DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status and Election
Claims 1-20 are pending. Applicant’s election without traverse of Group 1 directed to modified bacteriophages, encompassing claims 1- 12, in the response filed January 16, 2026 is acknowledged. Claims 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected groups, there being no allowable generic or linking claim. Applicant’s election of bacteriophages as the transducing particle is also acknowledged. During the course of examination, references teaching adenoviral vectors with modified host recognition elements compatible to a target cell of interest were found. The species examined now include both bacteriophages and adenoviruses since there isn’t a search burden to examine both species.
It is noted that the present Application is a DIV of parent Application 16/312,538, now US Patent 11,419,908. During prosecution of the ‘538 Application, groups substantially similar to groups 1 and 3 in the restriction requirement for the present application were subject to a restriction requirement. In the ‘538 application the claims directed to methods for preparing, identifying and/or isolating modified host recognition elements of a bacteriophage were elected and eventually patented, while the claims directed to bacteriophages comprising the modified host recognition elements were cancelled. As such, the claims in the ‘908 patent are barred from being used as a reference in a nonstatutory double patenting rejections under 35 USC 121.
Claims 1-12 and with the species of bacteriophages and adenoviruses are under examination.
Claim Objections
Claims 4, 9 and 12 are objected to because of the following informalities:
In claim 4, there needs to be a space or a dash between “T7” and “like” in line 2.
In claims 9 and 12, “comprise” in line 2 should be “comprises” to be grammatically correct.
Appropriate correction is required.
Claim Interpretation
The claims are directed to bacteriophages and/or transducing particles comprising a modified host recognition element. Claims 7, 8 and 11 recite “wherein said at least one host recognition element is prepared by a method comprising the steps of:” and “wherein said bacteriophage has an extended or modified host range and is prepared by a method comprising the steps of:”. Each of “prepared by a method comprising the steps of” is interpreted as a product-by-process limitation. As such, the claims do not actually require the steps recited in each of the claims. Rather the product-by-processes will be examined according to the structure of the host recognition elements and bacteriophages that are produced by the recited process steps. See. MPEP 2113.
Regarding claims 7 and 11, the recited steps (a)-(e) require introducing into a host cell nucleic acids that encode a host-recognition element and then transducing the host cell with a delivery vehicle that is deficient in that host-recognition element and recovering the delivery vehicles with the host-recognition element, introducing the recovered delivery vehicles into a second host, and isolating or characterizing the host recognition elements that comprise a “mutated host-recognition elements”. None of the steps distinguish the host recognition element from the element recited in claim 1, which already requires the function of “compatible to a target cell of interest”, which is interpreted being capable of being transduced into a target cell. Additionally, because the steps recite “isolating” the host recognition element, the remaining genetic elements recited in the process steps are not required elements in the bacteriophage or transducing particles.
Regarding claim 8, the recited steps (a)-(f) require introducing into a host cell nucleic acids that encodes a host-recognition element and then transducing the host cell with a delivery vehicle that is deficient in that host-recognition element and recovering the delivery vehicles with the host-recognition element, introducing the recovered delivery vehicles into a second host, and introducing into third host cells the delivery vehicles with the host-recognition element that is mutagenized. None of the steps distinguish the host recognition element from the element recited in claim 1, which already requires the function of “compatible to a target cell of interest”, which is interpreted being capable of being transduced into a target cell. Claim 8 merely requires the modified bacteriophage to have an extended or modified host range. Additionally, because the steps recite “isolating” the host recognition element, the remaining genetic elements recited in the process steps are not required elements in the bacteriophage. Finally, claim 8 is limited to transducing particles that are bacteriophages based on the “wherein” clause in lines 2-3.
Claim Rejections - 35 USC § 112(b)
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 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “at least one modified host recognition element or any variant, mutant, protein or fragment thereof, wherein said modified host recognition element is compatible to a target cell of interest”. It is not clear if the modified host recognition element need only be compatible with a target cell of interest or if the variant, mutant protein or fragment thereof must also have the recited function of being compatible with a target cell. If the variant, mutant, protein or fragment thereof does not need to be compatible, then it is not clear what the function of the variant, mutant, protein or fragment thereof would be. However, the wherein clause specifically only refers to the “modified host recognition element” as having the claimed function. Thus, it is confusing as to what requires the claimed function.
