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 .
DETAILED ACTION
1. The Amendment filed April 2, 2026 in response to the Office Action of October 02, 2025 is acknowledged and has been entered. Claims 2-5, 17, 25, 31 and 32 have been cancelled. Claims 1, 6, 8, 9, 13, 15, 16, 18-24, 26-30 and 33 have been amended. New claims 41-48 have been added.
2. Claims 1, 6-16, 18-24, 26-30 and 33-48 are currently being examined.
Drawings
3. Figure 1E should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP §608.02(g) and Cirelli et al. (Cell May 16, 2019 177: 1153-1171, IDS). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
4. Claims 36 and 45 are objected to because of the following informalities: It appears that saponin “Q-21” should be “QS-21”. See p. 23-lines 14-18 and p. 24-lines 6-16 of the specification. Appropriate correction is required.
New 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.
5. Claims 6-15, 29, 30, 33-36 and 44 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 6 recites the limitation "the method of claim 5" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 5 is cancelled. Claims 7-8 which depend from claim 6 are also rejected because they incorporate by reference the limitations of claim 6.
Claim 9 recites the limitation "wherein escalating dosing comprises" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite escalating dosing. Claims 10-14 which depend from claim 9 are also rejected because they incorporate by reference the limitations of claim 9.
Claim 15 recites the limitation "the method of claim 5" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 5 is cancelled.
Claim 29 recites the limitation "the antigen and/or adjuvant are administered" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 is drawn to co-administering an antigen and an adjuvant composition.
Claim 30 recites the limitation "the antigen and/or adjuvant composition are administered" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 is drawn to co-administering an antigen and an adjuvant composition.
Claim 33 recites the limitation "the particle " in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 is drawn to a non-liposome, non-micelle particle. Claims 34-36 which depend from claim 33 are also rejected because they incorporate by reference the limitations of claim 33.
Claim 44 recites the limitation "wherein (ii) the bolus boost administration" in line 1. There is insufficient antecedent basis for this limitation in the claim because claims 1 and 43 from which claim 44 depends do not recite a bolus boost administration.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claims 16-24, 26-28, 43, 44 and 46-48 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 16 is drawn to the method of claim 1, wherein (i) comprises administering the antigen and adjuvant composition in the same or different admixtures. Part (i) of claim 1 is drawn to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.” Thus given that claim 16 does not refer to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.”, claim 16 fails to include all the limitations of the claim upon which it depends.
Claim 18 which depends from claim 16 is also rejected because it incorporates by reference the limitations of claim 16.
Claim 19 is drawn to the method of claim 1, wherein (i) comprises administering the antigen and/or adjuvant composition by subcutaneous, intramuscular, or intravenous injection or infusion. Part (i) of claim 1 is drawn to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.” Thus, given that claim 19 does not refer to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.”, claim 19 fails to include all the limitations of the claim upon which it depends.
Claim 20 is drawn to the method of claim 1, wherein (i) comprises administering the antigen and adjuvant in the same admixture or different admixtures by subcutaneous administration according to the same schedule. Part (i) of claim 1 is drawn to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.” Thus, given that claim 20 does not refer to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.”, claim 20 fails to include all the limitations of the claim upon which it depends.
Claim 21 is drawn to the method of claim 1, wherein (ii) comprises administering one or more boost doses is between 11 and 35 weeks, or between 15 and 40 weeks, or between 20 and 35 weeks after the start or the conclusion of (i). Part (ii) of claim 1 is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. Thus, given that claim 21 does not refer to “one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery”, claim 21 fails to include all the limitations of the claim upon which it depends.
Claim 22 is drawn to the method of claim 1, wherein (ii) comprises administering one or more boost doses 25, 26, 27, 28, 29, 30, 32, 32, 33, 34, or 35 weeks after the start of (i). Part (ii) of claim 1 is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. Thus, given that claim 22 does not refer to “one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery”, claim 22 fails to include all the limitations of the claim upon which it depends.
Claim 23 is drawn to the method of claim 1, wherein (ii) comprises administering the antigen and adjuvant composition by a single bolus dose. Part (ii) of claim 1 is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. Claim 23 does not recite that the single bolus dose is a boost delivery to the subject of the antigen and adjuvant composition temporally delayed 10 weeks or more from a first prime delivery. Thus claim 23 fails to include all the limitations of the claim upon which it depends.
