DETAILED ACTION
Disposition of Claims
Claims 1-3, 7, 14-16, 25-26, 28-30, 39, 42-43, 50-51, and 54-56 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240415952A1, Published 12/19/2024.
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.
Of note, there is not an attorney of record on file due to a lack of an official power of attorney of record. While a customer number has been provided on the ADS submitted 05/22/2024, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
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 05/27/2026 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
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of implied phraseology (e.g. “The present disclosure provides…”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 of the reference to color in said drawings (see e.g. figure legend for Fig. 12). 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.
The disclosure is objected to because of the following informalities: at ¶[0116], there is a definition of “cytoplasmic tail” that goes on to state “In certain embodiments, a transmembrane domain comprises the amino acid sequence IKKTKKPTGAPPELSGVTNNGFIPHN of SEQ ID NO: 1.” This reference of “transmembrane domain” in this definition appears to be a typographical error.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See e.g. ¶[0087] and “ENPRRRR”, “GGGGS,”, “GYIPEAPRDGQAYVRKDGEWVLLSTFL”, “HHHHHHHH”, and “SAWSHPQFEK” sequences. Also ¶[0115-0116] with “GFIIVIILIAVLGSSMILVSIFII” and “IKKTKKPTGAPPELSGVTNNGFIPHN”.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 28 is objected to because of the following informalities: the wording of the claim is awkward, and to place the claim in better form, it is suggested the claim be amended along the lines of the following: “28. The viral vector of claim 1, wherein the F polypeptide comprises: a sequence that is at least 95% identical to SEQ ID NO: 3, or a sequence that comprises SEQ ID NO: 3.”
Appropriate correction is required.
Claims 54 and 56 are objected to because of the following informalities: in both claims, “of a claim 1” in the preamble should be “of claim 1”.
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.
Claims 3, 7, and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 3, 7, and 16, as drafted, are unclear as to what limitations must be present or are optional due to the phrasing of the claim, the use/absence of punctuation, and/or the use of coordinating conjunctions.
For instance, claim 3 recites a series of limitations following “wherein”. The limitations are separated by commas and semicolons, while the expressions “and/or” appear only between certain later limitations. It is unclear which limitations (e.g. F0 cleavage site mutation, signal peptide) are required in every embodiment, whether the tag sequence, foldon domain, and pre-fusion conformation are alternatives to one another, or whether any one of the listed features is sufficient to satisfy the claim. Accordingly, one of ordinary skill cannot determine which combination of the listed structural features is required by claim 3.
With claim 7, the claim recites several overlapping descriptions of substitutions at amino acid positions 160 and 46 of SEQ ID NO:1. The claim first recites substitutions at both positions, separately recites a genus of possible substitutions at 160, further recites the substitution specifically with phenylalanine at position 160, separately recites a genus of possible substitutions at position 46, and then recites a specific substitution with valine at position 46. The claim then recites another limitation encompassing a substitution at position 160 “and/or” a substitution at position 46. It is unclear which substitutions are required at positions 160 and 46, and whether the specific substitutions (e.g. valine at 46, phenylalanine at 160) are required or if the broader genus of possible amino acids at each position are allowed. Accordingly, one of ordinary skill cannot determine which combination of the listed structural features is required by claim 7.
Finally, with respect to claim 16, claim 15 already requires an amino acid substitution replacing threonine at position 160 and an amino acid substitution replacing asparagine at position 46 of SEQ ID NO:1. Claim 16 then recites a genus of possible substitutions at these positions, the specific T160F and N46V substitutions, at least 95% sequence identity to SEQ ID NO:7, and several additional structural limitations. These limitations are listed without a clear connector establishing whether they are cumulative or alternative, and the claim concludes with an optional pre-fusion limitation followed by “and/or” and a separate nucleic acid limitation. It is therefore unclear whether claim 16 requires the specific T160F and N46V substitutions, merely requires substitutions selected from the broader residue lists (if so, then there is a possible 35 USC 112d issue), or permits the sequence identity limitation to serve as an alternative to the expressly recited substitutions. Further, the requirement that the F polypeptide have at least 95% sequence identity to SEQ ID NO: 7 does not, by itself, require retention of every residue present in SEQ ID NO: 7. A polypeptide satisfying the recited identity threshold may differ from SEQ ID NO: 7 at positions falling within the permitted sequence variation, potentially including positions corresponding to T160F, N46V, Q100R, or S101R. The claim does not clearly state whether the expressly recited substitutions must remain invariant within every sequence satisfying the “at least 95% identity” limitation. It is also unclear whether the sequence identity limitation applies to a polypeptide that additionally contains all of the listed signal peptide, tag, foldon, and cleavage site features, or whether sequence identity to SEQ ID NO: 7 is merely one alternative among the listed limitations. Accordingly, one of ordinary skill cannot determine which combination of the listed structural features is required by claim 16.
For at least these reasons, claims 3, 7, and 16 are rejected on the grounds of being indefinite.
Claim 30 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 30 is drawn to the viral vector of claim 29, wherein the F polypeptide is a prefusion F polypeptide;
the viral vector backbone derived from a (PIV), optionally wherein the PIV is a chimeric rB/HPIV3 or a HPIV3;
the F polypeptide comprises amino acid substitution T160F replacing threonine at amino acid position 160 with phenylalanine, and amino acid substitution N46V replacing asparagine at amino acid position 46 with valine;
the F polypeptide comprises SEQ ID NO: 7; and/or
the viral vector further comprising a hMPV F nucleic acid molecule having at least 95% sequence identity to SEQ ID NO: 8, optionally wherein the nucleic acid molecule comprises SEQ ID NO: 8.
First, it is unclear if the citation within the parentheses (e.g. “(PIV)”) is a required element. It is assumed and will be interpreted that this limitation was not meant to be within parentheses.
Second, the recitation of “the F polypeptide comprises amino acid substitution T160F replacing threonine at amino acid position 160 with phenylalanine, and amino acid substitution N46V replacing asparagine at amino acid position 46 with valine;” is redundant – either one or the other should be recited for brevity. For instance, it is sufficient to claim “the F polypeptide comprises amino acid substitutions T160F and N46V”.
Finally, with respect to claim 30, the recitation of at least 95% sequence identity to SEQ ID NO:8 along with additional structural limitations, including the F polypeptide comprising SEQ ID NO: 7, and the use of the coordinating conjunction “and/or” makes it unclear which limitations are required and which are optional or alternative limitations. These limitations are listed without a clear connector establishing whether they are cumulative or alternative. The requirement that the F polypeptide have at least 95% sequence identity to SEQ ID NO: 8 does not, by itself, require retention of every residue present in SEQ ID NO: 7. A polypeptide satisfying the recited identity threshold may differ from SEQ ID NO: 7 at positions falling within the permitted sequence variation, potentially including positions corresponding to T160 and N46 . The claim does not clearly state whether the expressly recited substitutions must remain invariant within every sequence satisfying the “at least 95% identity” limitation. Accordingly, one of ordinary skill cannot determine which combination of the listed structural features is required by claim 30.
For at least these reasons, claim 30 is rejected on the grounds of being indefinite.
