DETAILED ACTION
Disposition of Claims
Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 were pending. Claims 2, 15-16, 20, 24, and 27 are cancelled. Amendments to claim 1, 17, and 21 are acknowledged and entered. Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20220031829A1, Published 02/03/2022.
The Power of Attorney filed on 02/28/2024 is acknowledged and entered.
Response to Arguments
Applicant's arguments filed 11/25/2025 regarding the previous Office action dated 08/26/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method of immunization against Neisseria meningitidis serogroups A, C, Y, and W-135 and human papilloma virus (HPV) without interference with the development of immunity against one or more types of HPV including HPV types 6 and 18, the method comprising:
co-administering a Neisseria meningitidis vaccine composition, an HPV Type 6 L1 protein, an HPV Type 11 L1 protein, an HPV Type 16 L1 protein, and an HPV Type 18 L1 protein to a subject in need thereof, wherein the HPV Type 6 L1 protein, the HPV Type 11 L1 protein, the HPV Type 16 L1 protein, and the HPV Type 18 L1 protein are each in the form of virus-like particles (VLPs), and
the Neisseria meningitidis vaccine composition comprises:
a) a first conjugate of MenA capsular polysaccharide to tetanus toxoid;
b) a second conjugate of MenC capsular polysaccharide to tetanus toxoid;
c) a third conjugate of MenW-135 capsular polysaccharide to tetanus toxoid;
d) a fourth conjugate of MenY capsular polysaccharide to tetanus toxoid; and
e) less than 20% free polysaccharide by weight; and
wherein the administration of the Neisseria meningitidis vaccine composition does not interfere with the development of immunity against HPV Types 6 and 18,
wherein the Neisseria meningitidis vaccine composition is administered as a first vaccine and a vaccine composition comprising the HPV Type 6 L1 protein, the HPV Type 11 L1 protein, the HPV Type 16 L1 protein, and the HPV Type 18 L1 protein is administered as a second vaccine;
wherein "does not interfere" means that coadministration of the first vaccine with the second vaccine to a treatment group gives a titer specific for an antigen of the second vaccine where the lower bound of its 95% confidence interval is greater than two thirds of the titer of a control group given only the second vaccine and that coadministration of the first vaccine with the second vaccine to a treatment group gives an amount of seroconversion against an antigen of the second vaccine where the lower bound of its 95% confidence interval is greater than 90% of the seroconversion of a control group given only the second vaccine.
Further limitations on the method according to claim 1 are wherein administration of the Neisseria meningitidis vaccine composition does not interfere with the development of immunity against (i) HPV Types 6, 11, and 18 or (ii) HPV types 6, 16, and 18 (claim 3); wherein the administration of the Neisseria meningitidis vaccine composition does not interfere with the development of immunity against HPV types 11 and 16 (claim 4); wherein the administration of the HPV types 6 and 18 L1 proteins does not interfere with the development of immunity against Neisseria meningitidis serogroups A, C, Y, and/or W-135 (claim 5); wherein interference or non- interference with the development of immunity against HPV Type 18 is determined by comparing (i) the geometric mean antibody titer specific for HPV Type 18 L1 protein in a first treatment group treated with the Neisseria meningitidis vaccine composition and co-administered with the HPV Type 18 L1 protein with (ii) the geometric mean antibody titer specific for HPV Type 18 L1 protein in a second treatment group treated with the HPV Type 18 L1 protein without the Neisseria meningitidis vaccine composition (claim 6); wherein the coadministration of the Neisseria meningitidis vaccine composition and the HPV protein does not result in increased risk of injection site swelling relative to administration of the HPV type 18 L1 protein without the Neisseria meningitidis vaccine composition (claim 7); further comprising co-administering a diphtheria-tetanus-pertussis vaccine with the Neisseria meningitidis vaccine composition (claim 8), wherein the diphtheria-tetanus- pertussis vaccine is Tetanus, diphtheria, acellular pertussis (Tdap) vaccine or DTaP5, optionally wherein the administration of the diphtheria-tetanus-pertussis vaccine does not interfere with the development of immunity against Neisseria meningitidis serogroups A, C, Y, and/or W-135 (claim 18); wherein:
(i) the second conjugate is a population comprising double-end-linked conjugated polysaccharides and single-end-linked conjugated polysaccharides which both are attached to the tetanus toxoid through a secondary amine, and/or the polysaccharides of the second conjugate have an O-acetylation level of 0.3 mol/mg polysaccharide to 1.6 mol/mg polysaccharide;
(ii) the second conjugate is a population comprising single-end-linked conjugated polysaccharides which are attached to the tetanus toxoid through a secondary amine, wherein the single-end-linked conjugated polysaccharides have a terminal unlinked saccharide, optionally wherein the terminal saccharide has a primary hydroxyl or secondary amine linkage at the 7 position, or wherein the reducing end is modified with a (2-hydroxy)ethoxy or secondary amine linkage;
(iii) the MenA capsular polysaccharide is attached to the tetanus toxoid through a linker comprising a carbamate, a spacer, and an amide, wherein the spacer is between the carbamate and the amide and comprises 2-10 linear carbons, and/or the first conjugate has a polysaccharide to tetanus toxoid mass ratio of 0.3 to 1.5;
(iv) the MenA capsular polysaccharide is attached to the tetanus toxoid through a linker comprising a carbamate, a spacer, and an amide, optionally wherein the spacer is between the carbamate and the amide and comprises 2-10 linear carbons;
(v) the MenC, MenW-135, and MenY capsular polysaccharides are attached to the tetanus toxoid through a secondary amine; and/or at least one of the conjugates has a weight average molecular weight ranging from 300 kDa to 1500 kDa;
(vi) one or more of the first, second, third, and fourth conjugates has a weight average molecular weight ranging from 300 kDa to 1500 kDa; and/or
