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
The current application claims priority to U.S. provisional application 63/387452, filed on 14 December 2022. The effective filing date is 14 December 2022.
Information Disclosure Statement
The information disclosure statement (IDS), filed on 01 October 2024, was considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-20 are the original claims. Claims 1-20 are pending and the subject of this office action.
Claim Objections
Claims 3, 12, 19, and 20 are objected to because of the following informalities: the claims refer to either a non-natural polypeptide that “has” an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6 (claims 3 and 12), or a non-natural polypeptide “having” at least 70% sequence identity to at least one of an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6 (claims 19 and 20). It is unclear if the claims are using the term “has” or “having” inclusively or exclusively. For example, if claim 3 was interpreted, so that “has” was exclusive, then the polypeptide that has SEQ ID NO: 3, is a 10 amino acid peptide. If “has” was being using inclusively, then the polypeptide that has SEQ ID NO: 3 may also comprise additional amino acids, and as such would also encompass SEQ ID NO: 1, which is much a longer amino acid sequence. MPEP 2111.03 provides guidance for defining the scope of claims regarding unrecited additional components or steps. In the context of transitional phrases, it defines “comprising”, as well synonyms (i.e. “including”, “containing”, or “characterized by”), to be inclusive, “consisting of” to be exclusive, and “having” to be inclusive or exclusive depending on the specification. In the current application/specification, there is no clear definition of how the applicant intended this term to be interpreted. For the purposes of the prior art search, the examiner has interpreted “has” and “having” to be inclusive. Additionally, if the applicant intended for “has” and “having” to be exclusive, then it must be stated that 35 U.S.C. 112(a) written description requirements have not been met for claims 3 and 12, see 35 U.S.C. 112(a) rejections of claims 5 and 14. This uncertainty could be averted by amending the claims to use the correct form of either “comprise” (for inclusive) or “consist” (for exclusive).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 and 11 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. The claims refer to a non-natural polypeptide sharing at least 75% sequence identity to MHC-1. MHC class 1 is a class of highly polymorphic molecular complexes, and not an individual moiety, that can be represented by a single amino acid sequence. The specification refers to a polypeptide, corresponding to the amino acid sequence referenced in SEQ ID NO:1, which is derived from HLA-C, a protein belonging to the MHC-1 class of proteins, however no HLA-C amino acid sequence is provided ([0095]). Furthermore, HLA-C is highly polymorphic, and unless a specific species is specified, no specific amino acid sequence can be assumed. As such, the instant claims, as written, are indefinite, because neither the prior art nor the specification provides an amino acid, against which sequence identity calculations may be performed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 19 and 20 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a product of nature without significantly more. The claims are directed towards
a composition of matter (“non-natural” polypeptides having at least 70% sequence identity to SEQ ID Nos: 1-6 and showing binding activity against the RBD domain of SARS-CoV-2). The specification provides no definition for what constitutes “non-natural”, and provides only one working exemplary embodiment, MH-1, which is comprised of SEQ ID NO:1. This example comprises a wild-type sequence from human HLA-C fragment, which is also present-in-part in the amino acid sequences represented by SEQ ID Nos: 3, 5, and 6. It is evident from claims 3, 12, and 20, that small stretches of the polypeptide fragments are of special interest to the applicant (i.e. SEQ ID Nos: 2-4), however there is no disclosed rationale or structure-function relationship teaching the importance of these sequences. The small and seemingly important peptide fragments, referenced in SEQ ID Nos: 2 and 3, share 100% sequence identity with wild-type MHC-1 molecules and are therefore considered products of nature. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim does not recite any additional elements. The applicant has failed to provide evidence that the disclosed invention displays markedly different properties from its natural counterpart (i.e. MHC-1 molecules or fragments thereof). This judicial exception is not integrated into a practical application because the polypeptides, comprising wild-type MHC-1 fragments, have not been shown to perform any function that naturally occurring MHC-1 molecules or fragments thereof are not capable of performing (i.e. binding the RBD domain of the SARS-CoV-2 spike protein), see MPEP 2106 for further guidance.
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.
WRITTEN DESCRIPTION
Claims 1-20 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 claims 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.
