DETAILED ACTION
Disposition of Claims
Claims 1-8, 13-15, 18, 21-25, and 28-30 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240269262A1, Published 08/15/2024.
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 05/24/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claim 4 is objected to because of the following informalities: the definition of the abbreviation “SARS-Cov-2” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … severe acute respiratory syndrome coronavirus type 2 (SARS-Cov-2)...).
Appropriate correction is required.
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 1 and dependent claims 2-7 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.
The terms “genomic area”, “very little”, and “little” in claim 1 are relative terms which renders the claim indefinite. The terms “genomic area”, “very little”, and “little” are 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. It is unclear the difference between “little” and “very little”, as no means to measure has been provided (e.g. wherein there is at most one amino acid and/or nucleotide mutation, wherein there is at least 95% sequence identity in that region amongst aligned genomes, etc.) Furthermore, as it is unclear as to the size of a “genomic area”, it is unclear if said “area” must be of a certain length, or be an identified open reading frame (ORF), etc., in order to be considered an “area” that can be aligned and analyzed to determine the differences between isolates.
Additionally, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “amino acid sequence areas” in claim 1 appears to be used by the claim to mean regions that are encoded or translated in the viral genome to make proteins, while the accepted meaning of such a region is “open reading frame (ORF)” or “putative protein-coding sequence” or “gene sequence” or “coding sequence” or fragments thereof of such ORFs or coding sequences. The term is indefinite because the specification does not clearly redefine the term. Dependent claims appear to confirm that the “amino acid sequence areas” are those regions which encode for an entire specific viral protein (see e.g. instant claims 6-7). Not all areas of a viral genome are encoded into proteins, so the term “ORF” or “coding sequence” is commonly used in the art to indicate areas which are putatively translated or have been confirmed to be translated regions.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 2-7 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claim 1 and dependent claims 2-7 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 1, as written, is drawn to: a method for making a vaccine against a virus, the method comprising:
(a) aligning genome sequences of at least two isolates, optionally, 1000, 10,000 or 100,000 isolates, of the virus;
(b) identifying genomic areas with no or very little viral sequence variation at a nucleotide level;
(c) identifying amino acid sequence areas with little or no sequence variation at an amino acid sequence level and aligning the identified amino acid sequence areas with the identified genomic areas;
(d) making a vaccine against the identified amino acid sequence areas with little or no sequence variation.
However, there are several confusing elements in the method as claimed. To begin with, the nexus between steps (a) and (b) and how they relate to later steps (c) and (d) is unclear, as the wording of the claim does not require the “vaccine” made in part (d) to have any relation to the data analysis performed in steps (a) and (b). Further, step (c) does not make it clear where the “amino acid sequence areas” are derived from – it is unclear if said areas were from the viruses analyzed in parts (a) and (b), or if they are derived from heterologous sources. Additionally, in arguendo if the origin of the amino acid and nucleic acid sequences is the same, it is unclear if the “areas” of part (c) are to be aligned with the corresponding genomic/nucleic acid areas of parts (a) and (b) (e.g. those areas which encode the sequences) or if the amino acid areas are to be aligned with any of the identified areas of parts (a) and (b). Even further, it is unclear how the amino acid sequences are to be aligned against the nucleic acid sequences (e.g. translated nucleic acid of (b) are aligned with amino acid sequences of (c), amino acid sequences are back translated then aligned with sequences of (b), etc.) Finally, it is unclear what is intended by ”making a vaccine against the identified amino acid sequence areas with little or no sequence variation”, as the actionable steps are not claimed (e.g. generating a subunit vaccine which comprises the identified amino acid sequences, raising antibodies against the identified amino acid sequences and using said antibodies as a therapeutic vaccine, inserting said amino acid sequence into a viral vector for use in a pharmaceutical composition, etc.) Such a vaccine is unclear as it is unclear as to the origin of the amino acid sequences, so it is unclear how one would generate such a composition, in what subject(s) said composition would be used, and against what pathogen said vaccine would be useful.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 2-7 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claims 8 and 18 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 8 is drawn to a polypeptide vaccine comprising a SARS-Cov-2 polypeptide of any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 or an immunogenic fragment thereof and a pharmaceutically acceptable excipient. The use of the indefinite article “a” before “SARS CoV-2 polypeptide” can be interpreted to read upon any polypeptide from any of the sequences listed in the sequences of the Markush group. However, further confusion arises as the use of “or an immunogenic fragment thereof” is included, as the use of the indefinite article “a” already implies full-length and fragments thereof. One suggestion is to use the definite article “the” to make it clear that the sequence must be either the full-length sequence of those listed in the Markush group or immunogenic fragments of said sequence, not any fragment of said sequence. Claim 18 is rejected for similar reasoning.
