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 .
Claim Rejections - 35 USC § 112 - withdrawn
The rejection of claims 1, 12-17 and 21-24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed December 29, 2025.
The rejection of claims 2-10 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, s withdrawn in view of the amendment filed December 29, 2025.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-17 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Palani et al. (WO 2017/100107 A2) in view of Day et al. (WO 2008/101017 A2).
Palani et al. teach co-agonist peptides of the human glucagon (GCG) receptor and the human glucagon-like protein (GLP-1) receptor (p. 4, lines 25-26; p. 25, lines 15-30).
Palani et al. teach that the peptides comprise the amino acid sequence of native human glucagon (Fig 1)
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
with differences to alter agonist activity of the GCG and GLP-1 receptors and enhance stability and half-life including:
an amino acid substitution at position 2 that renders the peptide resistant to cleavage and inactivation by dipeptidyl peptidase IV;
a lipid moiety covalently linked to at a lysine residue substituted for the tyrosine at position 10 to increase half-life;
0-10 additional substitutions to affect GCG and GLP-1 receptor activity; and
a protecting group at the C-terminus to stabilize against carboxypeptidases (p. 4, line 25 – p. 5, line p. 23, lines 17-25).
Palani et al. teach that the amino acid at position 2 is preferably replaced with D-Ser or Aib (p. 23, lines 26-28; Table 6).
Palani et al. teach that the lipid moiety conjugated to the lysine at position 10 may be a fatty acid with 13 to 20 methylene groups (HO2C(CH2)nCH3 wherein n is 11-18) or a fatty diacid (HO2C(CH2)nCO2H wherein n is 11-18) (p. 24, line 1 – p. 25, line 12). Palani et al. teach that the lipid moiety may be attached to lysine at position 10 via a g-Glu-g-Glu linker (p. 26, lines 1-9; p. 29, lines 1-3). Palani et al. teach that gEgEC16 is preferred at position 10 (Table 6).
Palani et al. teach that the additional substitutions may include substituting alanine for arginine at position 18 (p. 23, lines 29-30; Table 6).
Palani et al. teach that the co-agonist peptide may comprise a lysine residue at the C-terminus that is conjugated to a g-Glu residue to provide a KgE at position 30 and that the C-terminus may be amidated (p. 32, lines 3-8; Table 6).
The difference between the peptides of Palani et al. and the instant claims is the inclusion of a lactam bridge. Palani et al. do not teach that the peptide contains at least one lysine and one glutamic acid wherein one lysine and one glutamic acid cyclize to form a lactam containing ring.
Day et al. teach high potency glucagon agonist peptides that also exhibit increased activity at the GLP-1 receptor (p. 3, line 31 – p. 4, line 31). Day et al. teach that enhanced activity at the GLP-1 receptor is provided by stabilizing the alpha-helix structure in the C-terminal portion of glucagon (around amino acids 12-29) through formation of an intramolecular bridge between the side chains of two amino acids that are separated by three intervening amino acids. The bridge or linker is about 8 (or about 7-9) atoms in length and forms between side chains of amino acids at positions 12 and 16, positions 16 and 20, positions 20 and 24, or positions 24 and 28. The bridge or linker may be a lactam ring formed between the side chain of a lysine at positions 12, 20, or 28 and a glutamic acid at positions 16 or 24, wherein the lysine and glutamic acid are separated by three intervening residues (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10; SEQ ID NOs: 72-75, 77-80, 82-83, 85-86, 89-92, 94-97, 99-100, 102-103, 106-109, 111-114, 116-117, 119-120, 123-126, 128-131, 133-134, 136-137, 140-143, 145-148, 150-151, 153-154, 157-160, 162-165, 167-168, 170-171, 174-177, 179-182, 184-185, 187-188, 191-194, 196-199, 201-202, 204-205, 208-211, 213-216, 218-219, 221-222, 225-228, 230-233, 235-236, 238-239, 242-245, 247-250, 252-253, 255-256, 259-262, 264-267, 269-270, 272-273, 276-279, 281-284, 286-287, 289-290, 293-296, 298-301, 303-304, 306-307, 310-313, 315-318, 320-321, 323-324, 327-330, 332-335, 337-338, 340-341, 376-379, 381-384, 386-387, 390-393, 395-398, 400-401, 404-407, 409-412, 414-415, 418-421, 423-426, 428-429, 432-435, 437-440, 442-443, 446-449, 451-454, 456-457, 460-463, 465-468, 470-471, 474-477, 479-482, 484-485, 489, 491, 495, 497, 501, 503, 505-514, 517, 528).
It would have been obvious before the effective filing date of the claimed invention to incorporate the lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28 in the glucagon/GLP-1 co-agonists taught by Day et al. in the glucagon/GLP-1 co-agonists taught by Palani et al. The resulting peptides would be a peptide comprising the amino acid sequence of native human glucagon with the following changes:
D-Ser or Aib substituted for the Ser at position 2 for resistance to DPP-IV cleavage;
K(gEgEC16) substituted for the Tyr at position 10 to increase half-life;
Ala substituted for Arg at position 18;
absent or KgE at position 30 and optional C-terminal amidation; and
a lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28;
satisfying all of the limitations of claim 1-11. One of ordinary skill in the art would have been motivated to do so given that Day et al. teach the benefit of stabilizing the alpha-helix structure in the C-terminal portion of glucagon through the formation of lactam bridges at these positions (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10). In addition, Day et al. teach that it is advantageous to combine a modification at position 2, such as the replacement of Ser with D-Ser or Aib which is taught by Palani et al., with a lactam bridge between glutamic acid at position 16 and lysine at position 20 (or between 12 and 16 or between 20 and 24). Day et al. teach that the modification at position 2 can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). There would have been a reasonable expectation of success given that Day et al. teach the synthetic methods for forming the lactam bridge in the glucagon/GLP-1 co-agonist peptides (Example 11) and the incorporation of the lactam bridge into numerous sequences.
