DETAILED ACTION
Disposition of Claims
Claims 1-3, 5, 15, 18-19, 21, 23-24, 27, and 47-55 remain pending. Claims 4, 6-14, 16-17, 20, 22, 25-26, and 28-46 are cancelled. No amendments to the claims have been presented.
Election/Restrictions
Applicant’s election without traverse of Group III, claims 47-55, in the reply filed on 11/10/2025 is acknowledged.
Claims 1-3, 5, 15, 18-19, 21, 23-24, and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/2025.
Applicant’s election without traverse of linear B lymphocyte (LBL) epitope of SEQ ID NO:2, cytotoxic T lymphocyte (CTL) epitopes of SEQ ID NOs: 12, 13, 15, and 17, and helper T lymphocyte (HTL) epitopes of SEQ ID NOs: 6, 7, and 10, in the reply filed on 11/10/2025 is acknowledged. As noted by Applicant, said species are not presently encompassed by the elected invention.
Claims 47-55 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240009299A1, Published 01/11/2024.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/26/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings are objected to because Figure 2 references color in the figure legend, but the drawings are in black and white. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). 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.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology (e.g. the use of “thereof” and “e.g.” which is Latin for ”exempli gratia”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
See e.g. item 58 at ¶[0110] “http://www.expasy.org/tools/” .
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
Claim 47 and dependent claims 48-55 thereof 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 47 is drawn to a method, wherein one step provides for “identifying a plurality of putative epitopes for a target antigen molecule and any mutants or variants thereof” (lines 3-4). However, from the wording and punctuation of the claim, it is unclear if the “any mutants or variants thereof” refers to the “putative epitopes” or the “target antigen molecule”.
Additionally, the “selecting two or more candidate epitopes” in line 4 is unclear as it is not clear if this “selection” is done from any possible epitopes or if the candidate epitopes are selected from those identified from the “putative epitopes” in the earlier step.
For the purpose of examination, claim 47 will be interpreted as reading upon the following:
“Claim 47. A method for developing a single multi-epitope polypeptide comprising:
identifying a plurality of putative epitopes, wherein said putative epitopes are comprised within a target antigen molecule and also within any mutants or variants of said target antigen molecule;
selecting two or more candidate epitopes from the putative epitopes identified in part a) based on immune-relevant properties and/or antibody accessible surface area (AbASA); and
concatenating the two or more candidate epitopes from part b) into the single multi-epitope polypeptide. “
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 47 is rejected on the grounds of being indefinite. Claims 48-55 are also rejected since they depend from claim 47, but do not remedy these deficiencies of claim 47.
Claim 48 is 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 48 provides wherein the method is further comprising at least one or both of: assessing the plurality of putative epitopes for immune-relevant properties and/or antibody accessible surface area; and determining immune-relevant properties and structure of the single multi-epitope polypeptide. However, from the wording and punctuation in this claim, it is unclear as to which items are the “both” (e.g. it is unclear which is item a) and which is item b) as there are technically 3 items/limitations listed in the claim.) Since this is a method claim, it is suggested the “two” options from the “at least one or both” should be selected/performed. Additionally, it is unclear from the wording of the claim if the “assessing the plurality of putative epitopes for immune-relevant properties and/or antibody accessible surface area” is an additional step as the term “further comprising” is used (e.g. this step is performed twice, as a similar step is already recited in claim 47). Finally, it would be helpful to state at what step in the method these additional “further” steps are performed.
For the purpose of prior art, the claim will be interpreted as reading upon the following, but must be amended for clarity:
“Claim 48 The method of claim 47, further comprising at least one or both of the following steps:
after step a) and before step b), assessing the plurality of putative epitopes for immune-relevant properties and/or antibody accessible surface area; and
after step c), determining immune-relevant properties and structure of the single multi-epitope polypeptide.”
For at least these reasons, the metes and bounds of claim 48 are unclear.
