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 .
DETAILED ACTION
Amendments
In the reply filed 04/22/2026, Applicant has amended claims 6 and 8-9.
Claim Status
Claims 6-10 are pending and are considered on the merits.
Withdrawn Claim Objections
The prior objection to claim 6 because of typographical error and abbreviation is withdrawn in light of Applicant’s amendment to the claim.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of claims 6-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for reciting relative terms is withdrawn in light of Applicant’s amendment to claims 6 and 8 to recite numerical sizes of VLDLs.
Withdrawn Claim Rejections - 35 USC § 112(d)
The prior rejection of claim 9 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s amendment to the claim.
New Claim Rejections - 35 USC § 112(a)
NEW MATTER
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 9 recites new limitation that the method “further comprising adding dimethyl sulfoxide during the step of administering the test substance to the human fatty-liver model cell culture”. This new limitation represents new matter. In amended cases, subject matter not disclosed in the original application is sometimes added and a claim directed thereto. Such a claim is rejected on the ground that it recites elements without support in the original disclosure under 35 U.S.C. 112, first paragraph, Waldemar Link, GmbH & Co. v. Osteonics Corp. 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 2163.06 - § 2163.07(b) for a discussion of the relationship of new matter to 35 U.S.C. 112, first paragraph. New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04 to § 608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific percentages or compounds after a broader original disclosure constitutes new matter.
In the instant case, a review of the specification by the Examiner only found support of dimethyl sulfoxide (DMSO) being added during cell culture of human hepatocytes (e.g., [0036], [0058], [0072], and see Medium B containing DMSO in page 54 for culturing hepatocytes), but did NOT find any specific basis for the newly recited limitation of “adding dimethyl sulfoxide during the step of administering the test substance to the human fatty-liver model cell culture”. It is noted that during the step of administering the test substance to the cell culture, “a medium of PXB-cells prepared above was exchanged with medium D containing 0.75 mM oleic acid” ([0112]), or “exchanged with mediums D containing 1 nM or 5 nM lomitapide” ([0117]), or “exchanged with mediums D containing 10 µM, 50 µM or 100 µM fenofibrate” ([0123]), and medium D does NOT comprise DMSO (see “Medium D” in page 54).
Withdrawn Claim Rejections - 35 USC § 101
The prior rejection of claims 6-10 under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter, is withdrawn in light of Applicant’s amendment to claim 6 to recite new limitation of “measuring” Large-VLDL, which may not be performed mentally.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 6-10 under 35 U.S.C. 103 as being unpatentable over Hata in view of Khetani, Fon Tacer, Wojczynski and Packard is withdrawn in light of Applicant’s amendment to claims 6 and 8 to recite new limitation of the numerical sizes of the VLDL fractions as determined by peak values measured by HPLC, which is not discussed in the prior rejection.
New 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, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
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 6-10 are rejected under 35 U.S.C. 103 as being unpatentable over Hata et al. (Biomedical Research (Tokyo). 2020 Feb. 1st, 41(1): 33-42, cited in IDS 08/23/2023) in view of Khetani et al., (US 2018/0172668, cited in IDS 04/21/2025), Fon Tacer et al., (J Lipids. 2011:783976, p. 1-14. Prior art of record), Packard et al., (Front. Endocrinol. 2020;11:252, p. 1-15. Prior art of record) and Okazaki et al., (Arterioscler Thromb Vasc Biol. 2005; 25:578-584).
With respect to claim 6, Hata teaches a method for screening anti-lipidemic drugs using an in vitro system (see e.g., title and abstract), thus teaches the preamble a method for screening for a substance having an effect on dyslipidemia.
