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 .
DETAILED ACTION
Priority
Application 18/535,116 claims priority from PROVISIONAL 63/387,100 filed on December 13, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted have been considered by the examiner.
Status of applications, Amendments, and/or Claims
The Response filed 6 July 2026 has been entered in full. Claims 2, 8-15, 22-34, 38, 41-42, 44-54 have been canceled without prejudice or disclaimer, and claims 1, 5, 17, 19-21, 37, 43 have been currently amended. Claims 55-69 are new.
Therefore, claims 1, 3-7, 16-21, 35-37, 39-40, 43, 55-69 are the subject of this Office Action.
Withdrawn Objections and/or Rejections
The rejection of claims 19-20, 37, 43 on the ground of 35 U.S.C 112 (b) as failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor as set forth at pp. 3 are withdrawn in view of Applicant’s amendments of the claims.
The rejections of claims 1, 3-6, 8, 16-20, 35-37, 39, 43, and 54 on the ground of 35 U.S.C 102 rejection as set forth at pp. 18-23 are withdrawn in view of Applicant’s amendments and/or cancellations of the claims.
New and modified Claim rejections - 35 USC § 103
Necessitated by Amendment
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, 3-7, 16-20, 35-37, 39, 43, 55-69 are under 35 U.S.C. 103 as being unpatentable over Sidhu et al. (US 8481692 B2; hereafter Sidhu; PTO-892) in view of Davis et al. (US 8552165 B2; hereafter Davis; PTO-892).
Sidhu teaches the immunogenic composition comprising an adjuvant, which is pertinent to claims 1-7, 21, 35-37, 39. See for example, claim 20.
Sidhu teaches “an immunogenic composition that includes a mutant Clostridium difficile toxin A and/or a mutant Clostridium difficile toxin B”. The methods of treating or the methods of inducing an immune response includes an immunogenic composition that further includes an adjuvant. See column 3; lines 30-46.
Sidhu also teaches that “yet, another exemplary adjuvant is a CpG oligonucleotide, most preferably a CpG oligodeoxynucleotides (CpG ODN) or a saponin and an immunostimulatory oligonucleotide, such as a CpG oligonucleotide. In a preferred embodiment, the adjuvant is a CpG oligonucleotide, most preferably a CpG oligodeoxynucleotides (CpGODN). Preferred CpGODN are of the B Class that preferentially activate B cells. In aspects of the invention, the CpG ODN has the nucleic acid sequence 5' T*C*G*T*C*G*T*T*T*T*T*C*G*G*T*G*C*T*T*T*T 3' (SEQ ID NO: 48) wherein * indicates a phosphorothioate 10 linkage. The CpG ODN of this sequence is known as CpG 24555. In a preferred embodiment, CpG 24555 is used together with an aluminium hydroxide salt such as Alhydrogel, which is pertinent to claims 1, 3-4. See for example Colum 53; lines 66-67; Column 54; lines 1-13.
Sidhu teaches that “Optionally, the pharmaceutical composition includes two or more different adjuvants. Preferred combinations of adjuvants include any combination of adjuvants including, for example, at least two of the following adjuvants: alum, MPL, QS-21, ISCOMATRIX, CpG, and Alhydrogel”, which is pertinent to claims 1, 3-4. See for example, column 54; lines 35-41.
Sidhu teaches that exemplary buffers include phosphate (such as potassium phosphate, sodium phosphate); acetate (such as sodium acetate); succinate (such as sodium succinate); glycine; histidine; carbonate, Tris (tris(hydroxymethyl)aminomethane), and/or bicarbonate (such as ammonium bicarbonate) buffers. The composition includes histidine buffer. Preferred amounts of histidine buffer include from a minimum of about 1 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM to a maximum of about 100 mM, 50 mM, 20 mM, 19 mM, 18 mM, 17 mM, 16 mM, 15 mM, 14 mM, 13 mM, 12 mM, or 11 mM. Any minimum value can be combined with any maximum value to define a suitable range. In one embodiment, the composition includes about 8 mM to 12 mM histidine buffer, most preferably, 10 mM histidine buffer, for example, per 0.5 mL dose. The composition includes phosphate buffer. Preferred amounts of phosphate buffer include from a minimum of about 1 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM to a maximum of about 100 mM, 50 mM, 20 mM, 19 mM, 18 mM, 17 mM, 16 mM, 15 mM, 14 mM, 13 mM, 12 mM, or 11 mM. Any minimum value can be combined with any maximum value to define a suitable range. In one embodiment, the composition includes about 8 mM to 12 mM phosphate buffer, most preferably, 10 mM phosphate buffer, for example, per 0.5 mL dose, which is pertinent to claims 16-17. See for example, See column 52; lines 34-43.
