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
Applicants’ election without traverse of Claims 1 and 4-13 drawn to the elected species of the PHHPs; and Claims 1 and 4-13 read on the elected species, in the reply filed on April 27, 2026, is acknowledged.
The species of claims 1 and 4-13 which read on the elected species has been considered. Claims 1 and 4-13 are hereby examined on the merits.
Claim 2 is cancelled and claims 3, 14 and 16-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 27, 2026.
Priority
This application is a continuation of and claims priority to co-pending Patent Cooperation Treaty International Application Serial No. PCT/US2022/013851, filed January 26, 2022, designating the United States, which claims priority to U.S. Provisional Patent Application Serial No. 63/142,219, filed January 27, 2021.
Status of Claims
Claim 1 is amended, claim 2 is cancelled, and claims 3, 14 and 16-19 are withdrawn for further consideration, as filed on April 27, 2026.
Claims 1 and 4-13 are hereby examined on the merits.
Information Disclosure Statement
The IDS filed on July 29, 2024, is under consideration.
Claim Objections
Claim 12 is objected to because of the following informalities: “isoelectric” is misspelled in the claim recitation “peptide has an isolectric point”.
Appropriate correction is required.
Specification
The use of the terms Tween, Invitrogen, PerkinElmer, which are trade names or a mark used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Interpretation
Claims 1 and 4-13 are drawn to the elected species of the PHHPs.
BRI of claim 1 and elected species, “a positive, helical, and hydrophobic peptide (PHlP) comprising at least one amphipathic beta strand-turn-alpha helix (PTa) motif domain, wherein the PHHP further comprises one of the following amino acid sequences or substantially homologous sequences”, the scope of the peptides defined using “comprising” and “further comprises” terminology, is being interpreted as open-ended, in which additional chemical moieties, e.g., amino acid residues, can be present and covalently attached to either terminus of the amino acid sequences.
BRI of claims 4 and 6-8, recite “further comprising” terminology, is being interpreted as open-ended, in which additional chemical moieties, e.g., amino acid residues, can be present and covalently attached to either terminus of the amino acid sequences.
BRI of claim 12, recite “the peptide has an isoelectric point greater than about 12.5”. The specification does not state the isoelectric points of the sequences in the instantly claimed invention. As the PHHPs comprise consideration number of basic amino acid residues, therefore, the isoelectric point for the PHHPs is being interpreted as greater than physiological pH (7.4).
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 and 4 - 13 are rejected under 35 U.S.C. 103 as being unpatentable over US 20170042975 (published December 12, 2019; cited in IDS filed July 29, 2024 ) in view of Milletti (“Cell-penetrating peptides: classes, origin, and current landscape”; Drug Discovery Today, Pages: 850-860, Volume: Volume 17, Issues 15–16; published on March 23, 2012).
Regarding claim 1: US’975 discloses peptide comprising 12 to 50 amino acid residues comprising at least two peptide moieties, wherein said at least two peptide moieties are: (a) at least two beta-strands; (b) at least two alpha-helices; or (c) at least one beta-strand and at least one alpha-helix, wherein said beta-strands and/or alpha-helices are separated from each other by at least one turn; wherein the peptide has a net positive charge of +7 or more (see claim 1). US’975 teaches that the peptide preferably exhibits amphipathic properties, i.e., the peptide may comprise hydrophobic and hydrophilic regions (see [0046]).
US’975 discloses the peptides are preferably designed as “membrane active peptides”, i.e. peptides that have—due to their physicochemical properties—an affinity to membranes (see [0037]); however, US’975 is silent about the cell penetrating ability of the peptides.
Milletti teaches cell-penetrating peptides (CPPs) can target intracellular proteins and also carry other cargoes (e.g. other peptides, small molecules or proteins) into the cell, thus
offering great potential as future therapeutics (see Abstract). Milletti discusses cell-penetrating peptides (CPPs) are a class of diverse peptides, typically with 5–30 amino acids, that unlike most peptides can cross the cellular membrane; CPPs have been used for a variety of applications - CPPs can act as vectors for siRNA nucleotides, small molecules, proteins, and for other peptides, both in vitro and in vivo; and importantly, not only can a CPP be used to carry a functional peptide inside the cell, but it can also incorporate a functional motif (see page 850, left col, paragraph 3). Regarding cationic CPPs, Milletti teaches arginine-based peptides (from R3 to R12) have shown that the minimal sequence for cellular uptake is octaarginine (R8), and that increasing the number of arginines increases the level of uptake (see page 851, right col, paragraph 5), and that at least eight positive charges are needed for efficient uptake of several other cationic CPPs (see page 852, left col, paragraph 1). Milletti teaches a special case of cationic CPPs are nuclear localization sequences (NLSs); NLSs are short peptides based on lysine-, arginine or proline-rich motifs that can be transported to the nucleus through the nuclear pore complex, which is a multimeric complex containing 50–100 different proteins; NLSs can be further divided into monopartite and bipartite signals, which consist, respectively, of one or two clusters of four or more basic amino acids; i.e., KRPAATKKAGQAKKKL, PKKKRKV, SKKKKTKV, GRKRKKRT, ERKKRRRE, etc. (see page 852, left col, paragraph 2).