Claim 26 which depends from claim 23 is also rejected because it incorporates by reference the limitations of claim 23.
Claim 24 is drawn to the method of claim 1, wherein (ii) comprises administering the antigen and adjuvant in the same or different admixtures. Part (ii) of claim 1 is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. Thus, given that claim 24 does not refer to “one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery”, claim 24 fails to include all the limitations of the claim upon which it depends.
Claim 27 is drawn to the method of claim 1, wherein (ii) comprises administering the antigen and/or adjuvant composition by subcutaneous, intramuscular, or intravenous injection or infusion. Part (ii) of claim 1 is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. Thus, given that claim 27 does not refer to “one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery”, claim 27 fails to include all the limitations of the claim upon which it depends.
Claim 28 is drawn to the method of claim 1, wherein (ii) comprises administering the antigen and adjuvant composition in the same admixture or different admixtures by subcutaneous administration according the same schedule. Part (ii) of claim 1 is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. Thus, given that claim 28 does not refer to “one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery”, claim 28 fails to include all the limitations of the claim upon which it depends.
Claim 43 is drawn to the method of claim 1, wherein (i) comprises six prime administrations over 21 days. Part (i) of claim 1 is drawn to “one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject.” Thus given that claim 43 does not refer to (i) escalating dose prime deliveries of antigen and adjuvant, claim 43 fails to include all the limitations of the claim upon which it depends.
Claim 44 is the method of claim 43, wherein (ii) the bolus boost administration is at least 7 weeks after the end of the prime administrations. Part (ii) of claim 1, from claim 43 ultimately depends, is drawn to one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery. A bolus boost administration that is at least 7 weeks after the end of the prime administrations is a broader time frame that 10 weeks or more. Thus claim 44 fails to include all the limitations of the claim upon which it depends
Claim 46 is drawn to the method of claim 45 comprising six prime administrations over 21 days and the bolus boost administration is 7 weeks after the end of the prime administration. Claim 45 is drawn to administering . . . at least two or more escalating dose prime administrations followed by a bolus boost administration. Thus, given that claim 46 is not refer to administering . . . at least two or more escalating dose prime administrations followed by a bolus boost administration, thus claim 46 fails to include all the limitations of the claim upon which it depends.
Claims 47-48 which depend from claim 46 are also rejected because they incorporate by reference the limitations of claim 46.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Rejections Maintained
Claim Rejections - 35 USC § 103
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.
7. Claim(s) 1, 6-16, 18-22, 24, 27-30, 33-38, and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0085756 A1 (Irvine et al. Mar. 19, 2020, IDS), “Irvine” in view of Cirelli et al. (Cell May 16, 2019 177: 1153-1171, IDS), “Cirelli”.
Irvine teaches non-liposome, non-micelle particles formed of a lipid, an additional adjuvant such as a TLR4 agonist, a sterol, and a saponin are provided. The particles are porous, cage-like nanoparticles, also referred to as nanocages, and are typically between about 30 nm and about 60 nm. In some embodiments, the nanocages include or are administered in combination with an antigen. The particles can increase immune responses and are particularly useful as adjuvants in vaccine applications and related methods of treatment. Preferred lipids, additional adjuvants including TLR4 agonists, sterols, and saponins, methods of making the nanocages, and method of using them are also provided. See abstract.
Irvine teaches the nanocage adjuvants alone or more typically in combination with an antigen can be administered as a vaccine that includes a first (“prime”) and optionally one or more (“boost”) administrations. Thus in some embodiments, a vaccine is administered 2, 3, 4, or more times, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, weeks, months, or years apart. See ¶¶ 0198 and 0199.
Irvine teaches that the compositions are administered by subcutaneous, intramuscular, intradermal, subcutaneous, intravenous injection or by infusion with an infusion pump. See ¶¶ 0020 and 0134-0136 and Example 6.
Irvine teaches incorporating the compositions into polymeric implants, which can effect a sustained release of the composition to the immediate area of the implant. See ¶ 0136.
Regarding claims 9-14, it is noted that the claims further limit escalating dosing, but do not exclude the other alternatives of claim 5 from which the claims depend.
