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
Acknowledgement is hereby made of receipt and entry of the communication filed on May 10, 2026. Claims 1-16 are pending. Claims 13-15 are withdrawn. Claims 1-12 and 16 are currently examined.
Election/Restrictions
Applicant's election with traverse of Group I (Claims 1-12 and 16), directed to a coronavirus SARS-CoV-2 nanoemulsion vaccine formulation, in the reply filed on May 10, 2026, is acknowledged. For the species election requirement, Applicant elects: 1) polysorbate for emulsifier, and 2) methoxy polyethylene-glycol polycaprolactone for block copolymer.
Applicant argues that an examination of the disclosure of Brito reveals that the composition of the nanoemulsion vaccine formulation disclosed by Brito is different from the SARS-CoV-2 vaccine formulation as claimed. Applicant argues that in the present application, a TLR7 agonist is conjugated to an antigen polypeptide (an immunogen), and it is not a portion of the squalene-based oil-in-water nanoemulsion, and that the vaccine formulation as claimed comprises a TLR7 agonist coupling antigen polypeptide and a squalene-based oil-in-water nanoemulsion.
Applicant’s arguments are not persuasive. Even though combined teachings of Brito and Chen fail to suggest an invention as specified in the amended claims, prior art references are identified suggesting the amended claims. See discussions in the art rejections below.
For the reasons above, the Restriction is deemed to be proper, and is made Final. Accordingly, claims 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group.
Specification – Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) as follows:
The specification does not contain sequence identifiers (SEQ ID NO:) in all locations where sequences are disclosed, see at least FIGs 1-2. To correct this, the sequences in figures can be referred to in either the figure or the Brief Description of Drawings. If the prior filed Sequence Listing does not contain updated sequences, Applicant is also required to submit a replacement Sequence Listing that includes all updated sequences.
Full compliance with the sequence rules is required in response to this Office Action. A complete response to this office action should include both compliance with the sequence rules and a response to the Office Action set forth below. Failure to fully comply with both these requirements in the time period set forth in this Office Action will be held non-responsive.
Claim Objection
Claim 1 is objected to for reciting an abbreviation RBM in the claim set without spelling it out the first time it appears.
Applicant is required to make proper corrections.
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.
Claims 1-12 and 16 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection has the following grounds.
A. The base claim 1 recites a structure of Formula I: Z-(J-U)n (I). The claim defines elements Z and U, but does not define elements J and n. Therefore, the vaccine polypeptide having a structure of formula I is not clear.
It is noticed that the specification describes a structure of formula I, with the n being 0 or a positive integer and J being a chemical bond or linker. See [0038]-[0043]. To expedite examination, the formula I of claim 1 is interpreted based on the definition in [0038]-[0043] of the specification.
B. Claim 10 recites limitations (a), (b), and (c) without a conjunction word linking them. It is not clear if all of the three limitations are required.
Additionally, it is not clear how to interpret the limitation “wherein the structure of the antigen polypeptide is as shown in Formula II: X1-X-X2 (II)” recited in claim 10. E.g., it is not clear if the claimed antigen polypeptide must comprise or consist of the sequence specified in Formula II, or any “structure” contained in a sequence specified by Formula II would suffice, or anything else.
To facilitate examination, the antigen polypeptide recited in claim 10 is considered as “comprising” a sequence specified by Formula II.
C. Claim 12 recites “having a good stability” which is not clear since it is not clear what stability is considered as good and what is not. Additionally, the two limitations (1) and (2) are not linked by a conjunction word. It is not clear if both of them are required.
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
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 of this title, 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.
Claims 1-9, 11-12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Francica et al. (bioRxiv [Preprint]. 2021 Mar 2:2021. 03.02.433390) and/or Arunachalam et al. (Nature, 594:253–258; published on Apr. 19, 2021), in view of Newman et al. (Advanced Drug Delivery Reviews 32 (1998) 199–223) and/or Danafar (Cogent Medicine, 2016, 3:1, 1142411).
