Office Action 3: Non-Final Rejection (2024-04-19)
Rejection types: 102 - Lack of Novelty, 103 - Obviousness, 112 - Written Description/Enablement

CLAIMS:
AMENDMENTS TO THE CLAIMS:

Set forth below in ascending order, with status identifiers, is a complete listing of all

claims currently under examination. Changes to any amended claims are indicated by \[\[double

brackets\]\], and or underlining. This listing also reflects any cancellation and or addition of claims.

1-96. (Cancelled)295

97\. (Currently Amended) A solution comprising a purified population of human norovirus Virus-Like Particles (VLPs), wherein the norovirus VLPs comprise at least genogroup II VLPs, wherein said solution contains no more than about 80% residual contaminating protein relative to said VLPs, and wherein the genogroup II VLPs are substantially free of a truncated VP1 subunit .

98\. (Previously Presented) The solution of claim 97, wherein the genogroup II VLPs are genogroup II, genotype 4 VLPs.

99\. (Cancelled)

100\. (Previously Presented) The solution of claim 97, wherein the solution contains less than about 1% VLPs with a truncated VP1 subunit.

101\. (Previously Presented) The solution of claim 97, wherein the solution contains no more than about 10% residual contaminating protein relative to VLP.

102\. (Previously Presented) The solution of claim 97, wherein the VLPs are soluble and structurally intact.

103\. (Previously Presented) The solution of claim 97, wherein the solution is suitable for use in a commercial process.

104\. (Previously Presented) The solution of claim 97, wherein the solution is derived from a cell lysate, culture supernatant, or filtrate containing the VLPs.

105\. (Previously Presented) The solution of claim 104, wherein the solution contains at least about 50%, at least about 65%, or at least about 75% of the VLPs as compared to the lysate, supernatant, or filtrate.

106\. (Previously Presented) The solution of claim 104, wherein the ratio of the VLPs to residual contaminating protein is increased at least about ten-fold, at least about fifty-fold, or at least about ninety-fold as compared to the lysate, supernatant or filtrate.

107\. (Previously Presented) The solution of claim 104, wherein the solution contains no more than about 35% residual contaminating nucleic acid relative to the lysate, supernatant, or filtrate.

108\. (Previously Presented) The solution of claim 104, wherein the solution contains no more than about 5%, no more than about 2%, or no more than about 1% residual contaminating nucleic acid relative to the lysate, supernatant, or filtrate.

109\. (Previously Presented) The solution of claim 104, wherein the lysate, supernatant, or filtrate comprises a live virus other than a human norovirus, and wherein the level of live virus in the solution is less than 10% of the level of the live virus in the lysate, supernatant, or filtrate.

110\. (Previously Presented) The solution of claim 109, wherein the level of live virus in the solution is at least about 104, at least about 105, at least about 106, or at least about 107 fold less than in the lysate, supernatant, or filtrate.

111\. (Currently Amended) The solution of claim 109, wherein the live virus is ,a production virus, or a contaminating virus.

112\. (Previously Presented) The solution of claim 109, wherein the live virus is a production virus that was used to generate the norovirus VLPs.

113\. (Previously Presented) The solution of claim 109, wherein the virus is a rotavirus, a baculovirus, or a retrovirus.

114\. (Previously Presented) A vaccine comprising the norovirus VLPs obtained from the solution of claim 97.

115\. (Previously Presented) The vaccine of claim 114, wherein the vaccine comprises 5-200 g of the norovirus VLPs.

116\. (Previously Presented) The vaccine of claim 114, wherein the vaccine further comprises an adjuvant.

117\. (Previously Presented) The vaccine of claim 114, wherein the vaccine further comprises aluminum hydroxide.

118\. (Previously Presented) The vaccine of claim 114, wherein the vaccine further comprises a buffer.

119\. (Previously Presented) The vaccine of claim 114, wherein the vaccine further comprises L-histidine or imidazole.

120\. (Previously Presented) The vaccine of claim 114, wherein the vaccine is formulated for parenteral administration.

121\. (Previously Presented) The vaccine of claim 114, wherein the pH of the vaccine is from about 6.0 to about 7.0.

