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 II, claims 14-16, 20, 21, 24, 26, and 30-32, in the reply filed on May 29th, 2026 is acknowledged.
Applicant’s election without traverse of KQKFKFKFKQK (SEQ ID NO: 3) as the species of positive peptide; EQEFEFEFEQE (SEQ ID NO: 2) as the species of positive peptide; one as the number of crowding agents; and polyethylene glycol 2000 (PEG 2000) as the exact species of crowding agent in the reply filed on May 29th, 2026 is acknowledged.
Claims 1-3, 7-9, 12-13, 33, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 May 29th, 2026.
Priority
The instant application claims priority to 371 National Stage Application PCT/US2022/025426, filed April 19th, 2022, under 35 U.S.C. 119(a)-(d), and claims benefit to provisional application 63176870, filed April 19th, 2021, under 35 U.S.C.119 (e). The priority date of April 19th, 2021 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 15th, 2024 and May 29th, 2026 is considered by the examiner. The IDS filed on May 15th, 2024 is missing the reference Krylov, D. and Vinson, C.R. (2001). Leucine Zipper. In eLS, (Ed.). https://doi.org/10.1038/npg.els.0003001. Appropriate correction is required.
Claims Status
The claims listing filed on May 15th, 2024 is pending. Claims 1-3, 7-9, 12-13, 33, and 36 are withdrawn from further consideration for the reasons set forth in the restriction requirement, 37 CFR 1.142(b). Claims 14-16. 20-21, 24, 26, and 30-32 are being examined on the merits in this office action.
Claim Objections
Claim 20 objected to because of the following informalities: The repetition of crowding agent in its IUPAC form in parentheses. Appropriate correction is required either by referring to the crowding agents by their IUPAC name, or their commonly known name to improve the clarity of the claim.
Claim 32 is objected to because of the following informalities: The claim should be written as “wherein the at least one positive peptide and/or at least one negative peptide is/are a fusion protein with at least one cargo” to be consistent with the number of peptides that may be a fusion protein. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 14-16, 20-21, 24, 26, and 30-32 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. While the applicant does have support for a method comprising of positive peptides SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+), the negative peptides SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), and crowding agents Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50, they do not have support a method comprising contacting the complete genus of co-assembling peptides and crowding agents.
Claim 14 recites a “method comprising contacting a plurality of co-assembling peptides with at least one type of crowding agent.” However, the specification does not support that the inventors possess the complete recited genus.
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 inventors provide direction by teaching the peptide synthesis and purification of complimentary peptides SEQ ID NO: 2 and 1 (CATCH +/-), and their respective mutants, SEQ ID NO: 22 and 23 (mCATCH +/-) [pg 55 line 14]. The co-assembly of these peptides is characterized by ThT fluorimetry, TEM, CS and fluorescence microscopy [pg 60 and line 6 and Fig. 14-22]. The applicant goes on to show the particle formation of crowders [pg 78 line 18]. While Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 induce particle formation, SDS, CHAPS, deoxycholate, benzalkonium chloride, and BSA are unsuccessful [Fig 54-55]. Additionally, when combined with CATCH (6−)-GFP (green fluorescent protein) and Tween 20, CATCH (6−) and mutant CATCH (4+) (mCATCH (4+)) are not able induce particle formation. The co-assembling peptides reduced to practice by the applicant are not representative of the entire genus of co-assembling peptides claimed. Nor, would one of ordinary skill in the art be able to attest to the complete genus of co-assembling peptides’ ability to co-assemble in a composition also comprising at least one crowding agent. Perhaps the crowding agent will not allow the peptides to form fibrils. Thus, while the applicant has support for the method comprising of positive peptides SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+), the negative peptides SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), and crowding agents Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50, they do not have support a method comprising contacting the complete genus of co-assembling peptides and crowding agents.
Regarding claim 15, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent wherein the co-assembling peptides comprise at least one positive peptide of (a) and at least one negative peptide of (b).