For at least these reasons, claims 8 and 18 are rejected on the grounds of being indefinite.
Claim 18 and dependent claims 21-25 and 28-29 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 18 is drawn to a polynucleotide vaccine comprising a polynucleotide encoding a SARS-Cov-2 polypeptide of any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 or immunogenic fragment thereof linked to a heterologous promoter and a pharmaceutically acceptable excipient. However, from the wording of the claim and the punctuation utilized in the claim, it is unclear if only the nucleic acid encoding the “immunogenic fragment thereof” is linked to a heterologous promoter or if the nucleic acid is linked to the heterologous promoter and said nucleic acid encodes either the full-length polypeptide or immunogenic fragment thereof. One way of clarifying the claim would be amending the claim along the lines of the following if the latter interpretation is correct:
“18. A polynucleotide vaccine comprising:
a SARS-Cov-2 polynucleotide linked to a heterologous promoter, wherein said polynucleotide encodes the polypeptide selected from the group consisting of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 or an immunogenic fragment thereof, and
a pharmaceutically acceptable excipient.”
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 18 is rejected on the grounds of being indefinite. Claims 21-25 and 28-29 are also rejected since they depend from claim 18, but do not remedy these deficiencies of claim 18.
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 1 is drawn to a method for making a vaccine against a virus, the method comprising:
(a) aligning genome sequences of at least two isolates, optionally, 1000, 10,000 or 100,000 isolates, of the virus;
(b) identifying genomic areas with no or very little viral sequence variation at a nucleotide level;
(c) identifying amino acid sequence areas with little or no sequence variation at an amino acid sequence level and aligning the identified amino acid sequence areas with the identified genomic areas;
(d) making a vaccine against the identified amino acid sequence areas with little or no sequence variation.
Further limitations on the method of claim 1 are wherein the identified genomic and amino acid areas each constitute less than 10%, 5%, or 1% of the total genomic and amino acid areas (claim 2), wherein the identified genomic and amino acid areas each have less than 10%, 5% or 1% of the mean variation in genomic and amino acid areas of the same length throughout the genome (claim 3); wherein the virus is severe acute respiratory syndrome coronavirus type 2 (SARS-Cov-2)(claim 4), wherein the identified amino acid sequence area is any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 (claim 5), wherein the identified amino acid sequence area is SARS-Cov-2 RNA-dependent RNA polymerase (SEQ ID NO: 1)(claim 6), and wherein the identified amino acid sequence area is SARS-Cov-2 spike glycoprotein (SEQ ID NO:322)(claim 7).
Claim 8 is drawn to a polypeptide vaccine comprising the SARS-Cov-2 polypeptide of any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 or an immunogenic fragment thereof and a pharmaceutically acceptable excipient.
Further limitations on the polypeptide vaccine of claim 8 are wherein the SARS-Cov-2 polypeptide or fragment is linked to a heterologous carrier to help elicit an immune response (claim 13); wherein the pharmaceutically acceptable excipient is an adjuvant that helps elicit an immune response (claim 14); wherein the fragment has up to 10, 25, 50, or 100 contiguous amino acids of any one of SEQ ID NOs: 1, 4-5, 111-320, 322, 941-942, and 971-1026 (claim 15).
Claim 18 is drawn to a polynucleotide vaccine comprising a polynucleotide encoding the SARS-Cov-2 polypeptide of any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 or immunogenic fragment thereof linked to a heterologous promoter and a pharmaceutically acceptable excipient.
