DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/04/2026 has been entered.
Status of Claims
Claims 1, 3-4, 6-11, 13-14 and 19-22 are pending following the Reply filed 06/04/2026. Claim 5 has been cancelled. Claims 1, 6 and 11 have been amended without introducing new matter. All pending claims have been examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 06/05/2026 has been considered by the examiner.
Withdrawn
Any objection or rejection of claim 5 is moot because the claim has been cancelled.
The rejection of claim 11 under 35 U.S.C. 112(b) is withdrawn in light of the amendments.
The written description rejection under 35 U.S.C. 112(a) is withdrawn in light of the amendments. In particular, the claims have amended to no longer recite variants of the chimeric bacteriophage lysins. See Response to Arguments for further discussion.
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 (previously cited).
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):
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76
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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):
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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 the 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):
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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):
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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 LysEF-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):
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636
975
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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) 3-4 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):
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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.
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 (previously cited) 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:
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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:
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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):
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186
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60
538
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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:
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720
646
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571
642
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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 states that the Office Action based the rejection on the inclusion of "variant" language and percentage identity language in the claim. Applicant has amended claim 1 from which all rejected claims depend and requests reconsideration and withdrawal of the rejection.
Applicant’s arguments have been fully considered and they are persuasive.
The amendments to the claims have narrowed the scope of the claimed invention to the exemplified bacteriophage lysins of Applicant’s disclosure, which are now required to comprise the same sequences used in Applicant’s Examples. Therefore, the specification provides adequate written support for the claimed chimeric lysins. Accordingly, the rejection has been withdrawn.
Regarding the rejections under 35 USC 103, specifically, claim 1 according to limitation b) amino acids 1-165 and 170-338 set forth in SEQ ID NO: 9, Applicant argues that Loessner and Dong address fundamentally different technical problems. Loessner
is directed to bacteriophage lysins derived from Staphylococcus phages and is concerned with designing lysins for killing Staphylococcus species within that technical framework. In contrast, Dong is explicitly directed to expanding host range beyond Staphylococcus by extending lytic activity against Streptococcus and Enterococcus. Accordingly, Dong does not provide a teaching or incentive to import an enterococcal CBD into a Staphylococcus-centered design objective, as required by Loessner and the claimed invention. Applicant states that the Examiner's reasoning that both Loessner and Dong relate generally to chimeric bacteriophage lysins useful for killing Gram-positive bacteria is insufficient to establish proper motivation to combine the specific teachings of these reference.
Applicant’s arguments have been fully considered but they are not persuasive.
First, the rejection does not merely assert that both Loessner and Dong “generally” relate to chimeric bacteriophage lysins to establish motivation to combine the references. As discussed in the rejection, a person of skill would have been motivated to apply the combination in order to address the need of providing novel antimicrobials with a broad range of activity against Gram-positive bacteria, including Staphylococcus.
Second, in response to applicant's argument that Dong is directed to expanding host range beyond Staphylococcus while Loessner is directed to killing Staphylococcus species, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, Dong teaches host range expansion of chimeric lysins against Staphylococcus, and there is no requirement that Loessner also teach host range expansion for a person of skill to have an incentive to combine these teachings.
Applicant further argues that in "Response to Arguments" on pages 39-40, the Examiner alleges that Dong provides a motivation to alter the teachings of Loessner to obtain lysins active against both Enterococcus and Staphylococcus species. However, as discussed above, Dong is directed to cross-genus host-range expansion, which is unrelated to the technical problem starting from Loessner, which is designing lysins effective against Staphylococcus species. The reliance on Dong therefore reflects a shift to a different technical objective and involves hindsight reasoning.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, it is unclear how the examiner’s response to argument invokes “improper hindsight” as Dong explicitly teaches (as acknowledged in Applicant’s argument) expanding cross-genus host-range in lysins that already have activity against Staphylococcus. As previously discussed, there is no requirement that every reference used in the rejection provide the same teaching or suggestion which would have lead one to combine their teachings.
Regarding the contention that “Dong is directed to cross-genus host-range expansion, which is unrelated to the technical problem starting from Loessner, which is designing lysins effective against Staphylococcus”, Applicant is reminded that “[t]he use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). See also MPEP 2123. Furthermore, the test for obviousness is not whether the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, Loessner teaches endolysins effective against Staphylococcus, and Dong suggests the modification of endolysins effective against Staphylococcus to expand host range. Therefore, the subject matter of Loessner and Dong are clearly related, and there is no requirement that both references disclose the same “technical problem”.
