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 .
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other form of browser-executable code. See page 1, line 20, and page 2, line 28. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claims Summary
Claim 1 is directed to a method of treating recovered COVID-19 patients comprising administering a vaccine composition comprising the receptor binding domain (RBD) of the SARS-CoV-2 virus. Claim 11 is directed to a method of delivering effective protective immunity comprising administering a vaccine composition comprising the SARS-CoV-2 RBD to subjects previously immunized with one or more vaccines selected from adenovirus, inactivated virus, attenuated virus and mRNA-based vaccines. The RBD is understood from the specification to be protein (see paragraph [0011] of the published application, US 20240042013). In claim 2, the recovered patients have a humoral immunity characterized by at least one of the following conditions: response titer against RBD is less than 1:1000; inhibitory capacity of RBD-ACE2 protein interaction is less than 50% at a 1:100 dilution; and/or SARS-CoV-2 neutralizing antibody titer is less than 1:160. In claim 12, protective immunity is considered effective where at least one of the following conditions is achieved: response titer against RBD is greater than 1:1000; inhibitory capacity of RBD-ACE2 protein interaction is greater than 50% at a 1:100 dilution; or SARS-CoV-2 neutralizing antibody titer is greater than 1:160.
The vaccine composition comprises a covalent conjugate comprising the RBD and a carrier protein selected from TT, DT and CRM197 (claim 3), and additionally selected from DT mutant (claim 13). The RBD is adsorbed on Al(OH)3 (claims 4 and 14), and the vaccine composition comprises an immunopotentiator (claims 5 and 15), specifically, N. meningitidis outer membrane vesicle (claims 6 and 16). The RBD is in monomer form (claims 7 and 17), or in dimer form (claims 8 and 18). The vaccine is administered intramuscularly or subcutaneously according to an immunization schedule comprising a range of 1-3 doses of between 1-100 µg of RBD, at intervals of 21-28 days (claim 9), resulting in producing a hyperimmune plasma with a high SARS-CoV-2 neutralizing capacity.
Claim Objections
Claims 11-18 are objected to because of the following informalities:
Claim 11 and dependent claims 12-18 recite “previously immunized with one or more vaccines”, without indicating that the vaccine(s) is a SARS-CoV-2 vaccine(s). The specification as a whole is clearly directed to SARS-CoV-2 vaccines when referring to previous immunizations (see abstract, and Examples 3 and 4). Appropriate correction is required.
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.
Claims 1-10 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 1 and dependent claims 2-10 are directed to treating recovered COVID-19 patients. Since recovered patients are not sick, it is not clear what the treatment is for. The claims do not indicate any marker that defines treatment, nor does the specification provide a definition of “treatment” in this context. It appears that the “treatment” may be the induction of a high SARS-CoV-2 neutralizing capacity in patients (as recited in claim 10), but it is not clearly set forth such that the metes and bounds of the treatment method can be determined.
Regarding claim 10, the term “high” in the context of “high SARS-CoV-2 neutralizing capacity” is a relative term which renders the claim indefinite. The term “high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The metes and bounds of the claim cannot be determined without a definition of “high”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Florian Krammer (Nature, 10/22/2020, published online 09/23/2020, 586:516-527, cited in the IDS filed 04/03/2024). Claim 11 is directed to a method of delivering effective protective immunity comprising administering a vaccine composition comprising the SARS-CoV-2 RBD to subjects previously immunized with one or more vaccines selected from adenovirus, inactivated virus, attenuated virus and mRNA-based vaccines.
Krammer discloses a heterologous prime-boost regimen comprising a virus-vectored prime, such as an adenovirus vector vaccine, followed by an adjuvanted S protein (which contains the RBD portion) vaccine boost (see Table 1, and page 525, right column, third full paragraph). Although Krammer does not report on protective immunity, this is expected to be a natural outcome of doing what the prior art suggests since the claimed method steps are the same as those of the prior art. Therefore, the claim is anticipated by the prior art.
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.
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.
Claims 1, 2, 4, 5, 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (US Patent 10,953,089 B1, filed 08/19/2020) in view of Seow et al. (Nature Microbiology, issued December 2020, published 10/26/2020, 5:1598-1607, “Seow”, cited in the IDS filed 04/03/2024). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Smith discloses vaccine compositions comprising S polypeptides from SARS-CoV-2, such as the RBD, for stimulating immune responses (see col. 8, line 35 through col. 9, line 3) (claim 1, aspect of RBD vaccine). The composition comprising the polypeptide is administered in a single dose, or in a prime-boost protocol, with a boost being between about 2 to about 6 weeks after the prime dose, for example a boost at day 28 (see col. 28, lines 18-26) (claim 9, aspect of immunization schedule). Adjuvants are contemplated, including but not limited to nanoparticles comprising the polypeptides which are bound to alum, such as Al(OH)3 (see col. 23, lines 50-52 and 61-62) (claims 4 and 5). Administration is intramuscular or subcutaneous, among other routes of administration (see col. 28, lines 5-17) (claim 9, aspect of administration routes). Doses range between about 1 µg and about 100 µg, among other values (see col. 28, lines 38-61) (claim 9, aspect of dose amount).
