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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/01/2025 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-32, 34 and 37 drawn to a GIP receptor agonist peptide) in the reply filed on June 11th 2024 is acknowledged. Additionally, Applicant’s election without traverse of SEQ ID NO: 26 as Species A (i.e., a single and specific GIP receptor agonist peptide indicating single and specific formula and sequence identification number) in the reply filed on June 11th 2024 is acknowledged. Note: Applicant’s elected species (i.e., SEQ ID NO: 26) is not recited in the claims of the elected invention. However, SEQ ID NO: 26 is a species of SEQ ID NO: 358 and recites P1-Tyr-A2-Glu-Gly-Thr-A6-A7-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-Asn-Trp-Leu-Leu-A28-A29-A3 0-A31-A32-A33-A34-A35-A36-A37-A38-A39-P2 (i.e., SEQ ID NO: 358).
Claims 1-56 are currently pending and claims 6-13, 15, 18, 24-26, 29-30, 34 and 37 are under consideration as claims 1-5, 14, 16-17 and 19-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, claims 33, 35-36, 38-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 11th 2024.
Claims 27-32, were inadvertently misclassified in the restriction mailed on 05/22/2024. Since these claims are drawn to a product comprising the GIP receptor agonist peptide according to claim 6, the claims are hereby rejoined and fully examined.
Status of Claims
Claims 1-56 were originally filed on December 17th 2021.
The amendment received on October 6th 2023, amended claims 1, 5-6, 8, 12, 16 and 18-23.
The amendment received on March 28th 2025, amended claims 6-9, 12-13, 15-16, 18-30, 33-35, 37, 41-46, 4-9 and 51-54.
The amendment received on September 2nd 2025, amended claims 6-7.
Claims 1-56 are currently pending and claims 6-13, 15, 18, 24-32, 34 and 37 are under consideration.
Priority
The present application claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 62/994,716 filed March 25th 2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C 120, 121, or 365 (c ) is acknowledged.
Sequence Interpretation
Regarding claim 6, please note that given that there is no specified transitional phrase recited, the Examiner is interpreting the scope of a GIP receptor agonist peptide represented by formula (IV) as open-ended, requiring 100% identity to SEQ ID NO: 358 with the variability limited to the recited modifications for P1, P2, A2, A6, A7, A13-A14, A16-A18, A20-A21, and A28-A39 with any N- and/or C-terminal additions when P1 is absent and/or P2 is -OH. Additionally, based on this interpretation the GIP receptor agonist peptide encompasses where a peptide comprising SEQ ID NO: 358 is part of a larger peptide sequence, or the GIP receptor agonist could also be a peptide sequence solely comprising SEQ ID NO: 358. Similarly, in light of the phrase “is selected from the group consisting of”, the Examiner is interpreting the scope of the linker in the residue Lys(R) as close-ended, requiring 100% identity and the same length to SEQ ID NOs: 310, 311, 317, 313, 318, 309, 319, 314, 315, 310 and 312.
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Additionally, regarding the linker, the elected species is 2OEGgEgE as the linker with the following structure (see instant specification, pg. 101).
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The linker 2OEGgEgE consists of 2 gamma Glu units (i.e., γGlu) linked to OEG (i.e., OEG=AEEA=PEG3). However, upon comparing the structure of gEgE to the structures of (γGlu)2 in (γGlu)2-PEG3 (see instant specification, pg. 99) and OEG=AEEA=PEG3 (see instant specification, pg. 101) (note: OEG is the same structurally as PEG3), it is noted that the stereochemical conformation of gEgE differs from (γGlu)2. As such, the Examiner is interpreting the scope of the gEgE in the elected 2OEGgEgE as γGlu-γGlu with different stereochemistry. Regarding claim 8, please note that in light of the phrase “is selected from the group consisting of”, the Examiner is interpreting the scope of L as close-ended, requiring 100% identity to SEQ ID NOs: 310, 313, 318, 309, 319, 314, 315, 310, and 312.
Response to Arguments
1. Applicants’ arguments, see Remarks, filed 09/02/2025, with respect to the 35 U.S.C. 103 as being unpatentable over Levy et al., WO2006/086769 A2 published on August 17th 2006 (herein after “Levy’), as evidenced by Northwestern Medicine, GERD Symptoms You Shouldn't Ignore, 2019, pp. 1-2, retrieved from https://www.nm.org/healthbeat/healthy-tips/gerd-symptoms-you-shouldnt-ignore on 05/28/2025 (here in after “NW Medicine”), in view of Dimarchi et al., US2015/0368310 A1 published on December 17th 2015 (herein after “Dimarchi”), and Caslo ApS., Peptide Synthesis with Modifications., 2013, pp. 1-7 available at https://www.caslo.com/peptide-modifications.html (herein after “Caslo”), have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection of claims 6-13, 15, 18, 24-26, 29-30, 34 and 37 has been maintained.
2. Applicants’ arguments, see Remarks, filed 09/02/2025, with respect to the 35 U.S.C. 103 as being unpatentable over Levy et al., WO2006/086769 A2 published on August 17th 2006 (herein after “Levy’), in view of Dimarchi et al., US2015/0368310 A1 published on December 17th 2015 (herein after “Dimarchi”) and Caslo ApS., Peptide Synthesis with Modifications., 2013, pp. 1-7 available at https://www.caslo.com/peptide-modifications.html (herein after “Caslo”), and in further view of Levy et al., US2011/0136737 A1 published on June 9th 2011 (herein after “Levy 2”); been fully considered but are not persuasive. The 35 U.S.C. 103 rejection of claims 26 has been maintained.
