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 .
Status of Claims
Claims 1, 3-11, 13-14 and 19-22 are pending following the Reply filed 12/08/2025. Claims 2, 12 and 15 have been cancelled. Claims 1, 3-11, 13-14 and 19-21 have been amended and claim 22 has been added without introducing new matter. Claims 1, 3-11, 13-14 and 19-22 have been examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 12/12/2025 has been considered by the examiner.
Notice
Applicant is reminded that when amending claims, the text of any deleted matter must be shown by strike-through or double brackets.
In the previous claim set filed 05/12/2023, claim 13 recites:
“The composition of claim 12, further comprising…”
In the present claim set filed 12/08/2025, amended claim 13 recites:
“A composition comprising one or more chimeric bacteriophage lysins of claim 1, further comprising…”
Note that the preamble, “The composition of claim 12” has been fully replaced by the new preamble, “A composition comprising…” without annotations to denote what text was removed, for example, “A composition comprising one or more chimeric bacteriophage lysins of claim 1
Per 37 C.F.R. 1.121 (see section (c)(2)), all claims being currently amended in an
amendment paper shall be presented in the claim listing, indicate a status of "currently
amended," and be submitted with markings to indicate the changes that have been made relative
to the immediate prior version of the claims. The text of any deleted matter must be shown by
strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject
matter must be shown by being placed within double brackets if strike-through cannot be easily
perceived.
Since the above-mentioned reply appears to be bona fide, and no other errors or omissions appear in the pending claim set, examination of the claims has proceeded on the merits.
Withdrawn
Any objection or rejection of claims 2, 12 or 15 is moot because the claims have been cancelled.
Objections of claims 1, 3-10, 14 and 19-21 are withdrawn in light of the amendments.
Rejections of claims 1, 3-11, 13-14, 19 and 21 under 35 U.S.C. 112(b) are withdrawn in light of the amendments.
Rejections of claims 1, 6, 10, 11-13, 19 and 21 under 35 U.S.C. 102 are withdrawn in light of the amendments.
Maintained Rejections and New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(b)
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 11 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 recites the limitation, “iv) the nucleic acid sequence in d) has at least 85% sequence identity to SEQ ID NO: 16” in line 5. There is insufficient antecedent basis for this limitation in the claim. Note that claim 1 has been amended to remove limitation “d)”.
Suggestion to obviate the rejection: remove the limitation recited in line 5.
Claim Rejections - 35 USC § 112(a) – Written Description
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, 3-4, 6-11, 13-14, and 19-22 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.
Brief Statement of the Issue(s)
The claims are directed to variants of a chimeric bacteriophage lysin, wherein the variants are generically defined using functional limitations that do not clearly correspond to any particular set of prior art structures. The specification fails to provide sufficient structural/functional teachings as to permit a skilled artisan to envisage the full scope of the claimed genus.
Claim Scope
Claim 1 is representative of the pending claims scope and recites a chimeric bacteriophage lysin, wherein the chimeric bacteriophage lysin comprises a variant comprising a sequence having at least 90% or at least 95% sequence identity to the amino acid sequence set forth in a) SEQ ID NO: 11, b) SEQ ID NO: 9, or c) SEQ ID NO: 13, wherein the variant is capable of killing staphylococci.
Claim 6 recites the variants further having killing activity against: (i) E. faecalis and/or S. hominis and/or S. epidermis in human sweat (relevant to variants of SEQ ID NO: 11); or (ii) S. hominis and S. epidermis in human sweat (relevant to variants of SEQ ID NO: 9).
Claim 7 recites the variants of SEQ ID NO: 11 further having killing activity against methicillin-resistant and methicillin-sensitive strains of S. aureus.
Claim 8 recites the variants of SEQ ID NO: 11 further having killing activity against Rifampicin resistant strains of E. faecalis and vancomycin resistant strains of E. faecalis.
Claim 9 recites the variants of SEQ ID NO: 11 further having killing activity over a pH range of about 4-10 and/or a salt concentration of about 0-500 mM NaCl.
As relevant to the scope of the claims, the recited SEQ ID NOs comprise 242 to 338 amino acid residues. Reetz, MT. (previously cited) teaches that in an enzyme composed of 300 residues, 5700 mutants are possible from a single random amino acid substitution, 16 million in the case of two substitutions, and 30 billion in the case of three substitutions.
Thus, it is unclear if the claim scope encompasses trillions of species or perhaps only a few in view of the functional limitations set forth in the claim(s). Accordingly, the claim scope reasonably appears to be vast and highly varied.
Actual Reduction to Practice
The inventor discloses that to produce 2 chimeric lysins, the C-terminal cell wall binding domain (CBD) of the native lysins, PlyV12 and LysEF-P10, was amplified as inserts for the chimeric lysins, P10N-V12C and V12N-P10C, respectively (see amended specification at pg. 9, lines 2-5). The chimeric lysins were subjected to dose response assays, turbidity assays for profiling their optimal pH and salt concentrations, and measured for lytic activity (see pg. 11, lines 20-28).
The inventor discloses that further chimeric lysins were obtained by creating a library using Golden Gate assembly (see pg. 16, line 24), and a library of 100 chimeric lysins was generated by shuffling the catalytic and cell-wall binding domains of 10 naturally occurring lysins using this cloning technique (see pg. 16, lines 28-30). The respective domains were identified by integrating the information from a list of sequence and structure prediction software and are represented by the amino acid sequences LKCHAPV12 (SEQ ID NO: 9), V12NM3 (SEQ ID NO: 13), and LKNM3 (SEQ ID NO: 15) (see pg. 16, line 31 to pg. 17, line 5). The domains of each chimera were fused with a GSSG peptide linker, because it was a partial byproduct of Golden Gate assembly and the addition of a short linker has been previously shown to improve soluble expression as well as antibacterial activity (see pg. 17, lines 5-9).
