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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 26 April 2026 has been entered.
Claim Status
The amended claim set filed on 24 April 2026 is acknowledged. Claims 1-2, 5-6, 9-12, and 14-20 are currently pending. Of those, claims 1-2, 5-6, 9, and 20 are amended. There are no new claims and claims 14-20 are withdrawn. Claims 3-4, 7-8, and 13 are cancelled. Claims 1-2, 5-6, and 9-12 will be examined on the merits herein.
Response to Amendment
Applicants arguments filed 24 April 2026 are acknowledged. For clarity, in this Action, the arguments will be referred to as “Remarks” and the Final Office Action mailed 31 October 2025 will be referred to as “FOA”.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 April 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Rejection(s) Withdrawn
The rejection of claim 13 under 35 U.S.C. 112(b) is moot because the claim is cancelled.
Rejection(s) Maintained
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 102
Claims 1 and 9-12 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by van der Ley et al (US 2020/0085933 A1; herein “van der Ley”) for the reasons of record and the reasons herein.
The following rejection has been amended to reflect the amendments to the claims.
Regarding claims 1 and 9, van der Ley teaches Bordetella pertussis (B. pertussis) B1917 strains in which the chromosomal lpxD gene was replaced with the lpxD gene from Pseudomonas aeruginosa (P. aeruginosa), i.e., genomic insertion of a heterologous gene (para. 221). Van der Ley teaches that the P. aeruginosa LpxD protein expressed in B. pertussis B1917 has an amino acid sequence shown in SEQ ID NO: 4 (para. 136 and Table 2A), which is identical to instant SEQ ID NO: 4 (see alignment below), i.e., at least 95% sequence identity.
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Figure 1: Alignment of instant SEQ ID NO: 4 (Qy) with the P. aeruginosa LpxD protein (SEQ ID NO: 4) of van der Ley.
Regarding claim 10, van der Ley teaches that the B. pertussis chromosomal lpxA and lpxD genes (i.e., endogenous genes) were replaced by the corresponding P. aeruginosa genes (para. 221), meaning that the endogenous gene is inactivated.
Regarding claim 11, van der Ley teaches that P. aeruginosa LpxD attaches acyl chains C12 in length to the 2 and 2’ carbons of lipid A (Fig. 1F) (i.e. at least 30% of the C2 and C2’ acyl chains are from about C10 to about C12 in length). The wild type B. pertussis lipid A is penta-acylated and asymmetrical, having a C14 acyl chain on the 3’ carbon, a C10 acyl chain on the 3 carbon, and both the 2’ and 2 carbons having C14 primary acyl chains (the 2’ acyl chain has a secondary acyl chain; see Fig. 1A).
Regarding claim 12, van der Ley teaches that the purified lipopolysaccharides (LPS) containing the modified lipid A produced by either the LpxA or LpxD mutant B. pertussis was injected into rabbits in order to test pyrogenicity (i.e., the ability to cause fever, an inflammatory response to substances, including endotoxins) of the LPS (para. 222-230). The test demonstrated that the purified LPS from both mutant strains of B. pertussis shows reduced pyrogenicity (i.e., reduced inflammatory response triggered by TLR4 activation) compared to the wild type B. pertussis strain (para. 231-232).
Response to arguments
Applicant argues (Remarks, pg. 5) that claim 1 has been amended to incorporate the features of claims 4 and 8, thus rendering moot the rejection.
This argument has been fully considered but is not persuasive. As written, amended claim 1 only requires (i) or (ii). As set forth in the amended 102 rejection above and in the Non-Final Office Action mailed 3 March 2025 (para. 20), van der Ley teaches genomic insertion of the gene encoding P. aeruginosa LpxD protein, which is identical to instant SEQ ID NO: 4. Thus, van der Ley teaches the limitation of (ii) and therefore anticipates claim 1.
