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 .
Election/Restrictions
Applicants’ election of Group I (Claims 1, 2, 4-7 and 9-18) drawn to the elected species of “single and specific number of non-identical peptides - SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and PLGA; and Claims 1, 2, 4-7 and 9-18 read on the elected species, in the reply filed on July 24, 2026, is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The species of claims 1, 2, 4-7 and 9-18 which read on the elected species has been considered. Claims 1, 2, 4-7 and 9-18 are hereby examined on the merits.
Claim 3, 8, and 22 are cancelled and claims 19-21, 23, and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 24, 2026.
Priority
This application is a 371 of PCT/US22/71868 April 22, 2022, and claims priority from U.S. Provisional Patent Application No. 63/178,888, filed on April 23, 2021.
Status of Claims
Claims 1, 2, 4-7, 9-21, 23 and 24 are pending. Claims 1, 2, 5, 6, 14-20 and 24 are amended, and claims 3, 8 and 22 are cancelled. Claims 19-21, 23 and 24 are withdrawn.
Claims 1, 2, 4-7 and 9-18 are hereby examined on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDS’) filed on 08/06/2024 and 01/13/2025 are under consideration.
The information disclosure statement (IDS) submitted on 07/24/2026 has been reviewed. However, the IDS fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Foreign patent WO 2016/089818 has not been considered. All references have been considered, except where lined through.
Claim Interpretation
Claims 1, 2, 4-7 and 9-18 are drawn to the elected species of the (i) peptides - SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and (ii) biodegradable poly - PLGA.
BRI of claims 1, 16, and elected species, “each polymer microsphere comprising: a. non-identical peptides comprising SEQ ID NO: 1, SEQ ID NO: 2, and SEQ IDNO: 3”, the scope of the peptides defined using “comprising” is being interpreted as open-ended, in which additional chemical moieties, e.g., amino acid residues, can be present and covalently attached to either terminus of the amino acid sequences. Also, the instant specification states that “if reference is made to microsphere formulation comprising polymer microspheres, and “each polymer microsphere” is said to have a particular peptide content, if there are 10 polymer microspheres, and only one or two of the polymer microspheres have the particular peptide content, then that subset of one or two polymer microspheres is intended to meet the limitation” (see instant specification [0048]), is being interpreted as the following possibilities: (a) each microsphere has one peptide incorporated, (ii) each microsphere has two peptides incorporated, (iii) each microsphere has all 3 peptides incorporated, and/or (vi) there is a mixture of all (i), (ii), and (iii) and microsphere with no peptides incorporated.
BRI of peptide sequences SEQ ID NO: 1, SEQ ID NO: 2, and SEQ IDNO: 3: all peptides have an isoelectric point greater than physiological pH, i.e., pH 7.4. In the instantly claimed invention, the specification states that “the pH is maintained around neutral by adjusting the buffer content as needed (pH 7 to about 8)” (see instant specification [0041]) and “the peptides include, but are not limited to, T-lymphocyte surface antigen acetate salts SEQ ID NO: 1 (Formula: C67H83N13O14; MW: 1,294.49), SEQ ID NO: 2 (Formula: C49H88N14O14; MW: 1,097.33), and SEQ ID NO: 3 (Formula: C49H77N11O14, MW: 1,044.23)” (see instant specification [0015]). Thus, all the claimed peptides are interpreted to be neutral charge in the microsphere buffer atmosphere.
Examiner’s Note: See Balmert et. al.
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 and 16 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.
Regarding claim 1, the recitation “a microsphere formulation, comprising: polymer microspheres, each polymer microsphere comprising: non-identical peptides comprising SEQ ID NO: 1, SEQ ID NO: 2, and SEQ IDNO: 3” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. It is unclear what “comprising: non-identical peptides comprising SEQ ID NO: 1, SEQ ID NO: 2, and SEQ IDNO: 3” is referred to. BRI of this limitation includes multiple, plausible combinations: (A) each microsphere comprises a mixture of peptide sequences including SEQ ID NOs: 1-3 (e.g., a single peptide comprising SEQ ID NOs: 1-3); (B) a compound of peptides linked together i.e., SEQ ID NO: 1, a second peptide is SEQ ID NO: 2 and a third peptide is SEQ ID NO: 3 are joined directly or with deletion or addition of intervening amino acids, or (C) each microsphere has one each peptide in it, i.e., SEQ ID NO: 1 is exclusively in one microsphere, and similarly other peptides are in each microsphere respectively.
As the language of a claim, given its broadest reasonable interpretation, is such that a person of ordinary skill in the relevant art would read it with more than one reasonable interpretation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph is appropriate. See MPEP 2173.02(I).