In regard to claims 1, 2, 4-11, and 13-18, the claims reference methods comprising non-natural polypeptides including a fragment of MHC-1. As discussed above, MHC 1 is a class of highly polymorphic molecular complexes. As written, the scopes of claims 1 and 10 extend to methods comprising any fragment of MHC 1 capable of satisfying the additional limitations of the claims, and as such each claim is attempting to claim a genus of methods. The applicant has only shown possession of one species of each method referenced in claim 1 and 10 (i.e. methods comprising MH-1, which corresponds to SEQ ID NO: 1). Critically, neither the current application nor the prior art sheds any light on the interaction between the selected region of the MHC-1 molecule, used in the disclosed working example, and the SARS-CoV-2 spike protein, that would allow one to predictably select additional polypeptides from other MHC-1, that would behave predictably in the context of the related claims. The applicant has not provided any evidence of a known structure or experimental data that would allow for the identification of critical interactions between the peptide and the spike protein, and as such the written description requirement for claims 1 and 10, as well as claims dependent on said claims, has not been met.
In regard to claims 5 and 14, the claims refer to methods utilizing non-natural polypeptides, wherein the polypeptide consists of between 10 and 400 amino acids. The current application only provides results supporting methods, as described for claims 1 and 10, in which a polypeptide, comprised of the amino acid sequence described by SEQ ID NO: 1, is utilized. This sequence is taught to be derived from HLA-C but also comprises several additional regions and domains (i.e. His-tag and mCherry domain) and is 359 amino acids in length. The applicant has not demonstrated that they possessed polypeptides of various lengths, spanning the broad range referenced in the claims, that also function in the claimed methods. In particular, the applicant has not demonstrated possession of a non-natural peptide of less than 30 amino acids in length. The relevance of this deficiency is taught by Merritt HI, et al. (2020) Bent Into Shape: Folded Peptides to Mimic Protein Structure and Modulate Protein Function. Pept Sci (Hoboken). 2020 Jan;112(1):e24145 (herein Merritt). Merritt teaches that the use of short peptides, derived from larger sequences, is challenging, because they rarely retain a defined fold, once excised from the native protein (Introduction paragraph 2). It is stated that peptides, less than 15 amino acids in length, often do not adopt stable secondary conformations. Also, tertiary structural motifs are often missing in peptides, less than 30 amino acids in length. Thus, short peptides (>30 amino acids in length), are not likely to adopt a native-like fold. SEQ ID NO: 2 and SEQ ID NO: 3, which is also found in SEQ ID Nos: 1, 5, and 6, correspond to amino acids of the alpha-chain of HLA-C, and when looking at the position, corresponding to these sequences, in a 2.5Å crystal structure of human HLA-C*06:02 (residues 122-131 of PDB ascension code 5XS3), one can observe that these amino acids make up part of a beta-strand and a beta-hairpin, which connects to a neighboring anti-parallel beta-strand to form a beta-sheet. When excising a 10 amino acid-long peptide, corresponding to SEQ ID Nos: 2 or 3, from their native context, it is highly unlikely that they will retain their native fold (beta-strand), especially when considering the absence of neighboring beta-strands, which normally stabilize the secondary structure via inter-strand hydrogen bonds. The applicant has demonstrated that a peptide, comprising SEQ ID NO: 1, is functional in the context of the methods referenced in claims 5 and 14. This peptide comprises the amino acid sequence defined in SEQ ID NO:3, as well as additional surrounding amino acids surrounding, from the native HLA-C protein, as well as a stabilizing mCherry domain ([0066]). These additional amino acids provide the necessary secondary and tertiary folding restraints for the peptide to adopt a native-like conformation. The applicant has not demonstrated that smaller peptide excisions would result in peptides that have adopted the intended conformation and are effective in the methods associated with the claims. Merritt et al do provide a review of various design strategies that were known in the art, near the time of filing, that allow for β-sheet peptide mimetics, but these techniques are all taught to be either still in development, possessing design limitations, or lacking working examples, and as such are by no means routine (Section 2: β-Sheet Peptide Mimetics).
In regard to claims 3, 12, 19, and 20, the claims refer to non-natural polypeptides including a fragment of MHC-1, wherein the polypeptide has an amino acid sequence sharing between 70 – 100% sequence identity with SEQ ID Nos: 1-6. The examples provided in the specification of the current application only include results related to experiments, comprising the MH-1 polypeptide, which is equivalent to SEQ ID NO:1. Thus, the applicant has only demonstrated possession of a polypeptide, comprising SEQ ID NO:1, that is capable of functioning within the limitations of the claims. Additionally, neither the current application nor the prior art sheds any light on the interaction between the selected region of the MHC-1 molecule and the SARS-CoV-2 spike protein, that would allow one to modify this sequence, in such a way that effects would be predictable in the context of the related claims. The applicant has not provided any evidence of a known structure or experimental data that would allow for the identification of critical interactions between the peptide and the spike protein, and as such any modification of the peptide sequence would have unpredictable effects in the context of the claimed methods of claims 3 and 12 or the binding activity of claims 19 and 20.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MATTHEW CURRAN METCALF/ Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