Claim 43 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 43 lists adjuvant administration, an additional vaccine, subject identity, and an antibody result, followed by “and/or”. The placement of the coordinating conjunction “and/or” does not clearly establish which limitations may be selected independently. One suggestion is to recite the limitations in a list along the lines of the following:
“43. The method of claim 42, wherein one or more of the following applies:
(a) the vaccine is co-administered with an adjuvant,
(b) the vaccine is administered in combination with an additional vaccine, optionally wherein the additional vaccine is a respiratory syncytial virus (RSV) vaccine or an influenza vaccine;
(c) the subject is human, optionally wherein the human subject is an infant, a toddler, or an older adult;
(d) the vaccine increases the serum concentration of neutralizing antibodies, and wherein the subject has pre-existing hMPV immunity.”
For at least these reasons, claim 43 is rejected on the grounds of being indefinite.
Claim 50 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 50 is drawn to “The viral vector of claim 1, in the manufacture of a medicament for eliciting an immune response to hMPV and HPIV3 or protecting a subject against hMPV infection and HPIV3 infection.” From the wording of the claim, it is unclear whether the claim is intended to be directed to the viral vector as a product, a method of manufacturing a medicament using the viral vector, or the use of the viral vector for manufacturing a medicament.
If the claim is intended to recite a method of manufacture, the claim does not identify any manufacturing step or action performed using the viral vector. If the claim is intended to recite a use, the claim does not clearly define the acts required by that use or the resulting medicament. If the claim is intended to remain a product claim, the phrase “in the manufacture of a medicament” does not clearly recite a structural limitation of the viral vector or otherwise define how the claimed vector differs from the viral vector of claim 1.
Accordingly, the metes and bounds of claim 50 are unclear.
Claim 51 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 51 is drawn to the method of:
(A) eliciting an immune response in a subject in need thereof, comprising administering to the subject, optionally intramuscularly, intranasally, intravenously, subcutaneously, or intradermally, a prophylactically effective amount of the viral vector of claim 1; or
(B) preventing an hMPV infection and an HPIV3 infection or reducing one or more symptoms of an hMPV infection and an HPIV3 infection, comprising administering to the subject, optionally intramuscularly, intranasally, intravenously, subcutaneously, or intradermally, a prophylactically effective amount of the viral vector of claim 1.
The alternative option (B) recites “preventing an hMPV infection and an HPIV3 infection or reducing one or more symptoms of an hMPV infection and an HPIV3 infection”, and it is unclear whether the method requires prevention of both infections, reduction of at least one symptom associated with each infection, reduction of a symptom associated with either infection, or some combination of prevention and symptom reduction as to the two infections.
For at least these reasons, the metes and bounds of claim 51 are unclear.
Claim 54 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 54 is drawn to the viral vector of a claim 1, for use in treating a subject in need thereof. It is unclear whether the phrase “for use in treating” merely states an intended use of the claimed viral vector or whether Applicant intends claim 54 to recite a method of treatment. If claim 54 is intended to be directed to a treatment method, the claim does not recite administering the viral vector or any other affirmative step. The claim also does not identify the disease, symptom, or other condition being treated. Accordingly, the acts required to practice the purported treatment method cannot be determined.
If claim 54 is meant to remain a product claim, it is unclear what limitation the phrase “for use in treating a subject in need thereof” imposes on the structure or properties of the viral vector of claim 1. The claim does not identify a particular treatment for which the vector must be suitable, and the phrase “in need thereof” does not identify the condition or treatment of which the subject is in need.
For at least these reasons, the metes and bounds of claim 54 are unclear.
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.
As defined by the art, a “human rhinovirus 3C (HRV-3C) protease cleavage site” specifically recognizes and cleaves the eight-residue sequence Leu-Glu-Val-Leu-Phe-Gln↓Gly-Pro (LEVLFQ↓GP).
As defined by the art, a “Strep II tag” is interpreted as an affinity peptide having the amino acid sequence WSHPQFEK, as further reflected in the disclosed constructs. The term is not interpreted as requiring a product obtained from a particular commercial source.
The term “lacks a transmembrane domain” means that the encoded hMPV F polypeptide does not contain the C-terminal membrane spanning region of hMPV F, exemplified by the approximately 23-amino acid sequence GFIIVIILIAVLGSSMILVSIFII of SEQ ID NO: 1.
The term “lacks a cytoplasmic tail” means that the polypeptide does not contain the C-terminal intracellular tail region, exemplified by the sequence IKKTKKPTGAPPELSGVTNNGFIPHN of SEQ ID NO: 1.
Claim 1 is drawn to a viral vector that encodes a human metapneumovirus (hMPV) F polypeptide antigen that lacks a transmembrane domain, lacks a cytoplasmic tail, and comprises a human rhinovirus 3C (HRV-3C) protease cleavage site.
Further limitations on the viral vector of claim 1 are wherein said vector comprises a viral vector backbone derived from a parainfluenza virus (PIV), optionally wherein the PIV is a chimeric bovine/human parainfluenza type 3 virus (rB/HPIV3) or a human parainfluenza type 3 virus (HPIV3)(claim 2); wherein:
said F polypeptide further comprises an F0 cleavage site mutation comprising amino acid substitutions Q100R and S101R, replacing glutamine at amino acid position 100 of SEQ ID NO: 1 with arginine, and replacing serine at amino acid position 101 of SEQ ID NO: 1 with arginine,
said F polypeptide further comprises a signal peptide;
said F polypeptide further comprises at least one tag sequence that is optionally an 8×His tag and/or a Strep II tag; and/or
said F polypeptide further comprises a foldon domain; and/or
the hMPV F polypeptide is a pre-fusion F polypeptide (claim 3); wherein the F polypeptide further comprises:
an amino acid substitution replacing the amino acid at position 160 of SEQ ID NO: 1, and an amino acid substitution replacing the amino acid position 46 of SEQ ID NO: 1;
an amino acid substitution replacing the amino acid at position 160 with phenylalanine, tryptophan, tyrosine, valine, alanine, isoleucine, or leucine;
an amino acid substitution replacing the amino acid position 160 with phenylalanine;
an amino acid substitution replacing the amino acid position 46 with valine, alanine, isoleucine, leucine, phenylalanine, tyrosine, or proline;
an amino acid substitution replacing the amino acid position 46 with valine;
an amino acid substitution replacing the amino acid at position 160 of SEQ ID NO: 1 with phenylalanine, tryptophan, tyrosine, valine, alanine, isoleucine, or leucine and/or an amino acid substitution replacing the amino acid position 46 of SEQ ID NO: 1 with valine, alanine, isoleucine, leucine, phenylalanine, tyrosine, or proline; and/or
an amino acid substitution replacing threonine at amino acid position 160 of SEQ ID NO: 1, and an amino acid substitution replacing asparagine at amino acid position 46 of SEQ ID NO: 1 (claim 7); wherein the viral vector encodes a hMPV F polypeptide antigen,
wherein said F polypeptide lacks a transmembrane domain and lacks a cytoplasmic tail, and further comprises:
an F0 cleavage site mutation comprising amino acid substitutions Q100R and S101R; replacing glutamine at amino acid position 100 of SEQ ID NO: 1 with arginine, and replacing serine at amino acid position 101 of SEQ ID NO: 1 with arginine;
a HRV-3C protease cleavage site;
a heterologous signal peptide;
an 8×His tag and/or a Strep II tag; and
a foldon domain (claim 14);
wherein
the hMPV F is from A strain hMPV; and/or
the hMPV F is A1 subtype or A2 subtype hMPV (claim 26); wherein the F polypeptide comprises: a sequence that is at least 95% identical to SEQ ID NO: 3, or a sequence that comprises SEQ ID NO: 3 (claim 28); wherein the viral vector is in an immunogenic composition that elicits an immune response to hMPV and HPIV3 (claims 50); wherein the viral vector is in a vaccine composition (claim 54); and wherein the viral vector comprises a hMPV F nucleic acid molecule having at least 95% sequence identity to SEQ ID NO: 8, optionally wherein the nucleic acid molecule comprises SEQ ID NO: 8 (claim 56).
