Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Disposition of Claims
Claims 1-15 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250032601A1, Published 01/30/2025.
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 statements (IDS) submitted on 08/28/2024 and 06/05/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are 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.
Specification
The disclosure is objected to because of the following informalities: the specification states that an ELISpot procedure was performed “as previously described (REF 60),” but the specification does not resolve “REF 60” at that location into a bibliographic citation (¶[0261]).
Appropriate correction is required.
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 FIGs. 4, 5, 7, 24, 29 reference color. 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.
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 2-15 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 recites a vaccine polypeptide "having at least 90% sequence identity" to one of SEQ ID NOs:6, 20, 34, 41, or 42. However, the specification defines "sequence identity" in a manner that does not provide reasonably certain claim boundaries. Specifically, ¶[0221-0222] states that sequence identity is determined over an "aligned region," and further explain that the aligned region "may comprise the full length of one or both sequences or only a portion of one or both sequences"[emphasis added]. The specification additionally explains that a sequence may have different sequence identity values over different aligned regions.
Accordingly, the specification expressly permits the identity calculation to be performed over any selected aligned portion of the compared sequences rather than requiring comparison over the full length of the claimed reference sequence or over another objectively defined region. Because the specification places no minimum limitation on the length or coverage of the aligned region, a single pair of sequences may satisfy or fail the claimed "at least 90% sequence identity" limitation depending upon which aligned region is selected for comparison. The claims likewise do not specify whether the required sequence identity is determined over the entire length of the reference sequence, the entire length of the compared sequence, the length of the shorter sequence, a best local alignment, or some other objectively identifiable alignment. The claims also fail to define any minimum alignment coverage required for determining sequence identity.
As a result, one of ordinary skill in the art cannot determine with reasonable certainty whether a given polypeptide falls within or outside the scope of claim 1 because different aligned regions of the same pair of sequences may produce different sequence identity values, each of which would be permitted under the definition set forth in ¶[0221-0222]. Dependent claims 2-4 merely substitute different sequence identity thresholds and therefore do not cure this ambiguity.
Claims 5-8 introduce an additional ambiguity. These claims recite that "the polypeptide having SEQ ID NO:6 or 20 is encoded by a nucleic acid sequence having at least" the recited percentage sequence identity to SEQ ID NO:105 or 110, respectively. Claim 1, from which claims 5-8 depend, encompasses vaccine polypeptides having at least the recited percentage sequence identity to SEQ ID NOs:6, 20, 34, 41, or 42. It is therefore unclear whether the phrase "the polypeptide having SEQ ID NO:6 or 20" requires the exact amino acid sequence of SEQ ID NO:6 or SEQ ID NO:20, or instead refers to the broader class of polypeptides having the required sequence identity inherited from claim 1. The claim language does not clearly resolve whether "having SEQ ID NO:6 or 20" denotes the exact disclosed sequence or merely identifies the reference sequence against which sequence identity is measured. Furthermore, because the nucleotide sequence identity limitation in claims 5-8 incorporates the same definition of sequence identity set forth in ¶[0221-0222], the same uncertainty regarding selection of the aligned region is present for the nucleotide comparison.
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 2-15 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
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 vaccine polypeptide having at least 90% sequence identity to an amino acid sequence selected from any of SEQ ID NOs: 6, 20, 34, 41, or 42.
Further limitations on the vaccine polypeptide of claim 1 are wherein the polypeptide has at least 95% (claim 2), or at least 99% (claim 3), or 100% (claim 4) sequence identity to an amino acid sequence selected from any of SEQ ID NOs: 6, 20, 34, 41, or 42; wherein the polypeptide having SEQ ID NO:6 or 20 is encoded by a nucleic acid sequence having at least 90% (claim 5), or at least 95% (claim 6), or at least 99% (claim 7), or 100% (claim 8) sequence identity to a nucleic acid sequence shown in SEQ ID NOs: 105 or 110, respectively
Claim 9 is drawn to a vaccine composition comprising at least one of the vaccine polypeptides of claim 1 and a delivery vehicle.
Further limitations on the vaccine composition of claim 9 are wherein the delivery vehicle is a virus (claim 10), wherein the delivery vehicle virus is selected from the group consisting of an adenovirus, an adeno-associated virus, a retrovirus, an alphavirus, a paramyxovirus, and a rhabdovirus (claim 11); and wherein the delivery vehicle is a nanoparticle (claim 12).
Claim 13 is drawn to a method of vaccinating a subject, the method comprising:
administering the vaccine polypeptide of claim 1 to a subject in need of vaccination.
Further limitations on the method of claim 13, wherein the subject is selected from the group consisting of a human and a swine (claim 14); and wherein the administering step is repeated more than once (claim 15).
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 1-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally occurring influenza virus HA and/or NA nucleotide and/or protein sequences and compositions thereof without significantly more. The stepwise 101 streamlined analysis of the claims follows:
Step 1:
Claims 1-12 are directed to compositions of matter, namely polypeptides, polynucleotides that encode said polypeptides, and compositions which comprise said polypeptides or polynucleotides, and therefore fall within a statutory category of invention.
Step 2A, Prong One:
Claim 1 recites a vaccine polypeptide having at least 90% sequence identity to an amino acid sequence selected from SEQ ID NOs:6, 20, 34, 41, or 42, and the recited reference sequences correspond to influenza hemagglutinin (HA)(SEQ ID NOs: 6,20) or neuraminidase (NA)(SEQ ID NOs:34,41,42) proteins. Specifically, the specification identifies SEQ ID NO:6 as a human H1 HA Epigraph1 sequence, SEQ ID NO:20 as a human H3 HA Epigraph1 sequence, SEQ ID NO:34 as a human N1 NA Epigraph1 sequence, and SEQ ID NOs:41 and 42 as human N2 NA Epigraph1 and Epigraph2 sequences, respectively (¶[0079-0115]). The specification explains that the disclosed centralized sequences were generated from naturally occurring influenza sequences. For example, the specification states that the centralized sequences “were created using individual wild type sequences that represent the major branches of the representative phylogenetic tree”(¶[0020]). The specification further explains that Mosaic sequences are generated using natural influenza sequences and that the Epigraph approach similarly seeks to maximize coverage of clusters of influenza protein sequences (¶[0024-0026][0211]).
Although the specification describes the particular computationally generated vaccine sequences as unique sequences, claim 1 is not limited to those particular sequences, as claim 1 encompasses any vaccine polypeptide having at least 90% sequence identity to one of the five reference sequences. As discussed supra with respect to the rejection under 35 U.S.C. 112(b), ¶[0221-0222] define sequence identity based upon an aligned region that may comprise the full length of one or both sequences or only a portion thereof. Thus, the claim is substantially broader than the particular computationally generated sequences described as the preferred vaccine immunogens.