(vii) one or more of the first, second, third, and fourth conjugates have a polysaccharide to tetanus toxoid mass ratio of 0.3 to 1.5; optionally wherein molecular weight is determined by multi-angle light scattering (MALS)(claim 9); wherein the first, second, third, and/or fourth conjugates are a population comprising molecules with a molecular weight in the range of 700 kDa to 1400 kDa or 800 kDa to 1300 kDa, optionally wherein molecular weight is determined by multi-angle light scattering (MALS)(claim 10), wherein the first, second, third, and/or fourth conjugates are a population comprising molecules with a molecular weight in the range of 800 kDa to 1300 kDa (claim 23); wherein: (i) the MenC polysaccharide has a degree of O-acetylation ranging from 0.6 to 1.5 mol/mg polysaccharide or 0.8 to 1.4 mol/mg polysaccharide; (ii) the conjugate comprising MenC polysaccharide is a population comprising double- end-linked conjugated polysaccharides and single-end-linked conjugated polysaccharides, optionally wherein the single-end-linked polysaccharides of the second conjugate comprise a terminal unlinked saccharide, wherein the single-end-linked conjugated polysaccharides have a terminal unlinked saccharide, wherein the terminal saccharide has a primary hydroxyl at the 7 position, or wherein the reducing end is modified with a (2- hydroxy) ethoxy; (iii) the conjugate comprising MenC polysaccharide comprises one or more modifications chosen from (a) a primary hydroxyl at the 7 position, (b) a (2-hydroxy)ethoxy at the reducing end, and (c) a conjugation to the tetanus toxoid, wherein the modifications are present at no less than 25 nmol/mg polysaccharide; (iv) the conjugate of MenW-135 and/or MenY polysaccharide comprises one or more modifications chosen from (a) a primary hydroxyl at a position of a vicinal diol in a native MenW-135 or MenY polysaccharide and (b) a conjugation to the tetanus toxoid, wherein the modifications are present at no less than 60 nmol/mg polysaccharide; (v) the MenC polysaccharide is reduced in size by 3x-8x relative to native MenC polysaccharide; and/or (vi) the Neisseria meningitidis vaccine composition comprises less than 10% free polysaccharide by weight (claim 11); wherein: (i) the conjugate of the MenA capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.5 to 1.5 (ii) the conjugate of the MenC capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.3 to 1.1(iii) the conjugate of the MenY capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.3 to 1.1; and/or (iv) the conjugate of MenW-135 capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.3 to 1.3 (claim 12), wherein:(i) the conjugate of the MenA capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.7 to 1.4; (ii) the conjugate of the MenC capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.4 to 0.8; (iii) the conjugate of the MenY capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.5 to 1.3; and/or (iv) the conjugate of MenW-135 capsular polysaccharide to the tetanus toxoid has a polysaccharide to tetanus toxoid mass ratio of 0.6 to 1.3 (claim 22); wherein the polysaccharide of the MenA, MenC, MenW-135, or MenY conjugate is attached to the tetanus toxoid through a linker, optionally wherein: (i) the linker comprises 2-10 linear carbons; (ii) the linker is present in the MenA, MenC, MenW-135, or MenY conjugate at a ratio of one linker per 10-100 saccharide repeat units or 20-60 saccharide repeat units; and/or (iii) the linker comprises a spacer between a first carbonyl and a second carbonyl, and the spacer comprises 4-8 carbons (claim 13); wherein: (i) the MenA conjugate comprises a linker comprising a residue of a dihydrazide or a residue of adipic acid dihydrazide, optionally wherein the polysaccharide of the MenA capsular polysaccharide of the first conjugate is attached to the tetanus toxoid through a linker of formula I:
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158
454
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wherein PS indicates attachment to the polysaccharide and PR indicates attachment to the tetanus toxoid; and/or (ii) the polysaccharide of the MenC, MenW-135, and/or MenY conjugate is attached to the tetanus toxoid as shown in formula II: PR-NH-CH2-PS (II) wherein PS indicates attachment to the polysaccharide and PR indicates attachment to the tetanus toxoid (claim 14);
wherein (i) the HPV Type 6 L1 protein is present in a dose of 20 ug;
(ii) the HPV Type 11 L1 protein is present in a dose of 40 ug;
(iii) the HPV Type 16 L1 protein is present in a dose of 40 ug; and/or
(iv) the HPV Type 18 L1 protein is present in a dose of 20 ug (claim 17), wherein the HPV vaccine comprises one, two, three, four, or all of:(i) amorphous aluminum hydroxyphosphate sulfate adjuvant;(ii) sodium chloride;(iii) L-histidine;(iv) polysorbate 80; and/or (v) sodium borate (claim 19), wherein the HPV types in the HPV vaccine consist of HPV types 6, 11, 16, and 18 (claim 21); wherein interference or non-interference with the development of immunity against HPV Type 6 is determined by comparing (i) the geometric mean antibody titer specific for HPV Type 6 L1 protein in a first treatment group treated with the Neisseria meningitidis vaccine composition and coadministered with the HPV Type 6 L1 protein with (ii) the geometric mean antibody titer specific for HPV Type 6 L1 protein in a second treatment group treated with the HPV Type 6 L1 protein without the Neisseria meningitidis vaccine composition (claim 25); wherein the coadministration of the Neisseria meningitidis vaccine composition and the HPV Type 6 L1 protein does not result in increased risk of injection site swelling relative to administration of the HPV Type 6 L1 protein without the Neisseria meningitidis vaccine composition (claim 26); and wherein the administration of the HPV Type 11L1 protein and the HPV Type 16 L1 protein does not interfere with the development of immunity against Neisseria meningitidis serogroups A, C, Y, and/or W-135 (claim 28).
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 17 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn.) The rejection of Claim 21 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the amendments to the claim.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 under 35 U.S.C. 103 as being unpatentable over Bigio et. al. (US20100239600A1, Pub. 09/23/2010; CITED ART OF RECORD; hereafter “Bigio”) and further in view of
Anderson et. al. (WO2016132294A1, Pub. 08/25/2016; CITED ART OF RECORD; hereafter “Anderson”),
as evidenced by Merck & Co., Inc. (Merck & Co., Inc. GARDASIL® Package Insert. 2011, p. 1-28.; CITED ART OF RECORD; hereafter “Merck”);
Rivera et. al. (Rivera L, et. al. Vaccine. 2018 Jun 22;36(27):3967-3975. Epub 2018 May 19.; CITED ART OF RECORD; hereafter “Rivera”);
Shafer et. al. (Shafer DE, et. al. Vaccine. 2001 Jan 8;19(11-12):1547-58.; hereafter “Shafer”);
Simon et. al. (WO2012061400A2, Pub. 05/10/2012, hereafter “Simon”);and
Arguedas et. al. (Arguedas A, et. al. Vaccine. 2010 Apr 19;28(18):3171-9. Epub 2010 Feb 26.; CITED ART OF RECORD; hereafter “Arguedas”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Bigio et. al. (US20100239600A1, Pub. 09/23/2010; CITED ART OF RECORD; hereafter “Bigio”) and further in view of
Anderson et. al. (WO2016132294A1, Pub. 08/25/2016; CITED ART OF RECORD; hereafter “Anderson”), and
Sanofi Pasteur (Sanofi Pasteur. “Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Healthy Adolescents.” ClinicalTrials.gov ID NCT02199691; V1, 07/23/2014; hereafter “Sanofi Pasteur”);
as evidenced by Merck & Co., Inc. (Merck & Co., Inc. GARDASIL® Package Insert. 2011, p. 1-28.; CITED ART OF RECORD; hereafter “Merck”);
Rivera et. al. (Rivera L, et. al. Vaccine. 2018 Jun 22;36(27):3967-3975. Epub 2018 May 19.; CITED ART OF RECORD; hereafter “Rivera”);
Shafer et. al. (Shafer DE, et. al. Vaccine. 2001 Jan 8;19(11-12):1547-58.; hereafter “Shafer”);
Simon et. al. (WO2012061400A2, Pub. 05/10/2012, hereafter “Simon”);and
Arguedas et. al. (Arguedas A, et. al. Vaccine. 2010 Apr 19;28(18):3171-9. Epub 2010 Feb 26.; CITED ART OF RECORD; hereafter “Arguedas”.)