The positive peptide claimed can comprise of any sequence with the motif (A3-A1), wherein A3, A2, and A1 are selected from a positively charged or hydrophobic amino acid, wherein at least one is positively charged and one is hydrophobic. The negative peptide claimed can comprise of any sequence with the motif (B3-B1), wherein B3, B2, and B1 wherein at least one is negatively charged and one is hydrophobic. The crowding agent can be any crowding agent. There is substantial variation within the genus of the positive and negative peptide and the crowding agent. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) are not representative of every positive peptide claimed; SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every negative peptide claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 16, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent wherein the crowding agent is selected from (a), (b), or (c).
The co-assembling peptides claimed can comprise of any sequence. The crowding agent can be any crowding agent because non-ionic, charged, and zwitterionic cover all the possible charge states. There is substantial variation within the genus of co-assembling peptides and crowding agents. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) combined with SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every plurality of co-assembling peptides claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 are not representative of crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 20, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent wherein the crowding agent is selected from Polysorbate 20 or 80, (1,1,3,3-Tetramethylbutyl)phenyl- polyethylene glycol, Polyethylene glycol tert-octylphenyl ether, sodium dodecylsulfate, deoxycholate sodium, benzalkonium chloride, PEG 1000, 1550, 2000, 3350, 6000, 20000, or 50000, Ficoll 70 or 400, serum albumin, dextran (50k or 500k), or any combination thereof.
The co-assembling peptides claimed can comprise of any sequence. Therefore, there is substantial variation within the genus of co-assembling peptides. . SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) combined with SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every plurality of co-assembling peptides claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 21, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent, wherein at least one cargo is attached to (a), (b), or (c).
The positive and negative peptides claimed can comprise of any sequence and the crowding agent can be any crowding agent. Therefore, there is substantial variation in the genus claimed. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) are not representative of every positive peptide claimed; SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every negative peptide claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 24, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent wherein the concentration of the corwding agent is described by (a), (b), or (c).
The plurality of co-assembling peptide can comprise of any sequence and the crowding agent can be any crowding agent. Therefore, there is substantial variation in the genus claimed. . SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) combined with SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)),. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) combined with SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)); and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 26, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent; wherein the co-assembling peptides comprise at least one positive peptide of (a) and at least one negative peptide of (b); wherein the at least one positive peptide and the at least one negative peptide do not form a hydrogel or the co-assembling peptides form a nanoparticle.
The positive peptide claimed can comprise of any sequence with the motif (A3-A1), wherein A3, A2, and A1 are selected from a positively charged or hydrophobic amino acid, wherein at least one is positively charged and one is hydrophobic. The negative peptide claimed can comprise of any sequence with the motif (B3-B1), wherein B3, B2, and B1 wherein at least one is negatively charged and one is hydrophobic. The crowding agent can be any crowding agent. Therefore, is substantial variation within the genus of the positive and negative peptide and the crowding agent. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) are not representative of every positive peptide claimed; SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every negative peptide claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 30, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent, wherein at least one cargo is attached to at least one positive peptide and/or the at least one negative peptide prior to (a) or (b).
The positive and negative peptides claimed can comprise of any sequence and the crowding agent can be any crowding agent. Therefore, there is substantial variation in the genus claimed. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) are not representative of every positive peptide claimed; SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every negative peptide claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 31, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent, wherein at least one cargo is attached to at least one positive peptide and/or the at least one negative peptide after (a) or (b).
The positive and negative peptides claimed can comprise of any sequence and the crowding agent can be any crowding agent. Therefore, there is substantial variation in the genus claimed. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) are not representative of every positive peptide claimed; SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every negative peptide claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
Regarding claim 32, the specification does not support that the inventors, at the time of filing, possessed the complete recited genus of a plurality of co-assembling peptides with at least one type of crowding agent; wherein the co-assembling peptides comprise at least one positive peptide of (a) and at least one negative peptide of (b); wherein the at least one positive peptide or the at least one negative peptide is a fusion protein with at least one cargo.
