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 of PCT/EP2020/062645, filed May 7,
2020, with foreign application EP19173389.8, filed May 8, 2019.
Applicant’s amendment filed April 26, 2026 is acknowledged. Claims 3-4, 10, and 12-21 are canceled, claims 1, 5, 24, 28, 31-32, 34, 36, are amended, and claims 39-40 are newly added. Currently claims 1-2, 5-9, 11, and 22-40 are pending and under examination.
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.
Claims 1-2, 5-9, 22-24, 26-27, 34-40 are rejected under 35 U.S.C. 103 as being obvious over Thomas-White et al. (NCBI Accession # PKY96525.1, Direct Submission, Submitted 17-DEC-2017, Biology, Loyola University Chicago, 1032 W Sheridan Rd., Biology Department, LSB 317B, Chicago, IL 60660, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Thomas”) in view of Bumgarner et al. (NCBI Accession # PNP86798.1, Direct Submission, Submitted (29-MAR-2017) Microbiology, University of Washington, Box 358070, 1410 NE Campus Parkway, Seattle, WA 98195, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Bumgarner”), as evidenced by Donovan et al. (APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Apr. 2006, p. 2988–2996, cited in PTO-892 mailed 8/30/2024, hereinafter “Donovan”) and Schmelcher et al. (Future Microbiol. 2012 October; 7(10): 1147–1171, cited in PTO-892 mailed 8/30/2024, hereinafter “Schmelcher”).
Regarding claims 1, 5-7, 22-24, 34-40, Thomas teaches a 1,4-beta-N-acetylmuramidase [Gardnerella vaginalis] (Accession # PKY96525.1) with 100% sequence identity to SEQ ID NO: 2, 93% sequence identity to SEQ ID NO: 28, and 95% sequence identity to SEQ ID NO: 31 (See sequence comparison below). The 1,4-beta-N-acetylmuramidase also consists of a linker region between the catalytic domain (SEQ ID NO:2) and cell-wall binding domain (SEQ ID NO: 28) that is the amino acid sequence according to SEQ ID NO: 46 recited in claims 7 and 39-40 (See annotation of sequence below). The GenPept information sheet for PKY96525.1 teaches that the enzyme is a GH25_LytC-like enzyme, and the LytC lysozyme of Streptococcus pneumoniae is a bacterial cell wall hydrolase that cleaves the beta1-4-glycosydic bond located between the N-acetylmuramoyl-N-glucosaminyl residues of the cell wall polysaccharide chains, and indicates it has cell-wall binding domains (CBD) (pg. 2, “Region”).
Sequence comparison of PYK96525.1 and SEQ ID NO: 2
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546
771
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Sequence comparison of PYK96525.1 and SEQ ID NO: 28
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545
805
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Sequence comparison of PYK96525.1 and SEQ ID NO: 31
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485
807
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Annotated PYK96525.1: Red: SEQ ID NO:2; Yellow: L10 linker region SEQ ID NO: 46; Blue: SEQ ID NO: 31; Green: SEQ ID NO: 28
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Thomas does not teach the polypeptide comprises two domains wherein each of the two domains independently comprises a sequence of at least 96% identity to SEQ ID NO’s: 28 & 31.
However, Bumgarner teaches a 1,4-beta-N-acetylmuramidase from Gardnerella vaginalis that was isolated from vagina (Accession # PNP86798.1) with two cell-wall binding domains, the first with 96% identity to SEQ ID NO: 28 and the second (N-terminal to the first) with 100% sequence identity to SEQ ID NO: 31 (See sequence comparisons below). As evidenced by Donovan, fusion proteins of peptidoglycan hydrolase (i.e., endolysins) maintain their parental specificities according to each domain (title, pg. 2989, col. 2, para 1). Donovan further evidences that it is not uncommon for peptidoglycan hydrolases to possess multiple hydrolytic domains or for these domains to act independently of each other and even maintain their enzymatic activities in the presence of a nonfunctional second domain (pg. 2989, col. 1, para 4). It is further noted that domains from different genomes of different prophages in a recombinant endolysin is a well-understood evolutionary phenomenon. As evidenced by Schmelcher, natural chimeras exist, such as the Listeria phage endolysin PlyPSA, which has a cell-wall binding domain highly similar to other Listeria phage lysins, and an enzymatic domain related to amidase domains from Bacillus and Clostridium phages (pg. 11, para 1).
