DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 9/23/2022, 9/25/2024, and 7/14/2025 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-26 are pending, filed 9/7/2022. Claims 1-26 are under examination.
New Claim Objections
Claim 20 is objected to because of the following informalities. The image taken from the specification to resolve the previous rejection is largely illegible. If the image quality cannot be improved, it is recommended that the contents are manually transcribed. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 20 and 25 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Response to Arguments
Applicant’s arguments, see Applicant’s Reply, page 25, para. 7, filed 3/13/2026, with respect to claims 20 and 25 have been fully considered and are persuasive. The rejection of claims 20 and 25 has been withdrawn.
Claim 25 was previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. 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.
Response to Arguments
Applicant’s arguments, see Applicant’s Reply, page 25, para. 5, filed 3/13/2026, with respect to the rejection of claim 25 under U.S.C. 112(a) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made.
New 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 25 and 26 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 the agonism of GLP-1 or GLP-2 to a patient in need thereof suffering from insulin resistance, hyperglycemia, glucose intolerance, malabsorption disorders, intestinal failure, intestinal insufficiency, mucosal barrier disorders, gut inflammation, celiac disease, congenital and acquired digestion and malabsorption syndromes, mucosal damage, hyperglycemia during enteral and intestinal failure, acid-induced intestinal injury, arginine deficiency, obesity, chemotherapy-induced enteritis, diabetes, fat malabsorption, steatorrhea, gastric ulcers, gastrointestinal barrier disorders, Parkinson’s disease, sepsis, bacterial peritonitis, bowel trauma, bowel ischemia, mesenteric ischemia, short bowel syndrome, necrotizing enterocolitis, neonatal feeding intolerance, NSAID-induced intestinal damage, total parenteral nutrition damage to the gastrointestinal tract, neonatal nutritional insufficiency, radiation-induced enteritis, radiation-induced damage to the intestines, mucositis, pouchitis, ischemia, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, brush border enzyme deficiencies, glucose-galactose-malabsorption, fructose malabsorption, Fanconi-Bickel syndrome, congenital chloride/sodium diarrhoea, Lysinuric protein intolerance, primary biliary malabsorption, cystic fibrosis, chylomicron retention disease, hypobetalipoproteinemia, abetalipoproteinemia, microvillous atrophy, Tufting enteropathy, trichohepatoenteric syndrome, congenital malabsorptive diarrhoea, anendocrinosis, and protein-convertase 1/3 deficiency, does not reasonably provide enablement for treatment, as defined in the specification, of insulin resistance, hyperglycemia, glucose intolerance, malabsorption disorders, intestinal failure, intestinal insufficiency, mucosal barrier disorders, gut inflammation, celiac disease, congenital and acquired digestion and malabsorption syndromes, mucosal damage, hyperglycemia during enteral and intestinal failure, acid-induced intestinal injury, arginine deficiency, obesity, chemotherapy-induced enteritis, diabetes, fat malabsorption, steatorrhea, gastric ulcers, gastrointestinal barrier disorders, Parkinson’s disease, sepsis, bacterial peritonitis, bowel trauma, bowel ischemia, mesenteric ischemia, short bowel syndrome, necrotizing enterocolitis, neonatal feeding intolerance, NSAID-induced intestinal damage, total parenteral nutrition damage to the gastrointestinal tract, neonatal nutritional insufficiency, radiation-induced enteritis, radiation-induced damage to the intestines, mucositis, pouchitis, ischemia, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, brush border enzyme deficiencies, glucose-galactose-malabsorption, fructose malabsorption, Fanconi-Bickel syndrome, congenital chloride/sodium diarrhoea, Lysinuric protein intolerance, primary biliary malabsorption, cystic fibrosis, chylomicron retention disease, hypobetalipoproteinemia, abetalipoproteinemia, microvillous atrophy, Tufting enteropathy, trichohepatoenteric syndrome, congenital malabsorptive diarrhoea, anendocrinosis, and protein-convertase 1/3 deficiency. 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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
A wide range of different disorders is claimed by claim 25. These disorders have different underlying causes and affect different parts of the body.
(B) The nature of the invention;
The invention is a method of using the compound of claim 1 to treat a wide variety of disorders and diseases.
(C) The state of the prior art;
Nauck et al. (Nauck, et al. European journal of endocrinology 181.6: R211-R234 (2019)) discloses that all GLP-1 agonists do have some ability to reduce blood sugar:
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(Nauck et al., page R220, Fig. 3).