OFFICE ACTION:
The present application is being examined under the pre-AIA  first to invent provisions.
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection.  Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.  Applicant's submission filed on 12/4/2023 has been entered.
Applicants are informed that the rejections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant’s arguments and/or amendments.
Claim 97, 98 and 100-121 are examined on the merits.
Response to Arguments
Applicant's arguments filed 10/9/2023 have been fully considered but they are not persuasive. See responses below.
Claim Rejections - 35 USC § 112
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.
(New Rejection Necessitated by Amendments) Claims 97, 98 and 100-121 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 97 recites, “substantially free of a truncated VP1 subunit”.  However, this limitation is not defined as to the metes and bounds of “substantially free”.  The specification does not provide a specific definition of this term.  Therefore, it is unclear what the metes and bounds of “substantially free of a truncated VP1 subunit would be.  Claims 98 and 100-121 are also rejected since they depend from claim 97 but do not remedy this deficiency.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA  35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
(Prior Rejection Maintained) Claims 97, 98, 100-109, 111-118, 120 and 121 are rejected under pre-AIA  35 U.S.C. 102b as being anticipated by Richardson et al. (US PGPub 2012/0156243).
A solution comprising a purified population of human norovirus Virus-Like
Particles (VLPs), wherein the norovirus VLPs comprise at least genogroup II VLPs, wherein said
solution contains no more than about 80% residual contaminating protein relative to said VLPs,
and wherein the genogroup II VLPs are substantially free of a truncated VP1 subunit.
*The newly presented limitation of “substantially free of a truncated VP1 subunit” is not defined as to the metes and bounds of “substantially free”.  The specification does not provide a specific definition of this term.  Therefore, the interpretation of “substantially free of a truncated VP1 subunit” permits the presence of truncated VP1 subunit proteins in the norovirus solution.
The genogroup II VLPs are genogroup II, genotype 4 VLPs.
The solution contains no more than about 10% residual contaminating protein relative to VLP.
The VLPs are soluble and structurally intact.
The solution is suitable for use in a commercial process.
The solution is derived from a cell lysate, culture supernatant, or filtrate containing the VLPs.
The solution contains at least about 50%, at least about 65%, or at least about 75% of the VLPs as compared to the lysate, supernatant, or filtrate.
Wherein the ratio of the VLPs to residual contaminating protein is increased at least about ten-fold, at least about fifty-fold, or at least about ninety-fold as compared to the lysate, supernatant or filtrate.
Wherein the solution contains no more than about 35% residual contaminating nucleic acid relative to the lysate, supernatant, or filtrate.
Wherein the solution contains no more than about 5%, no more than about 2%, or no more than about 1% residual contaminating nucleic acid relative to the lysate, supernatant, or filtrate.
Wherein the lysate, supernatant, or filtrate comprises a live virus other than a human norovirus, and wherein the level of live virus in the solution is less than 10% of the level of the live virus in the lysate, supernatant, or filtrate.
Wherein the live virus is a production virus, or a contaminating virus.
Wherein the live virus is a production virus that was used to generate the norovirus VLPs.
Wherein the virus is a rotavirus, a baculovirus, or a retrovirus.
A vaccine comprising the norovirus VLPs obtained from the solution and the vaccine comprises 5-200 ug of the norovirus VLPs, wherein the vaccine further comprises an adjuvant,
wherein the vaccine further comprises aluminum hydroxide or the vaccine further comprises a buffer. The vaccine is formulated for parenteral administration and the pH of the vaccine is from about 6.0 to about 7.0.
The Prior Art:
Richardson et al. teach norovirus VLPs which possess full-length VP1 proteins or full-length VP1 and VP2 proteins. [see paragraph 39]  The VLPs of Richardson can be made by disassembly and reassembly of VLPs to provide homogenous and pure VLPs. [see paragraph 45]  The norovirus VLPs can contain VP1 subunits from genogroup I or II virus strains. [see paragraph 40 and claims 1 and 6]  It is also taught that a combination of VLPs from genogroups I and II can be formulated, such as Genogroup II, genotype 4. [see paragraph 40 and claim 18]  Richardson et al. further teach processing multivalent norovirus VLPs with VP1 and/or VP2 proteins and purifying these VLPs. [see paragraph 44]  The antigens of the Norovirus that are produced are to be placed in a “substantially pure form”. [see paragraph 70]  These VLPs are to be purified at different points of VLP formation (before or after mixing of the produced VP1 and/or VP2 proteins). [see paragraph 44]  Richardson et al. further teach that the VLPs can be formulated at a dosage of 1ug to 100 ug [see paragraph 62] and that routes of administration such as intranasal or intramuscular are contemplated. [see paragraph 63]  For the formulation of the norovirus antigenic composition of VLPs, buffers and/or adjuvants can be used, such as the adjuvant aluminum hydroxide. [see paragraphs 51-55 and 63]  Since one intended application of this VLP composition is to be delivered in vivo as a vaccine, the pH of this composition would be rendered similar to that of the recipient and therefore at a pH of about 7.0.  