Claim Rejections - 35 USC § 103
Claims 1-2, 5-6, and 9-12 remain rejected under 35 U.S.C. 103 as being unpatentable over van der Ley (US 2020/0085933 A1) in view of Sweet et al. (2002, J. Biol. Chem.; herein “Sweet”) for the reasons of record and the reasons herein.
The following amendment has been amended to reflect the claim amendments.
The teachings of van der Ley are set forth in para. 10-13 above and teach all limitations of claims 1 and 9-12.
Regarding claims 1-2, van der Ley also teaches that the chromosomal lpxA gene can be replaced with the lpxA gene from Pseudomonas aeruginosa (P. aeruginosa), and he P. aeruginosa lpxA gene used produces LpxA protein with an amino acid sequence given in SED ID NO: 1 (para. 134 and Table 2A), which comprises substitution mutations at positions 170 and an alanine at position 229 relative to instant SEQ ID NO: 1 (see alignment below).
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Figure 2: Alignment of instant SEQ ID NO: 1 (Qy) with the P. aeruginosa LpxA protein (SEQ ID NO: 1) of van der Ley (Db). Positions 170 and 229 relative to instant SEQ ID NO: 1 are indicated by arrows.
However, van der Ley does not teach an lpxA gene encoding an LpxA protein comprising a serine residue at position 170 relative to SEQ ID NO: 1, as in claims 1-2, an lpxA gene encoding a LpxA protein having at least 80% amino acid sequence identity to instant SEQ ID NOs: 1 or 2, as in claim 5, or an lpxA gene encoding a LpxA protein having an amino acid sequence of instant SEQ ID NO: 2, as in claim 6.
Regarding claims 1-2 and 11, Sweet teaches B. parapertussis LpxA which comprises a serine at position 170, relative to instant SEQ ID NO: 1, and an alanine at position 229, relative to instant SEQ ID NO: 1 (Fig. 3; see alignment below). Sweet also teaches that the residue at position 173 of Fig. 3 (which corresponds to position 170 of instant SEQ ID NO: 1) has been shown to be a chain length determinant, and that the occurrence of serine in that position indicates a specificity for short acyl chains (Fig. 3 caption). Sweet teaches that B. parapertussis LpxA has a strong preference for acyl chains C10 in length, meaning that the 3’ carbon of lipid A will have a C10 acyl chain (pg. 18282, right col. and Fig. 2). Sweet also teaches that the B. parapertussis lipid A is also asymmetrical and has a similar structure to B. pertussis lipid A (penta-acylated with primary acyl chains on the 3’, 2’, 3, and 2 carbons and a secondary acyl chain on the 2’ acyl chain), with the difference between the structures being the length of the 3’ and 3 acyl chains (Fig. 2).
Regarding claims 5-6, Sweet teaches the amino acid sequence of B. parapertussis LpxA (Fig. 3), which has 100% identity to instant SEQ ID NO: 2 (see alignment below).
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Figure 3: Alignment of instant SEQ ID NOs: 1 and 2 with the amino acid sequence of B. parapertussis LpxA given by Sweet. Positions 170 and 229 are indicated by a dot below the alignment.
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the recombinant B. pertussis bacterium taught by van der Ley by replacing the chromosomal lpxA gene in the same bacterium, and replacing the lpxA gene from P. aeruginosa with that of B. parapertussis, as taught by Sweet, thereby arriving at the claimed invention. The person of ordinary skill in the art would have been motivated to make the modification because lipid A molecules with shorter acyl chains are less likely to stimulate TLR4 and trigger an inflammatory response, which would be beneficial in vaccine or pharmaceutical compositions. The B. parapertussis LpxA has a preference for acyl chains C10 in length on the 3’ carbon of the lipid A backbone and P. aeruginosa LpxD has a preference for acyl chains C12 in length on the 2’ and 2 carbons. The lipid A produced using these proteins would result in a 3’ chain C10 in length and 2 and 2’ chains C12 in length, which are all shorter chains than C14 acyl chains on the 3’, 2, and 2’ positions of the WT B. pertussis lipid A. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because van der Ley demonstrates that recombinant B. pertussis strains expressing heterologous lpx genes are able to produce lipid A molecules that are less toxic than the WT lipid A, and van der Ley demonstrates that the length of the acyl chains produced by the recombinant B. pertussis is predictable based on the species of Lpx protein(s) used. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, 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 elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., the heterologous LpxA protein and LpxD protein, and B. pertussis bacteria where each endogenous gene is replaced with a heterologous gene) were known in the art. In addition, combining these elements yields composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
Applicant argues (Remarks, pg. 6) that MPEP 2145 states, "[r]ebuttal evidence and arguments can be presented in the specification ... Rebuttal evidence may include evidence of 'secondary considerations,' ... Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art" (emphasis added).