Claim 51 is 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 51 provides a Markush grouping of “wherein the plurality of epitopes comprises: a linear B lymphocyte (LBL) epitope, a cytotoxic T lymphocyte (CTL) epitope, and a helper T lymphocyte (HTL) epitope, and combinations thereof”. However, the use of “and” at line 2 and then “and combinations thereof” is confusing, as the first “and” already encompasses “and combinations thereof.” One suggestion is to delete the “and combinations thereof”, while another suggestion is to delete the first “and” and leave the “and combinations thereof”.
For at least these reasons, claim 51 is rejected on the grounds of being indefinite.
Claim 53 is 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 53 is drawn to the method of claim 47, wherein the selecting of two or more candidate epitopes comprises selecting putative epitopes: with little to no change in the AbASA across target antigen molecule and any mutants or variants thereof, in which each residue has greater than 0.25 A2 of AbASA; are immunogenic, antigenic, non-allergenic, and non-toxic; and/or elicit immune responses from IFN-y, IL-4, and IL-10. The limitation of “elicit immune responses from IFN-y, IL-4, and IL-10” is unclear, as the wording implies that the IFN-y is the target molecule that then provides the immune response, when IFN-y, IL-4, and IL-10 are all types of cytokines that regulate immune responses. Another issue is that this Markush group lists three cytokines that, depending on where their signaling pathway is elicited, can counteract each other. While IFN-y in general promotes a Th1-type immune response and IL-4/IL-10 is Th2-type, IFN-y can stimulate a pro-inflammatory immune response while IL-4/IL-10 promotes more of a suppression or downregulation of inflammation. Therefore, another suggestion is to list these three cytokines in the alternative (“or” or “and/or”) instead of only in the inclusive (“and”).
One way of more clearly wording the claim would be “…elicit IFN-y, IL-4, and/or IL-10-related immune responses.” Other suggestions would be “…; and/or the IFN-y, IL-4, and/or IL-10 signaling pathways are stimulated” ; “…and/or triggering immune responses with IL-4, IL-10, and/or IFN-y”; or “and/or orchestrating immune responses by producing IFN-y, IL-4, and/or IL-10”. Any of these suggestions make it more clear that the cytokine is the one modulating/regulating/inducing the response through a specific pathway.
Finally, in claim 53, it is unclear at line 6 what the distinction is between “immunogenic” and “antigenic”.
For at least these reasons, claim 53 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 47 is drawn to a method for developing a single multi-epitope polypeptide comprising:
identifying a plurality of putative epitopes, wherein said putative epitopes are comprised within a target antigen molecule and also within any mutants or variants of said target antigen molecule;
selecting two or more candidate epitopes from the putative epitopes identified in part a) based on immune-relevant properties and/or antibody accessible surface area (AbASA); and
concatenating the two or more candidate epitopes from part b) into the single multi-epitope polypeptide
Further limitations on the method of claim 47 are wherein the method is further comprising at least one or both of the following steps:
after step a) and before step b), assessing the plurality of putative epitopes for immune-relevant properties and/or antibody accessible surface area; and
after step c), determining immune-relevant properties and structure of the single multi-epitope polypeptide (claim 48);
further comprising characterizing simulated immune response of the single multi-epitope polypeptide with and without an adjuvant (claim 49); further comprising characterizing protein-protein interactions of the single multi-epitope polypeptide with one or more immune receptors (claim 50); wherein the plurality of epitopes comprises: a linear B lymphocyte (LBL) epitope, a cytotoxic T lymphocyte (CTL) epitope, and a helper T lymphocyte (HTL) epitope, and combinations thereof (claim 51); wherein the immune-relevant properties comprise one or more of: antigenicity, allergenicity, cytokine induction, IFN-y induction, solubility, physiochemical properties, and toxicity (claim 52); wherein the selecting of two or more candidate epitopes comprises selecting putative epitopes: with little to no change in the AbASA across target antigen molecule and any mutants or variants thereof, in which each residue has greater than 0.25 A2 of AbASA; are immunogenic, antigenic, non-allergenic, and non-toxic; and/or elicit IFN-y, IL-4, and/or IL-10-related immune responses (claim 53); wherein the concatenating comprises separating any pair of the two or more candidate epitopes with a linker in the multi-epitope polypeptide and/or merging overlapping epitopes (claim 54); and wherein the target antigen molecule is a viral surface protein (claim 55).