Moreover, even when sequence identity is determined over the full length of the compared proteins, the claimed percentage-identity range encompasses naturally occurring influenza HA and NA proteins. Naturally occurring influenza H1 HA, H3 HA, N1 NA, and N2 NA proteins exist having at least 90% sequence identity to the corresponding claimed reference sequences (See e.g. “.rup” UniProt search results from ABSS; See attached NCBI BLAST of SEQ ID NO: 6; Choi YK, et. al. Hemagglutinin [Influenza A virus (A/SW/MN/16419/01(H1N2))]; Dep. 10/09/2002; GenBank: AAL29713.1.) Accordingly, the broadest reasonable interpretation of claim 1 encompasses naturally occurring influenza proteins having the same amino acid sequence and the same inherent structural and functional characteristics that those proteins possess in nature.
A nature-based product is a product of nature exception when it does not exhibit markedly different characteristics from its naturally occurring counterpart. Markedly different characteristics may be based upon structure, function, or another property, but the characteristic relied upon must be a characteristic of the product required by the claim. The mere fact that particular disclosed embodiments were generated computationally does not impart a markedly different characteristic to every polypeptide encompassed by the broader claim.
Claim 1 does not require that the claimed polypeptide be computationally generated, recombinant, synthetic, isolated, modified, or otherwise structurally different from a naturally occurring influenza protein, nor does claim 1 require any particular amino acid substitution, deletion, insertion, fusion, or other structural modification that distinguishes the claimed polypeptide from naturally occurring HA or NA. The claim therefore reads directly upon naturally occurring influenza proteins satisfying the recited percentage-identity limitation. The recitation that the polypeptide is a “vaccine polypeptide” also does not provide a markedly different characteristic. The specification states that an antigen or immunogen refers to an “antigenic protein[] that induce[s] immune responses”(¶[0018]). Naturally occurring influenza HA and NA proteins are viral antigens and inherently possess antigenic properties capable of inducing an immune response. Characterizing such a naturally occurring influenza protein according to its intended use as a vaccine does not change its structure or confer a markedly different characteristic upon the protein itself.
Accordingly, claim 1 encompasses naturally occurring influenza HA and NA proteins having no markedly different structural, functional, or other characteristic relative to the same proteins in their natural state. Claim 1 therefore recites a product of nature judicial exception. Claims 2 and 3 narrow the sequence-identity threshold to at least 95% and at least 99%, respectively. These limitations do not require a structural modification or other characteristic distinguishing the claimed proteins from naturally occurring influenza proteins. To the extent naturally occurring HA or NA sequences satisfy these identity thresholds, the claims continue to encompass the naturally occurring protein itself and therefore continue to recite the product of nature exception. Claim 4 requires 100% sequence identity to one of SEQ ID NOs:6, 20, 34, 41, or 42; However, in view of the definition provided at ¶[0221-0222], the recitation of 100% sequence identity does not necessarily require identity over the full length of the reference sequence. The claim therefore encompasses naturally occurring influenza proteins having an aligned region that is 100% identical to a portion of the recited sequence, and such naturally occurring proteins do not acquire a markedly different characteristic merely because a portion thereof is identical to a portion of a computationally generated reference sequence. Claim 4 therefore also encompasses a product of nature.
Claims 5-8 additionally recite nucleic acid sequences encoding a polypeptide having SEQ ID NO:6 or 20, wherein the nucleic acid has the recited percentage sequence identity to SEQ ID NO:105 or 110. These limitations likewise do not require the nucleic acid to possess a markedly different characteristic relative to a naturally occurring influenza nucleic acid. Influenza viruses naturally contain nucleic acids encoding HA proteins, and the claimed percentage-identity genera encompass naturally occurring influenza nucleotide sequences. Again, under the definition of sequence identity in ¶[0221-0222], claims 5-8 encompass nucleotide sequences satisfying the stated identity based upon an aligned region comprising only a portion of the compared sequences. The claims do not require that the nucleic acid be cDNA, codon optimized, synthetic, incorporated into a recombinant construct, or otherwise structurally modified relative to naturally occurring influenza nucleic acid. Accordingly, to the extent the claims encompass a naturally occurring influenza nucleic acid having the recited sequence identity and encoding the corresponding naturally occurring HA protein, the claimed nucleic acid has the same nucleotide structure and inherent properties as its naturally occurring counterpart. Claims 5-8 therefore also recite a product of nature exception.
Step 2A, Prong Two:
Claims 1-8 do not recite additional elements that integrate the product of nature exception into a practical application. Claim 1 consists of the polypeptide itself, defined by sequence identity and its characterization as a vaccine polypeptide. Claims 2-4 merely change the percentage-identity threshold, while claims 5-8 further characterize the protein by reference to an encoding nucleic acid having the recited sequence identity. These limitations define or further describe the nature-based products themselves rather than applying the judicial exception in a manner that imposes a meaningful limit on the exception. Accordingly, claims 1-8 are directed to the product of nature exception under Step 2A.
Claims 9-12 recite “vaccine” compositions comprising at least one vaccine polypeptide of claim 1 and a delivery vehicle. Claim 10 specifies that the delivery vehicle is a virus, claim 11 identifies representative viral delivery vehicles, and claim 12 specifies that the delivery vehicle is a nanoparticle. The addition of a delivery vehicle does not require the naturally occurring influenza polypeptide encompassed by claim 1 to possess any markedly different characteristic from a naturally occurring influenza virion/virus/genome/protein. The claims do not require a covalent modification of the polypeptide, incorporation of the polypeptide into a particular engineered structure, or any other interaction with the delivery vehicle that alters the structure, function, or other properties of the naturally occurring protein. Rather, the delivery vehicle is recited as an additional component of a composition containing the product of nature, e.g. the influenza virus. The specification confirms that delivery vehicles are conventional means for administering the vaccine material, and broadly identifies representative delivery vehicles including viruses, pharmaceutically acceptable carriers such as saline, and nanoparticles such as lipid nanoparticles (¶[0015]). The delivery vehicle limitation therefore merely places the naturally occurring product into a conventional vaccine formulation or delivery environment without requiring a changed characteristic or other meaningful application that alters the nature of the claimed product. Accordingly, claims 9-12 do not integrate the product of nature exception into a practical application and are directed to the judicial exception under Step 2A.
Step 2B:
The claims are next considered to determine whether any additional element, or combination of elements, amounts to significantly more than the judicial exception. Claims 1-8 do not recite an additional element sufficient to amount to significantly more. The percentage identity limitations merely define the scope of the nature-based products, while the designation “vaccine polypeptide” states the intended use or inherent antigenic property of the claimed influenza protein. The encoding-nucleic-acid limitations of claims 5-8 likewise recite another nature-based product without requiring a non-natural structural or functional characteristic.
Claims 9-12 add a delivery vehicle; however, the specification describes viruses, pharmaceutically acceptable carriers, saline, and nanoparticles as representative delivery vehicles for vaccine administration (¶[0015-0016][0229]). The use of such conventional delivery vehicles with an influenza vaccine antigen amounts to no more than conventional formulation or delivery activity appended to the product of nature. Considered individually and as an ordered combination, these additional limitations do not transform the naturally occurring influenza polypeptide into patent eligible subject matter or otherwise provide significantly more than the judicial exception.