Sidhu teaches vaccines diluents, for saline, 60 mM NaCl is used as a diluent for the lyophilized drug product without any adjuvant to ensure an isotonic solution upon reconstitution, which is pertinent to claims 19, 57.
Sidhu teaches the pH of the buffer will generally be chosen to stabilize the active material of choice, and can be ascertainable by those in the art by known methods. Preferably, the pH of the buffer will be in the range of physiological pH. Thus, preferred pH ranges are from about 3 to about 8; more preferably, from about 6.0 to about 8.0; yet more preferably, from about 6.5 to about 7.5; and most preferably, at about 7.0 to about 7.2, which is pertinent to claim 20.
Sidhu teaches Toxoid A and Toxoid B in combination with the adjuvant Alhydrogel/ CpG 24555 at 0.2 or 0.4 and CpG 24555 at 1 mg/dose. See example 43; column 113; lines 29-44. Sidhu teaches that “typically, about 10, 20, 50 or 100 ug per immunogen is used for each human injections (column 58; lines 27-37). Sidhu also teaches Different ratios of mutant toxin A and mutant toxin B (10 ug of mutant A plus either 10, 50, or 100 ug of mutant B) formulated with Alh/CpG (250 ug/500 ug per dose), which is pertinent to claim 60. See column 112, lines 17-34.
Sidhu also teaches “The primary structure of triple mutant toxin A is shown in SEQ ID NO: 4. The NH.sub.2-terminal Met residue at position 1 of SEQ ID NO: 4 is originated from the initiation codon of SEQ ID NO: 12 and is absent in isolated protein (e.g., see SEQ ID NO: 84). Accordingly, in Example 12 to Example 45, "SEQ ID NO: 4" refers to SEQ ID NO: 4 wherein the initial methionine (at position 1) is absent” (847). Sidhu teaches “The primary structure of triple mutant toxin B is shown in SEQ ID NO: 6. The NH.sub.2-terminal Met residue at position 1 of SEQ ID NO: 6 is originating from the initiation codon and is absent in isolated protein (e.g., see SEQ ID NO: 86). Accordingly, in Example 12 to Example 45, "SEQ ID NO: 6" refers to SEQ ID NO: 6 wherein the initial methionine (at position 1) is absent”, which is pertinent to claims 35-36.
Sidhu teaches that SEQ ID: 4, 6, 84 and 86. These sequences are identical and equivalent to the same SEQ ID numbers in Sidhu’s teachings, which is pertinent to claims 35-36, 66-69. See Figure below.
Sidhu teaches that “It is understood that any of the inventive compositions, for example, immunogenic compositions including a mutant toxin A and/or mutant toxin B, can be combined in different ratios or amounts for therapeutic effect. For example, the mutant C. difficile TcdA and mutant C. difficile TcdB can be present in a immunogenic composition at a ratio in the range of 0.1:10 to 10:0.1, A:B. In another embodiment, for example, the mutant C. difficile TcdB and mutant C. difficile TcdA can be present in a immunogenic composition at a ratio in the range of 0.1:10 to 10:0.1, B:A. In one preferred embodiment, the ratio is such that the composition includes a greater total amount of a mutant TcdB than a total amount of mutant TcdA” which is pertinent to claims 37, 60.
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However, Sidhu does not explicitly teach 0.1 to 5 mg/mL CpG, wherein the composition does not comprise aluminum hydroxide (AI(OH)3 as claims 1, 5-7, 21, 40, 55, 59, 61-69.
Davis teaches that the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for CpG oligonucleotides which have been tested in humans (e.g., human clinical trials have been initiated) and for compounds which are known to exhibit similar pharmacological activities, such as other adjuvants, e.g., LT and other antigens for vaccination purposes. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art are well within the capabilities of the ordinarily skilled artisan, which is pertinent to claims 1, 5-7, 21, 37, 40, 43, 55, 59, 60-65, 67-68.