Hata teaches human hepatocytes are transplanted and repopulated in immunodeficient mice, and fresh hepatocytes are isolated from the humanized mouse livers (“PXB-cells”, p. 34, para. 1 and Fig 1), thus teaches a human liver model cell culture. Hata teaches evaluation of anti-lipidemic agents by administering a test substance such as fenofibrate to the human liver model cell culture (p. 39, right col., para “Evaluation of anti-lipidemic agents by lipoprotein profiles of PXB-cells”, see Table 4 and Fig. 6). Hata teaches the PXB-cells produce both VLDL and LDL, and mainly release cholesterol and triglycerides in the VLDL fraction (p. 38, right col., see Table 3 and Fig. 3), thus teaches the culture supernatant of the cells contains VLDL and LDL in which the VLDL is contained more than the LDL. Hata teaches the PXB-cells are obtained by culturing human hepatocytes derived from the humanized mouse livers in a medium containing dimethyl sulfoxide (DMSO, see p. 34, right col, para 1).
However, Hata is silent on the cell culture being a human fatty-liver model cell culture, nor teach the human hepatocytes are derived from fatty liver.
Khetani teaches a method for high throughput screening and evaluation of drug candidates using an in vitro human hepatocytes cell culture system (see e.g., abstract). Khetani teaches the hepatocytes may be obtained from human donors suffering from a liver disorder, such as non-alcoholic fatty liver disease (NAFLD) ([0008], [0012], also see reference claims 9-10 and 15-16). Thus, Khetani teaches a human fatty-liver model cell culture that is obtained by culturing human hepatocytes derived from fatty liver.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for screening for anti-lipidemic drugs using a human liver model cell culture disclosed by Hata, by substituting the human liver with human fatty liver (i.e., using a human fatty-liver model cell culture derived from fatty liver) as suggested by Khetani with a reasonable expectation of success. Since Hata aims to screen for anti-lipidemic drugs using a chimeric human liver model cell culture (see e.g., title and abstract), and since Khetani reduces to practice a method for high throughput screening and evaluation of drug candidates using human hepatocytes obtained from human donors suffering from non-alcoholic fatty liver disease (e.g., abstract, [0008], [0012], also see reference claims 9-10 and 15-16), one of ordinary skill in the art would have had a reason to derive human hepatocytes from fatty liver as suggested by Khetani in the method of Hata in order to screen for drug candidates to treat a liver disorder such as non-alcoholic fatty liver disease (see Khetani claims 15-16).
Furthermore, since prior art Fon Tacer teaches in nonalcoholic fatty liver disease, deregulation of fat metabolism in the fatty liver is accompanied by overproduction of very-low-density lipoproteins (VLDL) (p. 2, left col, para 2), and since Hata teaches the human hepatocytes (PXB-cells) produce both VLDL and LDL, and mainly release cholesterol and triglycerides in the VLDL fraction (p. 38, right col., see Table 3 and Fig. 3), one of ordinary skill in the art would have had a reasonable expectation of success in obtaining culture supernatant of the human hepatocytes derived from fatty liver that contains VLDL and LDL in which the VLDL is contained more than the LDL.
In regard to evaluating the anti-lipidemic effect of the test substance, Hata measures the lipoprotein profiles in the culture supernatant of PXB-cells treated with the test substance comparing to that of untreated control cells, including measuring the amount of VLDL, LDL and HDL fractions (p. 39, right col, para “Evaluation of anti-lipidemic agents by lipoprotein profiles of PXB-cells”, also see Table 4 and Fig. 6). Hata teaches the VLDL has a size of about 30-80 nm (p. 33, end of left col – right col).
However, Hata is silent on measuring an amount of Large-VLDL, nor teach the size of Large-VLDL.
Fon Tacer teaches fatty liver-associated dyslipidemic profile is characterized by increased large VLDL and small dense LDL, and decreased large HDL correlated with the intrahepatic lipid content (p. 2, left col., para 2).
