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
Claims 1-2, 5 and 8-11 are pending in the instant application. Claims 3-4 and 6-7 are cancelled. Claims 1 and 8-10 are withdrawn. Claim 11 is new.
Claims 2, 5 and 11 are under examination herein.
Priority
This application is a 371 of PCT/SE2020/050290 filed on 3/19/2020, which claims priority to SWEDEN 1950356-4 filed on 3/21/2019. Receipt is acknowledged of certified copies of papers in English required by 37 CFR 1.55.
The effective filing date for the application is March 21, 2019.
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.
Claims 2, 5 and new claim 11 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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 at the time the application was filed, had possession of the claimed invention.
Applicant is referred to MPEP 2163(II)(A)(3)(a)(i and ii), which states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
Claims 2, 5 and 11 are drawn to an isolated protein having an amino acid sequence according to SEQ ID NO:2 and functional variants thereof. The claims require functional variants “having an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having at least 80% of the DNase activity of the protein according to SEQ ID NO:2”. The specification does not disclose a representative number of functional variants that meet the required functional limitation of at least 80% of the DNase activity of the protein according to SEQ ID NO:2.
The current specification describes an isolated protein having the amino acid sequence according to SEQ ID NO:2 that has DNase activity (specification p.9, lines 25-27). The specification identifies that functional variants may be assessed for retained DNase activity at pH 7 and 32°C or at pH 6 and 25°C (specification p.9, line 34 – p.10, line 1). The specification states that such variants may be made using methods of protein engineering and site-directed mutagenesis which are well known in the art (specification p.10, lines 13-14). The specification further identifies that PG_1116 is a predicted protein of 939 amino acids (SEQ ID NO:2) that contains a DNase I domain, a TAT protein, a YhcR-OBF domain that could be important for recognition of specific patterns and a non-specific fungal domain of unknown function (specification p.18, lines 18-26).
The specification does not provide any guidance on the structure-function relationship of SEQ ID NO:2, does not provide any information on which amino acids can be varied or deleted while preserving the DNase function of the protein, nor any guidance on which amino acid residues of SEQ ID NO:2 are critical to determine what other proteins having an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having a least 80% of the DNase activity of the protein according to SEQ ID NO:2. Based on the lack of art-recognized structure-function relationship of SEQ ID NO:2 to other functional variants, it is highly unpredictable as to what other proteins of at least 95% identity to SEQ ID NO:2 would provide the instantly recited function.
The disclosure of a single species of a protein having an amino acid sequence according to SEQ ID NO:2 and having DNase activity is not considered to constitute a representative number of species of the genus of proteins having an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having a least 80% of the DNase activity of the protein according to SEQ ID NO:2, in view of the lack of any guidance as to which proteins having at least 60% amino acid identity to SEQ ID NO:2 will also have at least 80% DNase activity of the protein. Thus, one of ordinary skill in the art could not conclude that Applicant was in possession of any species of the claimed genus of proteins comprising an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having a least 80% of the DNase activity of the protein according to SEQ ID NO:2., as no functional variants are disclosed in the specification. This disclosure does not constitute a representative number of species of the genus in view of the potential breadth and variability in the genus, and so there is a failure to satisfy the written description requirement for the genus.
Response to Arguments
Applicant argues that the written description rejection should be withdrawn because claim 2 is directed to a narrowed class of proteins defined by the combination of sequence identity, retained DNase activity in the disclosed assay, activity assessed in the presence of 5% sebum, and the presence of a C-terminal DNase I domain (See Remarks dated 5/27/2026, p.5 2nd paragraph). Applicant argues that the originally filed specification further provides structural context by describing C-terminal DNase I domain comprising putative catalytic, DNA-binding, phosphate-binding and Mg-binding sites, and therefore the claims define a structurally and functionally bounded class of proteins rather than an open-ended set of variants (See Remarks dated 5/27/2026, p.5 paragraphs 3-4).
Applicant's arguments filed May 27, 2026 have been fully considered but they are not persuasive. The 112(a) written description rejection is based on whether one can truly ascertain that applicant was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams and formulas that fully set forth the claimed invention. A protein having 95% sequence homology to SEQ ID NO:2 permits 47 amino acids that can be altered. Assuming a single amino acid substitution, that is 20 possible amino acids in 47 possible locations, which results in 940 possible different sequences. If more than one amino acid is substituted, the possible number of sequences becomes exponentially larger. There is only one example in the specification that is reduced to practice. As discussed in the rejection above, the specification does not provide any guidance on the structure-function relationship of SEQ ID NO:2; does not provide any information on which amino acids can be varied or deleted while preserving the DNase function of the protein, nor provide any guidance on which amino acid residues of SEQ ID NO:2 are critical to determine what other proteins having an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having a least 80% of the DNase activity of the protein according to SEQ ID NO:2. Based on the lack of art-recognized structure-function relationship of SEQ ID NO:2 to other functional variants, it is highly unpredictable as to what other proteins of at least 95% identity to SEQ ID NO:2 would provide the instantly recited function. Thus, the unexpected results are not commensurate in scope with the claimed invention. See MPEP §716.02(b) which states "The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)”, and MPEP §716.02(d) which states “the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range”.