Claim 15 is drawn to a viral vector that encodes an hMPV F polypeptide antigen, wherein said F polypeptide lacks a transmembrane domain, lacks a cytoplasmic tail, and comprises an amino acid substitution replacing threonine at amino acid position 160 of SEQ ID NO: 1, and an amino acid substitution replacing asparagine at amino acid position 46 of SEQ ID NO: 1.
Further limitations on the viral vector of claim 15 are wherein said F polypeptide comprises:
an amino acid substitution replacing threonine at amino acid position 160 with phenylalanine, tryptophan, tyrosine, valine, alanine, isoleucine, or leucine;
an amino acid substitution T160F replacing threonine at amino acid position 160 with phenylalanine;
an amino acid substitution replacing asparagine at amino acid position 46 with valine, alanine, isoleucine, leucine, phenylalanine, tyrosine, or proline;
an amino acid substitution N46V replacing asparagine at amino acid position 46 with valine;
at least 95% sequence identity to SEQ ID NO: 7;
an F0 cleavage site mutation comprising amino acid substitutions Q100R and S101R, replacing glutamine at amino acid position 100 of SEQ ID NO: 1 with arginine, and replacing serine at amino acid position 101 of SEQ ID NO: 1 with arginine;
a signal peptide;
at least one tag sequence that is optionally an 8×His tag and/or a Strep II tag;
a foldon domain;
optionally wherein the hMPV F polypeptide is a pre-fusion F polypeptide; and/or
the viral vector further comprising a hMPV F nucleic acid molecule having at least 95% sequence identity to SEQ ID NO: 8, optionally wherein the nucleic acid molecule comprises SEQ ID NO: 8 (claim 16); that encodes an antigenic hMPV prefusion F polypeptide, wherein said prefusion F polypeptide lacks a transmembrane domain, lacks a cytoplasmic tail, and comprises:
an amino acid substitution T160F replacing threonine at amino acid position 160 of SEQ ID NO: 1 with phenylalanine, and an amino acid substitution N46V replacing asparagine at amino acid position 46 of SEQ ID NO: 1 with valine;
an F0 cleavage site mutation comprising amino acid substitutions Q100R and S101R; replacing glutamine at amino acid position 100 of SEQ ID NO: 1 with arginine, and replacing serine at amino acid position 101 of SEQ ID NO: 1 with arginine;
a HRV-3C protease cleavage site;
a signal peptide;
an 8×His tag and/or a Strep II tag; and
a foldon domain (claim 25).
Claim 29 is drawn to a viral vector encoding an hMPV F polypeptide, wherein said F polypeptide comprises at least 95% sequence identity to SEQ ID NO: 7.
Further limitations on the viral vector of claim 29 are wherein:
the F polypeptide is a prefusion F polypeptide;
the viral vector backbone derived from a (PIV), optionally wherein the PIV is a chimeric rB/HPIV3 or a HPIV3;
the F polypeptide comprises amino acid substitution T160F replacing threonine at amino acid position 160 with phenylalanine, and amino acid substitution N46V replacing asparagine at amino acid position 46 with valine;
the F polypeptide comprises SEQ ID NO: 7; and/or
the viral vector further comprising a hMPV F nucleic acid molecule having at least 95% sequence identity to SEQ ID NO: 8, optionally wherein the nucleic acid molecule comprises SEQ ID NO: 8 (claim 30).
Claim 39 is drawn to an live-attenuated virus or a pharmaceutical composition comprising the viral vector of claim 1, optionally wherein the live-attenuated virus or the pharmaceutical composition is comprised in a vaccine.
Claim 42 is drawn to a method of eliciting an immune response to hMPV and/or HPIV3 or protecting a subject against hMPV infection and/or HPIV3 infection, comprising administering the vaccine of claim 39 to a subject.
Further limitations of the method of claim 42 are wherein one or more of the following applies:
(a) the vaccine is co-administered with an adjuvant,
(b) the vaccine is administered in combination with an additional vaccine, optionally wherein the additional vaccine is a respiratory syncytial virus (RSV) vaccine or an influenza vaccine;
(c) the subject is human, optionally wherein the human subject is an infant, a toddler, or an older adult;
(d) the vaccine increases the serum concentration of neutralizing antibodies, and wherein the subject has pre-existing hMPV immunity (claim 43).
Claim 51 is drawn to the method of:
(A) eliciting an immune response in a subject in need thereof, comprising administering to the subject, by a route selected from intramuscular, intranasal, intravenous, subcutaneous, or intradermal administration, a prophylactically effective amount of the viral vector of claim 1; or
(B) preventing an hMPV infection and an HPIV3 infection or reducing one or more symptoms of an hMPV infection and an HPIV3 infection, comprising administering to the subject, by a route selected from intramuscular, intranasal, intravenous, subcutaneous, or intradermal administration, a prophylactically effective amount of the viral vector of claim 1.
Claim 55 is drawn to a kit comprising a container, wherein the container is comprising a single-use or multi-use dosage of the viral vector of claim 1, optionally wherein the container is a vial or a pre-filled syringe or injector.
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, 7, 14-16, 25-26, 28-30, 39, 42-43, 50-51, and 54-56 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 specifically disclosed rB/HPIV3 vectors encoding the tested hMPV F constructs, does not reasonably provide enablement for the broader viral vector, amino acid substitution, sequence identity, composition, and treatment scope encompassed by the claims. 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 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 viral vectors encoding modified hMPV F polypeptides, compositions and kits comprising said vectors, and methods of administering the vectors to elicit an immune response or provide protection against hMPV and HPIV3 infection. The breadth of “viral vector” is any virus that is engineered to encode said hMPV F polypeptide construct. The breadth of “HRV-3C protease cleavage site” is not limited to any particular location in the F protein. The F polypeptides further comprise substitution mutations at specific locations, namely positions 160 and 46 with respect to SEQ ID NO:1 numbering, and further comprise other structural elements, such as His tags, Strep II tags, signal peptides, and foldon domains, without noting where in the polypeptide said elements are located. Further claims also provide that the F protein is in a prefusion conformation without noting how said prefusion conformation is stabilized or provided.
The specification describes recombinant chimeric bovine/human parainfluenza type 3 virus vectors, identified as rB/HPIV3 or B/HPIV3 vectors, containing selected hMPV F inserts (¶[0225-0228]). The disclosed vectors were recovered in BHK BSR-T7/5 cells, passage in LLC-MK2 cells, evaluated in Vero and A549 cells, and administered intranasally to Golden Syrian hamsters (¶[0228-0236][0260-0270]). The specification also describes soluble hMPV F constructs containing selected combinations of transmembrane domain and cytoplasmic tail deletions, cleavage site changes, point mutations, a foldon domain, affinity tags, and an HRV-3C protease cleavage site (¶[0185-0203]). The principal mutation species selected for further characterization were the T160F/N46V and D185P constructs (¶[0242-0252]).