The inventor discloses that four engineered lysins, LKCHAPV12 (SEQ ID NO: 9), P10N-V12C (SEQ ID NO: 11), V12NM3 (SEQ ID NO: 13) and LKNM3 (SEQ ID NO: 15), were tested for their killing activity against odor-causing bacteria in human sweat (see pg. 18, lines 22-26; Table 3). The inventor notes that another 16 engineered lysins were tested but showed little activity in this assay, and the data is expressly “not shown” (see pg. 18, line 27). The inventor also discloses enhanced killing activity was achieved when combining LKCHAPV12 (SEQ ID NO: 9) and the native lysin, PlyV12 (see pg. 19, lines 15-17; Table 4).
In summary, Applicant discloses the shuffling of catalytic and cell wall-binding domains of bacteriophage lysins to produce four chimeric lysins which were shown to have the activities required by the functional limitations of the claims. However, the claims are further drawn to variants of these four chimeric lysins, none of which are described or characterized in Applicant’s Examples. While Applicant discusses the generation of other engineered lysins by the shuffling of these two domains, one cannot envisage from Applicant’s Examples which variants of the recited chimeric lysins would meet the functional limitations of the claims, as necessary for the claimed invention. Thus, zero examples of the claimed invention using “variants” of the four chimeric lysins were reduced to practice.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims encompass an essentially infinite number of variants, but zero were reduced to practice.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero variants of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
On page 8 of the specification, the term "variant" refers to an amino acid sequence that is altered by one or more amino acids, but retains the ability of the non-variant reference sequence to bind to and kill staphylococci (see lines 19-21). The specification states that the variant may have “conservative” changes or, more rarely, “non-conservative” changes, which can be determined by “using computer programs well known in the art, for example, DNASTAR®” (see lines 21-27). In some embodiments, the chimeric bacteriophage lysin variant comprises a sequence having at least 85%, at least 90% or at least 95% sequence identity to SEQ ID NO: 11, SEQ ID NO: 9, SEQ ID NO: 13, or SEQ ID NO: 15 (see pg. 8, line 30 to pg. 9, line 32).
Examiner notes that even a variant having 95% sequence identity with SEQ ID NO: 13 would contain 12 amino acid modifications. As discussed above, this amount of sequence variation includes billions, if not trillions, of potential variants. In view of Applicant’s discussion regarding the changes that can be made to the recited sequences, no “conservative” or “non-conservative” changes are recited as being specifically associated with the functions of the lysins. Accordingly, the specification fails to identify what potential structures correspond to the killing activity of the claimed variants, and which of these structures can be modified while retaining the specific killing activity of the lysins across the broad range of pH and salt-concentrations set forth in the claims.
Predictability in the Art
Manoharadas et al. (previously cited; hereafter, “Manoharadas”), teach the construction of a chimeric peptide against Enterococcus, BP404, that features the enzymatic domain from bacteriocin BacL1 and the cell wall binding domain from endolysin PlyV12 of phage ɸ1 (see Abstract), which was found to be active against two tested strains of E. faecalis (see pg. 2, para. 4). However, Manoharadas teaches that in comparison with the antibacterial activity exerted by BP404 against an E. faecalis clinical strain, lower activity was observed against the E. faecalis ATCC 29212 strain (see pg. 5, para. 2). Manoharadas speculated that swapping the cell wall binding domain of BacL1 with the cell wall binding domain from PlyV12 would be sufficient to make the chimeric lysin potent against E. faecalis strains; however, around 80% of BP404 was found not to bind to E. faecalis (see pg. 9, para. 4). Manoharadas was not sure why the binding efficiency of BP404 was less towards the tested E. faecalis, but Manoharadas suggests that because BP404 is an engineered protein with domains from two unrelated proteins linked together, the folding pattern of the protein could mask the active cell wall binding site (see pg. 10, para. 2). Manoharadas teaches that while several studies have pointed out the development of chimeric “enzybiotics” against pathogens, only a few studies were targeted against E. faecalis bacteria (see pg. 10, para. 3), and Manoharadas discloses that the present study, published in 2023, is among the first to develop a chimeric peptide against Enterococcus faecalis (see Abstract).
Antonova et al. (previously cited; hereafter “Antonova”) compared the effects of two different types of protein modifications on endolysin LysECD7 bactericidal activity in vitro and demonstrated that it is significantly modulated by specific permeabilizing antimicrobial peptides, as well as by widely used histidine tags (see Abstract). Antonova teaches that the activity of the obtained enzymes substantially depends on the method of biotechnological production, and that even relatively small histidine tags can decrease, increase, or modify functional activity of target molecules after fusion (see pg. 2, para. 2). Antonova discloses that how the activity of these endolysins is modified by polyhistidine tag fusion has not been specifically studied (see pg. 2, para. 2). Antonova teaches that a number of limitations in the use of the LysECD7-8his molecule were revealed that interfere with its further development in preclinical and clinical studies (see pg. 3, para. 2). Antonova teaches that histidine tagging definitely affects the bactericidal properties of endolysin, but the charge hypothesis does not completely explain these alterations, and the particular effects of different lengths of fusions are difficult to predict (see pg. 12, para. 4).
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of enzymatic structures and their corresponding functions. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures exactly what variants of a chimeric endolysin would be capable of performing the functional limitations of the claims.
Accordingly, in the absence of sufficient structure/function teachings identifying particular mutations in the recited chimeric lysins which retain killing activity against staphylococci (i.e., all claims), E. faecalis, S. hominis, and S. epidermis (i.e., claim 6), methicillin-resistant and methicillin-sensitive strains of S. aureus (i.e., claim 7), and Rifampicin and vancomycin resistant strains of E. faecalis (i.e., claim 8), over a broad range of pH and salt concentrations (i.e., claim 9), as required to practice the full scope of the claims, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope.
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures are included or excluded by the claim scope. This also means that the skilled artisan cannot envisage what structures infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
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.
Claim(s) 1, 6, 10, 13-14 and 19-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Loessner, et al. (US 9,789,167 B2; previously cited), hereafter, “Loessner”, and in further reference of Dong, et al. (cited in the IDS filed 05/12/2023 at Cite No. 2), hereafter, “Dong”, as further evidenced by GenBank AAT01859.1 (cited on Form 892).
