Office Action 2: Final Rejection (2023-04-12)
Rejection types: 102 - Lack of Novelty, 103 - Obviousness, 112 - Written Description/Enablement

CLAIMS:
IN 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\. (Previously Presented) 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 solution contains less than about 10% truncated VPI subunit.

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

99\. (New) The solution of claim 97, wherein the solution contains less than about 5% VLPs with a truncated VP1 subunit.

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

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

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

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

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

105\. (New) 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\. (New) 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\. (New) 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\. (New) 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\. (New) 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\. (New) 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\. (New) The solution of claim 109, wherein the live virus is a host cell virus, a production virus, or a contaminating virus.

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

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

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

115\. (New) The vaccine of claim 114, wherein the vaccine comprises 5-200 pg of the norovirus VLPs.

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

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

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

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

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

121\. (New) The vaccine of claim 114, wherein the pH of the vaccine is from about 6.0 to about 7.0.
2 3 4 275907684

OFFICE ACTION:
The present application is being examined under the pre-AIA  first to invent provisions.
DETAILED ACTION
Claim 97-121 are examined on the merits.  Claims 98-121 are newly presented.
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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/21/2022 is in compliance with the provisions of 37 CFR 1.97.  Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicant's arguments filed 12/21/2022 have been fully considered but they are not persuasive. See responses below.
Terminal Disclaimer
The terminal disclaimer filed on 12/21/2022 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent 10,167,320 has been reviewed and is accepted.  The terminal disclaimer has been recorded.
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) Claim 109-113 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 109 states: “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.”
The limitation of “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” is unclear how the “level of live virus…is less than 10% of the level of the live virus”.  In other words, how can a live virus be less than 10% of itself?  This uncertainty applies to claim 110 for the same reason.
Claims 111-113 are also rejected because they depend from claim 109, but do not remedy this deficiency.
Claim 111 recites “a host cell virus”.  However, since all viruses require a host cell to replicate, aren’t all viruses “host cell viruses”. Or is claim 111 attempting to specify a specific host cell virus that can only replicate in a transgenic cell which expresses key replication proteins in trans.
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 and extended to new claims) Claims 97-109, 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 solution contains less than about 10% truncated VP1 subunit.
The genogroup II VLPs are genogroup II, genotype 4 VLPs.
The solution contains less than about 5% or less than about 1% VLPs with a truncated VP1 subunit.
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 host cell virus, 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 containing less than about 10% truncated VP1 subunits.  Applicants state they were the first to disclose the previously unknown existence of truncated norovirus genogroup II VP1 subunit.  This truncated VP1 assembles into VLPs and co-purifies with full-length VLP.  Applicant’s also first discovered that treating this norovirus VLP composition with a low pH at the bulk bioreactor stage of production, selective removal of the VLPs containing N-terminal truncated product was achieved.  Without the low pH treatment, the resulting solution of norovirus VLPs would possess about 23% truncated VP1 subunits.
In response to applicant's argument that the references fail to show certain features of applicant’s invention, it is noted that the features upon which applicant relies (i.e., treatment of norovirus VLPs bulk production with a low pH solution) are not recited in the rejected claim(s).  Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims.  See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In addition, Richardson et al. teach in paragraph [0039]:
“The VLPs of the present invention can be formed from either the full length Norovirus capsid protein such as VP1 and/or VP2 proteins or certain VP1 or VP2 derivatives using standard methods in the art. Alternatively, the capsid protein used to form the VLP is a truncated capsid protein. In some embodiments, for example, at least one of the VLPs comprises a truncated VP1 protein. In other embodiments, all the VLPs comprise truncated VP1 proteins. The truncation may be an N- or C-terminal truncation. Truncated capsid proteins are suitably functional capsid protein derivatives. Functional capsid protein derivatives are capable of raising an immune response (if necessary, when suitably adjuvanted) in the same way as the immune response is raised by a VLP consisting of the full length capsid protein.”
Richardson et al., which was published before applicant’s priority date, recognized that Norovirus VP1 proteins in the form of a N-terminal truncation can form VLPs.  At least in paragraph 39, Richardson et al. teach that VLPs that possess full-length and/or truncated VP1 proteins can be produced.  In addition, based on their specific teachings of purifying their VLP composition, they also teach producing a solution comprising only norovirus VLPs comprosing full-length VP1.  Therefore, the norovirus VP1 VLPs of Richardson et al. would be in a pure form that either comprises only full-length VP1, VP1 and VP2, or full-length and truncated VP1 and/or VP2 proteins.  The VLPs that comprise full-length VP1 would be devoid contaminating proteins and nucleic acids, which is required by claims 97-101 and 106-108.   Furthermore, since the structural requirements of the claimed invention (Norovirus genogroup II VLPs) have been taught by Richardson et al., these VLPs would be inherently soluble and structurally intact and suitable for commercial use.
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.
(New Rejection Necessitated by Amendments) Claim 119 is rejected under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Richardson et al. as applied to claims 97-109, 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.
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 extension fee 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 date of this final action.