Applicant further argues that a skilled person would not have had a reasonable expectation of success that the resulting chimera would be functional, still less that it would exhibit killing activity against a plurality of Staphylococcus species, as required by amended claim 1. The present application confirms that extensive experimental screening was required to identify functional chimeric lysins: for example, Example 7 describes the construction and screening of a library of chimeric lysins, from which only a small subset displayed meaningful activity. Contrary to the Examiner's characterization of "predictable results", the proposed Loessner-Dong combination does not represent a routine or predictable modification, but rather an unpredictable endeavor lacking any reasonable expectation that the specific CD/CBD pairing defined in SEQ ID NO: 9 would work.
Applicant’s arguments have been fully considered but they are not persuasive.
First, Applicant is reminded that 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, the reason or motivation to modify Loessner based on Dong’s disclosure (i.e., to provide antimicrobials with activity against a broad range of Gram-positive bacteria, including Staphylococcus and Enterococcus) is not required to be the same as the advantage or result achieved by Applicant (e.g., to expand killing activity to a “plurality of Staphylococcus species”). See MPEP 2144(IV).
Regarding whether a skilled person would have had an expectation that the resulting chimera would be functional, the examiner sets forth the following evidence from Dong:
(1) Dong teaches that it “has been widely recognized that novel chimeric lysins could be generated by swapping CDs and CBDs from different native lysins due to the modular structure of lysins” (see pg. 213, col. 2, para. 3 to pg. 213, col. 1, para. 1).
(2) Dong discloses that due to this two-domain modular structure, “chimeric lysins with a catalytic domain and a bacterial cell binding domain from different native lysins have been constructed to generate novel lysins to control pathogenic bacteria in a variety of environments (Manoharadas et al., 2009; Idelevich et al., 2011; Pastagia et al., 2011; Schmelcher et al., 2012a,b; Mao et al., 2013; Yang et al., 2014)” (see pg. 210, col. 2, para. 1).
(3) Dong discloses that “[s]everal native lysins have been identified with broad lytic activity [against] more than one genus (Deutsch et al., 2004; Yoong et al., 2004; Son et al., 2012; Gilmer et al., 2013). One of them is lysin PlyV12, which can lyse not only Enterococcus but also several streptococcal and staphylococcal strains (Yoong et al., 2004). Recently, another lysin PlySs2 showed lytic activity against staphylococci, streptococci and Listeria (Gilmer et al., 2013)” (see pg. 210, col. 2, para. 3).
(4) Dong discloses “a novel chimeric lysin Ply187NV12C with an extended lytic spectrum was successfully generated by fusing the CD from a staphylococcal lysin Ply187 with the CBD from a lysin with lytic spectra across multiple genera (PlyV12)” (see pg. 214, col. 1, para. 2).
(5) Dong states, “it is clear that the binding domain V12C played a critical role on the extended activity of Ply187NV12C against streptococci and enterococci. While in the previous two chimeric lysins consisting of Ply187N (Yang et al., 2014) (Mao et al., 2013), the lytic spectra were all limited to staphylococcal strains since the CBDs used are specific to Staphylococci” (see pg. 214, col. 2, para. 2).
(6) Dong teaches that “[b]ecause most native lysins are specific only to one certain genus, native lysins with lytic spectra across multiple genera would be unique sources for identifying CDs and CBDs suitable for generating novel chimeric lysins with a wide lytic spectrum” (see pg. 213, col. 1, para. 1).
Thus, Dong teaches that the modular nature of bacteriophage lysins has been widely exploited in the art to produce chimeric lysins, particularly in the endeavor to expand host-range specificity. Further, Dong teaches the expectation that fusing a catalytic domain (CD) having narrow specificity (i.e., Staphylococci) with a binding domain (CBD) with specificity across multiple genera (i.e., Staphylococci, Enterococci, etc.) can result in a chimeric lysin with an extended lytic spectrum. Dong further demonstrates this result with the exemplified Ply187N-V12C which comprised a CD from a staphylococcal-specific lysin and the CBD from PlyV12 (see Abstract). Furthermore, Dong cites numerous examples of functional chimeric lysins that have been generated in the prior art to control pathogenic bacteria in a variety of environments.
