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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 1/5/2024, 9/9/2025, and 4/16/2026, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 32-53, filed 1/5/2024, are pending. Claims 32-53 are under examination.
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 32-42, 46-49, and 51 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.
Claim 32 recites an open-ended number of peptide sequences that all contain at least a first region and a second region. The transition phrase “comprising” allows for any number of additional residues. This results in a very broad claimed sequence space. Applicant discloses nine discrete examples with very similar sequences and more importantly, very similar lengths.
At the time the invention was made, the level of skill for preparing peptides with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure (length) provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally.
Applicant discloses nine combinations of regions that result in fourteen functional peptides. However, these peptides have similar length and very similar sequence identity. These similarities are shown below as a multiple sequence alignment:
CLUSTAL O(1.2.4) multiple sequence alignment
Ce16 DKEWALQKIYEIMRKLDEDGHAEASMRASDLIYEFMKKD 39
Ce14 DKEWALQKIYEIMRKLDEDGHAEASMRVSDLIYEEMKKD 39
Ce1 DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKD 39
Ce4 DKEWILQKIYEIMRKLDEDGHAEASMRVSDLIYEFMKKD 39
Ce15 DKEWILQKIYEVMRKLDEDGHAEASMRVSDLIYEFMKKD 39
Ce172 DKLWILQKIYEIMVRLDEEGHGEASLMVSDLIYEEMERD 39
Ce9 DKEWILQKIYEIMRRLDEEGHAEASMRVSDLIYEEMKKD 39
Ce59 DKEWILQKIYEIMRRLDEEGHGEASLRVSDLIYEFMKRD 39
Ce41 DKEWILQKIYEIMRRLDEEGHGEASLRVSDLIYEFMKKD 39
Ce149 DKEWILYKIYEIMVRLDEEGHGEASLMVSDLIYEFMERD 39
Ce174 DKEWILYKIYEIMQRLDEEGHGEASLMVSDLIYEFMKRD 39
Ce113 DKEWILQKIYEIMQRLDEEGHGEASLMVSDLIYEFMKRD 39
Ce173 DKLWILQKIYEIMQRLDEEGHGEASLMVSDLIYEFMKRD 39
** * * ****:* *** **.***: .****** *::*
Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus.
Specifically, Applicant discloses Table 1 and Table 2 which provide a skilled artisan the needed information to identify functional sequences with 80% sequence identity. This rejection is not based on sequence identity. Rather, the currently claimed genus includes peptides of great length, which expands the genus to a size wherein the provided examples are no longer representative.
In the general case, London et al. (London, et al. Structure 18.2: 188-199.(2010)) discloses that the median size of binding peptides is 40.3 +/- 26.5 (London et al., page 190, Table 1). This indicates that peptide size beyond a certain point tends to inhibit binding ability.
More specifically, this phenomenon has been reported in specific cases by O’Brien et al. (O'Brien, et al. Immunome research 4.1: 6 (2008)). O’Brien reports: “The data presented in Figure 2 allowed us to examine the limits of the effect with respect to final peptide length. By examining the log fold-change in affinity for MHC class II as the length of the peptide increases it can clearly be seen that the impact on affinity lessens. The regression plot also shows that at approximately 19 amino acids the effect of peptide elongation on affinity becomes zero. Elongating peptides beyond this point would – in the majority of cases – result in a diminished affinity. This seems logical: if no such ceiling existed for the positive effect of peptide length then sequence length alone would be the key determinant of peptide-MHC affinity. This discovery is also strengthened by the findings of Lippolis et al. who eluted and sequenced peptides from HLA-DR*0401 and found that the most abundant species within a family of nested peptides were between 14 and 21 residues in length [15]. Our findings do not however suggest that a single optimal length would exist for all peptides for all MHC class II alleles, and indeed the relative heterogeneity of peptides binding to MHC class II molecules is well reported [15–17]. However, this approximation to an optimal length is consistent for a large number of peptide sequences and a large number of MHC class II alleles. (O’Brien et al., page 4, col. 2, para. 2).
