DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the cited rejections 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.
3. Response to Election/Restriction filed on 6/10/2026 is acknowledged.
4. Claim filed on 7/16/2024 is acknowledged.
5. Claims 14 and 18 have been cancelled.
6. Claims 1-13, 15-17 and 19-22 are pending in this application.
7. Claims 8-13, 15-17 and 19-22 are withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claim 4 is withdrawn from consideration as being drawn to non-elected species.
8. Claims 1-3 and 5-7 are under examination.
Priority
9. The instant application is a 371 of PCT/US2022/034076 filed on 6/17/2022, which claims priority to US provisional application No. 63/211980 filed on 6/17/2021. US provisional application No. 63/211980 fails to provide support to instant claims 1-3 and 5-7. Therefore, the effective filing date of instant claims 1-3 and 5-7 is 6/17/2022.
Election/Restrictions
10. Applicant’s election without traverse of Group 1 (claims 1-7) and election without traverse of a rippled antiparallel cross-β dimer wherein both X1 and X2 are Y as species of a rippled antiparallel cross-β dimer in the reply filed on 6/10/2026 is acknowledged. Since the elected species is a subgenus, not a species; the Examiner telephoned Applicant’s representative, Brian E. Davy, for further species election. Applicant’s representative states on the phone that a rippled antiparallel cross-β dimer with one monomer being FYF and another monomer being fyf as the elected species of a rippled antiparallel cross-β dimer on 6/17/2026 (see PTO-413 mailed on 6/23/2026). The requirement is made FINAL in this office action.
Group 1 is drawn to a rippled antiparallel cross-β dimer comprising (L,L,L)-(FX1F)k dimerized with (D,D,D)-(FX2F)k, wherein X1 and X2 are independently selected from any amino acid, and wherein k is an integer of 1 or greater. A search was conducted on the elected species; and this appears to be free of prior art. A search was extended to the genus in claim 1; and prior art was found. Claim 4 is withdrawn from consideration as being drawn to non-elected species. Claims 1-3 and 5-7 are examined on the merits in this office action.
Sequence Non-Compliance
11. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below. All sequences disclosed in the application must comply with the requirements of 37 C.F.R. 1.821-1.825, not only those recited in the claims.
In the instant case, the instant specification discloses various amino acid sequences throughout the specification, for example, page 3, lines 12-13; page 11, lines 26 and 28; page 12, line 5; and page 15, lines 27 and 29. However, there is no sequence listing filed in instant application.
All such sequences are relevant for the purposes of building a comprehensive database and properly assessing prior art. It is therefore essential that all sequences, whether only disclosed or also claimed, be included in the database.
Objections
12. The specification is objected to for the following minor informality: The specification discloses various amino acid sequences throughout the specification, for example, page 3, lines 12-13; page 11, lines 26 and 28; page 12, line 5; and page 15, lines 27 and 29. However, there is no sequence listing filed in instant application; and they are missing the respective sequence identifier. Applicant is required to amend the specification to comply with 37 CFR 1.821(c) and 1.821(d).
13. The use of trademarks has been noted in this application, for example, Tween-20 on page 7, line 34 and many others throughout the specification. Each letter of the trademarks should be capitalized wherever it appears and be accompanied by the generic terminology. Although the use of trademarks is 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 trademarks.
Please note: The specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification (see MPEP § 608.01).
14. Claim 1 is objected to for the following minor informality: Applicant is suggested to amend claim 1 as “A rippled antiparallel cross-β dimer comprising: (a) a first monomer comprising the amino acid sequence (FX1F)k, wherein all the amino acids are in L-form; and (b) a second monomer comprising the amino acid sequence (fX2f)k, wherein all the amino acids are in D-form; and wherein X1 and X2 are independently selected from any amino acid, and each k is independently an integer of 1 or greater”.
Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
15. 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.
16. Claims 1-3 and 5-7 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 pre-AIA the applicant regards as the invention.
