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
Priority to US 62/951,503, filed 12/20/2019, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 1/12/2023 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, 2, 4, 16, 18, 20, 22, 24, 26, 27, 36, 38, 41, and 47, and 49-66 are pending. Claims 1-4, 16, 41, 47-49, 51 and 52 are under examination. Claims 18, 20, 22, 24, 26, 27, 36, 38, and 50 are currently withdrawn from examination. Claims 3, 17, 19, 21, 23, 25, 28-35, 37, 39, 40, 42-46, and 48 are canceled.
Specification
Previous Objection
The specification was previously objected to for Fig. 1B, Fig. 5, and Fig. 11 lacking SEQ ID NOs, and no SEQ ID NOs appear in the brief description of the drawings.
Response to Arguments
Applicant’s arguments, see Apply Reply page 1, para. 2, filed 11/12/2025, with respect to the objection to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Previous Objection
The specification was previously objected to for usage of a trade name or a mark used in commerce without proper annotation.
Response to Arguments
Applicant’s arguments, see Apply Reply page 1, para. 2, filed 11/12/2025, with respect to the objection to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Claim Interpretation
Supplemental Interpretation
For clarity of the record, claim 1 is interpreted to refer to peptides that have not yet undergone the reaction to form stapled side chains. Claim 2 is interpreted to refer to peptides that have undergone cross-linking reactions as to form the claimed stapled structures. Consequently, the scopes of these two claims encompass two structurally distinct genera and no duplicate claim objection has been rendered.
Previous Interpretation
Claim 41 was previously interpreted under USC 112(f) because it recites the words “means for” without also reciting sufficient structure. For purposes of examination, this claim encompasses all sequences reduced to practice found in Fig. 1B, Fig. 5, and Fig. 11. The presence of the stapling amino acids is a critical feature of these embodiments described by the present specification. Therefore, claim 41 was interpreted to not include pharmaceutical compositions that treat these diseases that do not comprise the sequences recited in Fig. 1B, Fig. 5, and Fig. 11 and lack these stapling amino acids.
Revised Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim 41 is interpreted under USC 112(f) because it recites the words “means for” without also reciting sufficient structure.
Applicant specification, page 11, line 14 recites: “Also provided herein is a pharmaceutical composition comprising any one of the foregoing peptides and a pharmaceutically acceptable carrier.
Also provided herein is a pharmaceutical composition comprising: (a) a means for treating diabetes, hyperglycemia, rapid gastric emptying, insulin resistance, cardiovascular disease, Alzheimer's disease, or Huntington's disease, and (b) a pharmaceutically acceptable carrier. In some instances, the means for treating diabetes, hyperglycemia, rapid gastric emptying, insulin resistance, cardiovascular disease, Alzheimer's disease, or Huntington's disease are stitched GLP-1 peptides.
Consequently, the scope of this claim is interpreted to include all stitched GLP-1 peptides.
Response to Arguments
Applicant's arguments, see Apply Reply page 2, para. 2, filed 11/12/2025. have been fully considered but they are not persuasive. Applicant is on record as disagreeing with the previous interpretation of this “means for” claim, but no substantive argument was presented. Consequently, this interpretation remains the interpretation for examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Previous Rejection
Claim 41 was 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 Apply Reply page 2, para. 2, filed 11/12/2025, with respect to claim 41 have been fully considered and are persuasive. The rejection of claim 41 has been withdrawn.
Previous Rejection
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 1-4, 16, 41, 47-49, and 51-52 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Response to Arguments
Applicant’s arguments, see Apply Reply page 3, para. 1, filed 11/12/2025, with respect to claims 1, 2, 4, 16, 41, 47, 49, 51, and 52 have been fully considered and are persuasive. The rejection of claims 1, 2, 4, 16, 41, 47, 49, 51, and 52 has been withdrawn. Claims 3 and 48 are canceled, making rejection of these claims moot.
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.
Previous Rejections
Claims 1-3, 16, and 47-48 were previously rejected under 35 U.S.C. 103 as being unpatentable over Walensky, et al. (WO2012006598, published 1/12/2012) in view of Schafmeister et al. (Schafmeister, et al. Journal of the American Chemical Society 122.24: 5891-5892 (2000)) and Suzuki et al. (Suzuki, et al Journal of medicinal chemistry 63.3: 905-927 (2019)).