Milletti teaches NLSs can be covalently attached to a hydrophobic peptide sequence to obtain an amphipathic CPP with a good uptake profile (see page 852, left col, paragraph 2), and primary amphipathic CPPs are chimeric peptides obtained by covalently attaching a hydrophobic domain for efficient targeting to cell membranes to a NLS (see page 852, left col, paragraph 3), e.g., tryptophan-rich cluster (KETWWETWWTEW), which has high affinity for membranes (see page 852, right col, paragraph 1). Milletti further teaches secondary amphipathic a-helical CPPs have a highly hydrophobic patch on one face, whereas the other face can be cationic, anionic, or polar; and even though most amphipathic CPPs are cationic, evidence suggests that membrane translocation is a consequence of amphiphilicity and not of positive charges (see page 853, left col, paragraph 1-2). Similarly, Milletti teaches an amphipathic b-sheet peptide is based on one hydrophobic and one hydrophilic stretch of amino acids exposed to the solvent (see page 854, right col, paragraph 5). Milletti provides several examples of designed CPPs and CPPs derived from peptide libraries (see Tables 1-6).
It would have been obvious to combine the teachings of US’975 and Milletti before the effective filing date of the claimed invention by considering attaching peptide moieties as taught by US’975 by covalently attaching a hydrophobic domain as taught by Milletti for constructing effective and stable peptides targeting cell membranes as claimed instantly. One of ordinary skill in the art would have been motivated to utilize the physico-chemical properties-based classification of CPPs as taught by Milletti as potent therapeutic polypeptides modified for improved activity with a reasonable expectation of success. Thus, one skilled in the art can design to generate peptides where each position corresponds to specific subsets of amino acids, chosen based on an amino acid preference model (see Milletti, page 855, right col, paragraph 1), and that positive charges and amphipathicity are important features for cell penetration, and these characteristics were carefully considered to design new synthetic CPPs (see Milletti, page 856, paragraph 1).
Regarding claims 4 and 5: US’975 teaches an isolated peptide to be used in the treatment …. consisting of 12 to 50 amino acid residues (see [0008]).
Regarding claim 6: US’975 teaches the peptide preferably exhibits amphipathic properties, i.e., the peptide comprise hydrophobic and hydrophilic regions (see [0046]).
Regarding claim 7: US’975 discloses peptide moieties are: (a) at least two beta-strands;
(b) at least two alpha-helices; or (c) at least one beta-strand and at least one alpha-helix, wherein said beta-strands and/or alpha-helices are separated from each other by at least one turn (see claim 1); coil structures (see FIG. 1, [0200]); and the turn according to the present invention may also be a loop (see [0029]). US’975 further teaches in the secondary structure prediction an arrangement of 2 β-strands with hydrophobic endings with a loop in the middle composed of cationic amino acids was predicted. According to other prediction studies the amphipathic distribution of amino acids with a loop between 2 β-strands or 2 α-helices seem to be important structural features for an active and specific peptide (see [0272]).
Regarding claim 8: US’975 discloses the peptide may comprise hydrophobic and hydrophilic regions (see [0046]). Additionally, Milletti teaches amino acid composition or amino acid repeat in the hydrophobic or hydrophilic face (see page 858, left col, paragraph 3).
Regarding claim 9: Milletti exemplifies amphipathic CPPs with domain regions (1-30) (see Table 2, row 2).
Regarding claim 10: US’975 teaches the dosage form such as injectable preparations (solutions, suspensions, emulsions, solids to be dissolved when used, etc.) (see [0120]); the pharmaceutical composition may consist of the peptide alone or may be in the form of a composition comprising the peptide and a pharmaceutically acceptable carrier (see [0118]); the composition can be administered, locally or systemically by injection (subcutaneous, intracutaneous, intravenous, intraperitoneal, etc.), eye dropping, instillation, percutaneous administration, oral administration, inhalation, etc.; the peptides of the present invention can also be directly injected (see [0119]). [Note: Thus, implying the peptides are soluble at aqueous solutions and at physiologic pH].
US’975 further teaches the peptides may form a salt by addition of an acid, examples …of organic carboxylic acids (such as acetic acid, propionic acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, and salicylic acid), acidic sugars such as glucuronic acid, galacturonic acid, gluconic acid, ascorbic acid, etc., acidic polysaccharides such as hyaluronic acid, chondroitin sulfates, alginic acid, or organic sulfonic acids (such as methanesulfonic acid, and p-toluenesulfonic acid), and the like (see [0043]); and the peptides may form a salt with a basic substance, examples of the salt include, for example, pharmaceutically acceptable salts selected from salts … with organic bases, such as diethanolamine salts, cyclohexylamine salts and the like (see [0044]).
Regarding claims 11-13: US’975 teaches the peptides have a net positive charge of +7 or more (for the purpose of a formal definition for the present invention, the net positive charge can be regarded as being defined at pH 7.4 in PBS buffer (phosphate buffered saline: 20 mM NaPi, 130 mM NaCl, pH 7.4)). This means that the peptides of the present invention may have preferably a net positive charge of +8, +9, +10, +11, +12, +13, +14, +15 or even of +20. A net positive charge of at least +7 of the peptides of the present invention results in a better adsorption to the target membrane (negatively charged) and better stabilization of the secondary structure by hydrogen bridge bonds. For example, a peptide with three lysine and four arginine residues has a net positive charge of +7 at a pH below 10.5 (pK lysine ˜10.5; arginine would even be positively charged at pH 12.5!) (see [0036]).
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 9-5 PM.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
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