DETAILED ACTION
This office action is in response to applicant’s filing dated July 9, 2026.
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 Claims
Claims 1, 6-8, and 10-17 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed July 9, 2026. Acknowledgement is made of Applicant's amendment of claims 1, 6-8, 10, and 13-15; and cancelation of claims 2-5 and 9.
Applicants elected without traverse Group I, drawn to a pharmaceutical composition comprising (A) a therapeutically effective amount of the first ingredient wherein the first ingredient is a berberine analog, (B) a therapeutically effective amount of a second active ingredient, which is a JAK inhibitor as the elected invention and berberrubine:
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as the elected compound of Formula (II), (III), or (IV) species and tofacitinib:
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as the JAK inhibitor species in the reply filed on September 30, 2025. The requirement is still deemed proper. Claims 10, 11, and 15-17 remain withdrawn.
Claims 1, 6-8, and 12-14 are presently under examination as they relate to the elected species: Berberrubine and Tofacitinib.
Priority
The present application is a 371 of PCT/CN2021/083421 filed on March 26, 2021, which claims benefit of foreign priority to CHINA 202010225184.7 filed on March 26, 2020.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Withdrawn Objections and/or Rejections
Claim Rejections - 35 USC § 112
The rejection of claims 1, 7, and 8 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 has been rendered moot in view of the amendment.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
Claim Rejections - 35 USC § 103
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.
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 1, 6, 8, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN108272802 A, cited in the IDS filed September 26, 2022, machine translation obtained from WIPO PatentScope January 21, 2026) in view of Yu et al (PLoS ONE, 2018; 13(3): e0194069 pp. 1-15, cited in a previous Office Action).
Regarding claims 1, 6, and 12-14, Li teaches a combined drug for relieving and treating ulcerative colitis comprising berberine and tofacitinib (claim 1). Li does not teach the composition comprises berberrubine.
However, Yu teaches berberrubine (BB) is deemed as one of the major active metabolite of berberine (BBR), a naturally-occurring isoquinoline alkaloid with appreciable anti-UC (ulcerative colitis) effect; BB exerted similar effect to its analogue BBR and positive control in attenuating DSS(dextran sodium sulfate )-induced UC with much lower dosage and similar mechanism; BB possesses pronounced anti-UC effect similar to BBR and sulfasalazine with much smaller dosage(abstract). Yu teaches the chemical structures of berberine and berberrubine (Fig. 1):
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Berberine differs from berberrubine in that berberine contains an O-CH3 in position 9, while berberrubine contains an -OH. Thus, Yu establishes that berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects.
As such, since Li teaches a combined drug for relieving and treating ulcerative colitis comprising berberine and tofacitinib, and since Yu teaches that berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute berberine with berberrubine in the composition taught by Li with an expectation of success, since the prior art establishes that berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects. One of ordinary skill in the art would have been further motivated to substitute berberine with berberrubine since the prior art teaches berberrubine exerted similar effect to its analogue berberine with much lower dosage and similar mechanism.
Regarding the ratio of instant claims 1 and 12, Li teaches the amount of berberine in the combined drug is preferably berberine in an amount of berberine (1/3-2/3) of berberine, and the dosage of tofacitinib is (2/3-1/3) of the conventional clinical dosage of tofacitinib, and in the amount of berberine (1 /3-2/3) + tofacitinib (1/3-2/3) = 1 (page 1, last paragraph); berberine was administered 40 mg/kg/d (page 2, Examples (3)) and tofacitinib was administered 30 mg/kg/d (page 2, Examples (4). An amount of 40 mg/kg/d of berberine and an amount of tofacitinib of 30 mg/kg tofacitinib would result in a ratio of first ingredient to second ingredient of about 1.3 : 1.
It would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts and ratios of berberine and tofacitinib taught by Li as a starting point for optimizing the amounts and ratio of berberrubine and tofacitinib utilized to produce a combination for the treatment of ulcerative colitis, since the prior art teaches berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects and because dosage and ratio are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claim 8, Li teaches separate treatment groups berberine was administered 40 mg/kg/d (page 2, Examples (3)) and tofacitinib was administered 30 mg/kg/d (page 2, Examples (4)) and a combined treatment group (page 2, Examples (5)). Thus, Li suggests administration of separate compositions. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to make a kit comprising a composition comprising berberrubine and a composition comprising tofacitinib for the treatment of ulcerative colitis with a reasonable expectation of success, since the prior art establishes that separate compositions comprising berberrubine and tofacitinib are known in the art.