However, the claims are not limited to the disclosed embodiments. The claims also encompass any viral vector encoding any hMPV F polypeptide satisfying the recited antigen limitations. The claims therefore include materially different viral vector systems having different genomes, replication strategies, packaging limits, insertion sites, expression controls, cellular tropisms, antigen presentation properties, and routes of administration. While claim 2 narrows the vector to a backbone derived from a parainfluenza virus, it is not limited to the disclosed rB/HPIV3 backbone. The recitation that the PIV is optionally rB/HPIV3 or HPIV3 leaves the claim open to other human, bovine, murine, or chimeric parainfluenza virus-backbones. The specification does not provide working examples for that broader PIV genus.
Claim 30 recites a PIV limitation together with several other limitations using an unclear set of alternatives. Even if the PIV limitation is treated as mandatory, claim 30 continues to encompass a broad PIV genus and the “at least 95% identity” genera of claims 29 and 30. Claims 7 and 15-16 additionally encompass broad groups of amino acid substitutions at positions 46 and 160. Claim 15 fails to identify the replacing amino acids and therefore covers every paired combination of non-native amino acids at those positions. Claim 16 recites several residue alternative and also includes amino acid and nucleic acid sequences defined by at least 95% sequence identity. Claims 28-30 broadly encompass F polypeptides having at least 95% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 7. Claims 16, 30, and 56 encompass nucleic acid molecules having at least 95% sequence identity to SEQ ID NO: 8. These identity limitations permit changes throughout the engineered F construct and do not clearly require retention of every residue associated with prefusion stability, cleavage, trimerization, expression, or antigenicity.
The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, Battles et. al. (Battles MB, et. al. Nat Commun. 2017 Nov 16;8(1):1528.) developed different F ectodomain prefusion stabilization strategies which produced dramatically different results. Certain constructs were poorly expressed, one cavity-filling substitution prevented expression entirely, three proposed disulfide variants were not expressed at detectable levels, and another candidate became unstable after purification. Battles ultimately selected one construct after comparing expression, proteolytic processing, antibody binding, purification yield, and conformational stability. Battles showed that point mutations intended to stabilized hMPV F were generally not interchangeable. The reported failures demonstrate that structure-based selection supplied candidates for testing, but did not reliably predict expression, cleavage, stability, or retention of the desired prefusion antigenic character. These results are consistent with the variability shown by the instant specification’s own candidate screening experiments.
Tang et. al. (Tang RS, et. al. Vaccine. 2005 Feb 25;23(14):1657-67.) established that one specifically constructed b/hPIV3 vector could express hMPV F and provide protective immunity under the tested conditions. Tang did not establish that an hMPV F insert could be transferred without material redevelopment to any viral vector backbone, nor did the reference provide a general rule predicting expression, attenuation, replication, immunogenicity, or protection across unrelated vector systems.
Russell et. al. (Russell CJ, et. al. Virology. 2017 Sep;509:60-66. Epub 2017 Jun 9.) confirms that another respiratory virus vector could be developed to carry a truncated hMPV F antigen. However, the reference describes a separately engineered construct, a particular insertion arrangement, and empirical testing in a different animal model. The existence of that discrete platform does not supply a general method that would permit one skilled in the art to select any viral vector and reasonably expect it to express the presently claimed engineered F antigens with suitable stability, replication, attenuation, and immunogenicity.
Yang et. al. (Yang CF, et. al. Virol J. 2009 Sep 9;6:138.) shows that a numerical identity threshold near 95% can encompass sequences from materially different hMPV lineages and sublineages. Sequence identity alone does not identify which changes may be introduced into the present engineered constructs while retaining the arrangement of the cleavage site mutations, stabilizing mutations, linker regions, affinity tags, foldon domain, and antigenic properties.
The art was not sufficiently predictable to support extrapolation from the empirically optimized disclosed hMPV embodiments in the specific PIV3 vectors to the broader claimed scope of viral vectors, F protein configurations with percent identities, and methods of use therapeutically. Accordingly, the results obtained using the disclosed embodiments would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with reverse genetics, viral vector engineering and recovery, recombinant protein expression and purification, site-directed mutagenesis, sequence alignment, consensus sequence generation and codon optimization, cell culture propagation, plaque assays, neutralization assays, and animal challenge studies. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which viral vectors, insertion positions into said vectors, promoter/transcriptional arrangements for heterologous protein expression, and mutation combinations in the F protein would satisfy the claimed limitations and produce operative embodiments.
Working examples. The specification provides working examples directed mainly to eight B/HPIV3 vectors expressing selected forms of hMPV F (Examples 1-8; ¶[0225-0271]). The animal experiments used one intranasal dose of the B/HPIV3 vectors in Golden Syrian hamsters, followed by challenge with the sub-group A strain CAN97-83 (¶[0262-0271]). The protein engineering work began with 21 candidate hMPV prefusion F protein constructs (¶[0237-0239]). Only nine protein antigens were produced and only four reached approximately 90% purity by SDS-PAGE (¶[0240- 241]). K138F was discontinued after forming aggregates, while another candidate was discontinued based on its antibody results. The T160F/N46V and D185P species were selected for additional characterization (¶[0242-0246]; Table 2). The viral vector results also showed context-dependent performance. The specification states that codon optimization “did not increase expression and indeed the BBopt optimization unpredictably decreased expression”(¶[0260]). The B/HPIV3 vectors carrying the BBopt-based constructs generally produced less hMPV F than the corresponding GSopt constructs (¶[0257-0261]). Protection in the lower respiratory tract was less consistent than protection in the nasal turbinates. The specification states that the lung results were “less clear” and three tested vectors did not provide significant protection in the lungs (¶[0267-0269]).
The specification does not provide working examples directed to any other viral vectors, such as adenoviruses, adeno-associated virus, herpesvirus, poxvirus, alphavirus, vesicular stomatitis virus, Newcastle disease virus, or another unrelated viral-vector platform. It does not provide a working example using a non-rB/HPIV3 PIV backbone. The specification fails to test the large number of paired position 46/160 substitution mutations or the amino acid or nucleic acid variants permitted by the “at least 95% identity” limitations. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides substantial guidance regarding construction, recovery, propagation, and testing of an rB/HPIV3 vector containing an hMPV F insert (¶[0140-0167][0225-0234]). The specification also supplies the exact sequences of selected F constructs and describes assays that may be used to evaluate expression, conformation, stability, antibody binding, immunogenicity, and protection (¶[0191-0202][0237-0270]).
However, the specification does not provide sufficient guidance regarding adapting the claimed F constructs to the full range of viral vector backbones encompassed by the claims. In particular, the specification does not explain how to select a compatible insertion site in the viral vector genome, transcriptional control arrangement (e.g. with herpesviral vectors, there are temporally regulated native promoters), genome orientation within the selected viral vector, packaging strategy (e.g. if the expressed protein should be “within” the vector or expressed on the outer surface of the virion), or attenuation scheme of the vector. Nor does it explain how the encoded soluble, tagged, and foldon-containing F polypeptides would affect replication or stability in each viral system.