These claims are directed to a coronavirus SARS-CoV-2 nanoemulsion vaccine formulation, which comprises:
(a) a coronavirus SARS-CoV-2 vaccine polypeptide, comprising an antigen polypeptide and a TLR7 agonist conjugated to the antigen polypeptide; wherein the vaccine polypeptide has a structure of Formula I or comprises an oligomer with a structure of Formula I:
Z-(J-U)n (I)
wherein,
Z is an antigen polypeptide with at least one T cell epitope and/or at least one B cell epitope of a coronavirus SARS-CoV-2 S protein; and the antigen polypeptide has an amino acid sequence derived from a RBM region of the S protein;
each U is independently a TLR7 agonist;
(b) an adjuvant, which is a squalene-based oil-in-water nanoemulsion; wherein the adjuvant comprises an oil phase portion and an aqueous phase portion, wherein the oil phase portion of the adjuvant comprises: 1-15% (w/w) squalene, 0-15% (w/w) a-tocopherol, and 0.1- 10.0% (w/w) emulsifier; and wherein the aqueous phase portion of the adjuvant comprises: 0.005- 10% (w/w) block copolymer and an aqueous medium, calculated by the total weight of the formulation; and
(c) a pharmaceutically acceptable carrier, excipient or diluent.
As indicated in the 112(b) rejection above, the base claim 1 defines elements Z and U in formula (I), but does not define elements J and n. To facilitate examination, the formula I of claim 1 is interpreted based on the definition in the specification [0038]-[0043], with the n being 0 or a positive integer and J being a chemical bind or linker. When n takes the value of 0, the element U, i.e., a TLR7 agonist, is not required.
Francica teaches a study on formulating a soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) with the adjuvant AS03 and administration of the formulation to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FC receptors mediating effector functions in vitro. The data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials. See Abstract.
Francica teaches that the well characterized adjuvant, AS03, is an oil-in-water emulsion composed of squalene, polysorbate 80, and α-tocopherol. AS03 potently induces antibodies and has been shown to increase vaccine durability, promote heterologous strain cross-reactivity, and to have dose-sparing effects. It was licensed for use in vaccines against pandemic influenza in Europe, with approximately 90 million doses administered. See lines 99-103.
Arunachalam teaches a study evaluating the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (RBD–NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. The authors evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD–NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD–NP in AS03 (RBD–NP-AS03), and correlated with protection from infection. RBD–NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD–NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD–NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD–NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD–NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343). See Abstract.
Accordingly, both Francica and Arunachalam teach a SARS-CoV-2 nanoemulsion vaccine formulation comprising a SARS-CoV-2 S polypeptide that comprises an amino acid sequence of the S protein RBD and adjuvant AS03 which comprises squalene, a-tocopherol, and emulsifier (polysorbate 80). Here, SARS-CoV-2 S polypeptide antigens contained in the nanoemulsion vaccine formulations of Francica and Arunachalam read on the claimed formula I when n takes the value 0.
However, Francica and Arunachalam are silent on the inclusion of a block copolymer in the squalene-based oil-in-water nanoemulsion adjuvant (e.g., AS03). They are silent on if the concentrations of ingredients included in the squalene-based oil-in-water nanoemulsion adjuvant (AS03) are in the ranges as claimed.
Newman reviews the studies on the development of adjuvant-active nonionic block copolymers. It teaches that nonionic block copolymers are surfactants synthesized using propylene oxide (PO) and ethylene oxide (EO) which are organized as ‘blocks’ of polyoxyethylene (POE) and polyoxypropylene (POP). These copolymers can be designed and synthesized using variable amounts of the PO and EO and with differential arrangement of the POP and POE blocks so that individual products have unique physicochemical properties. The copolymers that have been most thoroughly evaluated in vaccine research are linear with the polymer blocks organized as POE–POP–POE. Low molecular weight (MW) copolymers, 3–6 kDa, of this type have been used in oil-based emulsion formulations, whereas high-MW copolymers, .9 kDa, can be used in aqueous formulations. The adjuvant activity of nonionic block copolymers is influenced greatly by the size of the POP core block. As the size of this block is increased so is the adjuvant activity of the copolymer; peak activity is achieved using copolymers with POP cores that are 12–15 kDa. However, adjuvant activity is also affected by the amount of POE with low concentrations, 5–10%, being optimal. The type of immune responses produced is also influenced by the POE content. Copolymers with 10% POE preferentially augment Type 2 helper T-lymphocyte responses which support antibody responses, including mucosal antibody responses. Copolymers with,10% POE augment both Type 1 and Type 2 helper T-lymphocyte responses, which support a broader range of antibody responses and cellular immune responses. This property may allow for vaccines to be ‘customized’ by using adjuvant-active nonionic block copolymers that will augment the most appropriate types of immune responses. See Abstract.
