DETAILED ACTION
Acknowledgment and entry of the Amendment submitted on 12/5/25 is made. Claims 1 and 7-21 are currently pending.
Claims 7-15 and 18-21 are currently withdrawn from consideration for being drawn to a non-elected invention.
Claims 1, 16 and 17 are currently under examination.
Claim Rejections - 35 USC § 112-2nd paragraph
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.
Claims 1, 16 and 17 are 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 1 recites “Staphylococcus aureus-derived toxins.” The term “derived” does not provide the character or properties from the source that are to be retained in the final product, e.g., paper is derived from wood but is very different from wood. It appears HLAH35L and LukAE323AB are variant toxins and LukS is an isolated toxin (wild-type) from S.aureus. The term “derived” may be deleted from the claim. Appropriate clarification and/or correction is requested.
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.
Claim(s) 1, 16 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kailasan et al (Toxins. June 14, 2019. Vol. 11. Article 339, pp. 1-21; provided by Applicants) in view of Dumont et al (Infect. Immun. March 2014. 82(3): 1268-1276; provided by Applicants) and Taylor et al (US 2105/165015).
Kailasan teaches that targeting virulence by toxoid vaccines represents a novel approach to preventing mortality and morbidity that are caused by S. aureus. Kailasan et al generated a library of mutations that targeted functional domains within the LukAB heterodimer to identify attenuated toxoids as potential vaccine candidates. The mutants were evaluated based on expression, solubility, yield, biophysical properties, cytotoxicity, and immunogenicity, and several fully attenuated LukAB toxoids that were capable of eliciting high neutralizing antibody titers were identified. The reference also teaches that a polyclonal antibody cocktail consisting of Leukocidal toxin S (LukS), LukF and Leukocidal toxin AB (LukAB), and gamma-hemolysin (HlgA) can achieve100% neutralization of toxicity in most virulent strains of S. aureus infectious diseases using the mixture (see abstract and pages 2, 11 and 14). Kailsan also teaches that in the Hla, N terminal residues H35 and H48 are substituted, e.g., H35Leu and H48L. See pages 5, 11 and 14. The reference also indicates that residue E323 within the rim domain of LukA is critical to LukAB-mediated cytotoxicity (see page 2). Kailsan teaches that among the pore-forming toxins, S. aureus produces single component alpha hemolysin (Hla or α-toxin) and bicomponent pore-forming toxins (BCPFTs), Panton-Valentine leukocidin (PVL; composed of LukS-PV and LukF-PV), Leukocidin AB (LukAB), Leukocidin ED (LukED), and γ-hemolysins (HlgAB and HlgCB). While Hla is secreted as a monomer and oligomerizes on the plasma membrane of target cells upon interaction with its specific cellular receptor ADAM10, the BCPFTs are produced from two distinct polypeptides, S (~32.4 kDa) and F (~34.6 kDa), which have β-barrel structures and hetero-oligomerize in a stepwise fashion with alternating S (LukS-PV, LukE, HlgA, HlgC, and LukA) and F (LukF-PV, LukD, HlgB, and LukB) subunits on the cell surface. Section 2.5 recites: multiple pore-forming toxins, including Hla, PVL, LukED, HlgAB, HlgCB, and LukAB, mediate the cytotoxic activity of SA. Compositions of toxoids were used to raise rabbit polyclonal antibodies raised against LukAD39ALukBR23E (αLukAB), two PVL subunit toxoids LukSmut9 (αLukS) and LukFmut1 (αLukF), which we previously reported, or the toxoid HlaH35LH48L (αHla; alpha hemolysin). Discussion: Several epidemiological studies indicate that the SA toxins are important vaccine targets. We have previously developed vaccine candidates for PVL subunits that elicit cross-reactivity to HlgAB, HlgCB, and LukED. LukAB plays a significant role in mediating SA virulence and its potency is most comparable to PVL. The last sentence under “3. Discussion” recites:
Our findings indicate that a multivalent approach targeting the related leukotoxins PVL (LukS), LukED, HlgAB, HlgCB, and the divergent LukAB, as well as the single component Hla is critical for protection against cytolytic activity of the most prevalent S. aureus strains. These data strongly support the development of a multivalent toxoid vaccine for S. aureus, which covers all major pore-forming toxins.
However, Kailasan does not particularly teach that the 323 AA of LukAB is substituted, and/or substituted with Ala or that the composition may further comprise antibiotics.
Dumont et al indicates that glutamic acid at position 323 in the C terminus of LukA is critical for LukAB cytotoxicity and discloses an E323A substitution (see pages 1268, 1273 and 1274, figures 4 and 5).