Regarding claim 12, Palani et al. teach a pharmaceutical composition comprising the GCG/GLP-1 agonist peptides and a pharmaceutically-acceptable carrier (p. 7, lines 16-18; pp. 33-48).
Regarding claims 13 and 16, Palani et al. teach a method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the GCG/GLP-1 agonist peptides (p. 7, line 19 – p. 8, line 2; p. 48).
Regarding claims 14 and 17, Palani et al. teach that the metabolic disease or disorder may be diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or obesity (page 8, lines 10-30; p. 48).
Regarding claim 15, Palani et al. teach that the diabetes is chosen from type I diabetes, type II diabetes, and gestational diabetes (page 8, lines 10-30; p. 48).
Regarding claims 21-24, Palani et al. teach that the GCG/GLP-1 agonist peptides can be combined with insulin such as insulin detemir, glargine, Levemir, glulisine, degludec, or lispro to treat the metabolic disorders (page 9, lines 1-30; p. 49).
Claims 1-17 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Carrington et al. (WO 2016/065090) in view of Day et al. (WO 2008/101017 A2).
Carrington et al. teach peptide analogs of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have relatively balanced agonist activity at the glucagon-like peptide 1 (GLP-1) receptor and the glucagon (GCG) receptor, and the use of such GLP-1 receptor/GCG receptor co-agonists for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity (p. 1, lines 8-14).
Carrington et al. teach a peptide comprising the amino acid sequence of native human glucagon
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
with the following changes:
the L-serine at position 2 is replaced with a D-serine, L-alanine, Aib, or 1-amino-cyclobutane carboxylic acid;
the tyrosine at position 10 is replaced with (i) L-lysine conjugated to a palmitoyl group by either a gamma-glutamic acid (γΕ) spacer or a gamma-glutamic acid-gamma-glutamic acid dipeptide (γΕγΕ) spacer or (ii) para-aminomethyl phenylalanine conjugated to a palmitoyl group by either a gamma-glutamic acid (γΕ) spacer or a gamma-glutamic acid-gamma-glutamic acid dipeptide (γΕγΕ) spacer; and
up to six additional substitutions (p. 5, lines 13-25).
Carrington et al. teach a peptide comprising the amino acid sequence of native human glucagon
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
with the following changes:
the L-serine at position 2 is replaced with a D-serine;
the tyrosine at position 10 is replaced with (i) L-lysine conjugated to a palmitoyl group by either a gamma-glutamic acid (γΕ) spacer or a gamma-glutamic acid-gamma-glutamic acid dipeptide (γΕγΕ) spacer or (ii) para-aminomethyl phenylalanine conjugated to a palmitoyl group by either a gamma-glutamic acid (γΕ) spacer or a gamma-glutamic acid-gamma-glutamic acid dipeptide (γΕγΕ) spacer;
the serine at position 16 is replaced with L-alanine;
the arginine at position 18 is replaced with L-alanine;
the methionine at position 27 is replaced with L-leucine; and
the asparagine at position 28 is replaced with L-aspartic acid (p. 9, lines 1-17).
Carrington et al. reduce to practice numerous examples wherein Tyr10 is replaced with K(gEgEC16) (Table 1).
Carrington et al. do not teach that the peptide contains at least one lysine and one glutamic acid wherein one lysine and one glutamic acid cyclize to form a lactam containing ring.
Day et al. teach high potency glucagon agonist peptides that also exhibit increased activity at the GLP-1 receptor (p. 3, line 31 – p. 4, line 31). Day et al. teach that enhanced activity at the GLP-1 receptor is provided by stabilizing the alpha-helix structure in the C-terminal portion of glucagon (around amino acids 12-29) through formation of an intramolecular bridge between the side chains of two amino acids that are separated by three intervening amino acids. The bridge or linker is about 8 (or about 7-9) atoms in length and forms between side chains of amino acids at positions 12 and 16, positions 16 and 20, positions 20 and 24, or positions 24 and 28. The bridge or linker may be a lactam ring formed between the side chain of a lysine at positions 12, 20, or 28 and a glutamic acid at positions 16 or 24, wherein the lysine and glutamic acid are separated by three intervening residues (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10; SEQ ID NOs: 72-75, 77-80, 82-83, 85-86, 89-92, 94-97, 99-100, 102-103, 106-109, 111-114, 116-117, 119-120, 123-126, 128-131, 133-134, 136-137, 140-143, 145-148, 150-151, 153-154, 157-160, 162-165, 167-168, 170-171, 174-177, 179-182, 184-185, 187-188, 191-194, 196-199, 201-202, 204-205, 208-211, 213-216, 218-219, 221-222, 225-228, 230-233, 235-236, 238-239, 242-245, 247-250, 252-253, 255-256, 259-262, 264-267, 269-270, 272-273, 276-279, 281-284, 286-287, 289-290, 293-296, 298-301, 303-304, 306-307, 310-313, 315-318, 320-321, 323-324, 327-330, 332-335, 337-338, 340-341, 376-379, 381-384, 386-387, 390-393, 395-398, 400-401, 404-407, 409-412, 414-415, 418-421, 423-426, 428-429, 432-435, 437-440, 442-443, 446-449, 451-454, 456-457, 460-463, 465-468, 470-471, 474-477, 479-482, 484-485, 489, 491, 495, 497, 501, 503, 505-514, 517, 528).
