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 .
Election/Restrictions
Applicant’s election without traverse of Group (I) in the reply filed on 03/14/2025 is maintained.
Applicant’s election without traverse of 3α, 6α, 7α, 12α-tetrahydroxy-5β-cholan-24-oic acid as the elected polyhydroxylated bile acid species and tropifexor as the elected farnesoid X receptor agonist in the reply filed on 03/14/2025 is maintained.
Priority
This application is a U.S. National Stage Application under 35 U.S.C. §371 of International Patent Application No. PCT/IB2020/055097 filed May 29, 2020, which claims the benefit of priority of U.S. Patent Application numbers 62/853,908 filed May 29, 2019.
Claims Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on October 21, 2025. Claims 1-12, 14-19, 21, and 24 are pending. Claims 13, 20 and 22-23 are canceled. Claims 9-12 and 14-19 and 21 are withdrawn. Claims 1-8 and 24 are examined in accordance to the elected compound species.
Action Summary
Claims 1and 2 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of the claim amendment.
Claims 1-8 and 24 rejected under 35 U.S.C. 103 as being unpatentable over Ling et al (US2012/0277198 A1) in view of Tully et al (J. Med. Chem. 2017, 60, 9960-9973), and Convert mg/kg to percent online calculator, https://www.convertunits.com/from/mg/kg/to/percent, accessed on 04/16/2025, are maintained, but modified and revisited in light of the claim amendment.
Claims 1-8 and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,543,220 B2 in view of Ling et al (US2012/0277198 A1), Tully et al (J. Med. Chem. 2017, 60, 9960-9973), and Convert mg/kg to percent online calculator, https://www.convertunits.com/from/mg/kg/to/percent, accessed on 04/16/2025, are maintained, but modified and revisited in light of the claim amendment.
Affidavit
The Declaration by Jonathan Ahab Sheps under 37 CFR 1.132 filed 10/21/2025 is insufficient to overcome the rejection of claim 2. The Declarant argues that the inoperable amount, subclinical amount, subtherapeutic amount and toxic amount are amounts that are readily determinable using standard technique.
In response, the Declarant’s argument is not persuasive. The Declarant clearly confirms the Examiner’s analysis that the inoperable amount, subclinical amount, subtherapeutic amount and toxic amount are amounts that are readily determinable using standard technique, rendering these amounts indefinite.
The Declarant argues that the term "inoperable amount" would be clearly understood by a person of ordinary skill in the art not to be "any amount that is lower than usually prescribed amount," as alleged by the Examiner, but rather an amount that does not have a therapeutic or clinical effect or benefit in the treatment of a GI or biliary disorder.
In response, the Declarant’s argument is not persuasive. Specifically, the specification clearly teaches the FXR agonist, such as OCA or tropifexor, may be used at a dosage "less than an effective dose." By "less than an effective dose" is meant a dose that is less than the dose used in current therapies or which exhibits no therapeutic benefit e.g., a subtherapeutic dose, a subclinical dose. (See paragraph [0085].) Therefore, the interpretation that inoperable amount (subclinical or subtherapeutic) to be any amount that is at or less than the dose used in current therapies as disclosed in paragraph [0085] of the specification, is clearly reasonable. T
The Declarant argue the data the data presented in the instant application at Example 2 show that administration of a combination of 1% THBA (3α, 6α, 7α, 12α-tetrahydroxy-5ß-cholan-24-oic acid) and different amounts of tropifexor (TXR) to Mdr2 mice provided protection from liver injury compared to tropifexor alone. Additional studies, as shown in Appendix B,
demonstrate that Mdr2⁻/- mice fed TXR in combination with 3α, 6α, 7α, 12α-tetrahydroxy-
5ß-cholan-24-oic acid (THBA), at higher dose combinations of 0.0003%, and 0.0001% (corresponding to 0.3 and 0.1 mg/kg doses and THBA/TXR ratios of 3333:1 and 1000:1), resulted in increased liver/body weight, suggesting some toxicity while lower dose
combinations of 0.00003%, 0.00001% and 0.000003% (0.03, 0.01 and 0.003 mg/kg
doses and THBA/TXR ratios of 3.3e5:1, 1e6:1 and 3.3e6:1) decreased liver/body weight,
suggesting protection, with all results being statistically significant (Appendix B, Figure 1).
