DETAILED ACTION
Disposition of Claims
Claims 1-10, 12-15, 17-31, and 33-36 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250082745A1, Published 03/13/2025.
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.
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 06/11/2024, 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 statement (IDS) submitted on 06/11/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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. “Bacteriophage λ are disclosed herein…” ; “Host bacterial cells also disclosed herein…”; “Methods also are disclosed for…” ; and “Furthermore, methods are disclosed…” A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See ¶[0253] “https://doi.org/10.1038/srep39076”.
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 drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. See Figures 6, 8, 11 – the “GGGGS” sequence should be identified with a SEQ ID NO: either in the figure itself or the figure legend. See Figure 10 – the GGGGSGGGGSGGGGS sequence should be identified with a SEQ ID NO: either in the figure itself or the figure legend.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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 15 is objected to because of the following informalities: at line 2, to place the claim in better form and make the reference in claim 17 clearer, it should recite “severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)”. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: “SEQ ID Nos:” at line 2 should be “SEQ ID NOs:”. Appropriate correction is required.
Claim 29 is objected to because of the following informalities: to place the claim in better form, it is suggested claim 29 be amended to clearly recite that the wild type D protein encoding sequence is separate from the lambda genome. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 and dependent claims 2-10, 12-15, 17-31, and 33-36 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “adjacent” in claim 1 is a relative term which renders the claim indefinite. The term “adjacent” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the plain meaning of the term, “adjacent” means being “next to or nearby, typically without intervening objects of the same kind.” Confusion arises when one turns to the specification for guidance, as at ¶[0091] it states:
“Adjacent” refers to a first nucleic acid sequence next to a second amino acid sequence. Thus, in the sequence A-B-C, A is 5′ to B and adjacent to B. However, A is 5′ to C but is not adjacent to C. B is 3′ of A and 5′ of C; B is adjacent to both A and C and is flanked by A and C.”[emphasis added].
These are two objects which are not of the same kind, and in that same paragraph, the use of “immediately” before “adjacent” implies that there are things that can be “non-immediately adjacent”. Therefore, it is unclear as to what is intended by the proximity of something being “adjacent” in the genome as claimed.
Furthermore, the nucleic acid encoding the protein D-heterologous protein fusion peptide is “inserted into a native gene D locus” is unclear as to whether said nucleic acid encoding said fusion peptide is inserted into this loci allowing for some native gene D nucleic acid to be retained or if it replaces the native gene D sequence at this loci. This creates further confusion with dependent claims, such as claims 26-27.
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 1-10, 12-15, 17-31, and 33-36 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claims 2-4 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 2-4 are rejected for claiming the limitation of amino acid or nucleotide sequence/regions without providing an appropriate frame of reference for said sequence/region. Said frame of reference can be provided by referencing a sequence disclosed within the application (i.e. a sequence with a SEQ ID NO: identifier).
For instance, the b region at ¶[0068] is noted as being from base pair 22689 to 26973 in a lambda genome that is 48502 base pairs in length, but a “base” sequence for the genome is not provided, and it is not clear what nucleotides, especially since it can be +/- 5% of this due to the use of the term “about” and the fact that the deletion in this region does not have to be a consecutive sequence deletion, making the metes and bounds of this region unclear. Claim 3 notes genes ea47, ea31, and ea59 are deleted from the b region of the lambda genome, while the specification notes that the b region comprises the genes “ea47, ea31, and eu59”. Claim 4 recites a lysine at position 158 in the E protein, but it is unclear as to the amino acid sequence of said E protein.
As the metes and bounds of these regions and sequences are unclear due to a lack of reference for these sequences/regions, the claims are rejected on the grounds of being indefinite.
Claim 6 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 6 recites that the linker comprises or consists of an amino acid sequence GGGS (SEQ ID NO: 3). However, the specification at ¶[0034-0035] notes that SEQ ID NO: 2 is an amino acid of an exemplary linker, while SEQ ID NO: 3 is the amino acid of a lambda phage E protein. It is therefore unclear whether claim 6 requires the five amino acid GGGGS linker, the E protein of SEQ ID NO:3, or a linker meeting both inconsistent descriptions.