It would have been obvious before the effective filing date of the claimed invention to incorporate the lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28 in the glucagon/GLP-1 co-agonists taught by Day et al. in the glucagon/GLP-1 co-agonists taught by Carrington et al. The resulting peptides would be a peptide comprising the amino acid sequence of native human glucagon with the following changes:
D-Ser substituted for the Ser at position 2;
K(gEgEC16) substituted for the Tyr at position 10;
Ala substituted for Ser at position 16;
Ala substituted for Arg at position 18;
Leu substituted for Met at position 27;
Asp substituted for Asn at position 28;
absent at position 30 and optional C-terminal amidation; and
a lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28;
satisfying all of the limitations of claim 1-10. One of ordinary skill in the art would have been motivated to do so given that Day et al. teach the benefit of stabilizing the alpha-helix structure in the C-terminal portion of glucagon through the formation of lactam bridges at these positions (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10). In addition, Day et al. teach that it is advantageous to combine a modification at position 2, such as the replacement of Ser with D-Ser which is taught by Carrington et al., with a lactam bridge between glutamic acid at position 16 and lysine at position 20 (or between 12 and 16 or between 20 and 24). Day et al. teach that the modification at position 2 can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). There would have been a reasonable expectation of success given that Day et al. teach the synthetic methods for forming the lactam bridge in the glucagon/GLP-1 co-agonist peptides (Example 11) and the incorporation of the lactam bridge into numerous sequences.
Regarding claim 12, Carrington et al. teach a pharmaceutical composition comprising the GCG/GLP-1 agonist peptides and a pharmaceutically-acceptable carrier (p. 31, line 20 – p. 36, line 2).
Regarding claims 13 and 16, Carrington et al. teach a method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the GCG/GLP-1 agonist peptides (p. 31, line 20 – p. 36, line 2; p. 45, lines 13 – 20).
Regarding claims 14 and 17, Carrington et al. teach that the metabolic disease or disorder may be diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or obesity (p. 31, line 20 – p. 36, line 2; p. 45, lines 16-17).
Regarding claim 15, Carrington et al. teach that the diabetes is chosen from type I diabetes, type II diabetes, and gestational diabetes (p. 31, line 20 – p. 36, line 2; p. 45, lines 18-19).
Regarding claims 21-24, Carrington et al. teach that the GCG/GLP-1 agonist peptides can be combined with insulin such as insulin detemir, glargine, levemir, glulisine, degludec, or lispro to treat the metabolic disorders (p. 46, lines 9-22).
Claims 1-17 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Bianchi et al. (US 10,413,593 B2) in view of Day et al. (WO 2008/101017 A2).
Bianchi et al teach peptide analogs of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have relatively balanced agonist activity at the glucagon-like peptide 1 (GLP-1) receptor and the glucagon (GCG) receptor, and the use of such GLP-1 receptor/GCG receptor co-agonists for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity (abstract).
Bianchi et al. teach a peptide comprising the structure
HsQGTFTSDK(γEγEC16)SKYLDARAAQDFVQWLLDT-NH2 (SEQ ID NO:10)
wherein “s” is D-serine;
the lysine at position 10 is conjugated via its epsilon amino group to a C16 fatty acid via a gamma-glutamic acid-gamma-glutamic acid dipeptide (γEγE) spacer; and
the peptide, or a pharmaceutically acceptable salt thereof, has a C-terminal amine (claim 11).
With respect to claim 1, the peptide of Bianchi et al. is the amino acid sequence of native human glucagon with the following changes:
L-Ser at position 2 is D-Ser;
Tyr at position 10 is K(gEgEC16);
Arg at position 18 is Ala;
position 30 is absent; and
Ser at position 16 is Ala;
Met at position 27 is Leu; and
Asn at position 28 is Asp.
The difference between the peptides of claim 1 and the peptide of Bianchi et al. is the presence of a lactam bridge. Bianchi et al. do not teach that the peptide contains at least one lysine and one glutamic acid wherein one lysine and one glutamic acid cyclize to form a lactam containing ring.
