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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application is a continuation of PCT/US2022/023029 filed on 04/01/2022 and claims domestic benefit to US provisional application no. 63/170,250 filed on 04/02/2021.
Status of the Claims
The claim amendments and remarks filed on 07/07/2026 is acknowledged. Claims 1, 13-14, 19, 44, and 75 are amended. Claims 3-4, 6-7, 9, 15-16, 20-21, 23-29, 31-37, 39-43, 45-50, 52-74, and 76-95 are cancelled.
Accordingly, claims 1-2, 5, 8, 10-14, 17-19, 22, 30, 38, 44, 51, and 75 are pending and being examined on the merits herein.
Withdrawn Rejections
The cancellation of claims 15 and 28 renders the prior art rejections over these claims moot.
The 35 USC 102 rejection over Oberli for claims 1, 18, 38, 44, and 51 and over Adamo for claims 1, 8, 18-19, 38, and 51 are withdrawn because the instant claims now require a new limitation in which PSII has an average molecular weight of at least 5 kDa, which was not previously considered in this rejection.
The 35 USC 103 rejection over Oberli in view of Scarselli for claims 1-2, 5, 10-14, 17, and 22 and over Adamo in view of Levine claims 1 and 30 are withdrawn because the instant claims now require a new limitation in which PSII has an average molecular weight of at least 5 kDa, which was not previously considered in this rejection.
The 35 USC 103 rejection over Dhere for claim 75 is withdrawn because the recited method now requires new limitations of utilizing DOC stripping followed by sequential ethanol and TCA precipitations, hydrophobic interaction chromatography, and anion exchange chromatography, which was not previously considered in this rejection.
The following grounds of rejection are new as necessitated by Applicant’s amendments.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites “wherein the cell-surface polysaccharide from C. difficile is an anionic cell-surface polysaccharide”.
Claim 8 depends from claim 1. Claim 1 recites “a cell-surface polysaccharide of Clostridiodes difficile (C. difficile), wherein the cell-surface polysaccharide comprises PSII …”.
Claim 8 fails to further limit the subject matter of the claim upon which it depends because as evidenced by Adamo et al. (ACS Chemical Biology, 2012 in PTO-892 dated 04/07/2026), the recited PSII in claim 1 is inherently a polyanionic polysaccharide (second to last paragraph left column page 1421).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 8, 18-19, 22, 38, and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Costantino et al. (US20130315959A1 in IDS filed 06/20/2024) and as evidenced by Adamo et al. (ACS Chemical Biology, 2012 in PTO-892 04/07/2026).
Costantino discloses the preparation of vaccines that contain bacterial saccharides from Clostridium difficile as well as methods of purifying bacterial saccharides (paragraph 0001).
Costantino demonstrates the purification of C. Difficile PS-II polysaccharides from C. Difficile bacterial cells (paragraphs 0315-0321). Constantino discloses that the Stoke-Mandeville strain was selected due to being the best producer and as evidenced by Adamo, Stoke-Mandeville strain is also referred to as ribotype 027 (first paragraph right column page 1422). Furthermore, Adamo provides evidence that native PSII is a polyanionic polysaccharide (second to last paragraph left column page 1421). Constantino provides a schematic of the purification process in Scheme 10 and Table 5 (paragraph 0316). One of the steps involves a tangential flow filtration (TFF) with membrane 5 kDa-cut off to concentrate the PS-II as disclosed in Table 5. This TFF purification step indicates that the purified PS-II have a molecular weight of at least 5 kDa or greater. Constantino discloses that this purification process resulted in low amounts of impurities in which less than 1% w/v protein was detected according the Bradford analysis and 1-3.5% w/v protein content according the HPAEC-PAD analysis (paragraph 0318 and Table 6). Constantino notes that the MicroBCA assay overestimated the amount of protein impurities due to interference by the mannose reducing sugar (paragraph 0318).
Constantino further demonstrates conjugating this purified PS-II to CRM197 (paragraphs 0322-0328). Constantino shows in Table 7 (paragraph 0328) the average degree of polymerization of the PS-II saccharhide as well as the mol/mol of PS-II / CRM197 conjugation, in which the conjugate A had an average degree of polymerization of 8 and a PS-II / CRM197 mol/mol ratio of 2.07.