The Prior Art
Bigio teaches methods of immunization against Neisseria meningitidis serogroups A, C, Y, and W-135 (¶[0018][0085-0096]). Bigio teaches the vaccination may additionally include viral antigens (¶[0072) wherein said antigens may be used as adjuvants in the invention in the form of virosomes or virus-like particles (VLPs)(¶[0112]). Bigio teaches that “conjugates purified by the invention may be formulated as a pharmaceutical composition by the addition of a pharmaceutically acceptable diluent or carrier. Such compositions may also comprise one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) further antigens, such as: (¶[0058])… Papovaviruses: Antigens may be derived from Papovaviruses, such as Papillomaviruses and Polyomaviruses. Papillomaviruses include HPV serotypes 1, 2, 4, 5, 6, 8, 11, 13, 16, 18, 31, 33, 35, 39, 41, 42, 47, 51, 57, 58, 63 and 65. Preferably, HPV antigens are derived from serotypes 6, 11, 16 or 18. HPV antigens may be selected from capsid proteins (L1) and (L2), or E1-E7, or fusions thereof. HPV antigens are preferably formulated into virus-like particles (VLPs). Polyomyavirus viruses include BK virus and JK virus. Polyomavirus antigens may be selected from VP1, VP2 or VP3.”(¶[0082]). Therefore, Bigio teaches viral antigens may be from human papilloma virus (HPV) (¶[0112]), such as HPV Types 6, 11, 16, and 18, and would include HPV L1 proteins formulated as VLPs (¶[0082]). As Bigio teaches the HPV L1-based VLP protein antigens would be adjuvanting, and thus co-administered with, the Neisseria meningitidis composition, this reads upon compositions which enhance and do not interfere with the development of immunity against Neisseria meningitidis.
Bigio teaches different forms of MenA, B, C, W135, and Y polysaccharides, such as MENITORIX®, which comprises Neisseria meningitidis group C (strain C11) polysaccharide conjugated to tetanus toxoid (TT) as carrier protein (¶[0013]). Bigio also teaches bacterial capsular polysaccharides which may be in the vaccine compositions, including Neisseria meningitidis serogroups A, B, C, W135 and/or Y polysaccharides (¶[0018]) and protein carriers that may be attached to the polysaccharides, such as TT (¶[0012]). Therefore, Bigio teaches at least one example of a Neisseria meningitidis polysaccharide conjugated to TT, and teaches that Neisseria meningitidis polysaccharides from A, B, C, W135, and/or Y serogroups may be attached to TT carrier proteins (¶[0012-0013][0020][0040][0065]; reference claims 1, 3-5, 9-11, 21-22).
With respect to the Neisseria meningitidis vaccine compositions, Bigio notes their teachings are “to provide an improved method of purifying saccharide antigen-carrier protein conjugates from impurities such as unconjugated carrier protein and unconjugated saccharide.”(¶[0007]). The teachings of Bigio not only remove unconjugated saccharide, but other protein contaminants, thus providing a purified antigen-carrier protein conjugate vaccine composition (¶[0010]). Bigio teaches that the final composition may still have small amounts of “free” (e.g. unconjugated) carrier, wherein the amount of free carrier protein is “no more than 5% of the total amount of the carrier protein in the composition as a whole (by weight); and more preferably present at less than 2%, more preferably less than 1%, preferably less than 0.5%” (¶[0035]), and conjugates with excess protein or excess saccharide may be purified to lower the ratio of saccharide:protein (w/w) to between 1:1.25 and 1:2.5 (¶[0036]). Bigio teaches that both unconjugated carrier protein and unconjugated saccharide should be removed from the vaccine mixture (¶[0005][0007]).
Bigio teaches further limitations of the instant claims. Bigio teaches that Bordetella pertussis (Pertussis), Corynebacterium diphtheriae (Diphtheria), and/or Clostridium tetani (Tetanus) antigens may be utilized, either as carrier proteins or for combination/co-administration/conjugation with the compositions (¶[0065-0066]; instant claim 8). Bigio teaches the amine linkages and polysaccharide to TT ratios as claimed in instant claims 9, 11-12, 22 (¶[0020][0036]). Bigio teaches wherein each of the saccharide antigens would have a molecular weight of 5 kDa or more, or 50 kDa or more (reference claims 7-8), and may be anywhere from 5-250 kDa or more; if each saccharide and TT was 250 kD, this would result in a total MW of about 1000 kDa (¶[0017]; instant claims 10, 23). Bigio teaches the saccharide antigen may be conjugated to the carrier protein via a linker (reference claim 13; ¶[0037][0040]), such as a C4 to C12 linear linker (¶[0042]; instant claim 13) or a adipic acid N-hydroxysuccinimido diester linker (¶[0043]; instant claim 14). Bigio teaches carriers of the instant compositions may include histidine buffers (¶[0087]), TWEEN™-80 (polysorbate-80; ¶[0088]), calcium salts, and aluminum hydroxide salt (¶[0087][0098-0100]; such as amorphous aluminum hydroxyphosphate adjuvant ¶[0100]; instant claim 19).
While Bigio teaches that multiple L1-VLP-based HPV antigens may be co-delivered in the vaccine compositions comprising the Neisseria meningitidis conjugate antigens, and Bigio teaches that ideally the HPV antigens are derived from serotypes 6, 11, 16, or 18, Bigio fails to explicitly teach that said HPV antigens are from a separate, quadrivalent HPV Type 6, 11, 16, and 18 recombinant vaccine, or to specifically teach the amount of each HPV L1 protein from each HPV subtype delivered. Further, while Bigio teaches the compositions may be administered with a diphtheria-tetanus-pertussis vaccine, Bigio fails to explicitly teach that said vaccine is a Tdap or DTaP5 vaccine. Bigio also failed to teach that the co-administration of a Neisseria meningitidis conjugate vaccine with a HPV multivalent vaccine did not result in interference against any of the delivered antigens, such as against HPV type 6, 11, 16, or 18 L1 antigens. Finally, while Bigio teaches that unconjugated proteins and polysaccharides should be removed from the vaccine composition, Bigio focuses on the removal of unconjugated proteins and not unconjugated polysaccharides. However, such combinations, limitations, and species of these specific genera were known in the art to a skilled artisan, as was testing for concomitant administration and potential interference of vaccines, as shown by Anderson and Sanofi Pasteur, and as evidenced by Merck, Rivera, Shafer, Simon, and Arguedas.
