DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 12, 2026 has been reviewed by the examiner and entered of record in the file.
3. Claim 27 is amended. No claim is canceled or added.
Status of the Claims
4. Claims 27-30, 32-35, 37, and 38 are present in the application.
5. Claim 32 remains withdrawn from consideration, without traverse, as drawn to non-elected subject matter.
6. Regarding claim 28, as set forth in the previous office action, the scope of the independent invention that encompasses the elected species is as follows:
Claim 28: a method of reducing the side effects associated with an ASBT inhibitor treatment in an individual in need thereof by non-systemically administering a therapeutically effective amount of the ASBT inhibitor to the distal ileum, colon, or rectum of the individual, wherein the ASBTI is maralixibat,
further comprising administering a second agent that is selected from a proton pump inhibitor and a FXR agonist.
7. Claims 27-30, 33-35, 37 and 38 are under examination with the elected species and are the subject of this office action.
Information Disclosure Statement
8. The information disclosure statement (IDS) submitted on February 12, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Previous Claim Rejections - 35 USC § 103
9. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
10. Claims 27, 29, 33-35, 37 and 38 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Huang et al., J. Med. Chem. (2005), further in view of Abrahamsson, U.S. 2006/0199797 A1.
Claim 27, as amended, is drawn to a method of reducing side effects associated with Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) treatment in an individual in need thereof by non-systemically administering a therapeutically effective amount of the Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI):
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to the distal ileum, the colon, or the rectum of the individual, wherein the ABSTI increases the concentration of bile acids or salts thereof in the distal gastrointestinal tract of an individual (claim 30), wherein the ASBTI is administered orally, and wherein the therapeutically effective amount of the ASBTI is about 0.001 mg/day to about 100 mg/day.
11. Huang et al. demonstrate that apical sodium-codependent bile acid transporter (ASBT) inhibitors inhibit the reabsorption of bile acid, wherein non-systemic administration minimizes the potential side effects of said ASTB inhibitor:
“[s]ince the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug,”
(see Page 1, abstract). Huang et al. go on to teach the administration of compound 74, which demonstrates efficacy as a potent ASBT inhibitor in a rat:
“Benzylic DABCO quaternary ammonium analogue 74 is potent (IC50 =0.28 nM), nonhygroscopic (2% weight gain), and crystalline. It also showed efficacy in the rat gavage model.” [emphasis added] (see Page 5858, right column, second to last paragraph).
Compound 74 is the same compound instantly recited by Applicant, i.e., maralixibat:
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wherein “R” is OCH2C6H4(p)CH2(N+)DB, aka
(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]-phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo-[2.2.2]octane Chloride Salt (Page 5867, left column, last paragraph-right column, lines 1-7).
12. Huang et al. teach that when administered to rats in a rat fecal bile acid excretion model, the ASBTI agents demonstrate therapeutic efficacy for preventing the reabsorption of bile acids in said rats, i.e., by preventing reabsorption of bile acids in the distal gastrointestinal tract, the ASBTI increases the concentration of said bile acids (page 5860, left column, paragraph under “Conclusion,”). In particular, Huang et al. specifically demonstrate that compound 74 is efficacious in increasing fecal bile acid excretion in fecal samples when administered at dosage amounts of 5 mg/kg, 0.2 mg/kg and 0.04 mg/kg once daily. As such, compound 74 is efficacious in increasing the concentration of bile acids in the distal gastrointestinal tract when administered at a therapeutically effective amount of 5 mg/kg, 0.2 mg/kg or 0.04 mg/kg (see Table 6 and its summary, page 5860). And, a dosage of 5 mg/kg is equivalent to 1.5 mg/day; a dosage of 0.2 mg/kg is equivalent to a dose amount of 0.06 mg/day; and a dosage of 0.04 mg/kg is equivalent to a dose amount of 0.012 mg, each of which is within the range of “about 0.001 mg/day to about 100 mg/day,” required by claim 27 (assuming adult male rats weigh about 300 g, see page 5860, right column, under “Rat Fecal Bile Acid Excretion Model”).