Irvine teaches administering the subject an effective amount of the antigen in the same or a separate admixture (e.g., pharmaceutical composition) as the nanocage adjuvant in the same or different routes. ¶¶ 0020 and 0154 and claims 32 and 35-37 and Example 6.
Irvine teaches that nanocage adjuvant including an additional adjuvant such as a TLR4 agonist is administered to a subject in need thereof in an effective amount to increase an antigen-specific antibody response (e.g., IgG, IgG2a, IgG1, or a combination thereof), increase a response in germinal centers (e.g., increase the frequency of germinal center B cells, increase frequencies and/or activation T follicular helper (Tfh) cells, increase B cell presence or residence in dark zone of germinal center or a combination thereof). See ¶¶ 0159, 0229-0232, 0264, Fig. 2A-2B, Fig 3A-D, Fig. 11A-C and claim 26.
Irvine teaches that suitable ratios for the lipid, additional adjuvant (e.g., TLR4 agonist), sterol, and saponin components are provided. For example, in a particular embodiment, the lipid: additional adjuvant (e.g., TLR4 agonist):sterol: saponin are in a molar ratio of 2.5:1:10:10, or a variation thereof wherein the molar ratio of any one or more of the lipid, additional adjuvant, sterol, and/or saponin is increased or decreased by any value greater than 0 and up to about 3. See ¶¶ 0012 and 0120 and claim 4.
Irvine teaches that the lipid is DPPC, the additional adjuvant is a natural or synthetic MPLA, the sterol is cholesterol, and the saponin is Quil A in a molar ratio of 2.5:1:10:10. See ¶¶ 0016, 0122, and 0207 and claim 20.
Irvine teaches that saponin-MPLA nanoparticles are more immunogenic than other adjuvants. See Examples 2-8
Irvine teaches that antigen can be a viral antigen including an antigen isolated from a coronavirus. See ¶¶ 0089-0091.
Irvine teaches that the nanocages typically include one or more adjuvants in addition to a saponin, including TLR-4 agonists, PAMPs, a TLR ligand, a NOD ligand, an RLR ligand, a CLR ligand, and inflammasome inducer, a STING ligand, or a combination thereof.. See ¶¶ 0061-0075..
Irvine teaches as set forth above, but does not teach using an escalating the dose of antigen and/or adjuvant or using the MD39 HIV Env trimer.
Cirelli teaches that two independent methods of slow delivery immunization with soluble native-like HIV Env trimer BG505 Olio6CD4ko protein in a soluble ISCOM-class saponin adjuvant, Quil-A, of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH) cell responses and germinal center (GC) B cells with improved HIV Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous neutralizing antibodies (nAbs). See Summary, p. 1156-1st paragraph and p. e9- ISCOM-class saponin adjuvant.
Cirelli teaches that the adjuvant used for all the described studies was a ISCOM-like saponin nanoparticle comprised of self-assembled cholesterol phospholipid, DPPC, and quillaja saponin/Quil-A. See p. e9- ISCOM-class saponin adjuvant.
Cirelli teaches immunizing with the MD39 HIV env trimer to produce antibody responses. See p. e4-Chemicals, Peptides and Recombinant Proteins, p. e9-3rd and 6th paragraphs, p. e10-1st full paragraph, and Fig. S8(B).
Cirelli teaches three delivery strategies were tested: conventional bolus immunization via subcutaneous (s.c.) injection (n = 9), 2-week s.c. nonmechanical osmotic pumps (Ops) (n = 4) and 4-week s.c. OPs (n = 4) (Figure 1A). All immunizations were given bilaterally in the left and right thighs. See p. 1156-1st paragraph and Fig. 1A.
Cirelli teaches that the sustained delivery immunization enhance B-GC cell responses and higher nAb titers. See Figs. 1 and 3.
Cirelli teaches escalating dose immunization that enhance GC and nAb responses. Cirelli teaches the control group was given conventional bolus immunizations at week 0, week 10, and week 24, totaling 100 mg, 100 mg, and 300 mg of Olio6 native-like Env trimer protein, respectively, mixed with an ISCOM-class adjuvant. Escalating dose immunizations were administered as 7 injections over 2 weeks (Figure 6A), with a total antigen dose equivalent to that of the conventional bolus immunization group. See p. 1163-paragraph bridging the columns and Fig. 6A.
