DETAILED ACTION
Status of claim rejections
The rejection of record under 35 U.S.C. § 112(a) is maintained and set forth again below in response to Applicant’s arguments filed 10/14/2025.
Maintained 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 14, 16, 19-24, and 26-28 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 1398, 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 genus 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.”
The instant claims require a variant having DNase activity, wherein the variant
comprises at least five (or alternatively six, seven, eight, nine, or ten) substitutions selected from the group consisting of: T1I or T1V; G4K; S7G; K8R; S9I; S13Y; T22P; S25P; S27L; S27R; D32I, D32L, D32R, or D32V; L33R or L33K; S39P or S39C; G41P; S42G, S42H, or S42C; Q48D; D56I or D56L; S57W; S59V or S59C; N61E; T65L, T65V, T65M, or T65W; S66M, S66W, S66Y, or S66V; V76L; T77Y; F78L; P91L; S101; S106L, S106R, or S106H; Q109R, A112E; S116D; Tl27V; S130A or S130Y; T138D; Q140V or Q140G; S144P; A147H; C148A; W154Y; T157V; Y159A or Y159R; Kl60V; G162S, G162D, or G162C; Ql66D; S167L; Q174N; G175D or G175N; L177Y; N178D or N178E; S179L; C180A; and S181E or S181L, wherein
each position corresponds to the position of the polypeptide of SEQ ID NO: 1, and
the variant has at least 85% (or alternatively 90%) sequence identity to the amino acid sequence of SEQ ID NO: 1. Instant claim 28 further requires the variant to have improved detergent stability relative to the DNase of 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 DNase activity or improved detergent stability.
The instant claims are drawn to a vast genus encompassing innumerable permutations of different amino acid substitutions. In addition to these specific amino acid substitutions, the instant claims encompass additional substitutions, deletions, and/or additions across the entire length of SEQ ID NO: 1, so long as the variant retains at least 85% (or alternatively 90%) sequence identity to SEQ ID NO: 1, which encompasses trillions of sequences.
However, while the instant claims are drawn to a genus that comprises trillions of
sequences, the Specification has only adequately described and successfully reduced to practice a subset of variants tested in Examples 2-4, which are limited to very specific combinations of amino acid substitutions to only wild-type SEQ ID NO: 1. This is not representative of the extremely large genus encompasses trillions of variants containing specific and nonspecific substitutions across the entire length of SEQ ID NO: 1, as claimed.
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, prior art of record) 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, prior art of record) 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, the Specification must at least
describe the structural features that are required for the claimed function, in this case DNase activity and, in some embodiments, improved detergent stability. However, as discussed above, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to DNase activity or improved detergent stability. Instead, Applicant merely offers a cursory statement that any variant having DNase activity/improved detergent stability will work.
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 filed 10/14/2025 have been fully considered but they are not persuasive.
On pg. 7-9 of the remarks, Applicant argues the claimed variants are defined by structural features, namely a high sequence identity to SEQ ID NO 1. Applicant argues that there is a definitive relationship between protein function and % identity at amino acid level and that percent identity is highly predictive of protein function. Applicant argues that proteins that share 80% identity are known to possess the same catalytic/biochemical function as a conservative criterion for judging functional similarity (citing to Guo et al and Markiewicz, which was given their fullest consideration). Applicant also argues that the specification includes examples of amino acid sequences of 24 parent polypeptides having DNase activity that have 73-95% identity to SEQ ID NO: 1 and 55 polypeptides having at least 80% sequence identity were identified in a BLAST search. Applicant argues that each of these parent polypeptides could be used to generate a variant of the present invention. Applicant further argues that the specification has 160 polypeptide variants of SEQ ID NO:1 with up to 23 mutations (which has approx. 87% sequence identity to SEQ ID NO 1), and the examples show that the polypeptide variants have improved activity/stability in detergent assay such that polypeptides with 80% identity would be expected to have very similar 3D structures and would have DNase activities. Finally, Applicant argues the creation of 3D structure predictions using AlphaFold of SEQ ID NO 1, 2, 10, and 17 and compared the TM scores, which show that they have scores of 0.997, such that they have identical structures to SEQ ID NO: 1. Applicant concludes that the structural similarity is not just of the stable parts but also less structured loops and turns, such that other sequences having at least 85% sequence identity will have similar structures, and urges that the claimed mutations that stabilize the DNase of SEQ ID NO 1 will also stabilize other DNases having 80%+ sequence identity.