Constantino illustrates in Figure 8 the structure of this PS-II CRM197 conjugate shown below:
This hexasaccharide unit structure is identical to the Formula (l) structure recited in instant claim 19. Furthermore, the conjugate B disclosed in Table 7 (paragraph 0328) has a degree of polymerization of 8, which corresponds to a n number of 8 in this Formula (l) structure.
Constantino further demonstrates immunization studies in which mice were administered via intraperitoneal injection a 2.5 ug dosage of this PS-II CRM197 conjugate with MF59 and AlumOH as adjuvants. Injections were carried at 0, 21, and 35 days (paragraph 0329-0330).
Therefore, instant claims 1, 8, 1819, 22, 38, and 44 are anticipated.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Costantino et al. (US20130315959A1 in IDS filed 06/20/2024) and as evidenced by Adamo et al. (ACS Chemical Biology, 2012 in PTO-892 04/07/2026).
The teachings of Costantino are as described above and teach the composition of instant claim 1, as evidenced by Adamo, as discussed above.
Furthermore, Constantino demonstrates immunization studies in which mice were administered via intraperitoneal injection a 2.5 ug dosage of this PS-II CRM197 conjugate with MF59 and AlumOH as adjuvants. Injections were carried at 0, 21, and 35 days (paragraph 0329-0330). Constantino shows in Fig. 12 that the PSII CRM197 conjugate induced a very high anti-PSII IgG response in all immunized mice for both AlumOH and MF59 as adjuvant (paragraph 0335).
Constantino further teaches that their compositions can be administered by intravenous, intramuscular, or other modes of administration with intramuscular injection to the thigh or upper arm being preferred (paragraph 0201). Constantino teaches that dosage treatment can be a single dose schedule or a multiple dose schedule (paragraph 0203). Constantino teaches that multiple doses may be used in a primary immunization schedule and/or in a booster immunization schedule (paragraph 0203). Constantino teaches that a primary dose schedule may be followed by a booster dose schedule and that suitable timing between priming doses (e.g. between 4-16 weeks), and between priming and boosting, can be routinely determined (paragraph 0203).
Even though Constantino does not demonstrate intravenous or intramuscular administration, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified the method of Constantino for intravenous or intramuscular administration as disclosed in Constantino with a reasonable expectation of success because Constantino provides guidance that their compositions can be administered via intravenous or intramuscular injection.
Furthermore, an ordinary skilled artisan would have been able to routinely optimize and determine the optimal dosing interval and arrive at the claimed weekly or biweekly dosing intervals based on Constantino disclosing that their compositions can be administered as a multiple dose schedule in which the timing between each dosage can be routinely determined as well as demonstrating injecting the composition at Day 21 and Day 35 (bi-week) as described above. See MPEP 2144.05 II.
Claim(s) 2, 5, 10-14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Costantino et al. (US20130315959A1 in IDS filed 06/20/2024) and as evidenced by Adamo et al. (ACS Chemical Biology, 2012 in PTO-892 04/07/2026), as applied to claim 1 above, and further in view of Scarselli et al. (US20150132333A1 in PTO-892 dated 04/07/2026).
The teachings of Costantino are as described above and teach the composition of instant claim 1, as evidenced by Adamo, as discussed above.
Costantino, however, does not teach further comprising a recited second and third polypeptide in the recited ratios.
Scarselli discloses recombinant fragments of C. difficile TcdA and TcdB that may be used in the development of vaccines against C. difficile associated disease (Abstract).
Scarselli discloses their immunogenic composition comprises a ToxB (TcdB)-GT antigen comprising a polypeptide comprising an amino acid sequence 80% or more identical to a fragment of at least 7 consecutive amino acids of SEQ ID NO:18 or SEQ ID NO: 60 wherein the fragment comprises an epitope of SEQ ID NO:18 or SEQ ID NO: 60; and a ToxA (TcdA)-P5-6 antigen comprising an amino acid sequence 80% or more identical to SEQ ID NO:11 (claim 1). Scarselli discloses that their composition can further comprise one or more additional antigens such as a full length TcdB antigen (Toxoid B) (SEQ ID NO: 2) and a full-length TcdA antigen (Toxoid B) (SEQ ID NO:1) and others (claim 33). SEQ ID NO: 2 and SEQ ID NO: 1 of Scarselli contains the same sequences in instant SEQ ID NO: 1 and SEQ ID NO: 4, respectively. Scarselli discloses that at least two of the antigens comprise a hybrid (fused) polypeptide (claim 35).
