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 .
DETAILED ACTION
This application is a US national phase PCT/EP2020/081402, filed November 7, 2020, with provisional applications 62/933215 and 62/936977, filed November 8, 2019.
Claims 2-4, 9-11, and 20-31 are canceled, and claims 1, 5-8, 15-16, and 32 are amended. Claims 1, 5-8, 12-19, and 32-38 are pending and 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 1, 5-8, 12-16, 18-19, and 32-38 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 Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to "visualize or recognize the identity of the members of the genus."
Regarding claim 1, the specification does not sufficiently describe a polypeptide having deoxyribonuclease activity comprising substitutions at the recited amino acid (AA) positions and having at least 95% sequence identity to SEQ ID NO: 1.
The claims require a polypeptide having the deoxyribonuclease activity with at least 95% sequence identity to the SEQ ID NO: 1. However, the specification has failed to sufficiently describe the structural features that must be retained by members of the claimed genus as to establish a structure-function relationship with respect to the activity, only disclosing the variant has one or more specified AA substitutions. For example, SEQ ID: 1 is 260 amino acids long. A protein sharing only 95% identity relative to SEQ ID: 1 including substitutions S174, P197, and P227, could have anywhere from 1 to 10 additional substitutions, deletions or additions in any combination along any length of SEQ ID: 1. Thus, an enormous genus (209 = 5.1 x 1011 + 193 = 6.9 x 103) comprising literally more than billions of sequences is encompassed by the tremendously broad scope of the claims.
However, while the claims are drawn to a genus that comprises literally billions of sequences, the specification has only adequately described and successfully reduced to practice the full-length of SEQ ID NO’s: 3-7, 9-10, 12-13,15-18, 20-21, 23-24, 26-29, 31-42. This is not representative of the extremely large genus of sequences claimed, since only 34 other variants of SEQ ID NO: 1 is demonstrated to have deoxyribonuclease activity. At best, the specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Thus, one of skill in the art would readily appreciate that relying on a non-patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
Moreover, Friedberg (Brief. Bioinformatics (2006) 7: 225-242, cited in PTO-892 mailed 2/13/2025) teaches that homology-based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg also teaches that identification of functionally significant sub-regions is critical to functional annotation, and that often addition, deletion, or re-shuffling of domains can lead to errors in annotation (page 227, second column, page 228, first paragraph). Furthermore, Friedberg teaches that sequence-based tools are just not sensitive enough to identify functional protein similarity as databases get larger, and diversity of sequences gets larger (page 228, first full paragraph).
Thorton et al. (Nature structural biology, structural genomics supplement, November 2000, pgs. 991-994, cited in PTO-892 mailed 2/13/2025) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thorton et al. further describe examples of little correlation between specific enzyme function and overall protein structure (see page 992, right column, at lines 2-10).
Thus, when taken with the teachings of Friedberg and Thorton, one of skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function. In the absence of a representative number of examples and any art-recognized structure-function relationship, the specification must at least describe the structural features that are required for the claimed function, in this case, to the aforementioned activities. However, as discussed above, the specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to the activities. Instead, Applicant merely offers a statement that any polypeptide having the intended activity will work.
Claims 5, 7-8, 13-16, and 32 recite specific substitutions S174K, S174R, T177R, T177K, G105R, G105K, I130L, I130V, I130M, P197S, T205R, T205K, P227S, T14K, T14R, H44R, H44K, S75K, S75R, S138K, and S138R of the deoxyribonuclease variant, however only T14K, T14R, H44R, S75K, G105R, I130L, S138K, S174K, S174R, T177R, P197S, T205R, and P227S are demonstrated to have deoxyribonuclease activity as disclosed in the specification in Table 1. The specification mentions conservative and non-conservative amino acid substitutions [0036], but does not indicate whether the conservative substitution at the recited positions would retain function, nor whether or not that position is generally tolerant to substitutions based on structure. Therefore, the specification only demonstrates the single specific substitutions disclosed in Table 1 as having deoxyribonuclease activity, and does not describe possession of variants having alternative substitutions, even if such substitutions may be considered conservative. Claims 18-19 and 33-38 are likewise rejected since they fail to ameliorate the written description requirement of the base claims above upon which they depend.
Accordingly, the claims as currently written are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus at the time of filing.
Response to Arguments
Applicant’s arguments, see pages 8-9, filed June 2, 2026, with respect to claims 1, 5-7, 12-13, 18-19, and 37-38 have been fully considered and are persuasive. The 35 U.S.C. § 103 rejections of claims 1, 5-8, 12-16, 18-19, and 37-38 has been withdrawn.
Applicant's arguments, see pages 6-8, filed June 2, 2026 regarding the maintained U.S.C. § 112(a) rejection of claims 1, 5-8, 12-13, 16, 18-19, and 37-38 have been fully considered but they are not persuasive.