Anderson teaches methods of delivering a MenACWY conjugate vaccine, which is a quadrivalent meningococcal conjugate vaccine wherein the purified Neisseria meningitidis capsular polysaccharides are conjugated to carrier proteins, such as diphtheria or tetanus toxoid (reference claims 1, 12; NIMENRIX® p. 31, ¶3), wherein the capsular polysaccharides are from serogroups A, B, C, Y, and W135 (reference claims 1-16; p. 1, ¶3; p. 2, ¶1; p. 11, ¶3). The NIMENRIX® vaccine has each of the polysaccharides conjugated to tetanus toxoid (TT)(pp. 34-5, ¶ bridging pages), and the polysaccharides of Anderson and the commercially-available vaccines are noted as being purified (NB: the use of “purified” in the sense of chemical compositions means the composition likely had contaminants or impurities, such as unbound carriers or polysaccharides, removed or minimized)(p. 6, ¶4; p. 34, ¶1). Anderson teaches said N. meningitidis vaccine is administered concomitantly with immunogenic compositions against diphtheria, tetanus, and pertussis (dTap) and/or immunogenic composition against human papillomavirus (reference claim 1; p. 11, ¶4; instant claim 18). The “concomitant” administration of Anderson may be simultaneous or administered within 24 hours of each other (p. 7, ¶3). Said HPV immunogenic composition may be a quadrivalent Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine (p. 7, ¶1; p. 12, ¶3-4; pp. 28-29, ¶ bridging pages, p. 29, ¶2; e.g. GARDASIL® at p. 31, ¶3.) As evidenced by the teaching of Merck, the GARDASIL® HPV vaccine is a quadrivalent, recombinant HPV vaccine which inherently comprises in each 0.5 mL dose approximately 20 ug of HPV6 L1 protein, 40 ug of HPV11 L1 protein, 40 ug of HPV16 L1 protein, and 20 ug of HPV18 L1 protein, wherein the quadrivalent vaccine is prepared from purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV types 6, 11, 16, and 18 (p. 1, left col., ¶1; p. 12, “11. Description”; instant claims 17, 21). Anderson teaches the concomitant administration of HPV antigens and the Neisseria meningitidis capsular polysaccharides generated a non-inferior immune response when delivered together against both HPV and Neisseria meningitidis compared to the compositions administered alone, and similarly the concomitant administration of diphtheria, tetanus, and pertussis antigens and the Neisseria meningitidis capsular polysaccharides generated a non-inferior immune response when delivered together against diphtheria, tetanus, pertussis, and Neisseria meningitidis compared to the compositions administered alone, making it obvious to a skilled artisan to test for the difference (p. 12, ¶3 to p. 13, ¶1).
Anderson teaches that additional descriptive endpoints for determining the primary objective were the antibodies to the concomitant vaccine antigens measured as a geometric mean titer (GMT) or geometric mean concentrations (GMCs) at post-vaccination (p. 52, ¶5). Anderson therefore shows that methods of determination of interference or non-interference would be obvious to a skilled artisan and would be readily determined by analyzing such parameters as the GMT for each treatment group and comparing them to other treatment groups.
Sanofi Pasteur teaches a Phase II study of a quadrivalent meningococcal conjugate vaccine in healthy adolescents (Study Details: Study Identification). Sanofi Pasteur teaches the purpose of the trial was to evaluate the immunogenicity and safety of MenACYW conjugate vaccine compared to those of a licensed product, MENVEO® vaccine, and also evaluate MenACYW conjugate vaccine when given alone compared to when given with Tdap vaccine and HPV vaccine (Study Description: Brief Summary.) GARDASIL® was the HPV vaccine utilized in the study (Conditions: Keywords). The meningococcal vaccine delivered was a meningococcal polysaccharide (Serogroups A, C, Y, and W135) tetanus toxoid conjugate vaccine, delivered in 0.5 mL via intramuscular (IM) injection (MenACYW conjugate vaccine)(Arms and Interventions: Arms, Experimental: Study Groups 1 and 3). Sanofi Pasteur teaches the level of antibody titers against the meningococcal serogroups A, C, Y, and W135 would be measured, as well as the levels of anti-tetanus and anti-HPV antibody concentrations (Outcome Measures.)
The art was further apprised to the testing for the immunogenicity and potential interference from co-administration of Neisseria meningitidis vaccine compositions with HPV multivalent vaccine compositions, as evidenced by the teachings of Arguedas and Rivera.
Arguedas teaches testing subjects 11-18 years of age for receiving the MenACWY-CRM vaccine concomitantly or sequentially with Tdap (BOOSTRIX™) and HPV (GARDASIL™), wherein the HPV vaccines were virus-like particles (VLPs) comprising HPV L1 antigens from types 6, 11, 16, and 18 (Tables 2-4), and that said administration showed no interference, especially with respect to HPV types 6 and 18 (Table 4). Arguedas teaches concomitant administration of HPV, Tdap, and MenACWY-CRM vaccines would increase patient compliance and the overall immunogenicity does not appear to be affected by said concomitant administration (entire document; see abstract, “Sect. 4: Discussion” at p. 3176). Arguedas notes that the adverse effects were not increased with the combined delivery of vaccines, and the local reactions at administration sites were not significantly different from administration of these vaccines alone (Sect. 3.3.3. pp. 3175-6; instant claim 26.)
Rivera teaches the co-administration of MenACWY-TT (quadrivalent Neisseria meningitidis vaccine, wherein the Neisseria meningitidis vaccine antigens are conjugated to tetanus toxoid (TT) carriers), with Tdap and AS04-HPV16/18, and that co-administration did not show interference (entire document; see abstract.) Rivera teaches the reactogenicity was similar amongst all vaccine groups (Sect. 3.3, p. 3970) and teaches testing the interference by assessing GMT ratio (Tables 1-2). As noted in the supplemental data of Rivera, each 0.5 mL dose of the AS04-HPV-16/18 vaccine contains 20 μg of each HPV-16 and HPV-18 L1 virus-like particles, and the GSK proprietary Adjuvant System AS04 (Text S2. Vaccine description.)
Additionally, the purification of conjugated vaccines, such as purification of polysaccharide antigen-carrier protein conjugate vaccines from contaminating free or unbound polysaccharide and/or protein was an obvious optimization undertaken in the N. meningitidis vaccine art, as evidenced by the teachings of Shafer and Simon.
Shafer focuses on removal of unconjugated carrier protein, but notes that their studies proved this to be sufficient to retain similar immune responses without evidence of interference from remaining or residual unconjugated polysaccharide antigen. Shafer notes “There is considerable evidence suggesting that the presence of unconjugated polysaccharide along with the protein-conjugated polysaccharide suppresses the immune response to the polysaccharide… WHO and FDA, therefore, require that the amount of free polysaccharide in the conjugate vaccine be determined. However, determining the amount of free high molecular weight polysaccharide present in a high molecular weight conjugate can be challenging.”(p. 1548, left col., ¶1). Shafer then notes that their solid phase media preferentially bound to unconjugated protein, thus allowing removal of unconjugated protein carrier from the vaccine compositions (p. 1548, left col., ¶1). Shafer also teaches that certain Neisseria polysaccharide antigen-carrier conjugates contain phosphodiester linkages rendering them very susceptible to base hydrolysis, thus releasing free polysaccharide which may interfere with the immune response induced to the conjugated polypeptide (Sect. 3.7, “Immunogenicity of conjugates”.) However, the tests performed by Shafer compared the method of purifying the free protein carrier from the composition to the traditional methods which removed free carrier and free antigen from the compositions, and found that removal of the free carrier protein generated similar antibody titers, thus indicating their method of removing only the protein was sufficient (p. 1555, rt. Col.) Shafer notes that “since it is difficult to remove unconjugated high molecular weight polysaccharide from the protein-linked polysaccharide, it is preferable to use a chemical coupling scheme, which produces a product with low levels of free polysaccharide. Direct conjugation of proteins to CDAP-activated polysaccharides is one such chemistry, which can be used to link polysaccharides covalently to proteins with good efficiency which could interfere with the immune response induced to the conjugated polysaccharide (p. 1557, left col., ¶3).