For at least these reasons, claim 6 is rejected on the grounds of being indefinite.
Claim 7 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 7 recites that the “Sam7 gene” is genetically inactivated. The specification describes Sam7 as an S gene mutation that prevents holin synthesis (¶[0198]). The specification does not identify a distinct gene named “Sam7”. It is unclear whether claim 7 requires an S gene comprising the Sam7 mutation, a further inactivation of an already mutated S gene, or the inactivation of some other locus.
For at least these reasons, claim 7 is rejected on the grounds of being indefinite.
Claim 10 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 10 is drawn to “the bacteriophage λ of claim 1, wherein the heterologous antigen is 5 to 1500 amino acids in length of 28 10 200 amino acids in length.” It is unclear what length for the heterologous antigen is being claimed.
For at least these reasons, claim 10 is rejected on the grounds of being indefinite.
Claims 26-27 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 26 is drawn to the bacteriophage λ of claim 1, wherein the head further comprises wild-type D protein. Claim 27 notes said wild-type D protein comprises SEQ ID NO:1. However, it is unclear if this “wild-type D protein” means the D protein in the genome of claim 1 is SEQ ID NO:1, or if there is a mixture of D-fusion protein and D protein without any heterologous protein attached in the head of the phage virion. If there is a mixture of two as in the latter explanation, it is unclear how said non-fusion D protein is presented into the genome or system to result in a phage that has a mixture of D protein.
For at least these reasons, claims 26-27 are rejected on the grounds of being indefinite.
Claims 26, 29, 30, and 36 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 26, 29, 30, and 36 claim a “wild-type D protein” without providing a sequence or frame of reference as to determine what sequence would be considered “wild-type” and what D protein sequences are not “wild-type”. It is unclear if this is meant to be a specific sequence, or if these are only meant to be “naturally occurring D protein sequences”.
As the metes and bounds as to what is “wild-type” is unclear, the claims are rejected on the grounds of being indefinite.
Claim 31 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 31 is drawn to “inactivation of 6amb in the chromosome of the host bacterial cell”. It is unclear what “6amb” is in reference to. It appears as though this should be “lamB", but further clarification is required.
For at least these reasons, claim 31 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Note that “about” is interpreted per the specification as +/- 5% of the value (¶[0065]).
Claim 1 is drawn to a bacteriophage lambda (λ), comprising:
a head,
a tail, and
a lambda genome comprising a nucleic acid sequence encoding a fusion protein comprising a D protein linked to a heterologous antigen, wherein the nucleic acid sequence is inserted into a native gene D locus adjacent to gene E in the bacteriophage lambda genome, and wherein expression of the fusion protein results in the head of the bacteriophage lambda comprising the fusion protein.
Further limitations on the bacteriophage λ of claim 1 are wherein about 1 kilobases (kb) to about 5 kb of the b region of the lambda genome is deleted (claim 2); wherein genes ea47, ea31, and ea59 are deleted from the b region of the lambda genome (claim 3); wherein gene E encodes an E protein comprising a lysine at position 158 (claim 4); wherein the fusion protein comprises the D protein, a linker, and the heterologous antigen, wherein the linker is between the D protein and the heterologous antigen, and wherein the linker is 5 to 15 amino acids in length (claim 5), wherein the linker comprises or consists of amino acid sequence GGGGS (SEQ ID NO: 3)(claim 6); wherein the Sam7 mutation is present in the lambda genome (claim 7); wherein the nucleic acid sequence comprises a nucleic acid sequence encoding the D protein and a nucleic acid sequence encoding the heterologous antigen, wherein the nucleic acid sequence encoding the D protein is 5′ of the nucleic acid sequence encoding the heterologous antigen in the lambda genome (claim 8); wherein the nucleic acid sequence comprises a nucleic acid sequence encoding the D protein and a nucleic acid sequence encoding the heterologous antigen, wherein the nucleic acid sequence encoding the D protein is 3′ of the nucleic acid sequence encoding the heterologous antigen in the lambda genome (claim 9); wherein the heterologous antigen is 5 to 1500 amino acids in length of 28 10 200 amino acids in length (claim 10); wherein the D protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1 (claim 12), wherein the D protein comprises the amino acid sequence of SEQ ID NO: 1 (claim 13); wherein the heterologous antigen is a virus antigen (claim 14), wherein the virus antigen is an antigen from severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), human immunodeficiency virus (HIV), rotavirus, influenza virus, Dengue virus (DENV), Zika virus (ZIKV), Chikungunya virus (CHIKV), Foot and Mouth Disease (FMD) virus, or a porcine virus (claim 15); wherein the SARS-CoV-2 antigen comprises one of SEQ ID NO: 4, SEQ ID NOs: 39-52, and SEQ ID NO: 69 (claim 17); wherein the heterologous antigen is a tumor antigen (claim 18), wherein the tumor antigen is an antigen from melanoma, bladder cancer, breast cancer, colon cancer, carcinoma, sarcoma, renal cancer, thyroid cancer, brain cancer, lung cancer, prostate cancer, pancreatic cancer, a lymphoma, or a leukemia (claim 19), wherein the tumor antigen is a) a chronic lymphocytic leukemia antigen; or b) a glioblastoma antigen (claim 20), wherein
a) the chronic lymphocytic leukemia antigen comprises SEQ ID NO: 6; or
b) the glioblastoma antigen is an epithelial growth factor receptor version III antigen comprising one of SEQ ID Nos: 53-54 (claim 21); wherein the heterologous antigen is a bacterial antigen or a parasitic antigen (claim 22), wherein the parasitic antigen is a Plasmodium antigen or a Leishmania antigen (claim 23), wherein the Plasmodium antigen comprises SEQ ID NO: 5 (claim 24); wherein the lambda genome further encodes a side tail fiber (stf) fusion protein and/or a gpV fusion protein, wherein the side tail fiber fusion protein and/or the gpV fusion protein is expressed on the tail of the bacteriophage lambda (claim 25); wherein the head further comprises wild-type D protein (claim 26), and wherein the wild type D protein comprises the amino acid sequence of SEQ ID NO: 1 (claim 27)
Claim 28 is drawn to a host bacterial cell infected with the bacteriophage λ of claim 1, wherein the lambda genome becomes integrated into a chromosome of the host bacterial cell as a prophage.
Further limitations on the host bacterial cell of claim 28 are wherein the cell is further comprising an additional nucleic acid sequence encoding a separate wild type D protein inserted into the chromosome of the host bacterial cell (claim 29), further comprising an arabinose promoter operably linked to the nucleic acid sequence encoding the wild type D protein (claim 30); and further comprising
genetic inactivation of fhuA in the chromosome of the host bacterial cell; and/or
genetic inactivation of lamB in the chromosome of the host bacterial cell (claim 31).
Claim 33 is drawn to an immunogenic composition comprising an effective amount of the bacteriophage λ of claim 1, and a pharmaceutically acceptable carrier.
Claim 34 is drawn to a method of inducing an immune response to a heterologous antigen in a subject, comprising:
administering to the subject an effective amount of the immunogenic composition of claim 33,
thereby inducing an immune response to the heterologous antigen in the subject.
Claim 35 is drawn to a method of preparing bacteriophage λ, comprising:
propagating the host bacterial cell of claim 28;
inducing the lytic phase of the bacteriophage λ; and
isolating bacteriophage λ phage particles.
Further limitations on the method of claim 35 are wherein the host bacterial cell comprises a plasmid encoding wild-type D protein (claim 36).
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 1-10, 12-15, 18-20, 22-23, 25-31, and 33-36 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 preparation and use of limited bacteriophage lambda D-heterologous protein fusion constructs made in a defined phage and defined host bacterial cell system, does not reasonably provide enablement for the materially broader scope recited in the claims, such as any bacterial cell system with any heterologous protein fused to any D protein at the N- or C-terminus of said protein. 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 bacteriophage lambda particles having a D protein fused to a heterologous antigen at the native D locus adjacent gene E; host bacterial cells carrying such phages, immunogenic compositions comprising said phage, methods of inducing an immune response to said heterologous antigen through delivery of said compositions, and methods of producing said phages.