Regarding claim 1, Loessner teaches a composition to be used as an antimicrobial agent comprising a combination of enzymatic domains (see Abstract), preferably for killing a bacterium of the genus Staphylococcus, including a bacterium of the species Staphylococcus aureus (see col. 26, lines 15-19). Loessner teaches a polypeptide comprising at least one enzymatic active domain and a cell wall-binding domain (see col. 9, lines 36-40), wherein the enzymatic active domain is a domain having lytic activity, preferably exhibiting peptidoglycan hydrolase activity (see col. 3, lines 50-52) which is associated with Staphylococcus bacteriophage endolysins (see col. 2, lines 27-28). Loessner teaches the polypeptide preferably has 80-100% identity to SEQ ID NO: 36 (see col. 14, lines 29-33).
Regarding the limitation of “b)”, as shown in the following alignment, Loessner’s SEQ ID NO: 36 (bottom) comprises amino acids 1-165 of instant SEQ ID NO: 9 (top):
PNG
media_image1.png
76
649
media_image1.png
Greyscale
PNG
media_image1.png
76
649
media_image1.png
Greyscale
Loessner also teaches that most native Staphylococcus bacteriophage endolysins exhibiting peptidoglycan hydrolase activity consist of a C-terminal cell wall-binding domain (CBD) and an N-terminal domain exhibiting peptidoglycan hydrolase activity, also referred to as the “enzymatically active domain” (see col. 2, lines 27-38). Hence, Loessner teaches a chimeric bacteriophage lysin comprising the N-terminal catalytic domain as set forth in part “b)” of claim 1.
Loessner does not teach the lysin comprising an amino acid sequence set forth in amino acids 170-338 of SEQ ID NO: 9.
Dong teaches there is an ever-growing concern over the global spread of antibiotic resistance among human and animal pathogens, and phage lysins are promising antimicrobials against Gram-positive bacteria because of their high in vitro and in vivo antimicrobial efficiency, low occurrence of resistance, and wide availability from bacteriophages (see pg. 210, col. 2, para. 1). Dong teaches that phage endolysins of Gram-positive bacteria display a two-domain modular structure, which comprises an N-terminal catalytic domain (CD) and a C-terminal cell wall binding domain (CBD), which can be utilized by constructing chimeric lysins with a catalytic domain and a bacterial cell binding domain from different native lysins to control pathogenic bacteria in a variety of environments (see pg. 210, col. 2, para. 1). Dong teaches that most lysins reported so far have a narrow host range, rendering them either species or genus specific, and such specificity can be influenced by its CBD (see pg. 210, col. 2, para. 2).
Dong discloses a novel chimeric lysin (Ply187N-V12C) constructed by fusing the catalytic domain (Ply187N) of the bacteriophage lysin Ply 187 with the cell binding domain (146-314aa, V12C) (see pg. 210, col. 1). The results showed that the chimeric lysin had not only lytic activity similar to Ply187N against staphylococcal strains but also extended its lytic activity to streptococci and enterococci, such as Streptococcus dysgalactiae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecium and Enterococcus faecalis, which Ply187N could not lyse (see pg. 210, col. 1). Dong teaches that this work demonstrates that generating novel chimeric lysins with an extended lytic spectrum was feasible through fusing a catalytic domain with a cell-binding domain from lysins with lytic spectra across multiple genera (see pg. 210, col. 1).
Dong teaches the lysin PlyV12 is represented by GenBank accession No. AAT01859.1 (see Dong at pg. 216, col. 2, para. 2). As shown in the following alignment, amino acids 146-314 (the C-terminal CBD domain) of PlyV12 (bottom) are identical to amino acids 170-338 of instant SEQ ID NO: 9 (top):
PNG
media_image2.png
494
641
media_image2.png
Greyscale
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Loessner and Dong, because both references teach chimeric bacteriophage lysins which can be useful in killing Gram positive bacteria. One would have recognized that Dong specifically teaches a cell wall binding domain of a bacteriophage endolysin that can be fused to another lytic enzyme which Dong teaches may extend its lytic activity across a broader spectrum of bacteria. Hence, one would have been particularly motivated to apply the combination in order to address need of providing novel antimicrobials that have activity against a broad range of Gram-positive bacteria, including Staphylococcus. One would have also recognized from Loessner that the N-terminal region of bacteriophage lysins contains the catalytic domain, and from Dong that the C-terminal region contains the binding domain, which Dong demonstrates can be combined with the catalytic domain of other lytic enzymes to expand the lysin’s specificity. As Loessner and Dong teach effective lysins comprising these domains, and Dong further teaches the advantages of fusing the domains of different native lysins, specifically the CBD of PlyV12, a person of ordinary skill would have recognized there to be a reasonable expectation of success when combining these elements. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 6, Dong teaches the chimeric lysin (Ply187N-V12C) had increased killing activity against S. epidermidis XJ9 compared to either of the native lysins (see pg. 214, Table 1). Furthermore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In this case, there is no further structure recited in the present claim, and the killing activity of the chimeric lysin is an inherent property that would necessarily be present in the chimeric lysin of claims 1 and 6. See MPEP 2112.
Regarding claim 10, Loessner teaches a polynucleotide, SEQ ID NO: 35, which encodes the polypeptide of SEQ ID NO: 36 (see col. 21, lines 51-61). Likewise, GenBank AAT01859.1 provides the accession number (i.e., AY581208.1) for a nucleotide sequence encoding PlyV12 (see “DBSOURCE”). Dong discloses that plasmids comprising the gene encoding Ply187N-V12C were transformed into E. coli to produce the recombinant chimeric lysin (see pg. 217, col. 2). Hence, it would have been obvious to have provided a polynucleotide encoding the chimeric lysin, because this would be necessary in order to express and produce the lysin. One could have simply combined the nucleotide sequences provided by Loessner and GenBank, which encode the CD and CBD domains of the respective lysins, to have arrived at a polynucleotide that encodes the chimeric lysin. Furthermore, it is well within the ordinary skill in the art to construct nucleotide sequences that encode a given polypeptide sequence.
Regarding claim 13, Loessner teaches the composition further comprising an antibiotic (see col. 26, lines 19-27).