The specification also fails to identify which amino acid replacements at positions 46 and 160 will yield an expressed and antigenic hMPV F polypeptide. The broad residue categories at ¶[0033-0036] do not provide a rule that distinguishes successful paired substitutions from substitutions that prevent expression, promote aggregation, disrupt prefusion conformation, impair cleavage, or materially alter antigenicity.
With respect to the percent identity claims, the specification does not identify which positions within SEQ ID NOs: 3, 7, or 8 may be changed. It does not state which residues and domains must remain invariant, how many changes may be placed within a particular region, or whether substitutions, deletions, insertions, linker changes, tag changes, and cleavage site changes are equally permissible. The numerical identity threshold identifies the size of the claimed sequence space, but it does not guide the skilled artisan through that space.
The method claims present a further issue, as claims 42-43, 50, and alternative (B) of claim 51 require an immune response to, or protect against, both hMPV and HPIV3, yet the incorporated viral vector of claim 1 is not required to be an HPIV3 or PIV vector and is not required to have an HPIV3 antigen. The dual protection shown in the examples depends on the specific vector studied (B/HPIV3) supplying the HPIV3 component (¶[0262-0270]). The specification does not explain how a vector lacking a HPIV3 antigen would elicit any HPIV3-specific immune response, especially one that would be clinically useful.
The examples are also limited to intranasal (i.n.) administration of the B/HPIV3 vectors in hamsters. The specification does not provide comparative data for the intramuscular, intravenous, subcutaneous, or intradermal administration of the claimed viral vectors, or demonstrate protection in infants, toddlers, older adults, or subjects having pre-existing hMPV immunity. The existence of familiar administration routes does not establish that every claimed vector will remain viable, reach the appropriate tissue, express sufficient antigen, and produce the recited immune result by each route.
Quantity of experimentation necessary. To practice the full scope of the claims directed to the use of viral vectors, one skilled in the art would need to select candidate vector families and then design a platform-specific genome or expression cassette for each vector. The artisan would need to determine a compatible insertion site and regulatory arrangement, recover the recombinant vector, assess genetic stability, measure F expression, and determine whether the insert interferes with vector replication or attenuation. Candidates that survived that initial work would still require testing for antigen processing, proper protein conformation, immunogenicity, and protective activity in an in vivo system.
To practice the full substitution scope, one skilled in the art would need to prepare numerous F polypeptides containing different position 46 and 160 substitutions. Each candidate would need to be screened because the specification does not provide a reliable structure-function rule predicting which paired substitutions will be expressed, remain soluble, preserve a stable prefusion structure, and function as an antigen in the chosen in vivo systems when encoded by the selected viral vector.
To practice the sequence identity scope of the claims, one skilled in the art would first need to choose changes from the many positions determined by the 5% variation. The selected amino acid or nucleotide sequences would then need to be made and tested to determine whether they retained the required structural elements, expression properties from the viral vector, antigenic conformation, vector compatibility, and immune activity.
Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed limitations. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required 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, one skilled in the art would need to prepare and test additional viral vectors, F protein 46/160 substitution mutations, and F protein sequence % variants to determine which embodiments satisfy the claimed limitations. The applicant’s own results showed that related constructs differed in expression, aggregation, antibody response, and lower-respiratory tract protection. To ensure the breadth of the claims would work, a skilled artisan would be required to conduct a large research program across multiple vector platforms, multiple combination, and sequence variants to determine which embodiments work.
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 described selected rB/HPIV3 vectors encoding a small number of particular hMPV F constructs, but the claims also encompass materially different viral vector platforms and hMPV F protein constructs/sequences. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in the claims without undue experimentation.
Claims 1-3, 7, 14-16, 25-26, 28-30, 39, 42-43, 50-51, and 54-56 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 pre-AIA 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, 7, 14-16, 25-26, 28-30, 39, 42-43, 50-51, and 54-56 recite, directly or through dependent claims, viral vectors encoding hMPV F polypeptides which lack a transmembrane (TM) domain, lacks a cytoplasmic tail, and comprises an HRV-3C protease cleavage site. Claims 14 and 25 additionally recite Q100R/S101R substitution mutations, a signal peptide, one or more affinity tags, and a foldon domain. Further claims recite the F protein having substitutions at positions 160 and 46 of SEQ ID NO:1. Claim 15 broadly encompasses any paired replacement of threonine at position 160 and asparagine at position 46, while claim 16 recites broader residue alternatives, the specific T160F/N46V substitutions, and sequences having at least 95% identity to SEQ ID NOs: 7 and 8.
The specification describes particular engineered hMPV F protein constructs in which the transmembrane domain and cytoplasmic tail are removed and a defined C-terminal region containing a foldon domain, linkers, an HRV-3C protease cleavage site, and affinity tags are appended to the F protein ectodomain (¶[0186-0187][0191-0202]). The specification also describes specific T160F/N46V constructs and identifies its amino acid and nucleic acid sequences as SEQ ID NOs: 7 and 8 (¶[0200-0202]). The examples describe a panel of 21 candidate constructs, but only nine protein antigens were produced, four reached approximately 90% purity, and only the T160F/N46V and D185P constructs were selected for further physiochemical analysis (¶[0237-0252]). The viral vector studies likewise used a limited group of specifically designed B/HPIV3 constructs, and the specification reports that codon optimization and different mutations produced variable and sometimes reduced expression (¶[0225-0228][0257-0261]).
However, the scope of the claims is not limited to the embodiments described in the specification. The claims broadly encompass the HRV-3C protease cleavage site at anywhere in the F protein, and are drawn to further paired substitution mutations at positions 160 and 46. Likewise, the position and arrangements of the affinity tags, linkers, and foldon domains is not claimed and is broadly encompassed to anywhere within the engineered F protein.
The specification does not describe a sufficient number of species representative of the claimed scope. The specification also does not describe structural features common to the claimed genus which would allow one skilled in the art to recognize which additional species fall within the scope of the claimed invention. Instead, one skilled in the art would be required to select additional F proteins with the engineered structural features (e.g. percent identity, substitution mutations at 46/160, and heterologous tags, domains, and protease cleavage sites) not described in the specification and determine whether those additional embodiments satisfy the recited limitations.
The claimed F polypeptides are defined, at least in part, by the recited function of being an hMPV antigen. However, the specification does not establish a correlation between the disclosed structural features and the recited function sufficient to identify the additional substitution mutations at positions 46/160 of SEQ ID NO:1, locations of affinity tags, location of protease domains, and further mutations within the scope of 95% identity to SEQ ID NOs: 7 or 8 falling within the scope of the claim. The specification describes SEQ ID NOs: 7 and 8 at 100% identity which comprise all of the claimed elements at specific locations, but does not identify structural features common to the broader claimed genus which would allow one skilled in the art to recognize other members of the genus (e.g. no other mutants are generated of SEQ ID NOs: 7 or 8 that adjust the location of any of the affinity tags, foldon domains, linkers, or protease cleavage sites, nor are any other substitutions aside from the specific T160F/N46V constructs generated). While other variants appear to have been generated, some failed to produce viable polypeptides that were adequately inserted into the claimed chimeric PIV vector. These results show that different modifications were not interchangeable, and that most candidate constructs were not produced at useful levels, with some forming aggregates and others producing ineffective antibody responses. Furthermore, codon optimization did not increase expression and unpredictably decreased expression (¶[0214-0245][0257-0261]). The disclosure of the desired function, without a sufficient description of the claimed genus, does not demonstrate possession of the full scope of the claim.