13. Thus, Huang et al. disclose that non-systemically administering a therapeutically effective amount of the known ASBTI maralixibat to a rat increases the concentration of bile acids in the distal gastrointestinal tract of said rat, thereby minimizing or eliminating potential systemic side effects of said ASBTI, but do not teach oral administration.
14. Yet, Abrahamsson teaches that IBAT/ ASTBI compounds can be formulated for oral administration to a warm-blooded animal, e.g., as a tablet or capsule, (see paragraph [0234]). Abrahamsson specifically teaches the same IBAT/ ASTB inhibitor taught by Huang et al. and recited by Applicant, i.e., maralixibat, (see paragraph [0031]):
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which is the same compound instantly recited in claim 27 (see paragraphs [0013] and [0031]), wherein IBAT inhibitors are often referred to by different names including apical sodium dependent bile acid transporter (ASBT) inhibitors (paragraph [0019]-[0020]).
15. Abrahamsson goes on to teach that a therapeutically effective amount of the IBAT inhibitor is orally administered at a dose of 0.001 -50 mg/kg:
“The IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, will normally be administered to a warm- blooded animal at a unit dose within the range 0.5-5000 mg per square meter body area of the animal, i.e., approximately 0.001-50 mg/kg, and this would be expected to provide a therapeutically-effective dose. A unit dose from such as a tablet or capsule will usually contain, for example 0.05-250 mg of active ingredient. In one aspect of the invention a daily dose in the range of 0.01- 50 mg/kg is employed.” (paragraph [0238]).
A dose of 0.001 mg/kg -50 mg/kg is equivalent to a dose of about 0.3 mg/day to about 15,000 mg/day (assuming the warm-blooded animal is an adult male rat weighing about 300 g), which overlaps the range of 0.001 mg/day to about 100 mg/day, required by instant claim 27. And, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). See MPEP 2144.05.
16. Thus, it would have been obvious to one of skill in the art at the time the invention was made to orally administer maralixibat to a warm-blooded animal because of the convenience and ease of oral administration, wherein said administration is non-systemic and minimizes the potential side effects of IBAT/ ASTB inhibitors. One of ordinary skill in the art would have been motivated to administer maralixibat via oral administration to an individual in need thereof, resulting in the practice of claim 27, with a reasonable expectation of success.
Claim 29 is drawn to claim 27 and limits the patient population to a prematurely born infant, an enterally-fed infant or a formula-fed infant.
17. Huang et al. disclose that the non-systemic administration of the ASBTI maralixibat to an individual increases the concentration of bile acids in the distal gastrointestinal tract of said individual, thereby minimizing or eliminating potential systemic side effects of said ASBTI, but do not teach wherein the individual is an infant.
18. Abrahamsson teaches that “there is provided a method of treatment and/or prophylaxis of constipation, in a warm-blooded animal, such as man, in need of such treatment and/or prophylaxis which comprises administering to said animal an effective amount of an IBAT inhibitor,” (paragraph [0236]). Abrahamsson does not further limit the patient population, and teaches that the IBAT inhibitor/ ASBTI compound would be effective in the treatment of constipation in general, which embraces any subject population, including an infant. Therefore one of skill in the art would have been motivated at the time of filing to administer maralixibat to a warm-blooded animal in need thereof, non-systemically to the distal ileum, colon, or rectum of said mammal, including a prematurely born infant, an enterally-fed infant or a formula-fed infant.
As such, claim 29 is prima facie obvious.
Claim 33 is drawn to claim 27 and limits the administration to before the ingestion of food. Claim 34 is drawn to claim 27, and limits the administration to less than about 60 minutes before ingestion of food. Claim 35 is drawn to claim 27, and limits the administration to less than about 30 minutes before ingestion of food.
19. Huang et al. additionally teach that the ASBTI was administered once a day in the morning (page 5860, right column, under “Rat Fecal Bile Acid Excretion Model, Animal Handling and Dosing”). And, dose regimen optimization is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Likewise, optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. Thus one of ordinary skill in the art would have been motivated at the time of filing to optimize the timing of the administration of maralixibat relative to meals, in particular, before the ingestion of food, since the efficacy following administration of an ASBT inhibitor may range from a few minutes to several hours, depending upon the effect of food ingesting, the properties of each therapeutic compound and the age and condition of the individual.