Regarding claim 14, Dong discloses that compared with their parental lysins, the activity of Ply187N-V12C was about the same as Ply187N and PlyV12 against staphylococcus, and slightly inferior to PlyV12 against enterococcus (see pg. 214, col. 1, para. 2). Hence, while the chimeric lysin had an extended lytic spectrum, a person of skill would have recognized that there would still be some advantages of using the native lysin of PlyV12. Further, Loessner teaches that the simultaneous application of two or more enzymatically active domains with distinct target bond specificities confer synergistic effects (see col. 2, lines 49-51), and Loessner teaches embodiments wherein the composition comprises additional bactericidal agents (see col. 26, lines 24-27). Therefore, a person of ordinary skill would have also recognized there to be an advantage when combining multiple lysins with different specificities and would have expected the combination to result in a more effective composition for killing a wider range of bacteria. As shown in the following alignment, instant SEQ ID NO: 17 (top) is nearly identical to GenBank AAT01859.1 representing PlyV12 (bottom):
PNG
media_image3.png
499
648
media_image3.png
Greyscale
Examiner notes that the last 7 residues of instant SEQ ID NO: 17 are not shown in the alignment, due to a C-terminal 6xHis tag (A-H-H-H-H-H-H) which was added to the claimed sequence for affinity chromatography purification (see, e.g., instant specification at pg. 6, lines 6-8). Loessner teaches that the polypeptides of the invention preferably comprise a 6x His tag (H-H-H-H-H-H) for “ease of purification” (see col. 4, lines 36-41). Hence, the prior art sequence clearly retains the cell wall-binding domain which is pertinent to the functioning of the enzyme, and the addition of amino acids to accommodate the inclusion of a C-terminal HisTag for easier purification is well within the ordinary skill in the art, requiring no more than routine optimization for a person of ordinary skill to have arrived at the claimed PlyV12 sequence.
Regarding claim 19, Loessner teaches the composition comprising the polypeptide can be used to treat animals, including humans, infected with S. aureus (see col. 27, lines 60-65) by administering the composition to the individual (see col. 27, lines 45-50). Dong teaches that Ply187N-V12C maintained lytic activity against all the S. aureus strains tested (see pg. 211, col. 2, para. 2). Hence, it would have been obvious to have administered the chimeric lysin to treat a staphylococcal infection.
Regarding claim 20, Loessner teaches the method may be used for the prevention of a microbial related condition in an individual (see col. 27, lines 45-50) and suitable routes of administration include topical administrations (see col. 27, line 65 to col. 28, line 3). Loessner teaches that infectious diseases caused by Staphylococcus which may be prevented by the method include skin infections (see col. 26, lines 62-64; col. 27, lines 1-10).
Claim interpretation: The “method of prophylaxis” recited in parent claim 19 is interpreted to be directed to administering the one or more chimeric bacteriophage lysins to any mammal, because prevention (prophylaxis) does not require the mammal to have an infection when administered the lysins. Therefore, the method of prophylaxis of claim 20 is reasonably interpreted to include administering the lysin(s) to any human. Further, the “body odor” caused by the infection is an inherent property of the bacteria themselves, and neither the bacteria nor the body odor are required to be present in the method of prophylaxis.
Therefore, the effect of preventing an infection by body odor-causing bacteria is an inherent property of the method that is necessarily present in the prior art combination. As the claim does not recite any further method step, and is directed to any human, the further limitation of the claim is an inherent effect of administering the lysin. See MPEP 2112.
Regarding claim 21, Loessner teaches a method for controlling microbial contamination
on food or feed processing equipment and on food or feed containers comprising contacting the composition with said equipment or containers (see col. 28, lines 31-40). Hence, it would have been obvious to have used a bactericidally effective amount of the chimeric lysin in the same manner taught by Loessner to decontaminate inanimate surfaces (equipment or containers) suspected of containing infectious bacteria (microbial contamination associated with food).
Regarding claim 22, the claim is obvious for the same reasons as claim 14.
Claim(s) 1 and 7-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dong and GenBank AAT01859.1, as applied to claims 1, 6, 10, 13-14 and 19-22 above, and further in view of Cheng, et al. (previously cited), hereafter “Cheng”, as further evidenced by GenBank AQT27695.1 (previously cited).
Dong discloses a novel chimeric lysin (Ply187N-V12C) constructed by fusing the catalytic domain (Ply187N) of the bacteriophage lysin Ply 187 with the cell binding domain (146-314aa, V12C) (see pg. 210, col. 1). The results showed that the chimeric lysin had not only lytic activity similar to Ply187N against staphylococcal strains but also extended its lytic activity to streptococci and enterococci, such as Streptococcus dysgalactiae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecium and Enterococcus faecalis, which Ply187N could not lyse (see pg. 210, col. 1). Dong teaches that this work demonstrates that generating novel chimeric lysins with an extended lytic spectrum was feasible through fusing a catalytic domain with a cell-binding domain from lysins with lytic spectra across multiple genera (see pg. 210, col. 1).
Dong teaches the lysin PlyV12 is represented by GenBank accession No. AAT01859.1 (see Dong at pg. 216, col. 2, para. 2). As shown in the following alignment, amino acids 146-314 (the C-terminal CBD domain) of PlyV12 (bottom) are identical to amino acids 146-314 of instant SEQ ID NO: 11 (top):
PNG
media_image4.png
92
651
media_image4.png
Greyscale
PNG
media_image4.png
92
651
media_image4.png
Greyscale
Hence, Dong teaches a chimeric bacteriophage lysin comprising the C-terminal region of instant SEQ ID NO: 11 (amino acids 146-314) which contains the binding domain of the chimeric lysin as set forth in part “a)” of claim 1.
Dong does not teach the lysin comprising the N-terminal catalytic domain as set forth in instant SEQ ID NO: 11.
Cheng teaches a new lysin derived from an isolated Enterococcus faecalis phage called LysEF-P10 which shares only 61% amino acid identity with its closest homologues (see Abstract) and was studied in vitro and in vivo as an alternative treatment strategy for multidrug-resistant E. faecalis infections (see pg. 2, para. 1). Cheng teaches that bacteriophage lysins have received considerable attention as alternative antibacterial agents due to the emergence of multidrug-resistant bacteria and show great potential for combating antibiotic-resistant Gram-positive pathogens (see pg. 1, para. 1). Cheng discloses that LyseEF-P10 showed efficient bactericidal activity against E. faecalis and was able to kill 32/36 of a panel of diverse E. faecalis isolates, including of 20/22 vancomycin-resistant strains (see pg. 2, para. 6). Cheng teaches that compared with the very narrow infective range of the host phage (EF-P10), LysEF-P10 showed a much broader bactericidal range, not only killing antibiotic-sensitive E. faecalis strains but also multidrug-resistant strains, including vancomycin-resistant E. faecalis strains (see pg. 6, para. 1).