Significant improvements in all liver indicators were observed for all five combinations of
TXR and THBA, compared to the control diet (Appendix B, Figure 2). When comparing
combinations vs mono-treatments, reduced levels of liver indicators appeared in the two lower concentration combination groups (0.00001% and 0.000003%), with the lowest TXR.
In response, the Examiner does not dispute the data in Example 2 of the instant application significantly improves all liver indicators compared to control. However, the Examiner contends such data is not commensurate in scope with the claim. Specifically, the data uses lower dose combinations of 0.00003%, 0.00001% and 0.000003% (0.03, 0.01 and 0.003 mg/kg doses and THBA/TXR ratios of 3.3e5:1, 1e6:1 and 3.3e6:1) decreased liver/body weight. In contrast, 0.00003%, 0.00001% and 0.000003% (0.03, 0.01 and 0.003 mg/kg doses and THBA/TXR are not in the claim. The claim broadly discloses any amount of THBA and any amount of TXR. The claim also recites a broad class of polyhydroxylated bile and a broad class of Farnesoid X receptor agonist while only THBA in combination with TXR/OCA are exemplified. 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). Furthermore, the prior art alone or combination does not teach or suggest a combination of polyhydroxylated bile and an inoperable amount of Farnesoid X receptor agonist. Ling teaches an exemplary range for therapeutically or prophylactically effective amounts of tetrahydroxylated bile acid is 3α, 6α, 7α, 12α-tetrahydroxy-5β-cholan-24-oic acid ranging from 5-50 mg/day/kg of body weight of the subject e.g., a human cholestasis and nonalcoholic steatohepatitis. (See paragraph [0084].) Based on the convert mg/kg to percent online calculator, the 5 mg/kg amounts to 0.0005%. Tully teaches Initial BSEP induction in the liver appeared at the lowest dose tested (0.003 mg/kg) tropifexor, and maximal BSEP target gene induction was achieved above 0.1 mg/kg. Activation of FXR in the liver resulted in the downregulation of sterol 12-α hydroxylase (CYP8B1) gene transcription, thereby reducing the conversion of cholesterol to bile acids. Expression of CYP8B1 mRNA following 14-day treatment with 1 was already apparent at the lowest dose (0.003mg/kg). (See first paragraph of the left column of page 9965.) Since the 0.003 mg/kg appears to be lower than the most effective amount 0.1 mg/kg, the 0.003 mg/kg is considered to be an inoperable amount (i.e., subclinical or subtherapeutic) dose. Based on the convert mg/kg to percent online calculator, the 0.003 mg/kg amounts to 0.0000003%. I/5 (one-fifth) or 0.2 of 0.1 is 0.02. Therefore, the 0.003 mg/kg is less 0.02 mg/kg which is one-fifth of 0.1 mg/kg, meeting the limitation of claim 2. A POSA can reasonably expect combining 3α, 6α, 7α, 12α-tetrahydroxy-5β-cholan-24-oic acid in the amount of 5 mg/kg which amounts to 0.0005% with tropifexor in the amount of 0.003 mg/kg which amounts to 0.0000003% to give Applicant’s asserted unexpected result.