The specification's description of the particular Epigraph sequences as computationally generated, unique, or not naturally occurring does not alter this finding. Patent eligibility is determined from the subject matter actually encompassed by the claims. Claims 1-12 are not limited to the particular non-naturally occurring Epigraph sequences, nor do they require the structural characteristics that allegedly distinguish those particular sequences from naturally occurring influenza proteins. Instead, the percentage identity language encompasses naturally occurring HA and NA proteins and, in claims 5-8, naturally occurring influenza nucleic acids. Accordingly, claims 1-12 are directed to a product of nature judicial exception and do not recite additional elements that integrate the exception into a practical application or amount to significantly more than the judicial exception, and are therefore patentably ineligible.
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 1-3, 5-7, and 9-15 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 written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claims 1-3 recite vaccine polypeptides having at least 90%, 95%, or 99% sequence identity, respectively, to an amino acid sequence selected from SEQ ID NOs:6, 20, 34, 41, or 42. SEQ ID NO:6 is identified in the specification as a universal HA vaccine from human H1 influenza A serotypes generated using Epigraph1; SEQ ID NO:20 is the corresponding human H3 Epigraph1 HA sequence; SEQ ID NO:34 is a human N1 Epigraph1 NA sequence; and SEQ ID NOs:41 and 42 are human N2 Epigraph1 and Epigraph2 NA sequences, respectively (¶[0079-0115]).
The specification describes particular computational approaches used to generate centralized influenza vaccine sequences. For example, the disclosure explains that Mosaic genes are generated by in silico recombination of full-length natural sequences with preference for repeated 9-mer sequences, while the Epigraph approach is a multi-immunogen approach designed to maximize coverage across clusters of protein sequences (¶[0025-0026][0207-0217]). The specification further describes particular Epigraph sequences generated using the disclosed computational approach and identifies the claimed SEQ ID NOs as specific resulting vaccine sequences. The specification distinguishes these designed sequences from naturally occurring influenza sequences, and states that “the genes described herein are unique and do not exist in nature”(¶[0201]). The disclosure further explains that the genetic relationships between the vaccine genes and wild-type circulating genes are shown in FIGS. 9-23 and characterizes the disclosed vaccine genes as “unique universal vaccine genes”(¶[0232-0233]). Thus, the disclosure demonstrates possession of particular computationally generated centralized vaccine sequences and particular combinations thereof.
However, claims 1-3 are not limited to the Epigraph sequences described in the specification, nor are they limited to sequences generated using the Epigraph method. The claims broadly encompass any polypeptide meeting the recited percentage sequence identity to one of the five reference sequences and qualifying as a “vaccine polypeptide.” The scope resulting from this language is particularly broad when the claims are read according to the express definition of sequence identity provided in the specification (see 35 USC 112b rejection supra). The specification at ¶[0221-0222] explains that “sequence identity” is determined based upon an aligned region and that the aligned region may comprise either the full length sequence or only a portion of one or both compared sequences. The specification further recognizes that different aligned regions of the same sequences may yield different sequence identity values. The definition does not require the aligned region to extend over the full length of SEQ ID NO:6, 20, 34, 41, or 42, and does not identify a minimum proportion of the reference sequence that must be represented in the aligned region.
Accordingly, the claimed genera are not restricted to only the full-length polypeptides differing from the disclosed Epigraph sequences by 10%, 5%, or 1% of their amino acid residues, because under the definition provided in ¶[0221-0222], the claims additionally encompass polypeptides having the required identity over only a portion of the reference sequence. This scope includes fragments and variants substantially different from the complete disclosed Epigraph proteins, as well as naturally occurring influenza proteins containing regions having the recited identity to portions of the reference sequences (see 35 USC 101 rejection supra). The claims may further encompass polypeptides having additional sequence outside the aligned region because the unaligned portion does not necessarily contribute to the stated percentage identity.
This breadth is significant in the present disclosure, as the specification acknowledges substantial sequence diversity among naturally occurring influenza proteins. For example, the specification states that the maximum genetic distance between wild-type H1, H2, H3, and H5 genes was 20.7%, 7.9%, 14.7%, and 5.1%, respectively, and further states that HA subtypes “can be up to 60% divergent and still have identical functionality”(¶[0239]). The claimed identity thresholds, particularly when calculated over only an aligned portion rather than the complete protein, therefore encompass a substantially broader collection of structures than the particular computationally generated Epigraph proteins described as the invention. The specification does not describe a sufficient number of species representative of this scope. Although the disclosure provides numerous particular centralized sequences, those sequences were intentionally generated using specified computational approaches, and were then selected as vaccine candidates. Disclosure of those selected sequences does not demonstrate possession of every polypeptide that shares a locally aligned region having 90%, 95%, or 99% identity to one of the five reference sequences, nor does disclosure of the specific Epigraph sequences reasonably convey possession of the innumerable fragments, naturally occurring proteins, extended proteins, or other variants that satisfy the claimed identity calculation when only a portion of the sequence is aligned.
The specification also does not identify structural features common to this broader genus which would allow one skilled in the art to recognize its members as the vaccine polypeptides regarded by the inventor as the invention. The disclosed Epigraph sequences were selected based upon a particular computational strategy intended to maximize potential T- and B-cell epitope coverage (¶[0026][0211-0216][0247]). In contrast, claims 1-3 do not require preservation of those selected epitopes, do not require that a variant retain particular residues or regions of the disclosed Epigraph sequence, and do not require that the sequence have been produced by the disclosed computational process.
The claimed polypeptides are also defined, at least in part, by the term “vaccine polypeptide.” The specification states that antigen and immunogen refer to “antigenic proteins that induce immune responses”(¶[0018]), and describes a universal vaccine as providing protection against most variants within an influenza subtype and against subtypes within groups 1 and 2 influenza viruses (¶[0018-0019]). The specification, however, does not establish a structural correlation sufficient to identify which members of the expansive sequence-identity genera of claims 1-3 retain the vaccine properties attributed to the disclosed Epigraph sequences. For example, the disclosure does not identify which amino acid positions in SEQ ID NOs: 6, 20, 34, 41, or 42 may be substituted or deleted while retaining the relevant immunogenic properties, nor does it identify a minimum fragment that retains the disclosed vaccine properties, or establish that a polypeptide containing only a locally homologous region of one of the reference sequences possesses the vaccine properties attributed to the complete computationally designed immunogen. Instead, the disclosure provides selected complete sequences and experimental or predicted results for particular centralized vaccine constructs. The specification therefore does not provide a representative number of species across the actual breadth produced by the percentage-identity language, nor does it disclose structural features that distinguish members of the claimed vaccine-polypeptide genus from the much larger collection of sequences satisfying the numerical identity limitation. The disclosure of the desired vaccine activity together with selected Epigraph sequences does not reasonably convey possession of that broader genus.
