of the protein. Applicant argues that Examples 7-8 show the truncated forms of SCARF2 comprising an amino acid sequence shown in SEQ ID NO: 9 (comprising EGF 1-7) or SEQ ID NO: 10 (comprising EGF 4-6) exhibit specific and strong binding interactions with the HBV. Applicant argues that as demonstrated in the present application, not all mutant clones with individual deletions of the 7 EGF-like domains function equivalently. Applicant argues that the application shows the claimed truncated forms of SCARF2 must at least comprise domains 4, 5 and 6, such as the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10, or having a sequence that has at least 90% identity to SEQ ID NO: 9 or 10, are responsible for specific and strong binding interactions with HBV. Applicant argues that the results of the present application are unexpected in view of the disclosure of BC172421.1, Ishii, alone or in combination.
Applicant argues that claims 3-6 are either directly or indirectly dependent on claim 1, thus are consequently not obvious over Ishii and the additional secondary references. Applicant argues that the present disclosure relates to identifying specific factors required for HBV viral entry. The teachings of Nakagawa relate to the effects of CREB3L3 transcriptional regulation on energy a lipid metabolism and are silent to the effects of CREB3L3 on HBV viral entry. The Applicant argues that these are two different aspects of biology and that there is no reasonable expectation of success in one field that would carry over to another. Applicant argues that because Nakagawa characterizes the effects of CREB3L3 transcriptional regulation on energy and lipid metabolism does not necessarily make it obvious that the model is sufficient to study mechanisms of viral entry.
Applicant argues that Nikolaou relate to optimizing an in vitro model to study hepatocyte fatty acid and glucose metabolism, and is silent to the effects of HBV viral entry. Applicant argues that because Nikolaou characterizes HepG2 cells as a good in vitro model to study hepatocyte lipid metabolism does not necessarily make it obvious that the model is sufficient to study mechanism of viral entry.
Applicant's arguments are not persuasive. Ishii teaches SREC-II interact with the SREC-I through its extracellular domain (which is expected to comprise the sequences of homology to SEQ ID NO: 9 and SEQ ID NO: 10). Ishii further teaches construction and expression of cytoplasmic receptor domain deleted form of SREC-I (see Abstract). Based on the structural and functional similarity of SREC-I and SREC-II, one of skill in the art would have found it obvious to expand the study of Ishii to SREC-II of human origin, as disclosed in GenBank: BC172421.1 (extracellular domain of human SREC-II is expected to comprise the sequences of SEQ ID NO: 9 and SEQ ID NO: 10). One would have been motivated to delineate the domain functions of human SREC-II in a way similar to that disclosed in Ishii.
Nakagawa teaches that CREB3L3 is a host transcription regulator that is involved in energy and lipid metabolism in liver cells and that its regulation functions have been studied by overexpression of CREB3L3 through an exogenously introduced gene. One would have found it obvious to study the combined effect of SREC-II and CREB3L3 proteins overexpressed in affecting lipid metabolism pathways based on teachings of Ishii and Nakagawa.
Nikolaou teaches that HepG2 is a good in vitro model for the study of lipid metabolism in liver and that addition of DMSO help to improve the cell line functions to more closely resemble primary hepatocytes. One would have found it obvious to modify the studies of Ishii by substituting the CHO cells in the study with the HepG2 cells to better study the SREC-I/II interactions in hepatocytes.
Claims 3-6 depend from claim 1 which is directed to a cell expressing a human SREC-II with C-terminus truncated, related with lipid metabolism, and suggested by Ishii and Genbank: BC172421. By calling it a “host factor for hepatitis B virus (HBV) infection" does not change the nature of the claimed host factor being SREC-II and the claimed cell being a cell expressing a C-terminally truncated human SREC-II.
As to the arguments about unexpected results, Applicant's attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., to evaluate if the claimed invention produces unexpected results, one must consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671