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 .
Claim Status
Claims 19, 21, 26-31, and 126-127 are pending.
Claims 19, 21, 26-31, and 126 are currently amended and claim 127 is new.
Claims 1-18, 20, 22-25, and 32-125 are cancelled.
Claims 19, 21, 26-31, and 126-127 have been examined.
Priority
This application is a DIV of 16/459,303 07/01/2019 PAT 11951165
16/459,303 has PRO 62/693,981 07/04/2018
16/459,303 has PRO 62/693,978 07/04/2018
16/459,303 is a CIP of 15/859,251 12/29/2017 PAT 11998599
15/859,251 has PRO 62/591,160 11/27/2017
15/859,251 has PRO 62/568,201 10/04/2017
15/859,251 has PRO 62/530,803 07/10/2017
15/859,251 has PRO 62/441,115 12/30/2016
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/29/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objection and Rejection
The objection of claim 36 is withdrawn because applicant canceled claim 36.
The rejection of Claims 19-37 and 126 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ) is withdrawn because the amendment to claim 19 overcomes the rejection.
New Ground of Objection and Rejection
Claim Objections
Claims 19 and 126 are objected to because of the following informalities:
The phrase “the sequence set forth in SEQ ID NO: 14” in claims 19 and 126 should be “the sequence of SEQ ID NO: 14”.
Furthermore, the phrase “one of residues 213 and 215” should be “one of residues 213 or 215”.
Appropriate correction is required.
New Ground of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19, 21, 26-31, and 126-127 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention for the reasons as follows.
The specification failed to provide a representative number for the entire genus of a carrier protein “at least 90% identical to the sequence set forth in SEO ID NO: 14”.
SEQ ID NO: 14 consists of 536 amino acid residues in length. A protein with 90% identity to SEQ ID NO: 14 as claimed would have amino acid residues between 482 and 595 in length comprising numerous insertions, deletions, and/or substitutions, which is insufficient to be supported by the limited disclosure of SEQ ID Nos: 1 and 9-14 consisting of 535 or 536 amino acid residues.
The specification failed to establish a structure-function correlation between the position of a substituted amino acid residue by pAMF and antigen conjugation to a carrier protein.
The specification disclosed modification of non-natural amino acid (nnAA) at many positions such as Lys, Phe, Asp, Asn, Glu, Gln, Arg, Ser, and Thr [0142,0166] with 1-15 nnAA residues [0129,0167]. The site-specific conjugation is merely incorporation of the pAMF via orthogonal synthesis for site-specific reaction to link a functionalized antigen via click chemistry rection between azide and alkyne. Thus, the specification failed to establish a structure-function correlation between the incorporated position of pAMF and antigen conjugation.
Claim 19 fails to satisfy written description requirements; thus, dependent claims 21, 26-31, and 126-127 are further rejected as depending on claim 19.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive because the amendments to claim 19 nor the arguments are applied to the new ground of rejection described above.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19, 21, 26-31, and 127 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 has a phrase of “a carrier protein comprises sequence at least 90% identical to the sequence set forth in SEQ ID NO: 14”. The metes and bounds of the phrase is unclear with respect to a carrier protein sequence because the claimed carrier protein sequences encompass a genus of a protein comprising various deletion, insertion, substitution, and combination thereof and ranged from 482 to 595 amino acid residue in length. All defined positions based on the sequence of SEQ ID: 14 may or may not be applied to another claimed carrier protein sequence with various deletion, insertion, substitution, and combination thereof. A reference protein sequence of SEQ ID NO: 14 should not become a variable of “at least 90% identical to the sequence set forth in SEQ ID NO: 14” to define other variables of positions for incorporating nnAA. In one claim interpretation, a carrier protein is SEQ ID NO: 14 and all nnAA positions are localized to the claimed positions. In another claim interpretation, a carrier protein with 90% identity of SEQ ID NO 14 comprising a combination of deletions, insertion, and substitution will have nnAA positions at unknown positions depending on the actual protein sequence of carrier protein with 90% identity of SEQ ID NO 14. For example, a carrier protein with 90% identity of SEQ ID NO 14 consists of 490 amino acids in length, it is unclear how the incorporated nnAA positions corresponding to the peptide sequence of SEQ ID NO: 14, rendering claim 19 indefinite. Claims 21, 26-31, and 127 are rejected as depending on claim 19.