Sequence comparison of PNP86798.1 and SEQ ID NO: 28
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358
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Sequence comparison of PNP86798.1 and SEQ ID NO: 31
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446
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Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to synthesize a polypeptide with naturally occurring domains from the Gardnerella vaginalis endolysin polypeptide PYK96525.1 comprising a N-terminal domain having 100% sequence identity to instant SEQ ID NO: 2, a C-terminal domain comprising two cell wall binding domains specific for G. vaginalis, and a linker comprising NVGLNGCKNGGS as taught by Thomas, and substitute the C-terminal domain to two different naturally occurring Gardnerella vaginalis cell-wall binding domains derived from PNP86798.1, wherein the first has 96% identity to SEQ ID NO: 28 and the second domain with 100% sequence identity to SEQ ID NO: 31 as taught by Bumgarner. One of ordinary skill in the art would have substituted known C-terminal domains of 1,4-beta-N-acetylmuramidase that are specific for Gardnerella vaginalis, as substituting different domains are known to maintain their parental specificities according to each domain as evidenced by Donovan. Further, it would have been prima facie obvious to construct a polypeptide comprising 1, 2, or 3 C-terminal domains as taught by Thomas.
Regarding claims 2, 8, 9, 26-27, Thomas and Bumgarner do not teach the specific activities recited in claims 2, 8, 9, 26, and 27. However, the activity claimed are inherent to the known proteins, and as evidenced by Donovan, fusion proteins of peptidoglycan hydrolase (i.e., endolysins) maintain their parental specificities according to each domain (title, pg. 2989, col. 2, para 1). Donovan further discloses that it is not uncommon for peptidoglycan hydrolases to possess multiple hydrolytic domains or for these domains to act independently of each other and even maintain their enzymatic activities in the presence of a nonfunctional second domain (pg. 2989, col. 1, para 4). It is further noted that domains from different genomes of different prophages in a recombinant endolysin is a well-understood evolutionary phenomenon. As evidenced by Schmelcher, natural chimeras exist, such as the Listeria phage endolysin PlyPSA, which has a cell-wall binding domain highly similar to other Listeria phage lysins, and an enzymatic domain related to amidase domains from Bacillus and Clostridium phages (pg. 11, para 1). "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Thus, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Thomas-White et al. (NCBI Accession # PKY96525.1, Direct Submission, Submitted 17-DEC-2017, Biology, Loyola University Chicago, 1032 W Sheridan Rd., Biology Department, LSB 317B, Chicago, IL 60660, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Thomas”) in view of Bumgarner (NCBI Accession # PNP86798.1, Direct Submission, Submitted (29-MAR-2017) Microbiology, University of Washington, Box 358070, 1410 NE Campus Parkway, Seattle, WA 98195, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Bumgarner”), as evidenced by Donovan and Schmelcher, as applied to claims 1-2, 5-9, 22-24, 26-27, 34-40 above, and further in view of Thomas-White et al. (NCBI Accession # PKZ59243, Direct Submission, Submitted (17-DEC-2017) Biology, Loyola University Chicago, 1032 W Sheridan Rd., Biology Department, LSB 317B, Chicago, IL 60660, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Thomas2”) and Schmelcher (Future Microbiol. 2012 October; 7(10): 1147–1171, cited in PTO-892 mailed 8/30/2024, hereinafter “Schmelcher”).
Thomas teaches PYK96525.1 that comprises a N-terminal domain that has 100% sequence identity to SEQ ID NO: 2, and 2 CBDs with a first domain comprising 93% sequence identity to SEQ ID NO: 28 located N-terminally to a second domain comprising 95% sequence identity to SEQ ID NO: 31, and a linker region. Bumgarner teaches PNP86798.1 that comprises a first with 96% identity to SEQ ID NO: 28 and the second (N-terminal to the first) with 100% sequence identity to SEQ ID NO: 31. Neither Thomas nor Bumgarner teach a polypeptide that comprises a sequence that is 100% identical to SEQ ID NO: 28.