Applicant also argues (Remarks, pg. 7-8) that the claimed B. pertussis strain (ΔLpxABpe/LpxABpa) has a fermentation profile that is “comparable” to that of the parental strain, Tohama I PTg, that the “comparability is ‘substantially similar’”, and that the growth rate of the claimed recombinant B. pertussis and the parental Tohama I strain “vary by ‘less than 20%’”; therefore, the data demonstrates that the surprising growth results of the claimed invention are of statistical significance.
This argument has been fully considered but is not persuasive. MPEP 716.02(b)(III) states (emphasis added), “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)”. While the data cited by the Applicant demonstrates comparable growth between the recombinant B. pertussis strain and the parental Tohama I strain, this does not demonstrate an unexpected improvement of the fermentation profile over the parental strain. In order to demonstrate that the claimed strain has an unexpectedly improved growth rate and/or fermentation profile compared to B. pertussis strain(s) with similar mutation, Applicant must present data showing that comparison. The data does not compare the claimed strain to the strain taught by the closest prior art (i.e., the B1917 strain of van der Ley); thus, the applicant has not demonstrated that the growth rate and/or fermentation profile of the claimed strain is significantly different from the strain taught by van der Ley.
Applicant argues (Remarks, pg. 9) that van der Ley is silent about the growth properties of the B1917 strain, does not present any growth data for the B1917 strain, and does not disclose or suggest that the B1917 strain shows an absence of growth defects or demonstrates a growth curve that is “substantially similar” to its parental strain.
Applicant also argues (Remarks, pg. 9) that van der Ley, alone or in combination with Sweet, does not teach or suggest the unexpected or surprising results of the claimed invention is necessarily present in the disclosed B1917 strain.
This argument has been fully considered but is not persuasive. Regarding the argument that van der Ley does not teach or suggest that the allegedly unexpected or surprising results of the claimed invention are necessarily present in the disclosed strain, MPEP 2145(II) states, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979).” Regarding the argument that van der Ley does not teach that the B1917 strain shows an absence of growth defects, MPEP 2112.01(I) states (emphasis added), “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). ‘When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.” In the instant case, the combination of van der Ley and Sweet is substantially identical to the claimed B. pertussis strain of the instant claims because it possesses all of the claimed limitations. Therefore, the combination of van der Ley and Sweet possesses the characteristics of the claimed product absent evidence to the contrary, because it is the same product. The data cited by the Applicant is not sufficient to demonstrate that the strain of van der Ley does not possess the characteristics of the claimed strain because the data is not commensurate in scope with the claimed invention and does not compare the claimed strain with the closest prior art, as discussed above.
New Objection(s)
Claim Objections
Claims 1-2 are newly objected to because of the following informalities:
In claim 1, line 7, the phrase “at least 95% amino acid sequence to SEQ ID NO: 3” should read “at least 95% amino acid sequence identity to SEQ ID NO: 3”;
In claim 2, line 3, “Serine” should not be capitalized; and
In claim 2, line 4, “Alanine” should not be capitalized.
Appropriate correction is required.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY M MORGAN whose telephone number is (703)756-5388. The examiner can normally be reached M-F 9-5 ET.
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/BAILEY M MORGAN/Examiner, Art Unit 1645
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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