Packard teaches increased levels of plasma triglyceride are associated with the accumulation of large, triglyceride-rich VLDL (VLDL1 particles with a diameter range of 50-80 nm, close to the claimed range of about 44.5 nm to about 64 nm) while smaller VLDL (VLDL2 which are 30-50 nm in diameter) show a moderate elevation (Figure 1A) (p. 2, right col, para “Accumulation of Large VLDL in Hypertriglyceridemia”). Packard teaches significant correlations are found between liver fat/ body fat mass and the VLDL1 synthesis rate (p. 7, left col, para 1-2, also see Fig 3A). Thus, both Fon Tacer and Packard suggest that Large-VLDL amount is characteristic in fatty liver-associated dyslipidemic profile and is correlated with liver fat. Packard further teaches that pharmacological interventions (such as statins) act on different mechanisms to modulate the amounts of VLDL1 and other fractions (see e.g., Fig 5).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for measuring and comparing lipoprotein profiles including VLDL in the human fatty-liver model cell culture suggested by Hata in view of Khetani and Fon Tacer, by combining measuring the amount of Large-VLDL among the amount of VLDL as one lipoprotein fraction as suggested by Fon Tacer and Packard with a reasonable expectation of success. Since Hata teaches measuring and comparing the lipoprotein profiles including the amount of VLDL to evaluate the anti-lipidemic effect of the test substance (see above), and since both Fon Tacer and Packard suggest that Large-VLDL amount is characteristic in fatty liver-associated dyslipidemic profile and is correlated with liver fat (see above) and Packard further teaches that pharmacological interventions (such as statins) modulate the amount of Large-VLDL and other fractions (see Fig 5), one of ordinary skill in the art would have had a reason to combine measuring the amount of Large-VLDL as an indicator for evaluating the anti-lipidemic effect of the test substance in the human fatty-liver model cell culture in order to take advantage of its being characteristic in fatty liver-associated dyslipidemic profile and its being modulated by pharmacological interventions.
However, Hata, Khetani, Fon Tacer and Packard do not specifically teach the size of Large-VLDL being determined by peak values measured by HPLC.
Okazaki teaches a method of identification lipoprotein subclasses by jigh-performance liquid chromatography (HPLC) (see e.g., title and abstract). Okazaki teaches by detecting peak values using HPLC (p. 579, left col, para “HPLC Method”), Large-VLDL is identified as having a size of about 44.5 nm to about 64 nm (see e.g., Table 2, the exact claimed range in claim 6), the total VLDL is identified as having a size of about 31.3 nm to about 64 nm (see e.g., Table 2, almost the exact claimed range in claim 6). The Medium-VLDL is identified as having a size of about 36.8 nm (see e.g., Table 2, the exact claimed range in claim 8) and the Small-VLDL is identified as having a size of about 31.3 nm (see e.g., Table 2, close to the claimed range in claim 8). Okazaki teaches this simple HPLC method may be applied for easy detection and evaluation of abnormal distribution of lipoprotein subclasses (see e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for measuring Large-VLDL and other subclasses of lipoproteins in the human fatty-liver model cell culture suggested by Hata in view of Khetani, Fon Tacer and Packard, by choosing to use HPLC and the parameters of peak values to measure the lipoprotein subclasses as suggested by Okazaki with a reasonable expectation of success. Since Okazaki reduces to practice a method of HPLC and the parameters of peak values to measure lipoprotein subclasses and teaches this simple HPLC method may be applied for easy detection and evaluation of abnormal distribution of lipoprotein subclasses (see e.g., abstract), one of ordinary skill in the art would have had a reason to choose the HPLC method and the peak values to measure the Large-VLDL and other subclasses of lipoproteins as suggested by Okazaki in order to take advantage of this simple method for easy detection and evaluation of the distribution of lipoprotein subclasses in the human fatty-liver model cell culture.
With respect to claim 7 directed to the cell culture being a monolayer cell culture, Hata teaches the PXB-cells are seeded and maintained in a 24-well microplate (p. 34, right col, para 1) and Figure 2 (a) shows the PXB-cells are cultured as a monolayer.
With respect to claim 8, as stated supra, Okazaki makes obvious the VLDL includes Large-VLDL, Medium-VLDL and Small-VLDL, and makes obvious the size of the Medium-VLDL and the size of the Small-VLDL determined by peak values measured by HPLC (see above).