Further limitations on the polynucleotide vaccine of claim 18 are wherein the vaccine is a DNA vaccine (claim 21) or an RNA vaccine (claim 22); wherein the SARS-Cov-2 polypeptide or fragment is linked to a heterologous carrier to help elicit an immune response (claim 23); wherein the pharmaceutically acceptable excipient is an adjuvant that helps elicit an immune response (claim 24); wherein the fragment has up to 10, 25, 50 or 100 contiguous amino acids of any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026 (claim 25); wherein the polynucleotide and heterologous promoter are components of a viral vector (claim 28); and wherein the polynucleotide and heterologous promoter are components of a bacterial vector or genome (claim 29).
Claim 30 is drawn to a method for effecting prophylaxis of or treating SARS-Cov-2 infection comprising a step of administering the polypeptide vaccine of claim 8 to a subject in need thereof.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally-occurring phenomena and abstract ideas without significantly more. The claims recite a method for making a vaccine against a virus, wherein at least two viral isolates have genomic sequences aligned and compared. As per the 35 USC 112b rejections supra, the interpretation of the claim is unclear, but under at least one reasonable interpretation, the elements in steps (c) and (d) are unrelated to the virus recited in the preamble and parts (a) and (b). Therefore, the amino acid sequence areas identified in part (c) can be unrelated to the virus of previous parts of the claim, or could be from the same virus. If they are from the same virus, this still equates to mental steps undertaken to show a natural correlation. Part (d) then recites “making a vaccine against the identified amino acid areas with little or no sequence variation.” Again, part (d) does not require the vaccine to be against the virus of the preamble.
As the claim is drawn to a method/process (Step 1: Yes), the claim is then analyzed to determine if there is a judicial exception. The claim cannot have a streamlined analysis due to the indefiniteness issues with said claim. Under one reasonable interpretation, the claim is directed to a natural phenomenon (isolates of viruses) and abstract ideas (mental analysis of genomic sequence comparison)(Step 2A: yes). The claim fails to recite additional elements that amount to significantly more than the judicial exception (Step 2B: No).
This judicial exception is not integrated into a practical application because the claims are identifying a natural phenomenon (e.g. genomic and/or protein sequences of naturally occurring viruses) and abstract ideas (identifying natural correlation between sequences through comparison of said sequences). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because “making the vaccine against the identified amino acids” under one reasonable interpretation does not directly relate to the virus identified in the preamble (see 35 USC 112b rejection supra) and therefore this step has an insignificant relationship to the exception (See MPEP §2106.04(d)(2)b). Additionally, the treatment is not particular to the virus of earlier steps and encompasses all applications of the amino acid of part (c) (See MPEP 2106.04(d)(2)a). Further additional dependent claims do not recite meaningful elements to draw the method to anything more than identification of a natural phenomenon. SARS CoV-2 is a naturally-occurring virus with many naturally-occurring variants, strains, and isolates. The sequences provided are merely identifying the regions in the genome which are meant to be compared, and SARS CoV-2 naturally comprises an RNA-dependent RNA polymerase and a spike (S) glycoprotein.
One suggestion to overcome this rejection is to impart meaningful limitations/steps that are directly related to the field of use. For instance, in part (c), it can be clarified that the consensus sequence identified is from the same virus as the preamble and earlier steps, and it can be clarified that the vaccine generated in part (d) then utilizes the identified consensus sequence from part (c) to generate a subunit vaccine for prophylactically or therapeutically treating the virus of earlier steps. See MPEP §2106.04(d)(2)a-c.
For at least these reasons, the methods are not drawn to patent eligible subject matter.
Claims 8, 15, 18, 22, 25, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally-occurring SARS CoV-2 sequences and methods of natural infection without significantly more. The claims recite polynucleotides and polypeptides within compositions that are “vaccines” that comprise pharmaceutically acceptable excipients. The methods recite administration of the composition to a subject in need thereof. This judicial exception is not integrated into a practical application because the sequences, compositions, and methods are recited at such a high level of generality that they read upon naturally occurring viruses, viral sequences, and methods of infection from said viruses. SEQ ID NO: 1, for instance, is a natural sequence of Orf1ab polyprotein from Wuhan-Hu-1 isolate (see ABSS sequence search).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims are not drawn to non-naturally occurring sequences, the claims do not require the pharmaceutically acceptable excipient to markedly alter or change the natural sequences, and the methods do not comprise specific, tangible steps or elements to distinguish them from natural infection. For instance, under one reasonable definition, the pharmaceutically acceptable excipient can include water (¶[0093]), which does not markedly or distinctly alter the virus, viral sequences, viral proteins, or components thereof. With respect to the method, the generically recited method of “administering” covers every potential method of delivering the naturally occurring viral products, such as natural infection (e.g. mucosal delivery after the virus is “administered” through a cough.) The resulting infection would therefore confer natural immunity to said virus.
