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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/21/25 has been entered.
Claim Status
Claim 2-9 are cancelled.
Claims 10-17 are new.
Claims 1 and 10-17 are pending.
Withdrawn rejections
Applicant's amendments and arguments filed 11/21/25 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Terminal Disclaimer
The terminal disclaimer filed on 11/21/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of application 18732612 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 and 10-17 are rejected under 35 U.S.C. 103(a) as being unpatentable over CN106176800A and Bhagat et al. (WO2005065291) and EP2545907 and Tanguay et al. (WO2019148278; IDS filed 5/8/25) and Carelli et al. (International Journal of Pharmaceutics 202 (2000) 103–112) and Colakuglu et al. (Cell 2020; 180:218-220) and Mendes et al. (Clinical and Molecular Hepatology 2020;26:595-605).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims a method of treating a subject having alcoholic hepatitis caused by PAMPs comprising endotoxins and CpG-DNA from gut microbes by administering a drug comprising a core granulate of cholestyramine, colesevelam or colestipol and a pH-sensitive coating layer comprising MMA and MAA in a molar ratio of approximately 1:2 or 1:1.
Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical metabolic disorder research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from metabolic disorder medicine including types of metabolic disorders and their risk factors, pharmaceutical formulation and chemistry— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1, 16 and 17, CN106176800A teaches oral treatment of metabolic disease produced due to enteric flora disturbance that includes hepatitis, hepatic fibrosis, type 2 diabetes, central obesity, endotoxemia, which is when components of the bacteria enter the blood stream and cause systemic inflammation which is linked to CVD, NASH and liver cirrhosis with a polycationic resin (Abstract; claims 1-2) as well as non-alcoholic fatty liver disease (NAFLD), steatohepatitis and hepatocarcinoma (Page 3, middle) where the virulence factor produced by enteric microorganisms, such as endotoxins and CpG-DNA, are removed or neutralized (Claims 7 and 10) and names cholestyramine, colestipol and colesevalam as polycationic resin particles to employ (Page 7, middle). Thus, the method of CN106176800A implicitly treats a subject having a metabolic disorder caused or promoted by pathogen-associated molecular patterns (PAMPs) by sequestration of PAMPs to form a sequestrant-PAMP complex that is naturally eliminated from the digestive tract of the subject along with the rest of the digestive contents. The same sequestrants taught by CN106176800A as claimed by Applicant naturally bind to the endotoxins or the CpG-DNA to form a sequestrant-PAMP complex thereby eliminating the endotoxins and the CpG-DNA from gut microbes.
Regarding claims 1, 16 and 17, CN106176800A teaches cholestyramine, colestipol and colesevalam as polycationic resin particles, which sequestrants comprises high molecular copolymers, which comprise three-dimensional framework of macromolecular hydrocarbon chains and having positively charged groups comprising amino groups (Page 7, middle). CN106176800A teaches oral administration to the digestive tract (Page 6, top).
Regarding claim 1, Bhagat et al. teach an enteric coating for a tablet for release in the ileum of the mammal (Claim 66) comprising colesevalam (Claim 71) and the enteric coating is acid resistant (Claim 73) and comprises a copolymer of MMA and MAA (Claim 74). Bhagat et al. teach that such polymers solubilize at about pH 6.0 or higher and target the jejunem and/or ileum (Page 11, lines 16-24), which are interpreted to be distal regions of the small intestine. Seal coating is also taught (Page 13, lines 6-8, 24-27; page 14, lines 5-10).
Regarding claims 1, 11 and 17, EP2545907 teaches that it is known in the art to granulate polyallyamine polymers, such as colesevelam, and produce a tablet or a mini-tablet (Abstract; claims 1, 8, 10 and 12; [0024]) or capsule (Claim 13). EP2545907 teaches a compressed core tablet with a hardness ranging from 70 to 195 Newtons (Example 7, [0073]) and teaches obtaining a tablet with the correct hardness [0026].