Claims 2-12 are rejected for depending from claim 1 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(a)
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 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-12 are indefinite for the reasons described above in paragraph 14. This rejection is directed to the interpretation that the at least one modified host recognition element and any variant, mutant, protein or fragment thereof all must have the function of “is compatible to a target cell of interest”.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims recite “at least one modified host recognition element or any variant, mutant, protein or fragment thereof, wherein said modified host recognition element is compatible to a target cell of interest”. Thus, the modified host recognition element or any variant, mutant, protein or fragment thereof must be capable of being “compatible” with a target cell of interest, which is interpreted as being able to bind to the outer layer of the cell to facilitate transduction of the bacteriophage or transducing particle into the cell. The genus of “modified host recognition elements” is large and diverse, encompassing spike/fiber proteins on virtually every virus and phage. Nobrega reviews the state of the art of bacteriophage targeting mechanisms as of 2018 (Nobrega et al, Nature Reviews Microbiology (2018), 16: 760-773). The tail structures are key determinants of the host specificity and infection process of tailed phages, which comprise receptor-binding proteins (RBPs) at the distal ends to interact with receptors on the bacterial cell surface (page 760, ¶2). Nobrega teaches that there is a “remarkable genetic diversity of both phage RBPs and bacterial receptors” which has made it difficult to study the mechanisms underlying their interactions (page 760, ¶2). Thus, there is a large diversity in the genus of “host recognition elements”, which does not even account for the myriad of spike proteins in animal viruses. Additionally, the claims recite “a variant, mutant, protein or fragment” of a host recognition element, which encompasses nearly limitless amino acid substitutions, deletions and addition in each of the already diverse set of phage RPBs and animal virus spike proteins. For the reasons recited below, Applicants have not sufficiently described the genus of modified host cell recognition elements, and fragments, variants and mutants of host recognition elements that have the function of being compatible to a target cell. The analysis below focuses on the lack of sufficient written description of modified bacteriophage host cell element because, based on the Specification and species election, it is Applicant’s preferred embodiment. However, the analysis also applies to the lack of written description of animal spike protein given the vast diversity of the genus and specificity between spike-receptor recognition.
The Specification lists 37 tail proteins from ~ 14 different phages that could be used in the invention (Table 2), and describes attempts to mutate the T7 gp11, gp12 and gp17 to screen for gp11, gp12 and gp17 variants that permit bacteriophage propagation (page 126). FIGs 4-5 shows 2 variants of gp17 and one variant of gp17 that permit phage propagation in bacterial cells. Thus, Applicants have described three single amino acid substitutions of two host recognition elements that are compatible with a target cell of interest, which are not representative of the breadth and diversity of the claimed genus. Additionally, Applicant does not provide a structure-function relationship between the amino acid substitutions and the overall mechanism of receptor binding and does not provide guidance on how the skilled artisan could use the two gp17 variants and the single gp12 variant from T7 phages to engineer other spike/tail proteins to recognize receptors on cell surfaces. Thus, based on the Applicant’s disclosure in the Specification it was not predictable how to engineer/modify additional phage and other viral spike/tail proteins in the claimed genus that retain or gain the capability of facilitating transduction.
Pires reviews efforts to engineer phages as of September 2016, three months after the effective filing date of the claimed invention (Pires et al., Microbiology and Molecular Biology Reviews (2016), 30: 523-543). Pires states that an individual phage typically infects a limited range of bacterial strains within a given species, and as a result, there have been efforts to expand the host range of bacteriophages (page 530, ¶5 through page 531, ¶4). Pires teaches that that swapping tail fiber proteins between phages T2 and PP01 allowed propagation of the phages in the opposite host (page 530, ¶6). Pires teaches hybrids made between tail fibers of T3 and T7 phages, between putative tail ORFs of JG004 and PaP1, and RBDs from IKe and fd phages modified host ranges of the respective phages (page 531, ¶1-3). However, Pires stresses that systematic, efficient and high-throughput construction of phages with desired host ranges has yet to be achieved (page 531, ¶4), underscoring the unpredictability of engineering tail/spike proteins that either retain or gain the function of being compatible to a cell of interest. Thus, the art recognizes that there is not sufficient structure-function relationship in the genus of viral/phage spike/tail proteins such that the skilled artisan could predict how to engineer the vast diversity of receptor-binding domains on the spike/tail proteins to be compatible with a cell of interest.