As such, claims 33-35 are prima face obvious.
Claim 38 is drawn to claim 27, and limits wherein less than 30% of the ASBTI is systemically absorbed, (more specifically, less than 10% (claim 37)).
20. Abrahamson additionally teaches the low systemic exposure of IBAT/ ASBT inhibitors: “IBAT inhibitors have very low bioavailability (<2%), in this case the systemic exposure is low resulting in a reduced risk of side effects,” (paragraph [0013]). Therefore, one of skill in the art would reasonably expect that the non-systemic administration of maralixibat to an individual in need thereof results in less than 2% bioavailability, i.e., the extent that maralixibat becomes completely available is less than 2%, or less than 2% absorption. Thus one skilled in the art would have been motivated at the time of filing to administer maralixibat to an individual in need thereof, via non-systemic administration, and would have awareness that less than 2% is systemically absorbed, thus reducing the side effects of IBAT/ ASBT inhibitor administration.
As such, claims 37 and 38 are prima facie obvious.
21. Claim 28 remains rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Huang et al., J. Med. Chem. (2005), in view of Abrahamsson, U.S. 2006/0199797 A1, as applied to claims 27, 29, 33-35, 37 and 38, above, and further in view of Evans et al., Am. J. Physiol. Gastrointest. Liver Physiol. (2009).
Claim 27 is addressed in detail, above.
Claim 28 is drawn to claim 27, further comprising administering a second agent, that is selected from a proton pump inhibitor and a FXR agonist.
22. Huang teaches the non-systemic administration of the ASBTI maralixibat to the distal ileum, colon, or rectum of an individual in need thereof, wherein said administration mitigates the side effects of said ASBTI, and wherein said administration is oral, at a therapeutically effective dose amount of 0.001 mg/day to 100 mg/day, but do not teach the administration of an additional agent that is a FXR agonist or a PPI.
23. Yet, Huang additionally suggests the administration of ASBTIs for lowering serum LDL levels and lowering cholesterol (page 5853, left column, under “Introduction”).
24. And, Evans et al. teach that the FXR agonist WAY-362450 demonstrates efficacy for regulating bile acid transport and lowering circulating cholesterol levels, and suggests its use in the treatment of dyslipidemia:
“These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia,”
(see abstract and page G543, left column, first paragraph- right column, first paragraph).
25. As such, it would have been obvious to one of skill in the art at the time the invention was made to combine Applicant’s instantly recited ASBTI inhibitor maralixibat with an FXR agonist to achieve an additive effect in the regulation of bile acid transport, for lowering cholesterol for the treatment of dyslipidemia, for example, in an individual in need thereof, while minimizing potential side effects of an IBAT/ASTB inhibitor in said individual. And, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.
26. Please refer to MPEP 2144.06 “I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE” wherein Kerkhoven is specifically referenced:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
27. As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when 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” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined.
28. Thus, it would have been obvious to one of skill in the art at the time the invention was made to administer maralixibat in combination with the FXR agonist WAY-362450, which is known to regulate bile acid transport, and would have had a reasonable expectation of success in achieving an additive effect in the inhibition of bile acid transport in an individual in need thereof, while minimizing potential side effects of IBAT/ASTB inhibitors in said individual.
As such, claim 28 is prima facie obvious.
Response to Arguments
29. Applicant traverses the previous obviousness rejection over Huang et al., Huang et al. in view of Abrahamsson, or Huang et al. in view of Abrahamsson, further in view of Evans et al., and argues the following:
Applicant argues that instant claims are not obvious over Huang, alone and/or in view of Evans or Abrahamsson for at least the reason of the superior and unexpected results described in the previously submitted declaration of Pamela Vig, Ph.D on July 23, 2025 (“Vig Declaration”). Applicant argues that Dr. Vig explains that ASBT inhibition reduces intestinal absorption of bile acids and increases fecal bile acid (fBA) excretion, by increasing the concentration of bile acids and salts thereof in the distal gastrointestinal tract (in paragraph 3 of the Vig Declaration).