5. Applicants’ arguments, see Remarks, filed 09/02/2025, with respect to the nonstatutory double patenting rejection, have been fully considered but are not persuasive. The nonstatutory double patenting rejection has been maintained.
Maintained/Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 6-13, 15, 18, 24-32, 34, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al., WO2006/086769 A2 published on August 17th 2006 (herein after “Levy’), as evidenced by Northwestern Medicine, GERD Symptoms You Shouldn't Ignore, 2019, pp. 1-2, retrieved from https://www.nm.org/healthbeat/healthy-tips/gerd-symptoms-you-shouldnt-ignore on 05/28/2025 (here in after “NW Medicine”), in view of Just et al., US 10,100,097 B2 Date of Patent: Oct. 16, 2018 (herein after “Just”), Dimarchi et al., US2015/0368310 A1 published on December 17th 2015 (herein after “Dimarchi”), and Caslo ApS. Peptide Synthesis with Modifications., 2013, pp. 1-7 available at https://www.caslo.com/peptide-modifications.html (herein after “Caslo”). Please note that the rejection has been modified necessitated by the amendments to claims 6-7.
Regarding claim 6, a GIP receptor agonist peptide represented by formula (IV): P1-Tyr-A2-Glu-Gly-Thr-A6-A7-Ser-Asp-Tyr-Ser-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20-A21-Phe-Val-Asn-Trp-Leu-Leu-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-P2 (SEQ ID NO: 358), or a pharmaceutically acceptable salt thereof; wherein P1 represents H, C1-6 alkyl, or absent; P2 represents -NH2 or -OH; A2 represents Aib, Gly, or Ser; A6 represents Phe or Leu; A7 represents Ile or Thr; A13 represents Ala, Aib, or Tyr; A14 represents Leu, Lys, or Lys(R); A16 represents Lys, Arg, or Ser; A17 represents Aib, Lys, or Lys(R); A18 represents Ala, His, Lys, or Lys(R); A20 represents Gln, Lys, Lys(R), or Aib; A21 represents Asp, Lys, Lys(R), or Asn; A28 represents Ala, Aib, or, Lys, Lys(R); A29 represents Gln, Lys, Lys(R), or Aib; A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac); A31 represents Pro, Gly, or a deletion; A32 represents Ser, Gly, or a deletion; A33 represents Ser, Gly, or a deletion; A34 represents Gly, Lys, or a deletion; A35 represents Ala, Ser, Lys, or a deletion; A36 represents Pro, Lys, or a deletion; A37 represents Pro, Lys, Gly, or a deletion; A38 represents Pro, Lys, or a deletion; and A39 represents Ser, Gly, Lys, or a deletion, wherein one of A14, A17, A18, A20, A21, A28, A29, or A30 is Lys(R), in which the (R) portion represents X-L-, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 30EGgE, 30EGgEgE, G2E3 (SEQ ID NO: 310), G3gEgE (SEQ ID NO: 311), G4E2 (SEQ ID NO:317), G4gE(SEQ ID NO: 313), G4gEgE (SEQ ID NO: 318), GGGGG (SEQ ID NO: 309),G5E (SEQ ID NO: 319), G5gE (SEQ ID NO: 314), G5gEgE (SEQ ID NO: 315), gE, gEgEgE, GGEEE (SEQ ID NO: 310), GGPAPAP (SEQ ID NO: 312), OEGgEgE, and OEGgEgEgE; and X represents C14-Cis monoacid or C14-Cis diacid:
Levy is in the field of GIP analogs and GIP hybrid polypeptides with selectable properties (see Levy, Abstract). Of particular interest are analogs modified at or near the dipeptidyl peptidase IV (DPP-IV) specific cleavage site, which improve DPP-IV resistance and consequently prolong half-life (see Levy, pg. 17, para[0077]). Levy teaches that the GIP analog or a GIP hybrid comprises a polypeptide comprising the formula D-L-C-S, wherein D comprises a dipeptidyl peptidase IV resistant GIP N-terminal region (see Levy, pg. 70, para[00264]). Levy’s GIP analog or hybrid comprises the sequence X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14, as the D region of the GIP analog (see Levy, pg. 72, para[00273]). It is noted that Levy’s D region of the GIP analog does not comprise H or C1-6 alkyl at the N-terminus (i.e., prior to X1), thereby corresponding to the absence of P1 as recited in instant claim 6. Amino acid alterations include modifications of the first 3 or 4 residues of GIP and/or the bond between residues 2 and 3, which is cleaved by DPP-IV (see Levy, pg. 17, para[0077]). Modifications and substitutions include N-terminal modifications, L-amino acids, D-amino acids, proteinogenic and non-proteinogenic amino acids (see Levy, pg. 17, para[0077]). Levy’s modifications can be combined with at least one other change such as a change that imparts DPP-IV resistance, reduces or eliminates oxidation, reduces renal clearance, improves receptor binding, or improves receptor activation (see Levy, pg. 19, para[0085]). Of further interest are analogs wherein the amino acid in the 2 or 3 position is substituted by lysine, serine, 4-amino butyric acid, Aib, D-alanine, Sarcosine or proline (see Levy, pg. 18, para[0079]). Levy’s X2 is an amino acid substitution or modification providing