Cirelli teaches significantly higher frequencies of B-GC cells in draining lymph nodes were observed at week 5 in the escalating dos group compared with the conventional bolus immunization group (Figures 6B, 6C,and S7A). Escalating doe immunization resulted in significantly more Env specific B and B-GC cells after the first immunization. See p. 1163-right column and Fig. 6B-6E.
Cirelli teaches that the escalating dose animals were given seven injections of Olio6 and saponin adjuvant in each thigh over 12 days (on days 0, 2, 4, 6, 8, 10, 12 for each immunization). The total doses of Olio6 at each injection during the first two immunizations were: 0.2, 0.43, 1.16, 3.15, 8.56, 23.3, 63.2 mg (the doses per immunization site were 0.1, 0.215, 0.58, 1.575, 4.28, 11.65, 31.6 mg). The total doses of Olio6 at each injection during the third immunization were: 0.6, 1.29, 3.48, 9.45, 25.68, 69.9, 189.6 mg (the doses per immunization site were 0.3, 0.645, 1.74, 4.725, 12.84, 34.95, 94.8 mg). The total doses of saponin adjuvant at each injection during all immunizations were: 0.75, 1.61, 4.35, 11.81,32.1, 87.38, 237.0U (the doses per immunization site were 0.375, 0.805, 2.175, 5.905, 16.05, 43.69, 118.5U). See p. e9-2nd paragraph.
Cirelli teaches that the third escalating does set was administered at weeks 24, 25, and 26 after the first dose. See Fig. 6A.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Irvine and Cirelli and use saponin-MPLA nanoparticles with the MD39 HIV Env trimer and escalate the dose of antigen/adjuvant compositions because Irvine teaches that saponin-MPLA nanoparticles are more immunogenic than other adjuvants and because Cirelli teaches escalating the immunization doses enhances the GC and neutralizing Ab responses to immunization with MD39. Given the benefits of escalating the immunization doses taught by Cirelli, one would have been motivated to escalate the immunization doses of Irvine with saponin-MPLA nanoparticles comprising the MD39 HIV Env trimer to enhance the GC and neutralizing Ab responses to immunization.
Response to Arguments
8. Applicant argues:
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Response to Arguments
9. Applicant’s arguments have been considered, but have not been found fully persuasive. The claims encompass co-administering to the subject an antigen and an adjuvant composition, the adjuvant composition comprising a non-liposome, non- micelle particle comprising of a lipid, a sterol, a saponin, and an additional adjuvant to induce an immune response against the antigen, the co-administering comprising (i) one or more escalating dose prime deliveries of antigen and adjuvant composition to the subject, and (ii) one or more boost deliveries of the antigen and adjuvant composition to the subject temporally delayed 10 weeks or more from a first prime delivery.
MPEP 716.02 (d) teaches:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”
However, the presented evidence is drawn to administering MD39 (50 μg protein) formulated with alum adjuvant (Group 1) in bolus doses compared to MD39 Env trimer formulated with the new ISCOM-type adjuvant saponin/MPLA nanoparticle (Groups 2 & 3) administered with an escalating dose and a bolus boost does. See page 74, lines 5-13 and Fig. 1A. Thus, presented evidence is drawn to administering a single species of antigen (MD39) with a single saponin/MPLA nanoparticle adjuvant composition for the escalating dose compared to a bolus dose with single antigen (MD39) with an adjuvant that is not a species of the claimed adjuvant. Additionally, the saponin/MPLA nanoparticle used is not clearly defined and it is unclear if fully meets the limitations of the claims. Thus, the presented evidence is not commensurate in scope with the and is not sufficient to support Applicant’s assertion of non-obviousness of the claimed invention.
Additionally, the number of Tier-2 viruses neutralized by the methods of Group 2 or Group and Cirelli or Silva do not appear significantly different. See Figs.7C and 7F. Also the number of tier-2 heterologous viruses is only repeatedly and substantially altered in Group 3. See Fig. 7H. Further, Irvine teaches that saponin-MPLA nanoparticles are more immunogenic than other adjuvants and Cirelli teaches escalating the immunization doses enhances the GC and neutralizing Ab responses to immunization with MD39 and targeted a more diverse set of epitopes (See abstract and Discussion). Thus, any improvements observed would not be unexpected. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. Thus, the rejection is maintained for the reasons previously set forth and above.