The specification describes a specific, defined platform based on a modified lambda prophage in an engineered E. coli host. The disclosed strains include, for example, a λc1857 Sam7 prophage having a gene E with an E158K substitution mutation and deletions of ea59, ea47, and ea31, in an MG1655-derived host having modifications including ΔlamB, ΔfhuA, and chromosomal arabinose-regulated D expression (¶[0253-0267]; Examples 1-5). The specification further describes selected D fusion constructs having a CLL CDR3 peptide, pfGARP segments, and SARS-CoV-2 segments (¶[0268-287]; Examples 6-7.) The specification describes the generation of SARS CoV-2 S protein displaying phage and delivers different constructs to BALB-c mice, and not all phage presentation systems resulted in an antigenic response (Examples 8-9, ¶[0288-0293]).
However, the claims are not limited to these disclosed constructs, the host background, or the disclosed antigen sequences. For instance, claims 14-15, 18-20, and 22-23 extend this scope to antigens from numerous viral, tumor, bacterial, and parasitic sources. Claims 12 and 13 further encompass additional stf and/or gpV fusion on the phage tail, including embodiments in which the head and tail display different antigens. Claims 28-31 and 35-36 extend the same breadth to host cell and production systems, while claims 33-34 extend it to immunogenic compositions and immune response methods.
The rejection is not based merely on an unrecited target antigen. Rather the specification treats partial stability, incorporation of the fusion protein into the head, plaque formation, viable virion production, and unpredictable immune responses to the exposed antigens as necessary indicia that a candidate D-fusion construct is operative. Claim 1 itself requires a bacteriophage generated from the genomic constructs claimed which has a head that comprises the D-heterologous antigen fusion protein. The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. Zanghi et. al. (Zanghi CN, et. al. Nucleic Acids Res. 2005 Oct 13;33(18):e160.) explains that some recombinant gpD derivatives are incompatible with assembly of stable λ particles. Zanghi addresses this limitation by co-complementing gpD-deficient λ lysogens with wild-type gpD and recombinant gpD fusions so that mosaic particles could be formed. Zanghi shows that the ability to prepare a gpD-fusion gene did not establish that the resulting fusion would be compatible with stable virion assembly, and required the presence of unfused, non-recombinant gpD in order to stably generate phage virions. Additionally, the different fusion proteins were incorporated at different ratios depending on the fusion partner with gpD.
Similarly, Gonzalez-Mora et. al. (González-Mora A, et. al. Vaccines (Basel). 2020 Sep 4;8(3):504.) explains that phage-displayed antigens may present problems, including protein aggregation and deficient phage assembly. Gonzalez-Mora further explains that these issues can negatively affect vaccine development because the displayed antigen may not be adequately presented or may lack the structural stability needed for the desired immune response. This reference shows that antigen display on a phage particle was not predictably interchangeable across heterologous antigens.
Nicastro et. al. (Nicastro J, et. al. Appl Microbiol Biotechnol. 2013 Sep;97(17):7791-804. Epub 2013 May 3.) teaches that while gpD fusions of various sizes have been successfully fused to both the amino and carboxy termini of the protein suggesting that the display of the fusions does not jeopardize the function of the bacteriophage or prevent fusion proteins from binding the capsid, that the C-terminus is generally more tolerant of fusions since the N-terminus is located closer to the 3-fold axis of the gpD trimer. Nicastro also teaches that a positive charge close to the signal sequence cleavage site or a large protein domain may impede capsid assembly, and that dual systems which incorporate a mix of wild-type gpD and gpD fusions is typically utilized to aid in proper assembly of the head, although this method is unpredictable in how much gpD fusion is ultimately incorporated. Nicastro teaches there are limitations to the foreign protein which can be fused to the gpD, particularly when considering the size and copy number of the displayed peptides as a result of the current display system design. The phage display system practice needs the optimization of fusion coat proteins to wild-type ones since a high ratio of fusion protein may lead to the inefficient assembly of phage particles and, depending on the application, a low ratio may not elicit the desired results. The system developed by Nicastro still showed that it varied with the gpD allele, host suppressor background, induction temperature, and level of gpD-fusion expression. Overall, the reported particle instability, variation in presentation of the foreign antigen, and reduced viability of the mature phage show that the overall result still depended on the particular fusion and production context.