Regarding claims 1, 12 and 16, Tanguay et al. teach cholestyramine formulations targeted for delivery to the ileum (Abstract; claims 1-37) in the form of minitabs (minitablets) or pellets [0022], where the minitabs are seal coated and then enteric coated ([00111-0014, 00117-00123, 00136]; claims 19, 29 and 35) where the seal coating protected the core from water exposure during the enteric coating process [00134] and report that: “… the use of a seal coat could significantly reduce variations in bursting profile by acting as a substrate for the enteric coating. The seal coat may also further reduce unwanted electrostatic interactions between cholestyramine and the enteric coating at the seam of the capsule.” [00144]. The purpose of the seal coating is explained as: “A seal coat had to be used to prevent interaction between the enteric coating and the resin and to provide a substrate for applying the enteric polymer.” [0074]. It is the Examiner’s position that the seal coating of Tanguay et al. reads on an “isolation layer” coating the cholestyramine core and the enteric coating is a pH-sensitive coating layer coating the isolation layer. The dosage form of Tanguay et al. releases in the distal part of the small intestine, preferable in the ileum (Claim 7) and to treat small intestinal bacterial overgrowth (SIBO) (Claims 43 and 58) thereby implicitly sequestrating PAMPs comprising endotoxins or CpG-DNA derived from gut microbes.
Regarding claim 1, Tanguay et al. teach enteric polymers comprising methyl methacrylate and methacrylic acid ([0046, 00124]; Table 12; [00164]) such as Eudragit® S100F, which is soluble in digestive fluids [0076-0078].
Regarding claim 1, Tanguay et al. teach a release at pH preferably greater than 6.2 such as 6.2-7 and preferably from 6.5-6.8 (Claims 2-3; [0041]).
Regarding claim 10, Tanguay et al. teach a core blend comprising lactose and magnesium stearate as well as PVP and HPC (Claim 18; [00114 and Table 10).
Regarding claim 11, Tanguay et al. teach obtaining minitabs with a hardness of 0.70 Kp and about 2 Kp [00115] where 1 Kp = 10 N.
Regarding claims 12 and 13, Tanguay et al. teach that the barrier coating “isolation layer” (Claim 22) can contain polyethylene glycol (Claim 23) and talc (Claim 24).
Regarding claim 14, Tanguay et al. teach triethyl citrate in the enteric pH-sensitive coating layer (Claims 22 and 26).
Regarding claim 15, Tanguay et al. teach filling size 00 capsules with 50 cholestyramine mini-tablets [00136] and the shape as being cylinders of 2.0 X 3.0 mm [00115], which is diameter by length, thus the diameter is approximately 2 mm.
Regarding claim 1, Carelli et al. teach that Eudragit L100 is MMA/MAA copolymer of 1:1 molar ratio that dissolves at pH values over 6.0 (jejunum) and Eudrogit S100 is a MMA/MAA copolymer of 1:2 molar ratio that dissolves at pH values over 7.0 (ileum) for site specific oral delivery to the jejunum or the ilium (Abstract; page 103 right column-page 104 top left column).
Regarding claim 1, Colakuglu et al. teach that Enterococcus faecalis is a critical contributor to alcoholic hepatitis (Abstract) where patients with alcoholic hepatitis had over 2700 fold increase in the bacterium Enterococcus faecalis with 30% of the strains having genes encoding an exotoxin (Page 218, left column). Thus, alcoholic hepatitis can be characterized as an enteric flora disturbance.
Regarding claim 1, Mendes et al. teach that: “Alcohol-associated intestinal dysbiosis and bacterial overgrowth can lead to a dysregulation of tryptophan metabolism and lower production of indoles… Chronic alcohol consumption is associated with reduced intestinal expression of Reg3β and Reg3γ, increased numbers of mucosa-associated bacteria and bacterial translocation. Translocated microbial products and viable bacteria reach the liver and activate the innate immune system. Release of inflammatory molecules promotes inflammation, contributes to hepatocyte death and results in a fibrotic response.” (Abstract). Mendes et al. teach that alcohol associated liver disease includes alcoholic hepatitis (Page 595, Introduction). Mendes et al. teach that alcohol use is associated with enteric dysbiosis and intestinal overgrowth (Page 596, left column Intestinal Dysbiosis). Mendes et al. teach: “chronic ethanol administration changes bacterial alpha diversity in the ileum, largely driven by an increase in gram negative bacteria. Moreover, gram-negative Prevotella not only increased in the mucus layer of the ileum but also in liver samples suggesting that translocation of viable bacteria to the liver might be associated with microbiota changes in the distal gastrointestinal tract.” (Page 599, right column).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and CN106176800A is that CN106176800A do not expressly teach treating alcoholic hepatitis with a drug that is targeted to deliver a sequestrant into distal region a small intestine wherein the sequestrant is formulated in the form of pellets or tablets for sequestration of the intestinal source of PAMPs; the pellets or tablets comprises a core granulate, an isolation layer, and a pH-sensitive coating layer; while the core granulate comprises a copolymer as an active pharmaceutical ingredient wherein the pH-sensitive coating layer allows the sequestrant to be targeted in the ileum for therapeutic application wherein the pH-sensitive coating layer comprises methyl methacrylate (MMA) and methacrylic acid (MAA) in a molar ratio of approximately 1:2 or 1:1 and wherein the pH-sensitive coating layer ensures that the sequestrant is released at a pH range of 6.5 to 7.5, allowing for targeted sequestration in the ileum. This deficiency in CN106176800A is cured by the teachings of Bhagat et al., EP2545907, Tanguay et al., Carelli et al., Colakuglu et al., and Mendes et al.
1. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of CN106176800A on a patient with alc0holic hepatitis by delivering a sequestrant into distal region a small intestine wherein the sequestrant is formulated in the form of pellets or tablets for sequestration of the intestinal source of PAMPs; the pellets or tablet comprises a core granulate, an isolation layer, and a pH-sensitive coating layer; while the core granulate comprises a copolymer as an active pharmaceutical ingredient wherein the pH-sensitive coating layer allows the sequestrant to be targeted in the ileum for therapeutic application wherein the pH-sensitive coating layer comprises methyl methacrylate (MMA) and methacrylic acid (MAA) in a molar ratio of approximately 1:2 or 1:1 and wherein the pH-sensitive coating layer ensures that the sequestrant is released at a pH range of 6.5 to 7.5, allowing for targeted sequestration in the ileum , as suggested by Bhagat et al., EP2545907, Tanguay et al., Carelli et al., Colakuglu et al., and Mendes et al. and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because for the following sound articulated reasoning with rational underpinning based upon the evidence. CN106176800A is directed to metabolic disease produced due to enteric flora disturbance. Colakuglu et al. teaches that alcoholic hepatitis is characterized by over proliferation of Enterococcus faecalis and thus an enteric flora disturbance. Mendes et al. teach that chronic ethanol administration changes the bacterial diversity in the ileum and that alcohol use is associated with enteric dysbiosis and intestinal overgrowth. Consequently, patients with alcoholic hepatitis fall within the scope of patients to be treated by CN105176800A with a reasonable expectation of success. In the treatment method, CN105176800A teaches administration to the digestive tract. The artisan would desire all of the active agent to reach the enteric flora and especially the ileum as suggested by Mendes et al. Bhagat et al. teach that: “An enteric coating delays the release of a drug and makes it possible for the drug to be released after passage through the stomach, e.g., a particular location within the intestinal tract.” Accordingly, the artisan would employ an enteric coated tablet of the active to delay the release until after it passes through the stomach with a reasonable expectation of success. Tanguay et al. and Bhagat et al. further guide the artisan to a pH-sensitive layer of MMA and MAA that ensures that the sequestrant is released at a pH range of 6.5 to 7.5, thereby targeting the ileum and avoiding release in the upper section of the small intestine. Carelli et al. teach that commercially available Eudragit L100 is a MMA/MAA copolymer of 1:1 molar ratio that dissolves at pH values over 6.0 (jejunum) and Eudragit S100 is a MMA/MAA copolymer of 1:2 molar ratio that dissolves at pH values over 7.0 (ileum) for site specific oral delivery to the jejunum or the ilium. Tanguay et al. further instruct the artisan that minitablets and pellets are interchangeable and that it is desirable to have a seal layer (isolation layer) to prevent interaction between the enteric coating and the resin and to provide a substrate for applying the enteric polymer. The ordinary artisan would modify CN106176800A with the teachings of Bhagat et al., Tanguay et al. and Carelli et al. and employ an isolating seal layer on the core prior to enteric coating with a pH-sensitive layer of MMA and MAA in an approximate 1:2 or 1:1 molar ratio that ensures that the sequestrant is released at a pH range of 6.5 to 7.5 thereby targeting the ileum with a reasonable expectation of success. The Examiner notes that neither CN106176800A nor Bhagat et al. appear to teach a core granulate. However, Tanguay et al. teaches a coated minitablet [00118], which ostensibly has a core that was coated, and Bhagat et al. teach a tablet core (Page 12, lines 3-8; page 13, lines 6-12) that comprises excipients (Page 14, line 29 through Page 15, line 6) and “conventional tableting technology” is used to make tablets (Page 9, lines 6-12). EP2545907 teaches that polyallylamine polymers such as colesevalam are granulated before direct compression into a tablet. Therefore, the ordinary artisan would have a reasonable expectation of success in making at least a tablet or pellet with a core granulate of the claimed sequestrants with an isolating seal coating on the core granulate and an enteric coating on the seal coating in the absence of convincing evidence to the contrary.