In regard to amended claims 23 and 26 and new claims 44-48, neither Irvine nor Cirelli not teach using an escalating dose in combination with a bolus dose and Cirelli teaches the advantages of using an escalating dose over a bolus dose. Thus, the rejection of amended claims 23 and 26 is withdrawn and new claims 44-48 are not rejected.
10. Claim(s) 1, 6-16, 18-22, 24, 27-30, and 33-43 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0085756 A1 (Irvine et al. Mar. 19, 2020, IDS), “Irvine” in view of Cirelli et al. (Cell May 16, 2019 177: 1153-1171, IDS), “Cirelli” as applied to claims 1, 6-16, 18-22, 24, 27-30, 33-38, and 41-43 are above, in further view of US 2023/0263882 A1 (Steinbuck et al. Aug. 24, 2023, filed June 25, 2021), “Steinbuck”.
Irvine and Cirelli teach as set forth above, but do not teach using a SARS-CoV-2 spike antigen.
Steinbuck teaches CpG-amphiphiles and corona virus antigens (e.g., a coronavirus spike protein, a peptide thereof, or a nucleic acid sequence encoding the same) for use in inducing an immune response in a subject, and methods of administering CpG-amphiphiles and coronavirus antigens (e.g., a coronavirus spike protein, a peptide thereof, a coronavirus nucleocapsid protein, a peptide thereof, or a nucleic acid sequence encoding the same) to induce an immune response in a subject. See abstract and ¶¶ 0005 and 0006.
Steinbuck teaches in some embodiments, the CpG-amphiphile and the coronavirus antigen or nucleic acid encoding the same are administered concurrently. In some embodiments, the CpG-amphiphile and the coronavirus antigen or nucleic acid encoding the same are administered sequentially. In some embodiments, the CpG-amphiphile is administered first, followed by administering of the coronavirus antigen or nucleic acid encoding the same. In some embodiments, the coronavirus antigen or nucleic acid encoding the same is administered first, followed by administering of CpG-amphiphile. See ¶¶ 0019, 0021, 0181, and 0207 and claims 1 and 38-42
Steinbuck teaches the CpG-amphiphile and the coronavirus antigen and the one or more additional therapeutics may be administered sequentially (e.g., 1 day apart, 2 days apart, 3 days apart, 1 week apart, 1 month apart, 6 months apart, or more) or substantially simultaneously (e.g., within 1 day). The CpG-amphiphile and the coronavirus antigen and the one or more additional therapeutics may be formulated in a single pharmaceutical composition or may be administered as separate pharmaceutical compositions. The CpG-amphiphile and the coronavirus antigen and the one or more additional therapeutics may be administered by the same route of administration or different routes of administration. The two or more agents may be administered at the same frequency or different frequencies. See ¶¶ 0207.
Regarding claims 6 and 7, it is noted that the claims further limit infusion, but do not exclude the other alternatives of claim 5 from which the claims depend.
Regarding claims 9-14, it is noted that the claims further limit escalating dosing, but do not exclude the other alternatives of claim 5 from which the claims depend.
Steinbuck teaches the dosage of the pharmaceutical compositions of the invention depends on factors including the route of administration and the physical characteristics, e.g., age, weight, general health, of the subject. Typically, the amount of a CpG-amphiphile and a coronavirus antigen (e.g., a coronavirus spike protein or a peptide thereof, and/or a coronavirus nucleocapsid protein or peptide thereof, or a nucleic acid sequence encoding the same) described herein contained within a single dose may be an amount that effectively induces an immune response in the subject without inducing significant toxicity. A pharmaceutical composition of the invention may include a dosage of a CpG-amphiphile and a coronavirus antigen (e.g., a coronavirus spike protein or a peptide thereof, and/or a coronavirus nucleocapsid protein or peptide thereof, or a nucleic acid sequence encoding the same) described herein ranging from 0.001 to 500 mg (e.g., 0.01, 0.05, 0.1, 0.2, 0.3, 0.5, 0.7, 0.8, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 100 mg, 250 mg, or 500 mg) and, in a more specific embodiment, about 0.1 to about 100 mg. The dosage may be adapted by the clinician in accordance with the different parameters of the subject. See ¶¶ 0177-0178.
