DETAILED ACTION
Notice of Pre-AIA or AIA Status
The inventor or joint inventor should note that the instant invention, 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 1-18 are pending in the instant invention. According to the Amendments to the Claims, filed March 29, 2026, claims 1-5 were amended.
Status of Priority Objection - Priority Date
This invention is a Continuation-In-Part (CIP) of US Application No. 18/112,329, filed February 21, 2023 and now US 11,976,063, which is a Continuation (CON) of US Application No. 17/204,776, filed March 17, 2021 and now US 11,685,735, which is a Continuation (CON) of US Application No. 16/351,819, filed March 13, 2019 and now US 10,988,471, which is a Divisional (DIV) of US Application No. 15/303,468, filed October 11, 2016 and now US 10,301,303, which is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/CN2015/085350, filed July 28, 2015, which claims priority under 35 U.S.C. § 119(e) to US Provisional Application No. 62/128,077, filed March 4, 2015.
Similarly, the inventor or joint inventor should further note that this invention’s claim to priority under 35 U.S.C. § 119(e) to US Provisional Application Nos.: a) 62/030,147, filed July 29, 2014; and b) 62/030,140, filed July 29, 2014, respectively, was objected to in the Non-Final Rejection, mailed on November 4, 2025. Consequently, the effective filing date, for examination and prosecution on the merits, is that of US Provisional Application No. 62/128,077, filed March 4, 2015.
Status of Restrictions / Election of Species
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The inventor’s or joint inventor’s affirmation of the following election, without traverse, in the reply filed on March 29, 2026, is acknowledged: a) Group I - claims 1-5; and b) berberine nor-ursodeoxycholic acid salt having formula (I) - p. 57, ¶[00203].
Similarly, the inventor or joint inventor should further note that the requirement was made FINAL in the Non-Final Rejection, mailed on November 4, 2025.
Likewise, the inventor or joint inventor should further note that this invention contains claims 6-18, drawn to nonelected inventions, without traverse, in the reply filed on March 29, 2026. A complete reply to the Final Rejection may include cancellation of nonelected claims or other appropriate action (37 CFR 1.144). See MPEP § 821.02.
Next, the inventor or joint inventor should further note that the sections of U.S.C. Title 35 that formed the basis of prior rejections formulated, as well as any references supporting said rejections, that are not included with this Office action, may be found in the Non-Final Rejection, mailed on November 4, 2025.
Moreover, the inventor or joint inventor should further note that any rejections and/or objections of record not explicitly addressed herein below, are hereby withdrawn, in light of the inventor’s or joint inventor’s arguments and/or the Amendments to the Claims, filed March 29, 2026.
Thus, a second Office action and prosecution on the merits of claims 1-5 is contained within.
New Specification Objection - Disclosure
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the inventor’s or joint inventor’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility invention should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase Not Applicable should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A
COMPACT DISC.
(f) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art (including information disclosed under 37 CFR 1.97
and 1.98).
(g) BRIEF SUMMARY OF THE INVENTION.
(h) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(i) DETAILED DESCRIPTION OF THE INVENTION.
(j) CLAIM OR CLAIMS (commencing on a separate sheet).
(k) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(l) SEQUENCE LISTING (See MPEP § 2424 and 37 CFR 1.821-1.825).
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(b) above and 37 CFR 1.77(c). Revisions should particularly include and/or address: a) section headings (b-i), where applicable; and b) bold-type, underline, and/or upper case formatting. Appropriate correction may be required.
New Claim Objections
Claim 1 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
An acid-base addition salt having the formula (I):
(X+)m(U-)n
(I)
wherein:
X+ is a cationic moiety of berberine having the following formula:
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;
U- is an anionic moiety of nor-ursodeoxycholic acid having the following formula:
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;
m is 1; and
n is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 3 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A pharmaceutical composition comprising the acid-base addition salt of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.
Appropriate correction is required. See MPEP § 2173.02.
Claim 5 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The pharmaceutical composition of claim 3, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent selected from the group consisting of N-acetylcysteine, S-adenosylmethionine, an omega-3 fatty acid, polyenylphosphatidylcholine, resveratrol, silymarin, vitamin D, and vitamin E.
Appropriate correction is required. See MPEP § 2173.02.
New Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112:
(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.