Day et al. teach high potency glucagon agonist peptides that also exhibit increased activity at the GLP-1 receptor (p. 3, line 31 – p. 4, line 31). Day et al. teach that enhanced activity at the GLP-1 receptor is provided by stabilizing the alpha-helix structure in the C-terminal portion of glucagon (around amino acids 12-29) through formation of an intramolecular bridge between the side chains of two amino acids that are separated by three intervening amino acids. The bridge or linker is about 8 (or about 7-9) atoms in length and forms between side chains of amino acids at positions 12 and 16, positions 16 and 20, positions 20 and 24, or positions 24 and 28. The bridge or linker may be a lactam ring formed between the side chain of a lysine at positions 12, 20, or 28 and a glutamic acid at positions 16 or 24, wherein the lysine and glutamic acid are separated by three intervening residues (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10; SEQ ID NOs: 72-75, 77-80, 82-83, 85-86, 89-92, 94-97, 99-100, 102-103, 106-109, 111-114, 116-117, 119-120, 123-126, 128-131, 133-134, 136-137, 140-143, 145-148, 150-151, 153-154, 157-160, 162-165, 167-168, 170-171, 174-177, 179-182, 184-185, 187-188, 191-194, 196-199, 201-202, 204-205, 208-211, 213-216, 218-219, 221-222, 225-228, 230-233, 235-236, 238-239, 242-245, 247-250, 252-253, 255-256, 259-262, 264-267, 269-270, 272-273, 276-279, 281-284, 286-287, 289-290, 293-296, 298-301, 303-304, 306-307, 310-313, 315-318, 320-321, 323-324, 327-330, 332-335, 337-338, 340-341, 376-379, 381-384, 386-387, 390-393, 395-398, 400-401, 404-407, 409-412, 414-415, 418-421, 423-426, 428-429, 432-435, 437-440, 442-443, 446-449, 451-454, 456-457, 460-463, 465-468, 470-471, 474-477, 479-482, 484-485, 489, 491, 495, 497, 501, 503, 505-514, 517, 528).
It would have been obvious before the effective filing date of the claimed invention to incorporate the lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28 in the glucagon/GLP-1 co-agonists taught by Day et al. in the glucagon/GLP-1 co-agonists taught by Bianchi et al. The resulting peptides would be a peptide comprising the amino acid sequence of native human glucagon with the following changes:
L-Ser at position 2 is D-Ser;
Tyr at position 10 is K(gEgEC16);
Arg at position 18 is Ala;
position 30 is absent;
Ser at position 16 is Ala;
Met at position 27 is Leu;
Asn at position 28 is Asp; and
a lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28;
satisfying all of the limitations of claim 1-11. One of ordinary skill in the art would have been motivated to do so given that Day et al. teach the benefit of stabilizing the alpha-helix structure in the C-terminal portion of glucagon through the formation of lactam bridges at these positions (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10). In addition, Day et al. teach that it is advantageous to combine a modification at position 2, such as the replacement of Ser with D-Ser which is taught by Bianchi et al., with a lactam bridge between glutamic acid at position 16 and lysine at position 20 (or between 12 and 16 or between 20 and 24). Day et al. teach that the modification at position 2 can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). There would have been a reasonable expectation of success given that Day et al. teach the synthetic methods for forming the lactam bridge in the glucagon/GLP-1 co-agonist peptides (Example 11) and the incorporation of the lactam bridge into numerous sequences.
Regarding claim 12, Bianchi et al. teach a pharmaceutical composition comprising the GCG/GLP-1 agonist peptides and a pharmaceutically-acceptable carrier (claim 13).
Regarding claims 13 and 16, Bianchi et al. teach a method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the GCG/GLP-1 agonist peptides (claim 20).
Regarding claims 14 and 17, Bianchi et al. teach that the metabolic disease or disorder may be diabetes or obesity (claim 20).
Regarding claim 15, Bianchi et al. teach that the diabetes is chosen from type I diabetes, type II diabetes, and gestational diabetes (claim 21).
Regarding claims 21-24, Bianchi et al. teach that the GCG/GLP-1 agonist peptides can be combined with insulin such as insulin detemir, glargine, levemir, glulisine, degludec, or lispro to treat the metabolic disorders (claim 24).
Response to Arguments
Applicant's arguments filed December 29, 2025, have been fully considered but they are not persuasive. Applicant traverses the rejection on the grounds that there is a lack of motivation to combine each of the three primary references with the secondary reference Day. Applicant argues that although Day teaches a means to improve stability of peptides, the primary references do not teach a lack of stability in the disclosed peptides. Applicant argues that there is no motivation to improve stability by the means discloses in Day from the universe of possible modifications. Applicant argues that there is no experimental data in Day showing that a lactam ring exhibited increased activity at the GLP-1 or glucagon receptor.
These arguments are not persuasive because there is a specific teaching in Day et al. that would motivate one of ordinary skill in the art to use lactam bridges to stabilize the peptides of the primary references. That is Day et al. teach that the replacement of Ser with D-Ser or Aib at position 2, which is taught by each of the primary references, can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). Although the primary references do not explicitly teach a deficiency in the peptides, one of ordinary skill in the art would understand based on Day that peptides with D-Ser or Aib at position can benefit from stabilization of the helix by introduction of a lactam bridge. A person of ordinary skill in the art can readily identify this structural feature in the primary references and make the modification of Day accordingly with an expectation of success. In contrast to Applicant’s argument, Day present data showing that the introduction of a lactam can improve activity at the glucagon receptor and is compatible with co-agonist activity (see e.g. page 84, lines 25-30; Table 9, Table 12).
There is no evidence on record that the claimed peptides have properties that are unexpected in view of the prior art. On the contrary, the activity of the claimed peptides reported in the original specification is consistent with the primary references and with Day.