Scarselli discloses their compositions comprise additional adjuvants including aluminum salts, complete Freund’s adjuvant, and others (paragraph 0196). Scarselli discloses that the use of an aluminum hydroxide and/or aluminum phosphate adjuvant is particular preferred, and antigens are generally adsorbed to these salts (paragraph 0212).
Scarselli discloses that a combination of full length inactivated Toxoid A and Toxoid B was used as a positive control, and that this combination may be considered to represent a “gold standard” against which the combinations of the invention may be compared (paragraph 0371). Scarselli demonstrates that hamsters were immunized with each Toxoid at 5 ug dosages adjuvanted with MF59 (paragraph 0372), and that immunization with full length Toxoid A and B protected 83% of hamsters against the B1 strain (paragraph 0374).
It would have been prima facie obvious before the effective filing date of the claimed invention to have combined the 2.5 ug PS-II CRM197 conjugate composition of Constantino with the immunogenic compositions of Scarselli such as the composition comprising Toxoid A + Toxoid B at 5 ug each to arrive at the claimed invention.
One of ordinary skill in the art would have combined these compositions with a reasonable expectation of success because both Constantino and Scarselli teach compositions that are useful for the same purpose as a vaccine against C. difficile infection. See MPEP 2144.06.
In regards to instant claim 10, it would have been prima facie obvious before the effective filing date of the claimed invention to have fused a toxoid A antigen and a toxoid B antigen as disclosed in Scarselli in the combined compositions of Constantino and Scarselli described above.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and have a reasonable expectation of success in doing so because Scarselli provides guidance of forming hybrid (fused) polypeptides with any two of their disclosed toxoid A and toxoid B antigens.
Claim(s) 30 is rejected under 35 U.S.C. 103 as being unpatentable over Costantino et al. (US20130315959A1 in IDS filed 06/20/2024) and as evidenced by Adamo et al. (ACS Chemical Biology, 2012 in PTO-892 04/07/2026), as applied to claim 1 above, and further in view of Levine et al. (US20130129776A1 in PTO-892 dated 04/07/2026).
The teachings of Costantino are as described above and teach the composition of instant claim 1, as evidenced by Adamo, as discussed above.
Furthermore, Costantino teaches that their PS-ll saccharides can be conjugated to the carrier molecule via a linker (paragraph 0021 and 0102). Constantino teaches that any suitable conjugation reaction can be used with any suitable linker where necessary and further discloses that the attachment of the saccharide to the carrier is preferably via a —NH2 group e.g. in the side chain of a lysine residue in a carrier protein as well as via a -SH (thiol) in the chain of a cysteine residue, or of an arginine residue (paragraph 0103). Constantino discloses that the linker is attached via the α-O-position at the reducing terminal saccharide of the PS-II saccharide (paragraph 0040), and that the linker be a 1-aminopropyl group and further discloses that a type of linkage can involve reductive amination of the polysaccharide, coupling the resulting amino group with one end of an adipic acid linker group, and then coupling a protein to the other end of the adipic acid linker group (paragraph 0040). Constantino further discloses other linker types such as B-propionamido, nitrophenyl-ethylamine, haloacyl halides, glycosidic linkages, 6-aminocaproic acid, ADH, and C4 to C12 moieties (paragraph 0040).
Even though Costantino teaches the conjugation of the PS-II to the CRM197 carrier using a chemical linker, Costantino does not teach the chemical linker comprises a thiosuccinimide or thioester.
Levine discloses vaccines comprising a hapten antigen conjugated to a carrier antigen, wherein at least one of the hapten antigens or carrier antigens is characteristic of the Salmonella enterica serovar. (Abstract). Levin discloses that the hapten is a polysaccharide from the Salmonella enterica serovar (COPS) (claim 4), and the carrier is a phase 1 flagella protein (FliC) or an antigenic fragment or derivative thereof from the Salmonella enterica serovar (claim 3).