Further, by virtue of their dependency on claim 1, claim 16 is also rejected.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, 4-7, 9-14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Herst et. al (“An effective CTL peptide vaccine for Ebola Zaire Based on Survivors’ CD8+ targeting of a particular nucleocapsid protein epitope with potential implications for COVID-19 vaccine design”; C.V. Herst, S. Burkholz, J.Sidney, A. Sette, P.E. Harris, S. Massey, T. Brasel, E. Cunha-Neto, D.S. Rosa, W.C.H. Chao, R. Carback, T. Hodge, L. Wang, S. Ciotlos, P. Lloyd, R. Rubsamen; Vaccine 38 (2020) 4464–4475; published April 28, 2020; cited in IDS filed July 24, 2026 ) in view of US 20110212138 (published September 1, 2011), and further in view of Ashland (accessed as early as July 15, 2019).
Herst et. al. discloses an effective CTL (cytotoxic T-lymphocyte) peptide vaccine for Ebola Zaire based on survivors’ CD8+ targeting of a particular nucleocapsid protein epitope with potential implications for COVID-19 vaccine design. Herst et. al. designed an adjuvanted microsphere peptide vaccine formulation (see Abstract); microsphere peptide vaccine platform incorporates unmodified peptides… nucleocapsid protein considered essential for virus replication (see page 4468, right col, paragraph 4), epitope resides in a sequence conserved across multiple EBOV strains (see page 4469, left col, paragraph 1). Herst et. al. further teaches the nucleocapsid proteins in SARS-CoV-1 are also essential for that virus to function normally (see page 4469, right col, paragraph 1) suggests that a CTL vaccine targeting coronavirus nucleocapsid could be effective against SARS-CoV-1 or SARS-CoV-2 (see page 4470, left col, paragraph 1). Herst et. al. demonstrated that an adjuvanted, microsphere-based, synthetic CTL peptide vaccine platform producing a protective immune response 14 days after a single
administration (see page 4470, left col, paragraph 1). Herst et. al teaches nucleocapsid proteins within SARS-CoV-2 contain multiple Class I epitopes with predicted HLA (human leukocyte antigen) restrictions ….a similar approach to a CTL vaccine design may be possible for that virus (see Abstract).
Regarding claim 1: Herst et. al. used biodegradable dry powder, PLGA microsphere, synthetic vaccine platform adjuvanted with … TLR-9 agonists (see page 4465, left col, paragraph 6). Herst et. al. dosed three groups of mice, …. with the adjuvanted microsphere vaccine formulation containing NP44-52 and VG-19, with each peptide in a distinct microsphere population (see Table 2 (Group 3, 5 and 7); page 4465, right col, paragraph 9).
Examiner’s Note: This is in correlation with the instantly claimed invention which specifies “if reference is made to microsphere formulation comprising polymer microspheres, and “each polymer microsphere” is said to have a particular peptide content, if there are 10 polymer microspheres, and only one or two of the polymer microspheres have the particular peptide content, then that subset of one or two polymer microspheres is intended to meet the limitation” (see instant specification [0048]). Also, see Claim Interpretation above.
Regarding the peptides sequences incorporated in the microspheres, Herst et. al. suggests that the same approach could be applied to SARS-CoV-2 which has conserved regions in nucleocapsid which is located within the virus (see multiple sequence alignment in Supplementary Material Fig. 7 and Supplementary Material Fig. 8). Herst et. al. discloses the peptides as LSPRWYFYY, LLLDRLNQL, and KTFPPTEPK (see Table 6, Supplementary Material); which are identical to SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, as instantly claimed.
Herst et. al. further discloses the adjuvanted microspheres used in this study were manufactured to be nominally the same size as antigen presenting cells (about 11 μm) (see page 1, section 1., Supplementary Material); adjuvanted microspheres nominally 11 μm in diameter (geometric standard deviation 1.2) (see page 3, section 3. Supplementary Material). Herst et. al. teaches the composition of 11 μm PLGA adjuvanted microspheres used for the
study, which is loaded peptide component is 0.1% w/w (see Table 12, Supplementary Material).
However, Herst et. al. does not specifically teach about the polymer efficacy and integrity properties, nor do they disclose the range of peptide drug load utilized as claimed in the instant invention.
US’138 teaches a manufactured pre-mixed formulation for injection comprising a suspension of (i) a pharmaceutically acceptable non-aqueous carrier and (ii) microspheres which comprise a biocompatible, biodegradable polymer and an active pharmaceutical ingredient (see claim 119).
Regarding claim 2: US’138 discloses the formulations generally contain from about 0.01% (w/w)…. of the active pharmaceutical ingredient (based on the total weight of the composition); for example, the amount of active pharmaceutical ingredient can be from about 0.1% (w/w)… in certain embodiments, the range of loading is between about 0.1% (w/w) to about 10% (w/w), for example, from 0.5% (w/w) to about 5% (w/w), or from 1% to 5% (w/w) (see [0051]).