For these reasons, the rejections are maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-17 and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,413,593 B2 in view of Day et al. (WO 2008/101017 A2). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 11 of U.S. Patent No. 10,413,593 B2 recites a peptide comprising the structure
HsQGTFTSDK(γEγEC16)SKYLDARAAQDFVQWLLDT-NH2 (SEQ ID NO:10)
wherein “s” is D-serine;
the lysine at position 10 is conjugated via its epsilon amino group to a C16 fatty acid via a gamma-glutamic acid-gamma-glutamic acid dipeptide (γEγE) spacer; and
the peptide, or a pharmaceutically acceptable salt thereof, has a C-terminal amine (claim 11).
With respect to claim 1, the patented peptide is the amino acid sequence of native human glucagon with the following changes:
L-Ser at position 2 is D-Ser;
Tyr at position 10 is K(gEgEC16);
Arg at position 18 is Ala;
position 30 is absent; and
Ser at position 16 is Ala;
Met at position 27 is Leu; and
Asn at position 28 is Asp.
The difference between the peptides of claim 1 and the patented peptide is the presence of a lactam bridge. U.S. Patent No. 10,413,593 B2 does not claim that the peptide contains at least one lysine and one glutamic acid wherein one lysine and one glutamic acid cyclize to form a lactam containing ring.
Day et al. teach high potency glucagon agonist peptides that also exhibit increased activity at the GLP-1 receptor (p. 3, line 31 – p. 4, line 31). Day et al. teach that enhanced activity at the GLP-1 receptor is provided by stabilizing the alpha-helix structure in the C-terminal portion of glucagon (around amino acids 12-29) through formation of an intramolecular bridge between the side chains of two amino acids that are separated by three intervening amino acids. The bridge or linker is about 8 (or about 7-9) atoms in length and forms between side chains of amino acids at positions 12 and 16, positions 16 and 20, positions 20 and 24, or positions 24 and 28. The bridge or linker may be a lactam ring formed between the side chain of a lysine at positions 12, 20, or 28 and a glutamic acid at positions 16 or 24, wherein the lysine and glutamic acid are separated by three intervening residues (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10; SEQ ID NOs: 72-75, 77-80, 82-83, 85-86, 89-92, 94-97, 99-100, 102-103, 106-109, 111-114, 116-117, 119-120, 123-126, 128-131, 133-134, 136-137, 140-143, 145-148, 150-151, 153-154, 157-160, 162-165, 167-168, 170-171, 174-177, 179-182, 184-185, 187-188, 191-194, 196-199, 201-202, 204-205, 208-211, 213-216, 218-219, 221-222, 225-228, 230-233, 235-236, 238-239, 242-245, 247-250, 252-253, 255-256, 259-262, 264-267, 269-270, 272-273, 276-279, 281-284, 286-287, 289-290, 293-296, 298-301, 303-304, 306-307, 310-313, 315-318, 320-321, 323-324, 327-330, 332-335, 337-338, 340-341, 376-379, 381-384, 386-387, 390-393, 395-398, 400-401, 404-407, 409-412, 414-415, 418-421, 423-426, 428-429, 432-435, 437-440, 442-443, 446-449, 451-454, 456-457, 460-463, 465-468, 470-471, 474-477, 479-482, 484-485, 489, 491, 495, 497, 501, 503, 505-514, 517, 528).
It would have been obvious before the effective filing date of the claimed invention to incorporate the lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28 in the glucagon/GLP-1 co-agonists taught by Day et al. in the peptide claimed in U.S. Patent No. 10,413,593 B2. The resulting peptides would be a peptide comprising the amino acid sequence of native human glucagon with the following changes:
L-Ser at position 2 is D-Ser;
Tyr at position 10 is K(gEgEC16);
Arg at position 18 is Ala;
position 30 is absent;
Ser at position 16 is Ala;
Met at position 27 is Leu;
Asn at position 28 is Asp; and
a lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28;
satisfying all of the limitations of claim 1-11. One of ordinary skill in the art would have been motivated to do so given that Day et al. teach the benefit of stabilizing the alpha-helix structure in the C-terminal portion of glucagon through the formation of lactam bridges at these positions (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10). In addition, Day et al. teach that it is advantageous to combine a modification at position 2, such as the replacement of Ser with D-Ser which is claimed in U.S. Patent No. 10,413,593 B2, with a lactam bridge between glutamic acid at position 16 and lysine at position 20 (or between 12 and 16 or between 20 and 24). Day et al. teach that the modification at position 2 can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). There would have been a reasonable expectation of success given that Day et al. teach the synthetic methods for forming the lactam bridge in the glucagon/GLP-1 co-agonist peptides (Example 11) and the incorporation of the lactam bridge into numerous sequences.
Regarding claim 12, patented claim 13 recites a pharmaceutical composition comprising the GCG/GLP-1 agonist peptides and a pharmaceutically-acceptable carrier.
Regarding claims 13 and 16, patented claim 20 recites a method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the GCG/GLP-1 agonist peptides.
Regarding claims 14 and 17, patented claim 20 requires that the metabolic disease or disorder may be diabetes or obesity.
Regarding claim 15, patented claim 21 requires that the diabetes is chosen from type I diabetes, type II diabetes, and gestational diabetes.