In regard to the limitation that the Large-VLDL is contained in a ratio of 70 mass% or more of total VLDLs, it must be noted that these wherein clauses do not recite an active step in the claimed method, but only the results of the step of the human fatty-liver model cell culture being obtained by culturing human hepatocytes derived from fatty liver as suggested by Hata in view of Khetani and Fon Tacer. MPEP 2111.04 I states a whereby clause (or a wherein clause) “in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, these wherein clauses do not provide any patentable weight in determining patentability of the claimed method.
Nevertheless, Packard teaches increased levels of plasma triglyceride are associated with the accumulation of large, triglyceride-rich VLDL (VLDL1 particles with a diameter range of 50-80 nm) containing about 70% triglyceride by mass, while smaller VLDL (VLDL2 which are 30-50 nm in diameter and consist of about 30% triglyceride) show a moderate elevation (Figure 1A) (p. 2, right col, para “Accumulation of Large VLDL and Remnants in Hypertriglyceridemia”). Figure 1A shows VLDL1 (i.e., Large-VLDL) is contained in a ratio of 70 mass% or more of total VLDLs in hypertriglyceridemia (VLDL1/(VLDL1+VLDL2) = ~200/(200+40) = 83%).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have appreciated that the Large-VLDL in the method suggested by Hata in view of Khetani, Fon Tacer, Packard and Okazaki, is likely contained in a ratio of 70 mass% or more of total VLDLs as suggested by Packard since the suggested method uses a human fatty-liver model cell culture that is characterized by increased large VLDL (Fon Tacer, p. 2, left col., para 2) and Packard teaches large VLDL is accumulated in hypertriglyceridemia and is contained in a ratio of 70 mass% or more of total VLDLs (p. 2, right col, para “Accumulation of Large VLDL and Remnants in Hypertriglyceridemia” and Figure 1A).
With respect to claim 9 directed to adding DMSO during administering the test substance to the human fatty-liver model cell culture, as stated supra, Hata teaches the human liver model PXB-cells are cultured in a medium containing dimethyl sulfoxide (DMSO, see p. 34, right col, para 1), and teaches treating the PXB-cells with a test substance fenofibrate (e.g., p. 39, right col, para 2). Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen to add DMSO during administering the test substance to the human fatty-liver model cell culture as suggested by Hata in order to maintain the human fatty-liver model cell culture for drug screening.
With respect to claim 10 directed to the human hepatocytes being collected from a chimeric non-human animal having human hepatocytes, as stated supra, Hata teaches human hepatocytes are transplanted and repopulated in immunodeficient mice (i.e., a chimeric non-human animal), and fresh human hepatocytes are isolated from the humanized mouse livers (“PXB-cells”, p. 34, para. 1 and Fig 1).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 04/22/2026 are acknowledged.
Applicant argues that none of the cited documents describe screening for a substance having an effect on dyslipidemia based on an effect (i.e. increase or decrease) of an amount of Large-VLDL among an amount of VLDL as a screening parameter in the human fatty-liver model cells of the present invention (Remarks, p. 5).
Applicant’s arguments have been fully considered but they are not persuasive.
As discussed above, Hata measures the lipoprotein profiles in the culture supernatant of PXB-cells treated with the test substances, including measuring the amount of VLDL, LDL and HDL fractions as screening parameters (see e.g., Table 4 and Fig. 6). The only difference between Hata and the instant invention is that Hata does not specifically use the amount of Large-VLDL (a subclass of VLDL) as a screening parameter. Fon Tacer and Packard are cited to suggest that the amount of Large-VLDL is characteristic in fatty liver-associated dyslipidemic profile and is correlated with liver fat (see above). Packard further teaches that pharmacological interventions (such as statins) modulate the amounts of Large-VLDL and other subclasses (see e.g., Fig 5). Accordingly, one of ordinary skill in the art would have combined measuring the amount of Large-VLDL as a screening parameter for evaluating the test substances in order to take advantage of its being characteristic in fatty liver-associated dyslipidemic profile and its being modulated by pharmacological interventions as suggested by Fon Tacer and Packard.