It is unclear with respect to the phrase “the 4-6 nnAArs are at 4-6 of: one of residues 25, 34, 38, or 40; one of residues 213 and 215; residue 245: residue 265; residue 386; and residue 527 in the sequence set forth in SEQ ID NO: 14”. A carrier protein comprising different polypeptide sequence at least 90% identical to the sequence set forth in SEQ ID NO: 14 has length ranged from 482 to 595 amino acids. Thus, it is unclear with the correlation of incorporated nnAA position numbers in a carrier protein corresponding to SEQ ID NO: 14 such as a carrier protein with 482 or 590 amino acids in length.
The rejection may be overcome by distinctly claim a polypeptide sequence of a carrier protein.
Modified Rejection
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
1. Claims 19, 21, 26-28, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Moginger et al. (Sci Rep. 2016 Feb 4:6:20488) in view of Boutureira et al. (Chem. Rev. 2015, 115, 2174−2195, previously cited 6/13/2025), Zimmerman et al. (Bioconjugate Chem. 2014, 25, 351−361, previously cited 6/13/2025), Zarei et al. (Journal of Immunology Research Volume 2016, Article ID 7203587, 18 pages, previously cited 6/13/2025), and evidenced by (a) Pecetta et al. (Vaccine 34 (2016) 2334–2341, previously cited 6/13/2025) and evidenced by (b) GeneBank AMV91693.1 (https://www.ncbi.nlm.nih. gov/protein/AMV91693.1?report= genbank&log$=prottop&blast_rank=1&RID=WU3RE6CT013, previously cited 6/13/2025).
Claim 1 is drawn to a protein-antigen conjugate comprising:
a carrier protein comprising at least 90% identical to SEQ ID NO: 14, and
the carrier protein further comprising a non-natural amino acid pAMF at 4-6 positions of SEQ ID NO: 14 at 4-6 positions selected from (a) one of residues 25, 34, 38, or 40, (b) one of residues 213 or 215, (c) residue 245, (d) residue 265, (e) residue 386, and (f) residue 527.
Moginger et al. teach a glycoconjugate vaccine comprising a carrier protein of CRM197 and polysaccharides (p2, Fig 1). Moginger et al. teach a conjugated antigen is a saccharide epitope from Streptococcus pneumoniae serotype 3 (p4, ST3). Moginger et al. suggest CRM197 comprising multiple lysine residues that can be functionalized for polysaccharide antigen conjugation (p9, Fig 8). Moginger et al. suggest one or more polysaccharides can be conjugated to CRM197 (p2, Fig 1). Moginger et al. teach preferred antigen conjugate sites are K37, a region K212 to K242, and K526 or others (p8, last para).
PNG
media_image1.png
130
430
media_image1.png
Greyscale
Pecetta et al. is cited as evidence to show the carrier protein of CRM197 inherently comprising a T-cell activating epitope (Title and Abstract; p2338, Fig 3). Pecetta et al. suggest T -cell activating epitope within CRM197 resulted in strong enhancement of immune response (p2338, col 2); thus, one of ordinary skill would have in the art would have known to keep at least one T-cell activating epitope not inactivated by the presence nnAA, GeneBank AMV91693.1 is further cited as evidence to show the polypeptide sequence of CRM197, 100% identity to the instant SEQ ID NO: 1 known in the art shown as follows. CRM197 of GeneBank AMV91693.1 has an additional methionine as the initial amino acid of protein
PNG
media_image2.png
288
331
media_image2.png
Greyscale
translation omitted from Moginger’s CRM197 sequence (p28, Supplementary Material with lower right number at p15), reading on at least 90% identical to the instant Seq ID NO; 14. Thus, the lysine residue numbers of Moginger’s CRM197 sequence can be normalized to the claimed lysine position number by adding a number of 1, reading on the limitation (i) of a carrier protein with at least 90% identical to the instant SEQ ID NO: 14.
Moginger et al. show the preferred antigen conjugate sites in CRM197 are K37, a region K212 to K242, and K526 (p8, last para) shown as follows (p9, Fig. 8), reading on K38 (the limitation (ii)(a)), K213 (the limitation (ii)(b)), and K527 (the limitation (ii)(f)) after normalization by counting the first translation initiation of methionine shown in GeneBank AMV91693.1.
Moginger et al. suggest one or more saccharide antigens can be randomly conjugated to multiple accessible lysine residues of a CRM197 carrier protein (p9, Fig 8), but unable to generate a homogenous antigen-CRM197 protein conjugate.