Simon recapitulates on the teachings of Bigio and Shafer with respect to unconjugated protein removal from protein-antigen conjugate vaccines, and provides a method to additionally remove unconjugated polysaccharide antigen from said compositions. Simon teaches methods for reducing the levels of free carbohydrate from a solution of protein-linked carbohydrate (conjugate) and non-linked carbohydrate using ion exchange membranes or monoliths, and teaches compositions and vaccines produced by said methods (entire document; see abstract, p. 1, ¶4). Simon teaches the methods can be used on polysaccharide antigen-protein carrier vaccines for Neisseria meningitidis, such as MenA/C/Y/W135 capsular polysaccharides (p. 12, ¶5; p. 13, ¶2-3; reference claims 27-28, 33-34). Simon teaches that a substantial portion or all of the free carbohydrate binds the matrix, and that about 80% or about 99% or more of the free carbohydrate can bind to the matrix (p. 10, ¶2; p. 12, ¶2; reference claim 42).
In summation, the art teaches concomitant administration of Neisseria meningitidis vaccine compositions with additional vaccines, including HPV and Tdap vaccines, and teaches that said co-administration does not result in interference, as evidenced by the teachings of Anderson, Arguedas, and Rivera, and the art additionally teaches the need for purification of unbound polysaccharide and carrier protein from the composition to also prevent any potential interference, as evidenced by the teachings of Shafer and Simon. Further, the prevention of interference does not appear to be tied to any specific, novel step that is not already taught in the prior art with respect to vaccine immunity and interference. Therefore, the functional limitations of instant claims 1, 5, 7, and 26 are negative limitations that would easily be prevented by following the guidance found in the prior art, as evidenced by the combined teachings of Anderson, Arguedas, Rivera, Shafer, Simon, and Bigio, such as the use of specific, well-tested, commercially available vaccines (as suggested by Anderson) and the required removal of contaminants, such as free or unbound polysaccharide, as noted by Bigio, Shafer, and Simon.
Given the teachings of Bigio, Anderson, Sanofi Pasteur, Arguedas, Rivera, Shafer, and Simon, one of skill in the art would be apprised as to commercial, quadrivalent L1-VLP-based HPV vaccines (e.g. GARDASIL®) and commercially available Neisseria meningitidis capsular conjugate vaccines (e.g. NIMENRIX®), and the suggestion to deliver or administer these vaccines concomitantly or simultaneously. One of skill in the art would find it obvious to deliver MenACWY-TT conjugated vaccines in combination with other vaccines, such as GARDASIL®, given the teachings of Sanofi Pasteur, and to determine the immunological outcomes of co-delivery of said vaccines. One of skill in the art would find it obvious to use Neisseria meningitidis capsular conjugate vaccines that comprised limited contaminants, such as limited free, unbound carrier protein and polysaccharide antigens, as suggested by the teachings of Bigio, Shafer, and Simon, thus adding an additional layer of safety to prevent interference from the presence of these unbound components. One of skill in the art would find it obvious to utilize a known HPV antigenic composition, such as GARDASIL® or HPV16/18, for delivery with the compositions of Bigio or Sanofi Pasteur, given the suggestion by Sanofi Pasteur, Anderson, Arguedas, and Rivera. Comparing the potential for interference between the two known vaccine compositions would also be obvious, given the teachings of Anderson, Arguedas, and Rivera to do so when delivering different antigens concomitantly. Therefore, the limitations of instant claims 1, 6, 17-18, 21, and 25 would be obvious to a skilled artisan, given the teachings of Bigio, Anderson, and Sanofi Pasteur as evidenced by Merck, Rivera, Arguedas, Shafer, and Simon.
Finally, the functional limitations of instant claims 3-4 would be inherent aspects of the system rendered obvious by Bigio, Anderson, Sanofi Pasteur, Arguedas, Rivera, Shafer, and Simon, as the compositions rendered obvious by Bigio, Anderson, Sanofi Pasteur, Arguedas, Rivera, Shafer, and Simon share the same structural elements of the instant independent claims.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Bigio in order to test for the potential of interference or enhancement with the concomitant administration of two or more known vaccines, thereby allowing a skilled artisan to know whether or not said vaccines could safely be delivered at the same time or be comprised within a singular composition. One would have been motivated to do so, given the suggestion by Sanofi Pasteur, Anderson, Rivera, and Arguedas that it was common practice in the art to assess the immune response elicited by the vaccines when delivered separately versus together. One would be further motivated to ensure the vaccine compositions were devoid of contaminating unbound polysaccharide antigen or carrier protein, as Bigio, Shafer, and Simon taught that vaccine regulatory authorities, such as the WHO and FDA, required the removal of these components, and Shafer and Simon provided methods for the skilled artisan to minimize both in polysaccharide antigen-carrier protein conjugate vaccines such as those for Neisseria meningitidis. There would have been a reasonable expectation of success, given the knowledge that Neisseria meningitidis and HPV commercial vaccine formulations were known and used in the art, as taught by Sanofi Pasteur, Anderson, Rivera, and Arguedas, and also given the knowledge that delivery of the antigens together was explicitly taught by Sanofi Pasteur and further suggested by Bigio, Anderson, Rivera, and Arguedas. There would be further expectation of success, given that Arguedas teaches the delivery of MenACWY-CRM with GARDASIL™ and Tdap vaccines, and shows no interference with the sequential or concomitant delivery of these vaccines, and given that Sanofi Pasteur was performing a Phase II clinical trial of a MenACWY-TT along with GARDASIL® to determine the effectiveness of delivering both vaccines together. There would be further expectation of success, given that Rivera teaches MenACWY-TT vaccine delivery with HPV-L1-VLP vaccines and Tdap vaccines, and that there was no interference observed with this concomitant delivery, thus suggesting the MenACWY carrier conjugation had no effect on eliciting interference with other Tdap or HPV vaccine formulations, and that the HPV L1-VLP vaccine formulations did not interfere with the MenACWY conjugate vaccines. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant's arguments filed 11/25/2025 have been fully considered. In light of the amendments to the claims, the previous rejection was withdrawn. However, a new rejection utilizing all the teachings from the previous rejection has been set forth with the addition of the “Sanofi Pasteur” reference. Therefore, the arguments as they relate to the previous teachings will be addressed as applicable herein.
Applicant argues that the instant claims are now commensurate in scope with the conditions which gave rise to the unexpected and/or surprising results, as claim 1 has been amended to specifically recite a definition of what is intended by the limitation “does not interfere”. However, the Office maintains that, despite the inclusion of this definition, the conditions which resulted in the unexpected and/or surprising results are still not commensurate in scope with the instant claims.