Finally, extension on the N-terminus or C-terminus can have variable effects on the binding affinity of a given peptide. Höring et al. (Höring, et al. The Journal of Immunology 163.8: 4434-4441. (1999)) discloses the following phenomenon:
“We found that H-2Kb molecules can accommodate extended peptides, but only if the extension occurs at the C-terminal peptide end, and that hydrophobic flanking regions are preferred. Peptides extended at their N terminus did not promote productive formation of the trimolecular complex. A structural basis for such findings comes from molecular modeling of a H-2Kb/12 mer complex and comparative analysis of MHC class I structures. “
Many explanations for this length ceiling present themselves. It may be that as peptides become very long they are no longer able to form favourable interactions with the MHC or TCR.” (Höring et al., Abstract).
Examining Applicant Figure 76, it is reasonable to conclude that a large swathes of the claimed genus would include residues that interferes with the claimed binding activity. Therefore, the provided examples are not representative of the enormous claimed genus.
Given the issue of the open-ended lengths of the claimed genus, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every polynucleotide molecule recited by claim 32.
Consequently, claim 32 is rejected.
Regarding claims 33-39, claim 32 is rejected as described above. These claims do not further limit the genus size of claim 32 and therefore one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every peptide molecule recited by these claims.
Claims 33-39 are rejected.
Regarding 40-42, claim 32 is rejected as described above. These claims limit the size of a given region of the peptide of claim 32, but do not limit the overall size of the total structure implied by the transitional phrase “comprising”. One of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every peptide molecule recited by these claims.
Claims 40-42 are rejected.
Regarding claim 51, claim 32 is rejected as described above. This claims does not further limit the genus size of claim 32 and therefore one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every peptide molecule recited by this claim.
Claims 51 is rejected.
Examiner Note: Due to the definite peptide lengths recited by claims 43-45, 50, and 52-53, these claims are not subject to this rejection. Similar requirements in the rejected claims would overcome this rejection.
Examiner Note 2: An enablement rejection was considered for claim 52. Claim 44, the claim from which claim 52 depends, recites SEQ ID NO: 54, which is Applicant variant Ce41. The specification states that Ce41 cannot bind the Omicron variants of SARS-CoV-2 in para. [0160]. However, claim 44, the claim from which claim 52 depends, recites SEQ ID NO: 55, which is Applicant variant Ce113. Ce113 is effective against Omicron as stated later in para. [0162]. Consequently, this claim is enabled against all the listed variants of claim 52.
Allowable Subject Matter
Claims 32-42, 46-49, and 51 are free of the prior art, but not allowable because of the 112(a) rejection made above.
Regarding the available prior art, Cao et al. (Cao, Science 370.6515: 426-431. (2020)) discloses the peptide LCB1:
DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER (Cao et al., Supplemental page 27, Table S2).
This peptide can be aligned against SEQ NO: 1 and SEQ ID NO: 2 of the current application:
#=======================================
#
# Aligned_sequences: 2
# 1:
# 2:
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 56
# Identity: 18/56 (32.1%)
# Similarity: 18/56 (32.1%)
# Gaps: 36/56 (64.3%)
# Score: 91.0
#
#
#=======================================
1 DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERL 50
||||||||||||||.|||.|
1 DKEWILQKIYEIMRRLDEEG------------------------------ 20
51 LEEVER 56
20 ------ 20
#---------------------------------------
#---------------------------------------
#=======================================
#
# Aligned_sequences: 2
# 1:
# 2:
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 56
# Identity: 15/56 (26.8%)
# Similarity: 17/56 (30.4%)
# Gaps: 37/56 (66.1%)
# Score: 79.0
#
#
#=======================================
1 DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERL 50
|.|||:|||||||||||:.
1 --------------------HGEASLRVSDLIYEFMKRD----------- 19
51 LEEVER 56
19 ------ 19
#---------------------------------------
#---------------------------------------
In order to fulfill the final clause of claim 1: “…and a bond is formed between an amino acid residue within 5 residues from N terminal in the sequence of the site in the first region that binds to the receptor binding domain (RBD) in SARS- CoV-2 and an amino acid residue within 5 residues from C terminal in the sequence of the site in the second region that binds to the receptor binding domain (RBD) in SARS-CoV-2, whereby the peptide binds to the receptor binding domain (RBD) in SARS-CoV-2.”, the third helix of Cao, DERLLEEAERLLEEVER, would have to be removed and furthermore compensatory mutations made as shown above.