Boutureira et al. teach introduction and (bio)orthogonal modification of unnatural moieties/amino acids to make site-selective modification of proteins (p2174, col 2, Introduction, para 1). Boutureira et al. teach bioorthogonal modification/substitution of lysine residues with unnatural moieties/amino acids for site-selective modification via click chemistry to make homogenous glycoprotein vaccines (p2175, col 2, last line 8-12) by beneficially controlling the number and sites of conjugation within a protein. Boutureira et al. suggest a modified protein for glycoprotein vaccines is a carrier protein of CRM197 (p2176, col 1, line 1-2) consistent with Moginger et al. described above. Boutureira et al. further show a click chemistry reaction between azide (N3) and cyclooctyne (p2183, col 2, para 1; Scheme 12). Zimmerman et al. is cited to show incorporation of pAMF comprising an azidomethyl group into a carrier protein (e.g., antibody) for site-specific conjugation to a cargo compound functionalized with Dibenzocyclooctyne (DBCO) well known in the art (Abstract; p354, Fig 1), reading on incorporated nnAA of pAMF into CRM197 carrier protein for site-specific conjugation of DBCO-functionalized polysaccharide antigens.
Moginger et al. in view of Boutureira et al. and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 do not specify a number of antigen conjugated to a carrier protein.
PNG
media_image3.png
264
400
media_image3.png
Greyscale
Similarly, Zarei et al. teach CRM197 as a carrier for polysaccharide vaccine conjugate (p4, col 1, para 1-2). Zarei et al. suggest each carrier protein of CRM197 conjugated to at least 4 polysaccharide antigens simultaneously shown as follows (p6, Fig 4). Although Zarei et al. explicitly show 4 polysaccharide antigens can be conjugated to a carrier protein, one of ordinary skill in the art would recognize the number of antigen conjugated to a carrier protein as a result effective variable to induce immunity and can be further optimized by routine experimentation such as clinical trials, reading on the carrier protein of CRM197 comprising 4 or more nnAA. It is noted that not all incorporated nnAAs (the number of nnAA can be more than 6) require to be conjugated to a saccharide antigen.
Moginger et al. teach preferred antigen conjugate sites are K37 (K38 after normalization), a region K212 (K213 after normalization) to K242, and K526 (K527 after normalization) (p8, last para) and suggest other lysine residues may also be used for conjugation to saccharide antigens. Zarei et al. suggest CRM197 conjugated to at least 4 saccharide antigens and with sufficient space among the conjugated antigens (p6, Fig 4). Moginger et al. further show other lysine residues suitable for conjugation of a saccharide antigen as follows (p9, Fig. 8). Thus, one of ordinary skill in the art would have been suggested and/or motivated to select suitable lysine residues with sufficient space among the conjugated antigens K37 (K38 after normalization), K212 (K213 after normalization), and K526 (K527 after normalization). The accessible K385 residue (K386 after normalization) shown as follows has sufficient space between K212 (K213 after normalization) and K526 (K527 after normalization), reading on the limitation (ii)(e) K386 as the of the nnAA
PNG
media_image4.png
556
342
media_image4.png
Greyscale
substituted position. Moginger et al. teach a region K212 to K242 comprising several lysine suitable for antigen conjugation (p8, last para). However, one of ordinary skill in the art would also recognize keeping sufficient space among the antigen conjugated residues as taught by Zarei (p6, Fig 4). Thus, one of ordinary skill in the art would have been taught and/or motivated to lysine outside the region of a region K212 to K242 according to Moginger et al. (p9, Fig. 8). One of ordinary skill in the art would at once envisage to incorporate pAMF at one or more residues of K244 (K245 after normalization), K264 (K265 after normalization) and/or K299 (K300 after normalization), reading on the limitations of residues (ii)(c) residue 245 and (ii)(d) residue 265.
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See MPEP 2123(I).