Regarding claims 21-24, patented claim 24 requires that the peptide is combined with insulin such as insulin detemir, glargine, levemir, glulisine, degludec, or lispro to treat the metabolic disorders.
Claims 1-17 and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 and 25-28 of copending Application No. 17/785,287 in view of Day et al. (WO 2008/101017 A2).
This is a provisional nonstatutory double patenting rejection.
Copending claim 1 recites a peptide comprising the amino acid sequence of native human glucagon HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO: 1) wherein
1) L-Serine at X2 is replaced with alpha-aminoisobutyric acid, or D-Serine;
2) Tyrosine at X10 is replaced with is Lysine, Lysine conjugated to a fatty acid, or Lysine conjugated to a fatty diacid (dependent claim 6 requires K(gEgEC16));
3) L-Serine at X16 is replaced with alpha-aminoisobutyric acid, Alanine, Glutamic acid, pra or Acb;
4) Arginine at X18 is replaced with Alanine;
5) X30 is absent or Lysine linked at the C-terminus to gamma-Glutamic acid; and
up to six additional amino acid substitutions selected from:
1) Arginine at X17 is optionally replaced with pra;
2) Glutamine at X20 is optionally replaced with Nle(FN3), or pra;
3) Aspartic acid at X21 is optionally replaced with Nle(FN3);
4) Glutamine at X24 is optionally replaced with Nle(FN3), pra or Acb;
5) Methionine at X27 is optionally replaced with Leucine, Norleucine, or L-Methionine sulphone;
6) Asparagine at X28 is optionally replaced with Aspartic acid, Nle(FN3), or pra;
provided the peptide contains at least one Nle(FN3)and one pra, or one Peg3N3Ala and one pra; wherein Nle(FN3)and pra cyclize to form a triazole containing ring, or Peg3N3Ala and pra cyclize to form a triazole containing ring; and wherein Acb is 1-aminocyclobutane-1-carboxylic acid, Nle(FN3) is 6-Azido-L-norleucine, Peg3N3Ala is O-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-L-serine, and pra is (R)-2-aminopent-4- ynoic acid; or a pharmaceutically acceptable salt thereof.
The difference between the peptides of claim 1 and the copending peptide is the presence of a lactam bridge instead of a triazole bridge. Copending Application No. 17,85,287 does not claim that the peptide contains at least one lysine and one glutamic acid wherein one lysine and one glutamic acid cyclize to form a lactam containing ring.
Day et al. teach high potency glucagon agonist peptides that also exhibit increased activity at the GLP-1 receptor (p. 3, line 31 – p. 4, line 31). Day et al. teach that enhanced activity at the GLP-1 receptor is provided by stabilizing the alpha-helix structure in the C-terminal portion of glucagon (around amino acids 12-29) through formation of an intramolecular bridge between the side chains of two amino acids that are separated by three intervening amino acids. The bridge or linker is about 8 (or about 7-9) atoms in length and forms between side chains of amino acids at positions 12 and 16, positions 16 and 20, positions 20 and 24, or positions 24 and 28. The bridge or linker may be a lactam ring formed between the side chain of a lysine at positions 12, 20, or 28 and a glutamic acid at positions 16 or 24, wherein the lysine and glutamic acid are separated by three intervening residues (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10; SEQ ID NOs: 72-75, 77-80, 82-83, 85-86, 89-92, 94-97, 99-100, 102-103, 106-109, 111-114, 116-117, 119-120, 123-126, 128-131, 133-134, 136-137, 140-143, 145-148, 150-151, 153-154, 157-160, 162-165, 167-168, 170-171, 174-177, 179-182, 184-185, 187-188, 191-194, 196-199, 201-202, 204-205, 208-211, 213-216, 218-219, 221-222, 225-228, 230-233, 235-236, 238-239, 242-245, 247-250, 252-253, 255-256, 259-262, 264-267, 269-270, 272-273, 276-279, 281-284, 286-287, 289-290, 293-296, 298-301, 303-304, 306-307, 310-313, 315-318, 320-321, 323-324, 327-330, 332-335, 337-338, 340-341, 376-379, 381-384, 386-387, 390-393, 395-398, 400-401, 404-407, 409-412, 414-415, 418-421, 423-426, 428-429, 432-435, 437-440, 442-443, 446-449, 451-454, 456-457, 460-463, 465-468, 470-471, 474-477, 479-482, 484-485, 489, 491, 495, 497, 501, 503, 505-514, 517, 528).