However, Thomas2 teaches a 1,4-beta-N-acetylmuramidase [Gardnerella vaginalis] (Accession # PKZ59243) with 100% sequence identity to SEQ ID NO: 28 (See sequence comparison below).
None of the prior art teach the specific combination of these two C-terminal domains taught by Bumgarner and Thomas2.
However, Schmelcher teaches evaluation of the effects of combining multiple CBDs on the binding properties (pg. 11, para 2). Schmelcher teaches their laboratory was able to demonstrate that combining the CBD of Listeria phage endolysin Ply500 (CBD500), which is specific for serovar 4, 5, and 6 strains, with that of PlyP35, which recognizes the majority of serovar 1, 2, and 3 strains, resulted in heterologous GFP fusion constructs that are able to recognize and brightly decorate a broad spectrum of Listeria cells from all species and serovars (pg. 11, para 2). Further, Schmelcher discloses new results from the laboratory with staphylococcal lysins suggest that binding affinity can be further potentiated with increasing copies of the same CBD in one fusion construct (pg. 11, para 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to synthesize a Gardnerella vaginalis endolysin polypeptide PYK96525.1 containing 2 CBDs as taught by Thomas, and substitute the CBDs with PKZ59243 that has 100% identity to SEQ ID NO: 28 taught by Thomas2 and PNP86798.1 that has 100% identity to SEQ ID NO: 31 taught by Bumgarner. One of ordinary skill in the art would have been motivated to substitute strain specific CBDs to create a highly effective endolysin that would increase cell-wall binding and exhibit enhanced lytic activities as taught by Schmelcher (pg. 12, para 1).
Sequence comparison of PKZ59243.1 and SEQ ID NO: 28
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Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Thomas and Bumgarner as evidenced by Donovan and Schmelcher as applied to claims 1-2, 5-9, 22-24, 26-27, 34-40 above, and further in view of Briers et al. (WO2012085259A2, cited in PTO-892 mailed 2/28/2025, hereinafter “Briers”).
Thomas and Bumgarner teach the polypeptide of claim 1 as discussed above, but do not teach a pharmaceutical composition comprising said polypeptide.
However, Briers teaches a fusion protein composed of an enzyme having the activity of degrading the cell wall of Gram-negative bacteria and/or Gram-positive bacteria and at least two peptide stretches fused to the enzyme at the N- or C-terminus (abstract). Briers teaches the fusion protein comprises a first amino acid sequence e.g. an endolysin, with a second and a third amino acid sequence, wherein the second and third amino acid sequences are preferably peptide stretches, in particular selected from the group consisting of cationic, polycationic, hydrophobic, amphipathic, sushi and antimicrobial peptides, preferably, said second and third amino acid sequence is foreign to and not substantially homologous with any domain of the first amino acid sequence (pg. 5, para 3). Briers teaches endolysins comprise at least one "enzymatically active domain" (EAD) having at least one of the following activities: N-acetyl-muramidase, inter alia, which is the same type of catalytic domain of the claimed invention (pg. 7, para 2). Briers teaches in addition, the endolysins may also contain regions which are enzymatically inactive and bind to the cell wall of the host bacteria, wherein said regions are CBDs (cell wall binding domains) (pg. 7, para 2). Briers teaches the composition is a pharmaceutical composition, said process comprising admixing one or more fusion protein and/or one or more hosts transformed with a nucleic acid comprising a nucleotide sequence encoding a fusion protein with a pharmaceutically acceptable diluent, excipient or carrier (pg. 41, para 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to synthesize A Gardnerella vaginalis endolysin polypeptide PYK96525.1 comprising a N-terminal domain having 100% sequence identity to instant SEQ ID NO: 2, a C-terminal domain comprising cell-wall binding domains, and a linker as taught by Thomas, and substitute the C-terminal domains with different Gardnerella vaginalis cell wall binding domains derived from PNP86798.1 that has 96% identity to SEQ ID NO: 28 and 100% sequence identity to SEQ ID NO: 31 as taught by Bumgarner, and formulate a pharmaceutical composition comprising the polypeptide as taught by Briers. One of ordinary skill in the art would have been motivated to make a pharmaceutical composition comprising the endolysin with a pharmaceutically acceptable diluent, as this is a well-understood, routine, and conventional laboratory practice as taught by Briers.
