DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicants’ response and amendment of 7/2/2025 are acknowledged. Claims 1,3,7,9,10,14 and 27 have been amended. Claims 2,4,6,8,13 and 15-17 have been canceled.
Claim Status
3. Claims 1, 3, 5, 7, 9-12, 14,18-19 and 27-30 are pending in this application. Claims 1, 3, 7, 9, 10,14 and 27 have been amended. Claims 2, 4, 6, 8,13 and 15-17 have been canceled. Claims 20-26 and 31-32 have been previously canceled. Claims 3, 5, 7, 9-12, 14, 19 and 27-30 have been withdrawn from further consideration as been drawn to non- elected inventions.
Claim Rejections - 35 USC § 103 Withdrawn
4. Rejection of claims 1 and 18 under 35 U.S.C. 103 as being unpatentable Schneewind et al. (WO 2011/005341 A2) in view Kort et al. (WO 2018232014 A1) further in view of Nagy et al. (20160108106 A1), is withdrawn in view of response and amendment of 7/2/2025.
New Rejection based on Applicants’ Amendments
Claim Rejections - 35 USC § 103
5. 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.
6. Claims 1 and 18 under 35 U.S.C. 103 as being unpatentable Schneewind et al. (WO 2011/005341 A2) in view Kort et al. (WO 2018232014 A1) in view of Nagy et al. (20160108106 A1. and further in view of Schneewind et al. US Patent 8821894.
The amended claims are drawn to”
Claim 1. An immunogenic composition comprising:
a Staphylococcus aureus protein A (SpA) variant polypeptide, wherein the SpA variant polypeptide comprises at least one SpA A, B, C, D, or E domain; and wherein the at least one domain has (i) lysine substitutions for glutamine residues corresponding to positions 9 and 10 of SEO ID NO:58 and (ii) a glutamate substitution for a serine residue corresponding to position 33 of SEO ID NO:58; and
a mutant staphylococcal leukocidin subunit polypeptide comprising:
a mutant LukAB dimer polypeptide,
wherein have the mutant LukAB dimer polypeptide has one or more amino acid substitutions, deletions, or a combination thereof,
such that the ability of the mutant LukAB dimer polypeptide to form pores in the surface of eukaryotic cells is disrupted, thereby reducing the toxicity of the mutant LukAB dimer polypeptide relative to the corresponding wild-type LukAB dimer polypeptide.
Schneewind et al. WO 2011/005341 A2 discloses an immunogenic composition comprising variant SpA from S. aureus leading to disrupted binding of SpA to Fc and VH3. In particular, the document discloses mutations in domain D of SpA at positions 9 or 10, 36 or 37, i.e. the same mutations as presently claimed (see claims). Schneewind et al. teach an isolated polypeptide, wherein the variant SpA comprises a variant domain D segment wherein the SpA variant has one or more amino acid substitution at amino acid position 9 or 10 of SEQ ID NO:2 wherein the amino acid substitution is a lysine residue for a glutamine residue (see claims). domains. In a further aspect the SpA variant comprises a combination of A, B, C, D, and E domains in various combinations and permutations. (See claim 7). Schneewind et al do not specifically teach LukA, LukB or LukAB.
Kort et al. WO 2018/232014 discloses immunogenic compositions and mutant LukA, LukB and/or LukAB subunits and successful use thereof as vaccines against S. aureus infection (see title and abstract and claims). Kort et al., provides methods of inducing an immune response against a LukAB-expressing S. aureus, methods of preventing or treating LukAB-expressing S. aureus infections, and compositions for preventing or treating LukAB-expressing S. aureus infections [para 21]. The mutant immunogenic elicits antibodies that can more effectively neutralize the action of the wild type toxin relative to the corresponding wild- type leukocidin subunit. Kort et al. claim 1 recite:
An isolated mutant staphylococcal leukocidin subunit polypeptide comprising a wild-type staphylococcal LukA subunit, a wild-type staphylococcal LukB subunit, or a wild-type staphylococcal LukAB dimer, except for having one or more amino acid substitutions, deletions, or a combination thereof at conserved residues in the LukA subunit, the LukB subunit, or in the LukAB dimer, wherein the amino acid substitutions, deletions, or a combination thereof are at conserved residues in the LukAB protomer/protomer interface region, the LukAB dimer/dimer interface region, the LukB membrane-binding cleft region, the LukB pore forming region, or any combination thereof, such that the ability of the leukocidin subunits to form dimers, to oligomerize, to form pores on the surface of eukaryotic cells, or any combination thereof is disrupted, thereby reducing the toxicity of the mutant leukocidin subunit or the mutant LukAB dimer relative to the corresponding wild-type leukocidin subunit or LukAB dimer ( see claim 1). The benefit for including LukA/LukB/LukAB is that LukAB dimer/dimer to oligomerize, to form pores on the surface of eukaryotic cells will help in inducing immune response..
