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 .
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant's arguments filed 12/22/2025 with respect to the claim rejections under 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant’s position is that 1) there is insufficient motivation for one of ordinary skill in the art to select a peptide from Dimarchi in view of Verdine and make the modifications leading to the instantly claimed peptides and 2) Dimarchi in view of Verdine do not disclose the functional features set forth in the instant application.
Regarding 1), MPEP 2143 states “The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) 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. In Ball Aerosol v. Ltd. Brands, 555 F.3d 984, 89 USPQ2d 1870 (Fed. Cir. 2009), the Federal Circuit offered additional instruction as to the need for an explicit analysis. The Federal Circuit explained that the Supreme Court’s requirement for an explicit analysis does not require record evidence of an explicit teaching of a motivation to combine in the prior art.”
In this case, although there is no explicit motivation to combine Dimarchi in view of Verdine, it is still obvious to do so. Dimarchi teaches glucagon peptide variants that can be further stabilized through the formation of an intramolecular ring between the amino acids at positions 20 and 24. Dimarchi further teaches that olefin metathesis can be used to crosslink one or two turns of the alpha helix of the analog using an all-hydrocarbon cross-linking system. In this case, the glucagon peptide variant comprises α-methylated amino acids bearing olefinic side chains of varying length and configured with either R or S stereochemistry at the i and i+4 positions. The peptides taught by Dimarchi only differ from the peptides of the instant claims 1 and 2 in that (S)-2-amino-2-methylhept-6-enoic acid is not explicitly used in the formation of an intramolecular ring. However, Verdine indicates that (S)-2-amino-2-methylhept-6-enoic acid can also be used in olefin metathesis to intramolecularly staple or cross-link helical peptides to improve their stability. Therefore, one of ordinary skill in the art could have substituted the amino acids at positions 20 and 24 taught by Dimarchi for (S)-2-amino-2-methylhept-6-enoic acid taught by Verdine, leading to predictable results – namely, increased stabilization of the alpha-helical structure of the peptide.
Regarding 2), Dimarchi teaches peptides virtual identical to the instantly claimed peptides, including elected SEQ ID NO: 12, with the exception that the amino acid species that form the intramolecular ring via olefin metathesis are not explicitly taught; Verdine remedies this by teaching said amino acid species are used in olefins metathesis reactions to form intramolecular rings. One skilled in the art would recognize that amino acid structure is the basis for peptide function; therefore, by disclosing the structure of the instant peptides/SEQ ID NO: 12, based upon the teachings of Dimarchi and Verdine, one skilled in the art would reasonably expect it to have the functional properties described in the instant application. Thus, Dimarchi in view of Verdine render the instant claims obvious.
Election/Restrictions
Applicant’s election of Group, I claims 1-19, drawn to a peptide comprising the amino acid sequence of native human glucagon, in addition to the species SEQ ID NO:12, in the reply filed on 7/15/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
Claims 1-24 and 28-31 are pending under examination. Claims 25-27 were previously cancelled. Claims 20-24 and 28-31 are withdrawn as non-elected inventions. Claims 1 and 5 are currently amended.
Priority
The application is the 371 national stage entry of PCT/US2020/065792, filed 12/18/2020, which claims priority to EP19425097.3, filed 12/23/2019. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Europe on 12/23/2019. It is noted, however, that applicant has not filed a certified copy of the EP19425097.3 application as required by 37 CFR 1.55.
Maintained/Modified - 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 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Dimarchi et al. (US 2014/0221283 A1, published 8/7/2014) in view of Verdine et al. (US 2011/0144306 A1, published 6/16/2011).
Dimarchi teaches peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor as compared to native glucagon (Abstract; [0007], [0046]). The peptides and variant peptides exhibit improvements in properties relative to native glucagon or native GLP-1, such as greater stability, greater solubility, a prolonged half-life in circulation, a delayed onset of action, an extended duration of action, a dampened peak (e.g., relatively decreased mean peak plasma concentration), and an improved resistance to proteases such as DPP-IV ([0047]).
Dimarchi teaches many modifications to improve human glucagon, such as substitution of the naturally-occurring Ser at position 2 for D-Ser ([0152]); substitution of the Tyr at position 10 for lysine ([0073-0074]); acylation of the peptide at position 10, which can transform a glucagon analog having little activity at the glucagon receptor to a glucagon analog having activity at both the glucagon and GLP-1 receptors ([0070]); and substitution of the naturally-occurring Ser at position 16 for Glu, which enhances potency ([0160-0161]). In other words, Dimarchi teaches glucagon variant peptides wherein X2 is D-Ser, X10 is Lys conjugated to a fatty acid, X16 is Glu, and X30 is absent.