Applicant further argues that the present application demonstrates that the effects of substances effective against dyslipidemia vary among Large-VLDL, Medium-VLDL, and Small-VLDL within the VLDL spectrum (e.g., lomitapide significantly affects Large-VLDL, fenofibrate influences Large, Medium, and Small-VLDL as a whole, and oleic acid exclusively increases Large-VLDL). The cited prior art references do not disclose or suggest that the effects of substances effective against dyslipidemia differ among Large-VLDL, Medium-VLDL, and Small-VLDL, so the beneficial effects of the presently claimed method are unexpected over the prior art (Remarks, p. 5-6).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to Applicant's argument, it is noted that the features upon which applicant relies (i.e., the demonstration that the effects of substances differ among Large-VLDL, Medium-VLDL, and Small-VLDL) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). See MPEP 2111.01 II.
Additionally, regarding the effects of substances differ among lipoprotein fractions, since the test substances may act on different targets involved in the production or clearance of different lipoprotein fractions, one of ordinary skill in the art would have immediately expected that the effects of substances would differ among lipoprotein fractions, as evidenced by Packard, who teaches that pharmacological interventions (such as statins, PCSK9i or Fibrates/SPPARaM) act on different mechanisms and target different receptors/enzymes to modulate the amount of different lipoprotein fractions (see e.g., Fig 5).
Furthermore, MPEP 716.02(d), states that unexpected results must be commensurate in scope with the claimed invention. In the instant case, the purported unexpected results are the demonstration that the effects of substances effective against dyslipidemia vary among Large-VLDL, Medium-VLDL, and Small-VLDL within the VLDL spectrum, which is not commensurate in scope with the claimed method for screening for a substance comprising administering a test substance to a human fatty-liver model cell culture and measuring an amount of Large-VLDL among an amount of VLDL in culture supernatant. In other words, the purported unexpected results are merely the intended results of the administering and measuring steps. MPEP 2111.04 I states a whereby clause (or a wherein clause) “in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”
Withdrawn Provisional Double Patenting Rejections
The prior provisional rejection of claims 6-10 on the ground of nonstatutory double patenting is withdrawn in light of Applicant’s amendment to claims 6 and 8 to recite new limitations regarding measuring Large-VLDL by HPLC.
New Provisional Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 6-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1-14 of copending Application No: 19/044,583 in view of Fon Tacer et al., (J Lipids. 2011:783976, p. 1-14. Prior art of record), Okazaki et al., (Arterioscler Thromb Vasc Biol. 2005; 25:578-584) and evidenced by Hata et al. (Biomedical Research (Tokyo). 2020 Feb. 1st, 41(1): 33-42, cited in IDS 08/23/2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending application claims recite a method for screening for a substance effective for human fatty liver, comprising the steps of culturing human hepatocytes derived from fatty liver with DMSO to obtain a culture of human fatty-liver model cells that secrete and/or accumulate lipid, administering a test substance to the culture of human fatty-liver model cells and comparing severity of fatty-liver symptoms between cells to which the test substance is administered and cells to which the test substance is not administered (reference claim 1, related to instant claims 6 and 9), wherein the human hepatocytes are collected from a chimeric non-human animal having human hepatocytes (reference claim 6, related to instant claim 10).
However, the copending claims are silent on the culture supernatant containing VLDL and LDL in which the VLDL is more than the LDL, nor recite measuring large-VLDL in culture supernatant having a size measured by HPLC in instant claim 6.
Fon Tacer teaches deregulation of fat metabolism in the fatty liver is accompanied by overproduction of very-low-density lipoproteins (VLDL), as well as small, dense LDL, and elevated VLDL is likely the key metabolic disturbance and correlates strongly with obesity and metabolic syndrome (p. 2, left col, para 2 and see Fig 1), thus suggests the culture supernatant of fatty-liver model cells contains VLDL and LDL in which the VLDL is more than the LDL. Fon Tacer teaches fatty liver-associated dyslipidemic profile is characterized by increased large VLDL and small dense LDL, and decreased large HDL correlated with the intrahepatic lipid content (p. 2, left col., para 2).