Ashland provides information for all Ashland products which varies by product family and grade (see page 2), including Poly(D,L-lactide-co-glycolide) DLG 7502A.
It would have been obvious to combine the teachings of Herst et. al. and US’138, utilizing the polymer properties as taught by Ashland before the effective filing date of the claimed invention by considering incorporating peptide in biodegradable microsphere as an effective and stable vaccine design. One of ordinary skill in the art would have been motivated to utilize the microsphere formulations taught by US’138 and Ashland for peptide incorporation targeting the nucleocapsid protein epitope of SARS-CoV-2 with a reasonable expectation of success in vaccine designing. Thus, one skilled in the art can adjust the vaccine formulation composition and drug load so that the peptide incorporated microspheres are optimally effective in eliciting cellular immune response.
Regarding claim 6 and 7: Ashland (accessed as early as July 15, 2019) teaches use of polymers for drug delivery, where Poly(D,L-lactide- co-glycolide) DLG 7502A has inherent viscosity range 0.1 – 0.3 dL/g (see page 4 and 5, Table viatel™ ultrapure polymers for drug delivery).
Regarding claims 4, 5, 9-14, 17, and 18: Herst et. al. discloses Composition of 11 μm PLGA adjuvanted microspheres used for the study
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(see Table 12, Supplementary material).
Thus, Herst et. al. used PLGA as biodegradable polymer; drug load of 0.1% w/w; CpG as toll-like receptor 9 agonist adjuvant; and sugar adjuvant including mannose.
Further, US’138 discloses the sugar may be, e.g., glucose, …mannose, … mannitol,…or a combination of two or more thereof (see [0006]); and the amount of sugar present in the microspheres can range from about 0.01% (w/w) (see [0053]); in certain embodiments, the range of loading (of the active pharmaceutical ingredient based on the total weight of the composition) is between about 0.1% (w/w) to about 10% (w/w), for example, from 0.5% (w/w) to about 5% (w/w), or from 1% to 5% (w/w) (see [0051]).
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Herst et. al (“An effective CTL peptide vaccine for Ebola Zaire Based on Survivors’ CD8+ targeting of a particular nucleocapsid protein epitope with potential implications for COVID-19 vaccine design”; C.V. Herst, S. Burkholz, J.Sidney, A. Sette, P.E. Harris, S. Massey, T. Brasel, E. Cunha-Neto,D.S. Rosa, W.C.H. Chao, R. Carback, T. Hodge, L. Wang, S. Ciotlos, P. Lloyd, R. Rubsamen; Vaccine 38 (2020) 4464–4475; published April 28, 2020; cited in IDS filed July 24, 2026 ) in view of US 20110212138 (published September 1, 2011), and Ashland (accessed as early as July 15, 2019), as previously applied to claims 1, 2, 4-7, 9-14, and 17, and further in view of AU2004259208 (published February 3, 2005, cited in IDS filed July 24, 2026).
The teachings of Herst et. al, US’138, and Ashland are discussed above. However, there was no mention of presence of residual solvents in the microsphere formulation processes and examples.
AU’208 discloses the process formulation - the co-solvents investigated had a small influence on particle size and core load; core loads were similar for the methanol (MeOH) and PEG co-solvents formulations; the highest core loads were obtained for the MeOH cosolvent with a ..buffered emulsion step, and for the dimethyl sulfoxide (DMSO) cosolvent; in vitro release kinetics were measured in either phosphate buffered saline (PBS, pH 7.2, 37oC) or 100 mM sodium acetate (see page 20-25, Table 1, and Table 2).
It would have been obvious to combine the teachings of Herst et. al., US’138, Ashland and AU’208, before the effective filing date of the claimed invention utilizing biodegradable microsphere formulations as an effective and stable carrier into which epitope/peptide can be incorporated. One of ordinary skill in the art would have been motivated to do so with an expectation to succeed in preparing potent peptide-based vaccine delivery.
Regarding claims 16 and 17: The teachings of Herst et. al, US’138, and Ashland are discussed above. AU’208 specifies Octreotide acetate (i.e., an octapeptide) encapsulation in PLGA microparticles, co- composition of median core load burst total solvent in aqueous particle (encaps. (%) Peptide organic Phase size eff) release phase (acylated); MeOH 1%, DMSO 1% (see Table 1).
Prior Art of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Balmert et. al. (“Positive Charge of “Sticky” Peptides and Proteins Impedes Release From Negatively Charged PLGA Matrices”; Stephen C. Balmert, Andrew C. Zmolek, Andrew J. Glowacki, Timothy D. Knab, Sam N. Rothstein, Joseph M. Wokpeta, Morgan V. Fedorchak, and Steven R. Little; J Mater Chem B Mater Biol Med.; 3(23): 4723–4734; published June 21, 2015)
Conclusion
No claim is allowed.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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