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
This office action is a response to applicant’s communication submitted January 23, 2026, wherein claim 3 is amended, claims 1, 2, and 5-7 are canceled, and new claims 9 and 10 are introduced. This application is a continuation of US application 16/823290, now US patent 11173199, filed March 18, 2020, which claims benefit of provisional application 62/934925, filed November 13, 2019.
Claims 3, 4, and 8-10 are pending in this application.
Claims 3, 4, and 8-10 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted January 23, 2026, with respect to the rejection of claims 1 and 2 under 35 USC 112(b) for reciting a broad range followed by a narrow range, has been fully considered and found to be persuasive to remove the rejection as claims 1 and 2 have been canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, submitted January 23, 2026, with respect to the rejection of claims 1-8 under 35 USC 112(b) for indefinitely reciting a process step in a claim directed to a composition of matter, has been fully considered and found to be persuasive to remove the rejection as the claims have been amended to describe the limitation as a property of the composition. Therefore the rejection is withdrawn.
The following rejections of record in the previous action are maintained:
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 3, 4, and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pier et al. (US patent 8492364, cited in PTO-1449) in view of Li Shihui et al. (Foreign publication CN108003225A, Reference and English machine translation included with PTO-1449, all citations herein are to the English machine translation)
Independent claim 3 claims a vaccine composition wherein the vaccine is a conjugate (A-B)x-C, wherein A is a possibly N-acetylated oligo-1,6-glucosamine oligosaccharide, B is a specific linker structure, and C is a tetanus toxoid carrier protein. This claim further defines the number of conjugated oligosaccharides, the length of the oligosaccharides, their degree of acetylation, the number of oligosaccharides attached to the tetanus toxoid, and the portion of the tetanus toxoid that is in monomeric form. Dependent claim 4 more specifically defines A as a non-acetylated pentasaccharide. Dependent claim 8 defines the amount of oligosaccharide-linked contaminants.
Regarding the elected species of heterogeneous compositions, this is interpreted to include any vaccine wherein there are more than one single species of oligosaccharide-TT conjugate, for example differing in the value of x, y, or the number of position of acetyl groups.
Pier et al. discloses vaccines comprising bacterial oligosaccharide antigens, for raising immune responses to infections including Staphylococcal infections. (column 2 lines 21-33) In one embodiment the oligosaccharide is an optionally acetylated oligo-beta-(1,6)-D-glucosamine. (column 2 lines 35-53) Pier et al. further discloses embodiments wherein the length of the oligosaccharide is 2-20 monomers, for example 5-11 monomers, and can be 0% acetylated. (column 4 line 32-40) Pier et al. further discloses conjugating the oligosaccharide to the carrier with a linker having the same structure B recited in the claims. (column 4 lines 41-55) In one embodiment the carrier is tetanus toxoid. (column 5 lines 28-30) Pier further discloses various ratios of oligosaccharide to carrier including 30:1, which falls within a reasonable interpretation of “about 31” and 40:1, which falls within a reasonable interpretation of “about 39” as recited in the present claims.
In view of the various characteristics of the conjugates described by Pier et al., one of ordinary skill in the art would have found it to be obvious to make a conjugate of poly-glucosamine and tetanus toxoid having the claimed linker and the specific characteristics recited in the present claims. One of ordinary skill in the art would have seen these conjugates as suggested by the various specific characteristics exemplified by the disclosure of Pier et al. Furthermore with respect to the definitions of x and y in the present claims, according to MPEP 2144.05, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” Therefore the disclosures of ranges of oligosaccharide length or copy number which encompass the presently claimed ranges would render said claimed amounts obvious.
Pier et al. does not specifically disclose the relative amounts of monomer and non-monomer tetanus toxoid. However, Li Shihui et al. discloses that there is a need for a method of obtaining tetanus toxoid with high monomer content. (p. 2 third paragraph) Li Shihui further discloses a method for purifying tetanus toxoid with improved monomer content, for use as a carrier for conjugate vaccine. (p. 2 fourth paragraph) By this method the monomer purity can be increased to above 95%. (p. 3 first paragraph) The monomer content is further disclosed to significantly affect the immunogenicity of the conjugate vaccine. (p. 5 paragraph 5) Example 3 on p. 8 (first paragraph) furthermore discloses purification of a sample having a monomer purity of 97.36% and a dimer content of 2.64%. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to use a highly pure TT monomer in the conjugates described by Pier et al. One of ordinary skill in the art would have been motivated to do so because Li Shihui specifically discloses that higher monomer purity and lower amounts of non-monomer (e.g. dimer) species is desirable to improve the immunogenicity of the conjugate vaccine.