Claims 5-7 further recite that a polypeptide having SEQ ID NO:6 or 20 is encoded by a nucleic acid sequence having at least 90%, 95%, or 99% sequence identity to SEQ ID NO:105 or 110, respectively. The specification identifies SEQ ID NO:105 as a nucleic acid encoding the human H1 Epigraph1 HA vaccine and SEQ ID NO:110 as a nucleic acid encoding the human H3 Epigraph1 HA vaccine (¶[0179-0184]). The specification therefore demonstrates possession of the particular nucleotide sequences of SEQ ID NOs:105 and 110. However, claims 5-7 encompass broader genera of nucleotide sequences defined by percentage identity, as the same definition in ¶[0221-0222] applies to the nucleotide sequence comparison, such that the required identity may be determined over an aligned region comprising only a portion of the compared nucleotide sequences. The claims are therefore not limited to synonymous or closely related full-length coding sequences encoding the disclosed Epigraph proteins.
The specification does not describe a representative number of nucleotide sequences across this scope or identify structural features common to the claimed nucleotide genus. In particular, the disclosure does not identify which nucleotide positions may vary, the extent to which sequence outside a locally aligned region may differ, or other structural boundaries sufficient to demonstrate possession of the broad group of nucleic acids encompassed by the claims. Disclosure of SEQ ID NOs:105 and 110 does not, without more, demonstrate possession of the much larger genus produced by applying the recited percentage identity to an aligned region that may comprise only a portion of the sequences.
Claims 9-12 recite vaccine compositions comprising at least one vaccine polypeptide of claim 1 and a delivery vehicle. The specification describes delivery of particular centralized influenza vaccine constructs using, for example, viral vectors and lipid nanoparticles. However, the additional delivery vehicle limitations do not cure the written description deficiency of the incorporated vaccine polypeptide genus. These claims continue to encompass compositions containing the unsupported fragments, naturally occurring sequences, and other variants encompassed by claim 1.
Claims 13-15 similarly recite methods of vaccinating a subject by administering the vaccine polypeptide of claim 1, as the specification describes vaccination using selected centralized influenza immunogens and reports immune responses and challenge studies using particular vaccine candidates. However, the method claims are not limited to those disclosed immunogens, as they continue to encompass administration of any polypeptide falling within the unsupported sequence genus of claim 1, including sequences satisfying the percentage identity limitation based upon only a portion of the reference sequence. Limiting the subject to a human or swine, or requiring repeated administration, does not supply written description support for the incorporated polypeptide genus.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in claims 1-3, 5-7, and 9-15 at the time the application was filed. Dependent claims 2-3, 5-7, 10-12, and 14-15 do not cure the deficiency because they continue to encompass sequence variants, fragments, and other polypeptides or nucleic acids not adequately described by the specification. The additional percentage-identity thresholds, delivery vehicles, subject limitations, and administration limitations do not provide adequate written-description support for the broader sequence genera incorporated from claims 1, 9, or 13.
Claims 1-15 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 the particular centralized influenza vaccine sequences and vaccine constructs described and tested therein, does not reasonably provide enablement for the substantially broader genera of polypeptides and nucleic acids encompassed by the claims. The specification does not enable any person skilled in the art to make and use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to influenza vaccine polypeptides based upon human H1 HA, H3 HA, N1 NA, and N2 NA Epigraph sequences, compositions containing such polypeptides, and methods of vaccination using the polypeptides. Claims 5-7 additionally encompass nucleic acid sequences encoding the recited H1 or H3 polypeptide and having at least 90%, 95%, or 99% sequence identity to SEQ ID NO:105 or 110, respectively.
The specification describes particular centralized influenza vaccine sequences generated using Consensus, Consensus of Unique Sequences, Mosaic, and Epigraph approaches. The Epigraph approach selects multiple immunogens intended to maximize coverage of common B- and T-cell epitopes represented within the sequence dataset (¶[0022-0027][0074-0200][0206-0211]). The specification identifies SEQ ID NO:6 as a human H1 Epigraph1 HA sequence, SEQ ID NO:20 as a human H3 Epigraph1 HA sequence, SEQ ID NO:34 as a human N1 Epigraph1 NA sequence, and SEQ ID NOs:41 and 42 as human N2 Epigraph1 and Epigraph2 NA sequences (¶[0079-0115]). The specification also provides experimental studies using selected centralized vaccine immunogens, where the disclosed studies evaluate expression, antibody responses, T-cell responses, and protection against selected influenza challenge viruses. For example, the disclosure reports that the Mosaic and CoUS HA vaccines induced equivalent or superior cellular immunity relative to wild-type comparator vaccines and that the Mosaic vaccine generated responses against a greater number of peptides (¶[0232-0250]). Additional studies evaluate centralized influenza immunogens in mouse challenge models and determine protection against selected homologous and heterologous influenza viruses (see e.g., ¶[0234-0284] and the studies associated with FIGS. 24-38.)
However, claims 1-4 are not limited to the particular centralized vaccine polypeptides described or tested in the specification. Claim 1 encompasses any vaccine polypeptide having at least 90% sequence identity to any one of SEQ ID NOs:6, 20, 34, 41, or 42. Claims 2 and 3 retain the same genus while increasing the numerical identity threshold to 95% and 99%, respectively. The breadth of these claims is particularly substantial in view of the express definition of sequence identity in ¶[0221-0222]. The specification provides that sequence identity may be determined over an aligned region and permits that aligned region to comprise only a portion of one or both compared sequences, and the claims do not require that the aligned region extend over the complete HA or NA reference sequence and do not establish a minimum sequence coverage for the identity calculation. While claim 4 encompasses the sequences at 100% identity, the definition of “sequence identity” allows the scope to encompass not only the full length sequences, which are enabled, but fragments thereof, which are not necessarily enabled. Accordingly, the claimed genera encompass more than close full-length variants of the disclosed Epigraph immunogens, as they encompass fragments and other proteins having the required identity over only a portion of a reference sequence, as well as proteins having substantially different sequence outside the aligned region. Even if the percentage identity were determined over the full length of the compared proteins, the claimed scope remains very broad, as even naturally occurring influenza H1 HA, H3 HA, N1 NA, and N2 NA proteins fall within the recited sequence-identity ranges. The specification itself recognizes substantial genetic diversity among circulating influenza sequences and states that the maximum genetic distances among the analyzed wild-type H1, H2, H3, and H5 genes were 20.7%, 7.9%, 14.7%, and 5.1%, respectively (¶[0234-0239]). Thus, a numerical identity threshold encompassing sequences differing at numerous amino acid positions includes substantial naturally occurring variation in addition to the particular computationally selected Epigraph sequences.