Claim Rejections - 35 USC § 112(a); First Paragraph
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 47-55 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 methods utilizing specific molecular dynamics simulations and immunoinformatics techniques to model and map the severe acute respiratory syndrome type 2 coronavirus (SARS CoV-2) spike (S) protein with respect to linear and conformational epitopes and generate a single SARS CoV-2 S protein polyepitope peptide, wherein each of the epitopes were separated by amino acid linkers, and wherein the polyepitope peptide comprised an 50S ribosomal L7/L12 protein adjuvant sequence, does not reasonably provide enablement for any method of generating any single multi-epitope polypeptide using any bioinformatics techniques and the combination of any epitopes from any type, sequence, and/or source. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a method for developing a single multi-epitope polypeptide comprising: a) identifying a plurality of putative epitopes, wherein said putative epitopes are comprised within a target antigen molecule and also within any mutants or variants of said target antigen molecule; b) selecting two or more candidate epitopes from the putative epitopes identified in part a) based on immune-relevant properties and/or antibody accessible surface area (AbASA); and c) concatenating the two or more candidate epitopes from part b) into the single multi-epitope polypeptide. The method does not require any specific tool, technique, or analysis to identify the plurality of putative epitopes in part a), nor does it require the target antigen molecule to be of any specific origin. The breadth of “target antigen” reasonably includes any molecule from any pathogen (e.g. bacterium, virus, parasite, protozoa, fungi, etc.), any cancer/tumor, and can be any material that would be considered “antigenic” in any species (e.g. rabbit proteins in a human would be recognized as foreign and are therefore “antigenic targets” under the breadth of the instant claims.) Epitope can be broadly interpreted as any relevant B-cell or T-cell epitope of any length, any linear or conformational epitope, and any subtype of any of the aforementioned epitope types (e.g. MHC Class I vs MHC Class II epitopes, Tregitopes, etc.) “Immune-relevant properties” reasonably includes those which would be context-dependent (e.g. extrinsic factors, such as host specificity (MHC polymorphism), immune status of the host, and immunodominance competition); physical and chemical properties (e.g. structural vs. linear (conformational) limitations, accessibility of epitopes (e.g. are the epitopes buried under a glycan shield or inaccessible in certain protein conformations), and post-translational modifications (e.g. glycosylation, phosphorylation, etc.)); host processing and presentation of the identified epitopes (e.g. epitopes may be identified via bioinformatics but never actually generated via proteasomal cleavage, class I MHC presentation requires TAP transporting of the epitope, etc.), and technical limitations in predictive algorithms (e.g. low predictive accuracy of epitope prediction tool models, affinity limitations against synthetic peptides vs. peptide in native conformation.) Further, the method requires a “concatemerization” of the identified epitopes in any order or conformation (e.g. N- vs. C-terminal placement, use of flexible/rigid linkers, etc.) and does not require the polyepitope protein to be generated in any specific system (e.g. synthetic formation of peptide, engineering and expression via bacterial or yeast systems, etc.)
State of the prior art/Predictability of the art. B- and T-cell epitopes can be determined by experimental methods. However, these methods are expensive and time consuming, resulting in the development of different epitope prediction methods utilizing the advances in immunoinformatic databases and tools. These epitope predictive methods have made epitope mapping easier and decreased the experimental effort and cost.