17. Claim 1 recites “A rippled antiparallel cross-β dimer comprising (L,L,L)-(FX1F)k dimerized with (D,D,D)-(FX2F)k, wherein X1 and X2 are independently selected from any amino acid, and wherein k is an integer of 1 or greater”. It is unclear whether k in each monomer needs to be the same or not. Therefore, the metes and bounds of instant claim 1 is vague and indefinite. Because claims 2, 3 and 5-7 depend from indefinite claim 1 and they do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
18. Claim 5 recites the limitation “wherein the dimer is water-soluble”. With regards to the term “water-soluble”, the instant specification discloses that “In certain embodiments, the dimers are water-soluble, i.e., capable of being dissolved in water” (see page 7, lines 8-9 of instant specification). However, it is unclear what the cutoff is between water-soluble and water-insoluble. As an example, the Styrene document (from https://www.inchem.org/documents/icsc/icsc/eics0073.htm, 2006, enclosed pages 1-2) indicates styrene has a water solubility of 0.03g/100ml at 20oC (see page 2, Section “PHYSICAL & CHEMICAL INFORMATION”). However, the Styrene document (from https://www.alfa-chemistry.com/product/styrene-stabilized-with-tbc-cas-100-42-5-446258.html, 2026, enclosed pages 1-4) explicilty states styrene is insoluble in water (see page 2, Section “Specification”). Therefore, the metes and bounds of instant claim 5 is vague and indefinite. Because claims 6 and 7 depend from indefinite claim 5 and they do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
19. Claim 6 recites the limitation “wherein the N-terminus of the (L,L,L)-(FX1F)k monomer comprises a free amine or a free carboxylate”; and claim 7 recites the limitation “wherein the N-terminus of the (D,D,D)-(FX2F)k monomer comprises a free amine or a free carboxylate”. It is well known in the peptide art that the N-terminus of a peptide can comprise a free amine. However, it is unclear what the recited “a free carboxylate” in such monomer means, in that whether it requires the N-terminus of the recited monomer needs to be Glu or Asp or not. Therefore, the metes and bounds of instant claim 6 or 7 is vague and indefinite.
Claim Rejections - 35 U.S.C. § 112 paragraph (a)
Written Description
20. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
21. Claims 1-3 and 5-7 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient” (MPEP § 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP § 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
In the instant case, claims 1-3 and 5-7 recite a rippled antiparallel cross-β dimer comprising (L,L,L)-(FX1F)k dimerized with (D,D,D)-(FX2F)k, wherein X1 and X2 are independently selected from any amino acid, and wherein k is an integer of 1 or greater.
The genus of instant claimed rippled antiparallel cross-β dimer is extremely broad, including any dimer comprising (L,L,L)-(FX1F)k dimerized with (D,D,D)-(FX2F)k; and the length of the monomer can be any number ≥ 3 amino acids.
The instant specification discloses rippled antiparallel cross-β dimers of FFF:fff, FYF:fyf, FWF:fwf and FWF:fyf as the examples of instant claimed rippled antiparallel cross-β dimer.
The issue at question is whether a person of ordinary skilled in the art would be able to determine what structural feature/amino acid sequence is required for the instant claimed monomers to have the functional characteristics of being a rippled antiparallel cross-β dimer or not.
(a) actual reduction to practice and (b) disclosure of drawings or structural chemical formulas:
In the instant case, the instant specification discloses rippled antiparallel cross-β dimers of FFF:fff, FYF:fyf, FWF:fwf and FWF:fyf as the examples of instant claimed rippled antiparallel cross-β dimer. And they are tested in the working examples in instant specification.
The instant specification further discloses the growth of the present understanding of the interplay of thermodynamics and kinetics that underline the formation of pleated vs rippled sheets remains extremely limited; and not all racemic peptide mixtures form rippled sheets.