Richardson et al. teach the use of baculovirus vectors to express the VLPs of human noroviruses and therefore, the suspension containing VLPs would possess the claimed “live virus” that can be a baculovirus that is used to generate VLPs, or also functioning as a production virus.  The use of this baculovirus to express capsid proteins which yield VLPs is beneficial since the VLPs spontaneously form upon the capsid protein expression. [see paragraphs 9, 34 and 39]
Therefore, these norovirus VLPs of Richardson et al. contain full-length VP1 subunits and do not possess contaminating proteins and inherently meet the purity requirement of claim 97.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
Richardson does not teach obtaining a solution comprising norovirus genogroup 2 VLPs wherein that is inherently substantially free of a truncated VP1 subunit.  Inherency cannot be tied to what may have occurred in the prior art, but what necessarily flows from the teachings of the prior art.   Moreover, in paragraph 39, Richardson specifically teaches that one formulation of norovirus VLPs is to be formed from full-length norovirus VP1 and/or VP2 proteins, but also teaches that truncated VP1 proteins are also contemplated and therefore this paragraph does not support the inherency of the claimed substantially free limitation.
In response, the newly presented limitation of “substantially free of a truncated VP1 subunit” is not defined as to the metes and bounds of “substantially free”.  The specification does not provide a specific definition of this term.  Therefore, the interpretation of “substantially free of a truncated VP1 subunit” at a minimum permits the presence of truncated VP1 subunit proteins in the norovirus solution.
Richardson et al. tested norovirus VLP compositions using SE-HPLC and while VLPs were detected, for many of the samples no fragments were detected during the elution (see Table 5 below).  In addition, paragraph 99 of Richardson et al. states “The VLP fragment that elutes from the column at around 32 min is a highly stable single species that results from destabilization and consequent disassembly of the VLP. Intermediate and smaller fragments were not observed.”
PNG
media_image1.png
727
886
media_image1.png
Greyscale
Therefore, in view of the lack of detecting a fragment of a VLP in this HPLC analysis, and since Richardson et al. teach that full-length VP1 VLPs are specifically desired and obtainable and in view of the instant invention permitting an undefined amount of truncated VP1 to be present (substantially free), the teachings of Richardson et al. inherently provide norovirus VLPs comprising VP1 that are at least substantially free of truncated VP1.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA  35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
(Prior Rejection Mantained) Claim 119 is rejected under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Richardson et al. as applied to claims 97, 98, 100-109, 111-118 and 120-121 above, and further in view of Volkin et al. (US Patent 6,251,678).
The claimed invention also requires that the vaccine further comprises L-histidine or imidazole.
The teachings of Richardson et al. are discussed above.  However, they do not teach the addition of L-histidine or imidazole with their norovirus VLP vaccine.
Volkin et al. teach the use of buffers containing L-histidine or imidazole to improved storage stability of HPV VLPs + aluminum adjuvant as these buffers controlled pH better. The amounts of L-histidine or imidazole ranged from about 2mM to about 100mM, preferably 10mM. [see column 3, lines 16-24].
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Richardson et al. in order to incorporate L-histidine or imidazole with their norovirus VLP vaccine compositions.  One would have been motivated to do so, given the suggestion by Richardson et al. that the norovirus based compositions be stabilized by means known in the art (paragraph 46).  There would have been a reasonable expectation of success, given the knowledge that L-histidine and imidazole can be used to improve stability of VLPs of another virus, HPV, as taught by Volkin et al.  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 have been fully considered, but are not persuasive:
The deficiencies of Richardson et al. are addressed in the preceding rejection.  Therefore, the deficiencies that Volkin et al. must render obvious related to the combination L-histidine or imidazole with the vaccine comprising the norovirus VLPs.  As summarized above, Volkin et al. does provide teachings in which L-histidine or imidazole is used to improve VLP storage.  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.
Conclusion
No claims are allowed.