Berberine nor-ursodeoxycholic acid salts having the formula (I)
Claims 1-5 are rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement because the claims contain subject matter, particularly berberine nor-ursodeoxycholic acid salts having the formula (I), which were not described in the specification in such a way as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use (perform) the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the instant invention, are summarized as follows:
(a) Breadth of the claims - the breadth of the claims includes berberine nor-
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ursodeoxy-cholic acid salts having the formula (I), shown to the right;
(b) Nature of the invention - the nature of the invention is evaluation of berberine nor-ursodeoxycholic acid salts having the formula (I), shown to the right above, and the pharmacokinetic behavior of these substances as pharmaceuticals;
(c) State of the prior art - Nature Reviews: Drug Discovery, as provided in the file and cited in the Non-Final Rejection, mailed on November 4, 2025, offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Moreover, CN 114716498, as provided in the file and cited in the Non-Final Rejection, mailed on November 4, 2025, provides a synthesis of the instantly recited berberine nor-ursodeoxycholic acid salts having the formula (I) {Guang, et al. CN 114716498, 2022};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s berberine nor-ursodeoxycholic acid salts having the formula (I) would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is unclear based on the combination of Example 7, on pages 69-73 of the instant specification, whether the instantly recited berberine nor-ursodeoxycholic acid salts having the formula (I) are enabled. Moreover, the following excerpt is taken from Dörwald, as provided in the file and cited in the Non-Final Rejection, mailed on November 4, 2025, which has relevance to the synthesis of berberine nor-ursodeoxycholic acid salts having the formula (I) {Dörwald, F. Zaragoza. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design, Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA, 2005, Preface}:
Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why.
Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work.
Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious).
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using berberine nor-ursodeoxycholic acid salts having the formula (I);
(g) Existence of working examples - the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited berberine nor-ursodeoxycholic acid salts having the formula (I). The specification lacks working examples of berberine nor-ursodeoxycholic acid salts having the formula (I).
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
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(h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure - predicting whether a recited compound is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Similarly, the specification, as originally filed, including any references incorporated therein, fails to provide the necessary support required by 35 U.S.C. § 112(a) to enable the instantly recited berberine nor-ursodeoxycholic acid salts having the formula (I). Thus, it is unclear, based on the guidance provided by the specification, whether a berberine nor-ursodeoxycholic acid salt having the formula (I), such as berberine nor-ursodeoxycholate (BNUDCA), shown to the left above, is either synthetically feasible or possesses utility as a pharmaceutical.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using berberine nor-ursodeoxycholic acid salts having the formula (I) is clearly justified.
New Claim Rejections - 35 U.S.C. § 112(d)
The following is a quotation of the fourth paragraph of 35 U.S.C. § 112:
(d) REFERENCE IN DEPENDENT FORMS. Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 4 and 5 are rejected under 35 U.S.C. § 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The inventor or joint inventor should note that claim 2 recites the limitation, The acid-base addition salt of claim 1, wherein the acid-base addition salt is…, in lines 1-3 of the claim. According to claim 1, the acid-base addition salt having the formula (I) is identical to the acid-base addition salt, as recited in claim 2. Consequently, since The acid-base addition salt of claim 1, wherein the acid-base addition salt is…, fails to specify a further limitation to the acid-base addition salt having the formula (I), as recited in claim 1, and/or fails to include all the limitations of the acid-base addition salt having the formula (I), as recited in claim 1, the instant dependent claim, and any additional dependent claims therefrom, are rendered improperly dependent under 35 U.S.C. § 112(d).
Similarly, the inventor or joint inventor should further note that the U.S. Court of Appeals for the Federal Circuit indicated that although the requirements of 35 U.S.C. § 112(d) are related to matters of form, non-compliance with 35 U.S.C. § 112(d) renders the claim unpatentable just as non-compliance with other subsections of 35 U.S.C. § 112 would. {See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92 (Fed. Cir. 2006)}.
Moreover, the inventor or joint inventor should further note that if a dependent claim does not comply with the requirements of 35 U.S.C. § 112(d) the dependent claim should be rejected under 35 U.S.C. § 112(d) as unpatentable rather than objecting to the claim. {See also MPEP § 608.01(n), Section III, Infringement Test for dependent claims}.
The examiner suggests the inventor or joint inventor (1) cancel the dependent claims, (2) amend the dependent claims to place the dependent claims in proper dependent form, particularly as stated in the section above entitled New Claim Objections, (3) rewrite the dependent claims in independent form, or (4) present a sufficient showing that the dependent claims comply with the statutory requirements, to overcome this rejection.
Allowable Subject Matter
No claims are allowed.
Conclusion
The inventor’s or joint inventor’s arguments and/or the Amendments to the Claims, filed March 29, 2026, necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). The inventor or joint inventor 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.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The Examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The Examiner is also available on alternate Fridays.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov.
/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624