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 .
Status of the Application
The amendment and remarks of 6 July 2026 are entered.
Claims 1-32, 34-43, 45, 46, 48, 50-76, 84, and 85 have been canceled. Claims 36, 37, 44, 47, 49, 77, 78, 80-83, and 86-93 are pending and are being examined on the merits.
The election requirement remains in effect.
The rejection of claims 36, 37, 44, 47. 49, and 76-85 under 35 U.S.C. 112(a) for scope of enablement is withdrawn in light of the amendment filed 6 July 2026.
The rejections under 35 U.S.C. 103 are withdrawn in light of the amendment filed 6 July 2026.
New grounds of rejection are presented below in response to Applicants’ amendment of 6 July 2026.
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.
1. Claims 36, 37, 49, 77, 78, 80-83, and 86-93 are rejected under 35 U.S.C. 103 as being unpatentable over Khaleghi et al. (Ther. Adv. Gastroenterol. 9:37-49, published 2016, hereafter referred to as Khaleghi), Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008, hereafter referred to as ‘493), and Madan (WO 2018/148655 A1, published 16 August 2018, filed 12 February 2018, priority to 10 February 2017, hereafter referred to as ‘655).
The Khaleghi art discloses usage of larazotide acetate (AT-1001) as a permeability regulator useful for treatment of celiac disease (see e.g. Abstract). Khaleghi describes larazotide as being useful for inhibiting intestinal permeability and as being tested in multiple phase I and II trials (see e.g. p.40-45). Khaleghi concludes that larazotide may be useful for long-term control of celiac disease (see e.g. p.46).
The difference between Khaleghi and the claimed invention is that Khaleghi only discusses larazotide acetate as an all-L-amino acid peptide of sequence GGVLVQPG and does not discuss sustained release in simulated intestinal fluid for at least 180 minutes and a dosage of about 0.5 mg or less.
The ‘493 art discloses peptide antagonists of tight junction opening based upon zonulin (see e.g. [0009]-[0010]). ‘493 those agonists with one or more D-amino acids, including where all non-glycine residues are D-amino acids, i.e. Gly-Gly-(d)Val-(d)Leu-(d)Val-(d)Gln-(d)Pro-Gly (see e.g. [0012]). ‘493 discloses Gly-Gly-(d)Val-(d)Leu-(d)Val-(d)Gln--Pro-Gly and Gly-Gly-Val-(d)Leu-(d)Val-(d)Gln-(d)Pro-Gly among variants of GGVLVQPG with one or more D-amino acids (see e.g. [0043]). ‘492 discloses using the peptides to treat celiac disease (see e.g. [0043]). Dosages can range from 1.0 µg to 1 g (see e.g. [0053]). The peptides may be formulated for enteric delivery (see [0057]). Excipients, i.e. carriers, may also be included (see e.g. [0016]).
The ‘655 art discloses larazotide or derivatives in a delayed-release formulation providing beads and a pH-dependent coating of a 1:1 copolymer of methacrylic acid and ethyl acrylate (see e.g. p.11 lines 3-18). The ‘655 art also discloses release profiles of at least 180 minutes, at least 210 minutes, or at least 240 minutes (see e.g. p.9 lines 9-16). ‘655 also discusses dosages of 0.5 mg to 5 mg (see e.g. p.8 lines 20-27). Initial release timing from 30-60 minutes is also discussed (see e.g. p.9 lines 11-16 and p.11 lines 19-31).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the treatment of celiac disease of Khaleghi could have been altered by using the D-amino acid-containing peptides of ‘493 for GI administration and in doing so treat a condition associated with gastric epithelial permeability by promoting tight junction integrity. Furthermore, given that ‘655 shows larazotide being in delayed-release formulations, this would have been an obvious choice for formulation within the dosage ranges as already found in ‘493. The rationale comes from Khaleghi suggesting the use of larazotide acetate for celiac disease, ‘493 disclosing both larazotide derivatives as well as suggesting their use in treating overlapping conditions, and ‘655 showing formulations of larazotide that are useful for sustained release. There would have been a reasonable expectation of success given the overlapping subject matter concerning preventing tight junction permeability and treating celiac disease in both Khaleghi and ‘493, and the known enteric coating for larazotide as found in ‘655. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claim 37, as noted above both Khaleghi and ‘493 disclose subjects having celiac disease.
With respect to claim 49, ‘493 suggests treatment of patients who have acute lung injury (see e.g. claim 14).
With respect to claims 77 and 78, the ‘493 application discloses doses starting at 1 µg and reaching 1 g (see e.g. [0053]). The specification suggests lower dosage was surprisingly effective, but as discussed, the ‘493 art already suggests low dosage ranges covering those claimed.
With respect to claim 80, the ‘493 application discloses enteric coated tablets for release in the duodenum or jejunum (see e.g. [0057]).
With respect to claim 81, the ‘493 application discloses release in 60 minutes (see e.g. [0058]-[0059]).
With respect to claim 82, the ‘655 art as discussed above provides for sustained release of at least 210 minutes.
With respect to claim 83, as noted above ‘655 provides for pH-dependent, delayed-release coating in the form of a 1:1 co-polymer of acrylate and methacrylate.
With respect to claims 86-88, as noted above ‘493 provides for dosages within the range as claimed.
With respect to claims 89-93, ‘655 provides for formulations allowing for release within 30-60 minutes and sustained release for at least 240 minutes, as well as the claimed coating.
2. Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Khaleghi et al. (Ther. Adv. Gastroenterol. 9:37-49, published 2016), Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008), and Madan (WO 2018/148655 A1, published 16 August 2018, filed 12 February 2018, priority to 10 February 2017) as applied to claim 36 above, and further in view of Zimmons J (Press Release, FirstWord PHARMA, https://firstwordpharma.com/story/4780289, 29 April 2019, hereafter referred to as Zimmons).
The relevance of Khaleghi, ‘493, and ‘655 is set forth above. The difference between the prior art references and the claimed invention is that neither disclose a patient with fatty liver disease, NAFLD, or NASH.
Zimmons discloses the application of larazotide acetate to treatment of NASH in subjects (see e.g. NASH Pre-clinical Data Highlights).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the larazotide acetate as found in Khaleghi could have been utilized to treat patients with NASH as in Zimmons, and similarly that the larazotide derivatives found in ‘493 could have been applied to the same patient populations given the highly similar nature of the underlying compound. The rationale comes from the compounds all being from the same base of larazotide acetate. There would have been a reasonable expectation of success because the ‘493 compounds merely introduce D-amino acids that are known in the art to offer protection against proteases in vivo. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
3. Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Khaleghi et al. (Ther. Adv. Gastroenterol. 9:37-49, published 2016) Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008), and Madan (WO 2018/148655 A1, published 16 August 2018, filed 12 February 2018, priority to 10 February 2017) as applied to claim 36 above, and further in view of Tamiz A (USP 8,785,374 B2, published 22 July 2014, hereafter referred to as ‘374).
The relevance of Khaleghi, ‘493, and ‘655 is set forth above. The difference between the prior art references and the claimed invention is that neither disclose a patient with type 1 diabetes.
The ‘374 application discloses larazotide and derivatives to treat excessive or undesirable permeability of a tissue containing tight junctions in a subject (see e.g. claim 1, SEQ ID NO: 1). ‘374 further discloses that the subject has type 1 diabetes (see e.g. claim 10). The ‘374 patent also discloses subjects with celiac disease (see e.g. claim 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the process of Khaleghi, ‘493, and ‘655 utilizing larazotide derivatives containing D-amino acids formulated for sustained release in simulated intestinal fluide for at least 180 minutes and about 0.5 mg or less to treat celiac disease could have been adapted based upon the larazotide derivatives and usage of ‘374 to treat patients with type 1 diabetes. The rationale comes from the overlapping subject matter of larazotide and derivatives found in Khaleghi, ‘493, ‘655, and ‘374. There would have been a reasonable expectation of success because Khaleghi, ‘493, and ’655 already lead one of ordinary skill in the art to treating celiac disease with larazotide derivatives, and ‘374 similarly suggests derivatives for both celiac disease and type 1 diabetes subjects. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments:
The previous rejections are withdrawn, however given that the new grounds of rejection are based upon a new combination of prior cited art the Examiner will respond to the Applicants’ arguments in the interests of compact prosecution.
The Applicants argue the claimed D-amino acid form of larazotide allows for a surprising use of lower concentrations as compared to larazotide. The Applicants allege that replacement of L-amino acids with D-amino acids results in a loss of potency and would be expected to bind to receptors with lower affinity.
The Examiner has considered the claim to dosage and does not find it persuasive given that the prior art already considered dosages covering the ranges as claimed. The allegations of loss of potency for a D-amino acid form and lower affinity towards receptors is merely a statement and not supported by any cited evidence or knowledge in the art that such alterations are necessarily deleterious to peptide function. For instance, contrary to Applicants’ assertion the art does not recognize that D-amino acid substitution has a negative impact on peptide function, as Domhan et al. (Molecules 24:2987, published 2019) indicates that an all-D-amino acid variant of the antimicrobial peptide ranalexin has no alteration to its antibacterial activity.
The Applicants argue D-larazotide offers similar or superior effects at the same or lower doses as compared to larazotide.
The Examiner argues the same or merely superior effects are not indicative of surprising results, especially given that the art does not recognize D-amino acids as being universally detrimental to peptide activity as well as the art already recognizing overlapping doses for larazotide.
The Applicants argue Khaleghi, ‘493, or ‘655 lead to the claimed composition and a dosage that would be superior to larazotide.
The Examiner disagrees. The Khaleghi and ‘493 art reasonably lead to an all-D-amino acid variant and doses. The ‘655 art additionally provides for doses, as well as the sustained release profile. Mere superiority to larazotide is not indicative of surprising results that might rebut a conclusion of obviousness.
The Applicants ‘493 does not provide motivation to select the claimed peptide, and that many of the disclosed variants were not active. The Applicants argue ‘493 does not teach any variants with better activity than larazotide. The Applicants argue no specific teaching of doses for variants and argue that ‘493 “most likely dosed in the range of 10 mg to 25 mg”. The Applicants argue this is an unexpected finding given this being 20 times higher than the claimed dose.
The Examiner disagrees. As noted, ‘493 explicitly states that one possible variant is where every amino acid except for glycine is in D-form. The failure of certain variants ignores the findings in ‘493 that many others were functional. The Applicants when discussing dosing ignore that the broader dose does encompass that claimed, and insert their own preference that the variants were “most likely dosed in the range of 10 mg to 25 mg” without any evidence to support this assertion. Given this, one cannot determine that a dose of about 0.5 mg or lower is unexpected, since there is no indication form ‘493 that higher doses were exclusively effective. This also ignores that ‘655 discusses larazotide doses within the range as claimed.
The Applicants’ arguments have been considered but are not persuasive.
Conclusion
No claims are allowed.
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.
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/Z.J.M/Patent Examiner, Art Unit 1658 /SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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