Applicant argues that at the time the present invention was made it was not known and could not have been predicted that oral administration of maralixibat could result in dose-independent, low treatment-emergent adverse effects (TEAEs), and to demonstrate the superior and unexpected effect of maralixibat according to the present claims, Dr. Vig presents the results of a Phase 1 dose-ranging clinical trial in overweight and obese adults. This study was conducted to assess dose-dependent fBA excretion with ASBTIs maralixibat and volixibat, while monitoring TEAEs. Applicant argues that maralixibat and volixibat unexpectedly greatly increased fBA excretion in a dose-dependent fashion with favorable pharmacodynamic endpoints and without significant TEAEs, even at the highest tested doses (poster presentation provided as Exhibit D, and Table 2, in the Vig Declaration).
Applicant contends that the incidence of TEAEs was not dose-dependent and was similar between maralixibat and volixibat, refering to Table 2 in the Vig Declaration. Applicant notes that the only incidence of TEAEs was not dose-dependent and was similar between maralixibat and volixibat, occurring in over 10% of the study population, being headache and diarrhea. Applicant alleges that the superior and unexpected results of the dose-independent reduced side effects are demonstrated over a range of doses in Table 2, and that the claims have been amended to recite a therapeutically effective amount of maralixibat encompassing the range of doses as shown in Table 2, thereby making the claims commensurate in scope with the data presented in the Vig Declaration. Applicant argues that they are not claiming a dose-dependent increase in the concentration of bile acids in the distal GI tract due to administration of maralixibat as noted by Examiner, but rather a therapeutically effective amount of maralixibat that has been demonstrated to result in reduced side effects.
30. Applicant's arguments have been fully considered but they are not persuasive. Throughout the Vig Declaration, and at least in paragraphs 15-17 below, Vig repeats the surprising and unexpected dose-dependent increase in fBA excretion resulting from administration of maralixibat at 50 mg BID:
“15. Surprisingly, the data from the study summarized in Figure 1 demonstrates a significant, dose dependent increase in fBA excretion up to the maximum tested doses of maralixibat and volixibat. 50 mg BID dosing unexpectedly led to numerically higher fBA excretion than the same total dose given QD.
16. It has further been surprisingly observed that ASBT inhibition in individual with cholestasis, who typically have impaired bile flow, results in lower rates of gastrointestinal disturbance compared with ASBT inhibition in individuals without cholestasis, who have normal bile flow.
17. Furthermore, 7aC4 levels generally increased with increasing doses of maralixibat; the greatest change was at 50 mg BID (Figure 2), which signifies de novo bile acid synthesis converting cholesterol to bile acids.” (Vig Declaration, page 5).
31. As Applicant alleges, Vig goes on to discuss that the incidence of TEAEs was not dose-dependent and was similar between maralixibat and volixibat, occurring in over 10% of the study population (paragraph 18 of the Vig Declaration at page 6). However, it is noted that the features upon which Applicant relies (i.e., reduced incidence of TEAEs at a dose amount of 10 mg QD, 20 mg QD, 50 mg QD, 100 mg QD, or 50 mg BID) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As claim 27 presently embraces a much broader range of any amount of maralixibat from 0.001 mg/day to about 100 mg/day, the instant claims are not drafted commensurate in scope with the unexpected results detailed in Table 2 (Vig Declaration, Exhibit D poster).
32. Applicant is reminded that “the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support” (In re Clemens, 622 F.2d 1029 (CCPA 1980)). Thus, in In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), factual evidence demonstrating a greater than expected result from the addition of 2% of an ingredient did not evidence unexpected results for the entire claimed range of about 1-3% of the ingredient. Rather, the nonobviousness of a broader range or genus can only be established by evidence based on unexpected results of a narrower range or genus when one of ordinary skill in the art would be able to determine a trend in the exemplified data allowing said artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48 (CCPA 1979). In the instant case, the claims are not drafted commensurate in scope with the unexpected results demonstrated in the Vig Declaration, i.e., reduced incidence of TEAEs following oral administration of maralixibat at a dosage amount of 10 mg QD, 20 mg QD, 50 mg QD, 100 mg QD, or 50 mg BID.