Regarding the limitation requiring that the composition “is stable against oligomerization and denaturation of the toxoid at a temperature between 2OC to 8OC,” this limitation as presently written describes a property of the claimed composition rather than a structural feature. Specifically, while the claims do not require that the composition itself presently be at a particular temperature, they require that the composition be stable against oligomerization and denaturation over extended periods of storage at the claimed temperature range. However, as disclosed by Ho et al., Xing et al., and Parveen et al. (References included with PTO-892) temperatures of 2-8OC are already recommended for storage of tetanus toxoid conjugate vaccines. In particular, Parveen et al. discloses that prior art tetanus toxoid vaccine formulations maintained safety, efficacy, and physicochemical characteristics after prolonged storage at 2-8C. (see p. 1273 table 1, p. 1274 tables 2-3) Xing et al. discloses that a prior art tetanus toxoid formulation retains its antigenicity during 80 days of storage at 4OC. Furthermore looking to the disclosure of the present application, (e.g. p. 8 paragraph 29) it appears that the stability described in the present disclosure is merely a property of the temperature at which it is maintained, rather than requiring some particular structural feature of the composition. Overall, the preponderance of the evidence indicates that this limitation is simply describing a property of existing tetanus toxoid formulations rather than requiring some positive structural difference that would distinguish the claimed formulations from other tetanus toxoid conjugate vaccines.
Regarding the limitation in claim 3 requiring that the amount of low detectable impurity in the composition be less than a certain percent, paragraph 30 on p. 8 of the present specification defines the detectable impurity as various compounds with a mw under 1000 that arise from toxoid degradation and are present in the tetanus toxoid composition. It is reasonably expected that the purification method described by Li Shihui, which separates the TT components by size, would remove any such contaminants originally present in the TT composition. (e.g. protein fragments) Furthermore the aforementioned example 3 form this reference specifically states that the monomer content is 97.36% and the dimer content is 2.64%, thereby leaving no room for additional components such as fragments of TT or other low molecular weight amines. Still further the purification protocol used to isolate this monomer involved elution from a gel chromatography column using an elution solution containing only phosphate buffer and sodium chloride, neither of which is a detectable impurity as defined in the present specification.
Regarding the limitation in claim 8 describing the amount of oligosaccharide-linked contaminant, paragraph 31 on p. 8 of the specification as originally filed defines these contaminants as being adducts of amine-containing degradation products of tetanus toxoid with the oligosaccharide. For the same reasons discussed above, it is reasonably concluded that the purified TT composition described by Li Shihui et al. contains at most trace amounts of such contaminants and would therefore meet this claim limitation.
Regarding claims 9 and 10, these claims require the presence of an adjuvant in the composition. Column 19 lines 43-63 of Pier et al. discloses the inclusion of an adjuvant in the composition, for example aluminum hydroxide, Freund’s adjuvant, or attenuated M. tuberculosis, for example, thereby infringing the limitations of these claims.
For these reasons the invention taken as a whole is prima facie obvious.
Double Patenting
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 3, 4, and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11173199 (Cited in PTO-1449, herein referred to as ‘199)
Claim 1 of ‘199 claims a composition comprising a pharmaceutically effective amount of a conjugate of the same formula (A-B)x-C, having the same structure as the conjugates recited in present claims 1-3 and values of x and y walling within the scope of present claims 1-3 and substantially overlapping those recited in present claim 5. This claim further requires that the composition have less than 3 wt% detectable impurities having a mw of less than 500000, which would include the detectable impurities recited in the present claims. Dependent claims 2-4 of ‘199 further define R, X, and y in manners that infringe or overlap with the present claims. Dependent claims 5 and 6 of ‘199 further define the same limitations regarding oligomerization and denaturation recited in the present claims. Dependent claim 7 of ‘199 recited the same specific limitation regarding oligosaccharide-linked contaminants recited in present claim 8. Dependent claim 8 of ‘199 specifically claims a conjugate where y is 3, x is 40, C is tetanus toxoid, and the oligosaccharide is a nonacetylated pentasaccharide.
