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 .
Election/Restrictions
Applicant’s election of invention I and the required species in the reply filed on 7/15/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 12-13, 21 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/15/26.
Claim 8 is withdrawn since it is drawn to a non-elected species.
Claims 1-7, 9, 10 and 14-19 are examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/19/24 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 2-7, 9, 10 and 14 are objected to because of the following informalities: these claims recites “A method of claim…”, however to place these claims in better form it is suggested that the claims be amended to recite, “The method of claim…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-7, 9-11 and 14 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant broadly claims a host cell or expression vector or nucleic acid containing the nucleic acids of claims 1-7, 9-11 and 14. The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or expression vector.
With respect to the unisolated host cells and transgenes as “nucleic acids” or “expression vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 183-191). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo a person having ordinary skill in the art could make a host organism with functional transgene that encodes the instantly recited SEQ ID NO: 1, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by expressing proteins, such as therapeutic antibodies. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nature Reviews Drug Discovery, Vol. 9, Pg. 325-337, 2010) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the therapeutic antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody binds a mammalian protein and so may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, previously raised and new, transgenes are not enabled.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation, "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use transgenic animals possessing the claimed host cells, nucleic acid, or expression vector, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed host cell, nucleic acid, or expression vector, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
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 1-7, 9-11 and 14-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites, “A nucleic acid vector composition comprising:
One or more enzymes and/or one or more fragments thereof;
A nucleic acid
One or more particles comprising hydrolysable silicon; and
One or more lipids.
However, it is unclear if the nucleic acid vector encodes an enzyme or fragment thereof and the nucleic acid or if the enzyme or fragment thereof are a separate component of the nucleic acid vector composition. Claims 2-7, 9-11 and 14-19 are also rejected because they depend from claim 1.
Claim 4 recites, “A nucleic acid vector composition according to claim 1, wherein the ratio of enzyme and/or fragment thereof to nucleic acid by weight is in the range of 1:1x10¹² to 1:1.” However, it is unclear if the ratio is relative to the nucleic acid of the claimed composition or nucleic acid sequences in general.
Claim 5 recites, “the one or more enzymes comprise one or more enzymes having an activity, on a nucleic acid substrate, of at least 1 µmol min⁻¹ at a pH of 7.4 and a temperature of 25 °C”, however, it is unclear if the one enzymes have activity on the nucleic acid of the composition or a different nucleic acid.
Claim 6 recites, A nucleic acid vector composition according to claim 1, which is in the form of a lipid nanoparticle. However, it is unclear if the entire vector composition (i.e., nucleic acid, silicon particle, lipid and enzyme or fragment thereof) is in the form of a lipid nanoparticle or if these components are separate.
Regarding claim 7, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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.
Claim 12 is rejected under 35 U.S.C. 102a1 as being anticipated by Shen et al (US PGPub 2016/0369269).
The claimed invention is drawn to a nucleic acid vector composition produced by the method of claim 12.
MPEP § 2113 recites, “Even though product-by-process claims are lim-ited by and defined by the process, determination of patentability is based on the product itself. The patent-ability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.”
In view of MPEP 2113, if the prior art teaches a nucleic acid vector composition comprising silicon particles and lipids, the claimed invention will be anticipated.
Shen et al. teach at claims 1 and 12-17, a composition for the sustained-release delivery of an active agent to a target cell of a subject in need thereof, comprising: (a) a population of polycation-functionalized nanoporous silicon first-stage particles, and (b) a population of second-stage particles contained substantially within the interior of the population of the first-stage particles, and wherein the second-stage particles comprise at least a first active agent.
A targeting moiety is a lipid and the second-stage particles comprise at least one active agent that is a biologically-active compound selected from the group consisting of peptides, proteins, therapeutic agents, diagnostic agents, non-biological materials, and combinations thereof. The at least one active agent that is a therapeutic agent, which is selected from the group consisting of a gene, a nucleic acid, an shRNA, an siRNA, a microRNA, a DNA fragment, an RNA fragment.
Therefore, Shen et al. anticipate the instant invention.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 1-3, 7, 9-11 and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Saffie-Siebert et al. (WO/20/193999), Shen et al (US PGPub 2016/0369269), JUNG YUNA ET AL. (MICROPOROUS AND MESOPOROUS MATERIALS, Vol. 310, 1 October 2020), and in view of Yu et al. (WO 2016/164987) and Ciaramella et al. (US PGPub 2016/0317647).