As per MPEP §716.02 (d), evidence of non-obviousness, such as unexpected results, must be commensurate in scope with the claimed invention, meaning that the evidence provided for in the specification and arguments must prove that the advantages of the claimed invention exist across the entire claimed range. A functional limitation often fails to make an invention non-obvious if the evidence only supports one specific embodiment, leaving broader, more functionally defined, and/or less optimized variations covered by the claims as still being obvious. Applicant points to the evidence that coadministration of a Neisseria meningitidis vaccine comprising polysaccharide-tetanus toxoid conjugates as presently recited does not interfere with the immunogenicity of an HPV vaccine as recite in the present claims. However, in the instant claims, the scope of many limitations is very broad, including, but not necessarily limited to, the breadth of the Neisseria meningitidis vaccine composition, the HPV vaccine composition, the dosage of the vaccines, the regimen of the vaccine administration, the route of administration of each vaccine, and the demographics of the subject receiving said vaccines.
Starting with the Neisseria meningitidis vaccine composition, said vaccine comprises (which allows for the use of additional, non-claimed embodiments or limitations):
a) a first conjugate of MenA capsular polysaccharide to tetanus toxoid;
b) a second conjugate of MenC capsular polysaccharide to tetanus toxoid;
c) a third conjugate of MenW-135 capsular polysaccharide to tetanus toxoid;
d) a fourth conjugate of MenY capsular polysaccharide to tetanus toxoid; and
e) less than 20% free polysaccharide by weight. First, the claimed capsular polysaccharide (CP) of each Neisseria meningitidis serogroup is reasonably drawn to cover the full-length molecule and fragments thereof, provided the fragments retain the essential structural or functional characteristics (e.g., antigenicity) of the full-length polysaccharide. CP are defined by their repeating units; fragments (e.g., produced by enzymatic cleavage) that retain these repeating units often maintain the same antigenic determinants, making them functional equivalents. In the context of vaccines, "capsular polysaccharide" usually encompasses purified, shorter chains or conjugated fragments that are used to elicit immune responses, not just the massive, membrane-bound, full-length structure (MPEP §2111). Substitutions and modifications of the CP can greatly affect the immunogenicity of the resulting conjugate (Berry DS, et. al. Infect Immun. 2002 Jul;70(7):3707-13.), while the 3D shape of the conjugate can affect the overall immunogenicity of the resulting conjugate (Xu M, et. al. Vaccine. 2015 Oct 26;33(43):5815-5821. Epub 2015 Sep 19.) Serogroup B meningococcal capsule is poorly immunogenic in all populations, even when coupled to carrier proteins, which is due to the serogroup B capsule structure mimicking human host polysialic acid moieties, such as the neural cell adhesion molecule, N-CAM (Tzeng YL, et. al. Crit Rev Microbiol. 2016 Sep;42(5):759-72. Epub 2015 Jun 19.) Additionally, while polysaccharide fragments isolated from the producing organism can be used for vaccine production, these are typically heterogenous. Post-filing art suggests that serogroup-specific glycosyltransferase enzymes from Neisseria may serve as an alternative and potentially controllable method to obtain capsular polysaccharides for production of homogeneous vaccines (Sharyan A, et. al. BMC Res Notes. 2018 Jul 16;11(1):482.) Therefore, there is significant uncertainty in the prior and even post-filing art with respect to the breadth of CP conjugates that would be useful in the method as claimed.
With respect to the tetanus toxoid (TT) which may be conjugated to said CP, the breadth is drawn to any known TT sequences which can reasonably be used for conjugation to CP. Tetanus Toxin, produced by Clostridium tetani, is a neurotoxin having a molecular weight of 150 kDa. It is made up of two parts: a 100 kDa heavy or B-chain and a 50 kDa light or A-chain. The chains are connected by a disulfide bond. The B-chain binds to disialogangliosides (GD2 and GD1b) on the neuronal membrane. The A-chain, a zinc endopeptidase, attacks the vesicle-associated membrane protein (VAMP). Tetanus Toxin Fragment C (Tet C or TTC) is a 50 kD polypeptide generated by protease cleavage (e.g., with papain) of Tetanus toxin, or through recombinant expression of the fragment. It corresponds to the 451 amino acids at the C-terminus (amino acid positions 865-1315). Fragment C has been shown to be non-toxic. Because it binds to neurons with high specificity and affinity, TTC finds use as a targeting molecule for neuronal drug delivery or for research purposes. TTC protein is also potentially useful as a vaccine carrier protein and for use in a vaccine to protect against C. tetani infection (US20140051093A1).
Different forms of TT which could be reasonably used for conjugation at the time of filing include:
Conventional Tetanus Toxoid (TT/TTxd): The standard, chemically detoxified tetanus toxin protein, commonly used in licensed vaccines like Hib, Meningococcal (MenA, C, W, Y), and Pneumococcal (18C) conjugates.
Tetanus Toxin Fragment C (TTC): A smaller, non-toxic fragment of the tetanus toxin used in research for conjugation, noted for its neuronal binding properties and ability to act as a carrier.
Other Non-toxic mutants of TT
TT may be conjugated to the CP through a variety of chemical reactions and/or through the use of various linking agents, may be in purified or unpurified form (e.g. unpurified may have more toxic contaminants typically found in tetanus vaccines), and also be bound at different ratios of saccharide to carrier protein (US20180214532A1).
Turning to the HPV L1 proteins from the noted serotypes claimed, said HPV L1 proteins are broadly claimed as “in the form of virus-like particles.” First, the claimed HPV L1 proteins of each serotype is reasonably drawn to cover the full-length molecule and fragments thereof, provided the fragments retain the essential structural or functional characteristics (e.g., antigenicity) of the full-length L1 protein. Additionally, while the L1 protein may self-assemble into non-infectious shells made from this major capsid protein, how these proteins are made can have distinct variations on their antigenicity due to post-translational modifications. Licensed HPV vaccines which utilize these VLP-based systems differ in the antigen expression system used, antigen composition and adjuvants included. For instance both GARDASIL® and GARDASIL®9 products are produced in yeast and formulated with amorphous aluminum hydroxyphosphate sulfate (AAHS) adjuvant, which has an increased capacity to bind to L1 VLPs compared with other aluminum salts. In contrast, CERVARIX® is produced in insect cells using a baculovirus expression vector system and adjuvanted with AS04 which contains aluminum hydroxide plus an additional immunostimulant, the toll-like receptor 4 agonist monophosphoryl lipid A. AS04 has been shown to enhance innate as well as humoral and cell-mediated immune responses, and may be responsible for differences in the overall immunogenicity described in head-to-head studies of the two vaccines. Other differences between the vaccines include the concentration of each of the L1 VLPs, and the ratio of antigen to adjuvant. GARDASIL® has two-fold higher concentrations of HPV-16 L1 VLP and an equal concentration of HPV-18 L1 VLP compared with CERVARIX®. GARDASILl®9 contains twice the amount of HPV-18 L1 VLP, 50% more HPV-16 antigen and more than twice the level of adjuvant contained in GARDASIL® (Pinto LA, et. al. Vaccine. 2018 Aug 6;36(32 Pt A):4792-4799. Epub 2018 Feb 1.) Additionally, the breadth of HPV L1 compositions within VLPs is reasonably considered to encompass L1-based VLPs which comprise chimeric proteins or additional protein antigens from HPV or other heterologous sources (Matić S, et. al. BMC Biotechnol. 2011 Nov 15;11:106.; Greenstone HL, et. al. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1800-5.)