Claims 4, 41, 49 and 51-52 were previously rejected under 35 U.S.C. 103 as being unpatentable over Walensky, et al. (WO2012006598, published 1/12/2012) in view of Schafmeister et al. (Schafmeister, et al. Journal of the American Chemical Society 122.24: 5891-5892 (2000)), Suzuki et al. (Suzuki, et al Journal of medicinal chemistry 63.3: 905-927 (2019)), Chee et al. (Chee, et al. PLoS One 12.12: e0189379 (2017)) and Verdine et al. (WO 2008/121767, published 10/9/2008).
Response to Arguments
Applicant’s arguments, see Apply Reply page 4, para. 2, filed 11/12/2025, with respect to claims 1, 2, 4, 16, 41, 47, 49, 51, and 52 have been fully considered and are persuasive. The rejections of claims 1, 2, 4, 16, 41, 47, 49, 51, and 52 have been withdrawn. Claims 3 and 48 are canceled, making rejection of these claims moot.
New Rejections
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 41 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alavi et al. (Alavi, et al. Molecular pharmaceutics 16.6: 2278-2295. (2019)).
Claim 41 has been interpreted to include all stitched GLP-1 peptides as described above. Alavi discloses stapling as a strategy to modify GLP-1 peptides:
“Stapled peptides, as a class of cyclic peptides, are modified by the insertion of aliphatic bridges to increase cell penetration, (211) serum stability, (214) and target binding affinity. Stapled peptides have received considerable attention as the next-generation of therapeutic compounds to target protein–protein interactions. (215) For example, a stapled Bcl-2 homology 3 (BH3)-helix demonstrated increased stability compared to the native BH3 interacting-domain death agonist (BID) BH3 peptide in mouse serum (half-life, 3.1 vs 29.4 h)” (Alavi et al., page 2286, col. 2, para. 3).
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(Alavi et al., page 2284, Fig. 4).
Alavi also discloses that GLP-1 peptides can be used to treat conditions including diabetes: “GLP-1 is a post-translational proteolytic product and tissue specific peptide derived from the proglucagon gene. GLP-1 is released from intestinal L-cells in response to nutrient ingestion. (40) This peptide hormone lowers blood glucose levels (BGLs) and people’s weight by reducing appetite and glucagon secretion, increasing glucose-dependent insulin release, and delaying gastric emptying. (41) Also, GLP-1 improves memory and learning; (42) has neuroprotective and anti-inflammatory properties; (43) has cardioprotective function during myocardial ischemia, which together reduce cardiovascular disease risk factors, such as hypertension, dyslipidaemia, and obesity; (44) improves hepatocyte function; (45) and regulates energy balance through food intake regulation (energy inflow) and energy consumption (energy outflow).” (Alavi, et al., page 2279, col. 2, para. 2).
Consequently, claim 41 is anticipated by Alavi et al. and rejected.
Allowable Subject Matter
Walensky et al., US 9,296,805, published 3/29/2016, discloses the amino acid sequence HAEGTFTSDXSSYLEGXAAKEFIXWLVXGRGR (SEQ ID NO: 47). This sequence is comparable to the presently disclosed peptide. HJEGTFTSD8SSYLEG#AAKEFIZWLVKGR (SEQ ID NO: 61).
For comparison:
HAEGTFTSDXSSYLEGXAAKEFIXWLVXGRGR (SEQ ID NO: 47)
HJEGTFTSD8SSYLEG#AAKEFIZWLVKGR (SEQ ID NO: 61)
However, Walensky SEQ ID NO: 47 has two separate staples at positions 10 and 17 and then 24 and 28. This explains the extremely similar sequence alignment of the peptide of the present application stitched at positions 10, 17, and 24.
Furthermore, Hilinski et al. (Hilinski, et al. Journal of the American Chemical Society 136.35: 12314-12322. (2014)) discloses that stitched peptides are just stapled peptides that share a common attachment point: “Here we report a next-generation version of the hydrocarbon-stapling system in which dual hydrocarbon staples emerge from common attachment points in the peptide, thereby creating spiro macrocyclic ring junctions, a type of ring fusion known to be exceptionally rigidifying. To our knowledge, this is the first report of α-helical peptides stabilized by multiple connected staples. We envision this system of installing contiguous staples along one face of the α-helix as akin to peptide “stitching”” (Hilinski et al., page 12315, col. 1, para. 4).
Schafmeister et al. (Schafmeister, et al. Journal of the American Chemical Society 122.24: 5891-5892 (2000)) discloses the usage of olefinic side chains for the stapling, and by extension, stitching of amino acids:
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(Schafmeister et al., page 5891, Fig. 1).