In summary, given 1) the vast and highly diverse genus of viral/phage host recognition elements including variant, mutants, proteins and fragments thereof, 2) the reduction to practice in the Specification of one only three “variants thereof” of host recognition elements that facilitate phage transduction, and 3) the lack of understanding in the art regarding engineering receptor binding domains such that they are compatible to facilitate transduction in a particular cell type, species or strain, the skilled artisan would reasonably conclude that Applicant did not possess bacteriophages or transducing particles across the entire genus of host recognition elements including variant, mutants, proteins and fragments thereof, to facilitate transduction as claimed.
Claims 2-12 do not limit the genus of host recognition elements including variant, mutants, proteins and fragments thereof, and therefore the claims are not sufficiently described for the reasons described above for claim 1.
Claim Rejections - 35 USC § 102 - Krasnykh
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 1-2, 5-7 and 10-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krasnykh (Krasnykh et al., Journal of Virology (2001), 75: 4176-4183).
Regarding claims 1-2, Krasnykh teaches engineering adenovirus (Ad) vectors (i.e., transducing particles) to have altered tropisms (i.e., host ranges) (Abstract). Krasnykh teaches an Ad5 fiber – T4 phage fibritin chimera (i.e., a modified host recognition element) (FIG. 1). Krasnykh teaches Ad vectors comprising the Ad5 fiber – T4 fibritin chimera (page 4177, ¶6). Krasnykh teaches the Ad vectors with the chimeric tail/spike protein were capable of binding to a receptor of 293 cells (i.e., eukaryotic cells) for gene transfer (i.e., compatible to a target cell of interest) (FIG. 6). Krasnykh also teaches the Ad vectors comprise the luciferase gene (i.e., a nucleic acid molecule of interest) (page 4177, ¶6).
Regarding claims 5-6, Krasnykh teaches the chimera comprises the alpha-helical and foldon domain of the T4 bacteriophage fibritin tail protein (FIG 1).
Regarding claim 7, as indicated above in paragraph 10, the process steps (a)-(e) are product-by-process steps. There are no process steps that appear to limit the structure of the host recognition element since no steps limit the type of cloning and/or mutagenesis used to generate the nucleic acid molecules encoding the host recognition elements including variant, mutants, proteins and fragments thereof. Krasnykh teaches the Ad5 fiber – T4 fibritin chimera can be produced/propagated in 293 cells (page 4177, ¶6) and therefore the Ad vector comprising the Ad5 fiber – T4 fibritin chimera could be produced by the claimed process steps.
Regarding claim 10, Krasnykh teaches the Ad vector comprising the Ad5 fiber – T4 fibritin chimera in a composition with 293 cells (page 4177, ¶8; FIG 6).
Regarding claim 11, as indicated above in paragraph 10, the process steps (a)-(e) are product-by-process steps. There are no process steps that appear to limit the structure of the host recognition element since no steps limit the type of cloning and/or mutagenesis used to generate the nucleic acid molecules encoding the host recognition elements including variant, mutants, proteins and fragments thereof. Krasnykh teaches the Ad5 fiber – T4 fibritin chimera can be produced/propagated in 293 cells (page 4177, ¶6) and therefore the Ad vector comprising the Ad5 fiber – T4 fibritin chimera in the composition with the 293 cells could be produced by the claimed process steps.
Claim Rejections - 35 USC § 102 - Lin
Claims 1-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lin (Lin et al., PLoS One (2012), 7(2): e30954). Claims 9 and 12 are evidenced by Makarova (Makarova et al., Nat Rev Microbiol. (2011) 9(6): 467–477).
