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 .
Status of the Claims
Claims 14-24 are pending.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Instant application is a U.S. National Stage Entry of PCT/CN2022/093039, filed 05/16/2022. PCT/CN2022/093039 claims priority of foreign application CN202110531848.7, filed 05/14/2021. Therefore, the effective filing date is 05/14/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/14/2023, 01/12/2024, 06/11/2025, and 08/21/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 14, 16-19, 21, 23, and 24 are objected to because of the following informalities:
Claim 14 reads “…progressive hepatic fibrosis, or cirrhosis, the method is administered…” and should read “…progressive hepatic fibrosis, or cirrhosis, wherein the method is administered…”.
Claim 16 reads “…wherein the portal area fibrosis is characterized by the following: (1) the portal area fibrosis is characterized via an Ishak scoring system, which means hepatic fibrosis with an Ishak score of…”. For brevity, this should read “…wherein the portal area fibrosis is characterized by an Ishak score of…”.
In claim 17, the repetition of “the significant hepatic fibrosis is characterized via an Ishak scoring system, which means hepatic fibrosis with” should be removed from (1), and “the significant hepatic fibrosis is characterized by a liver stiffness measurement, which means hepatic fibrosis with” should be removed from (2).
Claims 18 and 19 should be corrected in the same way as described above for claim 17.
Claim 21 reads “wherein the pharmaceutically acceptable salt comprises the compound of formula (I) and selected from…” and should instead read “wherein the pharmaceutically acceptable salt of the compound of formula (I) is selected from…”.
Claim 21 capitalizes the word “Salts”, and this should instead be “salts”.
Claim 23 reads “…or the pharmaceutically acceptable salt thereof as claimed in claim 14…” and should read “…or the pharmaceutically acceptable salt thereof as in claim 14…”.
Claim 24 reads “The pharmaceutical composition as claimed in claim 23…” and should read “The pharmaceutical composition of claim 23…”.
Appropriate correction is required.
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.
Claims 14-24 are rejected under 35 U.S.C. 101 because the disclosed invention is inoperative and therefore lacks utility. Claim 14 recites “except that the method is not administered to the patient if they have both an ALT between 3 ULN and 8 ULN and TBIL(total bilirubin) greater than 2 ULN.” In the case that the patient has both an ALT between 3 ULN and 8 ULN and TBIL (total bilirubin) greater than 2 ULN, then the invention is inoperative, since there would be no invention or method to administer.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 14-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the method that is being administered when the patient has “both an ALT between 3 ULN and 8 ULN and TBIL(total bilirubin) greater than 2 ULN”.
Claims 14-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 14 recites a “prodrug”. “Prodrug” is not defined in applicant’s specification. It is unclear what functional group is to be attached to what atom of the formula (I) structure and how that prodrug moiety might be cleaved to form the formula (I) genus. The metes and bounds of the claims are not established, rendering claim 14 and those dependent claims 15-24 unclear.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim 16 recites the broad recitation “an Ishak score of ≥ 1”, and the claim also recites “an Ishak score of about 1-3” which is the narrower statement of the range/limitation.
Claim 18 recites the broad recitation “an LSM of about ≥ 9.0 kPa”, and the claim also recites “≥10.0 kPa” which is the narrower statement of the range/limitation.
Claim 19 recites the broad recitation “an Ishak score of ≥5”, and the claim also recites an Ishak score of “about 5-6” which is the narrower statement of the range/limitation.
Claim 19 recites the broad recitation “an LSM of about ≥ 12.0 kPa”, and the claim also recites an LSM of “about ≥ 13.0 kPa” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 14 recites the limitation "the compound of formula (I), the solvate, the hydrate, the prodrug, or the pharmaceutically acceptable salt" in line 4 of the claim. There is insufficient antecedent basis for this limitation in the claim. Claims 15-24 are rejected as being dependent upon claim 14, which lack antecedent basis.
This rejection would be overcome if every instance of “the” was changed to “a”.
Regarding claims 17 and 18, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 21, the phrase "including" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 14-16, 20, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shanghai Genomics, Inc. (A Phase II Clinical Trial of Hydronidone Capsules(F351) in Patients with Liver Fibrosis Induced by HBV Chronic Hepatitis (HBV), NIH NCT02499562, Version 1, 13 July 2015), cited by Applicant in the IDS.