Danafar teaches that Methoxypoly(ethylene glycol) Poly(caprolactone) (mPEG–PCL) copolymers are important synthetic biomedical materials with amphiphilicity, controlled biodegradability, and great biocompatibility. They have great potential application in the fields of nanotechnology, tissue engineering, pharmaceutics, and medicinal chemistry. mPEG–PCL copolymers are biodegradable, biocompatible, and semi-crystalline copolymers having a very low glass transition temperature. Due to their slow degradation, mPEG–PCLs are ideally suitable for long-term delivery extending over a period of more than one year. This has led to its application in the preparation of different delivery systems in the form of microspheres, nanospheres, micelles, polymersomes, nanogels, and implants. Various categories of drugs have been encapsulated in mPEG–PCL for targeted drug delivery and for controlled drug release. See Abstract.
Danafar teaches that mPEG–PCL block copolymer nanoparticles were applied as carriers for vaccine, protein, and gene drugs, particularly in a sustained/controlled release drug delivery system and targeted-drug delivery method that might increase drug effectiveness and decrease drug struggle, and that mPEG–PCL copolymer nanoparticles are largely dispersal- and deprivation-controlled release systems. See page 8, para 2. Figure 2 of Danafar indicates that mPEG–PCL copolymer can be incorporated in oil-in-water (o/w) emulsion.
Accordingly, teachings of Newman and Danafar indicate that block copolymers can be used as ingredients in vaccine adjuvants containing oil-based emulsions with properties that may augment functions of pharmaceutical formulations.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to introduce a block copolymer taught in Newman and Danafar into the oil-in-water nanoemulsion adjuvants, e.g., AS03, used in the studies of Francica and Arunachalam to test how the block copolymer can improve the adjuvant functions.
As to the claimed ranges of concentration and molecular weight of each components, according to section 2144.05 of the MPEP, differences in concentrations will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). Unless Applicant can show that the claimed concentration ranges are critical to the claimed immunogenic composition, these ranges are considered obvious through routine experimentation.
Regarding claim 4, one of skill in the art would have found it obvious to use squalene from any proper source, including ones as claimed.
Regarding claim 9, one of skill in the art would have found it obvious to use any proper isotonic regulator known and commonly used in the art as a vaccine excipient (e.g., a salt) which most adjuvant formulations are expected to contain.
Regarding claim 12, since the formulation suggested by the combined teachings of Francica, Arunachalam, Newman and Danafar is indistinguishable from the product as claimed, it is considered to have the same structural and functional properties as claimed.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Francica et al. (bioRxiv [Preprint]. 2021 Mar 2:2021. 03.02.433390) and/or Arunachalam et al. (Nature, 594:253–258; published on Apr. 19, 2021) in view of Newman et al. (Advanced Drug Delivery Reviews 32 (1998) 199–223) and/or Danafar (Cogent Medicine, 2016, 3:1, 1142411), as applied above, and further in view of Starzl et al. (US 2021/0347858 A1, published on Nov. 11, 2021; filed on Apr. 2, 2021).
Claim 10 specifies that “the structure of the antigen polypeptide is as shown in Formula II: X1-X-X2”. As indicated in the 112(b) rejection above, the antigen polypeptide recited in claim 10 is considered as “comprising” a sequence specified by Formula II.