One of ordinary skill in the art before the efrective filing date of this invention would have found it obvious to combine (i) Moginger et al. with (ii) Boutureira et al. in view of Zimmerman et al. because (a) Moginger et al. teach one or more saccharide antigens can be randomly conjugated to multiple accessible lysine residues of a CRM197 carrier protein (p9, Fig 8) but unable to generate a homogenous antigen-CRM197 protein conjugate, (b) Boutureira et al. teach introduction and (bio)orthogonal modification of unnatural moieties/amino acids to make site-selective modification of proteins (p2174, col 2, Introduction, para 1). Boutureira et al. teach bioorthogonal modification/substitution of lysine residues with unnatural moieties/amino acids for site-selective modification via click chemistry to make homogenous glycoprotein vaccines (p2175, col 2, last line 8-12) by beneficially controlling the number and sites of conjugation within a protein. Boutureira et al. further show a click chemistry reaction between azide (N3) and cyclooctyne (p2183, col 2, para 1; Scheme 12), and (c) Zimmerman et al. is cited to show incorporation of pAMF comprising an azidomethyl group into a carrier protein (e.g., antibody) for site-specific conjugation to a cargo compound functionalized with Dibenzocyclooctyne (DBCO) well known in the art (Abstract; p354, Fig 1). The combination would have reasonable expectation of success because (a) all references teach protein conjugate, (b) (bio)orthogonal method is able to introduce unnatural moieties/amino acids to make site-selective modification of proteins, and (c) incorporation of pAMF comprising an azidomethyl group into a carrier protein for site-specific conjugation to a cargo compound functionalized with Dibenzocyclooctyne (DBCO) well known in the art (See Zimmerman et al. Abstract; p354, Fig 1). Pecetta et al. is cited as evidence to show the carrier protein of CRM197 inherently comprising a T-cell activating epitope (Title and Abstract; p2338, Fig 3) resulted in strong enhancement of immune response (p2338, col 2). GeneBank AMV91693.1 is further cited as evidence to show the polypeptide sequence of CRM197, 100% identity to the instant SEQ ID NO: 1 known in the art. CRM197 of GeneBank AMV91693.1 has an additional methionine as the initial amino acid of protein translation omitted from Moginger’s CRM197 sequence (p28, Supplementary Material with lower right number at p15).
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Moginger et al. in view of Boutureira et al. and Zimmerman et al. and (ii) Zarei et al. because (a) Moginger et al. in view of Boutureira et al. and Zimmerman et al. teach a modified CRM197 carrier protein comprising multiple pAMF substituted lysine residues for site-specific conjugation to saccharide antigens and (b) Zarei et al. teach CRM197 as a carrier for polysaccharide vaccine conjugate (p4, col 1, para 1-2) and further suggest each carrier protein of CRM197 conjugated to at least 4 polysaccharide antigens simultaneously (p6, Fig 4). The combination would have reasonable expectation of success because both Moginger et al. and Zarei et al. teach the use of a CRM197 protein conjugated to multiple saccharide antigens.
PNG
media_image5.png
134
574
media_image5.png
Greyscale
With respect to claim 21, Zimmerman et al. show pAMF conjugated to Dibenzocyclooctyne (DBCO) via a triazole linkage (p354, fig 1C).
With respect to claims 26-28, Moginger et al. teach a conjugated antigen is a saccharide epitope from Streptococcus pneumoniae serotype 3 (p4, ST3).
With respect to claim 31, the limitation of “synthesis of the carrier protein under cell-free condition” is a product-by-process claim, which is examined as a product. The polypeptide sequence of CRM197, 100% identity to the instant SEQ ID NO: 1, was known in the art as evidenced GeneBank AMV91693.1, satisfying the limitation regardless a process to make CRM197. Zimmerman et al. teach incorporation of nnAA can be performed in cell free synthesis as a rapid, cost-effective, and virus-free procedure (p352, col 1, last para to col 2, para 1-2).
Applicant’s Arguments
The amendment to claim 19 overcomes the rejection of record (Remarks, p7, para 2).
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive because the arguments are not commensurate in scope of the claims. First of all, the sequence of a carrier protein “at least 90% identical to the sequence set forth in SEQ ID NO: 14” is unclear as described in the 112(a) rejection above. Secondly, the claimed carrier protein “comprises” 4-6 nnAA at the positions as claimed without excluding other positions substituted by nnAA. Namely, the carrier protein can contain multiple nnAAs at the claimed 4-6 positions as well as other compositions as well. The specification disclosed modification of non-natural amino acid (nnAA) at many positions such as Lys, Phe, Asp, Asn, Glu, Gln, Arg, Ser, and Thr [0142,0166] with 1-15 nnAA residues [0129,0167]. Furthermore, the cited prior art references provide guidance to select saccharide conjugated lysine residues at preferred positions with sufficient space among the conjugated saccharide antigens. One of ordinary skill in the art would found it obvious to include the 4-6 claimed positions for site-specific conjugate of saccharide antigens. See the rejection above in details not repeated here.