Claims 5-8 introduce additional breadth, as these claims encompass nucleic acid sequences having at least 90%, 95%, or 99% sequence identity to SEQ ID NO:105 or 110, respectively, and again, the definition of sequence identity in ¶[0221-0222] applies equally to these nucleotide limitations. Again, while claim 8 is drawn to 100% sequence identity, it is not over only the full lengths of these sequences, and is therefore drawn to a large number of non-enabled fragments of the sequences claimed. Therefore, the nucleotide claims are not limited to the disclosed coding sequences or to close full-length synonymous variants thereof. Claims 9-15 incorporate the broad polypeptide genus of claim 1. The recitation of a delivery vehicle, a particular class of delivery vehicle, administration to a human or swine, or repeated administration does not restrict the incorporated polypeptide genus to the centralized sequences shown by the disclosure to function as vaccine immunogens.
State of the prior art and predictability of the art. At the time the application was filed, one skilled in the art understood that influenza HA sequence variation could materially affect antigenicity and immune recognition. Koel et. al. (Koel BF, et. al. J Virol. 2015 Apr;89(7):3763-75. Epub 2015 Jan 21.), reported that “amino acid substitutions in the hemagglutinin protein can result in escape from neutralizing antibodies, affect viral fitness, and change receptor preference.” Koel further found that single substitutions near the receptor-binding site were sufficient to permit escape from antibodies specific for A(H1N1)pdm09 viruses. Thus, relatively small sequence changes could produce biologically significant changes in immune recognition, and the effect of a variant depended upon the identity and position of the substituted residue rather than merely the overall percentage sequence identity to a reference HA.
The state of the art likewise showed that sequence changes in influenza NA could alter antigenic properties. Air (Air GM. Influenza Other Respir Viruses. 2012 Jul;6(4):245-56. Epub 2011 Nov 16.), reviewed the structure, enzymatic activity, and antigenic significance of influenza NA and explained that NA is itself an antigenically significant influenza surface protein. Air further reported that even conservative mutations at critical antibody contact residues can abolish antibody binding, and discussed naturally occurring changes in residues forming NA antibody epitopes. Thus, the antigenic consequences of sequence variation in NA were dependent upon the particular residue and structural context and could not be predicted merely from a high overall percentage sequence identity.
Altman et. al. (Altman MO, et. al. Viral Immunol. 2018 Mar;31(2):142-149. Epub 2018 Jan 22.), explained that influenza A virus has a “remarkable ability” to evade existing immunity and that amino acid substitutions in the HA head enable escape from antibody-based immunity. Altman further described immune-driven evolution of both HA and NA and noted that NA accumulates surface amino acid substitutions in its globular domain consistent with immune selection. This evidence further shows that the antigenic properties of influenza surface proteins were sensitive to the location and nature of sequence variation, rather than being reliably determined by a broad numerical sequence-identity threshold.
The art therefore was not sufficiently predictable to support extrapolation from the particular computationally selected Epigraph sequences and tested vaccine constructs to every protein having the claimed sequence identity to those sequences. A polypeptide can remain highly identical to an HA or NA reference sequence while differing at residues important for antibody recognition, receptor interaction, protein conformation, or another property relevant to its performance as an influenza vaccine antigen. Conversely, a protein satisfying the applicant's identity definition through only a limited aligned region may differ substantially throughout the remainder of the molecule. Accordingly, the results obtained using the selected centralized immunogens do not reasonably establish that the broader claimed sequence genera can be used as vaccine polypeptides without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with methods for synthesizing or recombinantly expressing influenza proteins, preparing nucleic acids encoding such proteins, formulating vaccine compositions, and evaluating immunogenicity. One skilled in the art also would have been capable of performing sequence alignments and determining percentage sequence identity. The skilled artisan would likewise have known how to evaluate candidate immunogens using assays such as hemagglutination inhibition, neutralization, ELISpot, antibody-binding assays, and animal challenge studies. The specification itself employs such methods to evaluate selected vaccine candidates (¶[0232-0284] and the studies associated with FIGS. 24-38.
However, the availability of these techniques does not identify which members of the claimed sequence genera will possess the vaccine properties attributed to the disclosed centralized immunogens. The skilled artisan's ability to make a candidate and then test whether it works does not eliminate the experimentation required to identify operative members from the substantially broader claimed genus.
Working examples. The specification provides working studies directed to selected centralized influenza vaccine immunogens. These experiments include evaluation of particular HA vaccine sequences, measurement of cellular and humoral immune responses, and challenge of vaccinated animals with selected influenza strains. The specification reports, for example, that centralized immunogens could provide protection against divergent influenza challenge viruses and that selected Mosaic and CoUS HA vaccines produced broader cellular responses than wild-type comparator immunogens (¶[0232-0284]). The disclosure also provides studies directed to particular Epigraph vaccine candidates, including selected H3 vaccine constructs and challenge experiments. The reported experiments therefore provide evidence that particular computationally selected centralized sequences can function as vaccine immunogens.
The specification does not, however, provide working examples representative of the full sequence genera recited in claims 1-3, or the breadth of fragments in claim 4. It does not systematically prepare and test variants spanning the 90%, 95%, or 99% identity genera, and it does not demonstrate that fragments satisfying the identity definition over only a portion of the reference sequence function as the claimed vaccine polypeptides. Nor do the examples establish that naturally occurring HA and NA sequences encompassed by the numerical identity limitations provide the broad vaccine properties attributed to the selected Epigraph immunogens. This distinction is particularly apparent for the claimed NA species, as SEQ ID NOs:34, 41, and 42 are identified as particular Epigraph N1 and N2 sequences, but the disclosure does not provide a representative experimental analysis of the innumerable NA variants encompassed by the claimed percentage-identity genus. The disclosed examples therefore do not establish enablement across the full scope of claims 1-3. The specification likewise does not provide working examples representative of the nucleotide genera of claims 5-8, as it provides representative nucleotide sequences encoding selected vaccine proteins, including SEQ ID NOs:105 and 110, but does not prepare and evaluate a range of nucleotide sequences spanning the claimed percentage identity scope (e.g. full length or fragments thereof).
Guidance in the specification. The specification provides substantial guidance for generating the particular centralized influenza immunogens described therein, and it explains how sequence datasets were assembled and describes the computational approaches used for Consensus, CoUS, Mosaic, and Epigraph design. For example, the disclosure states that Mosaic genes were generated using in silico recombination with preference for repeated 9-mers and that Epigraph genes were designed to maximize coverage using multiple immunogens (¶[0022-0028][0211][0232-0267]). The specification further provides particular parameters used with the Mosaic and Epigraph software. The Epigraph sequences were generated using an unaligned sequence algorithm, an epitope length of nine, and a cocktail size of three (¶[0246-0249]). This guidance is useful for generating the particular type of computationally optimized immunogen that the inventors actually investigated.