Cheang et al. (Cheang, et al. ChemMedChem 13.7: 662-671 (2018)) discloses the alanine to Aib substitution present in the currently claimed peptides: “In addition, substitution of Ala8 for the non-natural amino acid 2-aminoisobutyric acid (Aib), as in semaglutide (Figure 3),18 or d-Ala10 also yield active GLP-1 analogs that are resistant to DPP-4 degradation.” (Cheang et al., page 664, col. 1, para. 2).
Walensky discloses the i+7+7 stitching scheme in Fig. 5B Panel K. Hilinski also discloses this stitching scheme as Entry XVII in Table 1. Arguably, a skilled artisan could employ the scanning method disclosed by Walensky to find the optimal stapling locations in the claimed peptides: “FIG. 4 shows how non-natural amino acids bearing hydrocarbon tethers (e.g., olefin tethers) can be inserted into the peptide sequence to generate singly stapled peptides. Staples can be located at (A) (i, i+3), (B) (i, i+4), and (C) (i, i+7) positions along the length of the peptide helix to generate a library of singly stapled peptides (i.e. “staple scan”) to identify optimal positioning for the desired biophysical and biological properties. (D) Further illustrates staple scanning to identify the optimal staple position(s) for achieving the desired biophysical, biological, and pharmacologic properties of a polypeptide agent of interest (e.g., exenatide). Staple scanning involves the sequential evaluation of staple positions along the length of the peptide sequence template. An i, i+4 staple scan starting at the N-terminus is shown.” (Walensky et al., col. 9, line 48; Fig. 4).
However, Hilinski also discloses that this scheme only results in a 54% conversion rate and 69% helicity. (Hilinski, page 12818, Table 1). Entries XII and XIII, i+4+7 and i+4+4, respectively, show superior properties in conversion rate and helicity. (Hilinski, page 12318, Table 1). Hilinski mentions this in the results section: “The i + 4 + 7 stitched peptide 4 displays the highest helical content of all the peptides studied here, 86%, which is far higher than that of its i, i + 7 single-stapled counterpart 10 (60%) (Figure 3B). Notably, the CD spectrum of 4 is not concentration dependent, suggesting that aggregation is not responsible for the high α-helicity of this stitched peptide (Figure S2A).” (Hilinski, et al, page 12318, col. 1., para. 2).
Consequently, a person of ordinary skill in the art would have a much stronger motivation to use an i + 4 + 7 stitch scheme as opposed to the i + 7 + 7 scheme embodied by the present application. For comparison the extremely similar SEQ ID NO: 47 of Walensky possesses an i + 7 and an i + 4 staple. Combined with Hilinski, this reasoning would lead a skilled artisan towards performing an i +4 + 7 stitch scan, or an i + 7 + 4 stitch scan, not an i + 7 +7 stitch scan, and the claimed peptides would not be discovered. For this reason, the claims are novel and nonobvious over the prior art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Election/Restrictions
Claim 2 directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 18, 22, 24, 27, and 38, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement between groups I-VI as set forth in the Office action mailed on 5/29/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim 4 is directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(b), claims 20, 26, 36, 38, and 50, directed to the process of making or using the allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104..
Because a claimed invention previously withdrawn from consideration under 37 CFR 1.142 has been rejoined, the restriction requirement between groups I-VI as set forth in the Office action mailed on 5/29/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
New Rejections
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 18, 20, and 63 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 reducing glucose levels and therefore ameliorating hyperglycemia or diabetes, does not reasonably provide enablement for inhibiting the diseases hyperglycemia or diabetes. 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.
Applicant specification recites: “The terms "treat" or "treating," as used herein, refers to alleviating, inhibiting, or ameliorating the disease or condition from which the subject is suffering.” (Specification, page 97, line 26).
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:
The breadth of the claims;
Claim 20 encompasses treating any hyperglycemic disease and any diabetic diease, including type I and II diabetes. Treating, as described above, includes inhibiting these diseases.
The nature of the invention;
The invention is a method of treating diabetes or hyperglycemia in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stitched peptide of claim 4 to the human subject.
The state of the prior art;
Zaccardi et al. discloses that type I diabetes is an autoimmune disorder that results in the destruction of pancreatic cells: (Zaccardi, et al. Postgraduate medical journal 92.1084: 63-69 (2016)): “It is now well-recognised that T1DM is an autoimmune disorder characterised by the destruction of insulin-producing pancreatic β-cells.17 Like many other immune-mediated diseases, T1DM shows heterogeneity in terms of age of onset, severity of autoimmune response, and efficacy of therapy.” (Zacchardi et al., page 64, col. 1, para. 3).
