DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of species c, filed October 20, 2025, is acknowledged. Claim 21 is directed to non-elected species, and is therefore withdrawn from consideration.
Claims Summary
Claim 1 is directed to a method to generate a vaccine composition for use against a SARS-CoV-2. The method comprises:
Identifying non-virion-integral proteins derived HLAI restricted epitopes (non-VIP-derived HLAI-HRE) from SARS-CoV-2; this next portion of the claim is directed to a product-by-process, i.e., the epitopes identified are by the following process;
Using standardized donor vectors for HLA and antigen ORF constructs paired with genomic receiver sites within functionally engineered immortal cell lines that represent programmable engineered APCs (eAPCs)
The eAPCs are then screened by mass spectrometry (MS) based methodologies to identify HLA-restricted antigens from integrated ORFs within the background of the intrinstic HLAI restricted repertoire derived from the eAPC proteins themselves and enables systematic analysis of the ORFs in single HLA backgrounds (monoalleleic);
Claim 26 is directed to an embodiment wherein there is an engineered TCR-presenting cell (eTPC)
It is noted that a non-VIP is any protein encoded in a viral genome that is expressed within infected host cells during the virus life-cycle and not represented within a virion (see paragraph [0301] of the published application US 2023/0145860)
It is noted that HLAI-HRE is any epitope that may be loaded specifically in an HLAI molecule for export to the cell surface for T-cell sampling (see paragraph [0291] of the published application US 2023/0145860)
It is noted that just because systematic analysis is enabled in single HLA backgrounds, no active method step is actually performed
According to MPEP 2113, the patentability of a product does not depend on its method of production. The structure implied by the process steps should be considered, however, product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. In this case, as long as non-VIP-derived HLAI-HRE from SARS-CoV-2 are identified, the process by which they are identified does not matter
Classifying immunogenicity of the identified non-VIP-derived HLAI-HRE in naïve CD8 T-cell populations isolated from donors without prior SARS-CoV-2 infection, and/or in memory CD8 T-cell populations from donors with confirmed active, latent or resolved SARS-CoV-2 infection
wherein multiple non-VIP-derived HLAI-HRE are selected for inclusion as to represent one or more HLAI-HRE in a selection of HLAI alleles that represents those alleles carried by at least 60% of individuals within the target population for which the vaccine composition is designed (claim 16)
wherein multiple non-VIP-derived HLAI-HRE are selected for inclusion as to represent one or more HLAI-HRE in a selection of one or more HLAI alleles that is carried by an individual for which the vaccine is designed (claim 17); and
Selecting non-VIP-derived HLAI-HRE with confirmed immunogenicity in naïve donors, or with observed CD8 T-cell responses in donors with confirmed active, latent or resolved SARS-CoV-2 infection; and
Providing the selected non-VIP-derived HLAI-HRE in the vaccine composition; wherein the selected non-VIP-derived HLAI-HRE is included with priority to HLAI-HRE of non-VIP from naïve donors, or with observed CD8 T-cell responses in donors confirmed with active and/or resolved SARS-CoV-2 infection (claim 26).
The vaccine composition comprises a vaccination vector comprising a recombinant RNA construct, with or without modified nucleotides (claim 18, elected species). The selected non-VIP-derived HLAI-HRE are incorporated into expression constructs which do not allow expression of functional non-VIP proteins in host cells upon vaccine delivery as to avoid immunoevasion activity of said viral non-VIP (claim 19). The method by which the non-VIP proteins are not expressed is by introducing point mutations and/or sequence insertions and/or sequence deletions within full-length non-VIP ORFs that inactivate protein function, among other methods (claim 20). The recombinant RNA construct further encodes one or more B-cell/Immunoglobulin epitopes so as to prime neutralizing Ig responses (claim 22). The recombinant RNA construct further encodes one or more selected HLAII-HRE epitopes so as to prime CD4 T-cell responses to support B-cell maturation and neutralizing antibody production, and/or promote commitment of non-VIP-derived HLAI-HRE-specific CD8 T-cell responses to memory differentiation (claim 23). The one or more B-cell/Immunoglobulin epitopes have been modified to remove HLAI-HRE from the VIP so as to avoid priming CD8 T-cell responses against VIP proteins upon vaccine delivery (claim 24).