However, the claims are not limited to sequences generated by those methods, as the specification does not provide corresponding guidance for determining which arbitrary sequence variants within the claimed identity genera will retain the vaccine properties of the disclosed Epigraph immunogens. It does not identify a set of amino acid positions that may be freely varied, specify positions that must remain unchanged, or provide a structural rule correlating a particular pattern of sequence variation with the required vaccine activity. This defect is significant because the disclosed design strategy itself does not treat all sequence positions as interchangeable. The Epigraph approach was specifically used to select sequences representing common B- and T-cell epitopes, and the Mosaic approach preferentially selected repeated nine-residue motifs (¶[0026][0215-0216][0247]). The specification therefore recognizes that the location and identity of particular residues and epitopes matter to the intended immunological properties, and a numerical percentage-identity threshold, on its own, does not preserve those selected features.
The specification also does not explain how much of SEQ ID NO:6, 20, 34, 41, or 42 must be present when the aligned region is only a portion of the compared sequences. Under the definition in ¶[0221-0222], a candidate may satisfy the claimed identity threshold based upon one region while differing substantially elsewhere. The disclosure provides no general teaching that allows one skilled in the art to predict whether such a sequence will function as the claimed vaccine polypeptide.
Quantity of experimentation necessary. To practice the full scope of claims 1-4, one skilled in the art would need to identify candidate sequences falling within the claimed percentage identity ranges, prepare or express those sequences, and determine whether the resulting peptides or polypeptides possess the vaccine properties required by the claims. Because the identity definition permits comparison over only a portion of the sequences, the potential candidates are not confined to a manageable set of close full-length substitutions of the disclosed Epigraph proteins, and includes fragments of these proteins that may have the claimed percent identity. The skilled artisan would then need to evaluate whether sequence changes preserve relevant antigenic structure and immune recognition, and, depending upon the candidate, this would require assessment of antibody responses, T-cell responses, cross-reactivity, and ultimately whether the candidate provides the intended vaccination effect against influenza. The prior art discussed above demonstrates why sequence identity alone would not answer these questions.
This experimentation would not merely involve routine confirmation of embodiments reasonably expected to work, as the skilled artisan would instead be required to screen members of a broad sequence genus in which the effect of a sequence change depends upon its position and structural context. A candidate having very high overall identity may differ at an antigenically important residue, while a candidate satisfying the claim through a locally aligned region may differ extensively elsewhere.
For claims 5-8, one skilled in the art would additionally need to identify nucleotide sequences satisfying the claimed identity limitation and determine whether those sequences, which could be full length or fragments thereof, encode the required polypeptide in a form suitable for the claimed vaccine subject matter. The applicant's definition again permits identity to be based upon only a portion of the compared nucleotide sequences, substantially increasing the number and structural diversity of sequences within the claimed genus. Claims 9-12 do not avoid this experimentation by adding a delivery vehicle, because before formulating the claimed composition, the skilled artisan must still determine which members of the incorporated claim 1 genus function as vaccine polypeptides. The specification broadly permits delivery using viral vectors or nanoparticles and identifies adenovirus, adeno-associated virus, retrovirus, alphavirus, paramyxovirus, rhabdovirus, and lipid nanoparticles as examples (¶[0015]). Those additional formulation choices do not provide guidance for selecting operative polypeptides from the underlying sequence genus. Claims 13-15 require the skilled artisan to select a member of the broad claim 1 genus for administration as a vaccine, and simply limiting the subject to a human or swine, or requiring repeated administration, does not identify which sequence variants within that genus will produce the required vaccination effect.
Although the individual techniques used to prepare and test candidate influenza immunogens were known, the relevant inquiry is not whether one skilled in the art could perform those assays; instead, the relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, the disclosure teaches how to generate and evaluate selected centralized immunogens but does not provide a reliable means of identifying the operative members of the much broader percentage identity genera without preparing and testing additional candidates.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes particular computationally generated influenza immunogens and provides experimental results for selected centralized vaccine constructs. The claims, however, encompass much more than those selected sequences, as they encompass any polypeptide satisfying the recited identity threshold, including naturally occurring HA and NA sequences, untested variants, and, under the definition in ¶[0221-0222], sequences satisfying the identity threshold over only a portion of the reference sequence. The specification does not disclose a general quality that reliably identifies which members of that broader genus will possess the vaccine properties attributed to the disclosed centralized immunogens, nor does it provide a rule that permits the skilled artisan to vary the reference sequences across the claimed range while predictably preserving the relevant immunological properties. Instead, practicing the breadth of the claims requires the skilled artisan to identify candidate sequences and determine experimentally whether each candidate provides the claimed vaccine function. That is materially different from using a disclosed general principle to make predictable substitutions or variants, as the disclosed Epigraph method provides a way to computationally select particular centralized immunogens, but the claims are not limited to products generated by that method. The specification therefore provides working embodiments and a method for producing additional selected vaccine designs, rather than enabling the full genus actually defined by the percentage-identity limitations.
Conclusion. For these reasons, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in claims 1-15 without undue experimentation.
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 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jasny et. al. (WO2017191258A1; Pub. 11/09/2017; hereafter “Jasny”.) NB: the WIPO document of Jasny is too large to be attached to the Office action; the U.S. PGPub filing of Jasny, US20210162037A1, is also cited on the PTO-892 for this reason.
The Prior Art
Jasny teaches influenza vaccines comprising antigenic peptides or proteins derived from influenza virus (entire document; see p. 4, ¶1). Jasny teaches that the influenza antigen is preferably an influenza hemagglutinin (HA) or neuraminidase (NA) protein and expressly identifies the amino acid sequences of the influenza proteins in Tables 1-4 (SEQ ID NOs: 1-30504; pp. 21-22, “Detailed Description”.) Jasny states that the vaccine comprises an mRNA encoding at least one antigenic peptide or protein derived from a protein of an influenza virus or a fragment or variant thereof, preferably any one of the hemagglutinin (HA) or neuraminidase (NA) proteins, as defined in Tables 1-4 (as shown in Figures 1-4). Jasny therefore teaches influenza HA and NA proteins as immunogenic vaccine antigens, and further demonstrates that mRNA encoding influenza HA and NA antigens induce antigen-specific immune responses in vivo (Example 2 at p. 113). Jasny teaches each of the five sequence alternatives encompassed by instant claim 1 (see table below; see alignments in ABSS .rapbm files for 16/098,834, related Jasny US app. filing) and teaches antigenic peptide or protein variants having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequences listed in Tables 1-4.
Instant
SEQ ID NO:
Jasny
SEQ ID NO:
% identity over
entire sequence
6
11136
100
20
12839
99.6
34
20709
100
41
22146
100
42
21830
93.2
Therefore, Jasny SEQ ID NOs: 11136, 12839, 20709, 22146, and 21830 each fall within at least one of the sequence alternatives recited in instant claims 1-4.
Regarding instant claims 5-7, Jasny further teaches nucleotide sequences encoding influenza HA polypeptides falling within the polypeptide genus of instant claim 1. Specifically, Jasny teaches SEQ ID NO: 157099, which encodes a polypeptide that is 99.7% identical over the entire length of the protein to instant SEQ ID NO:6, and Jasny also teaches SEQ ID NO: 165359, which encodes a polypeptide that is 99.6% identical over the entire length of the protein to instant SEQ ID NO: 20 (see alignments below). Therefore, the translated products of Jasny SEQ ID NOs: 157099 and 165359 satisfy the percent identity as set forth in instant claims 5-7.