Taylor teaches compositions comprising alpha-hemolysin (Hla) in combination with other S. aureus toxoids/antigens. Paragraph [0009] recites that one embodiment, the alpha-toxin antigen contains at least two alterations, relative to wild-type S. aureus alpha-toxin, that reduce its toxicity. Taylor teaches that position 35 of the Hla may be substituted and also specifically recites the substitution may be a “Leu”. The S. aureus alpha-toxin may comprises one or more amino acid substitution at an amino acid residue selected from the group consisting of: His.sup.35, His.sup.48, His.sup.144, His.sup.259, Asp.sup.24, Lys.sup.37, Lys.sup.58, Asp.sup.100, Ile.sup.107, Glu.sup.111, Met.sup.113, Asp.sup.127, Asp.sup.128, Gly.sup.130, Gly.sup.134, Lys.sup.147, Gln.sup.150, Asp.sup.152, Phe.sup.153, Lys.sup.154, Val.sup.169, Asn.sup.173, Arg.sup.200, Asn.sup.214 and Leu.sup.219. It is taught that the composition may comprise other antigens that are (ii) a LukS-PV subunit of S. aureus PVL, (iii) a HlgA S. aureus gamma-hemolysin subunit. Paragraph [0013] teaches that an agent selected from the group consisting of an anti-infective agent, an antibiotic agent, and an antimicrobial agent, such as vancomycin, lysostaphin or clindamycin may be used in the composition. Paragraph [0064] recites the composition may be a vaccine may be administered in conjunction with an anti-infective agent, an antibiotic agent, and/or an antimicrobial agent, in a combination therapy. Exemplary anti-infective agents include, but are not limited to vancomycin and lysostaphin. Exemplary antibiotic agents and antimicrobial agents include, but are not limited to penicillinase-resistant penicillins, cephalosporins and carbapenems, including vancomycin, lysostaphin, penicillin G, ampicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, cephalothin, cefazolin, cephalexin, cephradine, cefamandole, cefoxitin, imipenem, meropenem, gentamycin, teicoplanin, lincomycin and clindamycin.
Accordingly, the prior art cited above teach compositions which may comprise Hla, LukS, LukAB and HlgA. Taylor and Dumont are cited to show that substitutions to reduce toxicity in S. aureus toxoids to be used in treatment were well known in the prior art and specifically teach Hla35Leu of Hla and E323A substitution in LukAB, respectively. It is noted that Kailsan also teaches the substitution of 35HlaLeu. The use of antibiotics in these compositions would have been further obvious because Taylor teaches that a combination of antibiotic, such as vancomycin, in the S. aureus toxin compositions was well known to further aid in preventing, alleviating and treating Staphylococcus aureus. Kailsan and Taylor both teach that a multivalent toxoid vaccine for S. aureus, which covers all major pore-forming toxins is ideal.
Response to Applicants’ arguments:
Applicant notes the following differences with the Kailsan reference: i) LukF is not recited in the present claims, while Kailasan lacks HlgA which is recited in the present claims; ii) both the positions of the substituted residues and the types of substituted amino acids in the mutated LukAB and Hla differ; and iii) while the present claims recite the wild-type LukS, Kailasan uses a mutant LukS carrying T28F/K97A/S209A substitutions. Accordingly, they argue that the composition of claim 1 and Kailasan do not share any common elements in a sense that they differ entirely in both the overall toxin combination and the specific mutations applied thereto. Applicants further argue that Kailasan aimed at identifying attenuated mutants of LukAB for use as antigens for S. aureus vaccines, and merely combined HlaH35LH48L, LukST28F/K97A/S209A and LukFK102A as additional toxins to be used together with the final selected mutant LukAD39ABR23E for further enhanced neutralizing activity. In other words, Kailasan's combination is not one carefully selected based on the intensely searched cross-reactivity among antibodies against each toxin for the purpose of maximizing toxin neutralization range. Rather, it is merely a simple listing of known toxin mutants that could be co-administered with the primarily identified mutant LukAD39ABR23E. In contrast, the toxin combination of the present claims has been meticulously selected based on the antibody cross-reactivity for each toxin to maximize neutralization coverage with the minimal number of toxin components. As a result, it was found that when LukS, LukAB, and HlgA were combined, the antibodies generated by these toxins neutralized six different toxins, i.e. LukS, HlgA, HlgC, LukE, LukF, and LukAB, toward polymorphonuclear leukocytes (PMNs) (see Fig. 5). See results and additional arguments on pages 13-17 of Applicants’ response.
These arguments have been fully and carefully considered. 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).
Kailsan teach a multivalent approach targeting the related leukotoxins PVL (LukS), LukED, HlgAB, HlgCB, and the divergent LukAB, as well as the single component Hla is critical for protection against cytolytic activity of the most prevalent S. aureus strains. These data strongly support the development of a multivalent toxoid vaccine for S. aureus, which covers all major pore-forming toxins. Accordingly, the prior art cited above teach compositions which may comprise Hla, LukS, LukAB and HlgA. Taylor and Dumont are cited to show that substitutions to reduce toxicity in S. aureus toxoids to be used in treatment were well known in the prior art and specifically teach Hla35Leu of Hla and E323A substitution in LukAB, respectively. It is noted that Kailsan also teaches the substitution of 35HlaLeu. The use of antibiotics in these compositions would have been further obvious because Taylor teaches that a combination of antibiotic, such as vancomycin, in the S. aureus toxin compositions was well known to further aid in preventing, alleviating and treating Staphylococcus aureus. Kailsan and Taylor both teach that a multivalent toxoid vaccine for S. aureus, which covers all major pore-forming toxins is ideal.
The instant claims utilize the open language “comprising” which allows for additional ingredients even in major amounts. Accordingly, it would have been prima facie obvious to coming the very well known toxins in order to generate antibodies or an immune response since Kailsan teaches that their data strongly supports the development of a multivalent toxoid vaccine for S. aureus, which covers all major pore-forming toxins and Taylor teaches compositions comprising alpha-hemolysin (Hla) in combination with other, i.e., additional, S. aureus toxoids/antigens.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JENNIFER E GRASER/Primary Examiner, Art Unit 1645 2/17/26