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 . 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 Nov, 2025 has been entered.
Election/Restrictions
Applicants elected group III (polynucleotides) and a polynucleotide encoding SEQ ID 1 without traverse in the reply filed on 7 Feb, 2025. The elected species was found allowable in the office action of 14 Feb, 2025, but other embodiments in the claims were not.
Claims Status
Claims 46, 49, 50, 52, 53, 56, 57, 59-67, 69, 72, and 78 are pending.
Claims 46, 49, 50, 52, 53, 57, 59-67, 72, and 78 have been amended.
Claims 46, 49, 50, 52, 53, 56, 57, 59-65-67, 72, and 78 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claim 69 on the basis that it contains an improper Markush grouping of alternatives is hereby withdrawn due to amendment.
The rejection of claims 64, 69, 71, and 74 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to uncertainty as to the interpretation of “substantially maintains” is hereby withdrawn due to amendment.
The rejection of claims 64 and 69 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to uncertainty as to what activity is maintained is hereby withdrawn due to amendment.
The rejection of claim 69 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is hereby withdrawn due to amendment.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(a)
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 64 and 69 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 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.
The issue is which variants of SEQ IDs 1 are split intein N-fragments.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants have described polypeptides of SEQ ID 1, and have run coupling assays with different payloads attached to the N-terminus of this polypeptide (table 1, p57).
(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: Applicants are claiming a polynucleotide encoding an N-terminal intein fragment having at least 95% identity with SEQ ID 1. This is a functional requirement that, when paired with an appropriate C-terminal intein fragment, a polypeptide fused to the N-terminus of the intein N-fragment will be coupled with a polypeptide fused to the C-terminus of an intein C-fragment; excising the intein fragments. However, applicants have not described what parts of these polypeptides are required for this activity. A person of skill in the art would not know what sequence/hydrophobicity/charge features are necessary for the claimed activity. In essence, applicants have described their invention by function. That is not sufficient to meet the written description requirement.
While similar sequences have been described (note Mootz et al, US 20160319287, for example), they are defined by screening variants of native sequences, in the case of Mootz et al, using error prone PCR (paragraph 342). This does not give any information as to what portions of the sequences are important for activity.
As of applicant’s priority date, it was not possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about what residues are important, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: All of applicant’s examples use SEQ ID 1 bound to various polypeptides at the N-terminus. SEQ ID 1 is a consensus sequence of native intein N-terminal fragments (p65, 2nd paragraph). While the N-terminal Cys residue is clearly critical, it is not clear which of the other 29 residues of SEQ ID 1 are important. This yields 1160 possible sequences with at least 95% identity, assuming insertions are only 1 amino acid. A single sequence is not sufficient to allow a person of skill in the art to know which of these 1160 sequences will couple their attachments together. Thus, the claims lack written description.
response to applicant’s arguments
Applicants argue that the variants are limited to one amino acid mutation, and that the N-terminal Cys residue must not be changed.
Applicant's arguments filed 17 Nov, 2025 have been fully considered but they are not persuasive.
Applicant’s argument is that the amount of variation permitted is small, so a person of skill in the art would expect all variants to work. However, as noted in the rejection, a random mutation has roughly a one in three chance of abrogating activity in a random polypeptide. Applicant’s benchmark is higher than that; 50% N-terminal cleavage and/or trans-splicing activity. Without some information as to what residues are important and which ones are not, a person of skill in the art would not know which mutations will retain activity, which is the basis of the rejection.
New Rejections
Claim Rejections - 35 USC § 112(a)
The legal basis for rejections under this statute was given above, and will not be repeated here.
Claims 64 and 69 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 64, and claims dependent on it, has been amended to require the N-terminal Cys residue of SEQ ID 1 be maintained in all variants. However, a search of the disclosure does not mention holding this residue constant. Thus, this amendment constitutes new matter.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658