Claim Objections
Claim 26 is objected to for the following minor informality. In line 3, “and/ or” should not have a space between “and/” and “or”.
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, 16-20 and 22-26 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.
The term “standardized donor vector for HLA and antigen ORF constructs” in claim 1 is a relative term which renders the claim indefinite. The term “standardized” 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. Without further clarity as to the metes and bounds of the term, one would not know whether a given vector qualifies as a standardized donor vector for HLA and antigen ORF constructs. Claims 16-20 and 22-26 are included in this rejection at least because they depend from claim 1.
Claim 1 recites, “functionally engineered immortal cells lines”. The function referred to is not clearly set forth. The metes and bounds of the cell lines cannot be determined without an understanding of what function the cell lines have been engineered to provide.
Claim 1 recites, “mass spectrometry (MS) based methodologies”. The term “based” does not clearly set forth the metes and bounds of what methodologies qualify. Suggested language is “mass spectrometry (MS) methodologies”, which is clearly understood to mean any methodology that uses MS.
Claim 1 recites, “classifying immunogenicity of the identified non-VIP-derived HLAI-HRE”. It is not clear how immunogenicity can be classified when, after identifying epitopes, no immunogenicity has been observed according to claim 1 step a.
Claim 1, part b recites the limitation "prior target virus infection". There is insufficient antecedent basis for this limitation in the claim, as a target virus has not been identified. For purposes of compact prosecution, the target virus is SARS-CoV-2.
Claim 18 is directed to an embodiment wherein the vaccine composition comprises a vaccination vector, which is a recombinant RNA construct, with or without modified nucleotides (elected species). According to claim 1, from which claim 18 depends, the method of generating a vaccine results in a vaccine comprised of epitopes, which are a part of an antigen, understood to be protein (see paragraph [0281]) of the published application US 2023/0145860. It is not clear how the vaccine comprises both protein epitopes and also a recombinant RNA construct, unless there are two components in the vaccine. Further, claim 19 indicates that the epitopes are incorporated into expression constructs, which appears to imply that nucleic acid sequences encoding the epitopes are incorporated into expression constructs. Clarification and/or correction is required as to whether the vaccine comprises epitopes in protein form, or an RNA construct that expresses the epitopes. Claims 20 and 22-24 are included in this rejection as they depend from claim 18.
Claim 25 recites, “wherein step a further includes an engineered TCR-presenting cell (eTPC)”. It is not clear where or how the eTPC is “included” in step a. Thus, the metes and bounds of claim 25 cannot be determined.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 16-20 and 22-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method to generate an immunogenic composition against SARS-CoV-2, does not reasonably provide enablement for generating a vaccine against SARS-CoV-2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The breadth of the claims encompasses a method to generate a vaccine based on certain HLAI-HRE epitopes from SARS-CoV-2 non-virion-integral proteins, discovered during the process described in claim 1. A vaccine is understood to be capable of inducing protective immunity such that a vaccinated subject will not develop disease as a result of subsequent infection with SARS-CoV-2. The nature of the invention is the generation of a vaccine comprising certain HLAI-HRE epitopes from SARS-CoV-2 non-virion-integral proteins, which will be administered to a subject with the expectation of preventing disease.
The specification provides a method, but no epitopes have been identified, nor tested for efficacy as a vaccine. The state of the art with regard to SARS-CoV-2 epitope vaccination is that it is still under development. Solanki et al. (PeerJ, 2021, 9:e11126, DOI 10.7717/peerj.11126, 29 pages) discloses an immunoinformatic approach to generate a vaccine for SARS-CoV-2 using multiple epitopes to structural and non-structural proteins, noting that while in silico results look promising, the human immune response and efficacy needs to be determined via experimentation (see abstract and page 24, top paragraph). Khan et al. (Front. Immunol, 2023, 13:1001430, DOI 10.3389/fimmu.2022.1001430, 17 pages) reports on epitopes identified through immunoinformatics design for SARS-CoV-2, also noting that in silico results need to be further evaluated in experimentation (see abstract). Basu et al. (bioRxiv, March 2, 2020, https://doi.org/10.1101/2020.02.27.967422, cited in the IDS filed 9/27/2022) also reports on an immunoinformatics method to discover epitopes for vaccination against coronavirus. Basu et al. identified an MHCI restricted epitope and an MHCII restricted epitope from the HKU24, noting that the MHCI restricted epitope is represented in certain percentages in certain populations (see section 3.3), but notes that further experimental study is required (see abstract). Thus, it is clear from the art that immunoinformatic design, while producing promising epitopes, is not predictive of the human response, outside of the epitopes being immunogenic. Challenge experiments in acceptable animal models are evidence of protective efficacy in humans.