Beghetto et. al. (Beghetto E, et. al. Molecules. 2011 Apr 13;16(4):3089-105.) explains that proper display requires that a capsid fusion not interfere with phage morphogenesis. As the pIII/pIV proteins cannot tolerate positive charges, many cytoplasmic proteins cannot be translocated across bacterial membranes and correctly displayed as fusion proteins on the bacteriophage surface. Beghetto teaches that larger domains likely to interfere with morphogenesis were commonly displayed in two-gene systems containing both wild-type gpD and recombinant gpD. Beghetto describes λKM4 as using an amber-mutated genomic D gene together with an additional inducibly expressed D copy, confirming that fusion compatibility and productive display depended on the particular fusion and genetic context.
Pavoni et. al. (Pavoni E, et. al. BMC Cancer. 2004 Nov 12;4:78.) describes selected gpD/gpV dual-display constructs. Pavoni reports that a construct having both an scFv and GFP fused to gpD was unstable after amplification, and that large C- terminal gpD fusions could disturb phage assembly and reduce productivity. Their selected successful head-and-tail constructs used defined fusion proteins, positions, and expression arrangements; however, the reference does not provide a rule permitting prediction that arbitrary antigen combinations on D, gpV, and/or stf will form stable, immunogenic phage particles.
The prior art therefore provided methods for cloning, recombineering, inducing prophages, measuring phage titer, and testing candidate fusions. But the art also showed that the relevant results were context-dependent. The identity, length, folding, fusion orientation, and expression context of a heterologous protein could determine whether the phage assemble into stable, infectious particles.
Level of skill in the art. One skilled in the art would have been familiar with λ genetics, recombineering, plasmid transformation, prophage induction, Western blotting, plaque assays, and routine sequencing. 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 additional antigens, gpD variants, linker arrangements, bacterial host backgrounds, subjects receiving the compositions as vaccines, or multi-site display combinations would satisfy the claimed limitations, especially with respect to their use as a vaccine in any subject against cancer or pathogens.
Working examples. The working examples are limited to selected constructs. The specification reports a CLL CDR3 D fusion, selected pfGARP D fusions, and selected SARS-CoV-2 fusions (¶[0268-0271]). The SARS-CoV-2 work itself reports that some of the expressed D-fusion proteins were not only unstable, but also not immunogenic (¶[0271]; Fig. 12C; ¶[0289-0293].) The specification further explains that protein fusions at either the N- or C-terminus of D cause defects in active virion formation and plaque-forming ability because D interacts with E to stabilize the capsid (¶[0279]). For certain constructs, additional wild-type D expression was used to stabilize particles and improve phage production (¶[0278-0283]).
The immunogenicity data are narrower still. The disclosed mouse study tested selected SARS-CoV-2 phages, and a demonstrable response was reported for XTL-1380 and XTL-1382 at 10^9 particles per injection; a strong response was not observed at the lower tested doses (¶[0292-0293]). The specification does not provide working immunogenicity examples for the broader viral, tumor, bacterial, or parasitic antigens, or multi-site display scope (e.g. head and tail antigen expression) recited in the claims. No working examples are provided for stf-antigen fusions, gpV-antigen fusions combined with the claimed native D locus fusion, D proteins having the full claimed sequence identity range, or the broad host cell and production combination encompassed by claims 28-31 and 35-36.
Guidance in the specification. The specification provides details for constructing and testing the particular XTL host/phage platform. It describes modifying the phage genome and host chromosome, deleting the b region to provide cloning capacity, deleting lamB to reduce particle loss by adsorption, deleting fhuA, and using wild-type D expression from an arabinose-regulated locus or plasmid in selected circumstances (¶[0255-0257][0278-0284]).
However, the specification does not provide sufficient guidance for determining which additional antigens will remain stable when fused to D, which antigens require N-terminal versus C-terminal fusion, which linker configuration is appropriate, whether wild-type D complementation is necessary, the necessary level and timing of D expression, or whether the fusion remains compatible with E-dependent capsid stabilization. The specification also does not provide guidance for selecting antigens, insertion positions, or host/phage condition for the stf and gpV fusion combinations of claim 25.