This clinical study teaches a method of treating hepatic fibrosis in chronic viral hepatitis B patients comprising administering two 30 mg capsules of hydronidone, the compound of instant claim 14, three times per day, which is 180 mg per day (Description, Arms and Interventions). The Inclusion Criteria teaches that the method is administered to patients with an ALT less than 5-fold ULN (maximum), and the Exclusion Criteria teaches that the method is not administered to patients with TBiL greater than 3-fold ULN, as in instant claims 14, 20, and 22.
It is taught, in the Description, that treatment is aimed to decrease the hepatic fibrosis Ishak score by more than 1, as in instant claim 16. If the aim is to decrease the Ishak score by more than 1, then the existing Ishak score in the patients must be over 1.
Regarding instant claim 15, the prior art is silent regarding causing a reversal of liver fibrosis. However: causing a reversal of liver fibrosis will inevitably flow from the teachings of the prior art (see above rejection), since the same composition (180 mg hydronidone daily) is being administered to the same subjects (a subject with hepatic fibrosis and chronic viral hepatitis B). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
Apparently, Applicant has discovered a new property or advantage (causing a reversal of liver fibrosis) of the method taught by the prior art.
MPEP 2112 I states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
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 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Shanghai Genomics, Inc. (cited above).
The clinical study by Shanghai Genomics, Inc. teaches a method of treating hepatic fibrosis in chronic viral hepatitis B patients comprising administering two 30 mg capsules of hydronidone, the compound of instant claim 14, three times per day, which is 180 mg per day. See above rejection.
The clinical trial fails to specify that the method is administered to patients with an Ishak score of 5-6, as in instant claims 17-19.
However, an Ishak score of 5-6 indicates severe fibrosis, which would indicate that treatment should be performed on such an individual.
Therefore, it would be prima facie obvious to perform a method of treating hepatic fibrosis, wherein the patients have chronic viral hepatitis B, in patients that have severe hepatic fibrosis, indicated by an Ishak score of 5-6. One would be motivated to use a method of treating hepatic fibrosis in a patient with severe hepatic fibrosis, since this individual would be in the most need for treatment.
One of ordinary skill would have a reasonable expectation of success since the method in the clinical trial is taught to be aimed at decreasing the Ishak score by more than 1, and this method is used for the same purpose as the instant invention.
Claims 21, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Shanghai Genomics, Inc. (cited above), further in view of Yi (WO 2005047256 A1), cited by Applicant in the IDS.
The clinical study by Shanghai Genomics, Inc. teaches a method of treating hepatic fibrosis in chronic viral hepatitis B patients comprising administering two 30 mg capsules of hydronidone, the compound of instant claim 14, three times per day, which is 180 mg per day. See above rejection.
The clinical study fails to teach the composition of the capsules, as in instant claims 21, 23, and 24.
However, Li et al. teaches, in Example 5, a method of treating liver fibrosis wherein hydronidone is administered and shown to significantly improve the liver function. Li teaches, on page 2 paragraph 2, that chronic viral hepatitis B is the most common cause of liver fibrosis. In Example 6, Li teaches a composition comprising 100-500 mg hydronidone, 1-5 mg magnesium stearate, 1 mg silica, and 5-10 mg lactin (lactose), as in instant claims 21 and 23.
Regarding instant claim 24, the composition of Li differs from the instant composition in the concentrations of lactose monohydrate and hydronidone used. However, MPEP 2144.05 II. A. teaches that “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. Therefore, the difference in concentrations does not render the instant composition patentably new and would be considered routine experimentation.
It would be prima facie obvious to use and optimize the composition of Li in the method taught in the clinical study by Shanghai Genomics, Inc., since the composition is taught to be used for the same purpose.
One of ordinary skill would have a reasonable expectation of success in using the components of the pharmaceutical composition in the clinical trial to treat liver fibrosis in patients having chronic hepatitis B, since the composition is taught by Li to treat liver fibrosis and improve liver function.
Conclusion
Claims 14-24 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 7-3.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624