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 . 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 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.
Election/Restrictions
Applicants elected group I (peptides) and the peptide trifluoroethyl ligiratide without traverse in the reply filed on 21 Feb, 2019 and the phone call with Leslie Serunian, applicant’s representative, on 11 March, 2019. In the response of 2 March, 2023, applicants amended their claims so they no longer read on their elected species.
Applicants elected a peptide with at least 75% identity to GLP-1 with a TFE group on the N-terminus, with specific mutations and attachments, along with a drawing of a specific GLP-1 analog with a TFE group on the N-terminus. As applicants were required to elect a single, distinct, and disclosed polypeptide, this was interpreted as that specific GLP-1 analog with a TFE group on the N-terminus (liraglutide modified with alkylation with a TFE group on the N-terminus). Note that the current claims do not read on a sequence with the elected mutations and attachments, so even if the 75% identity to GLP-1 is given weight, it still does not read on the current claim set.
Claims Status
Claims 1, 2, 13, 14, 21, 26, 43, and 52-63 are pending.
Claim 1 has been amended.
Claims 59, 61, and 63 have been withdrawn due to an election/restriction requirement.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(d)
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 13 and 62 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. The rejected claims describe moieties with a C1 alkyl group. However, claim 1, from which these claims depend, require that the moiety be a C2-C16 alkyl, alkenyl, or alkynyl group, with optional substitutions. 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.
response to applicant’s arguments
Applicants state that they will correct this issue. However, until the issue is resolved, it will remain.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 13, 14, 21, 26, 43, 52, 56, 58, 60, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Merriam et al (Endocrine (2003) 22 p41-48) in view of DesMarteau et al (J. Fluorine Chem. (2007) 128 p1326-1334, previously cited) and Montero et al (J. Mol. Endocrin. (2000) 25 p157-168).
Applicants are claiming a small Markush group of peptides that have been modified by a hydrocarbon chain with optional modifications.
Merriam et al discuss growth hormone releasing hormone (GHRH) and growth hormone secretagogues in aging (title). This therapy is currently approved for treatment of idiopathic hypothalamic growth hormone deficiency in children (p43, 2nd column, 2nd paragraph). There have been a number of clinical trials of GHRH in normal aging (p44, 2nd column, 2nd paragraph, continues to p45, 1st column, 1st paragraph), showing benefits to this population (p45, 1st column, 3d paragraph, continues to 2nd column, 1st paragraph).
The difference between this reference and the instant claims is that this reference does not discuss a modified GHRH analog.
DesMarteau et al discuss addition of 2,2,2-trifluoroethane to the N-terminus of amino acids and small peptides (title) for the purpose of improving resistance to degradation by aminopeptidases (p1326, 2nd column, 2nd paragraph). An example discusses a purified solid form of a peptide (p1332, 2nd column, 5th paragraph). This reference discussed the modification claimed by applicant for much the same purpose.
Montero et al discuss the gene family that includes the GHRH family (title). The N-terminus of this peptide is tyrosine for human and many mammalian homologs, while some homologs have an N-terminal His. (fig 2, p158, near middle of page). This reference teaches the sequence of GHRH.
Therefore, it would be obvious to add trifluroethane to the N-terminus of the GHRH of Merriam et al, to improve resistance to degradation by aminopeptidases, as described by DesMarteau et al. As modification of the N-terminus for this purpose is common in the art, an artisan in this field would attempt this modification with a reasonable expectation of success.
Merriam et al discuss GHRH as a therapy. DesMarteau et al render obvious adding a trifluoroethyl group to the N-terminus. The trifluoroethyl group is a C2 alkyl substituted with three fluorines (halo). Thus, the combination of references renders obvious claims 1, 13, 14, 54, 56, 58, 60, and 62.
DesMarteau et al teach that this modification reduces susceptibility to proteases. Thus, the combination of references renders obvious claims 2 and 52.
Montero et al teach that the N-terminal amino acid in human GHRH is tyrosine. In the logic of the rejection, the trifluoroethyl group is placed on this residue, rendering obvious claims 21 and 43.
DesMarteau et al teach a pure compound, a pharmaceutically acceptable composition, rendering obvious claim 26.
response to applicant’s arguments
Applicants have not argued this rejection.