Cheng also discloses that unlike several other E. faecalis strains, LysEF-P10 did not kill E. faecium (see pg. 6, para. 1). Cheng teaches one such lysin, PlyV12 of phage ɸ1, to have the broadest lytic spectrum as it also acts against several streptococcal and staphylococcal strains (see pg. 6, para. 1).
Cheng teaches that a BLAST analysis against the Protein Data Bank (PDB) revealed that a region spanning 53% of LysEF-P10 (residues 14-141) contained residues that may play an important role in the catalytic activity of LysEF-P10 (see pg. 2, paras. 8-9). Cheng discloses that the complete genome sequence of EF-P10 is available in GenBank under accession number KY472224 which contains 127 putative open reading frames (ORFs), of which ORF 60 shares homology with several putative lysins and may encode the putative lysin protein of LysEF-P10 (see pg. 2, para. 4).
GenBank AQT27695.1 represents the translated CHAP domain protein of ORF 60, as disclosed by Cheng. As shown in the following alignment, this sequence (bottom) is identical to amino acids 1-145 of instant SEQ ID NO: 11 (top):
PNG
media_image5.png
636
975
media_image5.png
Greyscale
It would have been obvious at the time of filing to have arrived at the claimed invention by combining the teachings of Dong and Cheng, because both references teach endolysins, such as PlyV12, which are effective against Enterococcus. One would have recognized from Dong the advantages of fusing the C-terminal endolysin binding domain of PlyV12 to the catalytic domains of other endolysins which results in broadened activity against other genera of bacteria, including Enterococcus faecalis. One would have also recognized the potential for utilizing the broad specificity of LysEF-P10’s catalytic domain, particularly for its antimicrobial activity against Enterococcus faecalis, as taught by Cheng. One would have been particularly motivated to do so, because Dong and Cheng teaches such endolysins to be an effective solution to killing antibiotic-resistant bacteria. As Dong demonstrates PlyV12 can be fused to other lytic enzymes to extend its activity against Enterococcus, including Enterococcus faecium and Enterococcus faecalis, one would have recognized that the results of the combination would have been predictable with a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 7, Dong discloses that the chimeric lysin Ply187N-V12C maintained its lytic activity against all strains of Staphylococcus aureus tested, including methicillin-resistant strains of S. aureus (see pg. 211, col. 2, para. 2). Cheng teaches that the CHAP domain of LysEF-P10 shared the highest identity with the CHAP domain of Staphylococcus aureus (see pg. 2, para. 8) and that the PlyV12 endolysin of phage ɸ1 acts against several streptococcal and staphylococcal strains, as discussed above.
Furthermore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In this case, there is no further structure recited in the present claim, and the killing activity of the chimeric lysin is an inherent property that would necessarily be present in the chimeric lysin of claim 1, part “a)”. Because the limitations of the claimed product are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112.
Regarding claim 8, Cheng teaches LysEF-P10 had killing activity against vancomycin resistant strains of E. faecalis, and Dong teaches that the lytic activity of the chimeric lysin comprising PlyV12 was extended to E. faecalis, as discussed above. Hence, there would have been a reasonable expectation that the chimeric lysin would have retained this activity. Furthermore, there is no further structure recited in the present claim, and the killing activity of the chimeric lysin is an inherent property that would necessarily be present in the chimeric lysin of claim 1, part “a)”. Because the limitations of the claimed product are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112.
Regarding claim 9, Dong teaches that using the microplate assay and S. aureus N315 as the test strain, the activity of Ply187N-V12C was found optimum around pH 9.0, which was higher than that of Ply187N and similar to that of PlyV12 (see pg. 213, col. 2, para. 2). Further, Dong discloses that among the three lysins (the two native lysins and the chimeric lysin), Ply187N-V12C (the chimeric lysin) was the least sensitive to the ionic strength changes (increasing concentrations of NaCl in the lytic buffer) (see pg. 213, col. 2, para. 2). Dong discloses that Ply187N-V12C had the highest relative activity among the three lysins, from a NaCl concentration of 0-500 mM (see Fig. 5B).
Furthermore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In this case, there is no further structure recited in the present claim, and the chimeric lysin’s ability to maintain its killing activity under the claimed conditions is an inherent property that would necessarily be present in the chimeric lysin of claim 1, part “a)”. Because the limitations of the claimed product are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112.
Claim(s) 3-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Loessner, Dong, and GenBank AAT01859.1 as applied to claims 1, 6, 10, 13-14 and 19-22 above, and further in view of Biebl et al. (US 20190330608 A1; previously cited), hereafter “Biebl”.
Regarding claim 3, Loessner teaches a composition to be used as an antimicrobial agent comprising a combination of enzymatic domains (see Abstract), preferably for killing a bacterium of the genus Staphylococcus, including a bacterium of the species Staphylococcus aureus (see col. 26, lines 15-19). Loessner teaches a polypeptide comprising at least one enzymatic active domain and a cell wall-binding domain (see col. 9, lines 36-40), wherein the enzymatic active domain is a domain having lytic activity, preferably exhibiting peptidoglycan hydrolase activity (see col. 3, lines 50-52) which is associated with Staphylococcus bacteriophage endolysins (see col. 2, lines 27-28). Loessner teaches the polypeptide preferably has 80-100% identity to SEQ ID NO: 36 (see col. 14, lines 29-33).
Dong discloses a novel chimeric lysin (Ply187N-V12C) constructed by fusing the catalytic domain (Ply187N) of the bacteriophage lysin Ply 187 with the cell binding domain (146-314aa, V12C) (see pg. 210, col. 1). The results showed that the chimeric lysin had not only lytic activity similar to Ply187N against staphylococcal strains but also extended its lytic activity to streptococci and enterococci, such as Streptococcus dysgalactiae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecium and Enterococcus faecalis, which Ply187N could not lyse (see pg. 210, col. 1). Dong teaches that this work demonstrates that generating novel chimeric lysins with an extended lytic spectrum was feasible through fusing a catalytic domain with a cell-binding domain from lysins with lytic spectra across multiple genera (see pg. 210, col. 1).
