DETAILED ACTION/
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 9/24/24 was previously acknowledged.
The requirement was deemed proper and made FINAL.
Applicants elected Formula III, R is an unsubstituted alkyl group. R2 is an unsubstituted alkyl group, Q is an oligomer, L is one or more oligomers, M is one or more oligomers, R4 is hydrogen, R5 is hydrogen, n is 0 and Z is absent.
In the reply filed 4/11/25, Applicants amended claims 1, 8, 15-18, 22, 37 an added NEW claim 38. Claims 2-7, 11, 13-14 were cancelled.
In the reply filed 9/29/25, Applicants amended claims 1, 8-9 and 38 were amended. Claim 29 was canceled. Claim 39 is NEW.
Claims 1, 8-10, 12, 15-28 and 30-39 are pending.
Claims 12, 16-28 and 30-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Please note that claim 12 is withdrawn because Z was elected as absent.
Claims 1, 8-10, 15 and 37-39 read on elected Group I and the elected species and are under consideration.
Drawings
The drawings were received on 4/11/25. These drawings are accepted.
Claim Objections-Withdrawn
The objection to claims 1 and 38 is withdrawn due to amendment of the claims.
Claim Rejections - 35 USC § 112-Maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The rejection of claims 1, 8-10, 15, 37 and 39 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained. This rejection has been modified necessitated by amendment of the claims.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Scope of the claimed genus
Claim 1 is drawn to a compound of Formula III, III’ or III’’, wherein R1 and R2 are absent or an unsubstituted alkyl group…Q is an oligomer of amino acids comprising at least one lysine residue and at least one cysteine residue, L’ and M’ are absent, or one or more amino acids, R4 is a hydrogen…R5 is a hydrogen…, wherein n is zero or a positive integer and Z is optional and when present comprises a chemical probe and/or a biofunctional molecule, provided when the compound is formula III, R4 is hydrogen.,R 5 is hydrogen. Claim 8 is drawn to the compound of claim 1, wherein the oligomer is linear, cyclic or branched. Claim 9 is drawn to wherein the oligomer is unprotected. Claim 12 is drawn to wherein the compound is fluorescent. Claim 13 is drawn to the compound of Formula III. The USPTO provides claim terms with broadest reasonable interpretation in light of the specification. The instant specification defines “biofunctional molecule”: “In some forms, the biofunctional molecule can be a glycan, a peptide, an oligonucleotide, a protein, or a small molecule drug. In some forms, the functional molecule can be a glycan. In some forms, the functional molecule can be a peptide. In some forms, the functional molecule can be an oligonucleotide. In some forms, the functional molecule can be a protein. In some forms, the functional molecule can be a small molecule drug. In some forms, Z can contain two or more biofunctional molecules. In some forms, Z, if present, can contain a combination of luminescence probe and biofunctional molecule.” [0060]. With respect to Q, and the new limitation “oligomer”, the instant specification states [0114]: As used herein, the term “oligomer” refers to multimers of subunits (e.g., monomers, building blocks) having a small or moderate number of monomer resides. Notable examples of oligomers are peptides, oligonucleotides, and oligomers of synthetic monomers. A multimer is any chain of two or more monomer residues. An oligomer is any multimer having from two to 100 monomer residues. Generally, an oligomer can have from two to 100 monomer residues, preferably five to 50 monomer residues, most preferably from five to 20 monomer residues. A polymer is any multimer having 20 or more monomer residues. Generally, a polymer can have 50 or more monomer residues, 75 or more monomer residues, or 100 or more monomer residues. Thus, the terms multimers, oligomer, and polymer overlap, but oligomers and polymers have different length domains.
The instant specification does not define chemical probe.
Assessment of whether species are support in the original specification
Seventy-five embodiments of the invention of the claims were reduced to practice at the time of filing. Applicants disclosed the structures in PGPUB[0184] and claim 38.