DPP-IV resistance such as Aib, thereby constituting where instant A2 is Aib, as recited in instant claim 6. Levy goes on to teach that X6 is Phe or Ala (see Levy, pg. 73, para[00280]), thereby constituting where A6 represents Phe as recited in instant claim 6. X7 is Ile or Ala (see Levy, pg. 73, para[00281]), thereby constituting where A7 represents Ile as recited in instant claim 6. X13 is Ala, Tyr, Glutamine or Asp (see Levy, pg. 74, para[00287]), thereby constituting where A13 represents Ala as recited in instant claim 6. X14 is Met, Ala or Leu (see Levy, pg. 74, para[00288]), and that to eliminate or reduce oxidation, the methionine at position 14 is deleted or substituted, for example with leucine or other small hydrophobic amino acid (see Levy, pg. 18, para[0080]), thereby constituting where A14 represents Leu as recited in instant claim 6. Levy also teaches that the L (i.e., Linker) in the formula D-L-C-S can be absent or comprise the sequence X15-X16-X17-X18 (see Levy, pg. 76, para[00295]). Where X16 is K, G, E or a conservative amino acid change thereof or of a native X16 residue (see Levy, pg. 76, para[00296]), thereby constituting where A16 represents Lys as recited in instant claim 6. Levy teaches that a "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain, or physicochemical characteristics (e.g., electrostatic, hydrogen bonding, isosteric, hydrophobic features) (see Levy, pg. 86, para[00330]). It is noted that the native GIP sequence comprises Lys at position 16 (see Levy, pg. 15, para[0064]). Therefore when the original residue is Lys (K), “Exemplary Substitutions” are Arg; Gln; and Asn, with Arg being the “Preferred Substitution” (see Levy, pg. 87, para[00330]). Thereby Levy implies that the GIP analogs of the formula D-L-C-S contains X16 as part of the L segment (i.e., Linker), and that the lysine at X16 can be substituted by a preferred substitution such as Arg, thereby constituting where A16 represents Arg as recited in instant claim 6.
Levy teaches that X17 is I, Q ,E or a conservative amino acid change thereof or of a native X17 residue (see Levy, pg. 76, para[00296]). However, Levy does not expressly teach wherein A17 represents Aib, Lys, or Lys(R), as recited in instant claim 6.
Just teaches GIP-GLP1 dual acting receptor agonists are superior to existing and marketed GLP-1 analogues because the dual agonists offer improved glycemic control, and enhanced body weight loss (see column 2, lines 16-19). Just’s GIP analogues comprise non-conservative substitutions at one or more of amino acid positions 1, 2, 3, 7, 9, 13, 14, 15, 17, 19, 20, 21, 22, 23, 24, 27, 28, 29, and 30 of the wild-type GIP sequence in combination with Ile, Gln, Lys, Arg or Glu in position 17 (see column 2, lines 23-28). Thereby constituting wherein A17 represents Lys, as recited in instant claim 6. Just adds that the non-conservative and non-obvious substitution of Ile for Lys in position 17 may enhance GLP-1 receptor activity and in addition provide a handle for acylation to prolong half-life of the peptide (see column 11, lines 2-5). Just’s Formula I, depicts a GIP analogue or a pharmaceutical salt or solvate thereof (see column 2, lines 35-45). It is noted that the variables in the instantly claimed GIP receptor agonist peptide (i.e., Formula IV) correspond to Just’s Formula I, in particular Just’s variable X17 which is Ile, Lys, Gln, Arg or Glu (see column 2, lines 35-61).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the amino acid at position X17 (i.e., I, Q ,E or a conservative amino acid change thereof or of a native X17 residue) in Levy’s GIP analog for a non-conservative and non-obvious substitution of Ile for Lys as taught by Just. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Lys in position 17 (i.e., instant A17) may enhance GLP-1 receptor activity and in addition provide a handle for acylation to prolong half-life of the peptide as taught by Just. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that the GIP analog of Levy comprises Ile at position 17; and given that Just’s GIP analogues comprise non-conservative substitutions at one or more of amino acid positions 1, 2, 3, 7, 9, 13, 14, 15, 17, 19, 20, 21, 22, 23, 24, 27, 28, 29, and 30 of the wild-type GIP sequence and also offer improved glycemic control and enhanced body weight loss. Therefore, substituting Ile at position X17 of Levy’s GIP analog with Lys would support a GIP receptor (GIP) agonist peptide having formula (IV) (i.e., SEQ ID NO: 358. Which reads on the elected species SEQ ID NO: 26), or a pharmaceutically acceptable salt thereof, by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention with a reasonable expectation of success pursuant to KSR.