Claims 3, 4, and 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 7 of U.S. Patent No. 10828360 (Cited in PTO-1449, herein referred to as ‘360) in view of Li Shihui et al. (Foreign publication CN10803225A, Reference and English machine translation included with PTO-1449, all citations herein are to the English machine translation)
Claim 1 of ‘360 claims a method utilizing a conjugate of the same formula (A-B)x-C, having the same structure as the conjugates recited in the present claims and values of x and y substantially overlapping those recited in the claims. Dependent claims 2-3 further refer to a pharmaceutical composition comprising this conjugate and a diluent. Dependent claim 7 further defines C as a tetanus toxoid.
While the claims of ‘199 do not specifically state that the tetanus toxoid comprises monomer and dimer with less than 5% of higher oligomers, as required by the present claims, as discussed above under 35 USC 103, Li Shihui discloses increasing the monomer and dimer content to these levels and suggests that doing so is useful for making immunogenic conjugates. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to specifically make the conjugates described in the claims of ‘199 with a higher monomer content, in view of the suggestion that this would improve the immunogenicity of the conjugate.
Claims 3, 4, and 8 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-9 of copending Application No. 17/638732 (US pre-grant publication 2022/0280629, of record in previous action, herein referred to as ‘732)
Claims 1-3 of ‘069 claim a compound comprising a conjugate of the same formula (A-B)x-C, having the same structure as the conjugates recited in the present claims and values of x and y substantially overlapping those recited in the claims. Dependent claim 3 further defines the oligosaccharide as a nonacetylated pentasaccharide. Still further dependent claim 4 of ‘732 further defines the amount of non-monomeric toxoid as at most 5 percent. Finally, dependent claims 6-9 of ‘732 claim a pharmaceutically acceptable composition comprising said conjugate, and furthermore limiting the amount of low molecular weight amino compounds in the composition in the same manner as recited in the present claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of copending Application No. 17/777828 (US pre-grant publication 2023/0053458, cited in PTO-892, herein referred to as ‘828) in view of Pier et al. (US patent 8492364, cited in PTO-1449) in view of Li Shihui et al. (Foreign publication CN10803225A, Reference and English machine translation included with PTO-1449, all citations herein are to the English machine translation)
Claim 1 of ‘828 claims a method utilizing a conjugate of the same formula (A-B)x-C, having the same oligosaccharide and tetanus toxoid as the conjugates recited in the present claims and values of x and y substantially overlapping those recited in the claims. Dependent claim 7 further recites the same linker described in the present claims.
While the claims of ‘828 do not specifically claim a conjugate wherein the amount of monomer and low molecular weight contaminants are as presently claims, as described above under 35 USC 103, Piers et al. discloses a similar conjugate of a polyglucosamine to tetanus toxoid and further in view of Li Shihui et al. renders the present claims obvious, including the limitations directing to levels of contaminants. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to use a conjugate as described by Piers et al. in view of Li Shihui et al. in the method claimed by ‘396, as the cited references indicate that such a conjugate would have the same biological effect as recited by the claims of ‘828.
This is a provisional nonstatutory double patenting rejection.
Reasons for Allowance
Applicant’s arguments, submitted January 23, 2026, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant argues that the genus of conjugates described by Pier et al. is so broad that one of ordinary skill in the art would not have been motivated to select a specific oligosaccharide length of 5 glucosamine subunits and an oligosaccharide loading ratio of about 31-39 oligosaccharides per tetanus toxoid carrier. However, with respect to the size of the oligosaccharide, Piers et al. discloses four preferred values of 5, 7, 9, or 11. (column 5 lines 36-38) In this case the reference would be seen as suggesting any of these four specific values. Regarding the ratio of oligosaccharides per TT carrier, Piers et al. suggests a number of specific embodiments spanning the range of 1:1 to 100:1, including 30:1 and 40:1. (column 5 lines 33-35) In such a case, the description of specific values for this ratio would suggest to one of ordinary skill in the art that it is a result-effective variable which could be optimized so as to arrive at the presently claimed invention. While it is possible for such a finding of prima facie obviousness to be overcome by the presence of a teaching away from the claimed range or evidence that the specific claimed value is critical to the claimed invention, neither is presently the case.
