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Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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, see Pg 10-12, filed 8/22/2025, with respect to the rejection(s) of claim(s) 4-8, 22, 24, 26, 27, 29, 32-37, and 46 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amended claims.
Claim Status
Claims 4-8, 22, 24, 26-27, 29, 34-37, 46, and 51-57 are pending under examination. Claims 1-3, 9-21, 23, 25, 28, 30-33, 38-45 and 47-50 were previously cancelled. Claims 4-8, 22, 24, 26, 27, 29, 34-37, and 46 are currently amended. Claims 51-57 are new.
Priority
This application is the 371 of PCT/EP2019/072533, filed on 8/22/2019, which claims priority to GB1813678.8, filed on 8/22/2018.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The Examiner would recommend removal of the phrase “available for download from http://orbit.dtu.dk/files/127682557/PhD_thesis_Sofie_Trier.pdf” in lines 26-27.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 22, 24, 26, and 27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 22 depends from claim 51, which sequentially comes after it. Therefore, it is rejected as improperly depending on a subsequent claim. By virtue of their dependency on claim 22, claims 24, 26, and 27 are also rejected for this same reasoning.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 4-8, 29, 34, 36, 37, and 54-57 are rejected under 35 U.S.C. 103 as being unpatentable over Karsdal et al. (WO 2010/103045 A1, published 9/16/2010), Suva et al. (Suva LJ, Flannery MS, Caulfield MP, Findlay DM, Jüppner H, Goldring SR, Rosenblatt M, Chorev M. Design, synthesis and utility of novel benzophenone-containing calcitonin analogs for photoaffinity labeling the calcitonin receptor. J Pharmacol Exp Ther. 1997 Nov;283(2):876-84.), Ekwuribe et al. (US 6713452, published 3/30/04), and Karle (Karle IL. Controls exerted by the Aib residue: helix formation and helix reversal. Biopolymers. 2001;60(5):351-65.).
Karsdal teaches enterally administered calcitonin family members that are effective at treating Type I or Type II diabetes or metabolic syndrome in addition to mitigating insulin resistance and reducing serum glucose levels (Abstract). Karsdal teaches SEQ ID NO 11: CX1X2LXTCX3LX4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21GX22X23X24P,
wherein
X1 is A, G, or S; preferably S;
X2 is N or S; preferably N;
X3 is M or V; preferably V;
X4 is G or S; preferably G;
X5 is T, K, or A; preferably T or K; most preferably K;
X6 is L or Y; preferably L;
X7 is T, S, or W; preferably T or S; most preferably S;
X8 is Q, K, or R; preferably Q;
X9 is D, E, or N; preferably D or E; most preferably E;
X10 is F or L; preferably L;
X11 is N or H; preferably H;
X12 is K or N; preferably K;
X13 is F or L; preferably L;
X14 is H or Q; preferably Q;
X15 is T or R; preferably T;
X16 is F or Y; preferably Y;
X17 is p or S; preferably P;
X18 is Q, G or R; preferably Q or R; most preferably R;
X19 is T, I or M; preferably T;
X20 is A, N, D, S, or G; preferably N;
X21 is I, T, V or F; preferably T,
X22 is V, S, A, or P; preferably V, S, or A; most preferably S;
X23 is G or E; preferably G;
X24 is A or T; preferably T (Pg 12-13).
This reads on the instant SEQ ID NO: 13 wherein,
X1 (position 2, or X2 of the instant SEQ ID NO: 13) is A, G, or S;
X2 (X3) is N; X4 is G; X5 (X11) is T, or A; X6 (X12) is L or Y; X7 (X13) is T, S, or W; X8 (X14) is K, or R; X9 (X15) is D, E, or N; X10 (X16) is F or L; X11 (X17) is N or H; X12 (X18) is K or N; preferably K; X14 (X20) is H; X15 (X21) is T or R; X16 (X22) is F or Y; X17 (X23) is P or S; X18 (X24) is Q, G or R; X19 (X25) is T, I or M; X20 (X26) is A, N, S, or G; X21 (X27) is I, V or F; X22 (X29) is V, A, or P; X23 (X30) is E; and X24 (X31) is A.
Karsdal also teaches that calcitonin family members share a significant degree of sequence homology and structural similarities, including a region of predicted amphipathic alpha-helical structure from residues 8-18 or 8-22 (Pg 14, lines 19-25).
Karsdal does not teach that X3 (position 8 or X8 of the instant SEQ ID NO: 13) is Aib nor that X13 (X19 of instant SEQ ID NO: 13) is K comprising an acyl group, wherein the acyl group comprises a C16 or longer fatty acid or fatty diacid.