The examples provided by applicants are limited the structures cyclized via an isoindole structure, wherein the peptide contains a cysteine residue. The peptides also contain C-terminally amidated phenylalanine, N-terminal Acetylated lysine, N-terminal acetylated cysteine, amidated lysine, acetylated glutamic acid, amidated histidine and/or amidated serine. With respect to the term “oligomer” the instant specification states “Generally, an oligomer can have from two to 100 monomer residues” . The example provides are between 5 and 20 amino acids in length. Q was amended to include at least one cysteine and one lysine residues.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of the examples provided in claim 38.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the disclosure of the examples in PGPUB 0184 and claim 38 is not representative of the genus. The instant specification is drawn to cyclization of peptides containing a cysteine and lysine residues using OPA, wherein the peptide has specific amidated and/or acetylated residues. Although 75 examples seems like a large number, the variables recited in the claims are very broad and encompass a great number of compounds. However, the examples are narrow in scope. Q can be any oligomer comprising 2-100 amino acids and includes at least one cysteine and at least one lysine residue, however the examples are specific peptide sequences containing a cysteine and specific amidated and acetylated residues. For example, an oligomer from 2-100 residues in length comprising at least one lysine and at least one cysteine is extremely broad and encompasses an enormous number of compounds as the other 98 residues could be any natural or non-natural amino acids. The examples provided are also of a length of 5-20 residues. Therefore, due to the enormous number of compounds encompasses by the claims, the examples provided are not representative of the genus because the genus is large.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of Formula III, III’ and III’’. Zhang et al. (2019, cited on IDS). Zhang et al. demonstrate a novel highly chemoselective and operation-simple method directly cyclizing unprotected peptides, in which ortho-phthalaldehyde (OPA) is found to react with the lysine/N-terminus and cysteine within one unprotected peptide sequence effectively to form the isoindole-bridged cyclic peptides.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of the compounds presented in the specification [PGPUB0184] and claim 38.
Response to Arguments
Applicant's arguments filed have been fully considered but they are not persuasive. Applicants argue that whether the specification contains or lacks a representative number of species is not dispositive of written description, it constitutes only one way and not the only way that the written description can be satisfied. Applicant argue that the Q was limited to an oligomer containing at least one lysine and at least one cysteine. Applicants argue that the lysine and cysteine residue of Q link with each other to form the cyclic peptide or bicyclic peptide via OPA or TDA mediated cyclization.
This argument is not persuasive for the reasons presented above. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. In particular, the instant specification is drawn to cyclization of peptides containing a cysteine and lysine residues using OPA, wherein the peptide has specific amidated and/or acetylated residues. The examples are limited in length and have distinct structures. Although 75 examples seems like a large number, the variables recited in the claims are very broad and encompass a great number of compounds, while the examples are narrow in scope with respect to claim 1. For example, an oligomer from 2-100 residues in length comprising at least one lysine and at least one cysteine is extremely broad and encompasses an enormous number of compounds as the other 98 residues could be any natural or non-natural amino acids. Examples clustered around OPA cyclization chemistry does not show possession of the full breadth of the claims. Therefore, a person of ordinary skill in the art would not reasonably conclude that the inventors, at the time the application was filed had full possession of the compounds of claim 1.
For the reasons presented above, the rejection is maintained.
Claim Rejections - 35 USC § 102-Maintained
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Amended claims 1, 8-10, 15 and 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Portoghese et al. (II Farmaco 56(2001) 191-196)(cited on IDS and provided by Applicants). This rejection has been modified necessitated by amendment of the claims.