With regard to the limitation directed to an instruction for use, this limitation is not given patentable weight.
MPEP 2111.05 states:
To be given patentable weight, the printed matter and associated product must be in a functional relationship. A functional relationship can be found where the printed matter performs some function with respect to the product to which it is associated. See Lowry, 32 F.3d at 1584, 32 USPQ2d at 1035 (citing Gulack, 703 F.2d at 1386, 217 USPQ at 404).
Additionally, where the printed matter and product do not depend upon each other, no functional relationship exists. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864.
Taken together, all this would result in composition of claims 1, 6, 8, and 12-14 with a reasonable expectation of success.
New Objections and/or Rejections
Not Necessitated by Claim Amendment
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN108272802 A, cited in the IDS filed September 26, 2022, machine translation obtained from WIPO PatentScope January 21, 2026) in view of Yu et al (PLoS ONE, 2018; 13(3): e0194069 pp. 1-15, cited in a previous Office Action) as applied to claims 1, 6, 8, and 12-14 above, and further in view of Schentag et al (US 2015/0352189 A1).
The combination of Li and Yu teach all the limitations of claim 7 (see above 103 rejection), except wherein the pharmaceutical composition is an enteric-coated preparation.
However, Schentag teaches a pharmaceutical composition comprising a first and optionally a second active composition, said first active composition comprising an ileal brake hormone releasing substance encapsulated within an enteric coating which releases said substance within said subject’s ileum and ascending colon causing release of at least one ileal brake hormone from L-cells of said subject, said optional second active composition being formulated in immediate and/or early release form in an over-coating onto said enteric coating (abstract); where end result is restoration of the integrity of the small bowel, locally applying treatment to lower the luminal inflammation in diseases like ulcerative colitis is goal and these products are targeted for release also in the ileum or ascending colon; all components of the formulation need to be released at the same site in the intestine, so the coating used for release of the ileal brake hormone releasing substance is sufficient for the entire components, that is to incorporate the second active drug as well [0524]. Moreover, Schentag teaches berberine may be over-coated in a combination formulation [0507].
Since Li and Yu teach berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects and suggest a combined drug for relieving and treating ulcerative colitis comprising berberine and tofacitinib, and since Schentag teaches enteric coating to release ileum or ascending colon for locally applying a treatment to lower luminal inflammation in diseases like ulcerative colitis and that berberine can be enteric-coated with an over coating, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the a combined drug for relieving and treating ulcerative colitis comprising berberine and tofacitinib suggested by Li and Yu to enterically coat the combination to release in the ileum or ascending colon since the prior art teaches enteric coating for locally delivering drugs to treat ulcerative colitis.
Taken together, all this would result in the composition of claim 7 with a reasonable expectation of success.
Response to Arguments
The Declaration under 37 CFR 1.132 of Jianyong, Shou filed July 9, 2026 is insufficient to overcome the rejection of record as set forth above, and is addressed in the response to arguments set forth below.