Taken all these together, other than the limited examples, the instant specification fails to disclose the effect of either altering the amino acid sequence or the length of any one of the monomers on the functional characteristics of being a rippled antiparallel cross-β dimer. The instant specification does not describe a general correlation between structure and function for the claimed genus of dimers to be a rippled antiparallel cross-β dimers.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure:
As discussed above, in the instant case, based on the disclosure of instant specification, other than the limited examples, a person of ordinary skilled in the art would not be able to determine the effect of either altering the amino acid sequence or the length of any one of the monomers on the functional characteristics of being a rippled antiparallel cross-β dimer.
With regards to a rippled antiparallel cross-β dimer, Raskatov et al (Acc. Chem. Res., 2021, 54, pages 2488-2501, filed with IDS), throughout the literature, teach it is unpredictable whether any mixture of a peptide with its mirror image will form a rippled antiparallel cross-β dimer or not, for example, Abstract; page 2490, Figure 2; and page 2497-2499, Section “3. KINETICS, THERMODYNAMICS, AND UNRESOLVED CHALLENGES”.
Furthermore, it is well known in the peptide/protein art that even single amino acid changes or differences in the amino acid sequence of a protein/peptide can have dramatic effects on the protein/peptide’s function and/or properties. As an example of the unpredictable effects of mutations on protein/peptide’s function and/or properties, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section “CYSTIC FIBROSIS”. Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation ΔF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2nd paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. Although the disclosures of Drumm et al and Yampolsky et al are directed to proteins/peptides other than a rippled antiparallel cross-β dimer, they illustrate the inherent unpredictability with respect to the function and/or property of a given protein/peptide after even minor changes to the primary amino acid sequence.
Therefore, based on the state of art, a person of ordinary skilled in the art would not be able to determine the effect of either altering the amino acid sequence or the length of any one of the monomers on the functional characteristics of being a rippled antiparallel cross-β dimer.
(d) representative number of samples:
In the instant case, the genus of instant claimed rippled antiparallel cross-β dimer is extremely broad, including any dimer comprising (L,L,L)-(FX1F)k dimerized with (D,D,D)-(FX2F)k; and the length of the monomer can be any number ≥ 3 amino acids.
And, as discussed in (a) and (b) above, the instant specification discloses rippled antiparallel cross-β dimers of FFF:fff, FYF:fyf, FWF:fwf and FWF:fyf as the examples of instant claimed rippled antiparallel cross-β dimer. And they are tested in the working examples in instant specification.
The instant specification further disclosed the growth of the present understanding of the interplay of thermodynamics and kinetics that underline the formation of pleated vs rippled sheets remains extremely limited; and not all racemic peptide mixtures form rippled sheets.
Considering the broadness of the genus of instant claimed rippled antiparallel cross-β dimer, the instant specification fails to provide sufficient examples to describe the entire genus of rippled antiparallel cross-β dimer claimed.
Taken all these together, considering the state of the art and the disclosure in instant specification, it is deemed that the instant specification fails to provide adequate written description for the genus of rippled antiparallel cross-β dimer claimed; and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Rejections - 35 U.S.C. § 102(a)(1)
22. 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.
23. Claims 1-3 and 5-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kuhn et al (Chem. Sci., 2022, 13, pages 671-680, first published on 12/8/2021, filed with IDS).
The instant claims 1-3 and 5-7 are drawn to a rippled antiparallel cross-β dimer comprising (L,L,L)-(FX1F)k dimerized with (D,D,D)-(FX2F)k, wherein X1 and X2 are independently selected from any amino acid, and wherein k is an integer of 1 or greater.
Kuhn et al, throughout the literature, teach a rippled β-sheet fibril comprising a monomer FFF dimerized with a monomer fff, wherein the dimer is water-soluble, for example, page 673, Figure 2; and page 676, right column, Section “Crystallization”. It meets the limitations of instant claims 1-3 and 5-7.
Since the reference teaches all the limitations of instant claims 1-3 and 5-7; the reference anticipates instant claims 1-3 and 5-7.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LI N KOMATSU whose telephone number is (571)270-3534. The examiner can normally be reached Mon-Fri 8am-4pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached on 5712707430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LI N KOMATSU/Primary Examiner, Art Unit 1658
Prosecution Insights