In response, the examiner disagrees. The specification is limited to only the disclosed sequences as posited in the argument above. The specification does not reasonably provide support for the massive genus of potential DNase sequences harboring 80% sequence identity to SEQ ID NO: 1 that must also have improved detergent activity as instantly claimed. The 80% sequence identity claimed encompasses both specific and non-specific amino acid substitutions within a DNase and the specification has only adequately described and successfully reduced to practice a subset of variants tested in Examples 2-4, which are limited to very specific combinations of amino acid substitutions to only wild-type SEQ ID NO: 1. Second, while the examiner appreciates the data provided regarding the structural similarity, the examiner is not persuaded. The subset of variants that Applicant has successfully reduced to practice does not extend to any and all sequneces with 85% sequence identity to SEQ ID NO 1 for the same reasons as set forth above. Such conclusory statements such as “other sequences having at least 85% sequence identity will have similar structures, and . . . the claimed mutations that stabilize the DNase of SEQ ID NO 1 will also stabilize other DNases having 80%+ sequence identity” must be substantiated by empirical evidence on the record. An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
On pg. 10-12, Applicant argues that the Friedberg and Thorton reference (cited above) recognizes that a general rule that proteins with as low as 35% sequence identity typically have the same function but there are exceptions, that there is no evidence that an exception applies to polypeptides having at least 80% sequence identity to SEQ ID NO: 1, cites to the Devos reference that when two enzymes have more than 80% sequence identity, they also have the same enzymatic function defined by that EC number. Applicant argues Example 11B, claim 2 in the Written Description Training Materials (2008), claiming “an isolated nucleic acid sequence having 85% identity with activity Y” and asserts that knowledge in the art of genetic code would allow one of skill in the art, with the aid of a computer, to list all sequences capable of the function claimed, thus meeting the written description requirement. Applicant further argues that DNases are well-characterized and conserved regions can be readily recognized by those skilled in the art.
In response, the examiner disagrees. First, Friedberg is utilized for its teaching that homology-based transfer is not reliable for functional annotation even with high alignment percentages (pg. 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 (pg. 227, second column, pg. 228, first paragraph). 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). Likewise, Thorton teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thorton further describe examples of little correlation between specific enzyme function and overall protein structure (see page 992, right column, at lines 2-10). Neither reference have to disclose this information as it specifically relates to polypeptides having 80% sequence identity to SEQ ID NO:1 because one of ordinary skill would readily recognize that sequence homology alone cannot serve as the basis to describe members of a genus of proteins that have the recited function.
The nexus between structure of a polypeptide or nucleotide sequence having 85% identity to a specific sequence MUST be correlated with the function being claimed. Put simply, the problem lies not just in the structure of the sequence itself but with any variants/mutants encompassed by the claims that must retain DNase activity/improved detergent stability. The recitation of a polypeptide comprising (open language) with at least five substitutions, and with at least 85% amino acid sequence identity to SEQ ID NO: 1 represents a partial structure. That is, the claimed proteins share at least 85% of the structure of SEQ ID NO: 1, while 15% of the structure can vary. There is no teaching in the specification regarding which 15% of the structure can be varied (other than at least the specific mutants reduced to practice) while retaining the ability of the protein to have DNase activity/improved detergent stability. Further, there is no art-recognized correlation between any structure (other than SEQ ID NO: 1 and the variants reduced to practice in Examples 2-4) and the activity of improved detergent activity/having DNase activty, based on which those of ordinary skill in the art could predict which amino acids can vary from SEQ ID NO: 1 without losing the claimed function. Consequently, there is no information about which other amino acids can vary across SEQ ID NO:1 in the claimed genus of proteins and still retain the claimed function.
On pg. 12-16, Applicant argues US Pat Nos. 10,774,293, 11,441,136, and 11,447,723 (‘136 and ‘723 have reissue applications pending) that disclose DNases altered at other positions and the claims recite 90%, 90%, and 80% identity to SEQ ID NO 1, respectively. Applicant also argues PTAB decision in Boehringer regarding 90% homology argument made by Petitioner (which will not be repeated here). From this, Applicant argues that the PTAB’s reasoning supports the conclusion that the present application provides adequate written description for the claimed invention.
The examiner disagrees for the same reasons as set forth above. The nexus between structure of a polypeptide or nucleotide sequence having 85% identity to a specific sequence MUST be correlated with the function being claimed. Put simply, the problem lies not just in the structure of the sequence itself but with any variants/mutants encompassed by the claims that must retain DNase activity/improved detergent stability. The recitation of a polypeptide comprising (open language) with at least five substitutions, and with at least 85% amino acid sequence identity to SEQ ID NO: 1 represents a partial structure. That is, the claimed proteins share at least 85% of the structure of SEQ ID NO: 1, while 15% of the structure can vary. There is no teaching in the specification regarding which 15% of the structure can be varied (other than at least the specific mutants reduced to practice) while retaining the ability of the protein to have DNase activity/improved detergent stability. Thus, the rejections are maintained for the reasons set forth above.
Conclusion
NO CLAIMS 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGIANA C REGLAS whose telephone number is (571)270-0995. The examiner can normally be reached M-Th: 8:00am-2:00pm.
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/G.C.R./
Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672