Levine discloses that the hapten and carrier can be conjugated using known techniques and methods via coupling of available functional groups (such as amino, carboxyl, thio and aldehyde groups) (paragraph 0151). Levine discloses that the hapten and carrier can be chemically manipulated to bear functional groups, and that the presence of functional groups such as amino groups, carboxyl groups, aldehydes, hydrazides, epoxides, and thiols can facilitate covalent conjugation (paragraph 0152). Levine discloses that the use of various conventional crosslinking agents to conjugate the hapten and carrier including N-hydroxysuccinimide ester, GMBS (N-(-maleimidobutyryloxy)succinimide ester), and others (paragraphs 0157-0158).
Levine demonstrates the conjugation of COPS by aminooxy thio-ether chemistry, resulting in conjugates in which the carboxyl group present at the KDO terminus on COPS are conjugated at the polysaccharide terminus to one or more available lysine residues on the protein (paragraph 0280 and 0295). Here, COPS was thiolated via diaminooxy cysteamine, and the flagellin carrier was activated using sulfo-GMBS linker, and then conjugated together. The coupling chemistry described here results in a linker comprising a thiosuccinimide since the carboxyl group of the COPS is thiolated, and the carrier contains GMBS (succinimide ester linker).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the linking chemistry for the PS-II CRM197 conjugate disclosed in Costantino with the aminooxy thio-ether conjugation chemistry of Levine to link the PS-II to the CRM197 and arrive at the claimed invention.
One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Levine demonstrates the conjugation of a similar polysaccharide and carrier protein using known conventional conjugation techniques including the aminooxy thio-ether chemistry to conjugate a modified polysaccharide to the lysine residues on the protein, and Constantino also provides guidance of conjugating the PS-II polysaccharide to a protein carrier using known linker chemistries by conjugating the polysaccharide to the —NH2 group e.g. in the side chain of a lysine residue in the protein carrier.
Claim(s) 75 is rejected under 35 U.S.C. 103 as being unpatentable over Costantino et al. (US20130315959A1 in IDS filed 06/20/2024) in view of Dhere et al. (EP3789494A1 in PTO-892 dated 04/07/2026).
The teachings of Costantino are as described above.
Costantino discloses a method of purifying C. difficile PS-II cell wall saccharide from C. difficile bacterial cells (paragraphs 0065-0094 and 0315-0321).
Costantino discloses the C. difficile bacterial cells are obtained by fermentation (paragraph 0065) and may be centrifuged prior to release of saccharide (paragraph 0066) and may therefore start with bacterial cells in the form of a wet cell paste, which meets the step (a) limitation of obtaining a cell-surface extract of one or more strains of C. difficile.
Costantino further demonstrates in Table 5 (pages 34-35) the purification steps for the PS-II. First, protein contaminants were removed via CaCl2 and ethanol precipitation, nucleic acids were removed via enzymatic treatment (DNase, RNase, and Mutanolysin), then enzymes contaminants were removed via CaCl2 and ethanol precipitation. After, the precipitated PS-II was further purified using chromatography (anionic exchange and fractogel Q resin), concentrated using tangential flow filtration (TFF) with 5 kDa membrane cut-off, and then underwent further chromatography to remove positive charge containments (cationic exchange) and low molecular weight contaminants (size exclusion).
Constantino teaches a method of enriching for PS-II of C. difficile comprising the recited step (a) limitation of obtaining a cell-surface extract of C. difficile strain and further utilizing ethanol precipitation and anion exchange chromatography.
However, Constantino does not teach utilizing sodium deoxycholate (DOC) stripping followed by trichloroacetic acid (TCA) precipitation as well as hydrophobic interaction chromatography.
Dhere discloses a method for obtaining purified bacterial polysaccharides (Abstract).
Dhere discloses that the obtained purified polysaccharide can be from any bacteria including Clostridium difficile and others (paragraph 0062).
Dhere discloses their purification method comprises steps such as (a) providing a fermentation harvest comprising bacterial cell; (b) treating the fermentation harvest with a lytic agent to obtain a mixture of polysaccharide, proteins, nucleic acid and cell debris … (e) treating the concentrated and filtered cell free supernatant of step (d) with an acid having concentration in the range of 2 M to 5M at 20 °C to 60 °C and pH in the range of 0.1 to 2; and other purification/filtration steps to obtain purified and sized polysaccharide having protein content less than 3 % nucleic acid content and less than 2% CWP (paragraph 0080).