Karle teaches that the helix forming properties of Aib have been demonstrated in numerous crystal structure analyses of designed and naturally occurring peptides containing one or more Aib residues (Abstract); with rare exceptions, the presence of an Aib residue causes the backbone of a protein or peptide to fold into a 310, mixed 310-α, or α-helix. The helix-forming propensity of Aib has been shown to be strong enough to overcome disruptive residues in a sequence, such as Pro and Hyp residues, Gly-Gly segments, d-Ala-Gly segments, and even a β-residue-γ-residue segment (Pg 351 – 352, “Helix-Forming Propensity by Dialkyl Glycines”; Pg 360, “Conclusions”).
Suva teaches substitution of Leu at position 19 of salmon calcitonin for Lys(epsilon-p-benzoylbenzoyl) does not reduce its ability to engage receptors (Abstract; Pg 881, left column, first paragraph).
Ekwuribe teaches a mixture of conjugates in which each conjugate in the mixture comprises a calcitonin drug coupled to an oligomer that includes a polyalkylene glycol moiety. The mixture may be more effective at surviving an in vitro model of intestinal digestion than non-conjugated calcitonin. Furthermore, the mixture may exhibit a higher bioavailability than non-conjugated calcitonin (Abstract). The oligomer may comprise one or more other moieties including, but not limited to, additional hydrophilic moieties, lipophilic moieties, spacer moieties, linker moieties, and terminating moieties. (Col. 8, lines 45-51). The lipophilic moiety is preferably a saturated or unsaturated, linear or branched alkyl moiety or a saturated or unsaturated, linear or branched fatty acid moiety. When the lipophilic moiety is a fatty acid moiety, it is preferably a natural fatty acid moiety that is linear, saturated or unsaturated, having 2 to 18 carbon atoms (Col. 9, lines 16-29). Examples 41-44 further describe the process whereby oligomers are conjugated to salmon calcitonin, including stearate-PEG6-sCT (wherein PEG6 is a linker and stearate corresponds to C18 fatty acid) and stearate-PEG8-sCT (wherein PEG8 is a linker and stearate corresponds to C18 fatty acid; Col. 62 line 29 -59). The oligomer and additional moiety may be conjugated to lysine residues within the peptide sequence (Col. 11, lines 6-14).
Thus, regarding claims 4, 6, 7, 8, and 29, Karsdal teaches calcitonin variants and structural features thereof, including the presence of an alpha helix at positions 8-18 or 8-22. Karle teaches that Aib can initiate helix formation. Therefore, it would be prima facie obvious to incorporate Aib into position 8 of the calcitonin variant taught by Karsdal in order to further stabilize the helical structure of the calcitonin variant. One skilled in the art would have a reasonable expectation of success as it was already established that Aib could help initiate and stabilize helical protein structures.
Further, Suva teaches that modification of calcitonin at position 19 to include a Lys residue maintains its functionality. Ekwuribe further teaches calcitonin mimetics improved by the addition of polyalkylene glycol moiety conjugated to lipid moieties including C18 fatty acids, which can be conjugated to lysine residues in the peptide sequence. Therefore, it would be prima facie obvious to incorporate a Lys residue at position 19 and conjugate it to a polyalkylene glycol moiety with a lipid moiety in order to improve its longevity and bioavailability. One skilled in the art would have a reasonable expectation of success as this strategy had already been shown to improve the longevity and bioavailability of other calcitonin mimetics.
Regarding claims 5 and 54, Karsdal, Suva, Ekwuribe, and Karle do not teach introduction of Ala to positions 14 or 20, respectively. However, as stated above, one skilled in the art would recognize that calcitonin comprises an alpha helix from residues 8-18 or 8-22 depending on the species, which imparts its functionality. As these positions are typically occupied by Q, K, or R (position 14) and H or Q (position 20) per Karsdal, it would be obvious to one skilled in the art to substitute the residues at these positions for Ala residues in order to further stabilize the alpha helix structure and, by extension, the peptide.
Regarding claim 34, Ekwuribe teaches pharmaceutical compositions suitable for oral administration (Col. 45, lines 24-30), parenteral administration (Col. 45, lines 58-62), and injection (Col. 46 lines 1-6).
Regarding claims 36 and 37, Karsdal teaches suitable pharmaceutical carriers such as 5-CNAC, SNAD, and SNAC (Pg 24, lines 17-24).
Regarding 55, Karsdal teaches mimietics that include N-terminal acetylation (Pg 42, lines 1-9).
Regarding claims 56 and 57, Karsdal teaches that calcitonin family members share a significant degree of sequence homology and structural similarities, including a disulfide bridged loop of 6 or 7 amino acids at the N-terminus and a C-terminally amidated aromatic residue at the C-terminus (Pg 14, lines 19-25).