Steinbuck teaches pharmaceutical compositions of the invention that contain a CpG-amphiphile and a coronavirus antigen (e.g., a coronavirus spike protein or a peptide thereof, and/or a coronavirus nucleocapsid protein or peptide thereof, or a nucleic acid sequence encoding the same) described herein may be administered to a subject in need thereof, for example, one or more times (e.g., 1-10 times or more) daily, weekly, monthly, biannually, annually, or as medically necessary. See ¶¶ 0180.
Steinbuck teaches the CpG-amphiphile and the coronavirus antigen (e.g., a spike protein, peptide thereof, nucleocapsid protein, or nucleic acid encoding the same) is administered subcutaneously, intranasally, intratracheally, or by inhalation during mechanical ventilation. In one embodiment, the CpG-amphiphile is administered subcutaneously. See ¶¶ 0022, 0169 and 0176.
Steinbuck teaches the humoral immune response induced in mice was determined for C57Bl/6J mice that were administered three doses of 10 μg of a coronavirus spike protein (SEQ ID NO: 3) in combination with 100 μg Alum, 1 nmol soluble CpG, or 1 nmol AMP-CpG. See ¶¶ 0350-0355 and Fig. 20-22. Steinbuck teaches that the coronavirus spike protein and AMP-CpG immunization enabled at least 10-fold dose sparing of coronavirus spike protein antigen for induction of neutralizing, high titer, and optimal Th1 profile antibody responses against coronavirus spike protein. See ¶ 0355.
Steinbuck teaches CpG-amphiphile and a coronavirus antigen can be administered in sustained release formulations. See ¶¶ 0173 and 0208.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Irvine, Cirelli and Steinbuck and use a SARS-CoV-2 spike antigen as antigen because Irvine teaches that antigen can be a viral antigen including an antigen isolated from a coronavirus and Steinbuck teaches that immunization with coronavirus spike protein and the AMP-CpG adjuvant enabled at least 10-fold dose sparing of coronavirus spike protein antigen for induction of neutralizing, high titer, and optimal Th1 profile antibody responses against coronavirus spike protein. Given the effectiveness of SARS-CoV-2 spike antigen at inducing an immune response in combination with an adjuvant, one would have been motivated to use the spike antigen to stimulate an immune response against SARS-CoV-2.
Response to Arguments
11. Applicant argues that Steinbuck was cited merely because it refers to SARS-CoV-2 antigens (i.e., in claims 39 and 40), which are missing from Cirelli and Irvine. Steinbuck cannot cure the other deficiencies thereof discussed in more detail above. Thus, the claims are also non-obvious over the combination of Cirelli, Irvine, and Steinbuck
Applicant is reiterating the arguments set forth above, which were not found persuasive for the reasons set forth above. Thus, the rejection is maintained for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12. Claims 1, 6-16, 18-22, 24, 27-30, and 33-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,547,672 B2 (Irvine et al. Jan 10, 2023) in view of US 2020/0085756 A1 (Irvine et al. Mar. 19, 2020, IDS), “Irvine” in view of Cirelli et al. (Cell May 16, 2019 177: 1153-1171, IDS), “Cirelli” as applied to claims 1-38 above, in further view of US 2023/0263882 A1 (Steinbuck et al. Aug. 24, 2023, filed June 25, 2021), “Steinbuck”.
The ‘672 claims are drawn to:
1. A non-liposome, non-micelle, porous, cage-like particle comprising a phospholipid, a sterol, a saponin, and a pattern recognition receptor (PRR) ligand comprising a lipid.
3. The particle of claim 2, wherein the porous, cage-like nanoparticle is about 30 nm to about 60 nm.
4. The particle of claim 1 comprising phospholipid:PRR ligand:sterol:saponin in a molar ratio of 2.5:1:10:10, or a variation thereof wherein the molar ratio of lipid, PRR ligand, sterol, saponin or any combination thereof is increased or decreased by any value between about 0 and about 3.
17. The particle of claim 1, wherein the phospholipid is DPPC, the PRR ligand is a natural or synthetic MPLA, the sterol is cholesterol, and the saponin is Quil A or QS-21.