Dhere discloses the acid is selected from trifluoroacetic acid, trichloroacetic acid, and others (claim5 in Dhere), and that the lytic agent can be a chemical lytic agent such as deoxycholate sodium (DOC) and others (paragraph 0087).
Dhere discloses that the acid treatment step precipitates the impurities such as proteins and nucleic acids (paragraph 0070).
Dhere further discloses that their method may also comprise a step of treatment with one or more chemical/biological reagent at any stage of the method such as alcohol (ethanol, isopropanol), and others (claim 19 in Dhere and paragraph 0095).
Dhere discloses that their method may also include at least one chromatography step to obtain the purified and sized polysaccharide such as ion-exchange (cationic or anionic) hydrophobic-interaction, and others (paragraph 0095).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the purification process of Constantino by further including the sodium dexocyholate (DOC) as a lytic agent prior to removing impurities via precipitation as disclosed in Dhere and further including trichloroacetic acid (TCA) in the precipitation steps to remove the impurities as disclosed in Dhere as well as including a hydrophobic-interaction chromatography step to further purify the polysaccharides as disclosed in Dhere to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both Constantino and Dhere discloses a purification process to obtain purified bacterial polysaccharides such as from C. difficile that involves the same steps of removing contaminants present in the bacterial cell using reagent precipitation steps as well as chromatography steps to further purify.
Furthermore, the ordinary skilled artisan would have been able to routinely optimize and arrive at the sequential order of ethanol and TCA precipitation based on guidance from Dhere which teaches that the additional chemical/biological reagent treatment step such as ethanol can be performed at any stage of the purification method. See MPEP 2144.05 II. Also, MPEP 2144.04 IV C states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”.
Response to Arguments
Applicant’s arguments filed on 07/07/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant presents several arguments against the primary reference teachings of Oberli and Adamo, however Oberli is not cited in the new rejections, and Adamo is only used as evidence to show that the Stoke-Mandeville strain is also known as ribotype 027, and that native PS-II is an anionic polysaccharide. Therefore, Applicant’s arguments over these references are rendered moot.
Applicant states that the combination of the specific polysaccharide polymer of at least 5 kDa with recombinant toxoids at the claimed weight ratios (using CRM197 as the carrier) yields highly unexpected, synergistic protective immunity. Applicant points to FIGs. 20, 22, 26, and 29 as well as paragraphs 0236 and 0253-254 of the published application. Applicant states that immunization with the PSII-CRM197 conjugate alone did not prevent substantial weight loss or death in severe spore challenge models, whereas the conjugate combined recombinant toxoids (TcdA and TcdB) at the claimed ratios provided complete protection against weight loss and death.
In response to the showing of unexpected results, it is first noted that the showing of unexpected results cannot be used to overcome an anticipation rejection. See MPEP 2131.04. Therefore, since instant claims 1, 8, 18-19, 22, 38, and 44 are anticipated over Constantino as discussed above, Applicant’s arguments of unexpected results are rendered moot over these claims.
Furthermore, MPEP 716.02(e) states that the claimed subject matter must be compared with the closest prior art to be effective to rebut a prima facie case of obviousness.
In this case, the closest prior arts are Constantino and Scarselli. As described above, Constantino teaches compositions comprising the recited PSII-CRM197 conjugate with AlumOH and MF59 as adjuvants but does not teach or suggest including the recited second and third polypeptides that are either a toxoid of C. difficile toxin A or B. Furthermore, Scarselli teaches composition comprising the recited second and third polypeptides (Toxoid A and B) with MF59 as adjuvant as described above but does not teach the PSII-CRM197 conjugate.
Applicant has demonstrated in FIG. 22 and 29-31 that composition 1 (45 ug PSII-CRM197 and 5 ug each of toxoid A and B) with AlPO4, AlOH, and Advax as adjuvants resulted in less body weight loss compared to the PSII-CRM197 conjugate and the Toxoid A+B administered individually.