Davis teaches immunostimulatory oligonucleotides, such as CpG 24555 and methods of using immunostimulatory oligonucleotides to induce an antigen-specific immune response that can be useful as a prophylactic vaccine prevention (i.e., an infectious disease). Davis teaches that the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular CpG immunostimulatory oligonucleotide being administered, the size of the subject, or the severity of the disease or condition. Davis also teaches that “one of ordinary skill in the art can empirically determine the effective amount of a particular CpG immunostimulatory oligonucleotide and/or antigen and/or other therapeutic agent without necessitating undue experimentation in light of this disclosure”, which is pertinent to claims 1-7, 21, 40. “Typically range from about 0.1 ug to 50 mg per administration which, depending on the application, could be given daily, weekly, or monthly and any other amount of time therebetween. More typically local doses range from about 10 ug to 10 mg per administration, and optionally from about 100 ug to 1 mg, with 2-4 administrations being spaced days or weeks apart. More typically, immune stimulant doses range from 1 ug to 10 mg per administration, and most typically 10 ug to 1 mg, with daily or weekly administrations”, which is pertinent to claims which is pertinent to claims 1, 5-7, 21, 37, 40, 43, 55, 59, 61-65, 67-68. For example, column 27, lines 27-67.
Therefore, a skilled artisan could have at once envisaged swapping out the adjuvant of the immunogenic composition of Sidhu, because Sidhu teaches other adjuvants, including CpG ODN, such as CpG 24555 of Davis for eliciting immune response against an antigen, thereby arriving at the invention 1, 3-7, 16-20, 35-37, 39, 43, 55-69. It would have been obvious to substitute these known equivalents; MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Reasonable expectation of success would be expected because Sidhu teaches an immunogenic composition comprising Toxoid A/B in combination with any adjuvants, including CpGs and does not specify any adjuvant that should not be used in the composition.
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain 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, Sidhu teaches a product (and a method) that only differs from the claimed invention by the substitution of a single element (i.e. concentration of CpG 24555); the substituted element (3.6 mg/mL CpG 24555) was already known to be used to augment immune response, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of substituting an antigen for another with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results). Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Therefore, the inventions of claims 1, 3-7, 16-20, 35-37, 39, 43, 55-69 are rejected under 103.
Applicant’s arguments directed to previous rejections for the claims will be addressed below. See response to arguments.
Modified Double Patenting Rejections
Necessitated by Amendment
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-7, 16-21, 35-37, 39, 40, 43, 55-69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8-9, 10, 20 of Sidhu et al. (U.S. Patent No. US 8481692 B2; hereafter Sidhu; PTO-892) in view of Davis et al. (U.S. Patent No. 8552165 B2; hereafter Davis; PTO-892) and further view of Middaugh et al. (WO 2009035707 A1, hereafter Middaugh; PTO-892).
US Patent No. US 8481692 B2 claims SEQ ID NO: 84, 4 which is Clostridium difficile toxin A, and also a composition comprising same and an adjuvant. See '692, claims 1-2, 8, 20 for example. Patent '692 also claims that toxoid B (SEQ ID NO: 86, 6), should be included in the same composition; see claims 9-10. Patent '692
US Patent '692 also claims SEQ ID NO: 4, 6, which are the sequences of toxoid A and toxoid B, wherein the methionine residue at position 1 is optionally not present; see ‘692, claims 2, 10. Patent '692
However, '692 does not claim a CpG adjuvant as in claim 1 or the particular adjuvants recited in claims 3-4.