The specification describes specific T160F/N46V constructs in a B/HPIV3 vector background. However, the claims are not limited to those constructs. The claims also encompass constructs that differ in PIV vector identity and viral vector identity in general, as well as encompassing substitution mutations at the T160/N46 positions aside from the respective T and V substitutions. As stated supra, many of the other constructs with other mutations were not viable, and the specification does not describe representative examples across that scope or identify structural features sufficient to show possession of the broader group of constructs.
The specification describes amino acid and nucleic acid sequences of the F protein with the claimed structural elements in SEQ ID NOs: 7 and 8 that were successfully generated and tested in the in vitro and in vivo platforms and were sufficiently antigenic as expressed from the specific chimeric PIV background. However, the claims also encompass additional amino acid and nucleic acid sequences of the F protein with at least 95% identity to SEQ ID NOs: 7 or 8 and satisfying the ability to form a successfully encoded F polypeptide from a viral vector, as well as comprise the recited immunogenic capability in other claims. The specification does not identify which positions may be altered (e.g. which tags, protease cleavage sites, linkers, foldon domains, amino acids within the F protein sequence, etc.) while retaining the recited function, describe representative variants across the claimed scope, or identify structural features sufficient to distinguish operative variants from other sequences. Accordingly, the disclosure does not demonstrate possession of the broader claimed group of sequences.
The specification describes the use of the B/HPIV3 vector comprising SEQ ID NO: 8 (which encodes SEQ ID NO:7) to elicit an immune response to both HPIV3 and hMPV in the in vivo animal model. However, claims 42-43 and 51 broadly encompass delivery of the viral vector of claim 1 to elicit an immune response to HPIV3 alone, hMPV alone, or to both hMPV and HPIV3, through delivery of a composition comprising said viral vector to a subject. The viral vector of claim 1 does not require any antigen or aspect of any HPIV3 antigen to be present in the viral vector. The specification does not describe representative embodiments across the scope of vectors encompassed by claim 1 or otherwise demonstrate possession of the broader claimed method, and the disclosure of the results obtained with the B/HPIV3 vector comprising SEQ ID NO: 8 does not reasonably convey possession of methods using any vector encompassed by the limitations of instant claim 1 to elicit the immune responses or therapeutic responses in the claimed methods.
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 the claims at the time the application was filed.
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, 3, 14, 26, 28-30, 42-43, 51, and 54-55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by McLellan et. al. (US20240317810A1; Priority 10/09/2020; hereafter “McLellan”.)
The Prior Art
McLellan teaches prefusion stabilized hMPV protein sequences, as well as chimeric hMPV/RSV F proteins (entire document; see abstract) and teaches nucleic acid sequences encoding said proteins (¶[0007]; Table 1; ¶[0024-0025]). McLellan teaches the sequences may be encoded by a viral vector (¶[0110-0114]). McLellan teaches SEQ ID NO: 2, which is 98.4% identical across the full-length of instant SEQ ID NO: 7 (see ABSS alignment below; “Db”: SEQ ID NO:2, “Qy”: SEQ ID NO:7). McLellan also teaches SEQ ID NO: 9, which is 98.9% identical to SEQ ID NO: 3 (See ABSS search results for 18-578-966 in us-18-671-660-3.rapbm file in file wrapper for alignment). As the alignment shows, McLellan teaches the F protein sequence lacks the transmembrane and cytoplasmic domains and comprises an N-terminal signal sequence of MSWKVVIIFSLLITPQHG, an F0 cleavage site mutation comprising amino acid substitutions Q100R and S101R, an 8x His tag, a Strep II tag, a foldon domain, and a HRV-3C protease cleavage site (instant claims 1, 3, 14, 26, 28-30). McLellan teaches methods of eliciting an immune response to or preventing infection from hMPV through delivery of pharmaceutical formulations such as vaccines to the subject (¶[0025][0070-0072][0077][0133-0168]; reference claim 42; instant claims 42, 51, 54). McLellan teaches the formulations for delivery to a subject may comprise an adjuvant (¶[0023][0125]; reference claim 38) and that the subject may be human (¶[0070]; instant claim 43). McLellan teaches kits which comprise the vector composition aliquoted into a vial, test tube, syringe, or bottle (¶[0161-0165]; instant claim 55).
For at least these reasons, McLellan teaches the limitations of instant claims 1, 3, 14, 26, 28-30, 42-43, 51, and 54-55, and anticipates the limitations encompassed by said claims.
Query Match 98.4%; Score 2804; Length 551;
Best Local Similarity 98.4%;
Matches 542; Conservative 5; Mismatches 4; Indels 0; Gaps 0;
Qy 1 MSWKVVIIFSLLITPQHGLKESYLEESCSTITEGYLSVLRTGWYTVVFTLEVGDVENLTC 60
||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||
Db 1 MSWKVVIIFSLLITPQHGLKESYLEESCSTITEGYLSVLRTGWYTNVFTLEVGDVENLTC 60
Qy 61 SDGPSLIKTELDLTKSALRELKTVSADQLAREEQIENPRRRRFVLGAIA LGVATAAAVTA 120
:||||||||||||||||||||:||||||||||||||||||||||||||||||||||||||
Db 61 ADGPSLIKTELDLTKSALRELRTVSADQLAREEQIENPRRRRFVLGAIA LGVATAAAVTA 120
Qy 121 GVAIA KTIRLESEVTAIKNALKTTNEAVSTLGNGVRVLAFAVRELKDFVSKNLTRAINKN 180
|||||||||||||||||||||| |||||||||||||||| ||||||||||||||||||||
Db 121 GVAIA KTIRLESEVTAIKNALKKTNEAVSTLGNGVRVLATAVRELKDFVSKNLTRAINKN 180
Qy 181 KCDIDDLKMAVSFSQFNRRFLNVVRQFSDNAGITPAISLDLMTDAELARAVSNMPTSAGQ 240
|||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KCDIPDLKMAVSFSQFNRRFLNVVRQFSDNAGITPAISLDLMTDAELARAVSNMPTSAGQ 240
Qy 241 IKLMLENRAMVRRKGFGILIGVYGSSVIYMVQLPIFGVIDTPCWIVKAAPSCSEKKGNYA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 IKLMLENRAMVRRKGFGILIGVYGSSVIYMVQLPIFGVIDTPCWIVKAAPSCSEKKGNYA 300
Qy 301 CLLREDQGWYCQNAGSTVYYPNEKDCETRGDHVFCDTAAGINVAEQSKECNINISTTNYP 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CLLREDQGWYCQNAGSTVYYPNEKDCETRGDHVFCDTAAGINVAEQSKECNINISTTNYP 360
Qy 361 CKVSTGRHPISMVALSPLGALVACYKGVSCSIGSNRVGIIKQLNKGCSYITNQDADTVTI 420
|||||||:||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CKVSTGRNPISMVALSPLGALVACYKGVSCSIGSNRVGIIKQLNKGCSYITNQDADTVTI 420
Qy 421 DNTVYQLSKVEGEQHVIKGRPVSSSFDPIKFPEDQFNVALDQVFENIENSQALVDQSNRI 480
||||||||||||||||||||||||||||:||||||||||||||||:||||||||||||||
Db 421 DNTVYQLSKVEGEQHVIKGRPVSSSFDPVKFPEDQFNVALDQVFESIENSQALVDQSNRI 480
Qy 481 LSSAEKGNTGGGGSGYIPEAPRDGQAYVRKDGEWVLLSTFLGRSLEVLFQGPGHHHHHHH 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 LSSAEKGNTGGGGSGYIPEAPRDGQAYVRKDGEWVLLSTFLGRSLEVLFQGPGHHHHHHH 540
Qy 541 HSAWSHPQFEK 551
|||||||||||
Db 541 HSAWSHPQFEK 551
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 7, 15-16, 25-26, 39, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over McLellan as applied to claims 1, 3, 14, 26, 28-30, 42-43, 51, and 54-55 above, and further in view of Kwong et. al. (US20180008697A1, Pub. 01/11/2018; hereafter “Kwong”) and McLellan et. al. (US20230357327A1, Priority 10/09/2020; hereafter “McLellan-2023”.)