Claim Rejections - 35 USC § 112
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 2 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The recitation of the inoperable amount of a farnesoid X receptor agonist is less than or equal to one-fifth of the standard recommended dosage for the farnesoid X receptor agonist is considered new matter because such recitation is not supported by the specification. In fact, the specification teaches in some embodiments, the FXR agonist can be administered at less than or equal to one- fifth of the standard recommended dosage for that compound. Nowhere the specification relates the FXR agonist can be administered at less than or equal to one- fifth of the standard recommended dosage for that compound as bein the inoperable amount of farnesoid X receptor agonist. For example, OCA may be administered at less than or equal to one-fifth of about 5 - about 10 mg per day or any value in between (about 74- about 148 ug/kg daily for a person of about 70 kg body weight); EDP-305 may be administered at less than or equal to one-fifth of about 1 - about 2.5 mg per day or any value in between (about 14 - about 36 ug/kg daily for a person of about 70 kg body weight); Cilofexor may be administered at less than or equal to one-fifth of about 30 - about 100 mg per day or any value in between (about 0.45 - about 1.5 mg/kg or any value in between daily for a person of about 70 kg body weight); tropifexor may be administered at less than or equal to one- fifth of about 0.01 - about 0.03 mg per day or any value in between (about 0.15- about 0.45 ug/kg daily for a person of about 70 kg body weight); or LMB763 may be administered at less than or equal to one-fifth of about 5 mg per day (about 74 ug/kg daily for a person of about 70 kg body weight). Nowhere the specification discloses said recitation is defined as the inoperable amount.
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 1-8 and 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. The term “the inoperable amount is a subtherapeutic amount, a subclinical amount or a toxic amount” renders the claim indefinite because the scope of the encompassed amount is not clear. A person of ordinary skill in the art cannot determine the metes and bounds of subtherapeutic amount, a subclinical amount or a toxic amount. Specifically, the instant specification teaches the present invention provides a pharmaceutical composition comprising i) a polyhydroxylated bile acid; and ii) an inoperable amount of a farnesoid X receptor agonist, in combination with a pharmaceutically acceptable carrier. (See paragraph [0010].
The specification also teaches the inoperable amount of a farnesoid X receptor agonist may be a subtherapeutic amount or a toxic amount. (See paragraph [0011].)
Moreover, the specification teaches the present invention provides a method for enhancing the therapeutic effect of a farnesoid X receptor agonist by comprising i) a polyhydroxylated bile acid; and ii) an inoperable amount of a farnesoid X receptor agonist, in combination with a pharmaceutically acceptable carrier. (See paragraph [0014].)
Additionally, the specification teaches the amount of the FXR agonist can be an inoperable dose, for example a subtherapeutic dose, a subclinical dose, or a toxic dose. It is to be understood that an inoperable dose may vary depending on the subject or patient (e.g., adult, pediatric, geriatric or a subject or patient have a comorbidity that can affect dosage regimens). (See paragraph [0074].)
The specification teaches the FXR agonist can be administered at a dose at or below the minimal therapeutically effective dose or dose which exhibits no therapeutic benefit in the treatment of a GI or biliary disorder (a "subtherapeutic" dose). In some embodiments, the FXR agonist can be administered at a dose below the minimal dose used in standard clinical practice in the treatment of a GI or biliary disorder (a "subclinical" dose). For example, OCA may be administered at a dose less than about 5 - about 10 mg per day or any value in between (about 74 ug/kg daily for a person of about 70 kg body weight); tropifexor may be administered at a dose less than about 0.01 mg per day (about 0.15 ug/kg daily for a person of about 70 kg body weight). (See paragraph [0079].)
Lastly, the specification teaches the FXR agonist, such as OCA or tropifexor, may be used at a dosage "less than an effective dose." By "less than an effective dose" is meant a dose that is less than the dose used in current therapies or which exhibits no therapeutic benefit e.g., a subtherapeutic dose, a subclinical dose. (See paragraph [0085].)