The difference between the instant application and CN106176800A is that CN106176800A as modified by Bhagat et al., EP2545907, Tanguay et al., Carelli et al., Colakuglu et al., and Mendes et al. do not expressly teach the core granulate excipients of claim 10; the hardness of 5-15 N/mm of claim 11; the isolation layer comprising PEG and talc; the pH sensitive coating comprising triethyl citrate plasticizer; and the form of pellets or mini-tablets with a diameter of approximately 2 mm. This deficiency in CN106176800A as modified by Bhagat et al., EP2545907, Tanguay et al., Carelli et al., Colakuglu et al., and Mendes et al. is cured by the teachings of Tanguay et al.
2. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of CN106176800A as modified by Bhagat et al., EP2545907, Tanguay et al., Carelli et al., Colakuglu et al., and Mendes et al., with pellets or minitablets having the core granulate excipients of claim 10; the hardness of 5-15 N/mm of claim 11; the isolation layer comprising PEG and talc; the pH sensitive coating comprising triethyl citrate plasticizer; and the form of pellets or mini-tablets with a diameter of approximately 2 mm, as suggested by Tanguay et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because it is merely judicious selection of known excipients to formulate the core blend, the isolation layer and the pH-sensitive coating as suggested by Tanguay et al. The ordinary artisan would optimize the formulation to obtain the desired hardness, such as 5-15 N/mm, to at least withstand the formulation process and not crumble with a reasonable expectation of success. Especially with Tanguay et al. teaching Tanguay et al. teach obtaining minitabs with a hardness of 0.70 Kp and about 2 Kp, where 1 Kp = 10 N, and thus it is a result effect variable. A search of the instant specification does not reveal any indication of surprising or unexpected results achieved with any of the claimed excipients or the hardness range of 5-15 N/mm. Consequently, it is merely conventional use of known excipients for their intended purpose without anything more. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). Essentially, administration of the cholestyramine minitabs of Tanguay et al. in the method of CN106176800A for treating alcoholic hepatitis appears obvious in light of the combined references.
Response to Arguments:
Applicant’s arguments filed 11/21/25 have been carefully considered but are not persuasive.
On page 5 of remarks, Applicant asserts that CN1061076800A does not teach or suggest the specific combination for treatment of alcoholic hepatitis. Respectfully, the Examiner has a different perspective. As acknowledged by Applicant, CN1061076800A is directed to treating metabolic diseases associated with enteric microbiota imbalance. The Examiner has shown through the teachings of Colakuglu et al. and Mendes et al. that the ordinary artisan is aware that alcoholic hepatitis is associated with enteric microbiota imbalance and therefore within the scope of the method of CN1061076800A.
On pages 5-6 of remarks, Applicant asserts that Bhagat et al. do not teach treating alcoholic hepatitis. Respectfully, the Examiner is not relying upon Bhagat et al. for that teaching.
On pages 6-7 of remarks, Applicant asserts that EP2545907 do not teach treating alcoholic hepatitis. Respectfully, the Examiner is not relying upon EP2545907 for that teaching.
On page 7 of remarks, Applicant asserts that Tanguay et al. do not teach treating alcoholic hepatitis. Respectfully, the Examiner is not relying upon Tanguay et al. for that teaching.
On pages 7-8 of remarks, Applicant asserts unexpected therapeutic results in treating alcoholic hepatitis. Applicant states: “As demonstrated in Figures 15-20,
the formulation significantly reduces plasma endotoxin levels, systemic inflammatory
markers (including TNF-a and IL-113), liver injury indicators (ALT and AST), and
coagulation impairment in alcoholic hepatitis models. These results establish superior
efficacy compared to generalized approaches disclosed in the prior art.” Respectfully, the Examiner cannot agree because the comparison is not with the closest prior art of CN1061076800A directed to treatment of diseases caused by intestinal microflora disorder with the same active agents of cholestyramine, colesevelam, and colestipol. The Examiner has shown that alcoholic hepatitis is known in the art as being associated with enteric dysbiosis and intestinal overgrowth and thus within the scope of CN1061076800A. It is applicant’s burden to demonstrate unexpected results over the closest prior art. See MPEP 716.02, also 716.02 (a) - (g). While the data noted by Applicant including Examines 1-3 and 7; Figures 14-20, 23 and 24 is acknowledged, it is not probative of unexpected results because it is not a comparison with the closest prior art. The Examiner has carefully considered Applicant’s arguments but they are not persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613