One suggestion to overcome this rejection is to incorporate limitations from dependent claims not included in this rejection. Another suggestion is to clearly claim the compositions to comprise elements which are not naturally occurring (e.g. viral proteins which are conjugated to heterologous elements, such as tags or carriers, viral protein sequences which are not naturally occurring, vaccine compositions which comprise adjuvants, etc.) With respect to the method, another suggestion is to claim specific, tangible steps that cannot read on methods of natural infection (e.g. delivery of a specific amount of viral product, route of administration which cannot read upon natural infection, delivery of compositions which do not read upon naturally occurring elements, etc.)
For at least these reasons, the methods are not drawn to patent eligible subject matter.
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 1-8, 13-15, 18, 21-25, and 28-30 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 following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
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 .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which 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.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1-8, 13-15, 18, 21-25, and 28-30 are rejected as lacking adequate descriptive support for any method of generating any vaccine against any virus, especially any SARS CoV-2 polynucleotide or polypeptide vaccine compositions which result in said composition being effective therapeutically or prophylactically as a vaccine, especially when delivered via any method to any subject in need thereof.
In support of the claimed genera (any vaccine composition for any virus, or any SARS CoV-2 polynucleotide or polypeptide vaccine), the application discloses one example in which SARS CoV-2 genomic sequence alignments were performed, and analyzed for synonymous and non-synonymous mutations (Examples 1-2 starting at ¶[0094]; Figs. 1-2). The first analysis identified 106 “cold spot” regions which were “intolerant of change” (¶[0095-0096]; Fig. 3), wherein the viral RNA dependent RNA polymerase (RDRP; also known as non-structural protein 12 (nsp12)) was identified as being highly conserved (¶[0096]), while an additional analysis identified 28 additional “cold spots” (¶[0097-0098]), such as the region 111-137 within the spike glycoprotein (Fig. 4). Peripheral blood mononuclear cells (PBMCs) were collected from healthy donor (HD) or recovered COVID-19 patients (RP) (Example 4 starting at ¶[0100]) and were stimulated with full-length codon-optimized SARS CoV-2 spike (S) protein mRNA (¶[0105]). Stimulated T cells were expanded and exposed to spike protein subunit 1 (S1), subunit 2 (S2), or actin (Ac) peptide pools, wherein the peptides were 15mers with 11aa overlap of each protein (¶[0106-0108]). The T cells were analyzed for their response to the peptides and compared to the identified hypomutated regions of S protein (Examples 5-6, starting at ¶[0109]). Figs. 4-7 provide analysis on the epitopes, with SEQ ID NOs: 941 and 942 identified as hypomutated epitopes from S protein (¶[0111]).
With respect to the method to identify hypomutated regions, genomic analysis of known viral sequences of SARS CoV-2 genomes were compared and only open reading frames (ORFs) for known proteins were analyzed, as the specification notes that the comparison was done to determine synonymous vs. non-synonymous mutations. It is not clear how the genomes were analyzed with respect to the claimed method in instant claim 1, as it appears (in general terms) that only translated ORFs were ultimately under comparison. It is not clear as to what size/region is required to be deemed “hypomutated”, and if there is a specific threshold of genomes which must be analyzed (e.g. the region must be at least 5 amino acids in length and comprise no mutations across 90% of analyzed genomes, etc.).