The Prior Art
The teachings of McLellan have been set forth supra. While McLellan teaches that the hMPV F protein may be delivered via a viral vector, McLellan fails to teach that said vector may be a parainfluenza virus (PIV) vector, such as a chimeric human/bovine PIV or HPIV3. McLellan teaches hMPV F proteins but fails to teach delivery of specific strains or subsets of hMPV F protein, such as subgroup A, and while McLellan teaches stabilizing mutations to the hMPV F protein, McLellan fails to specifically teach T160 and/or N46 mutants. However, the use of PIV vectors to deliver hMPV F protein antigens was taught in the art, as were different hMPV subgroups and F protein stabilizing mutations, as shown by the teachings of Kwong and McLellan-2023.
Kwong teaches human metapneumovirus (MPV) F proteins stabilized in a prefusion conformation, nucleic acid molecules and vectors encoding these proteins, and methods of their use and production (entire document; see abstract; ¶[0016]). Kwong teaches immunization with different subgroup F proteins, such as subgroup A (including A1, A2) and B (¶[0028][0106][0108][0112]; instant claim 26). Kwong teaches the F protein may be delivered by a PIV vector, such as a HPIV3 or H/BPIV3 vector (¶[0299-0300]; instant claims 2, 50) and that the PIV may be attenuated (¶[0011][0299-0300]; instant claim 39). Kwong teaches the use of T160F mutations in the F protein (¶[0325][0359-0360]).
McLellan-2023 teaches engineered hMPV F proteins with enhanced conformational stability and/or antigenicity (entire document; see abstract.) McLellan-2023 teaches that cavity filling substitution mutations may be generated to N46 and to T160 (¶[0007][0009][0013-0014]; reference claims 73; Table 1), such as N46V (¶[0014]; Tables 1 and 3). McLellan-2023 expressly identifies N46V together with T160 substitution mutations as specific cavity-filling mutations (¶[0014]), and states that combining multiple beneficial mutations further improved the desired protein characteristics (¶[0006]). McLellan-2023 teaches that the cavity filling approach to mutations was very effective to stabilize loosely packed viral protein at prefusion conformation (¶[0051]).
Given the teachings of McLellan, one of skill in the art would be apprised to delivery of hMPV F protein constructs via viral vectors. Given the teachings of Kwong, a skilled artisan would appreciate that PIV viral vectors, such as h/bPIV or PIV3, could be engineered to deliver said hMPV F proteins, and elicit an antigenic response not only against the F protein, but PIV proteins as well. Given the guidance from McLellan-2023, a skilled artisan would be able to narrow down which mutations could be generated to the hMPV F protein in order to make said protein more stable. Given the guidance from Kwong and McLellan-2023, one obvious mutation to generate would be T160, such as T160F as taught by Kwong. Further obvious mutations would be N46V of McLellan-2023, as McLellan-2023 teaches that specific cavity filling mutations such as T160 and N46 were better in multiple mutations to stabilize the protein in the prefusion conformation and make the resulting protein more immunogenic. Therefore, arriving at the limitations of instant claims 2, 7, 15-16, 25-26, 39, and 50 would be obvious to a skilled artisan, given the teachings of McLellan in view of Kwong and McLellan-2023.
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 1-3, 14, 26, 28-30, 39, 42-43, 50-51, and 54-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 6 of U.S. Patent No. 7,820,181 in view of Skiadopoulos et. al. (US20040204581A1, Pub. 10/14/2002; hereafter “Skiadopoulos”) and McLellan (supra).
NB: While Skiadopoulos is the PGPub of the ‘181 patent, it is available as prior art and may be used as such in this NSDP rejection.
Both sets of claims are drawn to PIV vectors. The main differences are that the reference ‘181 claims do not require said PIV to encode a heterologous antigen, such as an F polypeptide, and the instant claims do not require the PIV to comprise the attenuating mutations noted in the ‘181 claims. However, such differences would be obvious, given the teachings of McLellan and Skiadopoulos. While the instant claims provide that the viral vector encodes an F polypeptide antigen that lacks a transmembrane domain, lacks a cytoplasmic tail, and comprises a human rhinovirus 3C (HRV-3C) protease cleavage site, such differences would be obvious, given the teachings of McLellan (detailed supra). McLellan also teaches the hMPV F protein can be encoded by a viral vector. Skiadopoulos teaches an infectious HPIV2 with attenuating mutations in the genome (entire document; see abstract.) Skiadopoulos teaches an isolated, infectious, self-replicating, recombinant human parainfluenza virus type 2 (HPIV2) comprising a PIV major nucleocapsid (N) protein, a PIV nucleocapsid phosphoprotein (P), a PIV large polymerase protein (L), and a partial or complete, polyhexameric recombinant HPIV2 genome or antigenome encoding one or more attenuating mutation(s) selected from amino acid substitution(s) or deletion(s) in the HPIV2 L polymerase at the amino acid corresponding to residue 11 of SEQ ID NO: 4 and/or residue 11 of SEQ ID NO: 10 (abstract; ¶[0024][0042][0051-0052][0061][0063][0067][0071][0088][0099][0111][0216][0326]; Example VI at ¶[0262]). Skiadopoulos teaches the PIV may encode heterologous genes from other viruses to generate a chimeric, multivalent vaccine (¶[0021][0033]) such as the F protein from hMPV (¶[0035]). Therefore, modification of the PIV to encode the hMPV F protein of the instant claims would be an obvious modification to the patented claims of the ‘181 patent, especially in light of the teachings of Skiadopoulos and McLellan.
Claims 1-3, 14, 26, 28-30, 39, 42-43, 50-51, and 54-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10 of U.S. Patent No. 7,919,301 in view of Skiadopoulos et. al. (US20040204581A1, Pub. 10/14/2002; hereafter “Skiadopoulos”) and McLellan (supra).
NB: While Skiadopoulos is the PGPub of the parent ‘181 patent, it is available as prior art and may be used as such in this NSDP rejection.
