The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicant’s remarks received January 5, 2026.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 2, 6-7, 11 are canceled. Claim 4 is withdrawn. Claims 1, 3, 5, 8-10, 12-20, to metabolic disease, hypercholesterolemia, cholesterol, atherosclerosis index, genotype C, SEQ ID NO: 23, myristic acid, simvastatin, are under consideration.
Priority: This application is a DIV of U.S. Application 16305790, now U.S. Patent 11633454, filed November 29, 2018, which is a 371 of PCT/CN2017/086558, filed May 31, 2017, which claims benefit of CN 201610370442.4, filed May 30, 2016. A copy of the foreign priority document has been received in the parent application (U.S. Application 16305790) on November 29, 2018, and is not in the English language.
Objections and Rejections
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.
Claims 1, 3, 5, 8-10, 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cleeves et al. (WO 2014072524; IDS 04.06.23, previously cited) in view of Mier et al. (US 9868768; previously cited). Claim 1 is drawn to a method of treating or preventing a metabolic disease, where the metabolic disease is hypercholesterolemia, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide or a pharmaceutical composition comprising the polypeptide to produce a serum concentration of the administered polypeptide at a concentration above a concentration threshold of 93 nmol/L, wherein the polypeptide comprises the amino acid sequence set forth in any one of SEQ ID NOS: 21-40, i.e. SEQ ID NO: 23.
Cleeves et al. disclose a method of treating a liver metabolic disease in a patient, comprising administering to the patient a therapeutically effective amount of a lipopeptide-based compound comprising SEQ ID NO: 18 (MyrB), where the liver involved metabolic disease is hyperlipidemia, where hyperlipidemia refers to hypercholesterolemia (at least p. 17-22, p. 42 claims 16-20). Cleeves et al. disclose SEQ ID NO: 18 is obtained from HBV preS/2-48 (genotype C) (at least p. 12) and has an amino acid sequence that differs from instant SEQ ID NO: 23 by one amino acid residue (at least p. 12, 15, 30). Cleeves et al. disclose SEQ ID NO: 18 has amino acid residue K45 while instant SEQ ID NO: 23 has amino acid residue Q45 at the C-terminus. Therefore, SEQ ID NO: 18 differs from instant SEQ ID NO: 23 by one amino acid residue. Cleeves et al. disclose therapeutically effective amounts of the lipopeptide-base compound include variants of SEQ ID NO: 18, having at least 90%, 95%, or 99% sequence identity, to SEQ ID NO: 18 (at least p. 12, 40). Cleeves et al. disclose a therapeutically effective amount of the lipopeptide-based compound refers to an amount that is sufficient to block or inhibit NTCP-mediated bile acid transport (p. 21). In order to inhibit substrate transport the lipopeptide-based compound is used in a dose where the concentration at the target site is above Ki of about 1 to 10 nm (p. 21). Cleeves et al. do not explicitly teach a variant of SEQ ID NO: 18 having the amino acid residue Q45.
Mier et al. disclose variants of HBV preS/2-48 (genotype C), including SEQ ID NO: 39, which comprises SEQ ID NO: 18 of Cleeves et al. and having the amino acid residue Q45 (at least col. 45-46, also Fig. 2). Mier et al. also disclose the preS-derived peptides are for treatment of liver diseases (at least col. 16-18).
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05.
Further, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. MPEP 2144.09.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed method of treating a metabolic disease in a subject in need thereof, comprising practicing the method of Cleeves et al. by administering to the subject a therapeutically effective amount of a polypeptide to produce a serum concentration of the administered polypeptide at a concentration threshold above a concentration threshold of 93 nmol/L by routine optimization or experimentation, wherein the polypeptide comprises SEQ ID NO: 39 of Mier et al. and is identical to instant SEQ ID NO: 23, and wherein the metabolic disease is hypercholesterolemia (instant claims 1, 3, 5, 8-10). It would have been obvious to arrive at the recited serum concentrations by routine experimentation or optimization to determine other concentrations present elsewhere in the patient’s body that also correlate with inhibiting NTCP-mediated bile acid transport. One of ordinary skill would have a reasonable motivation to do so because Cleeves et al. disclose the lipopeptide obtained from the preS-derived peptides of HBV are suitable for treatment of liver metabolic diseases and Mier et al. disclose preS-derived peptides of HBV, including instant SEQ ID NO: 23, which is a variant of the preS-derived peptide of HBV of SEQ ID NO: 18 of Cleeves et al. differing by one amino acid residue. One of ordinary skill would have a reasonable expectation of success that the preS-derived peptides of HBV of Cleeves et al. and Mier et al. allow for bidirectional regulation of NTCP-mediated bile acid uptake in the subject (instant claims 1, 15) because a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. MPEP 2112.01.