2. Claims 19, 21, 26-29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and evidenced by (b) GeneBank AMV91693.1 as applied to claims 19, 21, 26-28, 31 and further in view of Durando et al. (Clin Microbiol Infect 2013; 19(suppl.1): 1–9, previously cited 6/13/2025) and evidenced by Cohen et al. (US 2009/0269370 A1, previously cited 6/13/2025).
Claim 28 is drawn to drawn to an antigen as a capsular polysaccharide from various Streptococcus pneumoniae serotype.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 teach CRM197 conjugated to a capsular polysaccharide from Streptococcus pneumoniae serotype 3.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and evidenced by (b) GeneBank AMV91693.1 did not teach an antigen as a capsular polysaccharide from other Streptococcus pneumoniae serotype.
PNG
media_image6.png
224
320
media_image6.png
Greyscale
Durando et al. teach pneumococcal polysaccharide conjugate vaccine conjugated to CRM197 (Title). Durando et al. show different serotypes of pneumococcal polysaccharide can be conjugated to CRM197 to create multivalent vaccine conjugates well-known in the art (p3, Table 1), reading on claim 28.
With respect to claim 29, Zarei et al. teach cross-linked lattice polysaccharide antigen conjugate comprising multiple carrier proteins and polysaccharides shown as follows (p6, Fig 5). Cohen et al. is cited to show, advantageously, a conjugate of a bacterial CPS, bacterial capsular polysaccharide (defined as CPS at [0067]) including polysaccharide antigens from Streptococcus pneumoniae [0060], of about 50-100 kDa for a carrier protein [0062]. The molecular weight of CRM197 is about 58.5 KDa and the average weight of polysaccharide antigens as 75 kDa (average between 50 kDa +100 kDa). Thus, under Zarei’s vaccine conjugate shown above, a molecular weight of a vaccine conjugate is 58.5 x 7 (CRM197) + 75 kDa x 8 (polysaccharide) = 1009.5 kDa. Alternatively, one CRM197 can be conjugated with 9 or more polysaccharide antigens (WM=100 kDa each) for multivalent vaccine conjugate comprising various polysaccharide antigens from different serotype of Streptococcus pneumoniae taught by Durando et al. (p3, Table 1), further satisfying the limitation of 900 kDa.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (1) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 with (2) Durando et al. because (a) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 teach CRM197 conjugated to a capsular polysaccharide from Streptococcus pneumoniae serotype 3 and (b) Durando et al. show various of Streptococcus pneumoniae serotypes are also polysaccharide antigens in together with serotype 3 for multivalent vaccine design well-known in the art (p3, Table 1). The combination would have reasonable expectation of success because both Moginger et al. and Durando et al. teach polysaccharide antigen from Streptococcus pneumoniae serotype 3 for vaccine conjugate. Cohen et al. is cited to show, advantageously, a conjugate of a bacterial CPS, bacterial capsular polysaccharide (defined as CPS at [0067]) including polysaccharide antigens from Streptococcus pneumoniae [0060], of about 50-100 kDa for a carrier protein [0062].
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive. See response to arguments above.
3. Claims 19, 21, 26-28, and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 as applied to claims 19, 21, 26-28, 31 and further in view of Costantino (US 2009/0117148 A1, previously cited 6/13/2025).
Claim 30 is directed to weight ratio of polysaccharide to carrier protein.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 teach polysaccharides conjugated to a carrier protein of CRM197 as applied to 19, 21, 26-28, and 31 described above.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 do not teach weight ratio of polysaccharide to a carrier protein.
PNG
media_image7.png
262
629
media_image7.png
Greyscale
Similarly, Costantino shows polysaccharide antigens conjugated to CRM197 shown as follows (Fig 18, claim 3). Costantino teaches saccharide antigens from Streptococcus pneumoniae [0023, 0051]. Costantino suggests the weight ratio of saccharide antigen to a carrier protein is a result effective variable optimized between 0.5:1 (i.e. excess protein) and 5:1 (i.e. excess saccharide) [0024], reading on claim 30. Costantino teaches saccharide will typically be activated or functionalised prior to conjugation consistent with the teachings of Boutureira et al. and Zimmerman et al. described above.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (1) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 with (2) Costantino because (a) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references Pecetta et al. and GeneBank AMV91693.1 teach polysaccharides conjugated to a carrier protein of CRM197 and (b) Costantino suggests the weight ratio of saccharide antigen to a carrier protein is a result effective variable optimized between 0.5:1 (i.e. excess protein) and 5:1 (i.e. excess saccharide) [0024]. The combination would have reasonable expectation of success because all of Moginger et al., Boutureira et al., Zarei et al., and Costantino teach CRM197 as a carrier protein.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive. See response to arguments above.