However, as Fig. 2 shows below, not all GLP-1 agonists have the same abilities to treat secondary conditions such as renal benefits, reduction in albuminuria, slowed reduction in eGFR over time, renal endpoints, and they are not all equally tolerated as well by the kidneys.
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(Nauck et al., page R216, Fig. 2).
Trujillo et al. (Trujillo, et al. Therapeutic advances in endocrinology and metabolism 6.1: 19-28 (2015) discloses that different GLP-1 agonists posses different adverse side effect rates.
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(Trujillo, et al., page 24, Table 3).
Furthermore, Trujillo shows that not all GLP-1 agonists result in weight loss:
(Trujillo, et al., page 24, Table 3).
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(Trujillo, et al., page 22, Table 2).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of GLP-1/GLP-2 dual agonists is usually at least a Master’s level education.
(E) The level of predictability in the art;
Protein-protein interactions are generally unpredictable. Compounds that target metabolic processes frequently have off-target effects, as demonstrated by the adverse side effects above.
However, the structure-function relationship of GLP-1 agonists is more predictable due to the number of peptides that have been created and tested. Alavi et al. (Alavi, Molecular pharmaceutics 16.6: 2278-2295 (2019)) shows these structural similarities:
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(Alavi et al., page 2282, Fig. 3)
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant provides many structural examples and data that shows their efficacy as GLP-1 or GLP-2 agonists.
The specification defines treatment as “…to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or
potentially at risk of suffering from the disease or disorder in question. Thus, the term "treatment" covers both preventative (prophylactic) treatment and treatment where
measurable or detectable symptoms of the disease or disorder are being displayed.
to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term "treatment" covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed.”
No data is provided to show prevention of any of the diseases/disorders recited by claim 25, only agonism data and serum duration data.
Regarding claim 25, Applicant provides data showing GLP-1 and GLP-2 agonism but no actual data against the various disorders. As disclosed by Nauck and Trujillo, different GLP-1 agonists have different secondary effects and different tolerances. Therefore, activity against a given condition such as obesity (for which at least one GLP-1 agonist fails to improve weight loss) or more complicated conditions such as sepsis or Parkinson’s cannot be enabled merely from GLP-1 and GLP-2 agonism data.
Furthermore, neither the specification nor the prior art provides compelling data that shows prevention of the stated disorders in any subject that is potentially at risk of suffering from these disorders.
It would require undue experimentation to test the claimed composition for prevention of the recited disorders in any subject that is potentially at risk of suffering from these disorders.
Consequently, 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 and claim 25 is rejected.
Regarding claim 26, claim 25 is rejected as described above. No data is provided to support to treatment of Tufting enteropathy by the claimed composition.
Consequently, 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 and claim 26 is rejected.
Closest Prior Art
Claim 1 of the present application recites the following formulae:
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As compared to the available prior art, these formulae have three primary points of novelty. First, is the “R” group located on the N-terminal end of the formula. R is further disclosed to be:
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Such a ring “Q”, located at the N-terminal of the peptide, is not disclosed by the available prior art.
Second, the identity of the residues in positions AA10a and AA11a for formula 1a and positions AA11 and AA14 for formula 2a. In the prior sequences, such as those disclosed by Wisniewski et al. (Wiśniewski, et al. Journal of Medicinal Chemistry 59.7: 3129-3139 (2016)), this region is typically “LAAR”. In the case of formula 1a, AA10a is Lys or Glu, not Leu, Wa is Ala Ala as normal, but AA11a is Aib, Lys, Glu, or Asp, not Arg. In the case of formula 1b, AA11 is LysR or Glu, not Leu, AA12 and AA13 are both Ala as normal, but AA14 is Aib or Lys, not Arg. Consequently, the prior art sequences do not read on these positions, nor provide a person of ordinary skill in the art reasoning to make such mutations.
Third, prior art regarding GLP-1 agonists do not make use of lactam bridges as required by Applicant claim 1. The properties of lactam bridges were well-understood in the prior art as described by Taylor et al. (Taylor, et al. Peptide Science: Original Research on Biomolecules 66.1: 49-75 (2002). However, the prior art does not provide guidance on which residues of the GLP-1 peptide should be targeted for bridging, and therefore does not disclose various bridges recited by Applicant’s claims.
Allowable Subject Matter
Claims 1-19 and 21-24 are directed towards compounds that are free of the prior art as described above in “Closest Prior Art”. The specification discloses a representative number of examples and activity claimed in claims such 22 is fully enabled by said examples. Therefore, these claims are allowable as currently claimed.
Conclusion
Claim 20 is objected to.
Claims 25 and 26 are rejected.
Claims 1-19 and 21-24 are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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