In early 2020, at the onset of the COVID-19 pandemic caused by SARS CoV-2 infection, the landscape of in silico epitope prediction was primarily dominated by sequence-based machine learning (ML) algorithms, often integrated within the Immune Epitope Database (IEDB) analysis resource. While these tools were fast and crucial for rapid initial screening, their accuracy was mixed, particularly for conformational B-cell epitopes, and they required experimental validation to confirm actual immunogenicity. Recognition of epitopes by T cells occurs by the T-cell receptor (TCR). These epitopes must be displayed on the surface of antigen-presenting cells (APCs) bound to MHC molecules. T-cell epitopes are presented by MHC I and MHC II molecules that can stimulate CD8+ and CD4+ T-cells, respectively. The size of epitopes presented by MHC molecules is restricted depending on the processing pathway and the MHC binding. Therefore, prediction of peptide-MHC binding is the main basis to anticipate T-cell epitopes and the high degree of MHC polymorphism makes T-cell epitope prediction challenging. These prediction tools typically offered accurate results for T-cell epitopes because the majority of T-cell epitopes are linear (Martin W, et. al. Methods. 2003 Mar;29(3):289-98.), in contrast to the discontinuous B-cell epitopes which could give unreliable results in some cases (Hamed SM, et. al. Future Sci OA. 2023 Feb;16(3-06):FSO832. Epub 2023 Mar 6.; Wang P, et. al. PLoS Comput Biol. 2008 Apr 4;4(4):e1000048.; Galanis KA, et. al. Int J Mol Sci. 2021 Mar 22;22(6):3210.).
With respect to the use of bioinformatics to develop SARS CoV-2-based vaccines, the selection and design of protective immunogens against pathogens is a major challenge in vaccine development, especially for the newly emerging pathogens. Traditional methods based on lab experiments cannot meet the needs of the pressing situation in the event of an outbreak (Qiu T, et. al. Nat Commun. 2018 May 2;9(1):1772.; Chakraborty C, et. al. Eur Rev Med Pharmacol Sci. 2020 Apr;24(7):4016-4026.). As noted in Chen et. al. (Chen HZ, et. al. Infect Dis Poverty. 2020 Jul 10;9(1):88.), suitable antigenic SARS CoV-2 proteins are selected, wherein the S and nucleocapsid (N or NP) proteins were evaluated for epitopes (Fig. 1). The analysis included linear B-cell epitope, discontinuous B-cell epitope, HLA Class-I binding prediction, and HLA Class-II binding prediction studies, with the identified epitopes evaluated for various vaccine-relevant characteristics, such as antigenicity, surface accessibility, allergenicity, toxicity, and hydrophilicity. After suitable epitopes were reviewed and selected for these criterion, they are then developed into various vaccine platforms (Fig. 1). Chen then notes the identified epitopes from SARS CoV-2 could then be placed into a single, multi-epitope protein, wherein the epitopes were separated by flexible linkers and included a known adjuvanting epitope (PADRE) (p. 6, “Peptides selected and multi-epitope based vaccine design”.) Even with these bioinformatics tools, Chen noted that many of the potential epitopes could be allergens, and special attention should be paid to potential allergic reactions during the pre-clinical and clinical trial (p. 8, ¶ bridging cols.), and that while their models should work to induce both humoral and cellular immune responses, it was reiterated that they needed to be tested using both in vitro and in vivo models (p. 8, rt. Col.)
Working examples. The working example disclosed in the specification analyzed multiple conformations for the SARS CoV-2 spike glycoprotein, both in the wild-type as well as in 9 different mutated states (including high mannose N-glycan substituted systems), allowing for a broader reach with respect to B-cell epitope prediction as it was stated that simple sequential analysis only yielded 27 potential linear epitopes (¶[0090-0091]). After initial identification of the epitopes, a bioinformatics analysis to determine stability was performed (¶[0091]), as well as looking at the antibody accessible surface area (AbASA) to determine if certain epitopes would be shielded by the glycosylation of the wild-type protein (¶[0092]). Antigenic Linear B-cell Epitopes ElliPro12 was used to