The above references teach multiple sequences, but not specific sequences recited in clam 18.
Nagy et al. 20160108106 A1. teach SEQ ID NO:4 100% identical to SEQ ID NO:53 and SEQ ID NO:24 99% identical to SEQ ID NO: 16. See sequence alignment below. Nagy et al. teach an isolated Staphylococcus aureus leukocidin antigen comprising a (LukGH) also called Luk AB complex, wherein the LukGH complex comprises the (LukG) or LukA and (LukH)or LukB components as a dimer or oligomer. (See claims). Nagy et al. teach that the antigen, wherein the LukGH complex is composed of recombinant proteins and/or proteins derived from S. aureus strains (see claims). Nagy et al., teach the complex is cross-reactive among the different variants of this toxin and provides cross neutralizing potency. Additionally the complex inhibits S. aureus pathogenesis, pneumonia, bacteremia or sepsis, peritonitis and osteomyelitis.
None of the above references teach a glutamate substitution for a serine residue corresponding to position 33 of SEO ID NO:58.
Schneewind et al. US Patent 8821894 teach Staphylococcus aureus SpA protein variants as immunogenic compositions ) see title and abstract. Schneewind et al. US Patent 8821894 teach SEC ID NO:2 of the V H3 binding sub-domain of domain D is the same sequence as instant SEQ ID NO;58. s Schneewind et al. US Patent 8821894 teach S33 as a serine residue corresponding to position 33 which is important for reactivity (see columns 29,30).
Schneewind et al. US Patent 8821894, columns 3 and 4 recite: “ In further aspects, the amino acid glutamine (Q) at position 9 of SEQ ID NO:2 (or its analogous amino acid in other SpA domains) can be replaced with a different amino acid and In a further aspect, the glutamine at position 9 of SEQ ID NO:2, or its equivalent, can be substituted with a lysine or a glycine. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the substitutions can be explicitly excluded. Additionally. In another aspect, the amino acid glutamine (Q) at position 10 of SEQ ID NO:2 (or its analogous amino acid in other SpA domains) can be replaced with a different amino acid and In a further aspect, the glutamine at position 10 of SEQ ID NO:2, or its equivalent, can be substituted with a lysine or a glycine. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the substitutions can be explicitly excluded. Schneewind et al. US Patent 8821894 recited: In a further aspect a variant E domain comprises a substitution at positions 33, and/or 34 of SEQ ID NO:3.
The combination o In a further aspect the SpA variant includes (a) one or more amino acid substitution in an IgG Fc binding sub-domain of SpA domain D, or at a corresponding amino acid position in other IgG domains, In certain aspects amino acid residue Q9, Q10 (SEQ ID NO:2, QQNNFNKDQQSAFYEILNMPNLNEAQRNGFIQSLKDDPSQSTNVLGEAKKLNES) of the IgG Fc binding sub-domain of domain D are modified or substituted. In certain aspects amino acid residue S33 (SEQ ID NO:2) of the V H3 binding sub-domain of domain D are modified or substituted.
The combination of the above references teaches the claimed invention.
Therefore, it would have been prima facie obvious at the time of applicants’ invention combine the teachings of the above references in order to provide the claimed recombinant bacteria. The motivation to combine the teaching of Kort et al., teach mutant LukA, LukB and/or LukAB subunits and successful use as vaccines against S. aureus infection; Nagy et al. teach the LukGH complex is Nagy et al., teach the complex is provides cross neutralizing potency and inhibits S. aureus; and 8821894 treat treating or preventing a Staph infection. One of ordinary skill in the art would have a reasonable expectation of success by including the sequences of Nagy et al. in Kort and Schneewind to obtain the instant invention, because Kort et al., teach immunogenic compositions comprising mutant LukA, LukB and/or LukAB were successful use thereof as vaccines against S. aureus infection.
