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 .
Election/Restrictions
Applicant’s election without traverse of SEQ ID NO: 9 in the reply filed on September 22, 2025, is acknowledged. The elected species was searched and prior art was found.
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.
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.
Claims 1-11, 13-15, 19, and 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over Mroz et al. (NPL 34; IDS 3/10/2023) in view of Abraham et al. (WO 2020/023386 A1; IDS 3/10/2023), Hogendorf et al. (WO 2019/211451 A1), Asami et al. (WO 2018/181864 A1; IDS 3/10/2023), Shelton et al. (WO 2016/066744 A2; IDS 3/10/2023), Haack et al (WO 2014/096145 A1; IDS 3/10/2023), Haack et al. (WO 2014/096150 A1; IDS 3/10/2023), and Bastin et al. (Dual GIP–GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2019:12 1973–1985).
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Determining the scope and contents of the prior art.
Mroz et al. teach peptide-based selective GIPR agonists with optimized duration of action that consistently lower body weight in DIO mice with moderate efficacy relative to GLP-1R agonists (abstract). The GIPR agonists include hGIP Aib Cex*, which is closely related to instant Formula I (Table 1; See Supplemental Materials). The hGIP Aib Cex* contains Aib2 to protect against DPP-IV cleavage (p. 59, col 1) and the C-terminal extension of exendin-4 (Cex) to improve stability (p. 59, col 1). Mroz et al. attribute the effect on body weight to GIP-R agonist activity (abstract). The teaching of the primary reference maps to claim 1 as follows:
Claim 1
Primary Reference
A compound of formula I:
Mroz et al. teach hGIP Aib2 Cex* which has the structure of
R1 is H or C1-C4 alkyl
H
NH
NH
1
Tyr
Tyr
2
Aib
Aib
3
Glu
Glu
4
Gly
Gly
5
Thr
Thr
6
Phe
Phe
7
Ile
Ile
8
Ser
Ser
9
Asp
Asp
10
Leu
Tyr
Difference Tyr10 -> Leu
11
Ser
Ser
12
Ile
Ile
13
Aib
Ala
Difference Ala13 -> Aib
14
X14 is Lys wherein the -NH2 side chain group is functionalized by -Z1-Z2-C(O)-R5
Met
Difference Met14 -> modified Lys
In elected species SEQ ID NO: 9, X14 is K[{AEEA}2-gGlu-C18OH].
Z1 is gamma-glutamate, glycine, N-methyl-glycine, AEEA, {AEEA}2, {AEEA}3, Gly-Gly, {Gly}3, {N-MeGly}2, or {N-MeGly}3
Z2 is Gamma-Glu or gamma-Glu-gamma-Glu
R5 is –(CH2)15-22-COOH
15
Asp
Asp
16
Arg
Arg
17
Ile
Ile
18
His
His
19
Gln
Gln
20
X20
Gln
Difference Gln20 -> Glu or Aib
In elected species SEQ ID NO: 9, this position is Glu.
21
Glu
Asp
Difference Asp21 -> Glu
22
Phe
Phe
23
Ile
Val
Difference Val23 - > Ile
24
Glu
Asn
Difference Asn24 -> Glu
25
Trp
Trp
26
Leu
Leu
27
Leu
Leu
28
Ala
Ala
29
Gln
Gln
30
Gly
Gly
31
Pro
Pro
32
Ser
Ser
33
Ser
Ser
34
Gly
Gly
35
Ala
Ala
36
Pro
Pro
37
Pro
Pro
38
Pro
Pro
39
Ser
Ser
R2
Lys-NH2
Difference terminal group is OH or NH2
Or a salt or solvate thereof.
Ascertaining the differences between the prior art and the claims at issue.
Mroz et al. does not teach that the GIP-R agonist comprises:
Leu at position 10;
Aib at position 13;
a modified Lys at position 14;
Aib or Glu at position 20;
Ile at position 23;
Glu at position 24; and
termination at position 39.
Resolving the level of ordinary skill in the pertinent art.
The art teaches numerous examples of GIP-R agonists with improved stability and properties. The teaching of the secondary references map to claim 1 as follows:
Claim 1 Differences with Primary Reference
Secondary Reference
Tyr10 is Leu
Shelton et al. teach GIPR agonists wherein position 10 can be Leu (p. 4, line 10). The GIPR agonists have increased half-life in vivo and are useful for treating diabetes, obesity, and related disorders (p. 3, lines 30-36).