Claims 28-31 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Thomas-White et al. (NCBI Accession # PKY96525.1, Direct Submission, Submitted 17-DEC-2017, Biology, Loyola University Chicago, 1032 W Sheridan Rd., Biology Department, LSB 317B, Chicago, IL 60660, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Thomas”) in view of Briers (WO2012085259A2, cited in PTO-892 mailed 2/28/2025, hereinafter “Briers”).
Thomas teaches a 1,4-beta-N-acetylmuramidase [Gardnerella vaginalis] (Accession # PKY96525.1) having a sequence from N-terminus to C-terminus, with 100% sequence identity to SEQ ID NO: 2, 93% sequence identity to SEQ ID NO: 28, and 95% sequence identity to SEQ ID NO: 31 (See sequence comparison above), which meets the limitations of sequence identity in claims 28-31 and 33. The 1,4-beta-N-acetylmuramidase also consists of a linker region between the catalytic domain (SEQ ID NO:2) and cell-wall binding domain (SEQ ID NO: 28), wherein the linker is the amino acid sequence according to SEQ ID NO: 46 (See annotation of sequence above). The GenPept information sheet for PKY96525.1 teaches that the enzyme is a GH25_LytC-like enzyme, and the LytC lysozyme of Streptococcus pneumoniae is a bacterial cell wall hydrolase that cleaves the beta1-4-glycosydic bond located between the N-acetylmuramoyl-N-glucosaminyl residues of the cell wall polysaccharide chains, and indicates it has cell-wall binding domains (CBD) (pg. 2, “Region”).
Thomas does not teach the polypeptide further comprises a pharmaceutically acceptable carrier.
However, Briers teaches a fusion protein composed of an enzyme having the activity of degrading the cell wall of Gram-negative bacteria and/or Gram-positive bacteria and at least two peptide stretches fused to the enzyme at the N- or C-terminus (abstract). Briers teaches the fusion protein comprises a first amino acid sequence e.g. an endolysin, with a second and a third amino acid sequence, wherein the second and third amino acid sequences are preferably peptide stretches, in particular selected from the group consisting of cationic, polycationic, hydrophobic, amphipathic, sushi and antimicrobial peptides, preferably, said second and third amino acid sequence is foreign to and not substantially homologous with any domain of the first amino acid sequence (pg. 5, para 3). Briers teaches endolysins comprise at least one "enzymatically active domain" (EAD) having at least one of the following activities: N-acetyl-muramidase, inter alia, which is the same type of catalytic domain of the claimed invention (pg. 7, para 2). Briers teaches in addition, the endolysins may also contain regions which are enzymatically inactive and bind to the cell wall of the host bacteria, wherein said regions are CBDs (cell wall binding domains) (pg. 7, para 2). Briers teaches the composition is a pharmaceutical composition, said process comprising admixing one or more fusion protein and/or one or more hosts transformed with a nucleic acid comprising a nucleotide sequence encoding a fusion protein with a pharmaceutically acceptable diluent, excipient or carrier (pg. 41, para 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention formulate a pharmaceutical composition comprising an endolysin polypeptide as taught by Briers that comprises a Gardnerella vaginalis endolysin polypeptide PYK96525.1 comprising a N-terminal domain having 100% sequence identity to instant SEQ ID NO: 2, a C-terminal domain comprising at least 90% identity to SEQ ID NO’s: 28 & 31, and a linker as taught by Thomas,. One of ordinary skill in the art would have been motivated to formulate a pharmaceutical composition comprising the endolysin with a pharmaceutically acceptable diluent, as this is a well-understood, routine, and conventional laboratory practice as taught by Briers.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Thomas-White et al. (NCBI Accession # PKY96525.1, Direct Submission, Submitted 17-DEC-2017, Biology, Loyola University Chicago, 1032 W Sheridan Rd., Biology Department, LSB 317B, Chicago, IL 60660, USA, cited in PTO-892 mailed 8/30/2024, hereinafter “Thomas”) in view of Briers (WO2012085259A2, cited in PTO-892 mailed 2/28/2025, hereinafter “Briers”) as applied to claims 28-31 and 33 above, and further in view of Bumgarner and Schmelcher.