The positive peptide claimed can comprise of any sequence with the motif (A3-A1), wherein A3, A2, and A1 are selected from a positively charged or hydrophobic amino acid, wherein at least one is positively charged and one is hydrophobic. The negative peptide claimed can comprise of any sequence with the motif (B3-B1), wherein B3, B2, and B1 wherein at least one is negatively charged and one is hydrophobic. The crowding agent can be any crowding agent. Therefore, is substantial variation within the genus of the positive and negative peptide and the crowding agent. SEQ ID NO: 1 (CATCH (4+)), SEQ ID NO: 23 (mCATCH (4+)), SEQ ID NO: 3 (CATCH (6+)), SEQ ID NO: 5, SEQ ID NO: 6 (CATCH (2+)), and SEQ ID NO: 8 (CATCH (*4+) are not representative of every positive peptide claimed; SEQ ID NO: 2 (CATCH (6−)), SEQ ID NO: 22 (mCATCH (6-), SEQ ID NO: 4 (CATCH (4−)), SEQ ID NO: 7 (CATCH (2−)), are not representative of every negative peptide claimed; and Tween 20 and 80, PEG 1550, 2000, 3350, 6000, and 20000, Filcoll 70, and Dextran 50 do not represent every crowding agent claimed. Thus, while the specification supports possession of the co-assembling peptides and crowding agents reduced to practice, it does not support the broadest reasonable interpretation of the claim.
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 16, 20-21, 24, and 30-31 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 16 recites the phrase “selected from” after bullet (a). It is unclear if the phrase is used to select from the limitations of bullet (a)- a composition having a solid outer shell having a largest cross-sectional length of between 5 nm and 15 nm and a surfactant- or if it is used to select from the limitations of bullet (a), (b), or (c). Thus, the scope the claim is unclear.
If it is the former, the preface and bullet (a) should be written as: “The method of claim 14, wherein the crowding agent is: (a) [[selected from]] a composition having a solid outer shell having a largest cross- sectional length of between 5 nanometer (nm) and 15 nm [[and]] or a surfactant…”
If it is the latter, the preface and bullet (a) should be written as: “The method of claim 14, wherein the crowding agent is selected from: (a) [[selected from]] a composition having a solid outer shell having a largest cross- sectional length of between 5 nanometer (nm) and 15 nm and a surfactant…”
Claim 20 contains the trademark/trade name CHAPS. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate and, accordingly, the identification/description is indefinite.
Claim 20 also recites “dextran (50k or 500k).” It is unclear why the weight of dextran is in parentheses- if the applicant using parentheses to describe examples of weights or if only dextran 50 and dextran 500 are in the scope of the claim. Thus, claim 20 is indefinite.
Claim 21 recites the limitations "positive peptide" and ‘negative peptide’ in (a), (b), and (c). There is insufficient antecedent basis for this limitation in the claim. The base claim 14 does not recite a positive peptide or a negative peptide. Thus, the claim is indefinite as it is unclear what kind of peptide the cargo claimed is attached to.
Claims 30 and 31 are rejected for their dependency on base claim 21 and inability to overcome its indefiniteness.
Claim 21 also recites “optionally wherein the cargo is a protein, nucleic acid, or small molecule.” The exemplary phrase “optionally” is indefinite because no other options have been established for the cargo previously. There is no other alternative for what the cargo may be that could help define the scope covered by the claim [MPEP 2173.05 (h). Thus, claim 21 is indefinite.
Claims 30 and 31 are rejected for their dependency on base claim 21 and inability to overcome its indefiniteness.
Claim 24 recites the limitations “the concentration of the crowding agent in the solution is below the critical concentration required for the assembly of peptides into a fibrillar architecture in the absence of a crowding agent” and “the concentration of the surfactant is above the critical concentration required to form micelles/spherical structures.” These limitations are indefinite because the specification does not define these values and one of ordinary skill in the art would be unable to numerically define the concentrations as they are dependent on the type of co-assembling peptides and crowding agent. Thus, the scope of claim 24 is unclear, rendering it indefinite.
Claims 30 and 31 recites the limitation "the solution" in (a). There is insufficient antecedent basis for this limitation in the claim. The base claims 14 and 21 do not recite “a solution.” Thus, it is unclear what the order of the methods claimed comprise of, rendering claims 30 and 31 indefinite.