4. Claims 19, 21, 26-28, 31 and 126 are rejected under 35 U.S.C. 103 as being unpatentable over Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 as applied to claims 19, 21, 26-28, 31 and further in view of Hosaka et al. (J Biol Chem. 1991 Jul 5;266(19):12127-30, previously cited 6/13/2025).
Claim 126 is drawn to the carrier protein of CRM197 without a dipeptide Arg-Arg.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 show the carrier protein of CRM197 comprising an underlined dipeptide Arg-Arg shown as follows.
PNG
media_image1.png
130
430
media_image1.png
Greyscale
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 did not teach a reason to remove the dipeptide of Arg-Arg.
Hosaka et al. teach a peptide motif of Arg-X-(Arg/Lys)-Arg comprising an endoproteolysis site (Abstract; p12128, Fig 1). Since CRM197 protein comprises an endoprotease cleavage peptide sequence motif of rvrr, one of ordinary skill in the art would have found it obvious to modify the cleavage site of dipeptide Arg-Arg to produce protease resistant CRM197 without the dipeptide of Arg-Arg, reading on claim 126.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (1) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 with (2) Hosaka’s teaching of endoprotease cleavage peptide sequence motif because (A) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 teach a vaccine carrier protein of CRM197 comprising a tetrapeptide sequence of Arg-Val-Arg-Arg and (B) Hosaka et al. teach a peptide motif of Arg-X-(Arg/Lys)-Arg comprising an endoproteolysis site (Abstract; p12128, Fig 1). The combination would have reasonable expectation of success because GeneBank AMV91693.1 shows CRM197 protein comprising an endoprotease cleavage peptide sequence motif of Arg-Val-Arg-Arg.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive. See response to arguments above.
5. New claim 127 is rejected under 35 U.S.C. 103 as being unpatentable over Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 as applied to claims 19, 21, 26-28, 31 and further in view of Levesque et al. (Hum Vaccin. 2006 Mar-Apr;2(2):74-7.)
Claim 127 is drawn to a composition comprising the protein-antigen conjugate of claim 19 and an aluminum salt adjuvant.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 teach Streptococcus pneumoniae polysaccharide antigens conjugated to a carrier protein of CRM197 as applied to 19, 21, 26-28, and 31 described above.
Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 do not teach formulation of Streptococcus pneumoniae polysaccharide vaccine conjugated CRM197 with an aluminum salt adjuvant.
Levesque et al. teach “Association Between Immunogenicity and Adsorption of a Recombinant Streptococcus pneumoniae Vaccine Antigen by an Aluminum Adjuvant” (Title). Levesque et al. teach aluminum salts were the first widely used adjuvants and they are the only adjuvants licensed for use in multiple human vaccines known in the art (p74, Introduction, para 1). Levesque et al. teach the observed antibody concentrations for the first study are summarized in Table 2. It is clear that the antibody response induced by the AH (aluminum hydroxide) formulations are of higher concentration than either those induced by the corresponding AP formulations or the non-adjuvanted formulations (p76, col 1, Results and discussion, para 2-3). Because Levesque et al. teach beneficial addition of aluminum adjuvant in a formulation comprising Streptococcus pneumoniae vaccine antigen to enhance antibody production, one of ordinary skill in the art would have found it obvious to formulate the CRM197 conjugated Streptococcus pneumoniae polysaccharide vaccine antigen with aluminum hydroxide in one composition to enhance immunity against Streptococcus pneumoniae, reading on claim 127.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (1) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 with (2) Levesque’s aluminum adjuvant because (A) Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by references of Pecetta et al. and GeneBank AMV91693.1 teach Streptococcus pneumoniae polysaccharide antigens conjugated to a carrier protein of CRM197 and (B) Levesque et al. teach beneficial addition of aluminum adjuvant in a formulation comprising Streptococcus pneumoniae vaccine antigen to enhance antibody production (p76, col 1, Results and discussion, para 2-3). The combination would have reasonable expectation of success because Levesque et al. show the antibody response induced by the AH (aluminum hydroxide) formulations are of higher concentration than either those induced by the corresponding AP formulations or the non-adjuvanted formulations (p76, col 1, Results and discussion, para 2-3).