Applicant’s arguments identifying specific residues within SEQ ID NO:2 that are associated with the catalytic framework are noted. However, as applicant identifies, this information is not submitted as an amendment to the specification or claims, nor that this information was previously known in the art or routinely predictable. Thus, this information does not help to overcome the lack of description of the claimed invention regarding the genus of “functional variants” because as identified above, 95% identity allows 40 different amino acid substitutions within the sequence. If any of the residues applicant identified as associated with the catalytic framework are replaced within the 95% sequence identity, it is unpredictable as to whether the sequence will meet the requirement of having at least 80% of the DNase activity without having any structure-function relationship identified in the prior art or provided in the specification.
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.
Claims 2, 5 and new claim 11 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 2 recites “administering an effective amount of an isolated protein having an amino acid sequence according to SEQ ID NO:2 and functional variants thereof having an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having at least 80% of the DNase activity of the protein according to SEQ ID NO:2 in a quantitative assay of deoxyribonuclease activity at pH 7 and 32°C in the presence of 5% sebum wherein the C-terminus domain of the protein contains a DNase 1 domain to a subject in need thereof” in lines 9-14.
It is unclear what minimum structural requirement is required to meet the limitation “an amino acid sequence according to SEQ ID NO:2”, because it is unclear whether this phrase is requiring the full-length sequence with 100% identity to SEQ ID NO:2 or any fragment of SEQ ID NO:2.
There is insufficient antecedent basis for the phrase “the DNase activity of the protein” because there is no prior recitation of DNase activity, nor any identification that SEQ ID NO:2 has DNase activity. It is further unclear what structure is required to meet “at least 80% of the DNase activity of the protein according to SEQ ID NO:2”, because it is unclear what protein structure or which fragment of SEQ ID NO:2 is required for at least 80% DNase activity.
This rejection can be obviated by amending claim 2 to recite “A method for treatment and/or prevention of a disease of the skin caused or complicated by infections of one or more biofilm-forming bacteria and/or fungi selected from Propionibacterium acnes, Pseudomonas aeruginosa, Vibrio cholerae, Escherichia coli, Streptococcus pyogenes, Klebsiella pneumoniae, Acinetobacter baumannii, Aggregatibacter actinomycetemcomitans, Shewanella oneidensis, Staphylococcus haemolyticus, Haemophilus influenza, Staphylococcus aureus, Enterococcus faecalis, Listeria monocytogenes, Candida albicans, Aspergillus fumigatus, Streptococcus pneumonia, S. epidermidis, Micrococcus luteus, and Bacillus subtilis, comprising administering an effective amount of an isolated protein comprising SEQ ID NO:2”.
Response to Arguments
Applicant argues that the rejection should be withdrawn in light of the amendment suggested by the Examiner to reintroduce the language “and functional variants thereof” (See Remarks dated 5/27/2026, p.7, Section B).
Applicant's arguments filed May 27, 2026 have been fully considered but they are not persuasive. The amendment to claim 2 suggested by the Examiner was to delete the underlined phrase on p.8 in the non-final rejection mailed on 1/29/2026. The introduction of the limitation “and functional variants thereof” does not overcome the indefiniteness as identified in the rejection above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 5 and new claim 11 are rejected under 35 U.S.C. 103 as being unpatentable over Burgess et al. (WO 2011/098579 A1, published on August 18, 2011; previously cited) in view of Uniprot A0A239WTI0 (deposited in Uniprot on October 25, 2017, corresponding to EMBL SNV3786, https://www.uniprot.org/uniparc/UPI000B182024/entry/A0A239WTI0).
Regarding claim 2, Burgess teaches compounds, compositions and methods for biofilm disruption and prevention (abstract). Burgess teaches the pharmaceutical formulations comprising the microbial deoxyribonuclease compositions can be administered inter alia intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, orally and by inhalation (relevant to biofilm-forming bacteria; relevant to administering an isolated protein having DNase activity) (description p.12, [0072]). Burgess teaches a method of disrupting a biofilm on a patient comprising contacting a biofilm on a patient with any of the pharmaceutical compositions described herein (relevant to a method for treatment comprising administering to a subject in need thereof) (description p.8, [0039]). Burgess further teaches a method of preventing the formation of a biofilm on a patient comprising contacting a surface of a patient susceptible to biofilm formation with any of the pharmaceutical compositions described herein (relevant to a method of prevention comprising administering to a subject in need thereof) (description p.8, [0040]). Burgess teaches isolated microbial deoxyribonuclease polypeptides for use as a pharmaceutical, wherein said use is in the treatment of infections of the skin (description p.47, claim 19). Burgess teaches that the microbial deoxyribonuclease pharmaceutical compositions can affect bacteria including Staphylococcus aureus, Staphylococcus pyogenes, Streptococcus sp., Streptococcus pneumoniae, Enterococcus sp., Propionibacterium acnes, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Campylobacter jejuni ([00113]); Candida albicans ([00114]); Aspergillus fumigatus ([00114]); Haemophilus influenzae ([00115]; Staph. epidermidis ([00115]); Acinetobacter sp. ([00155]); Staphylococcus sp. ([00155]); Bacillus licheniformis ([00159]); Micrococcus sp. ([00168]); Bacillus subtilis ([00168]); and biofilms derived from Vibrio sp. ([00206]).