Levy’s L segment of formula D-L-C-S contains X18 which is H, R, A or a conservative amino acid thereof or of a native X18 residue (see Levy, pg. 76, para[00296]). Further exemplary substitutions are those derived from GIP of other (non-human) species, for example the histidine 18 replaced by alanine, arginine or lysine (see Levy, pg. 19, para[0082]), thereby constituting where A18 represents Ala, His, or Lys as recited in instant claim 6. The C region of Levy’s GIP analog contains the sequence X19-X20-X21-X22-X23-X24-X25-X26-X27-X28-X29-X30, each position being independently selected, wherein X20 is Q or a conservative amino acid substitution thereof (see Levy, pg. 76, para[00297]), thereby constituting where A20 represents Gln as recited in instant claim 6. X21 is D (see Levy, pg. 76, para[00297]), thereby constituting where A21 represents Asp as recited in instant claim 6. X28 is A, N, D, K, R, E or a conservative amino acid substitution thereof (see Levy, pg. 77, para[00297]), thereby constituting where instant A28 represents Ala or Lys as recited in instant claim 6. X29 is Q, G or a conservative amino acid substitution thereof or is absent (see Levy, pg. 77, para[00297]), thereby constituting where A29 is Gln recited in instant claim 6. X30 is K, G, R, P or a conservative amino acid substitution thereof or is absent (see Levy, pg. 77, para[00297]), thereby constituting where A30 represents Arg or Lys as recited in instant claim 6. The GIP analog or hybrid polypeptides of Levy’s invention may have one or more amino acid residues deleted from the amino acid sequence of native GIP, or a region S, alone or in combination with one or more insertions or substitutions (see Levy, pg. 88, para[00334]). In another embodiment, the GIP analog or hybrid polypeptide may have one or more amino acid residues deleted at amino acid positions 1 through 42 of a native GIP, GIP(1-30) (see Levy, pg. 88, para[00334]), thereby implying that residues 31-40 can be deleted. As such, the teachings of Levy constitute where A32-A39 are represented by a deletion as recited in instant claim 6. Levy also teaches that the hybrid region S consists of the sequence X31-X39, where X31 is Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or Nalkylalanine, G, S (see Levy, pg. 78, para[00301]) and that in further embodiments a Pro is retained at position X31 to interact with Trp at position X25 (see Levy, pg. 88, para[00336]), thereby constituting where A31 is represented by Pro and Gly as recited in instant claim 6. Additionally, it is noted that Levy teaches some embodiments where the linker is placed after X30 (i.e., YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-Linker-KCNTATCVLGRLSQELHRLQTYPRTNTGSETF or its Gly linker species analog YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-Gly-Gly-Gly-KCNTATCVLGRLSQELHRLQTYPRTNTGSETF) (see Levy, pg. 52, para[00217]). Levy also teaches that the Gly linker or spacer is 1 to 20 residues long and that in one embodiment a Gly linker is used, and in particular embodiments a three residue linker Gly-Gly-Gly (see Levy, pg. 52, para[00217]), thereby the teachings of Levy suggest the claim limitations where A31 is Gly as recited in instant claim 6 and in the elected species (i.e., SEQ ID NO: 26). It is also noted that Levy recites that the GIP analogs are preferably C-terminally amidated, in other words, the C-terminus of the peptides may have a free OH or -NH2 group (see Levy, pg. 85, para[00326]), thereby constituting where instant P2 is -NH2 or -OH as recited in instant claim 6.
However, Levy does not expressly teach wherein A14, A17, A18, A20, A21, A28, A29 or A30 is Lys(R), in which the (R) portion represents X-L-, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 30EGgE, 30EGgEgE, G2E3 (SEQ ID NO: 310), G3gEgE (SEQ ID NO: 311), G4E2 (SEQ ID NO:317), G4gE(SEQ ID NO: 313), G4gEgE (SEQ ID NO: 318), GGGGG (SEQ ID NO: 309),G5E (SEQ ID NO: 319), G5gE (SEQ ID NO: 314), G5gEgE (SEQ ID NO: 315), gE, gEgEgE, GGEEE (SEQ ID NO: 310), GGPAPAP (SEQ ID NO: 312), OEGgEgE, and OEGgEgEgE; and X represents C14-Cis monoacid or C14-Cis diacid, as recited in instant claim 6.
Regarding where A21 is Lys(R) (Applicant’s elected invention), in which the (R) portion represents X-L, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 30EGgE, 30EGgEgE, G2E3 (SEQ ID NO: 310), G3gEgE (SEQ ID NO: 311), G4E2 (SEQ ID NO:317), G4gE(SEQ ID NO: 313), G4gEgE (SEQ ID NO: 318), GGGGG (SEQ ID NO: 309),G5E (SEQ ID NO: 319), G5gE (SEQ ID NO: 314), G5gEgE (SEQ ID NO: 315), gE, gEgEgE, GGEEE (SEQ ID NO: 310), GGPAPAP (SEQ ID NO: 312), OEGgEgE, and OEGgEgEgE; and X represents C14-Cis monoacid or C14-Cis diacid: as recited in instant claim 6:
Dimarchi’s invention provides a peptide comprising the sequence of X1X2X3GTFTSDX10SKYLX15X16X17X18X19X20X21FVQWLX27X28X29X30PSSGX35PPPS (see Dimarchi, pg. 2, para[0033]), where the amino acid at position 21 is Lys, Arg, Orn, Citrulline, Glu, homoglutamic acid or homocysteic acid (see Dimarchi, pg. 26, para[0375]), thereby constituting where A21 represents Lys as recited in instant claim 6. Dimarchi also teaches that the glucagon analog is conjugated to a hydrophilic moiety via covalent linkage between a side chain of an amino acid of the glucagon analog and the hydrophilic moiety (see Dimarchi, pg. 39, para[0583]); or the glucagon analog is conjugated to a hydrophilic moiety via the side chain of an amino acid at position 16, 17, 21, 24, or 29, a position within a C-terminal extension, or the C-terminal amino acid, or a combination of these positions (see Dimarchi, pg. 39, para[0583]). The amino acid covalently linked to a hydrophilic moiety (e.g., the amino acid comprising a hydrophilic moiety) is a Cys, Lys, Orn, homo-Cys, or Ac-Phe, and the side chain of the amino acid is covalently bonded to a hydrophilic moiety (see Dimarchi, pg. 39, para[0583]). Dimarchi further teaches that the glucagon analogs can be further modified to improve its solubility and stability in aqueous solutions at physiological pH, while retaining the high biological activity relative to native glucagon (see Dimarchi, pg. 39, para[0579]). As such, Dimarchi’s teachings of an amino acid (i.e., Lys) comprising a hydrophilic moiety constitute where A21 represents Lys(R) as recited in instant claim 6. Dimarchi also teaches that the amino acid at position 21 is an amino acid comprising a side chain which is conjugated to a heterologous moiety (see Dimarchi, pg. 26, para[0375]), thereby constituting the (R) portion of the Lys residue at A21; and the heterologous moiety is a lipid (see Dimarchi, pg. 37, para[0561]), that is attached to the analog via a linker (see Dimarchi, pg. 37, para[0562]), thereby constituting the L portion of (R).