APPLICANT REBUTTAL: REMARKS
Claim Amendments
Upon entry of these amendments, claims 97, 98, and 101-121 are pending in the present application. Claims 1-96 and 99 were previously cancelled, without prejudice or disclaimer. In this response, claim 97 has been amended to recite that the genogroup II VLPs comprise less than 1% VLPs with a truncated VP1 subunit. Support for this amendment can be found in the specification at, e.g., paragraph [0085]. Claim 100 is hereby cancelled, without prejudice or disclaimer.
The above-noted amendments are supported by the application as originally filed and do not introduce any new matter. The amendments are made without prejudice to the prosecution of any cancelled or amended subject matter in one or more continuing application(s). Amendment and cancellation of certain claims is not to be construed as a dedication to the public of any of the subject matter of the claims as previously presented.
Examiner Interview Summary
Applicant thanks Examiner Blumel for the courtesy of the telephonic interview on July 8, 2024 with Applicant's representative, Alexia Dilg. As noted in the Examiner Interview Summary of July 11, 2024, the rejections under 35 USC § 112 and § 102 were discussed, along with possible claim amendments to overcome these rejections. No specific agreement was reached.
Claim Rejections - 35 USC §112
Claims 97, 98 and 100-121 were rejected under pre-AIA 35 U.S.C. § 112, second paragraph, as allegedly indefinite. In particular, the Office alleges that the specification does not provide a specific definition of the phrase "substantially free," and so contends that the metes and bounds of the limitation are not defined. See Office Action at page 3. Applicant respectfully disagrees. However, solely in the interest of expediting allowance of the instant application, and without prejudice or disclaimer, the phrase "substantially free" has been removed from claim 97. Instead, claim 97 now recites that the genogroup II VLPs comprise less than 1% VLPs with a truncated VP1 subunit, as supported by the specification at, e.g., paragraph [0085].
The metes and bounds of the amended claims are submitted to be clear and defined. Withdrawal of the indefiniteness rejection of the claims is therefore respectfully requested.
Claim Rejections - 35 USC §102
The Office has maintained the prior rejection of claims 97, 98, 100-109, 111-118, 120 and 121 under pre-AIA 35 U.S.C. § 102(b) as allegedly anticipated by Richardson et al. (U.S. Publication No. 2012/0156243), hereinafter "Richardson."
Specifically, the Office alleges that the teachings of Richardson disclose norovirus VLPs possessing full-length VP1 proteins or full-length VP1 and VP2 proteins, which are homogenous and pure. See Office Action, page 5. The Office further contends that the norovirus VLPs of Richardson contain full-length VP1 subunits and do not possess contaminating proteins, thereby inherently meeting the purity requirement of previously pending claim 97. Emphasis added. See Office Action page 8.
Applicant respectfully disagrees for at least the following reasons.
A reference cited under 35 U.S.C. § 102 must expressly or inherently describe each element set forth in the rejected claim. Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628, 631,
2 U.S.P.Q.2d 1051, 1053 (Fed. Cir. 1987).
As amended, claim 97 now recites that the solution containing norovirus genogroup 2 VLPs has less than 1% genogroup II VLPs with a truncated VPI subunit. Emphasis added. The present claims are based on the novel and surprising discovery of the existence of truncated genogroup II VP1 subunits arising from a proteolysis event during genogroup II VLP production and purification. The present inventors surprisingly discovered that this byproduct was present in solutions that were previously thought to be free of contaminant, as in, e.g., Richardson. This contaminant was not previously discovered because the truncated product still assembles into VLPs and furthermore co-elutes with full-length intact VLPs. See instant application at paragraph
[0140]. In view of this discovery, the inventors of the present application were able to remove the truncated VP1 subunits, thereby producing novel significantly purified genogroup II VLPs absent this contaminant.
In contrast, Richardson 1) neither recognizes the existence of the naturally occurring VP1 truncated subunit nor 2) teaches or performs any means for its removal. For these reasons, the solution as presently claimed is neither expressly nor inherently disclosed by Richardson. Applicant maintains that Richardson therefore fails to teach each and every element of the present claims.
The Office contends that the VLPs of Richardson do not possess contaminating proteins and inherently meet the purity requirement. See Office Action page 6. The Office bases its contention that Richardson inherently provides norovirus VLPs lacking truncated VP1 on the reference's SE-HPLC-based characterization of VLPs. See Office Action at pages 7 and 8, and Richardson at Table 7, reproduced for the Office's convenience below.
TABLE