Jasny nucleotide sequence SEQ ID NO: 157099 is 82.0% identical to instant SEQ ID NO: 105 when the nucleotide sequences are compared over their entire lengths; and Jasny SEQ ID NO: 16539 is 81.2% identical to instant SEQ ID NO:110 when compared over their entire lengths (see ABSS sequence alignments, .rnpbm files and 16/098,834 alignments). However, both Jasny nucleotide sequences contain portions that are 100% identical to corresponding portions of the instantly claimed nucleotide sequences. In the instant specification (and noted supra with the 112a/b rejections), ¶[0221-0222] expressly provide that sequence identity is determined over an aligned region and that the aligned region may comprise only a portion of one or both compared sequences, and the specification does not require the aligned region to extend over the entire nucleotide sequence and does not identify a minimum sequence coverage required for determining the required percentage identity. Importantly, these nucleotide sequences do not merely contain regions having the required sequence identity; they encode the corresponding highly homologous HA polypeptides. Translation of these nucleotide sequences of Jasny produce polypeptides having over 99% identity to instant SEQ ID NOs: 6 and 20. Therefore, while Jasny SEQ ID NOs: 157099 and 165359 have only 82.0% and 81.2% nucleotide identity, respectively, when compared globally to instant SEQ ID NO: 105 and 110, that global comparison does not define the scope of instant claims 5-8 under Applicant’s own definition. Each Jasny sequence contains an aligned region having 100% identity to the corresponding instant nucleotide sequence, and encodes a full-length HA polypeptide falling within the sequence identity genus of instant claim 1. Jasny therefore teaches every limitation as required by instant claims 5-8.
Jasny teaches vaccine compositions comprising mRNA encoding the influenza vaccine polypeptides along with vehicles, which are an agent, such as a carrier that may typically be used within a pharmaceutical composition or vaccine for facilitating administering of the components of the pharmaceutical composition or vaccine to an individual (p. 15, ¶1; reference claims 45, 66). Jasny teaches that the delivery vehicle may be a nanoparticle, such as a liposome, vesicle, nanoparticle, nanosphere, and polymer (p. 84, ¶3; reference claims 45, 53, 66). Jasny teaches methods of vaccinating a subject by administering a vaccine composition comprising mRNA encoding the influenza peptides or polypeptides, and notes that said methods are capable of raising immunity against seasonal or pandemic influenza virus strains (p, 2, ¶1; p. 3, ¶4-6; Examples 2-3; reference claims 74-76). Jasny teaches the vaccination of human subjects (p. 4, ¶5-6; p. 13, ¶2; p. 39, ¶2; p. 42, ¶2), and teaches repeated administration of the vaccine (p. 105, ¶4; Example 3, Example 6).
For at least these reasons, Jasny teaches the limitations of instant claims 1-8, and anticipates the invention encompassed by said claims.
Qy: translated SEQ ID NO: 157099 ; Db: SEQ ID NO:6
US-18-800-951-6
Query Match 99.7%; Score 3008; DB 1; Length 566;
Best Local Similarity 99.8%;
Matches 565; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCK 60
Qy 61 LRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETSSSDNGTCYPGDFIDYEELRE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETSSSDNGTCYPGDFIDYEELRE 120
Qy 121 QLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 QLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSK 180
Qy 181 SYINDKGKEVLVLWGIHHPSTSADQQSLYQNADAYVFVGTSRYSKKFKPEIAIRPKVRDQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SYINDKGKEVLVLWGIHHPSTSADQQSLYQNADAYVFVGTSRYSKKFKPEIAIRPKVRDQ 240
Qy 241 EGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPK 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPK 300
Qy 301 GAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNVPSIQPRGLFGAIA GFIEGGWTG 360
|||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||
Db 301 GAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNVPSIQSRGLFGAIA GFIEGGWTG 360
Qy 361 MVDGWYGYHHQNEQGSGYAADLKSTQNAIDKITNKVNSVIEKMNTQFTAVGKEFNHLEKR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 MVDGWYGYHHQNEQGSGYAADLKSTQNAIDKITNKVNSVIEKMNTQFTAVGKEFNHLEKR 420
Qy 421 IENLNKKVDDGFLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 IENLNKKVDDGFLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNG 480
Qy 481 CFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQILAIYSTVASS 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 CFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQILAIYSTVASS 540
Qy 541 LVLVVSLGAISFWMCSNGSLQCRICI 566
||||||||||||||||||||||||||
Db 541 LVLVVSLGAISFWMCSNGSLQCRICI 566
Qy: translated SEQ ID NO: 165359; Db: SEQ ID NO: 20
Query Match 99.6%; Score 3017; DB 1; Length 566;
Best Local Similarity 99.5%;
Matches 563; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MKTIIALSYILCLVFAQKLPGNDNSTATLCLGHHAVPNGTIVKTITNDQIEVTNATELVQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKTIIALSYILCLVFAQKLPGNDNSTATLCLGHHAVPNGTIVKTITNDQIEVTNATELVQ 60
Qy 61 NSSIGEICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERNKAYSNCYPYDVPD 120
||||||||||||||||||||||||||||||||||||||||||||||:|||||||||||||
Db 61 NSSIGEICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERSKAYSNCYPYDVPD 120
Qy 121 YASLRSLVASSGTLEFNNESFNWTGVTQNGTSSACIRRSNNSFFSRLNWLTHLNFKYPAL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 YASLRSLVASSGTLEFNNESFNWTGVTQNGTSSACIRRSNNSFFSRLNWLTHLNFKYPAL 180
Qy 181 NVTMPNNEQFDKLYIWGVHHPGTDKDQIFLYAQSSGRITVSTKRSQQAVIPNIGSRPRIR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 NVTMPNNEQFDKLYIWGVHHPGTDKDQIFLYAQSSGRITVSTKRSQQAVIPNIGSRPRIR 240
Qy 241 NIPSRISIYWTIVKPGDILLINSTGNLIAPRGYFKIRSGKSSIMRSDAPIGKCKSECITP 300
:|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DIPSRISIYWTIVKPGDILLINSTGNLIAPRGYFKIRSGKSSIMRSDAPIGKCKSECITP 300
Qy 301 NGSIPNDKPFQNVNRITYGACPRYVKQSTLKLATGMRNVPEKQTRGIFGAIA GFIENGWE 360
|||||||||||||||||||||||||||:||||||||||||||||||||||||||||||||
Db 301 NGSIPNDKPFQNVNRITYGACPRYVKQNTLKLATGMRNVPEKQTRGIFGAIA GFIENGWE 360
Qy 361 GMVDGWYGFRHQNSEGRGQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFSEVEG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GMVDGWYGFRHQNSEGRGQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFSEVEG 420
Qy 421 RIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTKKQLRENAEDMGN 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 RIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTKKQLRENAEDMGN 480
Qy 481 GCFKIYHKCDNACIGSIRNGTYDHDVYRDEALNNRFQIKGVELKSGYKDWILWISFAISC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GCFKIYHKCDNACIGSIRNGTYDHDVYRDEALNNRFQIKGVELKSGYKDWILWISFAISC 540
Qy 541 FLLCVALLGFIMWACQKGNIRCNICI 566
||||||||||||||||||||||||||
Db 541 FLLCVALLGFIMWACQKGNIRCNICI 566
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 9-15 are rejected under 35 U.S.C. 103 as being unpatentable over Jasny as applied to claims 1-8 above, and further in view of Nabel et. al. (US20140302079A1; Pub. 10/09/2014; hereafter “Nabel”.)