Additionally, Dimarchi teaches the alpha helix of the GIP agonist peptide can be stabilized with a cross-linking agent, such as a dicarboxylic acid, e.g., suberic acid (octanedioic acid), etc. can introduce a link between two functional groups of an amino acid side chain, such as a free amino, hydroxyl thiol group, and combinations thereof (see Dimarchi, pg. 21, para[0276]), thereby constituting a diacid. Therefore, an ordinary skill person would be motivated with reasonable expectation of success to introduce a dicarboxylic acid between the linker and the fatty acid. The GIP agonist peptides taught by Dimarchi comprise a non-native acylated group referred to as an “acylated amino acid,” regardless of how it is prepared, e.g., by incorporation of a previously-acylated amino acid into the peptide, or acylation of the peptide after synthesis (see Dimarchi, pg. 7, para[0142]). The acylated amino acid causes the GIP agonist peptide to have one or more of (i) a prolonged half-life in circulation, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) an improved resistance to proteases, such as DPP-IV, and (v) increased potency at any one or more of the GIP receptor, GLP-receptor, and glucagon receptor (see Dimarchi, pg. 8, para[0143]). The acylated amino acid or alkylated amino acid is linked to the acyl group or alkyl group via a spacer (see Dimarchi, pg. 31, para[0441]), where the spacer comprises one or two gamma-Glu (see Dimarchi, pg. 31, para[0441]), thereby constituting where the L portion contains γEγE as part of the linker. Although Dimarchi does not expressly teach adjusting the stereochemical conformation of γEγE, an ordinary skill artisan would be motivated with reasonable expectation of success given that the gEgE linker comprises a finite number of stereochemical conformations therefore it would be obvious to try a different stereochemical conformation of gEgE to arrive at the claim invention as recited in claims 10 and 11. As such, the teachings of Dimarchi suggest where the linker contains gEgE as recited in instant claim 6. The acyl group of the acylated amino acid can be of any size, e.g., any length carbon chain, and can be linear or branched (see Dimarchi, pg. 10, para[0170]). For example, the acyl group is a C4 to C30 fatty acid or a C12 to C18 fatty acid (see Dimarchi, pg. 10, para[0170]). The acyl group in some aspects is a C12 to C18 (e.g., C12, C13, C14, C15, C16, C17, C18) fatty acyl group (see Dimarchi, pg. 31, para[0442]), thereby constituting where X represents C14-C18- monoacid as recited in instant claim 6. Dimarchi also teaches that the spacer is a hydrophilic bifunctional spacer (see Dimarchi, pg. 9, para[0160]), and the hydrophilic bifunctional spacer comprises two or more reactive groups, e.g., an amine, a hydroxyl, a thiol, and a carboxyl group or any combinations thereof (see Dimarchi, pg. 9, para[0160]). In this regard, the spacer can comprise, for example, NH2(CH2CH2O)n(CH2)mCOOH, wherein m is any integer from 1 to 6 and n is any integer from 2 to 12, such as e.g., 8-amino-3,6-dioxaoctanioic acid (see Dimarchi, pg. 9, para[0160]). Dimarchi also adds that the spacer comprises a small polyethylene glycol moiety (PEG) comprising a structure [ —O—CH2—CH2—]n wherein n is an integer between 2 and 16, (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) (see Dimarchi, pg. 9, para[0161]) thereby constituting where n is 2 (i.e., diacid). Such small PEGs are referred as a “miniPEG” (see Dimarchi, pg. 9, para[0161]). The miniPEG is a functionalized miniPEG comprising one or more functional groups (see Dimarchi, pg. 9, para[0161]). Suitable functional groups include, but are not limited to, an amine, a hydroxyl, a thiol, and a carboxyl group or any combinations thereof (see Dimarchi, pg. 9, para[0161]).
Caslo teaches that a number of different types of linkers can be inserted between active groups and the peptide sequence (see Caslo, pg.5, second to last paragraph). The most commonly used linkers are aminohexanoic acid (Ahx) and 8-amino-3,6-dioxaoctanoic acid linker (also called OEG or miniPEG) (see Caslo, pg.5, second to last paragraph). Therefore, the teachings of Dimarchi when combined with the teachings of Caslo are suggestive of the claim limitations as recited in claim 6, where the linker comprises OEGgEgE and where X represents C14-C18 monoacid. However, when considering the teachings Dimarchi as a whole in combination with Caslo, an ordinary skilled artisan would be motivated with reasonable expectation of success to use a C15 dicarboxylic acid conjugated to a linker comprising 2OEGgEgE.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the amino acid at position X21 (i.e., Asp or D) present in the C region of Levy’s GIP analog with Lys comprising a hydrophilic heterologous lipid moiety (i.e., acyl group is a C4 to C30 fatty acid or a C12 to C18 fatty acid), linked via a spacer that comprises one or two gamma-Glu as taught by Dimarchi. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because substituting the amino acid residue at position A21 with a modified lysine such as Lys-2OEGgEgE-C15DA was known to cause the GIP agonist peptide to have a prolonged half-life in circulation, a delayed onset of action, an extended duration of action, an improved resistance to proteases and an increase potency at any one or more of the GIP receptor, GLP-receptor, and glucagon receptor as taught by Dimarchi; because it was also known that 8-amino-3,6-dioxaoctanoic acid linker (also called OEG or miniPEG) was known to be a commonly used linker as taught by Caslo.