Zacchardi also discloses that: “Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia.” (Zacchardi et al., page 63, Abstract).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
As mentioned above, Zacchardi discloses that: “Like many other immune-mediated diseases, T1DM shows heterogeneity in terms of age of onset, severity of autoimmune response, and efficacy of therapy.” (Zacchardi et al., page 64, col. 1, para. 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 discloses examples of the present invention reducing glucose concentration as demonstrated in Fig. 8 of the specification. However, no data is provided for inhibiting all forms of diabetes, specifically type I diabetes.
Regarding claim 18, claim 18 recites a method of treating diabetes or hyperglycemia in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stitched peptide of claim 2 to the human subject.
As discussed above, no data is presented in the specification nor any mechanism is provided in the prior art for the present invention inhibiting all forms of diabetes or hyperglycemia. It would require undue experimentation to test the claimed peptides against all the claimed forms of diabetes. Therefore, 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.
Claim 18 is rejected.
Regarding claim 20, claim 20 recites a method of treating diabetes or hyperglycemia in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stitched peptide of claim 4 to the human subject.
As discussed above, no data is presented in the specification nor any mechanism is provided in the prior art for the present invention inhibiting all forms of diabetes or hyperglycemia. It would require undue experimentation to test the claimed peptides against all the claimed forms of diabetes. Therefore, 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.
Claim 20 is rejected.
Regarding claim 63, claim 63 encompasses the same scope of diseases to be treated. Therefore, 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.
Claim 63 is rejected.
Claims 24, 26, and 62 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 ameliorating Alzheimer’s disease, does not reasonably provide enablement for inhibiting Alzheimer’s disease or treating Huntington’s disease. 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.
The terms "treat" or "treating," as used herein, refers to alleviating, inhibiting, or ameliorating the disease or condition from which the subject is suffering.
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:
The breadth of the claims;
The claims are not especially broad. The method is directed to the peptides of claim 4 in treating Alzheimer’s and Huntington’s diseases.
The nature of the invention;
A method of treating Alzheimer's disease or Huntington's disease in a human subject in need thereof, the method comprising administering a therapeutically- effective amount of the stitched peptide of claim 4 to the human subject.
The state of the prior art;
Hölscher (Hölscher, Christian. Neuropharmacology 136 : 251-259 2018)) discloses that GLP-1 agonists can ameliorate the effects of Alzheimer’s: “Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de-sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease.” (Hölscher, page 251, Abstract).
Hölscher also discloses: “Exendin-4 showed neuroprotective effects in other animal models of neurodegeneration as well (Eakin et al., 2013, Perry and Greig, 2005, Perry et al., 2007, Rachmany et al., 2013). Liraglutide (Victoza®), another drug on the market to treat diabetes (Courreges et al., 2008), reduced AD hallmarks such as memory loss, synapse loss, impaired synaptic transmission (LTP), chronic inflammation in the brain, and amyloid load in the brain after 8 weeks of once-daily treatment (McClean et al., 2011b).” (Hölscher, page 253, col. 2, para. 1).
However, Montojo et al. (Montojo, et al. Journal of Huntington's disease 6.3: 179-188 (2017)) discloses that as of 2017, links between glucose alteration and diabetes were weak:”
Based on several early human studies, and partially supported by the later murine-model assays, HD is associated with glucose alterations and diabetes, as occurs in other neurological diseases. However, the studies conducted before the HD-genetic diagnosis provided limited outcomes due to a very low number of participants, lack of clinical information and, potentially, an uncertain diagnosis. In addition, although the works carried out in HD-mice models reveal a significant association with glucose metabolism alterations and β-cell dysfunction, the development of diabetes was not indicated unanimously, being also irregular, the effects displayed by the hypoglycemic agents. Conversely, in the most recent publications with clinically and genetically substantiated HD participants, a very low prevalence of diabetes was recorded and no statistical differences in glucose metabolism related indexes or pancreas morphology were found, with the exception of one study performed in a well-characterized cohort of late-stage HD with a low BMI and normoglycemic levels. Follow-up of these patients would have provided useful information on the evolution of their glucose homeostatic parameters and the establishment, or not, of a diabetic state; however, the metabolic disturbances described in premanifest and manifest HD subjects appear not to translate to a clear diabetic phenotype.” (Montojo et al., page 186, col. 1, para. 2).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
Hölscher states: “Our understanding what causes progressive neurodegenerative disorders such as Alzheimer's or Parkinson's disease (PD) is still sketchy. The findings of Alois Alzheimer when staining the brain of a patient showed distinct protein aggregates which appeared to define the disease (Alzheimer, 1907, Alzheimer et al., 1995). However, as a good scientist, Dr. Alzheimer cautioned to jump to conclusions and reminded readers that this does not prove that these aggregates actually cause the disease.” (Hölscher, page 252, col. 1, para. 1).
