DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 6, 7, 21, 72, 74, 76-78, 89, 90, 92, 94, 96-98, 107-109 are pending in the application. Claims 98, 107-109 are withdrawn. Claims 1, 6, 7, 21, 72, 74, 76-78, 89, 90, 92, 94, 96-97 are currently under examination.
This office action is in response to the amendment filed on 9/29/2025.
All previous rejection not reiterated in this office action are withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 6, 7, 21, 71, 72, 74, 76, 77, 78, 92, 94, 96, 97 is/are rejected under 35 U.S.C. 103 as being unpatentable over Irvine (US20190358312, IDS), in view of Amstutz (US 11,466,062). This rejection is rewritten to address the amendment.
Irvine teaches immunogenic compositions and vaccines, and methods of coupling an antigen to an adjuvant (abstract). Irvine teaches site specific engineering of the interaction between antigens and aluminum hydroxide (alum), which results in eliciting enhanced humoral immunity to antigens of interest, and provides improved vaccines (paragraph [0006]). Irvine teaches the antigen is conjugated to the alum via a linker that comprises phosphoserine (PS) residues (paragraph [0006]). Irvine teaches that the PS linker comprises 2-12 phosphoserines (paragraph [0161]). Irvine teaches the immunogenic composition may have a wide variety of antigens including coronavirus (SARS) (paragraph [0189]). Irvine teaches when preparing for some immunization, an ISCOM-like nanoparticle that comprises self-assembled cholesterol, phospholipid and Quillaja saponin was prepared in formulation (paragraph [0290]).
However, Irvine does not teach the SARS is a SARS-CoV-2 spike glycoprotein variant, which comprises a receptor binding domain (RBD) having a mutation of at least one amino acid residue in an angiogenic-converting enzyme 2 (ACE2) receptor binding motif (RBM), wherein the residue is hydrophobic and within an aggregation-prone region of about 3-15 amino acid residues, wherein the mutation is a substitution with another amino acid.
Amstutz teaches the spike protein of SARS-CoV-2 mediates cell entry through binding to the human ACE2 receptor and the RBD in the spike protein forms the interface with ACE2. Amstutz teaches single amino acid substitution such as L452K is shown to increase the affinity for human ACE2. Amstutz teaches the RBD domain is also immunogenic, wherein F486 have been shown to be important for the binding of neutralizing antibodies (col. 63, lines 9-34).
It would have been obvious to an ordinary skilled in the art that SARS-CoV-2 spike protein variants comprising L452K and/or F486 substitution may be used as antigen in the immunogenic composition taught by Irvine because they are immunogenic according to the teaching from Amstutz. Since L452 and F486 are both hydrophobic and within an aggregation-prone region of the RBD to ACE2, it meets the limitation of the spike protein variant recited in (b). Since Irvine teaches the antigen within the immunogenic composition may be derived from any pathogen, including SARS, replacing one antigen with another antigen of similar structure such SARS-CoV2 as claimed would have been routine experimentation. Therefore, the claimed composition of claim 1 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 6 and 7, Irvine teaches the alum is aluminum hydroxide.
Regarding claim 21, Amstutz teaches L452K, which is within the spike protein of SARS-CoV-2 RBD. Since SEQ ID NO:1 encodes the SARS-CoV-2 RBD, L452K meets the limitation of within 122-126 of SEQ ID NO: 1.
Regarding claims 74, 76, 77, 78, Irvine teaches an ISCOM-like nanoparticle that comprises self-assembled cholesterol, phospholipid and Quillaja saponin (paragraph [0290]).
Regarding claim 72, Irvine teaches using porous beads for delivering the vaccine conjugates (paragraph [0235]).
Regarding claim 92, Irvine teaches the particle and the alum are bound by PS linkage (paragraph [0041]).
Regarding claim 94, Irvine teaches a metal hydroxide adjuvant particle includes numerous surface hydroxyl groups that are available for ligand exchange, and prepared to have a large number of antigens per adjuvant particle. Irvine teaches in one embodiment, the metal hydroxide adjuvant antigen to metal of from 1:1 to about 1:10 or even greater (paragraph [0222]). This ratio falls within the range of 1:500 to 500:1.