One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that the GIP analog of Levy comprises the amino acid sequence of YAEGTFISDYSIAMDKIRQQDFVNWLLAQK-Linker, where the Gly linker is 1 amino acid long (i.e., Gly), and given that a modified Lys such as Lys-2OEGgEgE-C15DA in order to improve solubility and stability in aqueous solutions at physiological pH while retaining the high biological activity relative to the native glucagon as well as resulting in one or more of (i) a prolonged half-life in circulation, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) an improved resistance to proteases, such as DPP-IV, and (v) increased potency at any one or more of the GIP receptor, GLP-receptor, and glucagon receptor. Therefore, substituting the Asp at position A21 with a modified lysine, where the modification comprises 2OEGgEgE-C15DA would support a GIP receptor (GIPR) agonist peptide having formula (IV) (i.e., SEQ ID NO: 358 which reads on the elected species SEQ ID NO: 26), or a pharmaceutically acceptable salt thereof, by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or utilizing the “Obvious to try” rationale – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success pursuant to KSR.
Regarding claim 7, wherein A14 represents Leu or Lys(R); A17 represents Aib, or Lys(R); A18 represents Ala, His, or Lys(R); A20 represents Gln, Lys(R), or Aib; A21 represents Asp, Lys(R), or Asn; A28 represents Ala, Aib, or Lys(R); A29 represents Gln, Lys(R), or Aib; and A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac):
As previously discussed, Levy teaches that to eliminate or reduce oxidation, the methionine at position 14 is deleted or substituted, for example with leucine or other small hydrophobic amino acid (see Levy, pg. 18, para[0080]), thereby constituting where A14 represents Leu as recited in instant claim 7.
With respect to wherein A17 represents Aib or Lys(R), as previously mentioned, Just teaches that GIP analogues comprise non-conservative substitutions at one or more of amino acid positions 1, 2, 3, 7, 9, 13, 14, 15, 17, 19, 20, 21, 22, 23, 24, 27, 28, 29, and 30 of the wild-type GIP sequence (see Just, column 2, lines 23-28). Just also teaches that a non-conservative substitution means any other substitution of an amino acid residue of the native human GIP sequence, e.g. such as substituting with a nonprotein amino acid (Sar, Nie, Aib, 1Nal) or substituting with an amino acid which does not belong to the same group (see Just, column 28, lines 66-67 and column 29, lines 1-3), thereby constituting wherein A17 represents Aib, as recited in instant claim 7.
Levy’s L segment of formula D-L-C-S contains X18 which is H, R, A or a conservative amino acid thereof or of a native X18 residue (see Levy, pg. 76, para[00296]), thereby constituting where A18 is Ala or His as recited in instant claim7. The C region of Levy’s GIP analog contains the sequence X19-X20-X21-X22-X23-X24-X25-X26-X27-X28-X29-X30, each position being independently selected, wherein X20 is Q or a conservative amino acid substitution thereof (see Levy, pg. 76, para[00297]), thereby constituting where A20 represents Gln as recited in instant claim 7. X21 is D (see Levy, pg. 76, para[00297]), thereby constituting where A21 represents Asp as recited in instant claim 7. X28 is A, N, D, K, R, E or a conservative amino acid substitution thereof (see Levy, pg. 77, para[00297]), thereby constituting where instant A28 represents Ala or Lys as recited in instant claim 7. X29 is Q, G or a conservative amino acid substitution thereof or is absent (see Levy, pg. 77, para[00297]), thereby constituting where A29 is Gln recited in instant claim 7. X30 is K, G, R, P or a conservative amino acid substitution thereof or is absent (see Levy, pg. 77, para[00297]), thereby constituting where A30 represents Arg or Lys as recited in instant claim 7.
Regarding claim 8, wherein A2 represents Aib; A17 represents Aib, Lys, or Lys(R); A20 represents Aib; and A28 represents Ala or Aib, wherein L is selected from the group consisting of 2OEG, 2OEGgE, 2OEGgEgE, G2E3 (SEQ ID NO:310), G4gE(SEQ ID NO: 313), G4gEgE (SEQ ID NO: 318), G5(SEQ ID NO: 309), G5E (SEQ ID NO: 319), G5gE (SEQ ID NO: 314), G5gEgE (SEQ ID NO: 315), gEgEgE, GGEEE (SEQ ID NO: 310), GGPAPAP (SEQ ID NO: 312),OEGgEgE, and OEGgEgEgE:
Levy teaches that amino acid alterations include modifications of the first 3 or 4 residues of GIP and/or the bond between residues 2 and 3, which is cleaved by DPP-IV (see Levy, pg. 17, para[0077]). Modifications and substitutions include N-terminal modifications, L-amino acids, D-amino acids, proteinogenic and non-proteinogenic amino acids (see Levy, pg. 17, para[0077]). Of further interest are analogs wherein the amino acid in the 2 or 3 position is substituted by lysine, serine, 4-amino butyric acid, Aib, D-alanine, Sarcosine or proline (see Levy, pg. 18, para[0079]), thereby constituting where instant A2 is Aib, as recited in instant claim 8. Levy also teaches wherein X28 is A, N, D, K, R, E or a conservative amino acid substitution thereof (see Levy, pg. 77, para[00297]), thereby constituting where instant A28 represents Ala as recited in instant claim 8.