Furthermore, Applicant has demonstrated in Tables 16 and 18 (pages 33-34) that the composition 1 with AlPO4 and AlOH as adjuvants induced greater anti-TxdA IgG compared to the 5 ug each Toxoid A/B and conjugate alone, and the composition 1 with AlOH as adjuvant induced greater anti-TxdB IgG compared to the 5 ug each Toxoid A/B and conjugate alone.
While Applicant appears to have demonstrated that the combined conjugate and Toxoid A/B composition with AlPO4 and AlOH as adjuvants induced less bodyweight loss and greater titer of anti-TxdA or anti-TxdB compared to the conjugate or Toxoid A/B alone, Applicant has not provided comparisons of formulations with MF59 as an adjuvant, which is within scope of the claims and an adjuvant used in the compositions of Constantino and Scarselli. The data from Applicant suggests that the type of adjuvant in the compositions is important as the combined compositions with Advax as the adjuvant does not appear to induce the alleged effects. In Fig. 29, the composition 1 with Advax had more body weight loss than the Toxoid A/B alone, and in Tables 16 and 18, the composition 1 with Advax induced about the same titer for anti-TxdA and significantly less titer for anti-TxdB compared to the Toxoid A/B alone.
Therefore, it is difficult to ascertain whether Applicant’s alleged unexpected results apply over the closest prior arts (Constantino and Scarselli) because these compositions included MF59 as an adjuvant, and Applicant has not provided comparative data for compositions with a similar adjuvant.
Furthermore, Applicant’s showing of unexpected results is not commensurate in scope with the instant claims.
MPEP 716.02(d) states that “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support” and “The nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof …”.
It is first noted that claim 51 does not require the Toxoid A and B as well as the adjuvant component, and Applicant’s data and alleged unexpected results are based on the combination of the recited PSII-CRM197 conjugate and Toxoid A/B with either AlPO4 or AlOH as adjuvants.
Furthermore, claims 2 and 5 do not recite an adjuvant and also do not limit the amount of the recited second and third polypeptide and also recite that these polynucleotides can be a fragment thereof.
Applicant has only provided data using 5 ug each of Toxoid A and B, and there is no further disclosure or suggestions in the disclosure that would allow an ordinary skilled artisan to reasonably determine that any amount of the recited second and third polynucleotide as well as any fragment thereof will result in the alleged unexpected effects. While claims 13-14 do narrow to specified ratios for the conjugate and either the recited second or third polynucleotide, it cannot be reasonably determined whether Applicant’s alleged unexpected results would apply over the recited ratios because Applicant has only provided one embodiment of the combination (45 ug PSII-CRM197 and 5 ug each of toxoid A and B).
Applicant states that there is no motivation and no reasonable expectation of success to apply the linking chemistry of Levine to a C. difficile PSII-CRM197 conjugate because Levine discloses linking a flagellin protein carrier which functions different than the CRM197 carrier.
Applicant’s arguments described above was not found persuasive because MPEP 2143 states that “an explicit analysis does not require record evidence of an explicit teaching of a motivation to combine in the prior art … [T]he analysis that “should be made explicit” refers not to the teachings in the prior art of a motivation to combine, but to the court’s analysis ... Under the flexible inquiry set forth by the Supreme Court, the district court therefore erred by failing to take account of ‘the inferences and creative steps,’ or even routine steps, that an inventor would employ and by failing to find a motivation to combine related pieces from the prior art”.
In this case, Levine demonstrates the conjugation of a polysaccharide to the lysine residue of the flagellin protein carrier using the aminooxy thio-ether chemistry, and Constantino also provides guidance of conjugating the PS-II polysaccharide to the CRM197 protein carrier using known linker chemistries such as to the —NH2 group e.g. in the side chain of a lysine residue in the protein carrier. Therefore, the ordinary skilled artisan would have substituted the linking chemistries with a reasonable expectation of success since both references teach linkages of a polysaccharide to the lysine residue of the protein carrier.
Applicant presents arguments against the teachings of Dhere for instant claim 75 on the basis that Dhere fails to teach the new method limitations of DOC stripping following by sequential ethanol and TCA precipitations, and hydrophobic interaction and anion exchange chromatography.
However, the new rejection is now over Constantino in view of Dhere and this combination of references provides guidance to arrive at the new method steps as discussed above.
Conclusion
No claim is found allowable.
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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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