Regarding Example 7 of Applicant’s disclosure, this section of the specification discloses that the library of chimeric lysins was generated by the shuffling of the CD and CBD domains of 10 naturally occurring lysins using a cloning technique called Golden Gate assembly (see the amended specification filed 05/12/2023 at pg. 16, lines 28-30). It should be noted that the specification does not disclose the identity or the specificity of the 10 naturally occurring lysins that were used. In view of the prior art of at least Dong, the shuffling of these domains to produce novel lysins is a well-known process in the art and appears to have been carried out by the inventors using known methods. Regarding the screening process, the specification states:
Furthermore, we used different screening assays compared to Duyvejonck et al. We performed turbidity reduction assay and lysate clearance assay. The turbidity reduction assay is a routine assay to evaluate the activity of lysins targeting Gram-positive bacteria [Yoong, P. et al., J Bacteriol 186:4808-4812 (2004); Binte Muhammad Jai,H.S., et al., Front. Microbiol. 11: 2868 (2020)]. The lysate clearance assay was developed with reference to Raz et al [Raz A, et al., Antimicrob Agents Chemother. 2019 63(7):e00024-19. doi: 10.1128/AAC.00024-19], which was originally intended to test lysin's activity against Gram-negative bacteria. 3 bacterial species were tested on the turbidity reduction assay, namely Staphylococcus hominis, Staphylococcus epidermidis, and Corynebacterium striatum. For lysate clearance assay, only S. epidermidis was tested as it is an assay to test for catalytic activity as a proxy to gauge the expressed protein is functional. (See pg. 18, lines 3-13; Brackets in original; Emphasis in bold added)
Therefore, this example discloses the screening of the chimeric lysins against only three species of bacterium (two Staphylococcus and one Corynebacterium) using methods that are known in the art. This is insufficient evidence to support Applicant’s argument that a skilled person would not have had a reasonable expectation of successfully obtaining a functional chimeric lysin.
Applicant argues that the specification demonstrates that lysin LKCHAPV12 (SEQ ID NO: 9) exhibited good killing activity on all tested staphylococcal species under standard in-vitro conditions, for example, in phosphate-buffered saline (PBS). In contrast, this was not the case for another 16 engineered lysins which were tested but showed little activity in the assay. Notably, LKCHAPV12 showed superior activity in human sweat compared to its parent lysin PlyV12. It also 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.
Applicant’s arguments have been fully considered but they are not persuasive.
The examiner notes that the “16 engineered lysins” that Applicant refers to appear to be discussed in Example 8 of the disclosure. The specification does not disclose the identity or specificity of these lysins and the data from this experiment is expressly “not shown” (see pg. 16, lines 27-28).
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 (e.g., broader host specificity) and would have had a reasonable expectation of successfully obtaining a lysin that has these properties, at least for the reasons 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, 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.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., preferential killing of Staphylococcus hominis over Staphylococcus epidermidis in sweat) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues that in "Response to Arguments", the Examiner alleged on page 41 that the disclosure of killing activity in human sweat is not the result of any structural difference and must be an "inherent" property of the chimeric bacteriophage lysin. However, the cited references do not disclose the specific sequence-defined construct of SEQ ID NO: 9 in its claimed form. In any event, the fact that numerous other engineered lysins showed little activity in the same sweat assay indicates that such performance is not an "inherent" property that would necessarily and invariably result from merely combining prior art domains.
Applicant’s arguments have been fully considered but they are not persuasive.
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). In the instant case, Applicant states that “the cited references do not disclose the specific sequence-defined construct of SEQ ID NO: 9 in its claimed form”. As discussed in the rejection, Loessner teaches the N-terminal domain of the claimed chimeric lysin, while Dong teaches the C-terminal domain and its use to generate chimeric constructs. Applicant is reminded that obviousness requires that the prior art included each element claimed, but not necessarily in a single prior art reference. See MPEP 2143(I)(A).
See also MPEP 2112(IV) which states:
"[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." Id. at 1195-96, 112 USPQ2d at 1952. But see, Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (Emphasis in bold added)
In the instant case, if one were to combine the elements (CD and CBD domains) taught by Loessner and Dong to arrive at a chimeric lysin having the same structure as instant SEQ ID NO: 9, this chimeric lysin would necessarily have had the same properties as the claimed product. "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).