As such, the previous rejection over Huang et al., Huang et al. in view of Abrahamsson, or Huang et al. in view of Abrahamsson, further in view of Evans et al. is maintained.
Previous Double Patenting Rejections
33. 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).
34. 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 §§ 706.02(l)(1) - 706.02(l)(3) 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).
35. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
36. Claims 27, 30, 37 and 38 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7 ,9 and 13-15 of U.S. Patent No. 10,188,646 B2.
37. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 27 recites a method of reducing the side effects associated with ASTB inhibitor treatment, comprising non-systemically administering to an individual in need thereof, a therapeutically effective amount of the Apical Sodium- dependent Bile Acid Transporter Inhibitor (ASBTI) maralixibat:
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to the distal ileum, the colon, or the rectum of the individual, wherein the ABSTI increases the concentration of bile acids or salts thereof in the distal gastrointestinal tract of an individual (claim 30).
Claim 38 is drawn to claim 27, and limits wherein less than 30% of the ASBTI is systemically absorbed, (more specifically, less than 10% (claim 37)).
38. U.S. Patent No. 10,188,646 B2 recites the following:
CLAIM 1 recites a method of treating or preventing obesity by increasing the concentration of bile acid in the distal gastrointestinal tract of a non-diabetic individual, comprising orally administering for local delivery to the distal ileum, the colon, or the rectum of the individual, a therapeutically effective amount of an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI), and wherein the ASBTI is formulated to be less than 10% systemically absorbed, wherein said ASBTI compound can be:
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(aka maralixibat), or a pharmaceutically acceptable salt thereof.
CLAIM 6 is drawn to claim 1, wherein the ASBTI is formulated to be less than 10% systemically absorbed.
CLAIM 7 is drawn to claim 6, and limits wherein the ASBTI is maralixibat or a pharmaceutically acceptable salt or solvate thereof.
CLAIM 9 is drawn to claim 6, and limits wherein the ASBTI is administered as a single dose of about 0.001 to about 30 mg/day.
CLAIM 13 recites a method of treating or preventing obesity by increasing the concentration of bile acid in the distal gastrointestinal tract of a non-diabetic individual, comprising orally administering for local delivery to the distal ileum, the colon, or the rectum of the individual, a therapeutically effective amount of an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI), and wherein the ASBTI is formulated to be less than 10% systemically absorbed, wherein said ASBTI compound can be
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(maralixibat), or a pharmaceutically acceptable salt or solvate thereof, and the Cmax of the therapeutically effective amount of the ASBTI is at least 80% reduced when compared to the Cmax of a systemically absorbed ASBTI.
CLAIM 14 is drawn to claim 13, and limits wherein the ASBTI is maralixibat or a pharmaceutically acceptable salt or solvate thereof.
CLAIM 15 is drawn to claim 13, wherein the ASBTI is administered as a single dose of about 0.001 to about 30 mg/day.
39. Thus, the claims of U.S. Pat. No. 10,188,646 B2 recite a method of orally administering Applicant’s recited ASTBI compound, maralixibat (specifically recited in claims 7, 11 and 14) for local delivery to the distal ileum, colon, or rectum of an individual to treat or prevent obesity by increasing the concentration of bile acid in the distal gastrointestinal tract. The claims of the U.S. Pat. No. 10,188,646 B2 recite the same mechanism that is instantly recited in claim 30, i.e., increasing the concentration of bile acid in the distal gastrointestinal tract of an individual.
40. One of ordinary skill in the art would immediately recognize that Applicant’s instant claim 30 recites the same activity of increasing bile acids and salts thereof in the distal gastrointestinal tract. While the instant claims do not recite a method of treating or preventing obesity, this result flows from the administration step itself, since a subject suffering from obesity meets the criteria of a subject in need of increasing the concentration of bile acids or bile salts in the distal gastrointestinal tract, and therefore the claims are not patentably distinct. As such, the method previously recited in U.S. Pat. No. 10,188,646 B2, is not patentably distinct from the method of the instant claims.