As discussed regarding claim 1, it would have been obvious in view of Loessner and Dong for one to have arrived at a chimeric lysin comprising limitation b), amino acids 1-165 and 170-338 set forth in instant SEQ ID NO: 9, by fusing the N-terminal CD region of Loessner’s SEQ ID NO: 36 and the C-terminal CBD region of PlyV12 taught by Dong.
Loessner and Dong do not teach the chimeric bacteriophage lysin, wherein the catalytic domain of the first phage lysin and the binding domain of the second phage lysin are fused by a linker peptide.
Biebl teaches antimicrobial agents active against Enterococcus bacteria, in particular, a polypeptide comprising a first and a second amino acid sequence (see Abstract), wherein the polypeptide may be a fusion protein in which the two amino acid sequences are combined and do not occur in this combination in nature (see pg. 1, para. [0007]). Biebl teaches that the invention makes use of enzymes degrading the bacterial cell wall, such as an endolysin, which is a peptidoglycan hydrolase typically encoded by bacteriophages (see pg. 1, para. [0003]). Biebl teaches that endolysins comprise at least one “enzymatically active domain” (catalytic domain) and also contain a region that binds to the cell wall of the host bacteria, called the cell wall binding domain (CBD) (see pg. 2, para. [0008]). Biebl teaches that derivatives of the endolysin according to SEQ ID NO: 1 are extremely useful components when designing antimicrobial agents against bacteria of the genus Enterococcus, and, in combination with specific types of peptides, show increased utility and activity, for example against Enterococcus faecalis bacteria, and are more pH tolerant than the wildtype endolysin (see pg. 4, para. [0029]). Biebl teaches that the polypeptide comprising the CBD preferably comprises an additional amino acid sequence of an enzyme capable of degrading the cell wall of bacteria, in particular Gram positive bacteria, and that the cell wall binding domain (CBD) of SEQ ID NO: 1 can be fused to many other lytic enzyme sequences (see pg. 5, para. [0039]). As shown in the following alignment, Biebl’s SEQ ID NO: 1 (bottom) comprises amino acids 170-338 of instant SEQ ID NO: 9 (top):
PNG
media_image6.png
359
648
media_image6.png
Greyscale
PNG
media_image7.png
217
975
media_image7.png
Greyscale
Biebl discloses that “[a]lready Dong et al. (Microb Biotechnol. 2015 March; 8(2):210-20) exemplified, that the cell wall binding domain (CBD) of SEQ ID NO: 1 can be fused to many other lytic enzyme sequences” (see pg. 5, para. [0039]). Hence, the CBD domain taught by Biebl is the same as the PlyV12 CBD domain taught by Dong, and both references teach this domain can be fused to other lytic enzymes to make them more effective against Enterococcus bacteria.
Regarding the further limitation of claim 3, Biebl teaches that the first and second amino acid sequences are preferably linked to each other directly or via a short linker of 1 to 5 amino acid residues (see pg. 7, para. [0049]).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Loessner, Dong and Biebl, because all references teach chimeric bacteriophage lysins which can be useful in killing Gram positive bacteria. One would have recognized that both Loessner and Dong teach such lysins are effective against Staphylococcus, and both Dong and Biebl teach that using the CBD of PlyV12 increases the lysin’s activity against Enterococcus bacteria. Biebl also teaches that this domain improves the pH tolerance of the lysin. Hence, one would have been particularly motivated to apply the combination in order to provide a more effective antimicrobial agent against Enterococcus. As Biebl and Dong both teach the PlyV12 CBD to have been successfully used to generate various chimeric lysins with advantageous properties, a person of ordinary skill would have recognized there to be a reasonable expectation of success when combining these elements. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 4, Biebl teaches that the first and second amino acid sequences are preferably linked to each other directly or via a short linker of 1 to 5 amino acid residues, and linker sequences are preferably flexible sequences, comprising one or more glycine residues, such as a glycine-serine linker (see pg. 7, para. [0049]). Examiner notes that amino acids 166-169 of SEQ ID NO: 9 are G-S-S-G. Hence, it would have been obvious in view of Biebl to have constructed a linker comprising this sequence or any glycine-serine sequence of 1 to 5 amino acids.
Regarding claim 5, limitation “b)” is directed to the chimeric lysin having the amino acid sequence set forth in SEQ ID NO: 9. As discussed regarding claim 1, the chimeric lysin comprising amino acids 1-165 and 170-338 would have been obvious in view of Loessner and Dong. As discussed regarding claim 4, it would have been obvious in view of Biebl to fuse these two regions with amino acids 166-169 of SEQ ID NO: 9. Hence, claim 5 is obvious for the same reasons as claims 1 and 4.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Loessner, Dong and GenBank AAT01859.1, as applied to claims 1, 6, 10, 13-14 and 19-22 above, as further evidenced by GenBank AY581208.1 (cited on Form 892) and Reznikoff, et al. (previously cited), hereafter “Reznikoff”,
Regarding claim 11, as discussed regarding claim 1, part “b”, Loessner’s SEQ ID NO: 36 comprises amino acids 1-165 of instant SEQ ID NO: 9, and Dong’s PlyV12 comprises amino acids 170-338 of instant SEQ ID NO: 9. As discussed regarding claim 10, Loessner teaches a polynucleotide, SEQ ID NO: 35, which encodes the polypeptide of SEQ ID NO: 36 (see col. 21, lines 51-61). Likewise, GenBank AAT01859.1 provides the accession number, AY581208.1, for a nucleotide sequence encoding PlyV12 (see “DBSOURCE”).
Here, amino acids 1-165 of SEQ ID NO: 9 can be encoded by nucleotides 97-601 of Loessner’s SEQ ID NO: 35, and amino acids 146-314 of SEQ ID NO: 9 can be encoded by nucleotides 430-941 of GenBank AY581208.1. Taken together, one may arrive at the following nucleotide sequence:
PNG
media_image8.png
245
746
media_image8.png
Greyscale
However, this sequence shares only 75.8% sequence identity with instant SEQ ID NO: 10.