Modified Rejection
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.
PNG
media_image8.png
606
482
media_image8.png
Greyscale
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 19, 21, 26-28, and 30-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3, and 8-9 of U.S. Patent No. 11,998,599 B2 (the ‘599 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘599 patent disclosed a cross-linked carrier protein-antigen conjugate shown as follows, satisfying the instant claim 19, 21, 27-28, and 31.
Claims 8-9 of the ‘599 patent disclosed the weight ratio of polysaccharides to carrier protein at lease 1.1 and 1.2 respectively, satisfying the instant claim 30.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive because the request of non-statutory double patenting rejection to be held in abeyance until allowable subject matter is identified does not overcome the ODP rejection of record.
Claims 19, 21, 26-28, 31 and 126 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4 of U.S. Patent No. 11,951,165 B2 (the ‘165 patent) in view of Moginger et al. (Sci Rep. 2016 Feb 4:6:20488) in view of Boutureira et al. (Chem. Rev. 2015, 115, 2174−2195), Zimmerman et al. (Bioconjugate Chem. 2014, 25, 351−361), Zarei et al. (Journal of Immunology Research Volume 2016, Article ID 7203587, 18 pages), and evidenced by (a) Pecetta et al. (Vaccine 34 (2016) 2334–2341.) and evidenced by (b) GeneBank AMV91693.1 (https://www.ncbi.nlm.nih. gov/protein/AMV91693.1?report= genbank&log$=prottop&blast_rank=1&RID=WU3RE6CT013).
PNG
media_image9.png
142
428
media_image9.png
Greyscale
Claim 1 the ‘165 patent disclosed a carrier protein comprising non-natural amino acids as follows. SEQ ID NO: 9 is 99% homology to this instant SEQ ID NO: 1 and the instant SEQ ID NO: 14 or CRM197.
Claim 1 the ‘165 patent do not teach the carrier protein conjugated to an antigen.
The relevancy of Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 teach CRM197 (at least 90% homology to conjugated to a capsular polysaccharide from Streptococcus pneumoniae serotype 3 teach CRM197 conjugated to a capsular polysaccharide from Streptococcus pneumoniae serotype 3 described above not repeated here.
Because Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1 teach the benefit for incorporated nnAA into a carrier protein CRM197 for site-specific conjugation of a capsular polysaccharide antigens, one of ordinary skill in the art would have found it obvious to combine the carrier protein of SEQ ID NO: 9 and nnAA conjugated positions taught by claim 1 of the ‘165 patent with Moginger et al. in view of Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1.
Thus, claim 1 of the ‘165 patent in view of Moginger et al., Boutureira et al., Zimmerman et al., Zarei et al., and evidenced by (a) Pecetta et al. and (b) GeneBank AMV91693.1. are obvious to the instant claims 19, 21, 26-28, and 31.
Claims 2 and 4 of the ‘165 patent disclosed the carrier protein does not contain a dipeptide of Arg-Arg, satisfying the instant claim 126.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive because the request of non-statutory double patenting rejection to be held in abeyance until allowable subject matter is identified does not overcome the ODP rejection of record.
Claims 19, 21, 26-28, 31, and 126 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-9 of U.S. Patent No. 12,252,454 B2 (the ‘454 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘454 patent disclosed a method of making a protein-antigen conjugate obvious to the claimed protein-antigen conjugate.
PNG
media_image10.png
360
514
media_image10.png
Greyscale
Claim 1 of the ‘454 patent disclosed a method of making a conjugate.
Claims 2 and 6 of the ‘454 patent disclosed the conjugate comprising a protein of SEQ ID Nos: 1 or 2. SEQ ID NO: 2 is a carrier protein of CRM197 incorporated with 6 pAMF substitutions at positions 34, 213, 245, 265, 386, and 527 shown as follows.
PNG
media_image11.png
368
428
media_image11.png
Greyscale
Claim 4 of the ‘454 patent disclosed CRM197 comprising 4-6 non-natural amino acids.