However, Levy does not expressly teach wherein A17 represents Aib, Lys, or Lys(R); A20 represents Aib; nor wherein L is selected from the group consisting of 2OEG, 2OEGgE, 2OEGgEgE, G2E3 (SEQ ID NO:310), G4gE(SEQ ID NO: 313), G4gEgE (SEQ ID NO: 318), G5(SEQ ID NO: 309), G5E (SEQ ID NO: 319), G5gE (SEQ ID NO: 314), G5gEgE (SEQ ID NO: 315), gEgEgE, GGEEE (SEQ ID NO: 310), GGPAPAP (SEQ ID NO: 312),OEGgEgE, and OEGgEgEgE.
Dimarchi’s glucagon analog comprises an amino acid modification at either or both of positions 17 and 18 (see Dimarchi, pg. 25, para[0356]). Dimarchi adds that the amino acid at position 17 is an aliphatic amino acid (see Dimarchi, pg. 25, para[0356]). Dimarchi also teaches that the GIP agonist peptide comprises at least one alpha helix promoting amino acid at one or more of positions 16-21 of the peptide analog (e.g., one or more of positions 16, 17, 18, 19, 20, 21) (see Dimarchi, pg. 18, para[0256]). The alpha helix promoting amino acid is an alpha, alpha di-substituted amino acid (see Dimarchi, pg. 18, para[0257]). The alpha, alpha di-substituted amino acid comprises R1 and R2, each of which is bonded to the alpha carbon, wherein each of R1 and R2 is independently selected from the group consisting of C1-C4 alkyl (see Dimarchi, pg. 18, para[0257]). Each of R1 and R2 is methyl, such that the alpha, alpha disubstituted amino acid is alpha-amino iso-butyric acid (AIB) (see Dimarchi, pg. 18, para[0257]). The alpha, alpha disubstituted amino acid is capable of stabilizing the alpha helix in the absence of a covalent bridge (see Dimarchi, pg. 18, para[0258]). Dimarchi’s GIP agonist peptide comprises one or more alpha, alpha di-substituted amino acids (i.e., amino iso-butyric acid (Aib)) at the C-terminus (around positions 12-29), at one, two, three, four, five, or all of positions 16, 17, 18, 19, 20, or 21 of the GIP agonist peptide (see Dimarchi, pg. 19, para[0258]). Dimarchi teaches that substitution of position 20 with AIB enhances GIP activity, in the absence of an intramolecular bridge e.g., a non-covalent intramolecular bridge (e.g., a salt bridge) or a covalent intramolecular bridge (e.g., a lactam) (see Dimarchi, pg. 19, para[0258]). As such the teachings of Dimarchi suggest where the amino acid at position 17 and at position A20 is Aib, thereby constituting where A17 represents Aib and wherein A20 represents Aib as recited in instant claim 9.
Regarding where L is selected from the group consisting of 2OEG, 2OEGgE, 2OEGgEgE, G2E3 (SEQ ID NO:310), G4gE(SEQ ID NO: 313), G4gEgE (SEQ ID NO: 318), G5(SEQ ID NO: 309), G5E (SEQ ID NO: 319), G5gE (SEQ ID NO: 314), G5gEgE (SEQ ID NO: 315), gEgEgE, GGEEE (SEQ ID NO: 310), GGPAPAP (SEQ ID NO: 312),OEGgEgE, and OEGgEgEgE:
The GIP agonist peptides taught by Dimarchi comprise a non-native acylated group referred to as an “acylated amino acid,” regardless of how it is prepared, e.g., by incorporation of a previously-acylated amino acid into the peptide, or acylation of the peptide after synthesis (see Dimarchi, pg. 7, para[0142]). The acylated amino acid causes the GIP agonist peptide to have one or more of (i) a prolonged half-life in circulation, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) an improved resistance to proteases, such as DPP-IV, and (v) increased potency at any one or more of the GIP receptor, GLP-receptor, and glucagon receptor (see Dimarchi, pg. 8, para[0143]). The acylated amino acid or alkylated amino acid is linked to the acyl group or alkyl group via a spacer (see Dimarchi, pg. 31, para[0441]); where the spacer comprises one or two gamma-Glu (see Dimarchi, pg. 31, para[0441]), thereby constituting where the L portion contains γEγE (i.e., gEgE) as part of the linker. Dimarchi also teaches that the spacer comprises a small polyethylene glycol moiety (PEG) comprising a structure [ —O—CH2—CH2—]n wherein n is an integer between 2 and 16, (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) (see Dimarchi, pg. 9, para[0161]) thereby constituting where n is 2 (i.e., diacid). Such small PEGs are referred as a “miniPEG” (see Dimarchi, pg. 9, para[0161]). The miniPEG is a functionalized miniPEG comprising one or more functional groups (see Dimarchi, pg. 9, para[0161]). Suitable functional groups include, but are not limited to, an amine, a hydroxyl, a thiol, and a carboxyl group or any combinations thereof (see Dimarchi, pg. 9, para[0161]). Caslo teaches that a number of different types of linkers can be inserted between active groups and the peptide sequence (see Caslo, pg.5, second to last paragraph). The most commonly used linkers are aminohexanoic acid (Ahx) and 8-amino-3,6-dioxaoctanoic acid linker (also called OEG or miniPEG) (see Caslo, pg.5, second to last paragraph). Therefore, the teachings of Dimarchi when combined with the teachings of Caslo are suggestive of the claim limitations as recited in claim 8, where the linker comprises OEGgEgE.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the amino acids at position X17 (i.e., I, Q, E or a conservative amino acid change thereof or of a native X17 residue) and X20 (i.e., Q or a conservative amino acid thereof), present in Levy’s GIP analog with Aib as taught by Dimarchi. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because it was known that the alpha, alpha disubstituted amino acid is capable of stabilizing the alpha helix in the absence of a covalent bridge, and because substitution of position 20 with AIB enhances GIP activity, in the absence of an intramolecular bridge e.g., a non-covalent intramolecular bridge (e.g., a salt bridge) or a covalent intramolecular bridge (e.g., a lactam). One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that Dimarchi’s GIP agonist peptide comprises one or more alpha, alpha di-substituted amino acids (i.e., amino iso-butyric acid (Aib)) at the C-terminus (around positions 12-29), at one, two, three, four, five, or all of positions 16, 17, 18, 19, 20, or 21 of the GIP agonist peptide.