US Patent '165 discloses SEQ ID NO:1, which is a CpG sequence identical to present SEQ ID NO:48, and discloses that it is immunostimulatory oligonucleotide (CpG 24555), suggesting that it can be used as an adjuvant. US Patent '165 discloses “CPG ODN 24555 advantageously allows generating poly-functional antigen-specific T cells populations when used as an adjuvant which can be of importance in a vaccine setting”. See column 2; lines 1-65; column 31; column 4; lines 1-30; column 9; lines 4-18. Patent '165
US Patent '165 discloses CPG 24555 is better than CPG 10103 for generating poly-functional antigen-specific T cells populations when used as an adjuvant to Hepatitis B Surface Antigen (HBsAg). See Figure 13A. “CpG 2455 was superior to CpG 10103 and CpG 7909 in augmenting Influenza A antigen (HA)-specific IgG”. See for example column 39; Table 3; Figure 15-16. Patent '165
US Patent '165 discloses “the importance of the poly-functionality of T cells in immunogenicity has been highlighted recently. In particular poly-functionality of antigen specific T cells in terms of chemokine production (such as IFN-gamma., TNF-alpha and IL-2) has been correlated in some instances to their protective potential (see e.g. Harari A, et al., Immunol Rev. 2006; 211:236-54, Makedonas G and Betts MR. Springer Semin Immunopathol. 2006; 28(3):209-19, Precopio M L et al., J Exp Med. 2007 204 (6):1405-16, Xu R et al. Vaccine. 2008; 26(37):4819-29) thought to be due to their better effector function compared to T cells that secrete but a single cytokine.”. See column 9, lines 4-15. Patent '165
US Patent '165 also discloses “method of inducing an antigen-specific immune response in a subject in need thereof comprises administering to a subject an antigen and an immunostimulatory oligonucleotide comprising nucleotide sequence SEQ ID NO: 1 in an effective amount to induce an antigen-specific immune response in said subject. In some embodiments, the antigen is a microbial antigen, a self-antigen or an addictive Substance”. For example, “the antigen is a nicotine hapten conjugated to the carrier, which the nicotine hapten is conjugated is diphtheria toxin (DT)”. See for example claim 1; column 3; lines 30-67; column 4; lines 1- 30. Patent '165
Claims 1, 64, 67 are included in this rejection as claim 20 of US ‘692 do not recite any adjuvant that should not be used.
Claims 5-6 are included in this rejection as '165 teaches 0.833 mg/ml CpG 24555; see column 40 lines 20-27. Patent '165
Claims 7, 21, 39-40 are included in this rejection as '165 provides guidance on how to optimize the dose of the CpG; see column 27; lines 27-67; column 28; lines 1-46. Patent '165
Claim 8 is included in this rejection as '165 teaches CpG and the adjuvant, aluminum hydroxide; see for example column 6, lines 55, figures 14-16. Patent '165
Claims 16, 18, 20 are included in this rejection as '165 teaches Phosphate buffered saline (PBS) at pH 7.2; see columns 32, lines 15-30 and sodium chloride; see column 29, lines 20-25. Patent '165
Claim 43 is included in this rejection as it does not limit the composition but rather recites an intended use.
However, neither Sidhu nor Davis teaches that histidine or phosphate buffer is at concentration of about 5 mM to 15 mM, or preferably 10 mM, as claim 17 or the sodium chloride at a concentration of about 20 mM to 100 mM as claim 19. US ‘692 and US ‘165 also do not teach about 3.6 mg/mL of CpG or CpG 24555, as claim 39 and 40, respectively or toxoid A and toxoid B in a ratio of about 3:1 to about 1:1 and/or the composition comprise 200 ug of toxoid as claims 37, 60.
WO ‘707 A1 teaches “the compositions of the invention include one or more compounds such as, for example, buffers (e.g., citrate, phosphate, glycine, histidine, carbonate, or bicarbonate; 5-100 mM. The buffer is selected from the group consisting of citrate, phosphate, glycine, histidine, carbonate, and bicarbonate, and is at a concentration of 5-100 mM. See US ‘707 claim 14.
WO ‘707 A1 teaches “the salts are selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and magnesium acetate, up to 150 mM. See WO ‘707 claim 21.
WO ‘707 A1 teaches “the compositions include both toxoid A and toxoid B, but compositions including only one of these are also included in the invention”. “The total amount of toxoid in the compositions can be e.g., 100 ng-1 mg, 100 ng-500 μg, 1-250 μg, 10-100 μg, 25-75 μg, or 50 μg, and the ratios may be 2:1, 3:1, or 3:2 (A:B). The compositions may optionally be stored in vial in single unit dosage”. See ‘707 page 7, lines 11-19; page 35; claims 4-6. “The toxoids A and B are present in the composition in a ratio of 3: 1 to 3:2, or 1 :1 (A:B)”. see ‘707 claim 6.