Smith does not disclose administration to convalescent COVID-19 patients, however, it would have been obvious to have done so with a reasonable expectation of success. Seow discloses waning antibody protection against SARS-CoV-2 reinfection, suggesting vaccine boosters for protection (see abstract). Some individuals that develop neutralizing antibody titers in the range of ID50 100-300 after infection, decline to baseline (less than 50) after about 50 days (see page 1604, left column, last full paragraph) (claim 2). One would have been motivated to boost individuals experiencing waning protection by receiving further immunization with Smith’s method (claim 1, aspect of immunizing recovered COVID-19 patients). Although Smith and Seow do not explicitly disclose the production of hyperimmune plasma with a high SARS-CoV-2 neutralizing capacity, these are natural outcomes of doing what the prior art suggests since the claimed method steps are the same as those of the prior art (claim 10). Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (US Patent 10,953,089 B1, filed 08/19/2020) in view of Seow et al. (Nature Microbiology, issued December 2020, published 10/26/2020, 5:1598-1607, “Seow”, cited in the IDS filed 04/03/2024), as applied to claim 1 above, and further in view of Arumugham et al. (US 2007/0134762 A1, “Arumugham”). Claim 3 is directed to an embodiment wherein the vaccine composition comprises a covalent conjugate of RBD and a carrier protein, such as TT, DT or CRM197.
The teachings of Smith and Seow are outlined above, neither of which disclose the use of carrier proteins. However, it would have been obvious to have used carrier protein with a reasonable expectation of success. One would have been motivated to improve the immunogenicity of Smith’s RBD (see Arumugham, paragraph [0004]). Arumugham discloses immunogenic peptide carrier conjugates comprising any immunogen, such as an immunogen from a coronavirus, and a carrier protein/polypeptide selected from TT, DT, CRM197, among others, using covalent linkages (see paragraphs [0011], [0019] and [0108]). Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (US Patent 10,953,089 B1, filed 08/19/2020) in view of Seow et al. (Nature Microbiology, issued December 2020, published 10/26/2020, 5:1598-1607, “Seow”, cited in the IDS filed 04/03/2024), as applied to claim 1, and further in view of Yang et al. (Nature, 10/22/2020, published online 07/29/2020, 586:572-577, “Yang”, cited in the IDS filed 04/03/2024). Claim 4 is directed to an embodiment wherein the RBD is adsorbed on Al(OH)3. Claim 4 has been rejected without the Yang reference, however, it is rejected here with the Yang reference in the instance that the RBD is directly adsorbed on Al(OH)3, as opposed to an embodiment wherein the RBD is part of a nanoparticle that is bound to Al(OH)3.
The teachings of Smith and Seow are outlined above. Smith does not explicitly disclose RBD adsorbed (directly) onto Al(OH)3 in the absence of a nanoparticle. However, it would have been obvious to have done so in view of Yang, which discloses RBD adsorbed onto Al(OH)3 (see abstract and page 573, right column, last full paragraph). One would have had a reasonable expectation of success since it the same protein (RBD) as that used by Smith. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (US Patent 10,953,089 B1, filed 08/19/2020) in view of Seow et al. (Nature Microbiology, issued December 2020, published 10/26/2020, 5:1598-1607, “Seow”, cited in the IDS filed 04/03/2024) and Yang et al. (Nature, 10/22/2020, published online 07/29/2020, 586:572-577, “Yang”, cited in the IDS filed 04/03/2024) as applied to claim 4 above, evidenced by Lan et al. (Nature, 05/14/2020, published 03/30/2020, 581:215-220, cited in the IDS filed 04/03/2024). Claims 7 and 8 are directed to embodiments wherein the RBD is monomeric or dimeric form.
The teachings of Smith, Seow and Yang are summarized above and are silent with regard to the form of RBD being monomeric or dimeric. However, it appears that monomeric and dimeric forms of RBD are naturally occurring, according to Lan’s Extended Data Figure 1, showing RBD monomers and dimers. Thus, it would be expected that either or both forms would have been present in the composition of Smith or Yang. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Florian Krammer (Nature, 10/22/2020, published online 09/23/2020, 586:516-527, cited in the IDS filed 04/03/2024) as applied to claim 11 above, and further in view of Seow et al. (Nature Microbiology, issued December 2020, published 10/26/2020, 5:1598-1607, “Seow”, cited in the IDS filed 04/03/2024). In claim 12, protective immunity is considered effective where at least one of the following conditions is achieved: response titer against RBD is greater than 1:1000; inhibitory capacity of RBD-ACE2 protein interaction is greater than 50% at a 1:100 dilution; or SARS-CoV-2 neutralizing antibody titer is greater than 1:160.
