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 .
The examiner reviewing your application at the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to examiner Jehanne Sitton.
Election/Restrictions
Applicants’ election of species viral antigen, without traverse, in the response filed 1/26/2026 is acknowledged. The election of species requirement between bacterial and viral antigen is withdrawn. Claims 16 and 19 are withdrawn from consideration as being directed to non-elected species. Claims 1-15, and 17-18 are examined herein.
Claim Rejections - 35 USC § 112
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.
Claims 1-15 and 17-18 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites step “a)” twice. It is not clear if this is a typographical error or if the steps are to be performed simultaneously. If the former is the case, the claims should be amended to reformat the steps so that each has its own designated step. If the latter is the case, it is suggested that the subject matter of both steps designated “a” be included in a single step.
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.
Claims 1-9, 14, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Aebig (Aebig et al; J Immunol Methods, vol 323, pp 139-146, 2007) in view of Murphy (Murphy et al; Analytical Biochemistry, vol 240, pages 273-282, 1996, cited in the IDS filed 11/27/2023), de Haas (de Haas et al; Water SA, vol 16, pages 55-65, 1990; cited in the IDS filed 1/26/2026), and Hiroshi (JP2011208953A; cited in the IDS filed 1/26/2026).
Aebig teaches that vaccines comprising unmethylated CpG containing oligonucleotides and alum provide enhanced immunostimulatory properties (see abstract, introduction). Aebig teaches measuring bound and free CpG oligonucleotides by spectrophotometry and electrophoresis (see whole document). Aebig does not teach quantitating CpG oligos using an acid, molybdate assay. However, Murphy teaches that the concentration of oligonucleotides can be determined using general phosphate analysis (GPA) (see abstract). Murphy teaches a procedure whereby nucleic acid oligomers are mixed with acid, including sulfuric acid (see pages 275-276). Murphy teaches that digestion occurs at 230°C (claim 2) which converts the phosphorus to orthophosphate. Murphy teaches reaction of orthophosphate with ammonium molybdate and ascorbic acid to produce a blue color. Murphy teaches recording absorbance at 820 nm and calculating the concentration of total phosphorus using standard curves followed by determining the concentration of oligonucleotides (see pages 276-277). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have substituted the CpG quantification method of the vaccine formulations containing alum, an antigen, and CpG oligonucleotides taught by Aebig with the general phosphate assay taught by Murphy because Murphy teaches it a practical application for quantifying oligomers.
Aebig and Murphy do not teach mixing sulfuric acid and ammonium persulfate to produce orthophosphate, reacting the orthophosphate with ammonium molybdate and antimony potassium tartrate, or measuring absorbance at 650 nm, however de Haas teaches a method of measuring total phosphate in sludge (see whole document), to include nucleic acids, by mixing the sample with sulfuric acid and ammonium persulfate (see page 56), reaction with ammonium molybdate and potassium antimonyl tartrate, and the addition of ascorbic acid (see pages 56, 57). De Haas also teaches calculating the concentration of total phosphorous using standard curves, as well as exemplifying the routine nature of optimizing the conditions of the assay (see figures, whole document). Additionally, Hiroshi also teaches a molybdate assay for measuring phosphorous in water which involves the use of sulfuric acid, hexamolybdenum hexamolybdate tetrahydrate, potassium antimonyl tartrate trihydrate, and ascorbic acid, to produce a blue color (pages 1-4). Hiroshi teaches measuring absorbance at 650 nm (page 5) and calculating the concentration of phosphorous in the complex with a standard curve (see figures). Hiroshi also teaches that substitution of different reagents is possible as well as providing examples of optimizing the method (see whole document). Therefore, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date to optimize the method of quantitating CpG oligonucleotides in the method of Aebig and Murphy, to include conditions taught by de Haas and Hiroshi to arrive at the claimed methods, with a reasonable expectation of success. The prior art teaches the routine use of the molybdate assay for quantifying phosphorous in different samples as well as the routine nature of manipulating the assay conditions and reagents to achieve optimal results. Given the teachings of the prior art cited, the claimed method is considered obvious absent secondary considerations.
With regard to claim 3, although the cited prior art does not state whether the steps are conducted in acid washed glassware. , Aebig does teach that vaccines were formulated under aseptic conditions. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have used aseptic techniques, including the known and routine use of acid washed glassware so as to avoid the introduction of contaminants into the method.
With regard to claim 4, de Haas teaches that color was developed at 25-30 °C for 30 minutes and read using a spectrophotometer.