Therefore, it would have been obvious to a PHOSITA to modify the invention claimed in Patent US ‘692 to include CpG 2455 and use the guide for use of CpGs as taught by US ‘165 and the buffer concentrations and amounts/ratios of toxoids A and B as taught by US ‘707, arriving at the invention of claims 1, 3-7, 16-21, 35-37, 39, 40, 43, 55-69.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Reasonable expectation of success would be expected because US ‘692 specifically suggests using an immunogenic composition comprising toxoid A and toxoid B, and adjuvants and does not specify any adjuvants that should not be used.
Also, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain 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, the prior art (the claims of US 8481692 B2) teaches a product that only differs from the claimed invention by the combination of a single component (i.e. a vaccinal adjuvant, CpG; CpG 24555, buffers, pH, antigens concentrations, salts) was already known and known to function as a vaccinal adjuvant, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of choosing an adjuvant disclosed as being useful with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results), particularly because U.S. Patent No. 8552165 B2 claims the use of the immunogenic composition comprising adjuvants, and teaches that CpG 24555 was known to be a potent vaccinal adjuvant.
Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Therefore, the inventions of claims 1, 3-7, 16-20, 35-37, 39, 43, 55-69 are rejected on the ground of nonstatutory double patenting as being unpatentable.
Applicant’s arguments directed to previous rejections will be addressed below. See response to arguments.
Claims 1, 3-7, 16-21, 35-37, 39, 40, 43, 55-69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-19, 30, 45-47, 49 of codepending Application No. 18/446,883 (‘883) in view of Davis (U.S. Patent No. 8552165 B2; hereafter Davis; PTO-892) and further view of Middaugh et al. (WO 2009035707 A1, hereafter Middaugh; PTO-892).
Application ‘883 claims administering 200 ug of SEQ ID NO: 84 and SEQ ID NO: 86; See for example claim 30, 45-46.
Application '883 claims administering an adjuvant in general; see claim 47-48.
However, Application ‘883 does not claim administering a CpG sequence in particular.
US ‘165 teaches CpG adjuvant as set forth in SEQ ID NO:48 and teaches that it can be used as an adjuvant; see for example claim 1; column 3; lines 30-67; column 4; lines 1- 30. Patent '165.
Claims 5-6, 55, 58 are included in this rejection as '165 teaches 0.833 mg/ml CpG 24555; see column 40 lines 20-27. Patent '165
Claims 3-7, 21, 39-40, 59-62 are included in this rejection as '165 provides guidance on how to optimize the dose of the CpG; see column 27; lines 27-67; column 28; lines 1-46. Patent '165.
Claims 16, 18, 20 are included in this rejection as '165 teaches Phosphate buffered saline (PBS) at pH 7.2; see columns 32, lines 15-30 and sodium chloride; see column 29, lines 20-25. Patent '165
Claim 43 is included in this rejection as ‘156 teaches formulations of CpG and antigens.
However, neither reference teaches histidine or phosphate buffer is at concentration of about 5 mM to 15 mM, as claim 17, 56-57 or the sodium chloride at a concentration of about 20 mM to 100 mM as claim 19.
Claim 17, 56-57 are included in this rejection as WO ‘707 A1 teaches phosphate and histidine buffer at concentrations at 5-100 mM. See ‘707 claim 14.
Claim 19 is included in this rejection as WO ‘707 A1 teaches sodium chloride, potassium chloride, magnesium chloride up to 150 mM.
Therefore, it would have been obvious to a PHOSITA to modify the invention claimed in application ‘833 to include histidine/Phosphate buffer concentrations, and sodium chloride amounts as taught by US ‘707, arriving at the invention of claims 17, 19.
Therefore, it would have been obvious to a person of ordinary skill in the art to modify the method claimed by '883's claim 30 and 45-47 by substituting in the CpG adjuvant of ‘165 arriving at the invention of claims 1, 3-7, 16-21, 35-37, 39, 40, 43, 55-69.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Reasonable expectation of success would be because application ‘883 specifically suggests immunogenic compositions comprising toxoid A and or/toxoid B but does not specify any adjuvant that should not be used.