41. Claims 27, 29, 30, 33-35, 37 and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, and 8-10 of U.S. Patent No. 10,251,880 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 27 recites a method of reducing the side effects associated with ASTB inhibitor treatment, comprising non-systemically administering to an individual in need thereof, a therapeutically effective amount of the Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) maralixibat:
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to the distal ileum, the colon, or the rectum of the individual, wherein the ABSTI increases the concentration of bile acids or salts thereof in the distal gastrointestinal tract of an individual (claim 30). Claim 29 is drawn to claim 27 and limits the patient population to a prematurely born infant, an enterally-fed infant or a formula-fed infant. Claim 33 is drawn to claim 27 and limits the administration to before the ingestion of food. Claim 34 is drawn to claim 27, and limits the administration to less than about 60 minutes before ingestion of food. Claim 35 is drawn to claim 27, and limits the administration to less than about 30 minutes before ingestion of food. Claim 38 is drawn to claim 27, and limits wherein less than 30% of the ASBTI is systemically absorbed, (more specifically, less than 10% (claim 37)).
42. U.S. Patent No. 10,251,880 B2 recites the following:
CLAIM 1 recites a method for treating an inflammatory intestinal condition comprising orally administering for local delivery to the distal ileum, the colon, or the rectum of an individual in need thereof, a pharmaceutical composition consisting of a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) and one or more pharmaceutical carriers, wherein the inflammatory intestinal condition is selected from the group consisting of gastritis, ulcerative colitis, gastroenteritis, radiation induced enteritis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, gastric carcinogenesis, and gastric carcinogenesis following gastric or bowel resection, wherein the ASBTI inhibitor is a compound of Formula II, more specifically the compound of CLAIM 8:
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(aka maralixibat), or a pharmaceutically acceptable salt thereof.
CLAIM 2 is drawn to claim 1, and limits wherein less than 10% of the ASBTI is systemically absorbed.
CLAIM 3 is drawn to claim 1, wherein the individual is a prematurely born infant, an enterally-fed infant, or a formula-fed infant.
CLAIM 4 is drawn to claim 1, and limits wherein the non-systemically administered ASBTI reduces intraenterocyte bile acids or reduces necrosis and/or damage to ileal architecture in an individual in need thereof.
CLAIM 9 is drawn to claim 1, and limits wherein the ASBTI is administered before ingestion of food, optionally wherein the ASBTI is administered less than about 60 minutes or less than about 30 minutes before ingestion of food.
CLAIM 10 is drawn to claim 1, and limits wherein the ASBTI is administered orally.
43. Thus, the claims of U.S. Patent No. 10,251,880 B2 recite a method of orally administering an ASTBI compound, wherein ASTBI compound is Applicant’s instantly elected compound, maralixibat, for local delivery to the distal ileum, colon, or rectum of an individual to treat an inflammatory intestinal condition. U.S. Patent No. 10,251,880 B2 teaches that local delivery to the distal ileum increases the concentration of bile acids, i.e., “contacting the distal ileum of an individual in need thereof with an ASTBI… and/or a FXR agonist… increases the concentration of bile acids and salts thereof… in the distal gastrointestinal tract of the individual,” (column 7, lines 51-54 and 65-67). As such, one of ordinary skill in the art would immediately recognize that Applicant’s recited compound would exhibit the same activity of increasing bile acids and salts thereof in the distal gastrointestinal tract as it demonstrated in U.S. Pat. No. 10,251,880. While the previously patented claims of U.S. Pat. No. 10,251,880 do not recite a method of reducing side effects of ASBTI treatment, this result flows from the administration step itself, since the patient population in both the patented claims as well as Applicant’s claims are the same, i.e., a patient in need of increasing the concentration of bile acids or bile salts in the distal gastrointestinal tract, and the active treatment step is the same, i.e., administering a therapeutically effective amount of the ASTBI inhibitor maralixibat. As such, the method previously recited in U.S. Pat. No. 10,251,880 B2 is not patentably distinct from the method of the instant claims.