In sum, there is no clear definition as to what the amount that is considered to be subclinical, subtherapeutic, or toxic amount is. In fact, the claim recites inoperable amount is a subtherapeutic amount, a subclinical amount or a toxic amount. However, the specification discloses the amount of the FXR agonist can be an inoperable dose, for example a subtherapeutic dose, a subclinical dose, or a toxic dose. The specification also teaches the inoperable amount of a farnesoid X receptor agonist may be a subtherapeutic amount or a toxic amount. The specification appears to use dose and an amount interchangeably. For example, if one were to consider the amount at paragraph [0074] of the specification, one would have to figure out what the subclinical or toxic amount is based on the subject or patient (e.g., adult, pediatric, geriatric or a subject or patient have a comorbidity that can affect dosage regimens). There is disclosure or examples of specific amount or dose that are considered as inoperable dose or amount or operable dose or amount, or a subtherapeutic dose or amount, a subclinical dose or amount, or a toxic dose or amount. Therefore, neither the specification nor the claims make it clear as to what amount that gives rise or results into a subtherapeutic amount, a subclinical amount or a toxic amount. The specification does not provide a standard for ascertain the requisite degree, and one of ordinary skill in the art would not reasonably apprise of the scope of inoperable amount that allows for a subtherapeutic amount, a subclinical amount or a toxic amount. For purpose of examination, the Examiner construes the inoperable amount (subclinical or subtherapeutic) to be any amount that is at or less than the dose used in current therapies as disclosed in paragraph [0085] of the specification. The Examiner also construes the inoperable amount to be a dose below the minimal dose used in standard clinical practice in the treatment of a GI or biliary disorder (a "subclinical" dose) or a dose less than about 0.01 mg per day as disclosed in paragraph [0079] of the specification.
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.
Claims 1-8 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Ling et al (US2012/0277198 A1) in view of Tully et al (J. Med. Chem. 2017, 60, 9960-9973), and Convert mg/kg to percent online calculator, https://www.convertunits.com/from/mg/kg/to/percent, accessed on 04/16/2025.
Ling teaches a pharmaceutical or nutritional composition or an article of manufacture comprising a tetrahydroxylated bile acid derivative together with a pharmaceutically acceptable carrier, together with instructions for use in treating biliary disorder or stimulating bile flow, wherein said tetrahydroxylated bile acid is 3α, 6α, 7α, 12α-tetrahydroxy-5β-cholan-24-oic acid and wherein said tetrahydroxylated bile acid is conjugated with a taurine, or a glycine. (See claims 18, 21-22, and 26.) The biliary disorder includes cholestasis and nonalcoholic steatohepatitis. (See claim 33.) Moreover, Ling teaches an exemplary range for therapeutically or prophylactically effective amounts of a compound may be 5-50 mg/day/kg of body weight of the subject e.g., a human. (See paragraph [0084].) Based on the convert mg/kg to percent online calculator, the 5 mg/kg amounts to 0.0005%.
Ling does not teach tropifexor as the elected farnesoid X receptor agonist in an inoperable amount. Moreover, Ling does not teach Ling does not teach the ratio of the farnesoid X receptor agonist to the polyhydroxylated bile acid is equal to or less than 1:100.
Tully teaches several farnesoid X receptor agonists such as tropifexor (LJN452)
that act as master regulators of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. (See Abstract.) Moreover, Trully teaches Initial BSEP induction in the liver appeared at the lowest dose tested (0.003 mg/kg), and maximal BSEP target gene induction was achieved above 0.1 mg/kg. Activation of FXR in the liver resulted in the downregulation of sterol 12-α hydroxylase (CYP8B1) gene transcription, thereby reducing the conversion of cholesterol to bile acids. Expression of CYP8B1 mRNA following 14-day treatment with 1 was already apparent at the lowest dose (0.003mg/kg). (See first paragraph of the left column of page 9965.) Since the 0.003 mg/kg appears to be lower than the most effective amount 0.1 mg/kg, the 0.003 mg/kg is considered to be an inoperable amount (i.e., subclinical or subtherapeutic) dose. Based on the convert mg/kg to percent online calculator, the 0.003 mg/kg amounts to 0.0000003%. I/5 (one-fifth) or 0.2 of 0.1 is 0.02. Therefore, the 0.003 mg/kg is less 0.02 which is one-fifth of 0.1 mg/kg, meeting the limitation of claim 2.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to combine the pharmaceutical composition disclosed by Ling’s reference with the pharmaceutical composition comprising 0.003 mg/kg tropifexor set forth by Tully because each is taught by the prior art to be useful for the same purpose (i.e., treating a biliary disorder that can include cholestasis and nonalcoholic steatohepatitis). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on October 21, 2025.