With respect to claims 1, 8-10, 15 and 37, Portoghese et al. teach the structure of Fig. 4 (p. 195, 1st col.) that meets the limitations of instantly claim Formula III, wherein R4 is hydrogen, R1 and R2 are unsubstituted alkyl groups, Q is a oligomer and L’ and M’ are absent or amino acids, R5 is hydrogen or unsubstituted carbonyl group, n is 0 and Z is absent. Portoghese et al. teach there are multiple conserved lysine and cysteine residues within the putative recognition loci in the opioid receptor (p. 194, 2nd col.). Portughese et al. teach that compound 5 is positioned within covalent bonding distance of both lysine and cysteine residues and further teaches reaction of the OPA moiety with neighboring lysine and cysteine residues (Fig. 4; p. 195, top of 1st col.; p. 195, 1st col. last para). Thus, the receptor portion show in Fig. 4 corresponds to the receptor amino acid segment involved in binding (i.e. neighboring lysine and cysteine residues) rather than the entire receptor, meeting the limitations of Q.
With respect to claims 8 and 9, the oligomer is a linear unprotected peptide.
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Response to Arguments
Applicant's arguments filed have been fully considered but they are not persuasive. Applicants argue that amendment of claim 1 to specify that Q is an oligomer of amino acids overcome the rejection.
This argument was considered but is not persuasive as the teachings of Portughese anticipate the limitations. As indicated above, Portughese et al. teach that compound 5 is positioned within covalent bonding distance of both lysine and cysteine residues and further teaches reaction of the OPA moiety with neighboring lysine and cysteine residues (Fig. 4; p. 195, top of 1st col.; p. 195, 1st col. last para). Thus, the receptor portion show in Fig. 4 corresponds to the receptor amino acid segment involved in binding (i.e. neighboring lysine and cysteine residues) rather than the entire receptor, meeting the limitations of Q. For the reasons presented above, the rejection is maintained.
Claim Rejections - 35 USC § 103-NEW
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.
New Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Portoghese et al. (II Farmaco 56(2001) 191-196)(cited on IDS and provided by Applicants) as applied to claims 1, 8-10, 15 and 37 above. This is a NEW rejection necessitated by addition of NEW claim 39.
The teachings of Portoghese et al. is presented above. The references does not teach Q is 5 to 20 amino acids. However, the teachings of Portoghese et al. are suggestive of the limitation.
It would have been obvious to a person of ordinary skill in the art to select an oligomer having a length of about 5 to 20 amino acids in view of the teachings of Portoghese et al. because the reference teaches that compound 5 is positioned within covalent bonding distance of neighboring lysine and cysteine residues at the receptor recognition site .
A person of ordinary skill in the art would understand that localized receptor recognition sites may vary in peptide length, including segments of 5 to 20 residues. Therefore, it would have been obvious to optimize the length of Q to about 5 to 20 amino acid residues in order to provide a recognition segment of sufficient size to maintain binding. There is a reasonable expectation of success given that Portoghese et al. reaches that the relevant interaction occurs at neighboring lysine and cysteine residues within a localized amino acid region.
Allowable Subject Matter
Claim 38 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The closest art of record for claim 38 is Zhang et al. (2019, cited on IDS). Zhang et al. demonstrate a novel highly chemoselective and operation-simple method directly cyclizing unprotected peptides, in which ortho-phthalaldehyde (OPA) is found to react with the lysine/N-terminus and cysteine within one unprotected peptide sequence effectively to form the isoindole-bridged cyclic peptides. In addition, OPA peptide cyclization can also be combined with native chemical ligation-mediated cyclization to generate bicyclic peptides. Zhang et al. demonstrate the OPA peptide cyclization product can further react with the N-maleimide moiety in a one-pot manner to introduce additional functional motifs, like a fluorophore probe, biomolecules (e.g., glycan, peptide, or DNA). This OPA-cyclization method extends the toolbox for integrating postcyclization modification and bioconjugation into peptide cyclization with an all-in-one manner strategy. However, Zhang et al. does not qualify as prior art as it was published after the filing date of the instant application.
Conclusion
Claims 1, 8-10, 15 and 37 are rejected.
Claim 38 is objected.
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 TARA L MARTINEZ whose telephone number is (571)270-1470. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/TARA L MARTINEZ/Examiner, Art Unit 1654
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