The teachings of Krammer are outlined above. Krammer does not disclose a particular titer against RBD, inhibitory capacity of RBD-ACE2 interaction, nor SARS-CoV2 neutralizing antibody titer. However, it would have been obvious to have used such measurements for protective immunity in view of Seow, with a reasonable expectation of success. Seow discloses that some individuals that develop neutralizing antibody titers in the range of ID50 100-300 after infection, decline to baseline (less than 50) after about 50 days (see page 1604, left column, last full paragraph), while some develop titers about greater than ID50 10,000 and maintain greater than 1,000 after 60 days (see abstract). Based Seow’s description of high and low levels of neutralizing antibodies, it would have been obvious to have considered the high levels to be indicative of protective immunity. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Florian Krammer (Nature, 10/22/2020, published online 09/23/2020, 586:516-527, cited in the IDS filed 04/03/2024) as applied to claim 11 above, and further in view of Arumugham et al. (US 2007/0134762 A1, “Arumugham”). Claim 13 is directed to an embodiment wherein the vaccine composition comprises a covalent conjugate of RBD and a carrier protein, such as TT, DT, DR mutant or CRM197.
The teachings of Krammer are outlined above and do not suggest the use of carrier proteins. However, it would have been obvious to have used carrier protein with a reasonable expectation of success. One would have been motivated to improve the immunogenicity of Krammer’s RBD (see Arumugham, paragraph [0004]). Arumugham discloses immunogenic peptide carrier conjugates comprising any immunogen, such as an immunogen from a coronavirus, and a carrier protein/polypeptide selected from TT, DT, CRM197, among others, using covalent linkages (see paragraphs [0011], [0019] and [0108]). Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Florian Krammer (Nature, 10/22/2020, published online 09/23/2020, 586:516-527, cited in the IDS filed 04/03/2024) as applied to claim 11 above, and further in view of Yang et al. (Nature, 10/22/2020, published online 07/29/2020, 586:572-577, “Yang”, cited in the IDS filed 04/03/2024). Claim 14 is directed to an embodiment wherein the RBD is adsorbed on Al(OH)3. Claim 15 is directed to a further embodiment wherein the composition comprises an immunopotentiator. The claims are correlated with the teachings of the prior art in bold font below.
The teachings of Krammer are outlined above. Krammer suggests using an adjuvanted RBD, but does not disclose RBD adsorbed on Al(OH)3. However, it would have been obvious to have done so in view of Yang, which discloses RBD adsorbed onto Al(OH)3 (see abstract and page 573, right column, last full paragraph) (claim 14). One would have been motivated to improve the immune response to the RBD protein by using the adjuvant (see Yang, abstract). The Al(OH)3 also serves as an immunopotentiator (claim 15). One would have had a reasonable expectation of success since it the same protein (RBD) as that suggested by Krammer. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Florian Krammer (Nature, 10/22/2020, published online 09/23/2020, 586:516-527, cited in the IDS filed 04/03/2024) and Yang et al. (Nature, 10/22/2020, published online 07/29/2020, 586:572-577, “Yang”, cited in the IDS filed 04/03/2024), as applied to claim 14 above, evidenced by Lan et al. (Nature, 05/14/2020, published 03/30/2020, 581:215-220, cited in the IDS filed 04/03/2024). Claims 17 and 18 are directed to embodiments wherein the RBD is monomeric or dimeric form.
The teachings of Krammer and Yang are summarized above and are silent with regard to the form of RBD being monomeric or dimeric. However, it appears that monomeric and dimeric forms of RBD are naturally occurring, according to Lan’s Extended Data Figure 1, showing RBD monomers and dimers. Thus, it would be expected that either or both forms would have been present in the composition of Smith or Yang. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Hansen et al. (Science, 08/21/2020, epublished 06/15/2020, 369:1010-1014, “Hansen”, cited in the IDS filed 04/03/2024) and the Supplementary Materials for Hansen’s article (available from science.sciencemag.org/cgi/content/full/science.abd0827/DC1, 30 pages, provided with this Office Action) discloses immunization of mice with a DNA plasmid encoding full-length SARS-CoV-2 S protein and boosted on days 9, 12 and 14 with recombinant RBD fused to a mouse Fc tag (RBD-mFc) mixed with CpG ODN and aluminum phosphate adjuvants (see Hansen, first page, bridging paragraph between cols. 2-3, and Supplementary Materials, second page, second full paragraph “Immunization”). Hansen does not teach or fairly suggest administration of mRNA boosted with RBD protein.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1672