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 14-16, 20-21, 24, 26, and 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Hudalla et al. (US20180044379A1; published 2018), in view of Ranamukhaarachchi et al. (S. K. Ranamukhaarachchi, R. N. Modi, A. Han, D. O. Velez, A. Kumar, A. J. Engler, S. I. Fraley; Macromolecular crowding tunes 3D collagen architecture and cell morphogenesis. Biomater. Sci. 2019; 7 (2): 618–633. ) and Kozer et al. (Kozer, N., Kuttner, Y. Y., Haran, G., & Schreiber, G. (2007). Protein-protein association in polymer solutions: from dilute to semi dilute to concentrated. Biophysical journal, 92(6), 2139–2149.).
In the reply filed on May 29th, 2026, applicant elected KQKFKFKFKQK (SEQ ID NO: 3) as the species of positive peptide; EQEFEFEFEQE (SEQ ID NO: 2) as the species of positive peptide; one as the number of crowding agents; and polyethylene glycol 2000 (PEG 2000) as the exact species of crowding agent. The following rejection is based on the elected species.
Hudalla et al. provide charge complementary peptides that can be optionally coupled to a cargo polypeptide that are capable of self-assembling under stimulating conditions and of forming supramolecular structures [Abstract]. Hudalla et al. claims a method comprising:
“Mixing a positive peptide and a negative peptide in a solution at a pH ranging from about 6.5 to about 8.5,
a positive peptide comprising at least 3 amino acids (A1-A3, as set forth sequentially from C to N terminus), wherein A1, A2, and A3 are each independently selected from a positively charged amino acid and a hydrophobic amino acid, and wherein at least one amino acid of A1-A3 is a positively charged amino acid and at least one amino acid of A1-A3 is a hydrophobic amino acid; and
a negative peptide comprising at least 3 amino acids (B1-B3), wherein B1, B2, and B3 are each independently selected from a negatively charged amino acid and a hydrophobic amino acid, and wherein at least one amino acid of B1-B3 is a negatively charged amino acid and at least one amino acid of B1-B3 is a hydrophobic amino acid” [claim 18]. Hudalla et al. specify that the positive peptide segment can have a sequence of KQKFKFKFKQK (SEQ ID NO: 3) (CATCH (6+)) and the negative peptide segment can have a sequence of EQEFEFEFEQE (SEQ ID NO: 2) (CATCH (6−)) [0137].
Hudalla et al. does not teach a method of preparing the compositions with at least one type of crowding agent.
Ranamukhaarachchi et al. establish an approach to tune collagen fibril architecture using PEG as an inert molecular crowding agent during gelation and cell embedding [Abstract line 5]. They find that crowding produces matrices with tighter fibril networks that are less susceptible to proteinase mediated degradation, but does not significantly alter matrix stiffness.
“We also demonstrate that linearly increasing the amount of PEG added during collagen assembly and cell embedding reliably tunes fibril topography without significantly altering matrix stiffness or ligand density. Increasing amounts of PEG result in tighter networks of collagen fibers that are less degradable. This combination of features has the effect of confining cells in a rounded shape, reducing contractility, inducing the expression of cell–cell adhesion proteins, and triggering collective morphogenesis. We find that matrix degradability and fibril length are the strongest predictors of cellular confinement.” [pg 619 pgh 1].
The assembly of collagen I solution in vitro into a fibrous 3D matrix is thought to be driven by diffusion-limited growth of nucleated monomers, which is tunable through macromolecular crowding [pg 619 pgh 2 line 4]. Ranamukhaarachchi et al. geos on to teach the method of adding PEG to a 3D culture in collagen I matrix [pg 627 pgh 4]. Ranamukhaarachchi et al. does not teach that PEG 2000 can be substituted for PEG 8000.
Kozer et al. followed the association and diffusion rates of TEM1-b-lactamase (TEM) and the b-lactamase inhibitor protein (BLIP) in the presence of crowding agents of varying molecular mass, from monomers (ethylene glycol, glycerol, or sucrose) to polymeric agents such as different polyethylene glycols (PEGs, 0.2–8 kDa) and Ficoll [Abstract line 3].