It would have been obvious before the effective filing date of the claimed invention to substitute the lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28 in the glucagon/GLP-1 co-agonists taught by Day et al. for the triazole bridge in the peptide claimed in copending Application No. 17/785,287. The resulting peptides would be a peptide comprising the amino acid sequence of native human glucagon with the following changes:
1) L-Serine at X2 is replaced with alpha-aminoisobutyric acid, or D-Serine;
2) Tyrosine at X10 is replaced with is Lysine, Lysine conjugated to a fatty acid, or Lysine conjugated to a fatty diacid (dependent claim 6 requires K(gEgEC16));
3) L-Serine at X16 is replaced with alpha-aminoisobutyric acid, Alanine, Glutamic acid, Lysine or Acb;
4) Arginine at X18 is replaced with Alanine;
5) X30 is absent or Lysine linked at the C-terminus to gamma-Glutamic acid; and
additional amino acid substitutions selected from:
1) Glutamine at X20 is optionally replaced with Glutamic Acid or Lysine;
2) Glutamine at X24 is optionally replaced with Glutamic Acid, Lysine or Acb;
3) Methionine at X27 is optionally replaced with Leucine, Norleucine, or L-Methionine sulphone;
4) Asparagine at X28 is optionally replaced with Aspartic acid, Glutamic Acid or Lysine;
and a lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28; satisfying all of the limitations of claim 1-11. One of ordinary skill in the art would have been motivated to do so given that Day et al. teach the benefit of stabilizing the alpha-helix structure in the C-terminal portion of glucagon through the formation of lactam bridges at these positions (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10). In addition, Day et al. teach that it is advantageous to combine a modification at position 2, such as the replacement of Ser with D-Ser which is claimed in copending Application No. 17/785,287, with a lactam bridge between glutamic acid at position 16 and lysine at position 20 (or between 12 and 16 or between 20 and 24). Day et al. teach that the modification at position 2 can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). There would have been a reasonable expectation of success given that Day et al. teach the synthetic methods for forming the lactam bridge in the glucagon/GLP-1 co-agonist peptides (Example 11) and the incorporation of the lactam bridge into numerous sequences.
Regarding claim 12, copending claim 16 recites a pharmaceutical composition comprising the peptides and a pharmaceutically-acceptable carrier.
Regarding claims 13 and 16, copending claim 17 recites a method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the peptides.
Regarding claims 14 and 17, copending claim 18 requires that the metabolic disease or disorder may be diabetes, NAFLD, NASH or obesity.
Regarding claim 15, copending claim 19 requires that the diabetes is chosen from type I diabetes, type II diabetes, and gestational diabetes.
Regarding claims 21-24, copending claim 26 requires that the peptide is combined with insulin such as insulin detemir, glargine, levemir, glulisine, degludec, or lispro to treat the metabolic disorders.
Claims 1-21 and 25-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 and 28-31 of copending Application No. 17/785,772 in view of Day et al. (WO 2008/101017 A2).
This is a provisional nonstatutory double patenting rejection.
Copending claim 3 recites a peptide comprising an analogue of the amino acid sequence of native human glucagon
HX2QGTFTSDX10SX12YLDX16X17AX19X20X21FVX24WLX27X28TX30 (SEQ ID NO: 20) wherein
X2 is a-aminoisobutyric acid, or D-serine;
X10 is lysine, lysine conjugated to a fatty acid, or lysine conjugated to a fatty diacid (dependent claim 13 requires K(gEgEC16));
X12 is (R)-2-amino-2-methyloct-7-enoic acid, or lysine;
X16 is a-aminoisobutyric acid or glutamic acid;
X17 is (R)-2-amino-2-methyloct-7-enoic acid, or arginine;
X19 is (S)-2-amino-2-methylnon-8-enoic acid, or alanine;
X20 is glutamine, (R)-2-amino-2-methyloct-7-enoic acid, (S)-2-amino-2-methylnon-8-enoic acid, or (S)-2-aminohept-6-enoic acid;
X21 is aspartic acid or (R)-2-amino-2-methyloct-7-enoic acid;
X24 is glutamine, (R)-2-amino-2-methyloct-7-enoic acid, (S)-2-amino-2-methylnon-8-enoic acid, or (S)-2-aminohept-6-enoic acid;
X27 is leucine, (S)-2-amino-2-methylnon-8-enoic acid, or methionine;
X28 is aspartic acid, (R)-2-amino-2-methyloct-7-enoic acid, (S)-2-amino-2-methylnon-8-enoic acid, or (S)-2-aminohept-6-enoic acid; and
X30 is absent or lysine conjugated by a g-glutamic acid spacer;
provided the peptide contains at least two residues selected from (R)-2-amino-2-methyloct-7-enoic acid, (S)-2-amino-2-methylnon-8-enoic acid, or (S)-2-aminohept-6-enoic acid, which cyclize to form a double bond-containing ring.
The difference between the peptides of claim 1 and the copending peptide is the presence of a double-bond bridge instead of a lactam bridge. Copending Application No. 17/785,772 does not claim that the peptide contains at least one Glu and Lys wherein Glu and Lys cyclize to form a lactam-containing ring.
Day et al. teach high potency glucagon agonist peptides that also exhibit increased activity at the GLP-1 receptor (p. 3, line 31 – p. 4, line 31). Day et al. teach that enhanced activity at the GLP-1 receptor is provided by stabilizing the alpha-helix structure in the C-terminal portion of glucagon (around amino acids 12-29) through formation of an intramolecular bridge between the side chains of two amino acids that are separated by three intervening amino acids. The bridge or linker is about 8 (or about 7-9) atoms in length and forms between side chains of amino acids at positions 12 and 16, positions 16 and 20, positions 20 and 24, or positions 24 and 28. The bridge or linker may be a lactam ring formed between the side chain of a lysine at positions 12, 20, or 28 and a glutamic acid at positions 16 or 24, wherein the lysine and glutamic acid are separated by three intervening residues (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10; SEQ ID NOs: 72-75, 77-80, 82-83, 85-86, 89-92, 94-97, 99-100, 102-103, 106-109, 111-114, 116-117, 119-120, 123-126, 128-131, 133-134, 136-137, 140-143, 145-148, 150-151, 153-154, 157-160, 162-165, 167-168, 170-171, 174-177, 179-182, 184-185, 187-188, 191-194, 196-199, 201-202, 204-205, 208-211, 213-216, 218-219, 221-222, 225-228, 230-233, 235-236, 238-239, 242-245, 247-250, 252-253, 255-256, 259-262, 264-267, 269-270, 272-273, 276-279, 281-284, 286-287, 289-290, 293-296, 298-301, 303-304, 306-307, 310-313, 315-318, 320-321, 323-324, 327-330, 332-335, 337-338, 340-341, 376-379, 381-384, 386-387, 390-393, 395-398, 400-401, 404-407, 409-412, 414-415, 418-421, 423-426, 428-429, 432-435, 437-440, 442-443, 446-449, 451-454, 456-457, 460-463, 465-468, 470-471, 474-477, 479-482, 484-485, 489, 491, 495, 497, 501, 503, 505-514, 517, 528).