It is noted that claim 1, from which claim 10 depends, specifies that the claimed vaccine formulation comprises a “SARS-CoV-2 vaccine polypeptide” which, in turn, comprises an “antigen polypeptide”.
Relevance of Francica, Arunachalam, Newman and Danafar is set forth above. However, they are silent on amino acid sequences of the SARS-CoV-2 S antigen polypeptides used in the studies.
Starzl teaches an invention involving methods and compositions are provided for rapid preparation of anti-SARS-Co V-2 protein polyclonal lgY antibodies. See Abstract. Starzl teaches that a vaccine composition is provided for production of polyclonal antibodies, the composition comprising a recombinant SARS-CoV-2-S-protein, and a recombinant SARS-CoV-2 N-protein, and a carrier, optionally comprising an adjuvant. The recombinant SARS-CoV-2-S-protein may comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 36, 37, 38, 39, 40, 41 or a fragment of at least 10, 20, 30, 40, 50, 60, 70, 80, 100, 150, or 200 contiguous amino acid residues thereof, or a substantially similar protein thereof. See [0036]. Here, SEQ ID NO: 15 of Starzl represents a 59-aa polypeptide, and comprises the 54-aa sequence of instant SEQ ID NO: 1.
Accordingly, Starzl teaches that a polypeptide comprising the claimed SEQ ID NO: 1 can be used as a SARS-CoV-2 vaccine antigen.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to use the SARS-CoV-2 S vaccine antigen polypeptides, include the polypeptide with SEQ ID NO: 15, disclosed in Starzl in the studies of Francica, Arunachalam, Newman and Danafar, since Starzl teaches that those SARS-CoV-2 antigen peptides are potential vaccine antigens for rapid induction of anti-SARS-CoV-2 antibodies.
Double Patenting Rejection
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-12 and 16 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-4, 6-11 and 15-16 of US Application 18008826 in view of Francica et al. (bioRxiv [Preprint]. 2021 Mar 2:2021. 03.02.433390), Arunachalam et al. (Nature, 594:253–258; published on Apr. 19, 2021), Newman et al. (Advanced Drug Delivery Reviews 32 (1998) 199–223), Danafar (Cogent Medicine, 2016, 3:1, 1142411), and/or Starzl et al. (US 2021/0347858 A1, published on Nov. 11, 2021; filed on Apr. 2, 2021), cited in the art rejections above.
Although the conflicting claims are not identical, they are not patentably distinct from each other. Both sets of claims encompass a vaccine polypeptide against SARS-CoV-2, wherein the vaccine polypeptide has a structure of Formula I: Z-(J-U)n (I). The differences between the two sets of claims include: (1) the reference claims specify that n is 1, 2, 3, 4, 5, or 6 while the instant claims do not specify n (which is currently interpreted as being 0 or a positive integer); (2) the reference claims specify the structure of the antigenic polypeptide as Formula II: X1-X-X2 (II) while the instant claims are mostly generic with the structure of the antigenic polypeptide, except for instant claim 10 which specifies Formula II; (3) reference claims 6-9 specify the molecular structure of the TLR7 agonist while instant claims are generic in TLR7 agonist structures; and (4) the instant claims specify that the SARS-CoV-2 vaccine polypeptide is comprised in a squalene-based oil-in-water nanoemulsion formulation, which is a limitation not required by the reference claims.
Regarding the differences (1)-(3), the SARS-CoV-2 vaccine polypeptide of the reference claims is encompassed by the more generic SARS-CoV-2 vaccine polypeptide of instant claims. Regarding the difference (4), the prior art references cited in the 103 rejections above teach the application of squalene-based oil-in-water nanoemulsion adjuvants in the formulation of SARS-CoV-2 vaccine.
Therefore, based on teachings of the prior art references, one of skill in the art would have found it obvious to arrive at the instant claims from the reference claims by introduction of the squalene-based oil-in-water nanoemulsion adjuvants taught in the prior art references into the formulation of SARS-CoV-2 vaccine polypeptide, as specified in instant claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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