18. The particle of claim 17, wherein the DPPC: MPLA: cholesterol: Quil A or DPPC:MPLA:cholesterol:QS-21 are in a molar ratio of 2.5:1:10:10.
22. A pharmaceutical composition comprising a plurality of the particle of claim 1 and a pharmaceutical carrier.
23. The pharmaceutical composition of claim 22, comprising an effective amount of the particles to increase an immune response in a subject in need thereof.
24. The pharmaceutical composition of claim 23, wherein the immune response is selected from the group consisting of increasing an antigen-specific antibody response, increasing a response in a germinal center, increasing plasma blast frequency, increasing inflammatory cytokine, increasing drainage of antigen from an injection site, increasing antigen accumulation in a lymph node, increasing permeability of a lymph node, increasing lymph flow, increasing antigen-specific B cell antigen uptake in a lymph nodes, or a combination thereof.
30. A method of treating a subject in need thereof comprising administering the subject the pharmaceutical composition of claim 22 in an effective amount to induce an immune response against an antigen.
31. The method of claim 30, wherein the antigen is derived from tumor cells or a microbe.
32. The method of claim 30, wherein the subject has or may develop a cancer or infection associated with tumor cells or microbe.
33. The method of claim 30 further comprising administering the subject an effective amount of the antigen.
34. The method of claim 33, wherein the antigen is in the same or a separate pharmaceutical composition from the particles.
35. The method of claim 30, wherein the particles alone or in combination with the antigen are administered to the subject by subcutaneous, intramuscular, intradermal, or intravenous injection.
The ‘672 claims teach as set forth above, but do not teach the temporal administration variations claimed or treating with a SARS-CoV-2 spike protein antigen.
Irvine, Cirelli, and Steinbuck teach as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘672 claims, Irvine, Cirelli, and Steinbuck and escalate the dose of antigen and/or adjuvant because Cirelli teaches escalating the immunization doses enhances the GC and neutralizing Ab responses to immunization. Given the benefits of escalating the immunization doses taught by Cirelli, one would have been motivated to escalate the immunization doses of the ‘672 claims to enhance the GC and neutralizing Ab responses to immunization.
Additionally it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘672 claims, Irvine, Cirelli and Steinbuck and use a SARS-CoV-2 spike antigen as antigen because the ‘672 claims teach treating an infection, Irvine teaches that antigen can be a viral antigen including an antigen isolated from a coronavirus and Steinbuck teaches that immunization with coronavirus spike protein and the AMP-CpG adjuvant enabled at least 10-fold dose sparing of coronavirus spike protein antigen for induction of neutralizing, high titer, and optimal Th1 profile antibody responses against coronavirus spike protein. Given the effectiveness of SARS-CoV-2 spike antigen at inducing an immune response in combination with an adjuvant, one would have been motivated to use the spike antigen to stimulate an immune response against SARS-CoV-2.
13. Claims 1, 6-16, 18-22, 24, 27-30, and 33-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,246,097 B2 (Irvine et al, Mar. 11, 2025) in view of US 2020/0085756 A1 (Irvine et al. Mar. 19, 2020, IDS), “Irvine” in view of Cirelli et al. (Cell May 16, 2019 177: 1153-1171, IDS), “Cirelli” as applied to claims 1-38 above, in further view of US 2023/0263882 A1 (Steinbuck et al. Aug. 24, 2023, filed June 25, 2021), “Steinbuck”.
The ‘097 claims are drawn to:
1. A porous or perforated non-liposome, non-micelle nanoparticle comprising a phospholipid, a sterol, a saponin, and a TLR4 agonist lipopolysaccharide (LPS) or a lipid A derivative thereof.
2. The particle of claim 1, wherein the saponin comprises Quil A or QS-21.
3. The particle of claim 1, wherein the nanoparticle is about 30 nm to about 60 nm.
4. The particle of claim 1, wherein the phospholipid is 2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).
5. The particle of claim 1, wherein the lipopolysaccharide (LPS) or lipid A derivative thereof is a natural or synthetic monophosphoryl lipid A (MPLA).
6. The particle of claim 5 comprising lipid: MPLA: sterol: saponin molar ratio of 2.5:1:10:10, or a variation thereof wherein the molar ratio of lipid, MPLA, sterol, saponin or any combination thereof is increased or decreased by any value between about 0 and about 3.