Experiment and sample identification, and results for testing the effect of sucrose, chitosan, and mannitol or combinations thereof on stability
of NV-VLP structure during freezing and
ly
ophilization.
Measured SE-HPLC
mean pmntein
concentration and peak Mean percent values of
eluti
o
n time
recovered protein as  Mass equivalents VLP
percent of theo
re
tical
S = sucrose
Theoretical    "VLP"    Fragment   Total
C = chitosan
Experiment   VLP conc
-15 min  -32 min    protein   "VLP"
M = mannitol
LE1-LE5
LG1-LG9
LG10
LG11
LG12
LG13
LJ1-LJ14
LIGId-S1
LIGId-Sa
LIGId-S2
LIGd-Sb
LIGld-S3
Table 7 of Richardson.
In particular, the Office cites to this table as allegedly demonstrating elution of full length VLP ("VLP" at 15 min), without truncated VP1 subunits (allegedly "Fragment" at 32 min). However, the "Fragment" referenced in this table is not the truncated VP1 subunit first discovered by the inventors of the present application. Rather, as taught by Richardson at paragraph [0099] (emphasis added): "The VLP fragment that elutes from the column at around 32 min is
a highly stable single species
that results from destabilization and consequent
disassembly of the VLP."
In this passage, Richardson describes that the "Fragment" referenced in Table 7 is a byproduct of VLP disassembly, not a truncation product. In fact, Richardson explicitly states "Intermediate and smaller fragments", such as, e.g., a VP1 truncation,
"were not observed."
Id, emphasis added.
In view of the teachings of the present application, Applicant submits that the truncated VP1 subunit was not observed by Richardson because this truncation product "assembles into VLPs and co-purifies with VLPs composed of the full-length VP1 subunit during downstream processing." Instant application at paragraph [0140]. Although this byproduct was not identified by Richardson, Applicant submits that it was nevertheless present in the compositions of Richardson.
In particular, absent steps to remove it (e.g., the low pH step taught by the present application), the present inventors found that there were significant levels of the VP1 N-terminal truncation product present after VLP purification: Table 5 reports that 23±13% of the genogroup II VLPs comprised the N-terminal truncation. By contrast, the present inventors were able to obtain a pure solution of genogroup II VLPs, exclusively composed of full length VP1 subunits (See Table 5, bottom row). In line with this, the presently amended claims recite compositions with genogroup II VLPs comprising
less than 1%
of the VP1 truncation.
For at least the foregoing reasons, in conjunction with those currently of record in previous responses to the Office, Applicant submits that the features of the pending claims are not inherently present in Richardson and are patentably distinguishable from the VLPs of Richardson. Withdrawal of the rejection under 35 U.S.C. § 102 is respectfully requested.
Claim Rejections - 35 USC §103
Claim 119 is rejected under pre-AIA 35 U.S.C. § 103(a) as allegedly obvious over Richardson, as applied to claims 97, 98, 100-109, 111-118 and 120-121, and further in view of Volkin et al. (U.S. Patent No. 6,251,678), hereinafter "Volkin." The Office alleges that it would be obvious to one of ordinary skill in the art to modify the compositions of Richardson by incorporating L-histidine or imidazole. Applicant respectfully disagrees for the reasons set forth below.
A primafacie case of obviousness requires a suggestion of all limitations in a claim. CFMT, Inc. v. Yieldup Int'l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003). Applicant respectfully submits that neither Richardson nor Volkin, either alone or in combination, suggest all limitations of the pending claims. The claims as amended read on a solution containing purified human norovirus VLPs, the solution containing genogroup II VLPs having less than 1% truncated VP1 subunits. Emphasis added.
As an initial matter, the presence of truncated VP1 subunits is inherent in the teachings of Richardson. The compositions of Richardson necessarily contain truncated VP1 subunits because no steps were taken to remove them, such as the low pH treatment of the present disclosure. See paragraph [0071] of the specification as filed. Accordingly, Richardson does not teach a solution containing norovirus genogroup II VLPs having less than 1% truncated VP1 subunits. Volkin is directed to vaccine formulations for human papillomavirus (HPV). Volkin does not teach a solution containing norovirus genogroup II VLPs having less than 1% truncated VP1 subunits. Thus, together, the references fail to teach, suggest, or motivate one of skill in the art to arrive at the current claims.
Applicant respectfully submits that the presently claimed solution is therefore novel and non-obvious because the cited references fail to disclose the claimed solution. Furthermore, the references fail to recognize any particular benefit of purifying a solution as claimed such that truncated VP1 subunits are present at a level of less than 1%.
For at least the foregoing reasons, Applicant submits that a case of obviousness has not been established, and respectfully requests withdrawal of the rejection under 35 U.S.C. § 103.
CONCLUSION