New Rejections
Claim Rejections - 35 USC § 103
The legal basis for rejections under this statute was given above, and will not be repeated here.
Claim(s) 1, 2, 13, 14, 21, 26, 43, 52-58, 60, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Munaf et al (Int. J. Peptides (2012) article ID 249827) in view of DesMarteau et al (J. Fluorine Chem. (2007) 128 p1326-1334, previously cited).
Applicants are claiming a small Markush group of peptides that have been modified by a hydrocarbon chain with optional modifications.
Munaf et al discuss the effects of GLP-1 agonists in heart failure (title). However, the half life of GLP-1 is only a few min, so longer lived analogs are needed for therapeutic relevance (2nd page, 2nd column, 2nd paragraph). Clinical trials of patients with heart failure discuss infusion of GLP-1 (3d page, 2nd column, 3d, 5th paragraphs, continues to 4th page, 1st column, 1st and 2nd paragraphs).
The difference between this reference and the instant claims is that this reference does not discuss a modified GLP-1 analog.
DesMarteau et al discuss addition of 2,2,2-trifluoroethane to the N-terminus of amino acids and small peptides (title) for the purpose of improving resistance to degradation by aminopeptidases (p1326, 2nd column, 2nd paragraph). An example discusses a purified solid form of a peptide (p1332, 2nd column, 5th paragraph). This reference discussed the modification claimed by applicant for much the same purpose.
Therefore, it would be obvious to add trifluroethane to the N-terminus of the GLP-1 of Munaf et al, to improve resistance to degradation by aminopeptidases, as described by DesMarteau et al and extend the plasma lifetime of the sequence. As modification of the N-terminus for this purpose is common in the art, an artisan in this field would attempt this modification with a reasonable expectation of success.
Munaf et al discusses GLP-1 infusions as therapy. DesMarteau et al render obvious adding a trifluoroethyl group to the N-terminus. The trifluoroethyl group is a C2 alkyl substituted with three fluorines (halo). Thus, the combination of references renders obvious claims 1, 13, 14, 53-58, 60, and 62.
DesMarteau et al teach that this modification reduces susceptibility to proteases. Thus, the combination of references renders obvious claims 2 and 52.
As evidenced by applicant’s claims, the N-terminus of GLP-1 is His. In the logic of the rejection, the trifluoroethyl group is placed on this residue, rendering obvious claims 21 and 43.
DesMarteau et al teach a pure compound, a pharmaceutically acceptable composition, rendering obvious claim 26.
response to applicant’s arguments
While this is a new rejection, it matches the new grounds of rejection by the board, so applicant’s arguments appear to be directed to this rejection. Applicants quote the decision by the board to argue that it is not possible to predict the effect of a group on the N-terminus of GLP-1 based on a modified enkephalin sequence, that there is no rationale to combine the references, that there is no reasonable expectation of success, that it would be expected that the modification would not be effective at a reasonable timescale, and that some modifications claimed produce improved activity. Some of these arguments are supported by a declaration by Prof. Paramjit Arora.
Applicant's arguments filed 17 Nov, 2025 have been fully considered but they are not persuasive.
Applicants argue that there is no way to predict the effects of the modification of Des Marteau et al, so there is no rationale to combine the references and no reasonable expectation of success. This is based on an out of context quote from the board decision and repetition of arguments made to the board. It is not clear how a statement from a board that affirmed the rejection renders the rejection invalid.
Applicants argue that there is no expectation that the claimed amendments would be effective on a clinically relevant timescale, supported by a declaration by Prof. Paramjit Arora. In the many, many references on record discussing modifications of GLP-1, there is no mention of the timescale of activity, nor does Prof Arora provide any evidence besides his opinion. Nor does a search of his work find any reference that suggests it is a concern in his own work (structurally constrained peptides). Given that there is extensive literature on record of modifications of various polypeptides without this being a concern, and nothing but Prof. Arora’s unsupported word, this is not persuasive (MPEP 716.01(c)(III)).
Finally, applicants argue that some embodiments of the claims produced improved activity. The board did not find this argument persuasive, and repeating it will not change that determination.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658