7. The particle of claim 5, wherein the MPLA is natural or synthetic 4′-monophosporyl lipid A (MPLA) or 3-O-deacylated monophosphoryl lipid A (3D-MPLA).
8. The particle of claim 1, wherein the sterol is cholesterol or a derivative thereof.
9. The particle of claim 1, wherein the saponin is a natural or synthetic saponin.
10. A method of making the particle of claim 1, comprising mixing the phospholipid, sterol, saponin, and lipopolysaccharide (LPS) or a lipid A derivative thereof in an aqueous carrier comprising detergent to form a solution and removing the detergent until the phospholipid, sterol, saponin, and lipopolysaccharide (LPS) or a lipid A derivative thereof self-assemble into porous or perforated nanoparticles.
11. A pharmaceutical composition comprising a plurality of the particle of claim 1 and a pharmaceutical carrier.
12. A method of treating a subject in need thereof comprising administering the subject the pharmaceutical composition of claim 11 in an effective amount to induce an immune response against an antigen.
13. A kit comprising a plurality of the particles of claim 1 in a lyophilized or dried form, or suspended in a pharmaceutically acceptable carrier.
14. The particle of claim 1, wherein the saponin is Quil A.
15. The particle of claim 14, wherein the sterol is cholesterol, the lipopolysaccharide (LPS) or a lipid A derivative thereof is MPLA, and the phospholipid is DPPC.
16. The particle of claim 1, the saponin is QS-21.
17. The particle of claim 16, wherein the sterol is cholesterol, the lipopolysaccharide (LPS) or a lipid A derivative thereof is MPLA, and the phospholipid is DPPC.
18. A porous or perforated non-liposome, non-micelle, cage-like nanoparticle comprising a phospholipid, cholesterol, QS-21, and MPLA.
19. The pharmaceutical composition of claim 11, further comprising an antigen.
20. The pharmaceutical composition of claim 19, wherein the antigen is derived from a source selected from the group consisting of a virus, bacterium, parasite, plant, protozoan, fungus, tissue and transformed cell.
The ‘097 claims teach as set forth above, but do not teach the temporal administration variations claimed or treating with a SARS-CoV-2 spike protein antigen.
Irvine, Cirelli, and Steinbuck teach as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘097 claims, Irvine, Cirelli, and Steinbuck and escalate the dose of antigen and/or adjuvant because Cirelli teaches escalating the immunization doses enhances the GC and neutralizing Ab responses to immunization. Given the benefits of escalating the immunization doses taught by Cirelli, one would have been motivated to escalate the immunization doses of the ‘097 claims to enhance the GC and neutralizing Ab responses to immunization.
Additionally it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘097 claims, Irvine, Cirelli and Steinbuck and use a SARS-CoV-2 spike antigen as antigen because the ‘097 claims teaches using an antigen from a virus, Irvine teaches that antigen can be a viral antigen including an antigen isolated from a coronavirus and Steinbuck teaches that immunization with coronavirus spike protein and the AMP-CpG adjuvant enabled at least 10-fold dose sparing of coronavirus spike protein antigen for induction of neutralizing, high titer, and optimal Th1 profile antibody responses against coronavirus spike protein. Given the effectiveness of SARS-CoV-2 spike antigen at inducing an immune response in combination with an adjuvant, one would have been motivated to use the spike antigen to stimulate an immune response against SARS-CoV-2.
Response to Arguments
14. Applicant argues that they traverse the rejection to the extent it is applied to the amended claims. To the extent that the rejection of nonstatutory double patenting applies to the amended claims,
Applicant’s arguments have been considered, but have not been found persuasive. The amended claims 1, 6-16, 18-22, 24, 27-30, and 33-43 remain obvious for the reasons previously set forth and above and a terminal has not been filed. Thus the rejections are maintained for the reasons of record.
Conclusion
15. All other objections and rejections recited in the Office Action of October 02, 2025 are withdrawn in view of Applicant’s amendments and arguments.
16. Claims 1, 6-16, 18-24, 26-30, 33-44 and 46-48 are rejected. Claims 36 and 45 are objected to. No claims allowed.
17. 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.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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/Peter J Reddig/
Primary Examiner, Art Unit 1642
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