With respect to the identified conserved epitopes, none of these identified epitopes were engineered into any type of immunogenic composition that was later tested in vivo to determine whether or not said compositions could induce a therapeutic or protective immune response against SARS CoV-2 challenge. None of the sequences were engineered into polynucleotide or polypeptide vaccines and tested for their efficacy against SARS CoV-2 challenge, with one or more SARS CoV-2 strains, variants, or mutants. None of the identified RDRP (nsp12) hypomutated regions appeared to have been tested for their ability to stimulate any sort of immune response. The HLA analysis for these regions was not evident, and it is unclear that these epitopes would be recognized on a significant scale globally in order to function as an effective vaccine. Further, none of the physicochemical characteristics, allergenicity, toxicity, hydropathy index, and stability of any of the identified hypomutated protein regions were estimated to demonstrate the specificity of the epitope candidates. No other viruses appear to have been subjected to the genomic analysis to determine hypomutated regions in their genome or ORFs, nor were any vaccines against any other viruses generated or tested. Only the SARS CoV-2 S polypeptides or polynucleotides appeared to have been attached to heterologous carriers at their N-terminus (e.g. “CASS” or similar carriers described in ¶[0074-0075]; see Table 1), no other peptides or polynucleotides were attached to any other heterologous carriers and tested for their immunogenicity. It is unclear what further modalities would be useful for delivery of the identified regions (e.g. plasmids, vectors, subunit vaccines, carriers, adjuvants, etc.). Thus, the application fails to provide a sufficient number of examples of species within the claimed genera.
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence that any hypomutated genomic region or hypomutated amino acid region identified through the method claimed would be sufficiently immunogenic in any vaccine composition of any modality in order to elicit a therapeutic and/or prophylactic immune response. Similarly, there is no evidence that the polynucleotide or polypeptide sequences which encode any portion of the amino acid sequences claimed in instant claims 8 or 18 can be therapeutic in any related vaccine composition or modality. It was not shown that any of the regions identified as being highly conserved were immunogenic in vivo, nor was it shown that any of the regions delivered in any type of composition could be protective against any viral challenge.
In general, due to the high level of uncertainty in the art, the teachings of the art fail to indicate that, without such evidence, those in the art would have expected the full scope of the claimed methods and compositions would confer the claimed ability to discover immunogenic conserved peptide regions of any size that could be delivered in any vaccine format or composition and be useful against heterologous or homologous viral challenge. For example, a search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, et. al. Science. 1990 Mar16;247(4948):1306-10; See page 1306). The art also shows that single amino acid mutations in the antibodies can greatly affect the ability of said antibody to bind to its target antigen (Winkler K, et. al. J Immunol. 2000 Oct 15;165(8):4505-14.; See also Kussie PH, et. al. J Immunol. 1994 Jan 1;152(1):146-52.) When single amino acid mutations are generated, or when the combination or order of CDRs within an antibody is altered, it affects the neutralizing capability of the resulting antibody or fragment thereof (Chen Z, et. al. Nat Commun. 2015 Mar 30;6:6714.) While these results focus on a specific class of proteins (antibodies), they highlight the pitfalls in attempting to describe a protein functionally and/or with a percent identity to known structural characteristics.
The art is apprised to the approach of targeting conserved epitopes present in the virus in order to develop a vaccine for viruses with multiple strains or variants. Conserved epitopes are epitopes that are relatively the same among different strains of a pathogen. For example, due to the multiple strains of influenza over the years, the means of developing a universal vaccine has been the use of the conserved epitopes on the hemagglutinin (HA stalk) or the matrix ectodomain (M2e). The strategy of using conserved epitopes has also been used in the development of preventative vaccines for HIV, dengue virus, Lassa fever virus (LASV), hepatitis virus, and Kaposi’s sarcoma-associated herpesvirus (KSHV). However, no universal vaccine for any of these viruses was or is clinically available (Sect. 3 of Olukitibi TA, et. al. Vaccines (Basel). 2023 Feb 24;11(3):545.)