The disclosure identifies candidate antigen sources, but it does not identify a common structural feature that separates antigens compatible with the claimed D-fusion platform from antigens that impair particle assembly, are degraded, have poor display, or fail to induce the claimed immune response.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to select additional antigens across the claimed pathogen and tumor classes; determine an appropriate D-fusion orientation, fusion junction, and linker; construct the corresponding prophage; and test whether the resulting particles from stable head, package phage genomes, form plaques, and display the selected antigen. For constructs showing impaired stability or production, the skilled artisan would need to further determine whether wild-type D supplementation is needed, whether the D source should be chromosomal or plasmid-based, the appropriate timing of induction, and the appropriate level of D expression. A separate program of construction and screening would be required for the added stf and/or gpV display embodiments. Claims 33 and 34 would further require testing whether each selected phage, composition, dose, regimen, and antigen produces the recited immune response in the claimed subject.
These tests would not be routine optimization of known, predictable parameters. It would require iterative preparation and screening to determine which combinations of antigen, D protein, fusion orientation, host modifications, genetic background, and expression conditions are operative.
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 selected D-fusion phages produced in a particular engineered λ/E. coli system, with selected peptide antigens and limited immunogenicity data. The claims encompass materially broader antigen classes, D variants, fusion orientations, multi-site head and tail display configurations of antigens, host-cell systems, production methods, compositions, and immune response methods. 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/or use the full scope of the invention recited in the claims without undue experimentation.
Claims 1-10, 12-15, 18-20, 22-31, and 33-36 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.
Claim 1 recites a bacteriophage λ having a nucleic acid sequence encoding a D protein linked to a heterologous antigen at the native D locus adjacent to gene E, wherein expression results in a phage head comprising the D antigen fusion protein. Further dependent claims limit the phage by particular genome modification, fusion orientation, linker length, D protein sequence identity, antigen classes, tail display fusion proteins, and wild-type D protein. Claims 28-31 recite host bacterial cells carrying the phage as a prophage. Claims 33 and 34 recite an immunogenic composition and a method of inducing an immune response using the broadly claimed phage. Claims 35 and 36 recite production of the broadly claimed phage.
The specification describes a limited set of D-fusion phages constructed in a particular λ prophage and host cell system. The disclosed host was derived from strain XTL981 and further engineered as strain XTL1026. The disclosed system included a λc1857 Sam7 prophage, deletion of lamB, deletion of fhuA, deletion of the att80 site, removal of 4285 bp from the phage b region including ea47, ea59, and ea31, and an E158K modification in gene E (¶[0253-0257]). The disclosure explains that the b region deletion provided room for cloning and encapsidation of DNA segments fused to D, and that deletion of lamB prevented released λ particles from being lost through adsorption to LamB receptors in the lysate (¶[0255]).
However, the scope of the claims is not limited to the embodiments described in the specification. The actual D fusion examples are limited. They include a CLL CDR3 peptide fusion, selected pfGARP fusion constructs, and selected SARS-CoV-2 peptide constructs (¶[0268-0271]). The tested SARS-CoV-2 constructs included peptide segments of approximately 23, 31, 33, 84, and 133 amino acids (¶[0289-0291]). The specification odes not describe representative D fusion phages across the full scope of the claimed genus, which includes heterologous antigens of unlimited identity, source, sequence size/length/overall charge, folding characteristics, and immunological target.
The claims are defined, at least in part, by the recited function of the expressed D-antigen fusion protein being incorporated into the phage head. However, the specification does not establish a correlation between the disclosed structural features of a heterologous antigen, the fusion junction, the D-protein sequence, the phage genome modifications, and the host cell genotype that would allow one skilled in the art to identify additional D-antigen fusion proteins that will fall within the scope of the claim to properly form a phage head.