(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 discloses examples of the present invention reducing glucose concentration as demonstrated in Fig. 8 of the specification. However, no data is provided for treating Alzheimer’s or Huntington’s diseases.
Regarding claim 24, claim 24 recites a method of treating Alzheimer's disease or Huntington's disease in a human subject in need thereof, the method comprising administering a therapeutically- effective amount of the stitched peptide of claim 2 to the human subject.
As discussed above, the prior art discloses that GLP-1 agonists may ameliorate some Alzheimer’s symptoms, but no data is provided in the specification or prior to show that GLP-1 agonists inhibit Alzheimer’s disease.
Regarding Huntington’s disease, the prior at suggests the link between GLP-1 agonists and treatment of Huntington’s disease is too weak to be considered enabled.
. It would require undue experimentation to determine if the claimed peptides can inhibit Alzheimer’s disease or establish a sufficient link between GLP-1 agonists and Huntington’s disease. Therefore, 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.
Claim 24 is rejected.
Regarding claim 26, claim 26 recites a method of treating Alzheimer's disease or Huntington's disease in a human subject in need thereof, the method comprising administering a therapeutically- effective amount of the stitched peptide of claim 4 to the human subject.
As discussed above, the prior art discloses that GLP-1 agonists may ameliorate some Alzheimer’s symptoms, but no data is provided in the specification or prior to show that GLP-1 agonists inhibit Alzheimer’s disease.
Regarding Huntington’s disease, the prior at suggests the link between GLP-1 agonists and treatment of Huntington’s disease is too weak to be considered enabled.
. It would require undue experimentation to determine if the claimed peptides can inhibit Alzheimer’s disease or establish a sufficient link between GLP-1 agonists and Huntington’s disease. Therefore, 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.
Claim 26 is rejected.
Regarding claim 62, claim 62 encompasses the same scope of diseases to be treated. Therefore, 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.
Claim 62 is rejected.
Claims 22, 36, and 60 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 treating cardiovascular disease wherein modulation of glucose level is an effective treatment and treating rapid gastric emptying and insulin resistance, does not reasonably provide enablement for treating all possible cardiovascular diseases. 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.
The terms "treat" or "treating," as used herein, refers to alleviating, inhibiting, or ameliorating the disease or condition from which the subject is suffering.
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:
The breadth of the claims;
The claims are broad in that any possible cardiovascular disease is claimed.
The nature of the invention;
A method of treating rapid gastric emptying, insulin resistance, or cardiovascular disease in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stitched peptide of claim 4 to the human subject.
The state of the prior art;
Gaziano et al. (Gaziano, Thomas, et al. Disease Control Priorities in Developing Countries. 2nd edition (2006)) discloses that cardiovascular diseases can have many underlying causes such as ischemia, stroke, congestive heart failure, and rheumatic heart disease. (Gaziano, pages 1 and 2, Topic headings).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
Cardiovascular disease is difficult to predict because of many risk factors. Gaziano discloses: “The risk of developing CVD depends to a large extent on the presence of several risk factors. The major risk factors for CVD include tobacco use, high blood pressure, high blood glucose, lipid abnormalities, obesity, and physical inactivity. The global variations in CVD rates are related to temporal and regional variations in these known risk factors.” (Gaziano, page 2, col. 4, para. 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 discloses examples of the present invention reducing glucose concentration as demonstrated in Fig. 8 of the specification. However, no data is provided for treating cardiovascular diseases.
Regarding claim 22, claim 22 recites a method of treating rapid gastric emptying, insulin resistance, or cardiovascular disease in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stitched peptide of claim 2 to the human subject.
It would require undue experimentation to determine if the claimed peptides could treat all possible cardiovascular diseases, including those diseases with causes not associated with glucose levels. Therefore, 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.
Claim 22 is rejected.
Regarding claim 36, claim 36 recites a method of treating rapid gastric emptying, insulin resistance, or cardiovascular disease in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stitched peptide of claim 4 to the human subject.
It would require undue experimentation to determine if the claimed peptides could treat all possible cardiovascular diseases, including those diseases with causes not associated with glucose levels. Therefore, 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.
Claim 36 is rejected.
Regarding claim 60, claim 60 encompasses the same scope of diseases to be treated. Therefore, 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.
Claim 60 is rejected.
Conclusion
Claims 1, 2, 4, 16, 27, 38, 47, 49-59, 61, and 64-66 are allowable
Claims 18, 20, 22, 24, 26, 36, 41, 60, 62, and 63 are rejected.
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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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654