First, 80% identity to a 19 residue segment only allows for 3.8 residues to be substituted, while there are four substitutions in the second helix of Cao. But more importantly, it is not obvious to remove the third helix of a three-helix bundle.
Bryson et al. (Bryson, et al. Protein Science 7.6: 1404-1414 (1998)) discloses that each helix of the three helix bundle satisfies electrostatic and hydrophobic interactions with the other two helices:
PNG
media_image1.png
153
438
media_image1.png
Greyscale
(Bryson et al., page 1405, Fig. 2)
Bryson summarizes the design requirements for such three helix bundles:
“These results illustrate a hierarchic approach to the design of native proteins beginning with the coordinates of an idealized coiled coil. The design began with idealized amphiphilic helices that hydrophobically associated into a coiled coil, and proceeded in several steps to include: (1) capping interactions at the ends of the helices; (2) electrostatic interactions between partially exposed side chains at the helix/helix interfaces; (3) a hydrophobic core that incorporated a variety of hydrophobic residues.” (Bryson et al., page 1411, col. 1, para. 4).
This is not to say that a three-helix to two-helix conversion is unknown in the art. However, it is known to result in non-functional proteins that require re-engineering:
“Many recent studies have focused on the Fc-binding domain of protein A as a model for understanding protein folding and molecular recognition (Figure 1). Its small size (58 residues) and simple structural features make it an attractive target for tertiary structure prediction algorithms [72–74]. Nord et al. [75] have begun to use this fold as a scaffolding for molecular recognition. They randomized the identities of 13 residues on the solvent-exposed positions in the protein and expressed the resulting protein on the surface of phage. The authors report that the resulting library is a viable starting point for selecting novel artificial antibodies. In a different approach, Braisted and Wells [76] have used phage display to reduce the size of this three-helix bundle down to a two-helix bundle with retention of its binding affinity. One helix was removed, resulting in a protein that failed to fold or bind IgG. To recover activity, the newly exposed sites on the remaining two helices were randomized and phage display was used to select miniaturized proteins that had regained the ability to fold and bind to IgG. Recently, the structure of this domain was solved using NMR spectroscopy [77]. The interhelical geometry found in the wild-type protein is maintained in the optimized dimer, although the ends of the helices tend to show excessive mobility. This dynamic behavior was successfully minimized through the addition of an intramolecular disulfide bond near the ends of the helices.” (Schneider et al., page R37, col. 2., para. 3).
Given that it required randomization followed by phage display to recover activity, this constitutes a teaching away from the removal of an entire helix. Even if modern folding programs make this process somewhat easier, this cannot be fairly characterized as an obvious molecule to create based off the available teachings of Cao and the other available prior art.
The other peptides disclosed by the current application are nearly identical to sequence to SEQ ID NO: 1 and SEQ ID NO:2, only different by a residue or two. Consequently, the same analysis applies to every disclosed set of sequences present in the application. In each case, novelty and nonobviousness lies in the binding clause above, which necessitates the removal of a helix. For the record, however, most of the substitutions are also non-conservative and therefore would be non-obvious outside the context of the removal of the third helix.
Claims 43-45 and 51-52 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
These claims recite closed-ended peptides of finite length that are novel and nonobvious for the reasons discussed above. This claim is not rejected under U.S.C 112(a) like the claims discussed above and therefore is free of the prior art and has no other rejections. However, they are dependent upon a rejected claim and therefore no allowable.
Claim 50 is allowable.
Regarding claim 50, this claim recites specific closed-ended peptides that are novel and nonobvious for the reasons discussed above. This claim is not rejected under U.S.C 112(a) like the claims discussed above and therefore is free of the prior art and has no other rejections. This claim is also not dependent upon a rejected claim.
Conclusion
Claims 43-45 and 51-52 are objected to.
Claims 50 is allowable.
Claims 32-42, 46-49, and 51 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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