DETAILED ACTION
Applicant’s amendment and remarks filed July 15, 2025 are acknowledged.
Specification
The disclosure remains objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See for example page 43; there may be other instances. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. This matter was not addressed in Applicant’s reply filed July 15, 2025.
Claims Summary
Claim 43 is directed to an isolated mixture of at least two different peptidogenic proteins derived from a starting protein. Each of the peptidogenic proteins has altered (i.e., increased (claim 53)) conformational dynamics and similar conformation compared to the starting protein. Each of the peptidogenic proteins comprises replacement of at least one non-surface amino acid residue in the starting protein with a different amino acid residue. The specification defines a “peptidogenic protein” as a mutated protein that has been modified in its amino acid sequence to alter its conformational dynamics as compared to the starting protein sequence while maintaining similar conformation to the starting protein. The specification defines “conformational dynamics” as the phenomena related conformational changes and flexibility of a protein structure in the spatial arrangement of atoms or groups of atoms with respect to each other in a protein molecule, including “breathing motions”, vibration, bending, twisting, rotation and other allowed modes of movement of the atoms joined by the covalent bonds in the protein molecule (see paragraph [0047]). The specification defines “similar conformation” to a starting protein if the 3-D structure is sufficiently maintained after mutating non-surface residues of the protein to allow for an antibody to cross react with both the peptidogenic protein and the starting protein (see paragraph [0049]).
In another embodiment, at least 1-20 amino acids of the peptidogenic proteins are replaced in the starting protein (claim 45). The starting protein is selected from a variety of proteins outlined in claim 49. The peptidogenic proteins are derived from the same starting protein, or from multiple starting proteins (claim 50). The mixture further comprises the starting protein (claim 52). Claim 51 is directed to a description of the polynucleotides encoding the proteins.
Claims 44 and 46 are directed to a number of embodiments that describe the alteration of conformational dynamics. Claim 47 is directed to embodiments that describe how the altered conformational dynamics are measured. Claim 48 is directed to embodiments that describe how similarity in conformation to the starting protein is measured.
Please note that according to MPEP 2113, the patentability of a product does not depend on its method of production. The structure implied by the process steps should be considered, however, product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. Product claims 43-53 recite product-by-process limitations about amino acid changes relative to a starting protein, methods of altering, methods of measuring, the polynucleotide encoding, etc.
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.
Claims 43-53 remain 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 are summarized above. Several terms in claim 43 and all dependent claims are not clearly set forth such that the metes and bounds of the claims can be determined. A “peptidogenic protein” refers to mutated protein modified in its amino acid sequence to alter its conformational dynamics compared to the starting protein sequence, while maintaining a similar conformation to the starting protein (see paragraph [0042] of the published application, US 20230042877). This definition is not clear because of the term “altered conformational dynamics”. The specification refers to conformational changes and flexibility of a protein structure in the spatial arrangement of atoms or groups of atoms with respect to each other in a protein molecule, including “breathing motions”, vibration, bending, twisting, rotation and other allowed modes of movement of the atoms joined by the covalent bonds in the protein molecule (see paragraph [0047]). However, the determination of whether the conformational dynamics have been altered is not clear. For example, the degree of change in vibration of atoms that would qualify as “altered” is not defined. For the same reason, the metes and bounds of peptidogenic proteins having “increased conformational dynamics” cannot be determined in claim 53. Lastly, the specification defines “similar conformation” to a starting protein if the 3-D structure is sufficiently maintained after mutating non-surface residues of the protein to allow for an antibody to cross react with both the peptidogenic protein and the starting protein (see paragraph [0049]). The term “similar” is relative. Even looking to the definition in the specification, it recites the relative term “sufficiently maintained”, which is subject to individual interpretation.
In the response filed July 15, 2025, Applicant argues that the term “altered conformational dynamics” would be clear to a person of ordinary skill in the art. Applicant notes that proteins are not static structures in solution as they are subject to forces that can cause motions, “breathing”, which change the geometry of the protein on a sub-picosecond timescale in a vast diversity of conformational states, referencing paragraph [0047] of the published application. With regard to the term “similar conformation”, Applicant argues that as long as an antibody can cross react with both the peptidogenic protein and the starting protein, the peptidogenic protein has a similar conformation to the starting protein (see paragraph [0049]).