Nonetheless, as shown in the following alignment, the translated products (amino acid sequences) of instant SEQ ID NO: 10 (top) and the nucleotide sequence derived from Loessner’s SEQ ID NO: 35 and GenBank AY581208.1 (bottom) share more than 99% similarity:
PNG
media_image9.png
491
646
media_image9.png
Greyscale
PNG
media_image10.png
30
144
media_image10.png
Greyscale
Furthermore, in view of Table 8-1 of Reznikoff (see pgs. 226-227), it can be seen that the same codons used in instant SEQ ID NO: 10 correspond with the same amino acids as in the prior art sequence above. For example, Reznikoff teaches that AAA and AAG both encode Lys, ACC and ACT both encode Thr, CAG and CAA both encode Gln, GCT and GCA both encode Ala, etc., as depicted in the partial alignment below between instant SEQ ID NO: 10 (top) and the prior art sequence (bottom):
PNG
media_image11.png
99
186
media_image11.png
Greyscale
PNG
media_image12.png
60
538
media_image12.png
Greyscale
By applying these modifications further to the full-length of the prior art nucleotide sequence, a person of skill could arrive at the following modified sequence (bottom) which has more than 85% sequence similarity with instant SEQ ID NO: 10 (top), as shown in the following alignment:
PNG
media_image13.png
720
646
media_image13.png
Greyscale
PNG
media_image14.png
571
642
media_image14.png
Greyscale
Thus, it would have been obvious for a person of ordinary skill to have arrived at the claimed sequence in view of Loessner and Dong as further evidenced by the codon table provided by Reznikoff, because to apply such changes, which are well known in the art, does not amount to anything more than routine optimization. It is well within the ordinary skill in the art to optimize the codon usage of any given nucleic acid sequence without changing the amino acid sequence that it encodes. Furthermore, the translated products of either sequence results in an endolysin comprising the same N-terminal catalytic domain and the same C-terminal cell wall binding domain, and a person of ordinary skill would have recognized that either nucleic acid sequence could be used to produce a polypeptide with the same functional domains, which would have been expected to perform the same functions and have the same activity.
Response to Arguments
Regarding the rejections under 35 USC 112(a), for failing to comply with the written description requirement, Applicant argues that the amended claimed variants are defined by a structural limitation in combination with a functional limitation, which together would clearly permit a skilled artisan to make and use the invention. Applicant argues that although additional variants (which have not been reduced to practice) falling within the scope of amended claim 1 are not individually disclosed, such variants would easily be obtainable by a skilled artisan based on the teachings of the application in combination with their common general knowledge. Applicant points to sections of the specification stating that the variants may have “conservative” changes or “non-conservative” changes determined by “using computer programs well known in the art”. Thus, identifying sensible sequence variants and verifying whether or not they retain the claimed functions would be routine experimentation.
Applicant’s arguments have been fully considered but they are not persuasive.
Here, whether the skilled artisan would be able to make and use the invention, by obtaining additional variants and verifying their activity, through no more than routine experimentation, is not a consideration under written description requirement, which is separate and distinct from the enablement requirement. See Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description") (Emphasis added).
Per MPEP 2163, 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 inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (Emphasis added). See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention (Emphasis added). Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).") (Emphasis added).
As discussed in the present rejection, the scope of the claims encompass a vast genus of potential variants. While it may be within the ordinary skill in the art to produce some functional variants through routine experimentation, a person of ordinary skill would not be able to envisage a priori the full scope of this genus in view of Applicant’s disclosure. Here, the specification does not disclose the reduction to practice of any variant of the claimed SEQ ID NOs, and there are no specific structure-function teachings to show possession of the genus. Note that claiming a “combination” of structural and functional limitations does not amount to providing sufficient structure-function teachings, as argued by Applicant. In order to provide sufficient disclosure of a structure-function relationship, one must disclose the correlation between the structure and the function being claimed. In the instant case, no such correlation has been disclosed in the specification with respect to the numerous variants of the claimed genus, and Applicant has not provided any evidence that any such correlation was known in the art at the time of filing.
Applicant further argues that sufficient disclosure of both the function and minimal structure required for each of the variants encompassed by the amended claims has been provided in the originally filed application. Applicant quotes Enza Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 964, 63 USPQ2d 1289, 1613 (Fed. Cir. 2002) ("Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.")
Applicant’s arguments have been fully considered but they are not persuasive, because the ”minimal structure” that Applicant describes are the sequences themselves, which must be altered in order to arrive at any of the claimed variants. As previously discussed, the specification fails to provide any “well-established correlation” between the structure and the function of the claimed variants, which would be necessary to satisfy the written description requirement based on “the disclosure of function and minimal structure”. See Enza Biochem, Inc. v. Gen-Probe, Inc., as quoted above.
Regarding the rejections under 35 USC 102, Applicant argues that claim 1 has been amended to remove limitation 1(d).
Applicant’s arguments have been fully considered and are persuasive, because Loessner does not anticipate the remaining limitations of the claim. Accordingly, the rejection has been withdrawn.
Regarding the rejection of claim 11 under 35 USC 103, Applicant argues that the amendment of claim 1 renders this rejection moot and requests withdrawal of the rejection accordingly.
Applicant’s arguments with respect to claim(s) 11 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Regarding the rejections under 35 USC 103 in view of Biebl and Loessner, Applicant argues that a person of ordinary skill would not be motivated to combine the teachings of Biebl and Loessner, because Biebl teaches antimicrobial agents active against Enterococcus bacteria, while in contrast, Loessner teaches a composition preferably for killing Staphylococcus.
Applicant’s arguments have been fully considered but they are not persuasive, because the present rejections, necessitated by amendment, also include the Dong reference, which teaches chimeric bacteriophage lysins which have killing activity against both Enterococcus and Staphylococcus. As discussed in the present rejections, both Dong and Biebl teach chimeric lysins comprising PlyV12, which Dong discloses to have extended lytic activity to Enterococcus when fused to the catalytic domain of a staphylococcal bacteriophage lysin. Here, Dong and Biebl reasonably provide sufficient motivation for one to have altered the teachings of Loessner, in order to provide a chimeric lysin with killing activity against antibiotic-resistant species of both staphylococcus (e.g., S. aureus) and enterococcus (e.g., S. faecalis).