Thomas teaches PYK96525.1 that comprises a N-terminal domain that has 100% sequence identity to SEQ ID NO: 2, and 2 CBD’s with a first domain comprising 93% sequence identity to SEQ ID NO: 28 located N-terminally to a second domain comprising 95% sequence identity to SEQ ID NO: 31, and a linker region.
Briers teaches pharmaceutical compositions comprising a structurally similar endolysin polypeptide comprising enzymatic domains and CBDs as the claimed polypeptide.
Neither Thomas nor Briers teach the pharmaceutical composition comprises a polypeptide with at least 95% identity to SEQ ID NO: 28.
However, Bumgarner teaches PNP86798.1 that comprises a domain that has 96% identity to SEQ ID NO: 28 (See sequence comparison above).
None of the prior art references teach the specific combination of these two C-terminal domains taught by Thomas and Bumgarner. However, Schmelcher teaches evaluation of the effects of combining multiple CBDs on the binding properties (pg. 11, para 2). Schmelcher teaches their laboratory was able to demonstrate that combining the CBD of Listeria phage endolysin Ply500 (CBD500), which is specific for serovar 4, 5, and 6 strains, with that of PlyP35, which recognizes the majority of serovar 1, 2, and 3 strains, resulted in heterologous GFP fusion constructs that are able to recognize and brightly decorate a broad spectrum of Listeria cells from all species and serovars (pg. 11, para 2). Further, Schmelcher discloses new results from the laboratory with staphylococcal lysins suggest that binding affinity can be further potentiated with increasing copies of the same CBD in one fusion construct (pg. 11, para 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to formulate a pharmaceutical composition as taught by Briers comprising a Gardnerella vaginalis endolysin polypeptide PYK96525.1 containing 2 CBDs, wherein the second N-terminal CBD has at least 95% identity to SEQ ID NO: 31 as taught by Thomas, and substitute the first CBD (that is C-terminal to the 2nd) with the CBD derived from PNP86798.1 that has at least 95% identity to SEQ ID NO: 28 as taught by Bumgarner. One of ordinary skill in the art would have been motivated to substitute strain specific CBDs to create a highly effective endolysin that would increase cell-wall binding and exhibit enhanced lytic activities as taught by Schmelcher (pg. 12, para 1).
Response to Arguments
Applicant's arguments filed April 24, 2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments directed to the 35 USC § 103, Applicant argues the references do not provide enough motivation to combine to arrive at the claimed invention. Applicant argues the Examiner has merely demonstrated each of the claimed elements were independently known in the art and has not provided evidence of a motivation to combine, specifically for selecting the specific sequences as opposed to the multitude of other Gardnerella phages, pointing to the NCBI database of 49.422 different endolysins. Applicant argues the skilled artisan with the cited prior art in-hand would have had no expectation that the claimed polypeptides would have been effective in killing Gardnerella, and would result in increased killing activity compared to naturally occurring endolysins. Applicant argues the practice of combining known CBD and catalytic domains from different phages to enhance endolysin activity is a general assertion that domain swapping has been practiced in the art and is insufficient to provide motivation for obviousness.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed in the 103 rejections, the claimed sequences were known in the prior art. Also known in the prior art was the practice for combining CBD’s, which retain parental specificities and catalytic domains from different endolysins/phages targeting different strains and species to enhance endolysin activity, as evidenced by Schmelcher and Donovan. One of ordinary skill in the art would have been motivated to recombine known domains for more effective killing of species that the domains naturally target, especially with known domains that have close sequence identity, such as the CBD domains in PYK96525.1 and PNP86798.1, which are both derived from G. vaginalis strains. The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Applicant's argument that the prior art does not explicitly teach recombinant Gardnerella polypeptides is not a basis for the obviousness rejection, since the prior art teaches the routine practice of recombining polypeptide/phage domains for enhanced endolysin activities, which would motivate one of ordinary skill in the art to look for known domains in the art and construct the claimed polypeptides of the present invention, thus the 103 rejections are maintained.