It would have been obvious before the effective filing date of the claimed invention to substitute the lactam bridge between lysine and glutamic acid side chains at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28 in the glucagon/GLP-1 co-agonists taught by Day et al. for the double bond-containing bridge in the peptide claimed in copending Application No. 17/785,772. The resulting peptides would be a peptide comprising
HX2QGTFTSDX10SX12YLDX16X17AX19X20X21FVX24WLX27X28TX30 (SEQ ID NO: 20) wherein
X2 is a-aminoisobutyric acid, or D-serine;
X10 is lysine, lysine conjugated to a fatty acid, or lysine conjugated to a fatty diacid, preferably K(gEgEC16);
X12 is glutamic acid, or lysine;
X16 is a-aminoisobutyric acid or glutamic acid;
X17 is glutamic acid, lysine, or arginine;
X19 is glutamic acid, lysine, or alanine;
X20 is glutamine, glutamic acid, or lysine;
X21 is aspartic acid, glutamic acid, or lysine;
X24 is glutamine, glutamic acid, or lysine;
X27 is leucine, glutamic acid, lysine, or methionine;
X28 is aspartic acid, glutamic acid, or lysine; and
X30 is absent or lysine conjugated by a g-glutamic acid spacer;
provided the peptide contains at least one glutamic acid and at least one lysine, which cyclize to form a lactam-containing ring, satisfying all of the limitations of claims 1-11. One of ordinary skill in the art would have been motivated to do so given that Day et al. teach the benefit of stabilizing the alpha-helix structure in the C-terminal portion of glucagon through the formation of lactam bridges at these positions (p. 6, lines 8-22; p. 22, lines 21-24; p. 28, line 4 – p. 29; p. 37, lines 15-29; Example 11; Tables 9-10). In addition, Day et al. teach that it is advantageous to combine a modification at position 2, such as the replacement of Ser with D-Ser which is claimed in copending Application No. 17/785,772, with a lactam bridge between glutamic acid at position 16 and lysine at position 20 (or between 12 and 16 or between 20 and 24). Day et al. teach that the modification at position 2 can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). There would have been a reasonable expectation of success given that Day et al. teach the synthetic methods for forming the lactam bridge in the glucagon/GLP-1 co-agonist peptides (Example 11) and the incorporation of the lactam bridge into numerous sequences.
Regarding claim 12, copending claim 19 recites a pharmaceutical composition comprising the peptides and a pharmaceutically-acceptable carrier.
Regarding claims 13 and 16, copending claim 20 recites a method for treating a patient for a metabolic disease or disorder comprising administering the patient an effective amount of the peptides.
Regarding claims 14 and 17, copending claim 21 requires that the metabolic disease or disorder may be diabetes, NAFLD, NASH or obesity.
Regarding claim 15, copending claim 22 requires that the diabetes is chosen from type I diabetes, type II diabetes, and gestational diabetes.
Regarding claims 21-24, copending claim 29 requires that the peptide is combined with insulin such as insulin detemir, glargine, levemir, glulisine, degludec, or lispro to treat the metabolic disorders.
Response to Arguments
Applicant's arguments filed December 29, 2025, have been fully considered but they are not persuasive. Applicant traverses the rejection on the grounds that there was no expectation of success from Day that the claimed peptides would be effective glucagon and GLP-1 receptor agonists.
These arguments are not persuasive because there is a specific teaching in Day et al. that would establish an expectation of success for using lactam bridges to stabilize the peptides of the reference patent/applications. That is Day et al. teach that the replacement of Ser with D-Ser or Aib at position 2, which is taught by each of the primary reference patent/applications, can reduce glucagon activity and that this activity can be restored by stabilizing the helix via the lactam bridge (p. 7, line 32 - p. 8, line 4). Although the primary reference patent/applications do not explicitly teach a deficiency in the peptides, one of ordinary skill in the art would understand based on Day that peptides with D-Ser or Aib at position can benefit from stabilization of the helix by introduction of a lactam bridge. A person of ordinary skill in the art can readily identify this structural feature in the primary references and make the modification of Day accordingly with an expectation of success.
There is no evidence on record that the claimed peptides have properties that are unexpected in view of the prior art. On the contrary, the activity of the claimed peptides reported in the original specification is consistent with the primary reference patent/applications and with Day.
For these reasons, the rejections are maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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