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 without traverse of Group I, claimed in claims 1, 3, 6-11, 35-36, 40-43, 49, 51 and 68 in the reply filed on 7/23/26 is acknowledged. Election was made without traverse of SEQ ID NO: 13 (StAMP #25) with a crosslink:
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Claims 1, 3, 6-11, 16, 35-36, 40-43, 49, 51 and 68-69 are pending.
Claims 6-8, 10-11, 16, 51, 53 and 69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 1, 3, 9, 35-36, 40-43, 49 and 68 read on the elected Group I and elected species and are under consideration.
Claim Rejections - 35 USC § 112
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.
Claims 1, 3, 9, 35, 36, 40-43 and 68 are rejected 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. 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The specification does not provide a representative number of species to support the genus claimed. While there is support for the StAMPs reduced to practice (SEQ ID NO: 1-31, 65-70, 74 and 77-78 with a single crosslink), there is no support for the complete claimed genus of claims 1 and 36 encompassing a peptide of 10 or more contiguous amino acids of Esculentin-1A comprising one internal crosslink connecting two crosslinked amino acids, optionally wherein the amino acid sequence includes 1 to 3 amino acid substitutions. A detailed analysis is below.
Claim 1 recites a peptide comprising 10 or more contiguous amino acids of Esculentin-1A and comprising exactly one internal crosslink connecting two crosslinked amino acids, wherein two amino acids of the 10 or more contiguous amino acids of Eculentin 1A are independently substituted by X1 and X2 and X1 and X2 are independently the crosslinked amino acids, optionally wherein the amino acid sequence includes 1 to 3 amino acid substitutions inclusive at positions other than X1 and X2 . Claim 36 is drawn to a peptide or pharmaceutically acceptable salt thereof, comprising 10 or more contiguous amino acids of Esculentin-1A and at least one internal dithio crosslink, wherein at least two amino acids of the 10 or more contiguous amino acids of Esculentin-1A are substituted by a pair of dithio-crosslinked amino acids; optionally wherein the amino acid sequence includes 1 to 3 additional amino acid substitutions, inclusive.
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, reduction to drawings, 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 inventor was in possession of the claimed genus [MPEP 2163 ii)].
The MPEP also states that the representative number of species means that the species which are adequately described are representative of the entire genus and 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 specification and claims provide representative species of SEQ ID NO: 1-31, 65-70, 74 and 77-78 with a single crosslink. The instant specification states that the peptides are StAMP species for broad-spectrum Gram-negative antimicrobial activity and selectivity over renal and hepatic cells (p. 84-85, Tables A-C). However, sequences reduced to practice by the applicant are not representative of the entire genus of claimed.
With respect to claim 1, the sequence claimed comprises of a minimum of 10 residues, and 3 (or 5 depending on claim interpretation, please see 112b rejection below), of which can be substituted with any amino acid. The substitutions can occur at any position of the peptide. If one considers that there are 20 natural amino acids and a great number of non-natural amino acids and the peptide can comprise 3 substitutions at any position, the number of peptides that can meet the structural limitations of the claim is enormous. With respect to claim 9, the peptide can comprise 1 to 6 substitutions. With respect to claim 36, the peptide can comprise at least two substitutions of Esculentin-1A by a pair of dithio-crosslinked amino acids, but can also contain an addition 1 to 3 amino acid substitutions. The limited number of examples is not representative of this great variation. Furthermore, the claimed StAMPs can have X1 and X2 forming any type of crosslink or amino acids that are capable of forming a crosslink. There is substantial variation within the genus, and SEQ ID NO: 1-31, 65-70, 74 and 77-78 are not representative of the genus because the genus is quite large. Importantly, it is established that a single amino acid substation can affect the function of the protein or peptide (Ng & Henikoff (2006)).
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 Esculentin-1A peptides of SEQ ID NO: 1-31,65-70,74 and 77-78.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 9, 35-36, 40-43 and 68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the amino acid sequence includes 1 to 3 amino acid substitutions, inclusive at position other than X1 and X2”. This limitation is indefinite because the intended scope of the term “inclusive” is unclear. It is unclear whether a total of 3 substitutions are allowed in the sequence with none of them occurring at X1 and X2 or if up to 3 substitutions are allowed in the sequence while also permitting substitutions at X1, and X2 (so a total of 5 substitutions are allowed). The number of substitutions and the position at which those substitutions can occur are unclear. Therefore, it is impossible to determine the metes and bounds of the claims.