In view of the breadth of the claims, the nature of the invention, the high level of skill in the art, the lack of working examples and limited guidance in the specification, the state of the art, and the low level of predictability to extrapolate in silico results to protective efficacy in humans, the claimed method is not enabled by the specification for the generation of vaccines against SARS-CoV-2. This rejection would be overcome if the claims were amended to remove vaccine embodiments in favor of immunogenic compositions.
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.
Claims 1, 16, 17 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Basu et al. (bioRxiv, March 2, 2020, https://doi.org/10.1101/2020.02.27.967422, cited in the IDS filed 9/27/2022, “Basu”) in view of Jarvis et al. (WO 2018/083316 A1, cited in the IDS filed 9/27/2022, “Jarvis”), Wan et al. (J. Virol., February 14, 2020, accepted manuscript published online December 11, 2019, 94:e0215-19, “Wan”) and Jaume et al. (J. Virol., 2011, 85(20):10582-10597).
The claims are summarized above and correlated with the teachings of the prior art in bold font below. The claims are rejected on the basis of their enabled embodiments, i.e., immunogenic compositions (see the rejection under 35 U.S.C. 112(a) above).
Basu discloses a method for designing coronavirus vaccines using immunoinformatics to find epitopes from non-structural protein 4 (see abstract). Basu exemplifies the method with HKU24, a betacoronavirus, but also suggests designing the same with 2019-nCoV (SARS-CoV-2), see pages 1-2, bridging paragraph, and page 3 top three paragraphs (claim 1, aspect of generating an immunogenic composition, non-VIP-derived epitopes from SARS-CoV-2). Basu classifies the predicted epitopes, which are inherently immunogenic, being epitopes (claim 1, aspects of classifying and selecting). Further selection of the epitopes is according to MHCI restriction and HLA alleles that are highly represented, e.g., at 58.87% in the population of China (see section 3.3) (claim 1, aspect of HLAI-restricted epitopes, and claim 17).
Basu does not disclose epitopes that are represented by at least 60% of individuals in a given population, however, it would have been obvious to have selected epitopes that are represented at an even higher level that Basu’s 58.87% in order that the epitopes have a higher likelihood of being immunologically relevant and immunogenic in more people (claim 16).
Basu does not disclose the process by which the epitopes are identified as set forth in instant claim 1 step a. As this part of the claim is constructed as a product-by-process claim, Basu only needs to show that non-VIP-derived HLAI-HRE are identified, which Basu does (as outlined above). However, for purposes of compact prosecution, it would have been obvious to have used Jarvis’ method employing eAPCs to identify epitopes. Jarvis discloses donor vectors paired with genomic receiver sites to introduce ORFs (comprising antigens) into APCs, programmable eAPCs, that are then screened using mass spectrometry in what appears to be the background of the instrinsic HLAI restriction repertoire from the eAPC proteins themselves (see abstract and page 59, second paragraph) (claim 1, part a). One would have been motivated to use Jarvis’ tangible method in place of Basu’s theoretical method of identifying epitopes in order to make an actual determination as to the immunogenicity of the epitopes, with a reasonable expectation of success (claim 1, part c, aspect of classifying and confirming immunogenicity).
Regarding claim 1 parts b and c, and claim 26, Basu does not disclose particular populations of donors or prioritizing epitopes based on populations of donors, however, it would have been obvious to have distinguished between identified epitopes from donors that are naïve, and those that are from donors having confirmed active, latent or resolved SARS-CoV-2 infection. One would have been motivated to make such a distinction because of the problem of antibody dependent enhancement (ADE) associated with prior infection with coronaviruses, as taught by Wan and Jaume. Wan discloses ADE as an important consideration in vaccine design (see abstract), as does Jaume, for SARS-CoV (see abstract). To consider the immune status of patient populations in the determination of relevant epitopes would have been obvious to one of ordinary skill in the art.
Therefore, the claimed invention 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.
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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