Regarding the rejections under 35 USC 103, specifically, claim 1 according to limitation “a) SEQ ID NO: 11”, Applicant argues that Dong is directed to engineering chimeric lysins to expand host range, demonstrating that fusing a catalytic domain with a heterologous binding domain may result in newly acquired lytic activity against additional genera. Cheng is concerned with characterizing the bactericidal properties of the native lysin LysEF-P10 against Enterococcus faecalis. However, the present claims are not directed to killing Enterococcus but instead require killing activity against a plurality of Staphylococcus species. Neither Dong nor Cheng is directed to, or concerned with, this technical objective.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the prior art references are not concerned with the same “technical objective” as recited in the claims, 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). As discussed in the present rejection, one would have recognized from Dong the advantages of fusing the C-terminal endolysin binding domain (CBD) of PlyV12 to the catalytic domains (CDs) of other endolysins, which results in broadened activity against other genera of bacteria, including Enterococcus species such as E. faecalis and E. faecium, and one would have also recognized the potential for utilizing the species-level specificity of LysEF-P10’s catalytic domain against numerous strains, including antibiotic-resistant strains, of Enterococcus faecalis, as taught by Cheng.
Applicant further argues that Cheng does not support the Examiner's allegation
that the catalytic domain of LysEF-P10 exhibits "broad specificity". Rather, Cheng teaches a narrow specificity of LysEF-P10 for killing E. faecalis strains, but not other bacteria including E. faecium. The Examiner's reasoning that the catalytic domain of LysEF-P10 could be used to achieve broader lytic activity is therefore not supported by Cheng. In particular, Cheng does not provide any teaching or suggestion that the catalytic domain could be used to confer activity against different bacterial species, let alone against Staphylococcus species.
Applicant’s arguments have been fully considered but they are not persuasive.
To clarify, the recitation of “broad specificity” in the context of LysEF-P10 refers to broad specificity at the species-level (i.e., Cheng teaches the lysin to be effective against numerous strains of E. Faecalis). As previously discussed, Dong teaches chimeric lysins comprising the CBD domain of PlyV12, which Dong discloses to have extended lytic activity to other genera, such as Enterococcus, including E. faecalis and E. faecium, when fused to the catalytic domain of lysins having narrower specificity. Therefore, Cheng indeed teaches a lysin having a catalytic domain (CD) with “narrow specificity” (i.e., specific to E. faecalis) which Dong suggests can be fused to CBDs having a broader specificity, such as the CBD of PlyV12. Furthermore, Cheng teaches this particular lysin to have advantageous effects against a plurality of E. Faecalis strains, but not to E. faecium, while Dong teaches PlyV12 to have extended lytic activity against Enterococcus, including E. faecium. Therefore, a person of skill would have envisaged multiple advantages when applying the combination to provide a chimeric lysin with killing activity against Enterococcus.
Applicant further argues that Cheng still does not teach that the LysEF-P10 catalytic domain is broadly usable beyond E. faecalis, nor does it provide any basis for expecting that this catalytic domain would be suitable for, or contribute to, killing activity against Staphylococcus species as required by the claims. Dong's disclosure regarding PlyV12-based chimeras does not cure this gap, because Dong's successful cross-genus constructs rely on different catalytic domains and do not establish that the particular LysEF-P10 catalytic domain would be an appropriate choice in the present context.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that Dong’s LysEF-P10 catalytic domain would not be an appropriate choice for killing activity against Staphylococcus species, “as required by the claims”, 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 skill would have recognized several potential advantages when applying the combination to provide a chimeric lysin with killing activity against Enterococcus, as discussed above.
Applicant further argues that even if the skilled person were to consider combining the teachings of the cited documents, they would not have a reasonable expectation of success that the resulting chimeric bacteriophage lysin would be functional, still less that it would exhibit killing activity against a plurality of Staphylococcus species, particularly in view of the specificity of LysEF-P10 for E. faecalis as taught in Cheng. In particular, Cheng itself teaches that LysEF-P10 exhibits narrow specificity for E. faecalis and does not lyse other bacteria, including E. faecium. In view of this teaching, the skilled person would have no reasonable expectation that combining this catalytic domain with a heterologous binding domain would result in a lysin having activity against a plurality of Staphylococcus species.
Applicant’s arguments have been fully considered but they are not persuasive.
First, Applicant is reminded that 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). The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). See MPEP 2144(IV). In the instant case, the reason or motivation to combine Dong and Cheng (i.e., to provide a lysin with enhanced killing activity against Enterococcus) is not required to be the same as the advantage or result achieved by Applicant (e.g., to provide a lysin with killing activity against a “plurality of Staphylococcus species”).