Additionally, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Levy and alkylate or acylate an amino acid as part of the GIP analogs and GIP hybrid polypeptides by linking an acyl group or alkyl group via a spacer comprising one or two gamma-Glu and small polyethylene glycol moiety (PEG) comprising a structure [ —O—CH2—CH2—]n wherein n is 2. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so given that it was known that acylated amino acids cause the GIP agonist peptide to have one or more of (i) a prolonged half-life in circulation, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) an improved resistance to proteases, such as DPP-IV, and (v) increased potency at any one or more of the GIP receptor, GLP-receptor, and glucagon receptor as taught by Dimarchi. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that most commonly used linkers are 8-amino-3,6-dioxaoctanoic acid linker (also called OEG or miniPEG) as taught by Caslo. Therefore, modifying Levy’s GIP analog by substituting the amino acids at positions X17 and X20 with Aib in addition to acylating one of the amino acid by linking the acyl group via a spacer comprising gEgE and 2 miniPEG (i.e., OEG), would support a GIP receptor (GIRP) agonist peptide having formula (IV) (i.e., SEQ ID NO: 358 which reads on the elected species SEQ ID NO: 26), or a pharmaceutically acceptable salt thereof wherein A17 represents Aib, A20 represents Aib and L is 2OEGgEgE by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or utilizing the “Obvious to try” rationale – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success pursuant to KSR.
Regarding claim 9, wherein A14 represents Leu or Lys(R); A17 represents Aib or Lys(R); A18 represents Ala, His, or Lys(R); A21 represents Asp, Lys(R), or Asn; A29 represents Gln, Lys(R), or Aib; and A30 represents Lys, Ser, Arg, Lys(R), or Lys(Ac):
Levy teaches that X14 is Met, Ala or Leu (see Levy, pg. 74, para[00288]), and that to eliminate or reduce oxidation, the methionine at position 14 is deleted or substituted, for example with leucine or other small hydrophobic amino acid (see Levy, pg. 18, para[0080]), thereby constituting where A14 represents Leu as recited in instant claim 9. Levy’s X17 is I, Q, E or a conservative amino acid change thereof or of a native X17 residue (see Levy, pg. 76, para[00296]), and that X18 which is H, R, A or a conservative amino acid thereof or of a native X18 residue (see Levy, pg. 76, para[00296]). Further exemplary substitutions are those derived from GIP of other (non-human) species, for example the histidine 18 replaced by alanine, arginine or lysine (see Levy, pg. 19, para[0082]), thereby constituting where A18 represents Ala, His, or Lys as recited in instant claim 9. Levy’s X21 is D (see Levy, pg. 76, para[00297]), thereby constituting where A21 represents Asp as recited in instant claim 9. Levy’s X29 is Q, G or a conservative amino acid substitution thereof or is absent (see Levy, pg. 77, para[00297]), thereby constituting where A29 is Gln recited in instant claim 9. X30 is K, G, R, P or a conservative amino acid substitution thereof or is absent (see Levy, pg. 77, para[00297]), thereby constituting where A30 represents Arg or Lys as recited in instant claim 9. However, Levy does not expressly teach wherein A17 represents Aib or Lys(R) as recited in instant claim 9.
As previously discussed, Dimarchi’s glucagon analog comprises an amino acid modification at either or both of positions 17 and 18 (see Dimarchi, pg. 25, para[0356]). Dimarchi adds that the amino acid at position 17 is an aliphatic amino acid (see Dimarchi, pg. 25, para[0356]). Dimarchi’s GIP agonist peptide comprises one or more alpha, alpha di-substituted amino acids (i.e., amino iso-butyric acid (Aib)) at the C-terminus (around positions 12-29), at one, two, three, four, five, or all of positions 16, 17, 18, 19, 20, or 21 of the GIP agonist peptide (see Dimarchi, pg. 19, para[0258]). The alpha, alpha disubstituted amino acid is capable of stabilizing the alpha helix in the absence of a covalent bridge (see Dimarchi,