APPLICANT REBUTTAL: REMARKS
Claim Amendments
Claim 97 is pending in the present application. Claims 1-96 were previously cancelled, without prejudice or disclaimer. In this response, claims 98-122 are newly added.
The newly added claims are supported by the application as originally filed. See, e.g., paragraphs [0085] and Table 5 (level of truncated VP1 subunits); paragraphs [0017] and [0083] (level of residual contaminating protein); paragraphs [0017] and [0050] (level of residual contaminating nucleic acid); paragraph [0130] (VLPs are soluble and structurally intact); paragraph [0084] (solution is suitable for commercial processes); paragraph [0017] (solution obtained from cell lysate, supernatant or filtrate); paragraph [0064] (amount of VLPs in solution compared to lysate, supernatant or filtrate); paragraphs [0019], [0033], and [0066]-[0067] (live virus); paragraph [0022] (vaccines); paragraph [0100] (VLP amount in vaccine); paragraphs [0091]-[0092] (vaccine adjuvants); and paragraph [0097] (vaccine buffers, pH values, parenteral administration).
No new matter is added by way of the foregoing amendments to the claims.
Examiner Interview Summary
Applicant thanks Examiner Blumel for the courtesy extended to Applicant's representative, Alexia Dilg, during the telephonic interview held on December 14, 2022, in which possible claim amendments were discussed. The Examiner agreed that a response featuring a claim set similar to that currently presented would be compliant and would not be considered a shift to claim another invention. The Examiner suggested alternative wording to certain proposed claims to improve clarity. No specific agreement was reached.
Claim Re
i
ections under 35 U.S.C. 102 - Anticipation
I.    Rejection over Richardson
Claim 97 was rejected under pre-AIA 35 U.S.C. § 102(b) as allegedly anticipated by U.S. Patent Publication No. 2012/0156243 (hereinafter, "Richardson").
The Office alleges that Richardson teaches "processing multivalent norovirus VLPs with VP1 and/or VP2 proteins and purifying these VLPs," and that 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 1 [claim 97]." Office Action at page 4.
Applicant respectfully disagrees.
A reference cited under 35 U.S.C. § 102 must expressly or inherently describe each element set forth in the rejected claim. VerdegaalBros. v. Union Oil Co. of California, 814 F.2d 628, 631, 2 U.S.P.Q.2d 1051, 1053 (Fed. Cir. 1987).
Claim 97 recites that the solution comprising norovirus genogroup 2 VLPs contains less than about 10% truncated VPJ subunit. Richardson does not disclose the solution of the current
claims.
In particular, the present application was
the first
to disclose the previously unknown existence of the truncated norovirus genogroup II VP1 subunit, which assembles into VLPs and co-purifies with full length VLPs. See, e.g., paragraph [0140] of the present disclosure, which teaches (emphasis added), "During production in the baculovirus expression system, the Consensus VP1 subunit can undergo proteolytic cleavage resulting in an N-terminal truncation production for a certain fraction of the expressed material. This proteolytic fragment
assembles into VLPs
and
co-purifies
with VLPs composed of the full-length VP1 subunit during downstream processing."
In addition to identifying the existence of the truncated VP1 subunit contaminant and the factors that complicated its identification and removal (VLP assembly and co-elution with full length product), the present application was also the first to identify means for its removal. In particular, paragraph [0140] teaches (emphasis added), "During development studies, it was discovered that low pH treatment of bulk bioreactor production cultures selectively removed the population of VLPs containing the N-terminal truncation product providing more homogenous material for downstream processing."
In contrast to the present application, Richardson 1) does not recognize the existence of the VP1 truncated subunit; 2) does not teach any means for its removal; and 3) does not carry out any means for its removal.
Richardson's solutions contain the truncated VP1 subunits because steps to remove such subunits, i.e., low pH treatment, are not provided or carried out in Richardson. Table 5 of the present specification shows that the low pH treatment step disclosed in the instant application resulted in a solution having 100% full-length VP1 subunits, whereas the same process
without
the low pH treatment resulted in a solution, such as Richardson's solution, having only about 77% full-length VP1 and
about 23
truncated VP1 subunit
in the solution. This is different from the claimed solution that comprises
a maximum of less than about
of the truncated VP1 subunits of norovirus.
Moreover, newly presented claims 99 and 100 recite that the solution comprises less than about 5% and less than about 1% of truncated VP1 subunits, respectively, such that Applicant submits that at least these claims should be exempt from the rejection.
In summation, the solutions provided in the present application are not the same as the solutions achieved in Richardson's disclosure. Richardson fails to teach each and every element of the present claims and, therefore, does not anticipate the present claims. In view of the foregoing, Applicant respectfully requests that the rejection under 35 U.S.C. §102 be withdrawn.
II.   Rejection over Almanza
Claim 97 was rejected under pre-AIA 35 U.S.C. § 102(b) as allegedly anticipated by Almanza et al., "Self-assembly of the recombinant capsid protein of a swine norovirus into virus- like particles and evaluation of monoclonal antibodies cross-reactive with a human strain from genogroup II," J. C/in. Microbiol. 2008 Dec;46(12):3971-9 (hereinafter, "Almanza").
Specifically, the Examiner alleges that Almanza teaches a solution containing full length VP1 subunits of norovirus VLPs without any truncated VP1 subunits. Office Action at p.5.
Applicant respectfully disagrees.
A reference cited under 35 U.S.C. § 102 must expressly or inherently describe each element set forth in the rejected claim. VerdegaalBros. v. Union Oil Co. of California, 814 F.2d 628, 631, 2 U.S.P.Q.2d 1051, 1053 (Fed. Cir. 1987).
Claim 97 recites a solution comprising a purified population of human norovirus VLPs, wherein the norovirus VLPs comprise at least genogroup II VLPs, and the solution contains less than about 10% truncated VPJ subunit. Almanza does not disclose the solution of the current
claims.
Almanza discloses a VLP solution consisting of swine Norovirus VLPs of genogroup II, genotype 11 (GIL. 11). Almanza does not disclose or suggest any solution comprising at least a human genogroup II VLP. At least because of this difference, Almanza fails to anticipate the present claims.
In addition, like Richardson, Almanza fails to teach or suggest a purified human norovirus genogroup II VLP solution with less than 10% truncated subunit, because Almanza 1) does not recognize the existence of the VP1 truncated subunit; 2) does not teach any means for its removal; and 3) does not carry out any means for its removal.
Almanza's purification methods merely employ the use of centrifugation and buffer treatment, as summarized by the Office Action at page 5. As discussed above and as shown in Table 5 of the specification as filed, without the low pH treatment step, a human norovirus genogroup II VLP solution contains the truncated VLPs. A purified solution of human genogroup II VLPs that lacks truncated VP1 subunits cannot be extrapolated from the methods for obtaining swine Norovirus VLPs taught in Almanza. Therefore, Almanza does not teach or suggest the claimed solution.
Applicant further notes that Almanza does not specifically determine, or even consider, the presence or absence of the truncated VLPs in its swine norovirus VLP solutions. The Examiner points to Figure 1 as support for alleging that Almanza's solution contains only full length VP1 subunits of swine norovirus VLPs and is free of their truncated counterparts. However, a lack of proof demonstrating the presence of the truncation product does not support a conclusion of its absence. This is particularly true in the present case, since Almanza does not reference the presence
or removal of truncated VLPs at all, and since the art did not recognize the existence of this product until the disclosure of the present application.
In particular, Figure 1 does not demonstrate the absence of the truncated VLPs in its swine norovirus VLP solutions. Figure 1(A) provides a gel image of the expression of the swine norovirus VLPs that is of poor resolution and without any discussion about truncated VLPs. Figure 1(B) provides a snapshot of a portion of an electron microscopy micrograph of the swine VLP solutions. The Examiner also relies on Almanza's statement that their VLPs are "morphologically similar to authentic Norovirus virions" as evidence that Almanza's solution only contains full- length VLPs. Office Action, p. 5. However, as taught in the present application, the truncation product still assembles into a VLP and co-purifies with the full length product, which suggests that one may not be able to tell solely based on the appearance of VLPs whether or not the VLPs comprised a truncated VP1 subunit. The person of ordinary skill in the art would understand that one could not conclude, based on morphological similarity of VLPs obtained by a particular method to a Norovirus virion, that the method achieves a solution that has less than 10% contaminating truncated VP1 subunits. Certainly, one could not reach such a conclusion with respect to human norovirus VLPs based on a study relating only to swine norovirus VLPs.
Neither of these images, and nothing in Almanza as a whole, are directed to the presence or absence of truncated versus full length VP1 subunits of norovirus VLPs. In other words, a skilled artisan viewing Figure 1 of Almanza simply would not be able to determine whether Almanza's solution is free of the truncated VLPs. The study moreover does not provide the skilled person with any information relevant to obtaining a human norovirus VLP solution that is free of truncated VP1 subunits. In contrast, Applicant's study of the presence or absence of the truncated versus full length VP 1 subunits of norovirus VLPs shows that the lack of low pH treatment will result in a significant fraction of truncated VLPs in the human norovirus VLP solution. See Table 5, specification as filed.
In summary, Almanza does not disclose or suggest all features of the present claims. For at least the foregoing reasons, Applicant submits that claim 97 is novel and respectfully requests withdrawal of the rejection under 35 U.S.C. § 102.
Double Patenting
Claim 97 was rejected on the ground of nonstatutory double patenting as allegedly unpatentable over claim 1 of U.S. Patent No. 10,167,320.
Without acquiescing to the merits of the rejection, Applicant submits herewith a terminal disclaimer over U.S. Patent No. 10,167,320. Withdrawal of the double patenting rejection of claim 97 is therefore respectfully requested.
CONCLUSION

NEXT 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.”
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727
886
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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.

CITED REFERENCE SUMMARIES: Ref US6251678B1: [content unavailable]
Ref US10167320: Claims:
1. A solution comprising a purified population of human norovirus 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 VLP, and wherein said solution is generated by a process comprising:
generating or obtaining a cell lysate, culture supernatant, or filtrate containing the norovirus VLPs, wherein said norovirus VLPs comprise at least a first subpopulation with full length VP1 subunit and a second subpopulation with truncated VP1 subunit of the norovirus VLPs;
adjusting the pH of the lysate, supernatant or filtrate to a pH of less than about 5 to generate a pH-adjusted solution;
removing the second subpopulation with truncated VP1 subunit of norovirus VLPs from the pH-adjusted solution using a filtration process to generate a filtered solution, wherein the filtered solution substantially retains the first subpopulation with full length VP1 subunit of norovirus VLPs;
and
wherein the solution comprises full length VP1 subunit of norovirus VLPs and is substantially free of norovirus VLPs with the truncated VP1 subunit, wherein the solution contains less than about 10% truncated VP1 subunit.
2. A vaccine comprising the norovirus VLPs prepared from the solution of claim 1.
3. The solution of claim 1, containing no more than about 35% residual contaminating nucleic acid relative to the lysate, supernatant or filtrate.
4. The solution of claim 1, wherein at least about 50% of the norovirus VLPs are recovered from the lysate, supernatant or filtrate.
5. The solution of claim 1, wherein the ratio of the norovirus VLPs to residual contaminating protein is increased at least about ten-fold as compared to the lysate, supernatant or filtrate.
6. The solution of claim 1, wherein the solution is suitable for use in a commercial process.
7. The solution of claim 1, wherein the process further comprises one or more of the following: centrifugation, precipitation, flocculation, settling, and filtration.
8. The solution of claim 6, wherein the commercial process has a processing volume of at least 20 liters.
9. The solution of claim 1, wherein the residual contaminating protein relative to VLP is measured by size exclusion chromatography and ELISA.
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.