The Prior Art
The teachings of Jasny have been set forth supra. While Jasny teaches immunogenic influenza HA and NA peptides and proteins, the compositions of Jasny in the vaccines and pharmaceutical compositions are preferably mRNA which encode said peptides/proteins, and not the proteins themselves. However, delivery of peptide or protein-based vaccines, especially for the treatment or prophylactic inhibition of influenza infection was known in the art, as evidenced by Nabel.
Nabel teaches influenza HA protein-based vaccines intended to induce neutralizing antibodies against influenza virus (entire document; see abstract.) Nabel teaches HA-ferritin nanoparticle vaccines in which an influenza HA protein is joined to a ferritin subunit and displayed on the surface of the assembled nanoparticle (reference claim 1; instant claims 9, 12). Nabel teaches H1 and H3 HA proteins, including HAs from A/New Caledonia/20/1999 (1999 NC, H1), A/California/04/2009 (2009 CA, H1), A/Singapore/1/1957 (1957 Sing, H2), A/Hong Kong/1/1968 (1968 HK, H3), A/Brisbane/10/2007 (2007 Bris, H3), A/Indonesia/05/2005 (2005 Indo, H5), and HAs from influenza B viruses, such as B/Florida/4/2006 (2006 Flo, B), A/Perth/16/2009 (2009 Per, H3), A/Brisbane/59/2007 (2007 Bris, H1), and B/Brisbane/60/2008 (2008 Bris, B)(¶[0004]). Nabel teaches nucleic acid constructs for the expression of the HA proteins, and states that the vector may be a viral vector, such as a cytomegalovirus (CMV), retrovirus, adenovirus, adeno-associated virus, herpes virus, vaccinia virus, poliovirus, Sindbis virus, or any other DNA or RNA virus vector (¶[0147]; instant claims 10-11). Nabel teaches methods to vaccinate an individual against influenza, wherein the method comprises administering a vaccine comprising the influenza HA-ferritin nanoparticles to an individual such that the nanoparticle elicits an immune response against influenza virus (reference claim 34; instant claim 13), wherein the individual may be any human or animal, such as a pig (¶[0102]; instant claim 14), and wherein the vaccination regimen includes a prime/boost protocol (¶[0174; instant claim 15).
Given the teachings of Jasny and Nabel, arriving at the pharmaceutical compositions and methods of delivery of said compositions would be obvious. One of ordinary skill would have recognized that particular HA sequences, such as those used in the platform of Nabel, could be replaced with other known influenza HA and/or NA proteins, such as those of Jasny. Such as substitution would have amounted to the use of a known influenza antigen with a known influenza vaccine delivery platform for its intended purpose. The successful vaccination studies of Nabel with H1 and H3 HA proteins would have provided a reasonable expectation that a H1 or H3 HA antigen taught by Jasny could likewise be administered in those platforms to elicit an influenza-specific immune response in the subject. Therefore, arriving at the limitations of instant claims 9-15 would be obvious to a skilled artisan, given the teachings of Jasny and Nabel.
It would have been obvious to one of ordinary skill in the art to modify the influenza vaccine compositions taught by Jasny to use the influenza HA protein delivery systems taught by Nabel, thereby providing the Jasny influenza HA vaccine polypeptides in a known viral vector or nanoparticle vaccine platform and administering the resulting composition to induce an immune response against influenza. One would have been motivated to do so, given the suggestion by Nabel that the influenza HA proteins can be delivered using viral vectors or displayed on ferritin nanoparticles for vaccination against influenza. There would have been a reasonable expectation of success, given the knowledge that Jasny teaches the recited HA sequences as influenza vaccine antigens suitable for eliciting an immune response, and also given the knowledge that Nabel successfully used influenza HA proteins in viral vector and nanoparticle vaccine formats and demonstrated that such compositions induce influenza-specific immune responses following administration. 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.
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 1-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,064,478. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘478 encompass influenza vaccine polypeptides having at least 90% sequence identity to an amino acid sequence selected from the group consisting of any of SEQ ID NOs: 21, 22, 87 and 88, wherein the polypeptide is encoded by a nucleic acid sequence having at least 90% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 111, 112, 121 and 122, respectively. The instantly claimed SEQ ID NO: 20 is likewise a human H3 Epigraph sequence and is 92.1% identical over the full length of the protein to SEQ ID NO: 21 and 91.5% identical over the full length of the protein to SEQ ID NO: 22. Therefore, the presently claimed H3 Epigraph polypeptide falls within the same closely related sequence genus as the H3 Epigraph polypeptides already claimed in ‘478.
The instantly claimed nucleotide sequence of SEQ ID NO: 110 is 76.7% identical over its entire length to SEQ ID NO: 111 from ‘478 and 79.6% identical over its entire length to SEQ ID NO: 112 from ‘478. However, SEQ ID NO: 110 contains aligned regions with both SEQ ID NOs: 111 and 112 that are 100% identical. The specification defines sequence identity such that the aligned region may comprise only a portion of one or both sequences. Accordingly, under the definition used by Applicant, the presently claimed nucleotide sequence falls within the percentage identity scope associated with the H3 Epigraph subject matter already claimed in ‘478.
Furthermore, both sets of claims are drawn to vaccine compositions comprising influenza vaccine peptides or proteins and a delivery vehicle; both sets of claims are drawn to viral vectors or nanoparticles as delivery vehicles. Both sets of claims encompass viral delivery vehicles including adenovirus, adeno-associated virus, retrovirus, alphavirus, paramyxovirus, and rhabdovirus. Both sets of claims are also drawn to methods of administering the influenza vaccine polypeptides or proteins to a subject to raise an immune response against influenza. Both sets of claims further encompass administration of the vaccine to humans or swine, and claim multiple administrations of the vaccine.
Therefore, taken as a whole, the instant claims are not patentably distinct from the ‘478 claims.
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.
US20140286981A1. Teaches mosaic in silico generated HA and NA sequences to maximize epitope coverage. Not utilized as rejection would be redundant to those set forth supra.
US20150044247A1. Teaches computationally optimized (COBRA) H3 HA sequences to maximize epitope coverage. Not utilized as rejection would be redundant to those set forth supra.
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
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