Abraham et al. also teach GIPR agonists wherein position 10 can be Leu (p. 2, line 24).
Haack et al (WO 2014/096145 A1) teach that Leu at position 10 leads to improved biophysical properties such as solubility and aggregation behavior in solution (p. 6, lines 4-10).
Ala13 is Aib
Asami et al. teach GIPR agonists wherein position 13 can be Aib (p. 4). The compounds have selective GIP-R agonist activity and can be used to treat diabetes and obesity (para. [00o8]-[0009]).
Abraham et al. also teach GIPR agonists wherein position 13 can be Aib (p. 3, line 1). The GIPR agonists have an extended duration of action and can be used for treating diabetes and obesity (abstract).
Bastin et al. teach that Aib at position 13 is important to maximize stabilization of the helix (p. 1982, col 2; Figure 2).
Met14 is a modified lysine
Abraham et al. teach GIPR agonists wherein position 14 is a lysine modified with a C16-22 fatty acid via an optional linker (p. 3, line 3).
The modification can be {AEEA}2-(g-Glu)-CO-(CH2)x-COOH, wherein x is 14, 16, 18, 20 (p. 6, line 1 – p. 7, line 5). See compound 27 which has K{AEEA}2-(g-Glu)-CO-(CH2)18-COOH. This compound has GIP-R agonist activity (Table 3).
Haack et al (WO 2014/096145 A1) teach exendin-4 analogues that activate the GIP receptor. The analogues are characterized by substituting the methionine at position 14 with an amino acid containing an amino group in the sidechain that is further modified by a lipophilic group or fatty acid and linker (p. 6, lines 24-29; p. 10, lines 14-18). GIPR agonists position 14 is a lysine modified with a C(O)R5 wherein R5 contains up to 50 or up to 100 carbon atoms (claim 1; Table 9). The GIPR agonists have an improved storage stability and protracted profile of action and can be used to treat diabetes and obesity (abstract).
Haack et al. (WO 2014/096150 A1) teach that exendin-4 derivatives with fatty acid acylated residues at position 14 leads to an improved pharmacokinetic profile and significantly higher GIPR activity (p. 6, lines 13-18; Example 5, Table 8).
Gln20 is Aib or Glu
Hogendorf et al. teach GIPR agonists wherein position 20 can be Aib or Glu (p. 18, line 18). Hogendorf et al. teach GIPR agonists with protracted action and improved stability useful for treating diabetes, obesity, and related conditions (p. 1, lines 28-29; p. 3, lines 17-30).
Bastin et al. teach that Aib at position 13 is important to prevent physiological degradation and inactivation by DPP4 (Figure 2).
Val23 is Ile
Abraham et al. teaches GIPR agonists wherein position 23 can be Ile (p. 3, line 18). The GIPR agonists have an extended duration of action and can be used for treating diabetes and obesity (abstract).
Haack et al (WO 2014/096145 A1) teach that Ile at position 23 leads to improved biophysical properties such as solubility and aggregation behavior in solution (p. 6, lines 6-10).
Asn24 is Glu
Abraham et al. teaches GIPR agonists wherein position 24 can be Glu (p. 3, line 20). The GIPR agonists have an extended duration of action and can be used for treating diabetes and obesity (abstract).
Haack et al (WO 2014/096145 A1) teach that Glu at position 24 leads to improved biophysical properties such as solubility and aggregation behavior in solution (p. 6, lines 6-10).
Ser39 is the C-terminal residue
Shelton et al. teach GIPR agonists that terminate at position 39 (p. 4, lines 27-29). The GIPR agonists have increased half-life in vivo and are useful for treating diabetes, obesity, and related disorders (p. 3, lines 30-36).
Abraham et al. also teach GIPR agonists that terminate at position 39 (see e.g. Compound 27). The GIPR agonists have an extended duration of action and can be used for treating diabetes and obesity (abstract).
Haack et al (WO 2014/096145 A1) also teach GIPR agonists that terminate at position 39 (Table 9). The GIPR agonists have an improved storage stability and protracted profile of action and can be used to treat diabetes and obesity (abstract).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification does not provide a comparison between the claimed invention and the closest prior art, hGIP Aib Cex*taught by Mroz et al.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the hGIP Aib Cex* taught by Mroz et al. such that Tyr10 is Leu, Ala13 is Aib, Met14 is K{AEEA}2-(g-Glu)-CO-(CH2)14-20-COOH, Gln20 is Aib or Glu, Val23 is Ile, Asn24 is Glu, and Ser39 is the C-terminal residue, yield a compound of instant Formula I and identical to elected species SEQ ID NO: 9. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). The relevant findings for this rationale are as follows.