Okazaki teaches a method of identification lipoprotein subclasses by jigh-performance liquid chromatography (HPLC) (see e.g., title and abstract). Okazaki teaches by detecting peak values using HPLC (p. 579, left col, para “HPLC Method”), Large-VLDL is identified as having a size of about 44.5 nm to about 64 nm (see e.g., Table 2, the exact claimed range in instant claim 6), the total VLDL is identified as having a size of about 31.3 nm to about 64 nm (see e.g., Table 2, almost the exact claimed range in instant claim 6). The Medium-VLDL is identified as having a size of about 36.8 nm (see e.g., Table 2, the exact claimed range in instant claim 8) and the Small-VLDL is identified as having a size of about 31.3 nm (see e.g., Table 2, close to the claimed range in instant claim 8). Okazaki teaches this simple HPLC method may be applied for easy detection and evaluation of abnormal distribution of lipoprotein subclasses (see e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising comparing fatty-liver symptoms in the human fatty-liver model cell culture recited in copending claims, by choosing measuring the amount of large VLDL as one fatty-liver marker as suggested by Fon Tacer and choosing to use the HPLC method as suggested by Okazaki with a reasonable expectation of success. Since Fon Tacer teaches increased amount of large VLDL is a characteristic in fatty liver-associated dyslipidemic profile that correlates with the intrahepatic lipid content (p. 2, left col., para 2), one of ordinary skill in the art would have had a reason to choose the amount of large VLDL as a screening marker in order to evaluate the anti-lipidemic effect of the test substance in the human fatty-liver model cell culture. Since Okazaki reduces to practice a method of HPLC and the parameters of peak values to measure lipoprotein subclasses and teaches this simple HPLC method may be applied for easy detection and evaluation of abnormal distribution of lipoprotein subclasses (see e.g., abstract), one of ordinary skill in the art would have had a reason to choose the HPLC method and the peak values to measure the Large-VLDL and other subclasses of lipoproteins as suggested by Okazaki in order to take advantage of this simple method for easy detection and evaluation of the distribution of lipoprotein subclasses in the human fatty-liver model cell culture.
Furthermore, since Fon Tacer teaches in nonalcoholic fatty liver disease, deregulation of fat metabolism in the fatty liver is accompanied by overproduction of very-low-density lipoproteins (VLDL) as well as small, dense LDL, and elevated VLDL is likely the key metabolic disturbance and correlates strongly with obesity and metabolic syndrome (p. 2, left col, para 2), one of ordinary skill in the art would have had a reasonable expectation of success in obtaining culture supernatant of the human hepatocytes derived from fatty liver that contains VLDL and LDL in which the VLDL is contained more than the LDL.
However, copending claims are silent on the cell culture being a monolayer cell culture in instant claim 7.
Regarding culturing human hepatocytes, prior art Hata evidences that the human hepatocytes (PXB-cells) are seeded and maintained in a 24-well microplate (p. 34, right col, para 1) and Figure 2 (a) shows the PXB-cells are cultured as a monolayer.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have appreciated that the human hepatocytes cell culture recited in copending claims would have been a monolayer cell culture as evidenced by Hata.
In regard to the wherein clause in instant claim 8, it must be noted that these wherein clauses do not recite an active step in the claimed method, but only the results of the step of the human fatty-liver model cell culture being obtained by culturing human hepatocytes derived from fatty liver recited in copending claims. Therefore, these wherein clauses do not provide any patentable weight in determining patentability of the instantly claimed method. See MPEP 2111.04 (I).
Since the instant application claims are obvious over cited application claims, in view of Fon Tacer, Okazaki and evidenced by Hata, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 04/22/2026 are acknowledged and have been discussed above.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights