Office Action 4: Notice of Allowance (2024-12-26)

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 underlinin. 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 omprise less than 1% VLPs with a truncated VP1 subunit.

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

99-100. (Cancelled)

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\. (Previously Presented) 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 pg 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
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.

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