(1) The prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components. In the instant case, the primary reference teaches hGIP Aib Cex* which differs from the claimed formula by the substitution of an amino acid residue for another at six positions and the termination of the peptide at position 39. Therefore, prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components.
(2) The substituted components and their functions were known in the art. Each of the substitutions are taught in the prior art including Tyr10 is Leu, Ala13 is Aib, Met14 is K{AEEA}2-(g-Glu)-CO-(CH2)14-20-COOH, Gln20 is Aib, Val23 is Ile, Asn24 is Glu, and Ser39 is the C-terminal residue, which are the substituted components. The function of each substitution is known in the art because the prior art teach that each of these substitutions is present in a GIP-1 R agonist that can be used to treat diabetes, obesity, and related conditions with extended duration of action. In addition, Haack et al (WO 2014/096145 A1) teach that Leu at position 10 leads to improved biophysical properties such as solubility and aggregation behavior in solution (p. 6, lines 4-10). Bastin et al. teach that Aib at position 13 is important to maximize stabilization of the helix (p. 1982, col 2; Figure 2). Haack et al. (WO 2014/096150 A1) teach that exendin-4 derivatives with fatty acid acylated residues at position 14 leads to an improved pharmacokinetic profile and significantly higher GIPR activity (p. 6, lines 13-18; Example 5, Table 8). Bastin et al. teach that Aib at position 13 is important to prevent physiological degradation and inactivation by DPP4 (Figure 2). Haack et al (WO 2014/096145 A1) teach that Ile at position 23 leads to improved biophysical properties such as solubility and aggregation behavior in solution (p. 6, lines 6-10). Haack et al (WO 2014/096145 A1) teach that Glu at position 24 leads to improved biophysical properties such as solubility and aggregation behavior in solution (p. 6, lines 6-10). Therefore, the substituted components and their functions were known in the art.
(3) One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. One of ordinary skill in the art would expect that each of the substitutions is compatible with a GIP-R agonist suitable for therapeutic use because each are taught in GIP-R agonists used for treating diabetes, obesity and related conditions, most with an improved profile of action. Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification does not provide a comparison between the claimed invention and the closest prior art, hGIP Aib Cex*taught by Mroz et al. Therefore, unexpected results have not been established.
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Therefore, claim 1 and the elected species SEQ ID NO: 9 of claims 10-11 are obvious over the cited art.
Regarding claim 2, Abraham et al. teach GIPR agonists wherein position 14 is a lysine modified with a C16-22 fatty acid via an optional linker (p. 3, line 3). The modification can be {AEEA}2-(g-Glu)-CO-(CH2)x-COOH, wherein x is 14, 16, 18, 20 (p. 6, line 1 – p. 7, line 5). See compound 27 which has K{AEEA}2-(g-Glu)-CO-(CH2)18-COOH. This corresponds to Z1 is {AEEA}2.
Regarding claim 3, Abraham et al. teach GIPR agonists wherein position 14 is a lysine modified with a C16-22 fatty acid via an optional linker (p. 3, line 3). The modification can be {AEEA}2-(g-Glu)-CO-(CH2)x-COOH, wherein x is 14, 16, 18, 20 (p. 6, line 1 – p. 7, line 5). See compound 27 which has K{AEEA}2-(g-Glu)-CO-(CH2)18-COOH.
Regarding claim 4, hGIP Aib Cex*taught by Mroz et al. has R1 is H. WO 2019/211451 A1 teaches GIPR agonists wherein position 20 can be Aib or Glu (p. 18, line 18).
Regarding claim 5, hGIP Aib Cex*taught by Mroz et al. has R1 is H. WO 2019/211451 A1 teaches GIPR agonists wherein position 20 can be Aib or Glu (p. 18, line 18).
Regarding claim 6, hGIP Aib Cex*taught by Mroz et al. has R1 is H and R2 is NH2 (C-terminus is amidated).
Regarding claim 7, hGIP Aib Cex*taught by Mroz et al. has R1 is H and R2 is NH2 (C-terminus is amidated). Hogendorf et al. teach GIPR agonists wherein position 20 can be Aib or Glu (p. 18, line 18).
Regarding claims 8 and 9, hGIP Aib Cex*taught by Mroz et al. has R1 is H and R2 is NH2 (C-terminus is amidated). Mroz et al. also teach peptides with an OH at the C-terminus (see supplemental materials).