Regarding claims 1-3, Lin teaches a recombinant tail-fiber protein that is a chimera between the gp17 proteins of T3 and T7 phages (i.e., a modified host recognition element) (Fig 2; page 4, ¶3). Lin teaches absorption of phage with the T3/T7 chimeric gp17 protein onto different E. coli strains (i.e., a bacteriophage comprising the modified host recognition element that is compatible to a prokaryotic cell of interest) (page 4, ¶4; Table 2).
Regarding claim 4, the Specification does not define a “T7-like virus”, which is interpreted as being derived from or having components of T7 phages. Lin teaches the phage with the chimeric T3/T7 tail protein is a hybrid T3/T7 phage (i.e., T7 like-virus) (page 2, ¶1).
Regarding claims 5-6, Lin teaches the chimera comprises portions of the T3 and T7 tail protein (FIG 1).
Regarding claim 7, as indicated above in paragraph 10, the process steps (a)-(e) are product-by-process steps. There are no process steps that appear to limit the structure of the host recognition element since no steps limit the type of cloning and/or mutagenesis used to generate the nucleic acid molecules encoding the host recognition elements including variant, mutants, proteins and fragments thereof. Lin teaches T3/T7 hybrid phage comprising the T3/T7 chimeric gp17 protein can be propagated in E. coli cells (page 4, ¶4; Table 2) and therefore the T3/T7 hybrid phage could be produced by the claimed process steps.
Regarding claim 8, as indicated above in paragraph 11, the process steps (a)-(f) are product-by-process steps. There are no process steps that appear to limit the structure of the host recognition element since no steps limit the type of cloning and/or mutagenesis used to generate the nucleic acid molecules encoding the host recognition elements including variant, mutants, proteins and fragments thereof. Lin teaches T3/T7 hybrid phage comprising the T3/T7 chimeric gp17 protein can be propagated in some E. coli strains to a greater extent than either the T3 or T7 phage (page 4, ¶4; Table 2). Thus, the T3/T7 hybrid phage has an extended host range and could be produced by the claimed process steps.
Regarding claim 9, the nucleic acid sequence of interest can either be (a) a cas gene and a spacer that targets a protospacer or (b) a protospacer. The Specification teaches that a protospacer can be comprised withing a gene encoding a toxin or essential genes of a lytic bacteriophage (pages 72-73), however this is not a limiting definition. Protospacers are known in the art as nucleic acid sequences, typically DNA of plasmids or phage genomes, that are targeted by a CRISPR-interference system and are adjacent to a short protospacer adjacent motif (PAM), which are very short sequences of 3-6 nucleotides (See Makarova et al., Nat Rev Microbiol. (2011) 9(6): 467–477; Figure 1). Thus, virtually any part of a phage genome can be a protospacer. Lin teaches the T3/T7 hybrid phage comprises a genome of over 30,000 base pairs of sequence, of which, any 20-60 nucleotide stretch is a potential protospacer sequence.
Regarding claim 10, Lin teaches T3/T7 hybrid phage comprising the T3/T7 chimeric gp17 protein in a composition with bacterial cells (page 4, ¶4; Table 2).
Regarding claim 11, as indicated above in paragraph 10, the process steps (a)-(e) are product-by-process steps. There are no process steps that appear to limit the structure of the host recognition element since no steps limit the type of cloning and/or mutagenesis used to generate the nucleic acid molecules encoding the host recognition elements including variant, mutants, proteins and fragments thereof. Lin teaches T3/T7 hybrid phage comprising the T3/T7 chimeric gp17 protein can be produced/propagated in E. coli cells (page 4, ¶4; Table 2) and therefore the T3/T7 hybrid phage in the composition with the E. coli cells could be produced by the claimed process steps.
Regarding claim 12, the nucleic acid sequence of interest can either be (a) a cas gene and a spacer that targets a protospacer or (b) a protospacer. As indicated above for claim 9, virtually any part of a phage genome can be a protospacer. Lin teaches the T3/T7 hybrid phage that is in a composition with E. coli cells comprises a genome of over 30,000 base pairs of sequence, of which, any 20-60 nucleotide stretch is a potential protospacer sequence.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635