In the dilute regime PEGs interfere with TEM-BLIP association by introducing a repulsive force due to solvophobic preferential hydration, which results in slower association than predicted by the SE (Stokes-Einstein) relation. Crossing over from the dilute to the semidilute regime results in positive deviations from SE behavior, i.e., relatively faster association rates. These can be attributed to the depletion interaction, which results in an effective attraction between the two proteins, winning over the repulsive force. In the concentrated regime, PEGs again dramatically slow down the association between TEM and BLIP, an effect that does not depend on the physical dimensions of PEGs, but rather on their mass concentration [Abstract line 11].
Thus, the physical dimensions of PEG are less important that the mass concentration when determining the rate of diffusion. Kozer et al. also foumd that lower MW molecules influence viscosities to a lesser extent than high MW molecules [pg 2141 pgh 9 and Fig 2A]. The molecular weights for PEG explored are 200, 600, 1000, 3350, 6000, and 8000.
Therefore, Kozer illustrates that it is routine optimization and a simple substitution to try different PEGs with varying molecular weights as crowding agents. It would have been obvious, prior to the effective filing date, for one of ordinary skill in the art to add another commercially available PEG, such as PEG 2000, as a crowding agent, to another species of self-assembling peptides, such as the co-assembling peptides taught by Hudalla et al. when preparing a composition comprising of peptides because Ranamukhaarachchi teaches that adding PEG tightens the self-assembling collagen’s network, increase endurability, and cellular confinement and Kozer et al. shows it is routine optimization to experiment with the physical dimensions of PEG to see how the rate of diffusion is affected.
Regarding claim 15, Hudalla et al. specify that the positive peptide segment can have a sequence of KQKFKFKFKQK and the negative peptide segment can have a sequence of EQEFEFEFEQE, corresponding to the elected species [0137].
Regarding claim 16, the elected species is PEG 2000, having a molecular mass in between 1000 and 10000000 Da. While Kozer et al. do not explicitly demonstrate the use of PEG 2000 when determining how the molecular mass affects the diffusion rate of TEM1-b-lactamase (TEM) and the b-lactamase inhibitor protein (BLIP), Kozer does demonstrate that it is routine optimization to experiment with the molecular mass of crowding agents, as they explore PEG 200, 600, 1000, 3350, 6000, and 8000 and Ficoll. Therefore, it would have been obvious to try crowding agents of different molecular mass, such as PEG 2000 as a crowding agent in the method taught by Hudalla et al. and Ranamukhaarachchi et al.
Regarding claim 20, the elected species is PEG 2000. While Kozer et al. do not explicitly demonstrate the use of PEG 2000 when determining how the molecular mass affects the diffusion rate of TEM1-b-lactamase (TEM) and the b-lactamase inhibitor protein (BLIP), Kozer does demonstrate that it is routine optimization to experiment with the molecular mass of crowding agents as they explore PEG 200, 600, 1000, 3350, 6000, and 8000 and Ficoll. Therefore, it would have been obvious to try crowding agents of different molecular mass, such as PEG 2000 as a crowding agent in the method taught by Hudalla et al. and Ranamukhaarachchi et al.
Regarding claim 21, Hudalla et al. claims “the set of charge complementary self-assembling peptides of claim 1, wherein the positive peptide, the negative peptide, or the positive and the negative peptide each further comprise one or more cargo polypeptides coupled to the N-terminus, the C terminus, or both the N-terminus and the C-terminus of the positive peptide, the negative peptide, or both the positive and the negative peptide” [claim 9]. Demonstrating the method, Hudalla teaches the nanofiber preparation of CATCH(-) integrated to fusion protein GFP [0190] and its incorporation into macroscopic hydrogels [0203]. Hudalla also teaches the expression and recovery of CATCH(−)GFP and its coassembly with CATCH peptides [0209-0212]. Thus, Hudalla makes obvious to a person of ordinary skill in the art adding at least one cargo in the method claimed.