Regarding instant claims 12-13, Cleeves et al. disclose the amino acid sequence of SEQ ID NO: 18 (MyrB) has a N-terminal myristic acid and a C-terminal amide (at least p. 28, 30). Therefore, it would have been obvious to incorporate a N-terminal myristic acid and a C-terminal amide in the amino acid sequence of SEQ ID NO: 39 of Mier et al.
Regarding instant claim 15, Cleeves et al. disclose MyrB binds to human NTCP (at least p. 28). Therefore, it would be obvious that the amino acid sequence of SEQ ID NO: 39 of Mier et al. would also bind to human NTCP.
Regarding instant claim 20, Cleeves et al. disclose the route of administration is selected from subcutaneous, intravenous, oral, nasal, intramuscular (at least p. 22, p. 44 claim 23).
Regarding instant claims 3, 5, since Cleeves et al. in view of Mier et al. disclose administering a therapeutically effective amount of a polypeptide that is structurally the same as the claimed polypeptide for treating the same patients recited, it would follow that the polypeptide (i.e. a polypeptide comprising SEQ ID NO: 39 of Mier et al.) administered in the method of Cleeves et al. comprises the properties or functionalities recited. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. MPEP 2112.01.
Regarding instant claim 16, as noted above, Cleeves et al. disclose a therapeutically effective amount of the lipopeptide-based compound refers to an amount that is sufficient to block or inhibit NTCP-mediated bile acid transport (p. 21). In order to inhibit substrate transport the lipopeptide-based compound is used in a dose where the concentration at the target site is above Ki of about 1 to 10 nm (p. 21). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the recited serum concentrations by routine experimentation to determine other concentrations present elsewhere in the patient’s body that also correlate with inhibiting NTCP-mediated bile acid transport. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05.
Regarding instant claim 17, Cleeves et al. disclose the MyrB is further combined with a second drug (at least p. 40 claim 10). Therefore, it would be obvious that the amino acid sequence of SEQ ID NO: 39 of Mier et al. can be further combined with a second drug.
Regarding instant claims 18-19, Cleeves et al. disclose that the MyrB blocks NTCP and bile acid uptake into hepatocytes which leads to intracellular deficiency of bile acid and which is compensated by increased cholesterol metabolism and absorption (at least p. 23-24). Cleeves et al. disclose that simvastatin is an antihyperlipidemic agent transported by NTCP (at least p. 26-27). Therefore, it would have obvious to administer simvastatin with the MyrB lipopeptide compound variant, which is the amino acid sequence of SEQ ID NO: 39 of Mier et al., to a subject in need thereof for treating hypercholesterolemia because the simvastatin would be further available to lower cholesterol.
Regarding instant claim 8, Cleeves et al. disclose SEQ ID NO: 18 has amino acid residue K45 while instant SEQ ID NO: 23 has amino acid residue Q45 at the C-terminus. Therefore, SEQ ID NO: 18 differs from instant SEQ ID NO: 23 by one amino acid residue. Cleeves et al. disclose therapeutically effective amounts of the lipopeptide-base compound include variants of SEQ ID NO: 18, having at least 90%, 95%, or 99% sequence identity, to SEQ ID NO: 18 (at least p. 12, 40). Mier et al. disclose variants of HBV preS/2-48 (genotype C), including SEQ ID NO: 39, which comprises SEQ ID NO: 18 of Cleeves et al. and having the amino acid residue Q45 (at least col. 45-46, also Fig. 2). Therefore, Mier et al. disclose preS-derived peptides of HBV, including instant SEQ ID NO: 23, which is a variant of the preS-derived peptide of HBV of SEQ ID NO: 18 of Cleeves et al. differing by one amino acid residue.
Reply: Applicant’s remarks have been considered but they are not persuasive. The reasons for maintaining the 103 rejection are the same as previously noted and are incorporated herein.
Applicant asserts that regarding the therapeutic amount, Cleeves et al. disclose a preferable therapeutically effective amount of the lipopeptide-based compound to inhibit NTCP-mediated bile acid uptake to be a daily dosage ranging from about 0.0014 mg/kg body weight to about 0.7 mg/kg body weight (Cleeves et al. p. 22). Applicant asserts that in contrast, example 2.4 of the instant specification demonstrates that to maintain a high serum concentration, Cmyr-47 was administered to dogs via daily subcutaneous injection, and only the highest dose of 3.6 mg/kg was able to reach a peak concentration (Cmax) above 500 ng/mL (i.e. 93 nmol/L). Applicant asserts that the therapeutically effective amount needed to reach a Cmax above 500 ng/mL is significantly higher than the dose range disclosed by Cleeves (0.0014 mg/kg to 0.7 mg/kg).