Also, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain 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, the prior art (the claims of application 18/446,883) teaches a method comprising a product that only differs from the claimed invention by the combination of a single component (i.e. adjuvant, CpG; CpG 24555) was already known and known to function as components used for boosting the immune response against vaccinal antigens therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of choosing an adjuvant disclosed as being useful with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results), particularly because CpG 24555’s adjuvant taught by US ‘165 was already known to be very effective for boosting immune response in a vaccinal composition comprising antigens.
Therefore, the inventions of claims 1, 3-7, 16-20, 35-37, 39, 43, 55-69 are rejected on the ground of nonstatutory double patenting as being unpatentable.
Applicant’s arguments directed to previous rejections will be addressed below. See response to arguments.
Response to Amendments
Applicant argues at pg. 6-11 of the Response (filed 1 July 2026) that “Sidhu does not disclose the presently claimed composition. Sidhu fails to meet this standard. In particular, Sidhu does not disclose a C. difficile toxoid A and toxoid B composition that (i) comprises a CpG adjuvant at a concentration of 0.1 to 5 mg/mL, and (ii) excludes aluminum hydroxide, as required by amended claim 1.To the contrary, the Office Action relies on disclosures in Sidhu that describe C. difficile toxoid formulations containing various adjuvants. However, the cited examples of Sidhu (e.g., Examples 42 and 43) solely assess formulations comprising aluminum hydroxide (AI(OH)3/alum/Alhydrogel), combinations of aluminum hydroxide and CpG (AI(OH)3/CpG), or alternative adjuvant systems such as ISCOMATRIX. Sidhu's disclosure of CpG occurs only in the context of formulations that include aluminum hydroxide (AI(OH)3/CpG), not CpG alone. Further, Sidhu explicitly teaches that "In a preferred embodiment, CpG 24555 is used together with an aluminum hydroxide salt such as Alhydrogel" and identifies such CpG/Alhydrogel formulations as exemplary embodiments, see col. 54, lines 11-13 and 39-41. Accordingly, Sidhu does not merely fail to disclose the claimed exclusion of aluminum hydroxide-it affirmatively teaches CpG-containing formulations in which aluminum hydroxide is present. “Sidhu does not disclose a single embodiment or disclosure describing a composition comprising a C. difficile toxoid A and toxoid B, and a CpG adjuvant comprising 0.1 to 5 mg/mL CpG, wherein the composition does not comprise aluminum hydroxide (AI(OH)3). Thus. Sidhu does not anticipate the claimed subject matter”.
“For at least these reasons, Applicant respectfully submits that Sidhu fails to disclose, either explicitly or inherently, a composition comprising a C. difficile toxoid A and toxoid B, and a CpG adjuvant comprising 0.1 to 5 mg/mL CpG, wherein the composition does not comprise aluminum hydroxide (AI(OH)3), as required by the pending claims. Accordingly, independent claims 1, 64 and 67, and the claims that depend therefrom, are novel over Sidhu”.
Applicant’s arguments have been fully considered, but not persuasive. Sidhu explicitly teaches “an immunogenic composition that includes a mutant Clostridium difficile toxin A and/or a mutant Clostridium difficile toxin B”. The methods of treating or the method of inducing an immune response includes an immunogenic composition that further includes an adjuvant. See column 3; lines 30-46. Sidhu also teaches that “yet, another exemplary adjuvant is a CpG oligonucleotide, most preferably a CpG oligodeoxynucleotides (CpG ODN) or a saponin and an immunostimulatory oligonucleotide, such as a CpG oligonucleotide. In a preferred embodiment, the adjuvant is a CpG oligonucleotide, most preferably a CpG oligodeoxynucleotides (CpGODN). Preferred CpGODN are of the B Class that preferentially activate B cells. In aspects of the invention, the CpG ODN has the nucleic acid sequence 5' T*C*G*T*C*G*T*T*T*T*T*C*G*G*T*G*C*T*T*T*T 3' (SEQ ID NO: 48) wherein * indicates a phosphorothioate 10 linkage. The CpG ODN of this sequence is known as CpG 24555. In a preferred embodiment, CpG 24555 is used together with an aluminium hydroxide salt such as Alhydrogel, which is pertinent to claims 1, 3-4. See for example Colum 53; lines 66-67; Column 54; lines 1-13.