More specifically, with respect to SARS CoV-2 antigenic regions and vaccine compositions, characterization of conserved regions in the S protein have highlighted regions in both S1 and S2 subunits which are highly conserved not only amongst SARS CoV-2, but other coronaviruses. Some monoclonal antibodies that recognize SARS-CoV and MERS-CoV could cross-react and cross-neutralize SARS-CoV-2 by recognizing the ACE2 binding sites on the SARS-CoV-2 RBD (p. 6, ¶3 of Olukitibi). However, as noted in the review by Olukitibi, the structural positioning of the S2 subunit might limit its ability to induce sterilizing immunity. The S2 is hidden under the S1 subunit protein, thereby being masked by the S1 subunit protein, resulting in the induction of weak immune responses during natural infection or when the whole spike protein is used in the vaccine development. Studies have demonstrated that a vaccine targeting the S2 can induce IgG, but in a lesser amount when compared with the S1 subunit protein. Another challenge is the length of the identified epitopes in the S2 region, as the conserved epitopes would likely have to be used with adjuvants or other immunogenic proteins in order to elicit a sufficient immune response in a vaccine setting. Olukitibi notes that the route of administration, vaccine modality (e.g. repeating epitopes on a polypeptide), and use of adjuvants is critical to the design of any SARS CoV-2 vaccine comprising conserved epitopes (Sect. 4 of Olukitibi). With respect to the RDRP of SARS CoV-2, in silico studies have identified potential T- and B- cell epitopes within this conserved protein, but in vivo and in vitro studies had yet to confirm what type of vaccine composition could deliver said antigens in a way to be effective therapeutically (Yashvardhini N, et. al. Can J Infect Dis Med Microbiol. 2021 Apr 20;2021:6627141.)
Thus, in view of the above, there would have been significant uncertainty as to which methods could specifically identify immunogenic hypomutated regions in any viral genome, including a SARS CoV-2 genome, wherein said regions would be sufficiently immunogenic in a therapeutic setting. It is unclear that the polypeptides and polynucleotides that encode any of the full length or fragments of SARS CoV-2 proteins identified would be useful in any vaccine modality, especially in methods that would therapeutically or prophylactically combat any viral challenge from any SARS CoV-2 isolate. In view of this uncertainty and the lack of sufficient examples of the claimed genera, the claims are rejected for lack of adequate written description support.
Claims 1-8, 13-15, 18, 21-25, and 28-30 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 identifying potential epitopes from conserved SARS CoV-2 ORFs, does not reasonably provide enablement for any method of identifying any conserved region in any virus and generating any vaccine from said region, or any SARS CoV-2 polypeptide or polynucleotide vaccine that comprises any of the sequences or fragments thereof in instant claims 8 and 18 or methods of using said vaccine compositions in treatment modalities. 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 making any vaccine against any virus through the identification of conserved regions in said viral genome. As set forth in the 35 USC 112b rejections supra, the method does not clearly claim that the identified conserved amino acid regions are of any specific size or are from the same virus for which the vaccine is being generated. The breadth of the method of claim 1 therefore is drawn to generating any vaccine against any virus by identifying conserved regions in any homologous or heterologous virus amino acid sequence and having said conserved amino acid sequence integrated in any format into any vaccine composition.
The claims are additionally drawn to polynucleotide or polypeptide vaccine compositions which comprise the sequences or any fragment thereof from any one of SEQ ID NOs:1, 4-5, 111-320, 322, 941-942, and 971-1026. The claims are drawn to methods of using said vaccine compositions in methods of treatment to inhibit any infection from any SARS CoV-2 isolate.
State of the prior art/Predictability of the art. The state of the art and predictability of the art was discussed supra with respect to the 35 USC 112a written description rejection. Briefly, while the art was apprised as to methods to identify conserved regions in viral genomes, it was not readily apparent that said conserved regions were sufficiently immunogenic in order to be useful in vaccine settings. This is true with coronaviruses, including SARS CoV-2, and other viruses, such as influenza and HIV.
Working examples. The working example disclosed in the specification was discussed supra with respect to the 35 USC 112a written description rejection. Briefly, the working example identified conserved regions in SARS CoV-2 only, namely the S protein and RDRP, and tested stimulated T cells from human patients to determine their ability to recognize conserved epitopes in the S protein. No in vivo studies were performed to show that said epitopes were immunogenic in humans or animal models, nor were any SARS CoV-2 challenge studies performed after inoculation of any type of vaccine from any conserved SARS CoV-2 epitopes. No other viruses were studied in the working examples.