Applicant further argues that even if the skilled person were to consider combining the teaching of these documents, they would not have a reasonable expectation of success that the resulting chimeric bacteriophage lysin would be functional, still less that it would have killing activity against a plurality of Staphylococcus species, as required by the claim. Thus, contrary to the examiner's assertion, it would not be obvious to a person skilled in
the art to fuse a CD of a staphylococcal phage lysin with a CBD of an enterococcal phage lysin, still less with any expectation that the resulting chimeric bacteriophage lysin would have killing activity against a plurality of Staphylococcus species, as required by claim 1.
Applicant’s arguments have been fully considered but they are not persuasive, because, as discussed in the present rejections, Dong teaches the expectation that combining a CD domain of a staphylococcal phage lysin with a CBD of an enterococcal phage lysin would have killing activity against a plurality of Staphylococcus and Enterococcus species, as demonstrated by Dong’s experiments. Furthermore, both Dong and Biebl exemplify PlyV12 for developing chimeric lysins with an extended lytic activity, and Dong discloses this lysin retained its killing activity against Staphylococcus.
Applicant further argues that LKCHAPV12 showed superior activity in human sweat compared to its parent lysin PlyV12, and it would not have been obvious to the skilled person that such a chimeric lysin would show preferential killing of Staphylococcus hominis over Staphylococcus epidermidis in sweat, as shown in Table 3 of the specification. These specific advantageous properties could not have been predicted by the skilled person from the prior art, therefore the present invention is not obvious.
In response to applicant's argument that one of the chimeric lysins had superior activity in human sweat, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, a person of ordinary skill would have had sufficient motivation to combine the prior art references for the advantages disclosed therein and would have arrived at a chimeric bacteriophage lysin that would have been reasonably expected to have the advantages described by the prior art. To show obviousness, it is not required that the prior art teaches the same advantages disclosed by Applicant, particularly where the claimed and prior art products possess the same structure.
Furthermore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In this case, the disclosure of having killing activity in human sweat is not the result of any difference in structure between the claimed product and the prior art combination, and must be an inherent property of the chimeric bacteriophage lysin. See, e.g., the present rejection of claim 6 under 35 USC 103.
Regarding the rejections under 35 U.S.C. 103 in view of Biebl and Cheng, Applicant argues that the examiner's assertion that "[i]n view of Cheng, one would have also recognized the potential for utilizing the broad specificity of LysEF-P10 catalytic domain." is not correct. The "broad specificity" referred to here by the examiner and disclosed in the final sentence on page 5 of Cheng is in the specific context of E. faecalis strains; contrary to the examiner's assertion, Cheng teaches a narrow specificity of LysEF-P10 for killing E. faecalis strains, but not other bacteria including E. faecium.
Applicant’s arguments have been fully considered but they are not persuasive, because the present rejections, necessitated by amendment, also include the Dong reference, which teaches chimeric bacteriophage lysins which have killing activity against both E. faecalis and E. faecium. As discussed in the present rejections, Dong teaches chimeric lysins comprising PlyV12, which Dong discloses to have extended lytic activity to Enterococcus, including E. faecalis and E. faecium, when fused to the catalytic domain of another bacteriophage lysin. Furthermore, the fact that Cheng teaches LysEF-P10 showed a much broader bactericidal range against E. faecalis compared to the host phage (“final sentence on page 5”) highlights a further advantage of selecting this lysin. The mere fact that this “broad specificity” is directed to the species level, as opposed to multiple genera, is a moot point, because a person of skill would still have recognized there to be an advantage, particularly when developing chimeric lysins to have killing activity against drug-resistant strains of Enterococcus. Furthermore, Dong teaches the CBD of PlyV12 to broaden specificity to multiple genera when fused to the CD of a lysin with a narrower specificity.
Applicant further argues that merely envisaging a chimeric lysin comprising a particular CD and CBD does not equate to successfully obtaining a functional version of said chimeric lysin. Thus, even if the skilled person were to consider combining the teaching of these documents, they would not have a reasonable expectation of success that the resulting chimeric bacteriophage lysin would be functional, still less that it would have killing activity against a plurality of Staphylococcus species, particularly in view of the specificity of LysEF-P10 for E. faecalis taught in Cheng.
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, Dong specifically teaches “that generating novel chimeric lysins with an extended lytic spectrum was feasible through fusing a catalytic domain with a cell-binding domain from lysins with lytic spectra across multiple genera” (see Abstract) and “[s]everal native lysins have been identified with broad lytic activity [in] more than one genus” and “[o]ne of them is PlyV12” (see pg. 210, col. 2, para. 3). Further, Dong teaches that phage endolysins of Gram-positive bacteria display a two-domain modular structure, which has been utilized numerous times in the art to generate novel lysins (see pg. 210, col. 2, para. 1). Therefore, a person of skill would have recognized there to be a reasonable expectation of success in obtaining a “functional version” of the chimeric lysin.
Applicant further argues that it is difficult to predict what the function of a chimeric lysin will be. The specification demonstrates that lysin P10N-V12C (SEQ ID NO: 11) exhibited high activity at a high pH, in contrast to both of the parent lysins LysEF-P10 and PlyV12 (see Figure 4A of the application as filed). This was shown up to pH 10, and is expected to be higher based on the observed trend. Lysins which retain high activity at a high pH are expected to be useful in alkaline compositions, for example laundry/fabric care or detergent based compositions.
Applicant’s arguments have been fully considered but they are not persuasive. As discussed in the present rejection of claim 9, Dong teaches that Ply187N-V12C was also found to have optimum activity at a higher pH than that of the parent lysins (see pg. 213, col. 2, para. 2). Furthermore, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. In the instant case, the features of the invention used in Applicant’s argument (i.e., the functional limitations of claim 9) are inherent properties of the chimeric bacteriophage lysin, as discussed in the present rejection.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS ARMATO whose telephone number is (703)756-5348. The examiner can normally be reached Mon-Fri 11:00am-7:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached at (571) 272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651