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 election of 1 December 2025 are entered.
Claims 1-32, 34, 38-43, 48, 50-63, 68, 69, 72, 74, and 75 have been canceled. Claims 33, 35-37, 44-47, 49, 64-67, 70, 71, 73, and 76-85 are pending. Claims 33, 35, 64-67, 70, 71, and 73 are withdrawn with traverse. Claims 36, 37, 44, 47, 49, and 76-85 are being examined on the merits.
Election/Restrictions
Applicant's election with traverse of Group II (claims 36, 37, 44, 47, 49, and 76-85 in the reply filed on 1 December 2025 is acknowledged. The traversal is on the ground(s) that groups II and III are not patentably distinct and that such a search would not be an undue burden. This is not found persuasive because search burden is not a consideration for evaluating unity of invention in a national stage entry.
The requirement is still deemed proper and is therefore made FINAL.
Claims 33, 35, 64-67, 70, 71, and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 1 December 2025.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 36, 37, 44, 47, 49, and 76-85 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating gastrointestinal epithelial permeability or pulmonary fibrosis, does not reasonably provide enablement for a method of treating or preventing a condition associated with gastrointestinal epithelial permeability. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The invention is drawn to a method of treating or preventing a condition associated with gastrointestinal epithelial permeability by administering a pharmaceutical composition comprising SEQ ID NO: 1 containing one or more D-amino acids to the GI of the subject.
Breadth of the Claims
The claims are somewhat narrow with respect to the pharmaceutical composition to be administered, as SEQ ID NO: 1 is only 8 amino acids in length. The claims are broad with respect to the actual condition being claimed, i.e. the condition associated with gastrointestinal epithelial permeability. There is no clear delineation between what conditions are or are not those associated with gastrointestinal epithelial permeability. Given the claim language of treatment and prevention, the method is also broad in that it provides both treatment and prophylaxis.
State of the Prior Art
As noted below, the prior art recognizes the base SEQ ID NO: 1 as useful for treating conditions where epithelial permeability is an issue, for instance celiac disease (see e.g. Khaleghi et al. Ther. Adv. Gastroenterol. 9:37-49, published 2016). See also Leffler et al. Gastroenterology 148:1311-1319, published February 2015 concerning use for celiac disease. Larazotide is also recognized as a potential therapeutic in acute respiratory distress syndrome or acute lung injury (see e.g. USP 10,723,763 B2), intestinal inflammation (see e.g. USP 7,582,603 B2), inhibiting intestinal permeability (see e.g. USP 8,183,211 B2), and treating diabetes in conjunction with insulin (see e.g. US 2007/0196272 A1).
The art generally does not recognize a “silver bullet” that treats any and all conditions associated with gastrointestinal epithelial permeability, let alone preventing those conditions.
Relative Skill of those in the Art
The skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
It is generally not predictable whether a given compound serves as a preventative against an entire genus of conditions as claimed.
Amount of Direction or Guidance Given
The specification guides that tight junction permeability allows for entry of pathogens, antigens, endotoxins, and pro-inflammatory substances into the body through the intestinal tract, triggering local or systemic inflammatory disease. The specification suggests treatment of a variety of conditions but offers no clear linkage between gastrointestinal permeability and development of the entire range of conditions (see e.g. p.3-4). Larazotide is described as being useful in celiac disease (see e.g. p.7). Formulations for specific targeting of ulcerative colitis or Crohn’s disease are described by utilizing delayed release coatings (see e.g. p.13). As one example, a variety of cancers from any tissue are described as being treated, but is not clear how the wide ranges of cancers are all linked to GI permeability (see e.g. p.24-25).
There is no real guidance on determining if the compositions serve to prevent the generic conditions as claimed.
Presence/Absence of Working Examples
The working examples generally concern an ischemic-injured porcine jejunum model. An additional model concerning the impact of the larazotide derivatives on a bleomycin-induced pulmonary fibrosis model. No examples show prevention of conditions associated with GI epithelial permeability.
Quantity of Experimentation Necessary
At issue is the fact that there is no clear linkage between gastrointestinal epithelial permeability and “conditions” in general. The skilled artisan in this case has no baseline for evaluating whether a given condition is or is not associated with GI epithelial permeability. As such, they are required to establish on their own a variety of model systems covering myriad conditions to see whether the larazotide derivatives as claimed are such that they treat the conditions. The skilled artisan is basically given a genus of conditions but left to their own to determine what conditions may fall under that genus. Such a level of experimentation is undue since they are offered little guidance from the specification and prior art as to a proper nexus between GI permeability and specific conditions beyond those enabled.
Furthermore, there is no real discussion or evidence that administration of any variant of SEQ ID NO: 1 having one or more D-amino acids serves to prevent all conditions associated with GI epithelial permeability. There is no real guidance on determining whether a patient will or will not develop such generic conditions, and as such the onus is entirely on the skilled artisan to determine if the claimed compounds prevent all such diseases. Such an effort is undue.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
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, 76-81, 84, and 85 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) and Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008, hereafter referred to as ‘493).
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 testing 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.
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 (see e.g. [0012]). ‘493 discloses Gly-Gly-Val-Leu-Val-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]). The peptides may be formulated for enteric delivery (see [0057]). Excipients, i.e. carriers, may also be included (see e.g. [0016]).
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. The rationale comes from Khaleghi suggesting the use of larazotide acetate for celiac disease and ‘493 disclosing both larazotide derivatives as well as suggesting their use in treating overlapping conditions. 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. 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 claim 76, as set forth above ‘493 discloses SEQ ID NO: 9.
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 suggest lower dosage was surprisingly effective, but as discussed, the ‘493 art already suggests low dosage ranges covering those claimed.
With respect to claims 79 and 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 84, ‘493 discloses formulations for “any type of delivery” which would encompass parenteral administration (see e.g. [0017]).
With respect to claim 85, the ‘493 application discloses pulmonary administration (see e.g. [0017]).
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) and Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008) 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 and ‘493 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) and Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008) 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 and ‘493 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 and ‘493 utilizing larazotide derivatives containing D-amino acids 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, and ‘374. There would have been a reasonable expectation of success because Khaleghi and ‘493 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.
4. Claims 82 and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Khaleghi et al. (Ther. Adv. Gastroenterol. 9:37-49, published 2016) and Tamiz A and Li M (WO 2008/154493 A2, published 18 December 2008) as applied to claim 36 above, and further in view of Madan (WO 2018/148655 A1, published 16 August 2018, filed 12 February 2018, priority to 10 February 2017, hereafter referred to as ‘655).
The relevance of Khaleghi and ‘493 is set forth above. The difference between the prior art references and the claimed invention is that neither discloses the claimed release profile or the specific pharmaceutical composition.
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).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Khaleghi and ‘493 by using the enteric release compositions of ‘655 for further delayed release in the small and/or large intestine. The rationale comes form ‘655 also disclosing larazotide or derivatives thereof in highly similar formulations and for overlapping use. There would have been a reasonable expectation of success because ‘493 already discloses enteric coated formulations for GI release and the skilled artisan in this case is merely applying highly similar formulations from ‘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.
Conclusion
No claims are allowed.
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/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658