Dimarchi also teaches that the alpha-helical structure of the peptide or variant peptide can be further stabilized through the inclusion of specific amino acids, such as alpha, alpha di-substituted amino acids that can form intramolecular rings, wherein they can have the same or different R groups/sidechains ([0131]-[0151]). Specifically, Dimarchi discloses embodiments wherein an intramolecular bridge is formed between two amino acids that are 3 amino acids apart, e.g., amino acids at positions i and i+4, wherein i is any integer between 12 and 24 (positionally within the sequence of the peptide), and, more particularly, can be formed between the amino acids and positions 20 and 24 ([0137]). Additionally, Dimarchi teaches that olefin metathesis is one approach that can be used to crosslink one or two turns of the alpha helix using an all-hydrocarbon cross-linking system. The glucagon analog in this instance comprises α-methylated amino acids bearing olefinic side chains of varying length and configured with either R or S stereochemistry at the i and i+4 positions. In some embodiments, the olefinic side comprise (CH2)n, wherein n is any integer between 1-6 ([0146]). The presence of a covalently formed ring between positions 20 and 24 may also contribute to protease resistance of the peptide variant ([0153]).
Dimarchi does not explicitly teach incorporating and cyclizing (S)-2-amino-2-methylhept-6-enoic acid at positions 20 and 24 of the glucagon peptide variant to form an intramolecular ring.
Verdine teaches methods for making large, semi-synthetic, stapled or stitched peptides through ligation of a stapled or stitched peptide to a larger protein (Abstract). The introduction of a staple to a peptide may alter its biological activity or may simply increase its stability ([0006]). Such technology can aid in the development of therapeutic proteins for the treatment of a variety of conditions, including diabetes ([0247]). Crosslinks or staples can be incorporated across one (i, i+3 or i, i+4) and/or two turns (i, i+7) of an α-helix. Preferably, alpha-methyl, alpha-alkenyl amino acids and alpha-alpha-dialkenyl amino acids are utilized to generate the
crosslinking moieties using an olefin metathesis reaction ([0202]). In one embodiment taught by Verdine, a staple is incorporated across one turn of a helix using (S)-2-amino-2-methylhept-6-enoic acid in both the i and i+4 positions ([0203]).
Thus, regarding claims 1 and 2, it would have been prima facie obvious to substitute a known element for another to obtain predictable results. Dimarchi teaches glucagon peptide variants that can be further stabilized through the formation of an intramolecular ring between the amino acids at positions 20 and 24. Dimarchi further teaches that olefin metathesis can be used to crosslink one or two turns of the alpha helix of the analog using an all-hydrocarbon cross-linking system. In this instance, the glucagon peptide variant comprises α-methylated amino acids bearing olefinic side chains of varying length and configured with either R or S stereochemistry at the i and i+4 positions. The peptides taught by Dimarchi only differ from the peptides of the instant claims 1 and 2 in that (S)-2-amino-2-methylhept-6-enoic acid is not explicitly used in the formation of an intramolecular ring. However, Verdine indicates that (S)-2-amino-2-methylhept-6-enoic acid can also be used in olefin metathesis to intramolecularly staple or cross-link helical peptides to improve their stability. Therefore, one of ordinary skill in the art could have substituted the amino acids at positions 20 and 24 taught by Dimarchi for (S)-2-amino-2-methylhept-6-enoic acid taught by Verdine, leading to predictable results – namely, increased stabilization of the alpha-helical structure of the peptide.
Regarding claims 3, 4, 6, 9, and 10, Dimarchi teaches further variants wherein X12 is Lys, X17 is Arg, X19 is Ala, X21 is Asp (see wild-type glucagon sequence, SEQ ID NO: 1, Pg 35), X27 is Leu ([0180]), X28 is Asp ([0168]). Dimarchi also teaches that the C-terminus of the glucagon variant peptides can be amidated ([0229]; Sequencing listing).
Regarding claims 5, 11, and 16, Dimarchi teaches that the acyl group of the acylated amino acid can be any size, e.g., any length carbon chain, linear or branched, from C4 to C30, including C16 ([0094]).
Regarding claims 7, 12, and 17, Dimarchi teaches that the acyl group can be covalently linked directly to an amino acid of the glucagon analog or indirectly to an amino acid of the glucagon analog via a spacer, wherein the spacer is positioned between the amino acid of the glucagon and the acyl group ([0073]). In some embodiments, the spacer is γ-Glu-γ-Glu ([0090]).
Regarding claims 8, 13, 14, and 15, Dimarchi teaches that the Lys at position 10 can be conjugated to a C16 fatty acid via a γ-Glu-γ-Glu spacer ([0090], [0094]).
Regarding claim 18, Dimarchi and Verdine teach SEQ ID NO: 12, wherein X2 is D-Ser (Dimarchi [0152]), X10 is Lys conjugated to γ-Glu-γ-Glu C16 fatty acid (Dimarchi [0070; 0073-0074]), X16 is Glu (Dimarchi [0160-0161]), X18 is Ala (Dimarchi, see wild-type glucagon sequence, SEQ ID NO: 1, Pg 35), X20 and X24 are both (S)-2-amino-2-methylhept-6-enoic acid (Dimarchi [0131-0151]; Verdine [0202-0203]), X27 is Leu (Dimarchi [0180]), X28 is Asp (Dimarchi [0168]), and the C-terminus is amidated (Dimarchi [0229]; Sequencing listing).
Regarding claim 19, Dimarchi further teaches pharmaceutical compositions comprising any of the peptides and variant peptides described and a pharmaceutically acceptable carrier ([0008], [0245], [0249]).
Conclusion
No claim is 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 Sara E Konopelski Snavely whose telephone number is (571)272-1841. The examiner can normally be reached Monday - Friday 9-6pm EST.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658