NEXT OFFICE ACTION: The present application is being examined under the pre-AIA  first to invent provisions.
DETAILED ACTION
Applicants are informed that the rejections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant’s arguments and/or amendments.
Claim 97, 98 and 100-121 are examined on the merits and are allowed.
Response to Arguments
Applicant's arguments filed 10/18/2024 have been fully considered but they are not persuasive. See responses below.
Conclusion
No claims are allowed.

CITED REFERENCE SUMMARIES: Ref US6251678: Claims:
1. A human papillomavirus (HPV) vaccine formulation comprising:
a) 10-200 mcg/ml of each HPV virus-like particle (VLP) type adsorbed onto aluminum, wherein the VLPs are selected from the group consisting of: HPV 6a, HPV 6b, HPV 11, HPV 16, HPV 18, and mixtures thereof;
b) a physiologically acceptable salt selected from the group consisting of: NaCl, KCl, Na2SO4, (NH4)2SO4, sodium phosphate and sodium citrate;
c) a histidine buffer which provides for a pH range of the vaccine solution of from about pH 6.0 to about 6.5; and
d) a non-ionic surfactant selected from the group consisting of: polyoxyethylene sorbitol fatty acid esters, polyoxyethylene alkyl esters, TRITON X-100®, TRITON X-114®, NP-40®, Span 85, and the Pluronic series of non-ionic surfactants.
2. A vaccine according to claim 1 wherein the salt is present in a concentration of from about 0.10M to about 0.5M.
3. A vaccine according to claim 2 wherein the salt is 0.32M NaCl.
4. A vaccine according to claim 1 wherein the buffer is present is a concentration of about 2 mM to about 100 mM.
5. An HPV vaccine according to claim 1 wherein the surfactant is present in a concentration of from about 0.0005% to about 0.5% (wt/vol).
6. A vaccine according to claim 1 which is in a aqueous solution.
7. A vaccine formulation according to claim 1 comprising:
a) 10-200 mcg/ml of each HPV virus-like particle (VLP) type adsorbed onto aluminum, wherein the VLPs are selected from the group consisting of: HPV 6a, HPV 6b, HPV 11, HPV 16, HPV 18, and mixtures thereof;
b) 0.32M NaCl;
c) 10 mM histidine buffer which provides for a pH of 6.2; and
d) 0.01% Polysorbate 80.
8. A vaccine according to claim 1 further comprising a polymeric polyanionic stabilizer.
9. A vaccine according to claim 8 wherein the stabilizer is selected from the group consisting of: carboxymethyl cellulose (CMC), heparin, Poly(Glu), Poly(Asp), Poly(Glu, Phe), oxidized glutathione, polycytidylic acid, polyadenylic acid, RNA, DNA, and serum albumins.
10. A vaccine according to claim 9 wherein the stabilizer is CMC.
11. A vaccine according to claim 8 wherein the concentration of the stabilizer is from about 0.01% to about 0.5% (by weight/volume).
12. An HPV vaccine formulation comprising:
a) 10-200 mcg/ml of each HPV virus-like particle (VLP) type adsorbed onto aluminum, wherein the VLPs are selected from the group consisting of: HPV 6a, HPV 6b, HPV 11, HPV 16, HPV 18, and mixtures thereof;
b) 0.32M NaCl;
c) 10 mM histidine buffer which provides for a pH of 6.2;
d) 0.01% Polysorbate 80; and
e) 0.05% CMC.
13. An HPV vaccine formulation comprising:
a) 10-200 mcg/ml of each HPV virus-like particle (VLP) type adsorbed onto aluminum, wherein the VLPs are selected from the group consisting of: HPV 6a, HPV 6b, HPV 11, HPV 16, HPV 18, and mixtures thereof;
b) 0.15M NaCl;
c) 0.05% CMC; and
d) an optional buffer which provides for a pH range of the vaccine solution of from about pH 6.0 to about 6.9 and/or non-ionic detergent.
14. A vaccine according to claim 12 which is in an aqueous solution.
Ref US20120156243: Claims:
A composition comprising at least one Norovirus antigen and at least one adjuvant, wherein the adjuvant is a toll-like receptor (TLR) agonist, and wherein the composition is formulated as a liquid. 2. The composition of claim 1, wherein the adjuvant is a toll-like receptor 4 (TLR-4) agonist. 3. The composition of claim 2, wherein the TLR-4 agonist is lipid A, synthetic lipid A, a lipid A mimetic, or a lipid A analog. 4. The composition of claim 2, wherein the TLR-4 agonist is monophosphoryl lipid A (MPL). 5. The composition of claim 1, wherein said Norovirus antigen comprises peptides, proteins Norovirus virus-like particles (VLPs), denatured VLPs, capsid monomers, capsid multimers, aggregates, or mixtures thereof. 6. The composition of claim 5, wherein said Norovirus antigen is selected from the group consisting of Norovirus genogroup I and genogroup II viral strains. 7. The composition of claim 5, wherein said Norovirus antigen comprises Norovirus VLPs. 8. The composition of claim 7, wherein said Norovirus VLPs comprise a capsid protein. 9. The composition of claim 8, wherein said capsid protein is selected from the group consisting of VP1 and VP2. 10. The composition of claim 7, wherein the VLPs are monovalent VLPs. 11. The composition of claim 7, wherein the VLPs are multivalent VLPs. 12. The composition of claim 11, wherein the multivalent VLPs are selected from the group consisting of genogroup I and genogroup II Noroviruses. 13. The composition of claim 7, wherein the Norovirus VLPs are produced in a recombinant cellular expression system or a baculovirus-infected cellular expression system. 14. The composition of claim 13, wherein the cellular expression system is selected from the group consisting of yeast, bacterial, insect, and mammalian expression system. 15. The composition of claim 1, further comprising a second Norovirus antigen. 16. The composition of claim 15, wherein said first and second Norovirus antigens are monovalent VLPs from different genogroups. 17. The composition of claim 16, wherein said first Norovirus antigen is a monovalent VLP comprising at least one capsid protein from a genogroup I Norovirus and said second Norovirus antigen is a monovalent VLP comprising at least one capsid protein from a genogroup II Norovirus. 18. The composition of claim 17, wherein the genogroup II Norovirus is a GII.4 Norovirus. 19. A vaccine formulation comprising the composition of claim 1. 20. The formulation of claim 19, wherein the Norovirus antigen is present in a concentration of from about 0.01% (w/w) to about 80% (w/w). 21. The formulation of claim 19, wherein the dosage of the Norovirus antigen is present in an amount of from about 1 μg to about 100 mg per dose. 22. The formulation of claim 21, wherein the dosage of the Norovirus antigen is from about 1 μg to about 1 mg per dose. 23. The formulation of claim 21, wherein the dosage of the Norovirus antigen is from about 1 μg to about 500 μg per dose. 24. The formulation of claim 21, wherein the dosage of the Norovirus antigen is from about 1 μg to about 150 μg per dose. 25. The composition of claim 1, wherein the composition is formulated for parenteral administration. 26. The composition of claim 1, further comprising oil. 27. The composition of claim 1, further comprising an aluminum salt. 28. The composition of claim 1, wherein the composition is formulated for intranasal administration. 29. The composition of claim 28, wherein the formulation is in the form of a nasal spray or nasal drops. 30. The composition of claim 28, further comprising chitosan. 31. A composition comprising at least one Norovirus antigen and an aluminum salt, wherein the composition is formulated as a liquid. 32. A method of inducing an immune response to Norovirus in a mammal comprising administering to the mammal a composition comprising a Norovirus antigen and at least one adjuvant, wherein said adjuvant is not a bacterial exotoxin, and wherein the Norovirus antigen is from a genogroup I or genogroup II Norovirus.