Applicant’s remarks are persuasive. In Applicant’s February 10, 2025 remarks (p. 8-9), Applicant previously asserted that Cleeves et al. disclose a range of 3.33 nmol/L to 1945.52 nmol/L of Cmyr-47. As also previously noted, MPEP 2144.05 notes that "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness.” Further, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”
In this instance, the claims recite administering a polypeptide, similar to the Cmyr-47 of Cleeves et al., to produce a serum concentration of the administered polypeptide at a concentration above 93 nmol/L, in a method for treating the same metabolic disease disclosed in Cleeves et al.
As acknowledged by Applicant, Cleeves et al. disclose a range of 3.33 nmol/L to 1945.52 nmol/L for the administered Cmyr-47 similar compounds.
Therefore, Cleeves et al. disclose administering therapeutically effective amounts of Cmyr-47 similar compounds that produce a serum concentration above the recited 93 nmol/L.
Applicant asserts that that at concentrations below 93 nmol/L, the polypeptides actually enhance NTCP-mediated bile acid uptake rather than inhibit it. Applicant asserts that a person of skill reading Cleeves et al. would be motivated to apply the low dosage that Cleeves et al. disclose to reach a low serum concentration, which teaches away from the presently claimed “above a concentration threshold of 93 nmol/L.”
Applicant’s remarks are not persuasive. It is known that “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123. In this instance, Cleeves et al. still disclose a concentration range comprising above 93 nmol/L for the administered polypeptide that is structurally similar to the claimed polypeptide for treating the same patients recited and at the same therapeutically effective amounts to achieve the same serum concentrations. As noted above, instant claim 1 only requires that the polypeptide (i.e. Cmyr-47) be administered at a therapeutically effective amount to produce a serum concentration of the administered polypeptide at a concentration above 93 nmol/L for treating the same patients disclosed in Cleeves et al.
Applicant asserts that Mier et al. describe hydrophobically modified preS-derived HBV peptides as delivery vehicles or targeting motifs for compounds to the liver. Applicant asserts that therefore, Mier et al. fail to disclose HBV preS/2-48 variants as active pharmaceutical ingredients for treating liver diseases, let alone teach or suggest the critical range of over 93 nmol/L.
Applicant’s remarks are not persuasive. Mier et al. is cited as a 103 reference with Cleeves et al., where Cleeves et al. has disclosed that HBV preS/2-48 variants are active pharmaceutical ingredients for treating liver diseases and further disclose the therapeutic range of over 93 nmol/L.
As noted in the 103 rejection above, Cleeves et al. disclose that the lipopeptide-base compound for treating hypercholesterolemia is SEQ ID NO: 18, which is obtained from HBV preS/2-48 (genotype C) (at least p. 12). SEQ ID NO: 18 has an amino acid sequence that differs from instant SEQ ID NO: 23 by one amino acid residue (at least p. 12, 15, 30). Cleeves et al. disclose SEQ ID NO: 18 has amino acid residue K45 while instant SEQ ID NO: 23 has amino acid residue Q45 at the C-terminus. Cleeves et al. disclose therapeutically effective amounts of the lipopeptide-base compound include variants of SEQ ID NO: 18, having at least 90%, 95%, or 99% sequence identity, to SEQ ID NO: 18 (at least p. 12, 40).
While Cleeves et al. do not explicitly teach a variant of SEQ ID NO: 18 having the amino acid residue Q45, Mier et al. disclose preS-derived peptides also for treating liver diseases, including variants of HBV preS/2-48 (genotype C), including SEQ ID NO: 39, which comprises SEQ ID NO: 18 of Cleeves et al. and having the amino acid residue Q45 (at least col. 45-46, also Fig. 2).
Therefore, it would have been obvious to one of ordinary skill to practice the method of Cleeves et al. by administering to the subject a therapeutically effective amount of a polypeptide derived from HBV preS/2-48 to produce a serum concentration of the administered polypeptide at a concentration threshold above a concentration threshold of 93 nmol/L by routine optimization or experimentation, wherein the polypeptide comprises SEQ ID NO: 39 of Mier et al. and is identical to instant SEQ ID NO: 23, and wherein the metabolic disease is hypercholesterolemia. It would have been obvious to arrive at the recited serum concentrations by routine experimentation or optimization to determine other concentrations present elsewhere in the patient’s body that also correlate with inhibiting NTCP-mediated bile acid transport. One of ordinary skill would have a reasonable motivation to do so because Cleeves et al. disclose the lipopeptide obtained from the preS-derived peptides of HBV are suitable for treatment of liver metabolic diseases and Mier et al. disclose preS-derived peptides of HBV, including instant SEQ ID NO: 23, which is a variant of the preS-derived peptide of HBV of SEQ ID NO: 18 of Cleeves et al. One of ordinary skill would have a reasonable expectation of success that the preS-derived peptides of HBV of Cleeves et al. and Mier et al. allow for bidirectional regulation of NTCP-mediated bile acid uptake in the subject (instant claims 1, 15) because a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. MPEP 2112.01.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached on M-F.
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/Marsha Tsay/Primary Examiner, Art Unit 1656