Regarding claim 24, Ranamukhaarachchi et al. introduce increasing amounts of 8 kDa PEG (0–10 mg ml-1) [labeled P0- P10] into a 2.5 mg ml-1 collagen I solution during polymerization [pg 619 pgh 3 line 2]. PEG is reconstituted in PBS and the appropriate amounts of PEG are added to 1x reconstitution buffer composed of sodium bicarbonate, HEPES free acid, and nanopure water [pg 627 pgh 4 line 5]. Estimating the density of the PBS and buffer to be equivalent to water, this translates to 0-1 wt%, overlapping with the claimed range. Thus, it would have been obvious to claim a method preparing a composition comprising a particle of a plurality of co-assembling peptides with a concentration of crowding agent taught by Ranamukhaarachchi et al., optimizing the concentration as needed.
Regarding claim 26, Hudalla et al. show transmission electron microscope (TEM) images of CATCH variant combinations that can demonstrate β-sheet nanofibers [0282 and Fig 45A-D]. Briefly, Formvar-carbon coated 400 mesh copper grids (FCF400-CU-UB, EMS) were floated on top of 20 μL of 1×PBS solutions containing CATCH peptides with or without CATCH(−)GFP, and then dried by tilting the grid on a Kimwipe. Samples were negatively stained with 2% uranyl acetate in water, and analyzed using a Hitachi H-7000. Therefore, Hudalla et al. teaches a method wherein the at least one positive peptide and the at least on negative peptide do not form a hydrogel, but rather form nanofibers.
Regarding claim 30, Hudalla et al. teaches the expression and purification of peptide fusion proteins comprising a positive or negative CATCH peptide linked to GFP before co-assembling [0181].
DNA encoding fusion proteins consisting of each CATCH peptide or mutant CATCH peptide linked to superfolder GFP by a serine-glycine linker was inserted into a pET-21d vector between the Ncol site and Xhol site (FIGS. 12-13). Recombinant plasmids were then transformed into One Shot TOP10 Chemically Competent E. coli (Thermo) and plated on ampicillin (100 μg/mL) LB/agar plates for 18 hours at 37° C. Isolated colonies from the plates were selected and cultured in 5 mL of LB media with 0.1 mg/mL ampicillin overnight in an orbital shaker at 225 RPM and 37° C. for 18 hours. Plasmid DNA was recovered with the Qiagen Plasmid Miniprep Kit, and sequenced using the Sanger method at the University of Florida Interdisciplinary Center for Biotechnology Research. Positive DNA sequences were then transformed into Origami B (DE3) Competent Cells (Novagen) and plated on ampicillin (0.1 mg/mL) and kanamycin (0.05 mg/mL) LB/agar plates for 18 hours at 37° C. [0182].
Nanofibers with integrated fusion proteins were then prepared by mixing stock solutions of CATCH(−)GFP, CATCH(−), and CATCH(+) [0190]. Thus, it is obvious over Hudalla et al. to attach the at least one cargo prior to its assembly.
Regarding claim 31, changes in the sequence of adding ingredients that require only ordinary skill in the art is considered a routine expedient. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930). The applicant does not rely on the criticality of the order in which the at least one cargo is attached to the at least one positive peptide or the at least one negative peptide for its self-assembly [MPEP 2144.04]. Therefore, the method claimed is obvious over Hudalla et al.
Regarding claim 32, Hudalla et al. claims “the set of charge complementary self-assembling peptides of claim 1, wherein the positive peptide, the negative peptide, or the positive and the negative peptide each further comprise one or more cargo polypeptides coupled to the N-terminus, the C terminus, or both the N-terminus and the C-terminus of the positive peptide, the negative peptide, or both the positive and the negative peptide” [claim 9]. Hudalla teaches the nanofiber preparation of CATCH(-) integrated to fusion protein GFP [0190] and its incorporation into macroscopic hydrogels [0203]. Hudalla also teaches the expression and recovery of CATCH(−)GFP and its coassembly with CATCH peptides [0209-0212]. Thus, Hudalla makes obvious to a person of oridinary skill in the art adding at least one cargo in the method claimed.
Conclusion
Claims 20 and 32 are objected to. Claims 16, 20-21, 24, and 30-31 are rejected under 35 U.S.C. 112(b). Claims 14-16, 20-21, 24, 26, and 30-32 are rejected under 35 U.S.C. 112(a). Claims 14-16, 20-21, 24, 26, and 30-32 are rejected under 35 U.S.C. 103.
Correspondence
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/SACHI JAUHARI/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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