Regarding an alleged teaching away, Applicant points to examples 7 and 8 in columns 28-30 of Pier et al., which use an oligosaccharide having 9 subunits, and a conjugate loading of 74 or 71 carbohydrate ligands per protein molecule, as a supposed teaching away from the presently claimed embodiment. However, as described in MPEP 2145(X)(D)(1), “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." Furthermore according to MPEP 2123(II), “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” The mere fact that the specific examples disclosed by Pier et al. have different values of x and y compared to the present claims does not constitute a teaching away from the claimed invention unless the prior art specifically criticizes or disparages embodiments having the claimed parameters.
Still further, Applicant points to post-filing data allegedly demonstrating that the claimed invention unexpectedly produces an immunogenic response in vivo. As an initial matter, while post-filing data can be relied upon to demonstrate evidence of secondary considerations to overcome a prima facie case of obviousness, such data must be introduced in a declaration under 37 CFR 1.132, or by citation of appropriate published references. Data presented informally in Applicant’s arguments cannot be used as the basis for overcoming a prima facie case of obviousness. Regarding the specific data described in post-filing figures 1 and 2, these data demonstrate that conjugates having the claimed structure produce an immune response. However, based on the totality of the disclosure of Pier et al., it is not surprising that these conjugates produce an immune response. Overcoming the prima facie case of obviousness would require that the data show that the claimed conjugates produce a superior immune response compared to the prior art conjugates. In the absence of comparative data, merely showing that the claimed conjugates are effective does not demonstrate a finding of unexpected results or criticality in the absence of any reason in the art to doubt their efficacy.
Applicant further points to paragraph 3 of the present disclosure, which allegedly demonstrates the unexpected nature of the presently claimed invention. However, looking to the cited portion of the disclosure, it appears to merely state that it is expected that loading more oligosaccharides per carrier subunit is expected to produce a higher antibody titer. There is no evidence that Applicant compared the presently claimed conjugates to higher-substituted conjugates. Based on the totality of the disclosure it seems that a substation degree of 31-39 was the highest degree that Applicant was able to achieve, and that this range was selected not because it is uniquely superior to higher degrees of substitution but because the synthesis used by Applicant could not produce higher degrees of substitution. Furthermore this citation does not appear to refer to a portion of the present specification, as paragraph 3 of the specification as presently pending does not match the text cited in the arguments. Overall, the present disclosure does not support any finding that conjugates having 31-39 saccharides per tetanus toxoid carrier are unexpectedly superior, or even equivalent, to the higher-substituted compositions described by Pier.
Finally, Applicant argues that the prior art does not disclose the unexpected stability of the claimed composition against oligomerization and denaturation at a temperature of between 2-8OC. In particular, Applicant argues that the stability of the claimed compositions is not necessarily present in prior art conjugates. Firstly, it is notes that Applicant does not describe any particular structural feature of the presently claimed compositions that leads to the particular stability properties described in the present claims. As described for example in paragraphs 9 and 29 of the present specification, tetanus toxoid monomers tend to oligomerize over time and this process is inhibited by storage between 2-8OC. Furthermore the adverse effect of oligomerization described by the present specification involves the loss of potential conjugation sites on the monomers as they aggregate to form oligomers, which would be manifest as an inability to achieve high substitution with the saccharide. However, it is evident from the disclosed examples of Pier et al. that the author of this reference was able to achieve higher substitution than even what Applicant was able to achieve. There is thus no reasonable chance that the tetanus toxoid used by Piers was oligomerized at the time of conjugation, as this would have resulted in a low degree of substitution. Furthermore there is no reasonable chance that, unlike other tetanus toxoid based vaccines, this prior art conjugate was somehow unstable at the typically used storage temperatures of 2-8OC. Note that the present claims are drawn to a pharmaceutical composition, and not to a method of storing a pharmaceutical composition.
Additionally, even if the claims were to be amended in such a way as to claim a process of storing a tetanus toxoid conjugate at a particular temperature, such a method would still be considered to be obvious over the cited references further in view of Ho et al. or Parveen et al., for example. (References included with PTO-892) Briefly, based on the disclosure of Ho et al. or Parveen et al., one of ordinary skill in the art would have expected that a refrigerated temperature of, for example, 4OC is appropriate for long-term storage of such vaccines.
Regarding the double patenting rejections, Applicant declines to traverse these rejections. Therefore they are deemed proper and maintained.
Conclusion
No claims are allowed in this action. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 3/20/2026