Regarding Applicant’s arguments directed to unexpected results, Applicant argues any alleged prima facie case of obviousness would be overcome by the unexpectedly superior activity of the claimed recombinant proteins and points to the specification discloses that “[s]urprisingly and unexpectedly, the inventor discovered that several recombinant endolysins have a stronger activity than any natural endolysin (H1B1 to H12B12), especially when viewed across all 4 Gardnerella strains tested (see FIGS. 8A to 8D), particularly H2B10, H2B11, and H2B12 have activity ranks 1, 2, and 3, respectively, and each is more active than any natural endolysin (see Table 5C).” Applicant argues overall, the polypeptides comprising H2 (i.e., SEQ ID NO: 2) and B10 (i.e., SEQ ID NO: 28 or 29), B11 (i.e., SEQ ID NO: 30 or 31), B12 (i.e., SEQ ID NO: 32 or 33), or B3 (i.e., SEQ ID NO: 19 or 20) exhibited the highest killing activity against Gardnerella (e.g., Example 4; Tables 5A-5C and 7; and Figures 8A-8D). Applicant argues each of these claimed polypeptides exhibited greater killing activity than H2B2 (EL2), which is identical to the endolysin disclosed in Thomas. In other words, the claimed polypeptides unexpectedly demonstrated greater killing activity than the closest prior art identified by the Examiner. Applicant argues that the Corsini declaration filed 4/24/2026 further demonstrates that endolysins H2B10, H2B10B11, H2B10B12, and H2B11B12 all exhibited significant lytic activity against G. vaginalis and G. swidsinskii strains. Thus, all combinations of the cell-wall binding domains B10, B11, or B12 achieve significant killing activity against Gardnerella, and in many cases have near-identical killing activity to the reference endolysin H2B10, thus overcome the alleged case of obviousness over the prior art.
In response, the Examiner recognizes Applicant has demonstrated enhanced killing activity toward Gardnerella using the recombinant endolysins H2B10, H2B11, and H2B12 which all contain the linker SEQ ID NO’s 45-46. However, there is no evidence that recombinant endolysins using any kind of linker and endolysins with any kind of combinations between SEQ ID NO: 2 and SEQ ID NO’s: 28-33 would unexpectedly exhibit this enhanced killing activity. For these endolysins encompassed by the broad wording of claim 1 and not solving the technical problem, there is no data showing that they have any unexpected or surprising activity over naturally occurring endolysins. Thus, the subject matter of claim 1 is considered to be directed to an arbitrary selection of an endolysin which the skilled person would arrive to without any inventive skills.
The declaration by Dr.Corsini under 37 CFR 1.132 filed April 24, 2026 is insufficient to overcome the rejection of claims 1-2, 5-9, 11, and 22-40 based upon the references Thomas, Bumgarner, Donovan, Schmelcher, Thomas2, and Briers applied under 35 U.S.C. §103 as set forth in the last Office action because: The experimental data provided by Dr. Corsini demonstrating that endolysins with combinations of cell-wall binding domains recited in the claims, in addition to those specifically exemplified in the application, as filed, also exhibit enhanced killing activity against Gardnerella, and the endolysins are named according to their structure, following the convention set out in Paragraph [0142] of the application as filed (see Paragraphs spanning pages 47 and 48 of the application, as filed). For example, endolysin H2B10B12 comprises the H2 catalytic domain in combination with B10 (SEQ ID NO: 28) and B12 (SEQ ID NO: 33) cell wall binding domains. The endolysin H2B10 comprises the H2 catalytic domain in combination with two B10 cell wall binding domains, SEQ ID NOs: 28 and 29 (also referred to as PM-477 in the application as filed). The Corsini Declaration provides evidence that further recombinant endolysins, H2B10B11, H2B10B12, H2B11B12, H2B11B10, H2B12B10, and H2B12B11, all exhibit enhanced killing activity against two strains of Gardnerella (G. vaginalis and G. swidsinskii) at equivalent lytic activity to H2B10. However, the affidavit does not support the unexpected enhanced killing activity of the recombinant endolysins, as the broad scope of claims encompass the two domains as also having the combination H2B11B12, which could encompass SEQ ID NO’s: 30-33, which does not appear to have enhanced killing activity according to Table 1 and Figure 2 on pages 5-6 of the affidavit, thus would not support the unexpected results argument.
Conclusion
Applicant's amendment necessitated the new ground(s) 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
/JESSICA EDWARDS/
Examiner, Art Unit 1657
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