Guidance in the specification. The specification provides guidance towards the analysis of the SARS CoV-2 genomes and the known ORFs from said genome to identify conserved, hypomutated regions in said ORFs. The regions identified must be of a certain minimum length to be an epitope (e.g. T cell epitopes generally range from 8-17 amino acids, while B-cell epitopes may be 5-25 amino acids long) in order to be “immunogenic”. The specification provides guidance towards fusing said epitopes to short carrier sequences and determining if said sequences have the ability to stimulate T cells. While prophetic guidance is provided by the specification as to how to deliver said peptides to a subject in need thereof, no conserved peptide epitopes or longer proteins thereof (or nucleotides encoding said proteins) were generated into any vaccine platform and tested for any prophylactic or therapeutic efficacy against any SARS CoV-2 challenge.
Amount of experimentation necessary. Additional research is required in order to determine how effective the method as claimed is in identifying any conserved epitopes from any virus that would be useful in any vaccine for vaccination against any heterologous or homologous virus. Additionally, further research is required to determine which amino acid sequences or fragments thereof identified in the instant claims would be useful in vaccine compositions, and how said amino acid sequences should be delivered to a subject in need thereof.
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 breadth of the method of identifying vaccine compositions comprised of conserved epitopes is extraordinarily large, and the art has clearly struggled in generating universal vaccines for various viruses using conserved epitopes or proteins. Additionally, the breadth of amino acid and nucleic acid sequences claimed (along with fragments and combinations thereof) is large, and would require undue experimentation to determine which would be useful as vaccines, especially in order to raise any therapeutic immune response against any SARS CoV-2 isolate.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed methods and compositions.
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 1-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Olvera et. al. (Olvera A, et. al. Vaccines (Basel). 2020 Aug 6;8(3):444.; hereafter “Olvera”.)
The Prior Art
Olvera teaches the generation of a SARS-CoV-2 2020 consensus sequence (CoV-2-cons) which is based on more than 1700 viral genome entries in NCBI and encompasses all described SARS-CoV-2 open reading frames (ORF), including recently described frame-shifted and length variant ORF. Based on these sequences, Olvera created curated overlapping peptide (OLP) lists containing between 1500 to 3000 peptides of 15 and 18 amino acids in length, overlapping by 10 or 11 residues, as ideal tools for the assessment of SARS-CoV-2-specific T cell immunity (instant claims 2, 4). Additionally, Olvera teaches identification of conserved protein fragments across the coronavirus family, and the use of the corresponding OLP to facilitate the identification of T cells that can potentially be cross-reactive with related viruses (entire document; see abstract.) Olvera teaches conserved coronavirus peptides were identified through alignment of the genomic sequences and analysis of protein fragments, wherein the fragment must be a minimum length of 8 amino acids (Sect. 2.3, p. 3; Sect. 3.5, p. 7; Table 3). Olvera teaches conserved coronavirus epitopes were also compared to SARS CoV-2 sequences, wherein 141 epitopes were identified and 125 utilized to generate an epitope map of the conserved regions (Sect. 2.4, p. 4; instant claim 3). Olvera then teaches that T cell responses to these identified regions could provide broad protection through the creation of a pan-coronavirus vaccine (pp. 8-9, ¶ bridging pages.) Olvera teaches that the S protein is the site of conserved epitopes; three identified epitopes listed in Table 3 of the S protein align with 100% to instant SEQ ID NO: 322 (instant claims 5, 7). Additionally, Olvera teaches conserved epitopes in the RDR polymerase that align with 100% identity to instant SEQ ID NO: 1 (Table 3, see alignment below; instant claim 6).
SEQIDNO:1 202 VGVLTLDNQDLNG 214
|||||||||||||
ORF1b-Olvera 1 VGVLTLDNQDLNG 13
As Olvera teaches conserved epitopes in SARS CoV-2 proteins, such as S and RDRP, and teaches the alignment of multiple SARS CoV-2 sequences and the identification of highly conserved epitopes throughout these genomes in the known ORFs of SARS CoV-2, and as Olvera teaches the inclusion of said sequences in vaccine compositions for treatment of SARS CoV-2 and other coronavirus infections, Olvera teaches every aspect of instant claim 1.
For at least these reasons, Olvera teaches the limitations of instant claims 1-7, and anticipates the invention encompassed by said claims.