Regarding claim 13, Mroz et al. and each of the cited references teach the GIP-R peptides in a pharmaceutical composition with a pharmaceutically-acceptable carrier. For example, in Hogendorf et al., see claim 104. See also Shelton et al. pp. 38-39. See also Haack et al (WO 2014/096145 A1) pp 13 and 49-50.
Regarding claims 14-15, 19, and 26, Mroz et al. teach that the GIP-R agonist peptides can treat obesity and lower body weight (Section 5). For example, in Hogendorf et al. e.g. see claim 119 which teaches treating, delaying, and preventing all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), gestational diabetes, and/or for reduction of HbA1C; and treating or preventing obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety, reducing of gastric motility, delaying gastric emptying, increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity; for weight maintenance after successful weight loss and treating of liver disorders, such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver inflammation or fatty liver. See also Shelton et al. pp. 35-38. See also Haack et al (WO 2014/096145 A1) pp 13, 49-50, and 60-68.
Regarding claim 22, Mroz et al. teach that the GIP-R agonist peptides function as agonists (Section 5).
Regarding claim 23, Mroz et al. teach peptide-based selective GIPR agonists with optimized duration of action that consistently lower body weight in DIO mice with moderate efficacy relative to GLP-1R agonists (abstract). The GIPR agonists include hGIP Aib Cex*, which is closely related to instant Formula I (Table 1; See Supplemental Materials). The hGIP Aib Cex* contains Aib2 to protect against DPP-IV cleavage (p. 59, col 1) and the C-terminal extension of exendin-4 (Cex) to improve stability (p. 59, col 1). Therefore, the GIP-R agonists have high chemical and physical stability. Haack et al. teach that substituting the methionine at position 14 with an amino acid containing an amino group in the sidechain that is further modified by a lipophilic group or fatty acid and linker eliminate oxidation that occurs at this site, maintains high solubility at physiological pH, and has high solution storage stability (p. 14, line 18 – p. 15, line 12).
Regarding claim 24, Shelton et al. teach that GIP-R agonists can be used in combination with other antidiabetic agents and GLP-1 R agonists (p. 40). See also Haack et al (WO 2014/096145 A1) pp 13, 49-50, and 60-68.
Regarding claim 25, Mroz et al. teach subcutaneous administration (Section 2.3).
Response to Arguments
Applicant's arguments filed March 3, 2026, have been fully considered but they are not persuasive.
Applicant describes the number of compounds disclosed in and the difference between the primary reference Mroz and each of Abraham, Hogendorf, Asami, Shelton, Haack ‘145, Hack ‘150, and Bastin. Applicant argues that based on these factors, one of ordinary skill in the art would not be motived to combine the cited references, that “picking and choosing” is required to arrive at the claimed invention, and that there was no reasonable expectation of success. Reply pages 8-11. This argument is not persuasive because Applicant has not responded to the rationale of rejection (i.e. simple substitution). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Each of the substitutions absent from the prior reference Mroz are known in the prior art to be useful in a GIP-1 R agonist that can be used to treat diabetes, obesity, and related conditions with extended duration of action. In other words, the functions of the substitutions Tyr10 to Leu, Ala13 to Aib, Met14 to K{AEEA}2-(g-Glu)-CO-(CH2)14-20-COOH, Gln20 to Aib, Val23 to Ile, Asn24 to Glu, and Ser39 to the C-terminal residue are known and predictable.
Applicant points to Examples 6-14 of the specification for evidence that “the claimed compounds demonstrate very high GIP receptor agonism, favorable solubility, favorable chemical and
physical stability (even in the presence of phenolic preservatives), high selectivity for GIP receptor versus GLP-1 receptor, prolonged half-life in various species (e.g., mice, rats, monkeys, and minipigs), and excellent in vivo activity in mice (i.e., induction significant and dose- dependent improvements in intraperitoneal glucose tolerance following intraperitoneal glucose loading)”. Applicant argues that “[t]hese surprising and superior effects of the claimed invention demonstrate strong evidence of inventiveness”. Reply pages 11-12. This argument is not persuasive. Applicant has not met the burden to establish that the results are unexpected and of practical and statistical significance. See MPEP 716.02(b)(I). As noted in the rejection, Applicant has not presented a comparison between the claimed invention and the closest prior art. See MPEP 716.02(e). Therefore, it is not possible to assess whether the claimed compounds exhibit superior properties that are unexpected in view of the prior art.
For these reasons, the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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