Sidhu also teaches that “Optionally, the pharmaceutical composition includes two or more different adjuvants. Preferred combinations of adjuvants include any combination of adjuvants including, for example, at least two of the following adjuvants: alum, MPL, QS-21, ISCOMATRIX, CpG, and Alhydrogel. An exemplary combination of adjuvants includes a combination of CpG and Alhydrogel.” See Column 54; lines 35-41. Sidhu also teaches immunogenic composition comprising an adjuvant. See for example claim 20. It is apparent that Sidhu provides examples of immunogenic composition comprising the antigens, which includes “An exemplary combination of adjuvants includes a combination of CpG and Alhydrogel” and does not limit the use of any sort of adjuvant in the immunogenic composition.
Applicant should recognize that Sidhu’s invention (U.S. Patent No. US 8481692 B2; hereafter Sidhu; PTO-892) is drawn to an immunogenic composition comprising an adjuvant, and not to an immunogenic composition comprising exclusively the adjuvants, CpG and Aluminum hydroxide as rhetoric argued by the applicant. Instead, US Pat. 8481692 B2 disclaims any combinations of adjuvants, including CpG and Aluminum hydroxide. It is evident that Sidhu solely provides examples of immunizations wherein the immunogenic composition comprises CpG and aluminum hydroxide or ISCOMATRIX, and the administration of these compositions comprising CpG and Aluminum hydroxide or ISCOMATRIX to a subject; however, it does not exclude the use of any sort of adjuvant in the immunogenic composition of Sidhu because Sidhu does teach an adjuvant, any adjuvant and does not teach any adjuvant that should not be used in the immunogenic composition. Sidhu’s exemplary immunizations comprising CpG and Aluminum hydroxide do not represent the whole invention of Sidhu but a small fraction of the invention.
Applicant also argues that neither Sidhu nor Davis teaches the range concentration of 0.1 to 5 mg/mL, 2.5mg/0.5 mL, about or 3.6 mg/mL, 1.8 mg/0.5 mL, about 1mg/mL, about 1.2 mg/mL CpG and CpG 24555. Applicant’s amended claims are drawn to phosphate range about 5-15mM, a range of 20mM to 100mM Sodium chloride concentration range, about or 10 mM histidine buffer and 10mM PBs buffer. However, applicants should recognize that one of skill in the art would immediately recognize the necessity to adjust buffers, buffer concentrations, replacement of buffers based on salt compositions, and the expected pH to maintain of the stability of a vaccinal formulation, which is detrimental with its efficacy. Furthermore, the examiner must point out that Sidhu does teach buffers. It is known in the art that once a vaccinal composition is altered, the pH might change, and the buffer composition must be adjusted to ultimately preserve the efficiency of the immunogenic composition. Yet, the applicant argues that Sidhu does not teach the range concentration of 0.1 to 5 mg/mL, and 0.25mg/0.5 mL, 3.6 mg/mL, 1.8 mg/0.5 mL, about 1mg/mL, about 1.2 mg/mL CpG and CpG 24555 in absence of aluminum hydroxide, and Davis does not even teach the toxoid antigens as claimed in the present invention. However, Davis teaches that the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for CpG oligonucleotides which have been tested in humans (e.g., human clinical trials have been initiated) and for compounds which are known to exhibit similar pharmacological activities, such as other adjuvants, e.g., LT and other antigens for vaccination purposes, and also teaches that one of skill in the art would know to make the adjustments of doses of CpG. Yet, the applicant argues that Davis does not teach the toxoid A/B antigens and the CpG in the same composition. However, Davis teaches an immunogenic composition with antigens and CpG 24555, and even though the applicant does not appreciate the teachings provided by the prior art, it is evident that CpG and any CpG variants, especially CpG 24555 are very well-known in the art for strongly boosting the immune response elicited by antigens. Further, Davis teaches the resources and ways on how to obtain the CpG concentrations for immunization and the used buffers. Thus, it would have been obvious to one skilled in the art to arrive at the same or similar concentrations of CpG claimed in the present invention.
Applicants argue at pg. 11-13 of the Response (filed 1 July 2026) that “The pending claims are patentably distinct from the claims of Sidhu and are nonobvious in view of Davis and Middaugh. The claims of Sidhu are directed to different subject matter and do not recite or require (i) any CpG adjuvant, (ii) any CpG adjuvant having a concentration of 0.1 to 5 mg/mL CpG, or (iii) the exclusion of aluminum hydroxide from a CpG-containing composition. These limitations distinguish the pending claims from the claimed subject matter of Sidhu.