predict the linear B-lymphocyte (LBL) epitopes for each of the 6 conformations for each of the nine mutant systems and the wild type (¶[0093]), as well as cytotoxic T lymphocyte (CTL) epitopes (¶[0094]), and helper T lymphocyte epitopes (¶[0095]). The multi-epitope polypeptide (COVCCF) was then generated (Example 3 at ¶[0096]), and comprised the 50S ribosomal L7/L12 protein (UniProt accession ID P9WHE3; SEQ ID NO: 18), a known TLR4 agonist, as well as the peptides separated by amino acid linkers, and included a his-tag at the C-terminus to aid in purification (¶[0096]; Fig. 3). The resulting COVCCF was analyzed for the ability to induce IFN-y-based and allergic immune responses (¶[0097]), was analyzed for overall solubility and other physiochemical properties (¶[0098]), was analyzed for predicted structure (¶[0099-0101]), and was analyzed for the ability to interact with certain toll-like receptors (TLRs), namely TLR2 and TLR4 (¶[0102-0103]). Overall, the resulting COVCCF consisted of antigenic, nontoxic, non-allergenic, and antibody accessible B-cell and T-cell epitopes; in addition, multiple helper T-cell epitopes, all of which were determined to induce cytokines important to innate immunity, such as IFN-γ, IL4, and IL10, were included (¶[0109]). It was stated the modeled immune response mimicked the actual immune response (¶[0105]), but it is unclear how said model was compared to an “actual immune response”, as it is not clear what experimental in vivo models were utilized (e.g. dosage, delivery, subject, serological status, etc.) No other SARS CoV-2 proteins aside from S protein were analyzed in this model. No other pathogens aside from SARS CoV-2 were tested, and no other allergenic or cancerous proteins were tested in this model. It is not clear if and how any actual in vitro or in vivo tests using the modeled COVCCF protein were performed, as all analyses appeared to be in silico.
Guidance in the specification. The specification provides guidance towards the biostatistical analysis of SARS CoV-2 spike (S) glycoprotein epitopes using specific software analyses that focus on conformational analysis of S proteins and mutants thereof. The analysis identified epitopes which were incorporated into a specific, singular multi-epitope protein separated by specific amino acid linkers in order to present the epitopes in the most antigenic conformation while providing a protein that remained soluble and immunogenic. Said protein analysis resulted in a multi-epitope protein that was linked to a known adjuvanting peptide along with a his tag to allow for isolation upon expression in a bacterial system. No other SARS CoV-2 proteins, mutants, or nucleic acids were analyzed or included in the multi-epitope protein. No in vitro or in vivo testing of the resulting multi-epitope protein was performed to determine the overall efficacy against SARS CoV-2 challenge. No other pathogens (bacteria, viruses, parasites, protozoa, fungi, etc.), cancers or malignancies, or allergenic proteins were tested in the system. No specific subjects (e.g. human, non-human primates, pigs, mice, rabbits, etc.) were tested to determine if the proteins were safe, antigenic, and elicited a sufficient immune response to provide any sort of therapeutic or prophylactic immune response in the host.
Amount of experimentation necessary. Additional research is required in order to determine how effective the system would be in generating any single multi-epitope polypeptide comprising any amount of two or more epitopes from any source arranged in any manner. It is not clear that the multi-epitope COVCCF protein generated in the examples retained the “epitopes” in such a way that they were recognized by any host immune system, as the COVCCF protein was not tested in any in vitro or in vivo setting. No clinical trials in humans with the COVCCF protein were performed. It is unclear what combination of epitopes is appropriate, or how many epitopes may be present in the resulting protein, and how said epitopes may be joined (e.g. linkers, and what types of linking agents), and whether or not said multi-epitope protein must comprise additional components (e.g. amino acids to aid in isolation and/or solubility, known adjuvanting epitopes, etc.)