Burgess does not disclose whether the microbial deoxyribonuclease has at least 95% homology to instant SEQ ID NO:2.
However, Uniprot A0A239WTI0 teaches a DNase I-like endonuclease/exonuclease/phosphatase family protein isolated from Cutibacterium granulosum (Uniprot reference A0A239WTI0 deposited in UniProt on October 25, 2017, available at A0A239WTI0 | UPI000B182024 | UniParc). As shown in the alignment below with SEQ ID NO:2 (Query) and Uniprot sequence (Subject), the amino acid sequence taught by Uniprot has 99% homology to instant SEQ ID NO:2.
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103
1255
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979
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Burgess to replace the microbial deoxyribonuclease taught by Burgess with the nuclease having 99% homology with instant SEQ ID NO:2 taught by Uniprot to arrive at the claimed invention. Both Burgess and Uniprot teach nucleases. One of ordinary skill in the art would have a reasonable expectation of success that replacing the microbial deoxyribonuclease taught by Burgess with the nuclease taught by Uniprot having 99% homology with instant SEQ ID NO:2 would predictably result in an isolated protein having at least 80% of the DNase activity of the protein according to SEQ ID NO:2, because the sequence taught by GenBank has 99% homology to instant SEQ ID NO:2, and it was known in the art at the time of invention that microbial deoxyribonucleases could be used to disrupt biofilms.
Regarding claim 5, Burgess teaches infection with one or more bacteria can result in diseases such as acne and impetigo (description p.22, [00113]).
Regarding claim 11, Burgess does not disclose whether the DNase I domain comprises putative catalytic active, DNA binding, phosphate binding and Mg binding sites.
However, Uniprot teaches that the amino acid sequence encodes a protein that is DNase I-like, classified as an endonuclease/exonuclease/phosphatase family protein; has catalytic activity, and is isolated from Cutibacterium granulosum. Further, the sequence of the Uniprot protein is 99% identical to instant SEQ ID NO:2. Therefore, the DNase1 domain of Uniprot would necessarily comprise putative catalytic active, DNA binding, phosphate binding and Mg binding sites.
Response to Arguments
Applicant argues that the rejection should be withdrawn in light of the amendment to claim 2 to specify an isolated protein having an amino acid sequence according to SEQ ID NO:2 and functional variants thereof having an amino acid sequence identity of at least 95% to SEQ ID NO:2, which is higher than the 94% homology to SEQ ID NO:2 in the GenBank reference (See Remarks dated 5/27/2026, p.7, Section C). Applicant refers Examiner to data in Exhibit A submitted with the amendment dated 10/27/2025 and argues that the DNase of Burgess failed to maintain its activity in the presence of 5% sebum while that disclosed remained active in 5% - 35% sebum (See Remarks dated 5/27/2026, p.7 Section C).
Applicant's arguments filed May 27, 2026 have been fully considered but they are not persuasive. As identified in the rejection above, Burgess in view of Uniprot teach the active method step comprising administering an effective amount of an isolated protein having an amino acid sequence identity of at least 95% to SEQ ID NO:2 and having at least 80% of the DNase activity of the protein according to SEQ ID NO:2. The limitation “in a quantitative assay of deoxyribonuclease activity at pH 7 and 32°C in the presence of 5% sebum” refer to conditions for determining deoxyribonuclease activity, and are not part of the active method step of administering to a subject in need thereof.
Burgess is relied upon to teach the active method steps of administering an isolated protein having DNase activity for treatment and/or prevention of a disease of the skin caused or complicated by infections of one or more biofilm-forming bacteria selected from Staphylococcus aureus, Staphylococcus pyogenes, Streptococcus sp., Streptococcus pneumoniae, Enterococcus sp., Propionibacterium acnes, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Campylobacter jejuni ([00113]); Candida albicans ([00114]); Aspergillus fumigatus ([00114]); Haemophilus influenzae ([00115]; Staph. epidermidis ([00115]); Acinetobacter sp. ([00155]); Staphylococcus sp. ([00155]); Bacillus licheniformis ([00159]); Micrococcus sp. ([00168]); Bacillus subtilis ([00168]); and biofilms derived from Vibrio sp. ([00206]). Burgess is not relied upon to teach instant SEQ ID NO:2.
Uniprot teaches an amino acid sequence of a nuclease with 99% homology to instant SEQ ID NO:2. One of ordinary skill in the art would have found it obvious to use a protein having DNase activity to treat a disease of the skin based on the teachings of Burgess. One of ordinary skill in the art would have reasonably expected that replacing the microbial deoxyribonuclease taught by Burgess with the nuclease taught by Uniprot would predictably result in an isolated protein having an amino acid sequence having an amino acid sequence identity of 99% to instant SEQ ID NO:2 and therefore also have at least 80% of the DNase activity due to the sequence homology.
Conclusion
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657
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