Claim 18 of the ‘454 patent disclosed compound X1 functionalized with a cyclooctyne group shown as follows for crosslinking to pAMF to create a protein conjugate via click chemistry resulting in a triazole linking moiety.
Claims 20-21 disclosed is X1 is a capsular polysaccharide from a bacterium comprising Streptococcus pneumoniae serotypes.
Thus, claims 1-2, 4, 18 and 20-21 are obvious to the instant claims 19, 21, 26-28, 31, and 126.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive because the request of non-statutory double patenting rejection to be held in abeyance until allowable subject matter is identified does not overcome the ODP rejection of record.
Claims 19-28 and 31-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21 and 23-25 of copending Application No. 18/637,101 (the ‘101 application, 5/30/2024) in view of Durando et al. (Clin Microbiol Infect 2013; 19(suppl.1): 1–9) and Zimmerman et al. (Bioconjugate Chem. 2014, 25, 351−361.).
PNG
media_image12.png
270
664
media_image12.png
Greyscale
Claims 21 and 25 of the ‘101 application disclosed a method of producing a protein conjugate comprising a carrier protein of CRM197 containing non-natural amino acids (nnAAs) crosslinked to antigen. In search for the scope of CRM197, the disclosed SEQ ID NO: 9 in sequence listing comprises nnAAs shown as X at amino acid positions 34, 213, 245, 265,386, and 527 shown as follows.
PNG
media_image13.png
154
692
media_image13.png
Greyscale
Claims 23-24 of the ‘101 application disclosed antigen functionalized with a cyclooctyne group as follows.
Claims 21 and 23-25 of the ‘101 application do not specify an antigen or nnAA structure.
Durando et al. is cited to show CRM197 is known to be a carrier for numerous capsular polysaccharide of various Streptococcus pneumoniae serotypes (Title; p3, Table 1). Thus, one of ordinary skill in the art would have found it obvious to conjugate cyclooctyne functionalized capsular polysaccharides from various Streptococcus pneumoniae serotypes to nnAA of CRM197 taught by claims 21 and 23-25 of the ‘101 application for vaccine design.
PNG
media_image14.png
134
569
media_image14.png
Greyscale
Zimmerman et al. teach incorporation of pAMF into a protein for orthogonal reaction (p335, col 1, Results). Zimmerman et al. show cycloaddition reaction between pAMF and cyclooctyne via click chemistry as follows (p354, Fig 1C). Because Zimmerman et al. show beneficial incorporation of pAMF into a carrier protein for site-specific conjugate to a moiety functionalized with cyclooctyne, one of ordinary skill in the art would have found it obvious to incorporate nnAA of pAMF into the carrier protein of CRM197 for crosslinking to an antigen functionalized with cyclooctyne.
Thus, claims 21 and 23-25 of the ‘101 application in view of Durando et al. and Zimmerman et al. are obvious to the instant claims 19, 21, 26-28, and 31.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 9/17/2025 have been fully considered but they are not persuasive because the request of non-statutory double patenting rejection to be held in abeyance until allowable subject matter is identified does not overcome the ODP rejection of record.
Claims 19-28, 31-37, and 126 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 11-12 of copending Application No. 19/051,741 (the ‘741 application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘741 application disclosed a protein conjugate obvious to the instant application.
PNG
media_image13.png
154
692
media_image13.png
Greyscale
PNG
media_image10.png
360
514
media_image10.png
Greyscale
Claim 1 of the ‘741 application disclosed a polypeptide conjugate made from crosslinking of azide functionalized polypeptide to a cyclooctyne linker functionalized antigen (shown above).
Claim 5 of the ‘741 application disclosed a polypeptide of SEQ ID NOs: 1 and 2. SEQ ID NO: 2 shown in the sequence listing is a recombinant CRM197 comprising 6 lysine residues substitutions by pAMF at amino acid positions 34, 213, 245, 265,386, and 527 shown as follows.
Claims 11-12 of the ‘741 application disclosed the antigen is a capsular polysaccharide from various serotypes of Streptococcus pneumoniae.
Thus, claims 1, 5, and 11-12 of the ‘741 application are obvious to the instant claims 19, 21, 26-28, 31 and 126.
Conclusion
No claim is allowed.
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 JIA-HAI LEE whose telephone number is (571)270-1691. The examiner can normally be reached Mon-Fri from 9:00 AM to 6:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.L/Examiner, Art Unit 1658
20-December-2025
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
Prosecution Insights