Applicant’s arguments have been fully considered, but not persuasive. The examiner must remind the applicant that obviousness/rationale was used to make the double-patenting rejections. Sidhu is the primary prior art used for the double-patenting rejection, because US Patent No. US 8481692 B2 claims all the structural elements of the immunogenic composition claimed in the present invention, including the use of any adjuvants in the composition. Furthermore, Davis and Middaugh support the motivation/rationale of one skilled in the art to modify the claims of US Patent No. US 8481692 B2 (Sidhu) thereby arriving to the claims of the present invention. The applicant should recognize that US Patent No. US 8481692 B2 (Sidhu) discloses the SEQ ID NO: 84, 4 which is Clostridium difficile toxin A, and a composition comprising same and an adjuvant. See '692, claims 1-2, 8, 20 for example. Patent '692 also claims that toxoid B (SEQ ID NO: 86, 6), should be included in the same composition; see claims 9-10. Patent '692. US ‘692 does not recite any adjuvant that should not be used as claim 20. However, US Patent No. US 8481692 B2 (Sidhu) does not specifically claim CpG or CpG 24555.
Furthermore, Davis (U.S. Patent No. 8552165 B2) teaches 0.833 mg/ml CpG 24555; see column 40 lines 20-27; Patent '165. Davis (U.S. Patent No. 8552165 B2) provides guidance on how to optimize the dose of the CpG; see column 27; lines 27-67; column 28; lines 1-46. Patent '165 Davis (U.S. Patent No. 8552165 B2) teaches Immunoregulatory oligonucleotides. teaches CpG; CpG24555 see for example, figure 1. Patent '165. However, it is also evident that Middaugh (WO 2009035707 A1) teaches compositions including toxoid A and toxoid B, total amount of toxoid A and B in the compositions, (e.g. 1-250 ug) and the buffers already taught by Sidhu. See ‘707 claim 6.
Yet, Applicant argues at the Response (filed 1 July 2026) that “The pending claims are patentably distinct from the claims of the '883 application and are nonobvious in view of Davis and Middaugh. The claims of the '883 application are directed to methods of administering C. difficile compositions and do not recite or require (i) any CpG adjuvant, (ii) any CpG adjuvant having a concentration of 0.1 to 5 mg/mL CpG, or (iii) the exclusion of aluminum hydroxide from a CpG-containing composition. These limitations distinguish the pending claims from the claimed subject matter of the '883 application”.
Applicant arguments have been fully considered, but not persuasive. Because Davis teaches a guide on how to use the stimulatory oligonucleotides, CpGs and examples of immunogenic compositions comprising CpGs, including CpG24555. Davis teaches immunogenic compositions comprising only CpG. Davis does not teach an example of a specific composition comprising Toxoid A/B, however Middaugh teaches the ratios of toxoid a/B, concentrations, compositions, doses, buffers, salts, pHs, formulations, and doses.
Therefore, it would have been obvious to one skilled in the art to combine the teachings of Sidhu, Davis and Middaugh because Sidhu teaches the immunogenic composition comprising Toxoid A/B and an adjuvant, Davis teaches immunostimulatory oligonucleotides, CpG ODN such as CpG 24555 in combination with antigens, and a guidance regarding the use of CpG and Middaugh teaches compositions comprising Toxoid A/B, antigen concentrations and vaccinal formulations comprising Toxoid A/B, including buffers.
It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon 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).
See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Furthermore, in response to applicant's argument that the examiner's conclusion of obviousness is based upon “most fairly be described as teachings” reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon straightforward evidences. 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).
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Furthermore, In re Kerkhoven (205 USPQ 1069, CCPA 1980) summarizes:
"It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for the same purpose in order to form a combination that is to be used for the very same purpose: the idea of combining them flows logically from their having been individually taught in the prior art."
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain 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".
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was filed to combine any adjuvants with the immunogenic composition of Sidhu because Sidhu does not only teach the combination, CpG and aluminum hydroxide but also teaches other adjuvants that could be used in the composition and does not specific any adjuvant that should not be used.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Advisory Information
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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