Regarding claim 96, Irvine teaches the particle may be delivered by pharmaceutical carrier (paragraph [0228]).
Regarding claim 97, Irvine teaches a universally-applicable strategy to enhance multiple facets of humoral immunity to subunit vaccines (paragraph [011]).
Claim(s) 89 and 90 is/are rejected under 35 U.S.C. 103 as being unpatentable over Irvine, Amstutz, as applied to claim 1 and 71 above, and further in view of Irvine2 (US2020/0085756, IDS).
The teaching from Irvine and Amstutz have been discussed above. However, neither teaches a composition that comprises lipid: additional adjuvant: sterol: saponin molar ratio of 2.5:1:10:10 or a variation thereof.
Irvine2 teaches non-liposome, non-micelle particles of a lipid, an additional adjuvant, a sterol, and a saponin, wherein the particles can increase immune responses and are particularly useful as adjuvants in vaccine application (paragraph [0010]). Irvine2 teaches suitable ratios for the lipid, additional adjuvant, sterol and saponin is a molar ratio of 2.5:1:10:10 (paragraph [0012]). Irvine 2 teaches the additional adjuvant includes TLR4 agonists such as MPLA (paragraph [0014]), the lipid includes DPPC, the sterol is cholesterol, and saponin is QuilA or a Q21 or analog (paragraph [0013]).
It would have been obvious to an ordinary skilled in the art to replace the ISCOM like particle lacking MPLA from Irvine with non-liposome, non-micelle particle comprising MPLA taught by Irvine2, thereby arriving at the claimed invention. The ordinary skilled in the art would be motivated to do so because Irvine2 explicitly teaches that the addition of MPLA as an additional adjuvant to the saponin nanoparticle yields a particle that is more immunogenic and more effective as an adjuvant than other saponin nanoparticle lacking MPLA (paragraph [0238]). The ordinary skilled in the art would have reasonable expectation of success to exchange the ISCOM like particle with additional adjuvant particle taught by Irvine2 following combined teaching from Irvine, Amstutz and Irvine2. Therefore, the claimed invention of claims 89 and 90 would have been prima facie obvious at the time the application was filed.
Response to Arguments
Applicant argues that Irvine and Amstutz do not teach the composition of the claimed invention and its surprising result that uses alum, a cost adjuvant with widespread clinical use, to elicit potent humoral immune responses and neutralization against SARS-CoV-2, by modifying the RBD antigen with a short peptide linker, RBD-pSer substantially extended the duration of antigen drainage from the injection site which lead to strong antigen-specific germinal center responses. Applicant states that further optimization with the addition of alum binding co-adjuvants was able to achieve continually higher and more consistent antibody and neutralization responses in mice as shown in Figure 12. Applicant states that the addition of SMNP to pSer:alum immunizations elicited more functional antibody responses, and the combination synergistically enhances immune responses to immunization.
The above arguments have been fully considered but deemed unpersuasive. As discussed in the above rejection, Irvine teaches site specific engineering of the interaction between antigens and aluminum hydroxide (alum), which results in eliciting enhanced humoral immunity to antigens of interest, and provides improved vaccines (paragraph [0006]). Irvine teaches the antigen is conjugated to the alum via a linker that comprises phosphoserine (PS) residues (paragraph [0006]). Irvine teaches that the PS linker comprises 2-12 phosphoserines (paragraph [0161]). Irvine teaches that the antigen retention is increased at the site of administration (paragraph [0244]). As such, the alleged advantage of conjugating alum through short peptide linker (taught by Irvine) and the antigen taught by Amstutz is already known in the art at the time of filing. As suggested by Applicant, the addition of alum binding co-adjuvants was an optimization process, which would have been routine experimentation rather than method of innovation. Therefore, for reasons discussed in previous office action and set forth above, this rejection is still deemed proper and thus maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637