With regard to claims 5 and 6, Aebig teaches vaccines were formulated in buffers comprising saline (see page 140) at pH of 7.4, 7.5, 8, etc.
With regard to claims 7 and 8, Murphy teaches reagent formulations devoid of phosphate as well as ensuring there was no extraneous phosphate contamination other than the oligomers (see whole document, and page 280 “Sources of Error”). Although Murphy does not teach buffers that contained phosphorous, Aebig teach vaccine formulations that contained phosphate buffer. Although Aebig and Murphy do not teach to subtract phosphate from the buffer from total phosphate concentration, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have accounted for phosphate concentration in addition to the oligomers, because Murphy teaches it is a concern for the experiment. In cases where phosphate was present in the buffer, it would have been obvious to account for the extra phosphate and to subtract it from the total phosphate concentration so as to arrive at an accurate phosphate concentration attributed to the CpG oligonucleotides.
With regard to claim 9, Aebig teaches CpG ODNs from 8-50 nucleotides of unmethylated CpG motifs (see whole document, page 140).
With regard to claims 14 and 15, Aebig teaches the antigen comprises at least one polypeptide which is a bacterial antigen (see whole document).
With regard to claim 18, Aebig teaches the vaccines were formulated to contain protein adsorbed to alum in saline (page 140). Aebig teaches CpG ODN was added to either alum or vaccine using aseptic techniques.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Aebig, Murphy, de Haas, and Hiroshi, as applied to claims 1-9, 14, 15, and 18 above, and further in view of Dechamps (WO 00/62802; cited in the IDS filed 1/26/2026).
The teachings of Aebig, Murphy, de Haas, and Hiroshi are set forth above and incorporated herein. Aebig, Murphy, de Haas, and Hiroshi do not teach wherein the antigen is a fusion protein, however Dechamps teaches vaccine formulations for RSV comprising antigen, alum, and CpG ODN’s (see whole document). Dechamps teaches the vaccine formulation with fusion proteins comprising two different antigens, the F and G protein. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have applied the CpG quantification method of Aebig, Murphy, de Haas, and Hiroshi to the vaccine formulations taught by Dechamps with a reasonable expectation of success for the obvious benefit of quantifying the CpG ODN in the vaccine formulation of Dechamps.
Claims 10, 11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Aebig, Murphy, de Haas, and Hiroshi as applied to claims 1-9, 14, and 18 above, and further in view of Nest (Nest et al; US 2002/0055477).
The teachings of Aebig, Murphy, de Haas, and Hiroshi are set forth above and incorporated herein. Aebig, Murphy, de Haas, and Hiroshi do not teach wherein the CpG ODN comprises the sequence of SEQ ID NO:3 or the sequence of SEQ ID NO:1, or wherein the CpG is double stranded with a phosphorothioate linkage. Nest teaches CpG ODN sequence of claimed SEQ ID NO: 1 and 3 (see whole document). Nest also teaches embodiments where the CpG ODN sequence is double-stranded and comprises at least one phosphorothioate linkage (whole document, abstract, para 0076). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have applied the known GpG ODNs to the method of Aebig, Murphy, de Haas, and Hiroshi, with a reasonable expectation of success so as to quantitate the CpG ODNs.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Aebig, Murphy, de Haas, and Hiroshi, as applied to claims 1-9, 14, 15, and 18 above, and further in view of Kandimalla (Kandimalla et al; US 2009/0060898 A1).
The teachings of Aebig, Murphy, de Haas, and Hiroshi are set forth above and incorporated herein. Aebig, Murphy, de Haas, and Hiroshi, do not teach wherein the oligonucleotide comprises a modified nucleoside, wherein the modified nucleoside is selected from the group consisting of 2'-deoxy-7-deazaguanosine, 2'-deoxy-6- thioguanosine, arabinoguanosine, 2'-deoxy-2'substituted arabinoguanosine, and 2' -0-substituted-arabinoguanosine. Kandimalla teaches immune regulatory oligonucleotide comprising modified nucleosides (para 0110) including 2'-deoxy-7- deazaguanosine, 2'-deoxy-6-thioguanosine, arabinoguanosine, 2'-deoxy-2'substituled-arabinoguanosine, and 2'-O-substituted- arabinoguanosine. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have substituted the known modified guanosines to the method of Aebig, Murphy, de Haas, and Hiroshi, with a reasonable expectation of success.
Conclusion
No claims are allowed.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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