44. Claims 27 and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of U.S. Patent No. 10,555,950 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 27 recites a method of reducing the side effects associated with ASTB inhibitor treatment, comprising non-systemically administering to an individual in need thereof, a therapeutically effective amount of the Apical Sodium- dependent Bile Acid Transporter Inhibitor (ASBTI) maralixibat:
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to the distal ileum, the colon, or the rectum of the individual, wherein the ABSTI increases the concentration of bile acids or salts thereof in the distal gastrointestinal tract of an individual (claim 30).
45. U.S. Patent No. 10,555,950 B2 recites the following:
CLAIM 2: A method of treating diabetes comprising administering to the distal ileum, the colon, or the rectum of a diabetic individual, a single pharmaceutical composition consisting of a therapeutically effective amount of an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) and one or more pharmaceutical carriers, wherein the ASBTI is
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or a pharmaceutically acceptable salt thereof.
46. Thus, U.S. Patent No. 10,555,950 B2 recites a method of administering Applicant’s instantly recited compound, maralixibat for local delivery to the distal ileum, colon, or rectum of an individual to treat diabetes. U.S. Pat. No. 10,555,950 B2 discusses that local delivery to the distal ileum increases the concentration of bile acids, i.e., “contacting the distal ileum of an individual in need thereof with an ASTBI… g. increases the concentration of bile acids and salts thereof… in the distal gastrointestinal tract of the individual,” (column 2, lines 8, 9, and 18-20). As such, one of ordinary skill in the art would immediately recognize that Applicant’s recited compound would exhibit the same activity of increasing bile acids and salts thereof in the distal gastrointestinal tract as it demonstrated in U.S. Pat. No. 10,555,950 B2. While the previously patented claims of U.S. Pat. No. 10,555,950 B2 do not recite a method of reducing side effects of ASBTI treatment, this result flows from the administration step itself, since the active step in both the patented claims as well as Applicant’s claims are the same, i.e., administering a therapeutically effective amount of the ASTBI inhibitor maralixibat. As such, the method previously recited in U.S. Pat. No. 10,555,950 B2 is not patentably distinct from the method of the instant claims.
47. Claims 27, 29, 30, 33-35, 37 and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, and 6-12 and 14-20 of U.S. Patent No. 11,260,053 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 27 recites a method of reducing the side effects associated with ASTB inhibitor treatment, comprising non-systemically administering to an individual in need thereof, a therapeutically effective amount of the Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) maralixibat:
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to the distal ileum, the colon, or the rectum of the individual, wherein the ABSTI increases the concentration of bile acids or salts thereof in the distal gastrointestinal tract of an individual (claim 30). Claim 28 is drawn to claim 27, further comprising administering a second agent that is selected from a proton pump inhibitor and a FXR agonist. Claim 29 is drawn to claim 27 and limits the patient population to a prematurely born infant, an enterally-fed infant or a formula-fed infant. Claim 33 is drawn to claim 27 and limits the administration to before the ingestion of food. Claim 34 is drawn to claim 27, and limits the administration to less than about 60 minutes before ingestion of food. Claim 35 is drawn to claim 27, and limits the administration to less than about 30 minutes before ingestion of food. Claim 38 is drawn to claim 27, and limits wherein less than 30% of the ASBTI is systemically absorbed, (more specifically, less than 10% (claim 37)).
48. U.S. Patent No. 11,260,053 B2 recites the following:
CLAIM 1: A method of increasing the concentration of bile acids and salts thereof in the distal gastrointestinal tract of an individual comprising administering an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) to the individual, wherein a therapeutically amount of the ASBTI is delivered to the distal ileum, the colon, or the rectum of an individual in need thereof, wherein the ASBTI is selected from
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and potassium((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydropyran-2-ylmethyl)sulphate ethanolate hydrate.
CLAIM 2 is drawn to claim 1, and further comprises administering a second agent selected from an enteroendocrine peptide enhancing agent, a nuclear farnesoid X receptor (FXR) agonist, a liver receptor homolog 1 (LRH-1), a DPP-IV inhibitor, a proton pump inhibitor, H2 antagonist, prokinetic agent, a biguanide, an incretin mimetic, a thiazolidinone, a mucoadhesive agent, and GLP-1 or an analog thereof.
