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 .
Priority
The instant application is the national stage entry of PCT/US2021/064359 filed 20 December 2021. Acknowledgement is made of the Applicant’s claim of domestic priority to provisional US applications 63/236,574 filed 24 August 2021, 63/175,693 filed 16 April 2021, and 63/128,983 filed 22 December 2020.
Examiner's Note
Applicant's amendments and arguments filed 9 February 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant's response, filed 9 February 2026, it is noted that claims 1, 5, 7, 9-10, 12-15, and 17-20 have been amended and no new matter or claims have been added. Support can be found in the claims as originally filed and the specification at [0120].
Status of the Claims
Claims 1-3 and 5-20 are pending.
Claims 1-3 and 5-20 are rejected.
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 1-3, 5-6, 10-16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Alpini et al. (US 2014/0079680) in view of Marrone et al. (International Union of Biochemistry and Molecular Biology, 69(12), 2017, Pages 978-984).
Alpini teaches compositions to treat a bile duct disease, such as biliary hyperplasia or primary biliary cirrhosis [0016] as well as alcohol-induced liver damage, steatosis, ductopenia, malignancy, cholangitis, cholangiocarcinoma, gall stone disease, and cholestasis [0029-0031, 0073] (claim 2). Cholestasis is characterized by a mechanical blockage in the bile ducts [0073]. The treatment composition comprises AANAT (aralkylamine N-acetyl-transferase) modulators/enhancers [0009] used in local administration to an individual to the liver [0027]. The composition comprising AANAT modulators can also comprise targeting moieties such as nanoparticles wherein the nanoparticle can comprise polyethyleneimine loaded into polylactide [0027]. The composition can further comprise a pharmaceutically acceptable carrier including aqueous solutions [0088, 0092].
Alpini does not teach retroductal delivery of the therapeutic agent.
Marrone teaches that retrograde biliary infusion (which is the same as retroductal delivery) allows transfer of the therapeutic (in this case, a gene) into the liver with negligible leakage (pg 983, ¶3).
It would have been prima facie obvious to prepare a composition comprising AANAT modulators (a therapeutic biologic) and polyethyleneimine nanoparticles (biliary-therapeutic enhancer) for the treatment of a liver condition such as biliary liver cirrhosis or cholestasis, wherein bile ducts are blocked prior to administering medication. Alpini teaches administering the composition locally to the liver, which is part of the biliary tract. Marrone is applied for its teaching that administration by retrograde biliary infusion allows transfer of the therapeutic into the liver with negligible leakage, thus providing motivation to use retroductal delivery of any drug meant to be administered to the liver. The resulting administration would necessarily result in an increased concentration of the therapeutic in the liver. That being said, however, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. Consistent with this reasoning, it would have been obvious to have selected various combinations of therapeutics and enhancers from within Alpini, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
The resulting composition renders obvious that of instant claims 15-16 and 19-20 as well as the composition that is used in the method of claim 1. Alpini further renders obvious the method of treating a liver condition comprising administering the composition directly to the liver wherein, in some conditions like cholestasis, the bile duct is blocked prior to treatment. Accordingly, claims 1-3, 5-6, 10-16, and 19-20 are obvious in view of the prior art.
Claims 1-3, 5-6, 10-16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Alpini et al. (US 2014/0079680) in view of Marrone et al. (International Union of Biochemistry and Molecular Biology, 69(12), 2017, Pages 978-984) in view of Jia (US 2020/0378991).
Alpini teaches compositions to treat a bile duct disease, such as biliary hyperplasia or primary biliary cirrhosis [0016] as well as alcohol-induced liver damage, steatosis, ductopenia, malignancy, cholangitis, cholangiocarcinoma, gall stone disease, and cholestasis [0029-0031, 0073] (claim 2). Cholestasis is characterized by a mechanical blockage in the bile ducts [0073]. The treatment composition comprises AANAT (aralkylamine N-acetyl-transferase) modulators/enhancers [0009] used in local administration to an individual to the liver [0027]. The composition comprising AANAT modulators can also comprise targeting moieties such as nanoparticles wherein the nanoparticle can comprise polyethyleneimine loaded into polylactide [0027]. The composition can further comprise a pharmaceutically acceptable carrier including aqueous solutions [0088, 0092].
Alpini does not teach wherein the composition further comprises a bile acid sequestrant as the biliary therapeutic enhancer.
Jia teaches a method of treating a subject that has liver disease such as fibrosis or cirrhosis [0175]. The treatment comprises a bile-acid binding resin such as colesevelam, cholestyramine, or colestipol [0183]. It is proposed by Jia that the bile acid binding resins can remove intestinal bile acids, leading to decreased bile acid enterohepatic circulation, thus, reducing the bile acids so as to prevent or treat the degree or severity of liver fibrosis, cirrhosis, or other liver damage diseases [0183].
It would have been prima facie obvious to prepare a composition comprising AANAT modulators (a therapeutic biologic) and polyethyleneimine nanoparticles (biliary-therapeutic enhancer) for the treatment of a liver condition such as biliary liver cirrhosis. Alpini teaches administering the composition locally to the liver, which is part of the biliary tract. That being said, however, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. Consistent with this reasoning, it would have been obvious to have selected various combinations of therapeutics and enhancers from within Alpini, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
The resulting composition renders obvious that of instant claims 15-16 and 19-20 as well as the composition that is used in the method of claim 1. Alpini further renders obvious the method of treating a liver condition comprising administering the composition directly to the liver. Looking to Marrone, the skilled artisan would have found it obvious to administer the therapeutic by retrograde biliary infusion, thus allowing transfer of the therapeutic into the liver with negligible leakage. It would have further been obvious to add a bile-acid binding resin such as colesevelam to the composition of Alpini since colesevelam is taught as being effective at treating cirrhosis and other liver damage diseases and Alpini is similarly towards treating cirrhosis and liver damage diseases. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (see MPEP § 2144.07).
Accordingly, claims 1-3 and 5-20 are obvious in view of the prior art.
Response to Arguments
Applicant's arguments filed 9 February 2026 have been fully considered but they are not persuasive. The Applicant argues, on page 12 of their remarks, that neither Alpini nor Jia teach blocking outflow from the bile duct during administration of the therapeutic nor do they teach retroductal delivery.
In response, the above rejection has been modified to address these new limitations in the independent claim.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ANDREW S ROSENTHAL whose telephone number is (571)272-6276. The examiner can normally be reached M-F 8-5pm EST.
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/ANDREW S ROSENTHAL/Primary Examiner, Art Unit 1613
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