The specification describes that the identity and length of the antigen fused to D can cause instability of the phage head and reduced phage yield (¶[0283]). The specification further explains that D fusions at either the N-terminus or C-terminus can impair virion formation and plaque-forming ability because D interacts with E to stabilize the capsid (¶[0279]). The disclosure reports that some D-fusion proteins were unstable, and that some constructs required ectopic expression of wild-type D to increase particle stability or phage yield (¶[0271][0278-0283]).
For example, the disclosed pfGARP D-fusion generated relatively poor phage yield from the native D locus, and ectopic expression of wild-type D from an arabinose-regulated chromosomal locus increased yield by approximately 4300-fold (¶[0281-0283]). Likewise, the disclosed CLL CDR3 D-fusion was improved by wild-type D expression from the genome of the bacterial host (¶[0283]). These disclosures show that whether a particular antigen can be fused to D while producing a stable, functional phage particle depends on antigen-specific and system-specific variables. The specification does not identify structural features common to the full genus that distinguish operative D-antigen fusion from fusions that destabilize the head, impair interaction with E protein, or require additional genetic compensation (e.g. additional expression of wild-type D).
Claim 12 additionally encompasses D proteins having at least 95% sequence identity to SEQ ID NO: 1. The specification identifies SEQ ID NO: 1 and generally refers to conservative substitutions, provided that the D protein is stably incorporated into the phage head (¶[0152-0153]. However, the specification does not identify which positions may be altered with which types of mutations while retaining the recited function of the D-antigen fusion into a functional phage head, or describe representative D variants across the claimed scope of the sequence identity range. Accordingly, the disclosure does not demonstrate possession of the broader claimed group of D-protein variants recited in instant claim 12.
Claim 25 further recites a phage having the D-antigen fusion of claim 1 and a side tail fiber fusion protein and/or gpV fusion protein expressed on the phage tail. The specification discusses gpV and stf as possible additional display sites (¶[0285]). However, the specification does not describe a representative number of phages having the claimed D fusion together with a gpV fusion, an stf fusion, or both tail fusions. Nor does the specification identify structural features, insertion positions, payload characteristics, or phage-genome features that would allow one skilled din the art to recognize operative multi-site D/gpV/stf display phages. The disclosure of a desired multi-site display result does not demonstrate possession of the full scope of claim 25.
Claims 28-31 and 35-36 recite host cells and production methods that incorporate the broad phage of claim 1. The specification describes a particular MG1655-derived host system having multiple defined chromosomal alterations and a particular λ prophage background (Example 1; ¶[0253-0257]). The claims, however, broadly encompass host bacterial cells and production methods outside the disclosed system, including cells lacking the disclosed deletions, cells lacking arabinose-regulated wild-type D complementation, and cells carrying phage genomes having different antigen payloads and genome-loading requirements. The specification does not describe representative host-cell and phage combinations across this scope, or identify characteristics that would distinguish combinations capable of producing the claimed D-antigen phage from combinations that do not.
Claims 33 and 34 retain the full breadth of claim 1 and further require an effective amount of the phage or administration sufficient to induce an immune response in any subject. The specification describes an in vivo immunogenicity study using selected SARS-CoV-2 peptide-displaying phages in BALB/c mice (¶[0292-0293]). However, the claims broadly encompass delivery of any of the phage of claim 1 to any host, wherein said phage comprises any antigen fused to D, and that said phage elicits an immune response to said antigen. The specification does not describe representative embodiments across that scope, such as immunogenic compositions, immune response methods across the claimed breadth of viral, tumor, bacterial, parasitic, or other heterologous antigens or otherwise demonstrate possession of the broader claimed method. The specification fails to provide identifying characteristics that would permit one of skill in the art to recognize, without further experimentation, which of the broadly claimed D-antigen fusion will produce the recited immune response in said subject.
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 1-10, 12-15, 18-20, 22-31, and 33-36 at the time the application was filed.
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.
Bush M, et. al. bioRxiv [Preprint]. 2026 Jan 21:2026.01.19.700330. Applicant-related post-filing art relevant to the instant invention.
Davenport BJ, et. al. bioRxiv 2021.11.08.467648. Teaches attachment of foreign antigen to gpD but does not teach insertion of D-antigen fusion protein into genome.
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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