Additionally, the breadth of the subject receiving the immunization and the timing of said immunization routine is not claimed and is very broad. With respect to vaccination against Neisseria meningitidis, despite the remarkable success of polysaccharide vaccines in preventing invasive disease, polysaccharides were not effective in protecting infants with their immature immune systems from pathogens. While there is no clear-cut age at which the immune system starts to produce antibodies against T-independent antigens, it is believed that polysaccharide vaccines are not effective in infants under the age of 24 months (Cadoz M. Vaccine. 1998 Aug-Sep;16(14-15):1391-5.) Conjugate vaccines to Neisseria meningitidis were essential in inducing a proper response in infants, yet response timing is crucial, as 3-month-old infants may have limited response to some formulations while 7 to 12-month-old infants show significant antibody production (Pollard AJ, et. al. Infect Immun. 1999 May;67(5):2441-51.) Likewise, in the elderly, when the B cell response was compared between young and elderly adults, elderly participants had a more blunted response to vaccination, and with Neisseria meningitidis infection in the elderly being rather uncommon, it was questioned as to whether or not such vaccine studies were even further warranted as to how to improve the immunogenicity of said conjugate vaccines in this population (Trzewikoswki de Lima G, et. al. J Aging Res. 2019 Aug 22;2019:9287121.)
Further, the concentration of antigens and other components, such as adjuvants, utilized in each vaccine is not claimed in the instant independent claim. As discussed above with respect to the HPV vaccines, the different commercial vaccines have different concentrations of antigens and adjuvants within their systems. As noted in Table 1 of the specification, GARDASIL® appears to be the only L1 VLP HPV vaccine studied in these experiments. It is unclear if CEVARIX®, which has a two-fold lower concentration of HPV-16 L1 VLPs compared to GARDASIL® and uses a different adjuvant system, would produce the same results with the CP-peptide conjugate vaccines tested.
Therefore, as the breadth of what is being claimed in the instant method is still very broad with respect to multiple limitations, including at least demographics, dosage, timing, and vaccine compositions, it remains that the functional limitation added to instant claim 1 is not commensurate in scope with the breadth of conditions actually tested to provide these surprising and/or unexpected results.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The arguments regarding the prior art also focus on how the prior art fails to suggest a method that would result in non-interference occurring. First, for the reasons set forth supra, the criticality of parameters in the claimed method have not been set forth in the claims, and the claims are not commensurate in scope with the surprising or unexpected results that resulted in non-interference as the claims are far broader than those parameters which resulted in said results, as the claims can be reasonably interpreted as reading upon a range of limitations (e.g. types of vaccines delivered, dosages, ratios, demographics, subjects, etc.) that goes well beyond the conditions which provided such results. Even in arguendo if the claims were commensurate in scope with said conditions, the prior art cited shows that 1) the MenACYW-TT vaccine (known now as MENQUADFI®; see teachings of Sanofi Pasteur) which was used in the instant experiments was known in the art, 2) the HPV vaccine which was used in the experiments was known in the art (GARDASIL®; see teachings of Sanofi Pasteur, Merck, and Anderson), and 3) delivery of these two compositions concomitantly was specifically taught in the art, as was the testing for immunological outcomes of said concomitant delivery (Sanofi Pasteur, see detailed analysis supra.) Post-filing art regarding the findings from the study taught by Sanofi Pasteur show that there was a non-inferior response when MenACYW-TT was co-administered with GARDASIL®(Chang LJ, et. al. Vaccine. 2020 Apr 23;38(19):3560-3569. Epub 2020 Mar 21.), which again supports the argument that the features claimed (e.g. non-interfering when delivered together) were inherent to the obvious methods.
Applicant provides arguments that a skilled artisan reading Bigio would have no reason to turn to Anderson. As the rejection has been amended to include Sanofi Pasteur, it is now a question as to whether or not, reading these three teachings, if a skilled artisan would find it obvious to deliver MenACWY-TT along with HPV vaccines such as GARDASIL® with a reasonable expectation to determine the immunogenicity of such a concomitant delivery and to determine if there would be interference. The Office has shown that it would be obvious, and would be further obvious as it was a common practice in the vaccine art to evaluate interference when delivering multiple antigens, as shown by the teachings of Rivera and Arguedas. Further dependent claimed limitations, such as the purity of said compositions, would be obvious to a skilled artisan, as the rationale for performing such purifications was known in the art, as evidenced by Shafer and Simon.
For at least these reasons, the arguments regarding the obvious nature of the instant claims remain unconvincing, and the claims remain rejected for being obvious in light of the prior art.
Double Patenting
The text regarding nonstatutory double patenting (NSDP) was presented in a previous Office action.
(Rejection withdrawn.) The rejection of Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,147,866 in view of Bigio, Anderson, Rivera, and Arguedas (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,707,514 in view of Bigio, Anderson, Rivera, and Arguedas (supra) ) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,147,866 in view of Sanofi Pasteur, Bigio, Anderson, Rivera, and Arguedas (supra).
Both the instant claims and the ‘866 claims are drawn to Neisseria meningitidis vaccine compositions comprising four different conjugates of capsular polysaccharides from MenA, MenC, MenW-135, and MenY, wherein the capsular polysaccharides are linked or conjugated to tetanus toxoid as a carrier protein. Both claim that the conjugates comprise double-end-linked conjugated polysaccharides and single-end-linked conjugated polysaccharide, wherein the polysaccharides of the second conjugate have an O-acetylation level of 0.3 μmol/mg polysaccharide to 1.6 μmol/mg polysaccharide. Both claim the capsular polysaccharide may be attached to the carrier protein through a linker comprising a carbamate, a spacer, and an amide, wherein the spacer is between the carbamate and the amide and comprises 2-10 linear carbons, and the first conjugate has a polysaccharide to carrier protein mass ratio of 0.3 to 1.5. Both claim the conjugates have an average molecular weight ranging from 300 kDa to 1500 kDa. Both claim the composition comprises less than 20% free polysaccharide by weight relative to total polysaccharide. Both claim the use of the same linker of Formula I. The main difference is the ‘866 claims are only drawn to the vaccine composition, while the instant claims are drawn to a method of delivering said composition along with HPV type 6, 11, 16, and 18 L1 proteins, wherein said composition comprises less than 20% free polysaccharide by weight, and wherein the coadministration does not result in any immune response interference against the HPV proteins. However, said differences would be obvious to a skilled artisan in light of the teachings of Bigio, Anderson, Sanofi Pasteur, Rivera, and Arguedas. For instance, coadministration of the two compositions would be obvious in light of the teachings of Sanofi Pasteur and Anderson, which teach the delivery of the MenACWY-TT vaccine along with HPV quadrivalent vaccines (see detailed analysis of Sanofi Pasteur and Anderson supra). Similarly, Arguedas teaches delivering the MenACWY-CRM vaccine concomitantly or sequentially with Tdap (BOOSTRIX™) and HPV (GARDASIL™), wherein the HPV vaccines were virus-like particles (VLPs) comprising HPV L1 antigens from types 6, 11, 16, and 18 (Tables 2-4), and that said administration showed no interference, especially with respect to HPV types 6 and 18 (Table 4). Rivera teaches the co-administration of MenACWY-TT (quadrivalent Neisseria meningitidis vaccine, wherein the Neisseria meningitidis vaccine antigens are conjugated to tetanus toxoid (TT) carriers), with Tdap and AS04-HPV16/18, and that co-administration did not show interference (entire document; see abstract.) Rivera teaches the reactogenicity was similar amongst all vaccine groups (Sect. 3.3, p. 3970) and teaches testing the interference by assessing GMT ratio (Tables 1-2). As Sanofi Pasteur, Anderson, Rivera, and Arguedas teach concomitant administration of an HPV vaccine and a N. meningitidis vaccine, and Anderson, Rivera, and Arguedas teach the concomitant delivery of the two distinct vaccines was noninferior compared to delivery of the single vaccines alone, it would be obvious to a skilled artisan to test the MenACWY-TT and quadrivalent HPV L1 VLP vaccine compositions together, as both were commercially available vaccines, to determine if interference or enhancement may occur, and a skilled artisan would have a reasonable expectation of success in that said compositions would likely not interfere with one another. Further, as Sanofi Pasteur teaches the Phase II clinical trials of delivering a commercially available HPV L1 VLP quadrivalent vaccine along with a MenACWY-TT vaccine, one would have a reasonable expectation of success with such a study entering not just a Phase I clinical trial, but a further Phase II clinical trial. Further, Bigio teaches the N. meningitidis vaccine of the instant claims and that said compositions may be delivered along with additional antigens, such as HPV type 6, 11, 16, and 18 L1 antigens, especially in VLP form. It would be obvious to try and to combine the N. meningitidis vaccine of the instant claims with other antigens, especially those already marketed and available as vaccines, such as Tdap, GARDASIL®, or DTaP5, in light of the teachings of the prior art as evidenced by Bigio, Anderson, Sanofi Pasteur, Rivera, and Arguedas.