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the sheer breadth of the limitations and possible permutations of the method result in undue experimentation to determine if the method as claimed would work on any other system aside from analysis of SARS CoV-2 S protein. The breadth of number of epitopes, epitope source, linkage of said epitopes, and methods for how said epitopes are identified, analyzed, and joined is so large that the experimentation required would be undue.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Claims 47-55 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to a method of producing a multi-epitope protein by any type of bioinformatics analysis to identify a plurality of any type of epitope, selecting said epitopes based upon any “immune relevant properties” and/or antibody accessible surface area (AbASA), and concatenating said plurality of epitopes into a single polypeptide. The claim limitation does not require that the “epitope” to possess any particular distinguishing feature or conserved structure, but only that it is an “epitope” that fits the vague criterion provided for in instant claim 47. Said epitope can therefore be from any protein of any source (depending on the species for which it would be an “antigenic epitope”, e.g. a rabbit protein would raise an immune response in a goat), which also includes, but is not limited to, any pathogen (e.g. viruses, bacteria, fungi, protozoa, and parasites), any allergen, and any cancer or tumor antigen, including chimeric proteins, fusion proteins, muteins and variants comprising an antigenic or immunogenic region of any size of any polypeptide. It is the examiner’s position that the disclosure of the instant application does not convey applicant’s possession of the claimed genus of “epitopes” from any source.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings or structural chemical formulas, or by disclosure of relevant, identifying characteristics, i.e., complete/partial structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, by predictability in the art, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997), the Court decided that adequate written description of genetic material '"requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." Id. 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406. A description of what the genetic material does, rather than of what it is, does not suffice, ld. While the instant claims are drawn to multi-epitope proteins, the cited case law is relevant because there is limited disclosure of the structure, formula, or physical properties of an "epitope" and there is only a disclosure of what the "epitope" does (protein which is immunogenic), rather than of what it is.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus. Regents of the University of California v. Eli Lilly& Co., 199 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly & Co., the court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. A "representative number of species" means that the species that are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP §2163 II.A.3a.ii. Further, even in cases were multiple species with in a claimed genus have been disclosed, such does not necessarily demonstrate possession of the genus. See, In re Smyth, 178 U.S.P.Q. 279 at 284-85 (CCPA 1973) (stating "where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus or combination claimed at a later date in the prosecution of a patent application."); and University of California v. Eli Lilly and Co., 43 USPQ2d 1398, at 1405 (Fed Cir 1997)(citing Smyth for support). Where there is uncertainty in the operability of undisclosed embodiments, an application may be found not to have provided adequate descriptive support for a claimed genus.
The specification discloses the reduction to practice of only SARS CoV-2 S protein epitopes within the claimed genus (see analysis supra with respect to the enablement rejection and the guidance in the specification.) This multi-epitope polypeptide generated from the SARS CoV-2 S protein, however, does not reflect the structures of the epitopes or immunogenic fragments/antigens within each polypeptide sequence. Consequently, there is no information about which and how many amino acids are required for raising an immune response, the source of the epitopes, which epitopes may/may not be included in the polypeptide, the number of maximum polypeptides which may be in the peptide, or the requirement of additional structures (e.g. linkers, tags, and protein adjuvant peptide sequences) that are necessary for generating the multi-epitope polypeptide.
There is no disclosure relating similarity of any partial structure of any epitope to conservation of the immunogenic function. It is known for proteins, albeit not in all cases, that amino acid addition(s), substitution(s) or deletion(s) can destroy the function of the epitope or abolish its ability. This lack of predictability of the relationship between the protein sequence and the immunogenic epitope function is well documented by Mateu et al. (Mateu MG, et. al. Eur J Immunol. 1992 Jun;22(6):1385-9.) and Greenspan et al. (Greenspan NS, Di Cera E. Defining epitopes: It's not as easy as it seems. Nat Biotechnol. 1999 Oct;17(10):936-7.). The effects of these changes are largely unpredictable as to which ones have a significant effect versus not. Thus, the specification fails to adequately describe at least a substantial number of members of the immunogenic fragment genus of “any putative epitopes” to which the claims are based.
In summary, one of skill in the art would not accept the disclosure of the SARS CoV-2 S protein epitope analysis and multi-epitope polypeptide generated therefrom as representative of all epitopes from all sources and any fragments, homologs, or variants thereof having immunogenic activity. The specific program or programs which may be used to analyze the desired functions (e.g. “immune-relevant properties” and “AbASA”) have not been claimed, nor fully explained within the disclosure aside from the limited guidance towards the use of the free open-source software GROMACS (¶[0071]). Further limitations in dependent claims are also so broadly claimed that it is unclear which analysis tools (e.g. in silico or in vitro/vivo) would or would not work within the method to identify the relevant functional characteristics (e.g. simulation of any immune response from the generated multi-epitope polypeptide, characterization of protein/protein interactions of the generated multi-epitope polypeptide). Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of all potential methods to identify any epitopes from any source which could be useful in the concatemeric multi-epitope protein based on the disclosure of the instant application. In conclusion, the specification, taken together with the pre-existing knowledge and the lack of predictability in the art, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claims 47-55.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (page 1115).