CLAIM 3 is drawn to claim 1, and limits wherein the individual is a prematurely born infant, an enterally-fed infant, or a formula-fed infant.
CLAM 4 is drawn to claim 1, wherein the ASBTI reduces intraenterocyte bile acids or reduces necrosis and/or damage to ileal architecture in an individual in need thereof.
CLAIM 6 is drawn to claim 2, wherein the FXR agonist is GW4064, GW9662, INT-747, T0901317, WAY-362450, fexaramine, cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodihydrofusidate, taurodeoxycholic acid, cholate, glycocholate, deoxycholate, taurocholate, taurodeoxycholate, chenodeoxycholic acid, or a salt thereof, or a combination thereof.
CLAIM 7 is drawn to claim 2, wherein the ASBTI and/or the second agent is administered before ingestion of food.
CLAIM 8 is drawn to claim 2, wherein the ASBTI and/or the second agent is administered less than about 60 minutes before ingestion of food.
CLAIM 9 is drawn to claim 2, wherein the ASBTI and/or the second agent is administered less than about 30 minutes before ingestion of food.
CLAIM 10 is drawn to claim 2, wherein the ASBTI and/or the second agent is administered orally.
CLAIM 11 is drawn to claim 2, wherein the ASBTI and/or the second agent is administered orally as an ileal-pH sensitive release or an enterically coated formulation.
CLAIM 12 is drawn to claim 2, wherein the ASBTI is
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CLAIM 14 is drawn to claim 1, wherein the subject does not have diabetes.
CLAIM 15 is drawn to claim 1, wherein the ASBTI is administered before ingestion of food.
CLAIM 16 is drawn to claim 1, wherein the ASBTI is administered less than about 60 minutes before ingestion of food.
CLAM 17 is drawn to claim 1, wherein the ASBTI is administered less than about 30 minutes before ingestion of food.
CLAIM 18 is drawn to claim 1, wherein the ASBTI is administered orally.
CLAIM 19 is drawn to claim 1, wherein the ASBTI is administered orally as an ileal-pH sensitive release or an enterically coated formulation.
CLAIM 20 is drawn to claim 1, wherein the ASBTI is
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49. Thus, the claims of U.S. Patent No. 11,260,053 B2 recite a method of increasing the concentration of bile acids or salts thereof in the distal gastrointestinal tract of an individual comprising orally administering an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) that is Applicant’s instantly recited compound, maralixibat, to the individual, wherein a therapeutically effective amount of the ASBTI is delivered to the distal ileum, the colon, or the rectum of an individual in need thereof. Applicant does not recite in the instant claims that the individual has diabetes. As such, one of ordinary skill in the art would immediately recognize that Applicant’s recited compound would exhibit the same activity of increasing bile acids and salts thereof in the distal gastrointestinal tract as recited in U.S. Pat. No. 11,260,053 B2. While the previously patented claims of U.S. Pat. No. 11,260,053 B2 do not recite a method of reducing side effects of ASBTI treatment, this result flows from the administration step itself, since the active step in both the patented claims as well as Applicant’s claims are the same, i.e., administering a therapeutically effective amount of the ASTBI inhibitor maralixibat. As such, the method previously recited in U.S. Pat. No. 11,260,053 B2 is not patentably distinct from the method of the instant claims.
50. Regarding the double patenting rejections over the claims of U.S. Patent No. 10,188,646 B2 and the claims of U.S. Patent No. 10,251,880 and/or the claims of U.S. Pat. No. 10,555,950 and/or the claims of U.S. Pat. No. 11,260,053, Applicant has requested to hold the double patenting rejections in abeyance until allowable subject matter in the present application has been formally acknowledged.
51. Thus, the previous double patenting rejections are maintained.
Conclusion
52. In conclusion, claims 27-30, 32-35, 37 and 38 are present in the application. Claim 32 is withdrawn from further consideration. Claims 27-30, 33-35, 37 and 38 are rejected. No claim is presently allowable.
53. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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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.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628