Claim(s) 4-8, 22, 24, 26, 27, 29, 34, 36, 37, 46, 51, 52, and 54-57 are rejected under 35 U.S.C. 103 as being unpatentable over Karsdal et al. (WO 2010/103045 A1, published 9/16/2010), Suva et al. (Suva LJ, Flannery MS, Caulfield MP, Findlay DM, Jüppner H, Goldring SR, Rosenblatt M, Chorev M. Design, synthesis and utility of novel benzophenone-containing calcitonin analogs for photoaffinity labeling the calcitonin receptor. J Pharmacol Exp Ther. 1997 Nov;283(2):876-84.), Ekwuribe et al. (US 6713452, published 3/30/04), and Karle (Karle IL. Controls exerted by the Aib residue: helix formation and helix reversal. Biopolymers. 2001;60(5):351-65.), as applied to claims 4-8, 29, 34, 36, 37, and 54-57 above, and further in view of Madsen et al. (US2013/0288960 A1, filed 11/9/11, published 10/31/13).
The teachings of Karsdal, Suva, Ekwuribe, and Karle have been set forth above. Karsdal, Suva, Ekwuribe, and Karle do not teach a linker comprising an E and/or an OEG amino acid linker.
Madsen teaches derivatives of GLP-1 to treat diabetes, which comprise a first and second K residue comprising protracting moieties, preferably selected from fatty diacids or fatty acids, attached to said K residues to improve receptor binding and half-life, conjugated via a linker, wherein the linker comprises Chem. 4:
PNG
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96
356
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Greyscale
, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5 (Abstract; [0079], [0120-0129]). When k=1 and n=1, the linker element may be designated OEG ([0080]).
Madsen teaches that, in certain embodiments, a GLP-1 derivative may have a linker that consists of two times Chem. 4, interconnected via an amide bond, the linker being connected at it’s *-NH end to the *-CO end of the protracting moiety (fatty acid or diacid) and at it’s *-CO end to the ε amino group of the first or the second K residue of the GLP-1 analogue (Pg 6, first column, “c”).
Thus, regarding claims 22, 26, 27, 51 and 52, Karsdal, Suva, Ekwuribe, and Karle teach a calcitonin variant with a C18 fatty acid conjugated to Lys at position 19 that can treat diabetes. Madsen teaches conjugating fatty acids and diacids to GLP-1 derivatives via the linker Chem 4 that can be used to treat diabetes. Therefore, it would be prima facie obvious to use the linker Chem 4 taught by Madsen to attach the C18 fatty acid taught by Karsdal, Suva, Ekwuribe, and Karle. One skilled in the art would have a reasonable expectation of success as it was already established that the addition of Chem 4 and fatty acid molecules to GLP-1 derivatives improved their receptor binding and half-life.
Regarding claim 24, Madsen teaches that a second linker element may follow the linker element Chem. 4:
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118
330
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Greyscale
that may be included p times, where p is an integer in the range of 1-3. This second linker element may also be referred to as gamma-Glu (gGlu) due to the fact that it is the gamma carboxy group of the amino acid glutamic acid which is here used for connection to another linker element, or to the epsilon-amino group of lysine ([0082]).
Regarding claim 46, Madsen teaches the addition of one or more pharmacologically active substances such as antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. Examples of which include lipase/amylase inhibitors and Gastric Inhibitory Polypeptide agonists or antagonists (GIP analogs), among others ([0180]).
Claim(s) 4-8, 29, 34-37, and 53-57 are rejected under 35 U.S.C. 103 as being unpatentable over Karsdal et al. (WO 2010/103045 A1, published 9/16/2010), Suva et al. (Suva LJ, Flannery MS, Caulfield MP, Findlay DM, Jüppner H, Goldring SR, Rosenblatt M, Chorev M. Design, synthesis and utility of novel benzophenone-containing calcitonin analogs for photoaffinity labeling the calcitonin receptor. J Pharmacol Exp Ther. 1997 Nov;283(2):876-84.), Ekwuribe et al. (US 6713452, published 3/30/04), and Karle (Karle IL. Controls exerted by the Aib residue: helix formation and helix reversal. Biopolymers. 2001;60(5):351-65.), as applied to claims 4-8, 22, 24, 26, 27, 29, 3437, 46, 51, 52, and 54-57 above, and further in view of Mehta et al. (WO 2013/067357 A1, published 5/10/2013).
The teachings of Karsdal, Suva, Ekwuribe, and Karle have been set forth above. Karsdal, Suva, Ekwuribe, and Karle do not teach coating the peptide with citric acid particles.
Mehta teaches calcitonin mimetic peptides formulated for oral administration comprising coated citric acid particles wherein the citric acid particles increases the oral bioavailability of the peptide (Claim 6, Pg 48).
Thus, regarding claim 35, it would be prima facie obvious to coat the peptide taught by Karsdal, Suva, Ekwuribe, and Karle in citric acid particles taught by Mehta in order to improve its bioavailability. One skilled in the art would have a reasonable expectation of success as other calcitonin mimetics had been previously prepared in such a manner, also increase their oral bioavailability.
Regarding claim 53, Mehta teaches calcitonin mimetics wherein position 30 is N (Table 1, Pg 7: mimetics UGP281, 283, 302, 303, 306).
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 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