Since Applicant’s arguments are the same argument presented in the Declaration/Affidavit section above, the same response applies.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-8 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,543,220 B2 in view of Ling et al (US2012/0277198 A1), Tully et al (J. Med. Chem. 2017, 60, 9960-9973), and Convert mg/kg to percent online calculator, https://www.convertunits.com/from/mg/kg/to/percent, accessed on 04/16/2025.
The U.S. patent claims teach a pharmaceutical or nutritional composition or an article of manufacture comprising a tetrahydroxylated bile acid derivative together with a pharmaceutically acceptable carrier, together with instructions for use in treating biliary disorder or stimulating bile flow, wherein said tetrahydroxylated bile acid is 3α, 6α, 7α, 12α-tetrahydroxy-5β-cholan-24-oic acid and wherein said tetrahydroxylated bile acid is conjugated with a taurine, or a glycine. The biliary disorder includes cholestasis and nonalcoholic steatohepatitis. (See claims 1-12.)
The U.S. patent claims do not teach tropifexor as the elected farnesoid X receptor agonist in an inoperable amount. Moreover, Ling does not teach Ling does not teach the ratio of the farnesoid X receptor agonist to the polyhydroxylated bile acid is equal to or less than 1:100.
Ling teaches a pharmaceutical or nutritional composition or an article of manufacture comprising a tetrahydroxylated bile acid derivative together with a pharmaceutically acceptable carrier, together with instructions for use in treating biliary disorder or stimulating bile flow, wherein said tetrahydroxylated bile acid is 3α, 6α, 7α, 12α-tetrahydroxy-5β-cholan-24-oic acid and wherein said tetrahydroxylated bile acid is conjugated with a taurine, or a glycine. (See claims 18, 21-22, and 26.) The biliary disorder includes cholestasis and nonalcoholic steatohepatitis. (See claim 33.) Moreover, Ling teaches an exemplary range for therapeutically or prophylactically effective amounts of a compound may be 5-50 mg/day/kg of body weight of the subject e.g., a human. (See paragraph [0084].) Based on the convert mg/kg to percent online calculator, the 5 mg/kg amounts to 0.0005%.
Tully teaches several farnesoid X receptor agonists such as trepifexor (LJN452)
that act as master regulators of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. (See Abstract.) Moreover, Trully teaches Initial BSEP induction in the liver appeared at the lowest dose tested (0.003 mg/kg), and maximal BSEP target gene induction was achieved above 0.1 mg/kg. Activation of FXR in the liver resulted in the downregulation of sterol 12-α hydroxylase (CYP8B1) gene transcription, thereby reducing the conversion of cholesterol to bile acids. Expression of CYP8B1 mRNA following 14-day treatment with 1 was already apparent at the lowest dose (0.003mg/kg). (See first paragraph of the left column of page 9965.) Since the 0.003 mg/kg appears to be lower than the most effective amount 0.1 mg/kg, the 0.003 mg/kg is considered to be an inoperable amount (i.e., subclinical or subtherapeutic) dose. Based on the convert mg/kg to percent online calculator, the 0.003 mg/kg amounts to 0.0000003%. I/5 (one-fifth) or 0.2 of 0.1 is 0.02. Therefore, the 0.003 mg/kg is less 0.02 which is one-fifth of 0.1 mg/kg, meeting the limitation of claim 2.
In sum, the ratio of tropifexor (0.0000003%) to THBA (0.0005%) is 1:1.6, meeting the ratio claimed in claim 2.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to combine the pharmaceutical composition disclosed by the U.S. patent claims and Ling’s references with the pharmaceutical composition set forth by Tully because each is taught by the prior art to be useful for the same purpose (i.e., treating a biliary disorder that can include cholestasis and nonalcoholic steatohepatitis). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
Since Applicant’s arguments are the same argument presented in the Declaration/Affidavit section above, the same response applies.
Conclusion
Claims 1-8 and 24 are not 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 JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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, Amy L Clark can be reached on 571-272-1310. 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.
/JEAN P CORNET/Primary Examiner, Art Unit 1628