Furthermore, 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, a person of skill would have had a reasonable expectation of arriving at a chimeric lysin with killing activity against Enterococcus. In particular, both lysins are taught to have killing activity against Enterococcus, and a person of skill would have had a reasonable expectation that a chimera utilizing these domains would have not only been functional, but would have also had killing activity against Enterococcus. See also the enumerated evidence (1-6) from Dong presented on pages 30-31 above.
Applicant further argues that in "Response to Arguments", the Examiner alleged on page 43 that obviousness does not require absolute predictability and that Dong teaches it is "feasible" to generate chimeric lysins by fusing catalytic and binding domains, including by using PlyV12, and therefore a person of skill would have had a reasonable expectation of success in obtaining a "functional version" of the chimera. However, a general statement of feasibility or modularity does not establish a reasonable expectation that the specific CD/CBD pairing required here (i.e., the LysEF-P10 catalytic domain in combination with a heterologous binding domain) would yield a functional lysin having the claimed activity against a plurality of Staphylococcus species.
Applicant’s arguments have been fully considered but they are not persuasive.
Regarding the alleged “general statement of feasibility or modularity”, all of Applicant’s arguments regarding “reasonable expectation of success” have been fully addressed above.
Regarding whether the prior art combination would have specifically yielded “a functional lysin having the claimed activity against a plurality of Staphylococcus species”, Applicant is reminded that 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). Whether or not a person of skill would have expected the claimed activity against Staphylococcus, a person of skill would have had a reasonable expectation that a chimera utilizing these domains would have not only been functional, but would have also had killing activity against Enterococcus, for at least the reasons set forth above.
Applicant further argues that the technical effects discussed above in respect of SEQ ID NO: 9 are equally demonstrated for the construct defined by SEQ ID NO: 11 under standard in-vitro conditions. In addition, the present application demonstrates that the chimeric lysin P10N-V12C (SEQ ID NO: 11) exhibits high activity at elevated pH, in contrast to both parent lysins LysEF-P10 and PlyV12 (see Figure 4A). The experimental results in the present application demonstrate that functional outcomes of CD/CBD recombination vary significantly depending on the specific pairing, and therefore such high-pH activity cannot be regarded as an inevitable property of all chimeric lysins. Accordingly, the observed effect is not a mere inherent consequence of the prior art combination.
Applicant’s arguments have been fully considered but they are not persuasive.
First, the examiner notes that the rejection does not state that the claimed functional limitation at issue (“has killing activity over a pH range of about 4-10”) is an “inevitable property of all chimeric lysins”. Rather, the rationale of the rejection is based upon the inherent properties of the structure arrived upon by combining the elements of the prior art disclosures. See MPEP 2112(IV) which states:
"[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." Id. at 1195-96, 112 USPQ2d at 1952. But see, Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (Emphasis in bold added)
In the instant case, if one were to combine the elements (CD and CBD domains) taught by
Dong and Cheng to arrive at a chimeric lysin having the same structure as instant SEQ ID NO: 11, this chimeric lysin would necessarily have the same properties as the claimed product. "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).
Regarding the rejections under 35 USC 103, specifically, claim 1 according to limitation “c) amino acids 1-145 and 150-242 set forth in SEQ ID NO: 13”, Applicant argues that the Office Action does not provide any specific reasoning as to why this construct would be obvious over the cited prior art. In the absence of any such analysis, and in view of the considerations set out above in relation to chimeric lysins, it is respectfully submitted that the subject-matter defined by SEQ ID NO: 13 likewise involves an inventive step.
Applicant’s arguments have been fully considered but they are not persuasive.
The absence of analysis regarding SEQ ID NO: 13 does not constitute any concession by the examiner regarding the patentability of the claims.
Applicant is reminded that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious. See, e.g., Fresenius USA, Inc. v. Baxter Int’l, Inc., 582 F.3d 1288, 1298, 92 USPQ2d 1163, 1171 (Fed. Cir. 2009)(the entire element is disclosed by the prior art if one alternative in the Markush group is in the prior art). In other words, when a claim requires selection of an element from a list of alternatives, the prior art teaches the element if one of the alternatives is taught by the prior art. See, e.g., Fresenius USA, Inc. v. Baxter Int’l, Inc., 582 F.3d 1288, 1298, 92 USPQ2d 1163, 1171 (Fed. Cir. 2009). See MPEP 803.02(A) and 2143.03.
Furthermore, Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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