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 47-48 and 50-55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Samad et. al. (Samad A, et. al. J Biomol Struct Dyn. 2022 Jan;40(1):14-30. Epub 2020 Jul 17.; CITED ART OF RECORD IN IDS DATED 04/26/2023; hereafter “Samad”.)
The Prior Art
Samad teaches the design of a SARS CoV-2 multi-epitope protein for use as a vaccine construct, wherein said vaccine construct comprised four potential epitopes from each of the three epitope classes such as cytotoxic T-lymphocytes (CTLs), helper T-lymphocyte (HTL), and linear B-lymphocyte (LBL) epitopes. Samad teaches that multiple sequences for SARS CoV-2 were analyzed (Sect. 2.1., “Proteome retrieval and antigen selection”) and the various epitopes identified were then subjected to further analysis to determine the estimation of population coverage for the HLA binding alleles for the identified antigens (Sect. 2.5, “Estimation of population coverage.”) Samad teaches the designed vaccine was antigenic, immunogenic, and non-allergenic with suitable physicochemical properties and has higher solubility, with the predicted vaccine structure being similar to the native protein. Samad teaches their analyses indicated a strong and stable binding interaction between the vaccine and the toll-like receptor (TLR4), wherein strong binding stability and structural compactness were also evident in molecular dynamics simulation. Samad teaches computer-generated immune simulations which showed that the vaccine could trigger real-life-like immune responses upon administration into humans, and that codon optimization based on Escherichia coli K12 resulted in optimal GC content and higher codon adaptation index (CAI) value followed by incorporating it into the cloning vector pET28þ(a) (entire document; see abstract.) Samad teaches the proteome retrieval and antigen selection of the SARS CoV-2 spike (S) surface protein (Sect. 2.1, p. 3; instant claim 55), followed by the prediction and assessment of CTL epitopes (Sect. 2.2, pp. 3-4), HTL epitopes (Sect. 2.3, p. 4), and LBL epitopes (Sect. 2.4, p. 4), wherein the identified epitopes were analyzed for their potential population coverage (Sect. 2.5, p. 4) along with peptide modeling of multi-epitope proteins and potential molecular docking to HLA alleles (Sect. 2.6, p. 4). Samad then teaches the generation of the vaccine construct which comprised the selected CTL, HTL, and LBL epitopes, wherein said construct had linkers separating the epitopes and a TLR4 agonist adjuvant (50S ribosomal protein L7/L12) was included to improve the immunogenicity of the overall polypeptide (Sect. 2.7, p. 4; Fig. 4; Sect. 3.7, p. 6; instant claims 47-48, 51, 54). Samad teaches modeling the molecular docking of the resultant polypeptide with the TLR4 receptor (Fig. 7; instant claim 50). Samad teaches the assessment of the epitopes for antigenicity, allergenicity, immunogenicity, and toxicity (Tables 1-3; instant claims 52-53).
Samad therefore teaches every aspect of instant claims 47-48 and 50-55, and anticipates the invention encompassed by said claims.
Claims 47-55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by De Groot et. al. (US20230242591A1; Priority Date 02/14/2020; hereafter “De Groot”; NB: in the interest of compact prosecution, the related family filings, including US PGPubs US20230151061A1 and US20230190915A1, are also included in this rejection.)