Claims 3 and 9 recite “the amino acid sequence includes 1 to 6 amino acid substitutions, inclusive at position other than X1 and X2”. This limitation is indefinite because the intended scope of the term “inclusive” is unclear. It is unclear whether a total of 6 substitutions are allowed in the sequence with none of them occurring at X1 and X2 or if up to 6 substitutions are allowed in the sequence while also permitting substitutions at X1, and X2 (so a total of 8 substitutions are allowed). The number of substitutions and the position at which those substitutions can occur are unclear. Therefore, it is impossible to determine the metes and bounds of the claims.
Claim 36 recites the limitation “ ..at least 2 amino acids of the 10 or more contiguous amino acids of Esculentin-1A are substituted by a pair of dithio-crosslinked amino acids; optionally wherein the amino acid sequence includes 1 to 3 amino acid substitutions, inclusive”. This limitation is indefinite because the phrase “at least two” permits two or more amino acids to be substituted, whereas the phrase “a pair” refers to two amino acids. It is unclear if the claim requires exactly two crosslinking amino acids forming a single pair or whether the claim permits more than two crosslinking amino acids.
Claims 35, 40-43 and 68 are rejected for depending from claim 1 and 35 and not correcting the deficiencies.
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 3 and 9 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 1 recites optionally 1 to 3 amino acid substitutions, while claims 3 and 9 depend from claim 1 and recite optionally 1 to 6 amino acid substitutions. The peptide of claim 1 can only have 1 to 3 substitutions, while the peptides of claim 3 and 9 can have 1 to 6 substitutions, which is outside the scope of the claim from which they depends. 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.
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.
Claims 1, 3, 9, 35-36, 40-43, 49 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Casciaro et al. (Frontiers in chemistry 4/25/2017 Vol. 5, Article 26) in view of Peraro et al. (Methods of Enzymology, Volume 580, Chapter 14: Conformational Restriction of Peptides Using Dithiol Bis-Alkylation).
Please note that the limitation following “optionally” is considered entirely optional and not a required limitation.
Casciaro et al. teach the peptide Esculentin-1A (GIFSKLAGKKIKNLLISGLKG-NH2) (Esc(1-21)) has been found to have a potent activity against the Gram-negative bacterium --Pseudomonas aeruginosa; a slightly weaker activity against Gram-positive bacteria and interesting immunomodulatory properties (Abstract and Fig. 1). The Esc(1-21) comprises 21 amino acids and comprises 10 or more contiguous amino acids or Esculentin-1A. Casciaro et al. teach modification of Esc(1-21) to improve stability, bioavailability and to decrease cytotoxicity without compromising its antimicrobial efficacy. Casciaro et al. teach Esculentin-1A adopts an amphipathic alpha helix structure (p. 2, 2nd col.) and this alpha helix conformation is reported to be correlation to the AMPs activity against gram positive bacteria. and to improve stability (p. 3, 2nd col. ).
Casciaro et al. do not teach Esc(1-21) comprises exactly one internal crosslink connecting two crosslinked amino acids wherein two amino acids of the 10 or more of Esculentin-1A are independently substituted by X1 and X2. However, the teachings of Peraro et al. cure this deficiency.
Peraro et al. teach that peptides have many advantages, but suffer from short half-life, sensitivity to proteases, poorly structured in aqueous solutions and poor membrane permeability (p. 304, Introduction). Peraro et al. teach conformational restriction of peptides by placing crosslinkable cysteine residues at the i and i+4 positions and crosslinking those residues (p. 309-311, para. 2.1-2.2). Peraro et al. teach the peptide was scanned for the best (i, i+4) staple location by moving the cysteines and then crosslinking (p. 311, 1st para.).
It would have been obvious to a person of ordinary skill in the art to modify the Esc(1-21) peptide of Casciaro et al. by substituting two amino acids with a crosslinkable amino acid at the i, i+4 positions as taught by Peraro et a. and then crosslinking those amino acids. A person of ordinary skill in the art would have a motivation to use the staple scanning technique taught by Peraro et al. to the Esc(1-21) peptide of Casciaro et al. because Casciaro et al. teach that modification of its alpha helical structure to improve properties such as stability and bioavailability was a goal. Therefore, a person of ordinary skill in the art would have a motivation to crosslink the Esc(1-21) peptide at position i, i+4 in order to improve stability, bioavailability and other properties. There is a reasonable expectation of success given that i, i+4 crosslinking is an established technique for conformationally constraining peptides as taught by Peraro et al.