Therefore, the instant claims are an obvious variation of the ‘866 claims, especially in light of the teachings of Bigio, Anderson, Sanofi Pasteur, Rivera, and Arguedas.
(New rejection – necessitated by amendment.) Claims 1, 3-14, 17-19, 21-23, 25-26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,707,514 in view of Bigio, Sanofi Pasteur, Anderson, Rivera, and Arguedas (supra).
Both the instant claims and the ‘514 claims are drawn to methods of vaccinating a subject against Neisseria meningitidis through delivery of Neisseria meningitidis vaccine compositions comprising four different conjugates of capsular polysaccharides from MenA, MenC, MenW-135, and MenY, wherein the capsular polysaccharides are linked or conjugated to tetanus toxoid as a carrier protein. Both claim that the conjugates comprise double-end-linked conjugated polysaccharides and single-end-linked conjugated polysaccharide, wherein the polysaccharides of the second conjugate have an O-acetylation level of 0.3 μmol/mg polysaccharide to 1.6 μmol/mg polysaccharide. Both claim the capsular polysaccharide may be attached to the carrier protein through a linker comprising a carbamate, a spacer, and an amide, wherein the spacer is between the carbamate and the amide and comprises 2-10 linear carbons, and the first conjugate has a polysaccharide to carrier protein mass ratio of 0.3 to 1.5. Both claim the conjugates have an average molecular weight ranging from 300 kDa to 1500 kDa. Both claim the composition comprises less than 20% free polysaccharide by weight relative to total polysaccharide. Both claim the use of the same linker of Formula I. The main difference is the instant claims are drawn to a method of delivering said composition along with HPV type 6, 11, 16, and 18 L1 proteins, and wherein the coadministration does not result in any immune response interference against the HPV proteins. However, said differences would be obvious to a skilled artisan in light of the teachings of Bigio, Sanofi Pasteur, Anderson, Rivera, and Arguedas. For instance, coadministration of the two compositions would be obvious in light of the teachings of Sanofi Pasteur and Anderson, which teach the delivery of the MenACWY-TT vaccine along with HPV quadrivalent vaccines (see detailed analysis of Sanofi Pasteur and Anderson supra). Similarly, Arguedas teaches delivering the MenACWY-CRM vaccine concomitantly or sequentially with Tdap (BOOSTRIX™) and HPV (GARDASIL™), wherein the HPV vaccines were virus-like particles (VLPs) comprising HPV L1 antigens from types 6, 11, 16, and 18 (Tables 2-4), and that said administration showed no interference, especially with respect to HPV types 6 and 18 (Table 4). Rivera teaches the co-administration of MenACWY-TT (quadrivalent Neisseria meningitidis vaccine, wherein the Neisseria meningitidis vaccine antigens are conjugated to tetanus toxoid (TT) carriers), with Tdap and AS04-HPV16/18, and that co-administration did not show interference (entire document; see abstract.) Rivera teaches the reactogenicity was similar amongst all vaccine groups (Sect. 3.3, p. 3970) and teaches testing the interference by assessing GMT ratio (Tables 1-2). As Sanofi Pasteur, Anderson, Rivera, and Arguedas teach concomitant administration of an HPV vaccine and a N. meningitidis vaccine, and Anderson, Rivera, and Arguedas teach the concomitant delivery of the two distinct vaccines was noninferior compared to delivery of the single vaccines alone, it would be obvious to a skilled artisan to test the MenACWY-TT and quadrivalent HPV L1 VLP vaccine compositions together, as both were commercially available vaccines, to determine if interference or enhancement may occur, and a skilled artisan would have a reasonable expectation of success in that said compositions would likely not interfere with one another. Further, as Sanofi Pasteur teaches the Phase II clinical trials of delivering a commercially available HPV L1 VLP quadrivalent vaccine along with a MenACWY-TT vaccine, one would have a reasonable expectation of success with such a study entering not just a Phase I clinical trial, but a further Phase II clinical trial. Further, Bigio teaches the N. meningitidis vaccine of the instant claims and that said compositions may be delivered along with additional antigens, such as HPV type 6, 11, 16, and 18 L1 antigens, especially in VLP form. It would be obvious to try and to combine the N. meningitidis vaccine of the instant claims with other antigens, especially those already marketed and available as vaccines, such as Tdap, GARDASIL®, or DTaP5, in light of the teachings of the prior art as evidenced by Bigio, Anderson, Sanofi Pasteur, Rivera, and Arguedas.
Therefore, the instant claims are an obvious variation of the ‘514 claims, especially in light of the teachings of Bigio, Anderson, Sanofi Pasteur, Rivera, and Arguedas.
Response to Arguments
Applicant's arguments filed 11/25/2025 have been fully considered. While the original NSDP rejections were withdrawn, new rejections over the same patents utilizing the additional teachings of Sanofi Pasteur was presented. Arguments regarding these rejections will therefore be addressed as applicable to the new rejections herein.
Applicant repeats the arguments regarding Bigio, Anderson, Rivera, and Arguedas. For the reasons detailed supra, said arguments were not persuasive. No additional arguments were presented regarding the patentable distinction between the instant claims and the ‘866 or ‘514 patent claims.
Conclusion
No claims are 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 RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/Primary Examiner, Art Unit 1671