Both sets of claims are drawn to PIV vectors which encode heterologous antigens, namely a hMPV antigen. The main differences are that the reference ‘301 claims do not require said heterologous antigen from hMPV to be an F polypeptide, and the instant claims do not require the PIV to comprise the attenuating mutations noted in the ‘301 claims. However, such differences would be obvious, given the teachings of McLellan and Skiadopoulos. While the instant claims provide that the viral vector encodes an F polypeptide antigen that lacks a transmembrane domain, lacks a cytoplasmic tail, and comprises a human rhinovirus 3C (HRV-3C) protease cleavage site, such differences would be obvious, given the teachings of McLellan (detailed supra). McLellan also teaches the hMPV F protein can be encoded by a viral vector. Skiadopoulos teaches an infectious HPIV2 with attenuating mutations in the genome (entire document; see abstract.) Skiadopoulos teaches an isolated, infectious, self-replicating, recombinant human parainfluenza virus type 2 (HPIV2) comprising a PIV major nucleocapsid (N) protein, a PIV nucleocapsid phosphoprotein (P), a PIV large polymerase protein (L), and a partial or complete, polyhexameric recombinant HPIV2 genome or antigenome encoding one or more attenuating mutation(s) selected from amino acid substitution(s) or deletion(s) in the HPIV2 L polymerase at the amino acid corresponding to position 20 of SEQ ID NO: 1 to an amino acid other than phenylalanine, to residue 11 of SEQ ID NO: 4, and/or residue 11 of SEQ ID NO: 10 (abstract; ¶[0024][0042][0051-0052][0061][0063][0067][0071][0088][0099][0111][0216][0326]; Example VI at ¶[0262]). Skiadopoulos teaches the PIV may encode heterologous genes from other viruses to generate a chimeric, multivalent vaccine (¶[0021][0033]) such as the F protein from hMPV (¶[0035]). Therefore, modification of the PIV to encode the hMPV F protein of the instant claims would be an obvious modification to the patented claims of the ‘301 patent, especially in light of the teachings of Skiadopoulos and McLellan.
Claims 1-3, 14, 26, 28-30, 39, 42-43, 50-51, and 54-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9-11 of U.S. Patent No. 8,367,074 in view of Skiadopoulos et. al. (US20040204581A1, Pub. 10/14/2002; hereafter “Skiadopoulos”) and McLellan (supra).
NB: While Skiadopoulos is the PGPub of the parent ‘181 patent, it is available as prior art and may be used as such in this NSDP rejection.
Both sets of claims are drawn to PIV vectors which encode heterologous antigens, namely a hMPV antigen. The main differences are that the reference ‘074 claims do not require said heterologous antigen from hMPV to be an F polypeptide, and the instant claims do not require the PIV to comprise the attenuating mutations noted in the ‘074 claims. However, such differences would be obvious, given the teachings of McLellan and Skiadopoulos. While the instant claims provide that the viral vector encodes an F polypeptide antigen that lacks a transmembrane domain, lacks a cytoplasmic tail, and comprises a human rhinovirus 3C (HRV-3C) protease cleavage site, such differences would be obvious, given the teachings of McLellan (detailed supra). McLellan also teaches the hMPV F protein can be encoded by a viral vector. Skiadopoulos teaches an infectious HPIV2 with attenuating mutations in the genome (entire document; see abstract.) Skiadopoulos teaches an isolated, infectious, self-replicating, recombinant human parainfluenza virus type 2 (HPIV2) comprising a PIV major nucleocapsid (N) protein, a PIV nucleocapsid phosphoprotein (P), a PIV large polymerase protein (L), and a partial or complete, polyhexameric recombinant HPIV2 genome or antigenome encoding one or more attenuating mutation(s) selected from amino acid substitution(s) or deletion(s) in the HPIV2 L polymerase at the amino acid corresponding: to a mutation deleting amino acids corresponding to residues 11 and 12 of SEQ ID NO: 13; to position 20 of SEQ ID NO: 1 to an amino acid other than phenylalanine, to residue 11 of SEQ ID NO: 4, and/or to residue 11 of SEQ ID NO: 10 (abstract; ¶[0024][0042][0051-0052][0061][0063][0067][0071][0088][0099][0111][0216][0326]; Example VI at ¶[0262]). Skiadopoulos teaches the PIV may encode heterologous genes from other viruses to generate a chimeric, multivalent vaccine (¶[0021][0033]) such as the F protein from hMPV (¶[0035]). Therefore, modification of the PIV to encode the hMPV F protein of the instant claims would be an obvious modification to the patented claims of the ‘074 patent, especially in light of the teachings of Skiadopoulos and McLellan.
Claims 1-3, 7, 14-16, 25-26, 28-30, 39, 42-43, 50-51, and 54-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7, 10, 19-20, 23, 28-29, 31-35, 36, 38, 63-64, 75-76, 92-101, 104 of copending Application No. 18/070,921 in view of Kwong (supra). Both sets of claims are drawn to a nucleic acid molecule encoding a hMPV prefusion F polypeptide antigen that lacks the transmembrane and cytoplasmic domains and comprises a HRV-3C protease cleavage site. Both sets of claims are drawn to the F antigen comprising a Q100R and S101R mutation, a signal peptide, a tag sequence (such as a His or Strep II tag), and a foldon domain. Both claim the F antigen comprises a T160F and N46V mutation. Both claim the F antigen is from an MPV A strain, such as the A1 or A2 subtype. Both claim the protein comprises SEQ ID NO: 3 or 7 and is encoded by SEQ ID NO: 8, wherein instant SEQ ID NOs: 3 and 7-8 and reference SEQ ID NOs: 3 and 7-8 from ‘921 are 100% identical. Both claim compositions which comprise the nucleic acid molecule, such as a vaccine. Both claim kits comprising the F antigen nucleic acid. Both claim the nucleotide is expressed by a vector. The main differences are that while both claim the nucleic acid is encoded by a vector, the instant claims provide for a viral vector. Also, the ‘921 claims are drawn to the nucleic acid encoding the F antigen to be mRNA. Both of these differences would be obvious modifications to the nucleic acid encoding the F antigen, especially in light of the teachings of Kwong.
While the instant claims do not claim that the nucleic acid is mRNA, this would be an obvious variation of the viral vectors of the instant claims, especially since they are drawn to RNA viruses encoding the F protein antigen. This would be further obvious given the teachings of Kwong, which teach the F protein antigen may be encoded by a viral vector, such as PIV, or mRNA (¶[0255]; reference claim 46). Kwong further teaches modified nucleotides (¶[0087]). Additionally, Kwong teaches that PIV-based viral vectors, such as attenuated HPIV3 vectors, may encode the F protein antigen. Therefore, the differences between the instant claims and the reference ‘921 claims are not patentably distinct, especially in light of the teachings of Kwong.
This is a provisional nonstatutory double patenting rejection.
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.
Cseke G, et. al. J Virol. 2007 Jan;81(2):698-707. Epub 2006 Oct 18. Teaches generation of soluble, epitope-tagged hMPV F proteins lacking transmembrane regions. Not utilized as rejection would be redundant to those set forth supra.
Cox RG, et. al. J Virol. 2014 Jun;88(11):6368-79. Epub 2014 Mar 26. Teaches VLPs bearing hMPV F proteins and use as a vaccine. Not utilized as rejection would be redundant to those set forth supra.
Hsieh CL, et. al. Nat Commun. 2022 Mar 14;13(1):1299. Post-filing art related to mutations generated to hMPV F protein to stabilize said protein in prefusion conformation.
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
Prosecution Insights