In response, the term “conformational dynamics” is understood. The question remains: how does one determine whether the conformational dynamics rise to the level of being altered? What degree of change in vibration, bending, twisting, rotation, etc. of the atoms qualifies as “altered”, or “increased” in the case of claim 53? Paragraph [0047] of the published application states that conformational molecular dynamics of protein is often studied using computer simulations. However, the specification has not provided definitive levels of change in vibration, bending, twisting, rotation, etc. of the atoms that qualify as altered, and in which types of solutions these changes take place. Further, while one antibody may bind to the peptidogenic protein and its starting protein, another antibody may not bind to both, depending on the epitope. In that case, it is not clear how to determine whether the structure is similar in conformation without being given an epitope with which to design the antibody binding assay. Therefore, the rejection is maintained for reasons of record.
Applicant may wish to consider removing the terms in question and proceeding with claim language that is strictly structural. For example, if any amino acid substitution necessarily alters the conformational dynamics, then the claims could be written using structural language (i.e., amino acid substitution) without the functional implications.
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 43-53 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.
The claims are directed to a large genus of peptidogenic proteins having altered conformational dynamics from a starting protein, and similar conformation to the starting protein. The peptidogenic proteins comprise replacement of at least one non-surface amino acid residue with a different amino acid residue relative to the starting protein.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In this case, the peptidogenic proteins’ structure is provided in the form of a protein that differs from a starting protein by at least one non-surface amino acid substitution. No particular peptidogenic proteins are claimed in terms of a definite structure (e.g., a polypeptide sequence with a sequence identifier). The function provided in the claims is altered conformational dynamics compared to the starting protein, as well as similar conformation to the starting protein.
“Peptidogenic protein” refers to mutated protein modified in its amino acid sequence to alter its conformational dynamics compared to the starting protein sequence, while maintaining a similar conformation to the starting protein (see paragraph [0042] of the published application, US 20230042877). “Altered conformational dynamics” refers to a change in conformational changes and flexibility of a protein structure in the spatial arrangement of atoms or groups of atoms with respect to each other in a protein molecule, including “breathing motions”, vibration, bending, twisting, rotation and other allowed modes of movement of the atoms joined by the covalent bonds in the protein molecule (see paragraph [0047]). “Similar conformation” to a starting protein refers the 3-D structure being sufficiently maintained after mutating non-surface residues of the protein to allow for an antibody to cross react with both the peptidogenic protein and the starting protein (see paragraph [0049]). These functions are not clearly set forth since there are no definitive levels that qualify as “altered” or similar.
Applicant has provided a structure in the form of a protein having an amino acid substitution at a non-surface residue. Also provided are ill-defined functions. There is no structure-function nexus with which to extrapolate other variant proteins. The specification provides a plethora of ideas for substitutions in a wide variety of proteins (see Tables 2-5), but the resulting functions were not determined. The examples in the specification speak to the experimentation process without any actual results. Thus it appears that Applicant’s invention is actually a method of deriving proteins, with no actual proteins in their possession. It does not appear that even one protein has been modified as claimed and shown to have the claimed functions. Given the minimal structure provided, the vague functions and the lack of a structure-function nexus, one would not be put in possession of the large genus of peptidogenic peptides having the claimed functions. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
In the remarks filed July 15, 2025, Applicant argues that an actual reduction to practice is not required, and that Table 4 and 5 provide numerous, specific mutations and starting proteins that will give rise to peptidogenic proteins. Applicant also points to claim 46 as providing amino acid substitutions and proteins in which to make the substitutions.
In response, Table 4 shows mutants of BPTI that are expected to knock out disulfide bonds or core residues while retaining 3D structure. Such mutants were not tested for their altered conformational dynamics or similar structure as determined by an antibody binding assay. Table 5 is a list of preferred targets with hypothetic mutations, none of which were tested for altered conformational dynamics or similar structure as determined by an antibody binding assay. Claim 46 is directed to a list of every amino acid and its conservative amino acids for substitution. Thus, there is nothing specific there in terms of which sequence exactly is to be modified with the conservative amino acid substitution. Further, the listing of proteins in which the substitutions can be made is only a list of proteins, none of which have been modified and shown to having the required altered conformational dynamics and similar structure as determined by an antibody that binds to an epitope that has not been provided. Therefore, the claims remain rejected for reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 43-53 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12, 13, 22 and 37-39 of copending Application No. 18/177,672 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are directed to a species of the instantly claimed genus (i.e., SARS-CoV-2 and generic constructs, respectively). A species anticipates a genus. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In the reply filed July 15, 2025, Applicant requests that this provisional rejection be held in abeyance until allowable subject matter is identified.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1671