The applied reference has a common inventor (William Martin) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
The Prior Art
De Groot teaches concatemeric, chimeric, or fusion polypeptides which comprise a plurality (e.g. two or more) of epitopes from SARS CoV-2 joined together in a single polypeptide (entire document; see abstract; ¶[0003][0026]). De Groot teaches methods of in silico identification of potential epitopes from different sequences of SARS CoV-2 variants to use in such a polypeptide (Example 1, starting at ¶[0465]; See also ¶[0459-0464][0468]). De Groot teaches using programs to determine helper T cell epitopes (¶[0459]) and other systems that can elucidate MHC Class-I and MHC Class-II HLA ligands and T cell epitopes (¶[0460-0464]). De Groot teaches T-cell epitopes are generally linear (¶[0060][0459]), and the epitopes would elicit cytotoxic T cell (CTL) responses (¶[0058][0068]), helper T cell responses (¶[0005][0007][0068][0319][0459]), or B cell responses (¶[0058][0423]). De Groot teaches methods for assessment of the binding capabilities (¶[0470]) as well as analysis of the resulting epitopes for sequence and structure (¶[0469]). De Groot then teaches the generation of the two or more candidate epitopes into a single peptide (¶[0469]; instant claims 47-48, 51). De Groot teaches the composition may be used with or without an adjuvant (¶[0029][0283]) and that the usefulness of components such as adjuvants can be determined by routine testing, such as ELISAs, seroneutralization assays, vaccination challenge evaluations, and antibody titrations of sera (¶[0301-0303]; instant claim 49). De Groot teaches analysis of the epitopes and their binding with MHC and/or T cell receptors (¶[0015][0039][0053][0060]; instant claim 50). De Groot teaches using a proprietary program to analyze the epitopes that also simultaneously assess mutated versions of the epitopes for their ability to bind to MHC class I and MHC Class II alleles (¶[0195-0196]; instant claim 52). De Groot teaches the peptide can elicit immune responses specific to IFN-gamma, IL-4, and/or IL-10 signaling pathways (¶[0063-0064][0087][0319][0520][0522][0529]; instant claim 53). De Groot teaches the epitopes may be linked together using linker sequences (¶[0075-0076]; instant claim 54). De Groot teaches the epitopes may be from the SARS CoV-2 spike surface protein (¶[0020][0042]; Figs. 11-28; instant claim 55).
For at least these reasons, De Groot teaches every aspect of instant claims 47-55, and anticipates the invention encompassed by said claims.
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.
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.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Samad as applied to claims 47-48 and 50-55 above, and further in view of Nagy et. al. (WO2022003119A1; Priority 07/01/2020; hereafter “Nagy”.)
The Prior Art
The teachings of Samad have been set forth supra. While Samad teaches the direct addition of adjuvanting epitopes to the polyprotein comprising the multiple epitopes from SARS CoV-2, Samad is silent as to testing the multiepitope polyprotein both with and without adjuvant. However, such testing was routinely done in the art, as evidenced by the teaching of Nagy.
Nagy teaches generation of a chimeric antigen comprising epitopes from the same region of different coronavirus species, or epitopes from distinct regions of different coronavirus proteins, including different SARS CoV-2 proteins, such as S and/or M proteins (entire document; see abstract.) Nagy teaches generation of this chimeric polypeptide and testing the immunogenicity of said peptide in a transgenic human ACE2-expressing mouse, wherein the inoculation of the polypeptide occurred both with and without alum adjuvant (Example 5 at p. 47).
Given the teachings of Nagy and Samad, one of skill in the art would be apprised as to the generation of polyproteins which comprised multiple epitopes from SARS CoV-2 antigenic proteins, such as S protein. Given the teachings of Nagy and Samad, one of skill in the art would be apprised as to the usefulness of including adjuvanting materials to these polyproteins. Given the teachings of Nagy, one of skill in the art would find it routine to determine the immune response in an in vivo model both with and without the presence of adjuvant. Therefore, arriving at the limitations of instant claim 49 would be routine optimization in the art and obvious for a skilled artisan to undertake, especially given the combined teachings of Nagy and Samad.
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Samad in order to test the immunogenicity both with and without an adjuvanting composition or sequence, thereby optimizing the immune response to the polyprotein in a host. One would have been motivated to do so, given the suggestion by Nagy that the method of inoculating a host with the polyprotein could be performed both with and without an adjuvant to determine the strength and type of immune response, as well as monitoring host reactogenicity to the different compositions. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
17795181: Applicant-related copending application whose pending claims do not currently read on the elected instant claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671