With respect to claim 3, Esc(1-21) contains 20 or more contiguous amino acids of Esculentin-1A.
With respect to claim 9, it would have been obvious to a person of ordinary skill in the art to optimize the location of the i, i+4 crosslinking residues within the Esc(1-21) peptide. Peraro et al. teach the peptide was scanned for the best (i, i+4) staple location by moving the cysteine residues to different positions along the peptide and then crosslinking (p. 311, 1st para), resulting in the peptides of claim 9 (SEQ ID NO: 1-17). Therefore, varying the position of the crosslinkable amino acid in a peptide for crosslinking is known in the art. A skilled artisan would have been motivated to evaluate and optimize the i, i+4 crosslink of Esc(1-21) as taught by Peraro et al. There is a reasonable expectation of success given that Peraro et al. teach a method of scanning the peptide for the best i, i+4 staple location and the method is routine in the art.
With respect to claims 35, 36 and 40-43, Peraro et al. teach applications and methods for dithiol bis-alkylation reactions for the production of cyclic peptides (Abstract). Peraro et al. teach the cysteines were placed at i, i+4 positions and crosslinking the two cysteine thiol groups with mxy (top of p. 311). Table 1 of Peraro et al. teach the crosslinking reaction:
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The structure above meets the limitation of the formula of claim 40, wherein n is 1 and L2 is substituted arylene. The structure above meets the limitation of the second structure of claim 41. n is 1 meeting the limitation of claim 42. The structure meets the limitation of the 1st structure of claim 43 (mxy) (non-elected species).
With respect to claim 49, as indicated above, the combination of Casciaro et al. and Peraro et al. make obvious SEQ ID NO: 1-17 and Peraro et al. teach the structure of X1-X2 is myx, resulting in StAMP #2, 5, 10, 14, 17, 20, 23, 26, 29, 32, 36, 39, 41, 42, 44, and 46 (non-elected species).
With respect to claim 68, Casciaro et al. teach Esc(1-21) in water, SDS or TFE (top of p. 4, 1st col.).
Claims 1, 3, 9, 35-36, 40-43, 49 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Casciaro et al. (Frontiers in chemistry 4/25/2017 Vol. 5, Article 26) in view of Peraro et al. (Methods of Enzymology, 2017;Volume 580, Chapter 14: Conformational Restriction of Peptides Using Dithiol Bis-Alkylation) in view of Diderich et al. (ACS Chem Biol 2016, 11,1422-1427).
Casciaro et al. and Peraro et al. are discussed in detail above. The references do not teach the elected species of butene crosslinker. However, the teachings of Diderich et al. cure this deficiency.
Diderich et al. teach alpha-helical peptides stabilized by linkages between amino acids (Abstract). Diderich et al. peptides containing cysteines at the i, i+4 position are modified with chemical bridges (Abstract). Diderich et al. teach Fig. 1, wherein TDBB to crosslink two cysteine residues resulting in a but linkage that meets the limitations of the 1st compound of claim 41 (elected species), the 3rd compound of claim 43 (elected species) and StAMP #25 of claim 49 (elected species).
It would have been obvious to a person of ordinary skill in the art to use Diderich’s butene containing crosslink because Diderich et al. teach it as a known cysteine crosslinking strategy that was reported to stabilize alpha-helical peptides. Furthermore, MPEP 2143 states: Exemplary rationales that may support a conclusion of obviousness include the rationale that simple substitution of one known element for another to obtain predictable results. To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
(2) a finding that the substituted components and their functions were known in the art;
(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
In the instant case, Diderich et al. teach crosslinking the alpha-helical peptides with a butene linker that differs from the dithiol myx linker of Peraro et al. The methods of crosslinking cysteine containing peptides is well known in the art. Peraro et al. teach the dithiol myx linker and Diderich et al. teach the butene linker for the same purpose. Substituting butene for myx is predictable as both are well known for crosslinking cysteines in alpha helical peptides in the i, i+4 position. There is a reasonable expectation of success given that both references demonstrate successful crosslinking residues at the i, i+4 positions using the known linker chemistries.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Primary Examiner, Art Unit 1654