Applicant argues:
The claimed combination of berberrubine and a JAK inhibitor exhibited unexpected synergistic effect, which are not taught or suggested by the prior art. Li asserts that the combination of berberine and tofacitinib has a synergistic effect in alleviating and treating UC, the data disclosed in Li do not establish the synergistic effect demonstrated by the presently claimed combination. As explained in the declaration, the results in Li fail to substantiate the asserted synergistic effect. Based on the specific disclosure in Li, a person of ordinary skill in the art (POSA) would have understood that the combination of berberine and tofacitinib could not exhibit a synergistic effect. It is well established that the outcome of combining two therapeutic agents is inherently unpredictable. Depending on the particular agents and treatment conditions, the combined effect may be synergistic, additive, antagonistic, or may exhibit no interaction at all. Accordingly, based on the disclosure of Li and Yu, a POSA would not have reasonably expected that combining berberrubine with a JAK inhibitor would produce a synergistic therapeutic effect. The synergistic effect demonstrated by the presently claimed combination, as evidenced by the present application and the Shou Declaration, is therefore unexpected.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As noted by Applicant, Li explicitly discloses that the combination of berberine and tofacitinib has a synergistic effect in alleviating and treating UC. The Examiner acknowledges that the declaration states that the data disclosed in Li does not support a synergistic effect. However, the Examiner notes that Fig 3 shows a greater effect compared to berberine alone or tofacitinib alone:
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In Fig 3A, it appears that there might be a slight overlap between the berberine alone group and berberine+tofacitinib group, the difference between berberine+tofacitinib group and the model is significantly lower than either of the berberine alone or tofacitinib alone compared to the model. Similarly, In Fig 3B, while the berberine+tofacitinib group appears to show some overlap with the tofacitinib alone group, the difference between berberine+tofacitinib group and the model is significantly lower than either of the berberine alone or tofacitinib alone compared to the model. Thus, Fig 3 appears to support the assertion that the combined effect of berberine+tofacitinib is greater than either monotherapy alone. Moreover, Fig 4 further supports that the assertion that the combined effect of berberine+tofacitinib is greater than either monotherapy alone:
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Thus, the skilled artisan would have a reasonable expectation that the combination of berberine and tofacitinib would have a synergistic effect. The Examiner further notes that it is not clear from the data provided in the specification that the combination of berberrubine and tofacitinib demonstrate synergistic properties. In Fig 1 and 2, there is very little difference between the treatment groups:
[AltContent: textbox (Oxa + Vehicle)][AltContent: textbox (Water + Vehicle)]
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It appears that the graphs in the arguments are the data provided in the spec where the Y-axis is set at maximum of 800 AUC(index*h) vs 1500 AUC(index*h) as shown in the specification. While the data appears to be expanded to show differences between the groups, the error bars between the groups overlap greatly between groups. While the treatment groups appear to differ from the Water + Vehicle and the Oxa + Vehicle groups, the treatment groups appear to have very little differences between the monotherapy groups or the combination groups with significant overlap between groups. It is unclear how the data relied upon establishes synergy. The Examiner further notes that it appears that the combination of Tofa_2mpk + BBR_2mpk is not much different from Tofa_2mpk alone or BBR_2mpk alone. Moreover, as set forth above, the prior art establishes that berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects. One of ordinary skill in the art would have a reasonable expectation that structurally similar compounds with similar activity would possess similar properties (e.g. synergistic effect in combination with the same drug).
Moreover, the data provided is not commensurate in scope with the instant claims. MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). A single combination in specific amounts would not be considered sufficient to support unexpected results for the full scope JAK inhibitors and full scope of ratio of berberrubine to JAK inhibitor of the instant claims.
Applicant argues:
Yu only discloses that berberrubine can replace berberine, and from the teaching of Yu it can be seen that when berberrubine replaces berberine, reducing the dosage to 10 mg/kg would not achieve a similar therapeutic effect. In fact, at a dose of 10 mg/kg, the DAI is comparable to that of the DSS model group, suggesting that berberrubine has only a very weak effect at this dosage. Therefore, the technical effect of the present invention, especially the degree of dosage reduction of berberrubine and tofacitinib, is highly unexpected in light of the teachings of prior arts.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, Li clearly demonstrates that the effect of the combination of berberine and tofacitinib is greater than the effect of berberine or tofacitinib monotherapy. Moreover, Yu teaches that 20 mg BB (berberrubine) has similar effect as 50 mg BBR (berberine) as shown in the figure presented in the arguments.
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Thus, Yu suggests that BB is more efficacious than BBR. As set forth above, the prior art establishes that berberine and berberrubine are structurally similar compounds and both possess anti-ulcerative colitis effects. One of ordinary skill in the art would have a reasonable expectation that structurally similar compounds with similar activity would possess similar properties (e.g. synergistic effect in combination with the same drug). Moreover, in view of the cited art, one of ordinary skill in the art would expect that berberrubine would show effects at lower doses than berberine since lower doses of berberrubine (20 mg) show similar effects as a higher dose of berberine (50 mg).
Conclusion
Claims 1, 6-8, and 10-14 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628
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