Moreover, Schnecwind et al. teach an isolated polypeptide, wherein the variant SpA comprises a variant domain D segment wherein the SpA variant has one or more amino acid substitution. Furthermore, Schneewind et al. US Patent 8821894 teach multiple substitutions for positions 9, 10 and S33 of sequence to also treat an S. aureus infection.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known compositions to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known compositions is likely to be obvious when it does no more than yield predictable results". It is well known to combine compositions to provide a better composition which function in a predictable manner to yield a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
US-14-892-925-24
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
Sequence 24, US/14892925
Publication No. US20160108106A1
GENERAL INFORMATION
APPLICANT: ARSANIS Biosciences GmbH
TITLE OF INVENTION: GENERATION OF HIGHLY POTENT ANTIBODIES NEUTRALIZING
TITLE OF INVENTION: THE LUKGH (LUKAB) TOXIN OF STAPHYLOCOCCUS AUREUS
FILE REFERENCE: AR004P
CURRENT APPLICATION NUMBER: US/14/892,925
CURRENT FILING DATE: 2015-11-20
NUMBER OF SEQ ID NOS: 28
SEQ ID NO 24
LENGTH: 324
TYPE: PRT
ORGANISM: Staphylococcus aureus
Query Match 99.8%; Score 1715; Length 324;
Best Local Similarity 99.7%;
Matches 323; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 NSAHKDSQDQNKKEHVDKSQQKDKRNVTNKDKNSTAPDDIGKNGKITKRTETVYDEKTNI 60
||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
Db 1 NSAHKDSQDQNKKEHVDKSQQKDKRNVTNKDKNSTVPDDIGKNGKITKRTETVYDEKTNI 60
Qy 61 LQNLQFDFIDDPTYDKNVLLVKKQGSIHSNLKFESHKEEKNSNWLKYPSEYHVDFQVKRN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LQNLQFDFIDDPTYDKNVLLVKKQGSIHSNLKFESHKEEKNSNWLKYPSEYHVDFQVKRN 120
Qy 121 RKTEILDQLPKNKISTAKVDSTFSYSSGGKFDSTKGIGRTSSNSYSKTISYNQQNYDTIA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RKTEILDQLPKNKISTAKVDSTFSYSSGGKFDSTKGIGRTSSNSYSKTISYNQQNYDTIA 180
Qy 181 SGKNNNWHVHWSVIANDLKYGGEVKNRNDELLFYRNTRIATVENPELSFASKYRYPALVR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGKNNNWHVHWSVIANDLKYGGEVKNRNDELLFYRNTRIATVENPELSFASKYRYPALVR 240
Qy 241 SGFNPEFLTYLSNEKSNEKTQFEVTYTRNQDILKNRPGIHYAPPILEKNKDGQRLIVTYE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SGFNPEFLTYLSNEKSNEKTQFEVTYTRNQDILKNRPGIHYAPPILEKNKDGQRLIVTYE 300
Qy 301 VDWKNKTVKVVDKYSDDNKPYKEG 324
||||||||||||||||||||||||
Db 301 VDWKNKTVKVVDKYSDDNKPYKEG 324
Applicants’ Arguments and Office Response
7. Applicant's arguments filed 7/2/2025 have been fully considered but they are not persuasive. Applicants’ argue:
Schneewind, Kort, and Nagy, alone and in combination, fail to disclose or suggest an immunogenic composition comprising (a) a SpA variant comprising a SpA, B, C, D, or E domain, wherein the domain has (i) lysine substitutions for glutamine residues corresponding to positions 9 and 10 of SEQID NO:58 and (ii) a glutamate substitution for a serine residue corresponding to position 33 of SEQ ID NO:58; and a mutant staphylococcal leucocidin subunit polypeptide comprising a mutant LukAB dimer polypeptide. As such, a person skill in the art would not have a reasonable expectation of success in arriving at the instantly claimed immunogenic compositions based on the disclosures of Schneewind, Kort, and Nagy, alone and in combination.
In response to Applicant's arguments it is the examiner’s position that newly issued rejection based on Schneewind, Kort, and Nagy and additionally, Schneewind et al. US Patent 8821894 teach substitutions for positions 9, 10 and 33 just as recited by the amended clams, see the above rejection.
Conclusion
8. No claims are allowed.
9. 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 KHATOL S SHAHNAN SHAH whose telephone number is (571)272-0863. The examiner can normally be reached on Mon-Tues , Thurs-Frid 12pm-8pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary B. Nickol can be reached on 571-272-0835. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Khatol S Shahnan-Shah/
Examiner, Art Unit 1645
September 27 2025
/JANA A HINES/Primary Examiner, Art Unit 1645