Claims 8, 13-15, 18, 21-25, and 28-30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Langedijk et. al. (US20210246170A1, Priority 01/31/2020; hereafter “Langedijk”.)
The Prior Art
Langedijk teaches immunogenic compositions and vaccines containing a coronavirus (e.g., Wuhan coronavirus (2019-nCoV; also referred to as SARS-CoV-2)) protein, such as the spike (S) protein, or a polynucleotide encoding a coronavirus (e.g. SARS-CoV-2) protein and uses thereof, such as methods of generating a protective anti-coronavirus immune response in a host (entire document; see abstract.) Langedijk teaches the vaccine compositions may be in pharmaceutically acceptable carriers, diluents, or excipients (¶[0042]), such as the use of nanoparticles, microspheres, and emulsions (¶[0451]). Langedijk teaches sequences for the SARS CoV-2 S protein, including SEQ ID NO: 29, which is 100% identical to instant SEQ ID NO:322 (see ABSS alignment for 17-163-357; instant claims 8, 15). Langedijk teaches that the S protein may be encoded by a nucleic acid, wherein the S protein is under the control of a heterologous promoter, such as the CMV immediate early promoter (¶[0018]; instant claims 18, 25). Langedijk teaches that the composition may comprise an adjuvant (¶[0042]), wherein the adjuvant may be a vector-encoded adjuvant, e.g. by using heterologous nucleic acid that encodes a fusion of the oligomerization domain of C4-binding protein (C4 bp) to the antigen of interest (¶[0313]; instant claims 13-14, 23-24). With respect to how the SARS CoV-2 material is delivered, the antigen may be delivered as a DNA vaccine (¶[0416-0147]; instant claim 21) or an RNA vaccine (¶[0035][0230]; instant claim 22). Langedijk also teaches the vaccine may be a vector, such as a bacterial or viral vector, wherein the vector comprises elements to encode the SARS CoV-2 antigen (¶[0038][0209][0231][0252-0254]; instant claims 28-29). Langedijk teaches methods for stimulating a prophylactic or therapeutic immune response in a subject in need thereof through administration of the SARS CoV-2 polynucleotide or polypeptide vaccine compositions (¶[0315][0460-0465]; instant claim 30).
For at least these reasons, Langedijk teaches the limitations of instant claims 8, 13-15, 18, 21-25, and 28-30, and anticipates the invention encompassed by said claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 8, 13-15, 18, 21-25, and 28-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-13, 16-20, 32, 35, 37, 45, and 49-51 of copending Application No. 17/914,894 in view of Langedijk (supra) and Khandhar et. al. (US20220096625A1; Priority 03/23/2020; hereafter “Khandhar”.)
Both sets of claims are drawn to SARS CoV-2 antigens in immunogenic compositions, especially for the delivery of said antigens to a subject in need thereof in order to raise a therapeutic immune response against SARS CoV-2. Both sets of claims are drawn to the delivery vehicle being RNA, especially RNA encoding S protein. Both claim sets are drawn to additional SARS CoV-2 antigens being present. The main difference is that the ‘894 claims provide for the RNA to be encapsulated in a nanoparticle. However, the use of nanoparticles to deliver RNA was known in the art, as suggested by Khandhar and Langedijk. Langedijk teaches the S protein sequence of SARS CoV-2, and teaches that the pharmaceutically acceptable vehicles useful for delivery include nanoparticles. Khandhar teaches the specifics about nanoparticles, such as the use of DOTAP or DOTMA-based nanoparticles in order to deliver RNA encoding SARS CoV-2 S proteins (entire document; see abstract; ¶[0222-0224]; reference claims 1-13.) Khandhar describes analysis of the polydispersity index to determine average nanoparticle size of about 61.9 nm (¶[0256]), analysis of the Z-potential (¶[0181]; Table 3), and average amount of RNA or DNA delivered in the nanoparticle (¶[0141]). Given the teachings of the prior art as evidenced by Langedijk and Khandhar, the nanoparticle delivery method for SARS CoV-2 antigens in an immunogenic formulation would be obvious modifications to make to delivery of said antigens, and the instant claims and ‘894 claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671