Applicant argues as amended, claim 1 recites "deoxyribonuclease comprising substitutions at amino acid positions S174, P197, and P227 corresponding to SEQ ID NO: 1, wherein the deoxyribonuclease has at least 95%, 98% or 99% sequence identity with SEQ ID NO: 1." The Office asserts that sequences with at least 95% identity with SEQ ID NO: 1 could have up to 13 substitutions, which could be up to trillions of possible sequences (Office action, page 4, second full paragraph). Applicant argues amended claim 1 requires three amino acid substitutions corresponding to SEQ ID NO: 1, so an amino acid sequence with at least 95% sequence identity to the recited sequence could have no more than ten additional substitutions. The specification describes how to determine sequence identity of DNases and describes conservative and non-conservative amino acid substitutions that could be made (paragraph [0036]). The specification also describes methods of assessing DNase I function, including DNase activity (e.g., paragraphs [0037-0038]), thermolability (e.g., paragraph [0040]), and salt-tolerance (e.g., paragraph [0043]). Applicant argues in the alignment shown on page 7, amino acids that are identical between all of the sequence are shown in black, while conservative substitutions are shaded gray, and non-conservative substitutions are shown in white. As is clear from this alignment, a variety of mammalian DNase I proteins include large regions of complete identity. In addition, in regions lacking complete identity between all of the sequences, there is substantial similarity between the sequences (noting that SEQ ID NO: 1 lacks the peptide signal sequence present in the other sequences and the human sequence is a splice variant including an additional exon). One of ordinary skill in the art could select appropriate positions to include substitutions, such as at positions where there are non-conservative amino acid differences between DNase sequences. Applicant argues the instant application therefore provides a complete structure and functional characteristics that describe the claimed polypeptides.
Although the Examiner recognizes Applicant has demonstrated conservative and non-conservative substitutions in the alignments of the various DNases, the Applicant has still not demonstrated a link between function and structure of the many substitutions at those positions, only possessing the specific substitutions S174K, S174R, P197S, and P227S, therefore the Examiner recommends to include only these specific substitutions in claim 1 to obviate the maintained 112(a) rejection. Dependent claims could include only substitutions T14K, T14R, H44R, S75K, G105R, I130L, S138K, T177R, T177K, T205K, and T205R, which have been demonstrated to have activity in Tables 1 & 2 of the specification, as well as demonstrated in the prior art as discussed in the previous 103 rejections in the Non-Final office action mailed March 2, 2026. Furthermore, claims 6-8, 12-13, and 16 recite “one or more substitutions”, which would still include billions of variants claimed (208 = 1.7 x 1010) at the 95% identity threshold.
Allowable Subject Matter
Claim 17 is allowed. Claim 17 is free of prior art. Regarding claim 17, as disclosed in the Specification, SEQ ID NO’s: 37-41 are genetically engineered deoxyribonucleases, which are synthetic mutants constructed and cloned by the inventor ([0059] & [0071]).
The following claims drafted by the examiner and considered to distinguish patentably over the art of record in this application, are presented to applicant for consideration:
A deoxyribonuclease comprising the full length sequence of SEQ ID NO:1 except for the following amino acid substitutions:
(1) S174K or S174R;
(2) P197S;
(3) P227S; and
(4) optionally at least one more amino acid substitution selected from the group consisting of: T14K, T14R, H44K, H44R, S75K, S75R, G105R, G105K, I130L, I130V, I130M, S138K, S138R, T177R, T177K, T205R, and T205K.
Cancel claims 5-8, 12-13, 16.
14. The deoxyribonuclease of claim 1,wherein the substitutions are S174K, P197S, P227S, S75K and S138K.
15. The deoxyribonuclease of claim 1,wherein the substitutions are S174K, P197S, P227S, T14K, H44R and G105R.
32. A deoxyribonuclease of claim 1, wherein the substitutions are a combination selected from the group consisting of:(a) H44R, S75K, G105R, I130L, S138K, S174R, P197S, and P227S;
(b) H44R, S75K, G105R, I130L, S138K, S174K, P197S, T205R, and P227S;
(c) H44R, S75K, G105R, I130L, S138K, S174K, P197S, and P227S;
(d) T14K, S75K, G105R, I130L, S138K, S174K, P197S and T205R; and
(e) T14K, S75K, G105R, I130L, S138K, S174K, P197S, and P227S,
wherein the amino acid positions correspond to SEQ ID NO:1.
The following is a statement of reasons for the indication of allowable subject matter:
Applicant has demonstrated possession of the genus of deoxyribonuclease variants comprising the full length of SEQ ID NO: 1 except for the particular substitution combinations recited in the claims. Furthermore, the claimed deoxyribonuclease variants with specific substitutions are not obvious over the prior art, and are genetically engineered deoxyribonucleases, which are synthetic mutants constructed and cloned by the inventor ([0059] & [0071]), thus are patent eligible.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA EDWARDS whose telephone number is (571)270-0938. The examiner can normally be reached M-F 8am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached at (571) 272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657
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