A composition comprising at least one Norovirus antigen and at least one adjuvant, wherein the adjuvant is a toll-like receptor (TLR) agonist, and wherein the composition is formulated as a liquid.
The composition of claim 1, wherein the adjuvant is a toll-like receptor 4 (TLR-4) agonist.
The composition of claim 2, wherein the TLR-4 agonist is lipid A, synthetic lipid A, a lipid A mimetic, or a lipid A analog.
The composition of claim 2, wherein the TLR-4 agonist is monophosphoryl lipid A (MPL).
The composition of claim 1, wherein said Norovirus antigen comprises peptides, proteins Norovirus virus-like particles (VLPs), denatured VLPs, capsid monomers, capsid multimers, aggregates, or mixtures thereof.
The composition of claim 5, wherein said Norovirus antigen is selected from the group consisting of Norovirus genogroup I and genogroup II viral strains.
The composition of claim 5, wherein said Norovirus antigen comprises Norovirus VLPs.
The composition of claim 7, wherein said Norovirus VLPs comprise a capsid protein.
The composition of claim 8, wherein said capsid protein is selected from the group consisting of VP1 and VP2.
The composition of claim 7, wherein the VLPs are monovalent VLPs.
The composition of claim 7, wherein the VLPs are multivalent VLPs.
The composition of claim 11, wherein the multivalent VLPs are selected from the group consisting of genogroup I and genogroup II Noroviruses.
The composition of claim 7, wherein the Norovirus VLPs are produced in a recombinant cellular expression system or a baculovirus-infected cellular expression system.
The composition of claim 13, wherein the cellular expression system is selected from the group consisting of yeast, bacterial, insect, and mammalian expression system.
The composition of claim 1, further comprising a second Norovirus antigen.
The composition of claim 15, wherein said first and second Norovirus antigens are monovalent VLPs from different genogroups.
The composition of claim 16, wherein said first Norovirus antigen is a monovalent VLP comprising at least one capsid protein from a genogroup I Norovirus and said second Norovirus antigen is a monovalent VLP comprising at least one capsid protein from a genogroup II Norovirus.
The composition of claim 17, wherein the genogroup II Norovirus is a GII.4 Norovirus.
A vaccine formulation comprising the composition of claim 1.
The formulation of claim 19, wherein the Norovirus antigen is present in a concentration of from about 0.01% (w/w) to about 80% (w/w).
The formulation of claim 19, wherein the dosage of the Norovirus antigen is present in an amount of from about 1 μg to about 100 mg per dose.
The formulation of claim 21, wherein the dosage of the Norovirus antigen is from about 1 μg to about 1 mg per dose.
The formulation of claim 21, wherein the dosage of the Norovirus antigen is from about 1 μg to about 500 μg per dose.
The formulation of claim 21, wherein the dosage of the Norovirus antigen is from about 1 μg to about 150 μg per dose.
The composition of claim 1, wherein the composition is formulated for parenteral administration.
The composition of claim 1, further comprising oil.
The composition of claim 1, further comprising an aluminum salt.
The composition of claim 1, wherein the composition is formulated for intranasal administration.
The composition of claim 28, wherein the formulation is in the form of a nasal spray or nasal drops.
The composition of claim 28, further comprising chitosan.
A composition comprising at least one Norovirus antigen and an aluminum salt, wherein the composition is formulated as a liquid.
A method of inducing an immune response to Norovirus in a mammal comprising administering to the mammal a composition comprising a Norovirus antigen and at least one adjuvant, wherein said adjuvant is not a bacterial exotoxin, and wherein the Norovirus antigen is from a genogroup I or genogroup II Norovirus.