Saffie-Siebert et al. concerns the use of silicon nanoparticles for the delivery of short interfering RNA, messenger RNA or another nucleic acid (page 1, lines 5 - 8). Said silicon
particles are preferably hydrolysable (page 8, line 6 - page 9, line 12). Saffie-Siebert et al. further discloses that the treatment of lipid treated nanoparticles (such as nanoparticles treated
with DOPE) with an amino acid, i.e. with glycine, histidine, or arginine has a stabilizing effect on the RNA (e.g. mRNA or siRNA) (see page 13, line 26 - page 14, line 7; page
15, lines 17 - 24). Several formulations comprising hydrolysable silicon particles, lipids,
amino acids and siRNA as active ingredient were generated (see Examples, pages 26 -
30). These formulations were further combined with lipofectamine (see page 35, line 20
- page 36, line 9) and the entrapment of mRNA by silicon nanoparticle formulations was
evaluated (see page 38; Figures 6 and 7). Saffie-Siebert et al. merely refers to mRNA, but does not disclose its way of production. Thus, the vector composition of Saffie-Siebert et al. comprise at least a nucleic acid, hydrolysable silicon and lipids, but do not necessarily comprise enzymes
(which, due to the production of the mRNA might be present in trace amounts).
Shen et al. teach at claims 1 and 12-17, a composition for the sustained-release delivery of an active agent to a target cell of a subject in need thereof, comprising: (a) a population of polycation-functionalized nanoporous silicon first-stage particles, and (b) a population of second-stage particles contained substantially within the interior of the population of the first-stage particles, and wherein the second-stage particles comprise at least a first active agent.
Shen et al. also teach a targeting moiety is a lipid and the second-stage particles comprise at least one active agent that is a biologically-active compound selected from the group consisting of peptides, proteins, therapeutic agents, diagnostic agents, non-biological materials, and combinations thereof. The at least one active agent that is a therapeutic agent, which is selected from the group consisting of a gene, a nucleic acid, an shRNA, an siRNA, a microRNA, a DNA fragment, an RNA fragment. These sequences appear to be the same structurally as presently claimed and would therefore possess a half-life in the pharmaceutical composition at 4-Celsius of at least 3 months or 6 months.
JUNG YUNA ET AL. is a review article on surface engineering of porous silicon nanomaterials for biomedical application (see Abstract). JUNG YUNA ET AL. states that porous silicon nanoparticles (pSiNPs) are a promising drug-delivery system (DDS) platform due to their remarkable features; (i) a high loading yield of the substrate (drugs, peptides, DNA/RNA, proteins, antibodies) and maintain the bioactivity of the encapsulated substrate, (ii) targeted
delivery (cells, organs, disease sites) with the incorporation of targeting moiety
(peptides, sugars, proteins, nucleic acids, etc.), (iii) in vivo biodegradation and fast
clearance of non-toxic side-product (silicic acid, Si(OH) 4), (iv) high biocompatibility, and
(v) multi-functional platforms (bio-imaging, theragnostic) (see page 1, column 1, para 1 ).
JUNG YUNA ET AL. further reads that pSiNPs have been incorporated into liposomes (see Figure Sa). JUNG YUNA ET AL. discloses that such liposome formulations are loaded with drugs or siRNA (see Figure Sa in combination with Figure 2 and Table 1 ).
Yu et al. discloses the use of mesoporous hollow nanoparticles as delivery system for pDNA and mRNA and their use in the field of vaccines (see Abstract; [0038]). Yu et al. further refers to enzyme formulation comprising such nanoparticles ([0032]. Example 10 discloses the
coating of silica particles with PEI in order to enhance the electrostatic attraction between pDNA and the particles (see [00174]).
Ciaramella et al. teach: [0092] The data described herein demonstrate that the formulations of the invention produced significant unexpected improvements over both existing protein antigen vaccines and mRNA vaccine formulations, including: 100% rescue from lethal influenza challenge with rapid onset of protective antibody titers after 1 week and high antibody titers, i.e., 50 fold over unmodified mRNA and 20 fold over the protein vaccine.
[0093] Additionally, the mRNA-LNP formulations of the invention were superior to other lipid formulations even when the dose of mRNA was significantly lower than in the other lipid formulations. For instance, the data described above was generated using 10 μg of mRNA in the mRNA-LNP formulations in contrast to 80 μg of mRNA in the mRNA-lipoplex formulation.
[0094] The formulations of the invention also showed strong efficacy in several non-rodent animal models, including non-human primates. Highly effective vaccination was observed in cynomoglus monkeys and ferrets. Cynomoglus monkeys were vaccinated with various doses of mRNA-LNP formulations (50 μg/dose, 200 pg/dose, 400 μg/dose). Quite surprisingly, the vaccine formulations of the invention at all doses measured significantly reduced viral titers in the lungs of ferrets when exposed to virus just 7 days following single vaccination. Statistically significant increases in antibody titer as measured by HAI and microneutralization were detected as early as 7 days following vaccination and through the entire length of the study (84 days). A single vaccination was able to eliminate all virus in most animals. Ciaramella et al. also teach [0095] The LNP used in the studies described herein has been used previously to deliver siRNA various in animal models as well as in humans. In view of the observations made in association with the siRNA delivery of LNP formulations, the fact that LNP is useful in vaccines is quite surprising. It has been observed that therapeutic delivery of siRNA formulated in LNP causes an undesirable inflammatory response associated with a transient IgM response, typically leading to a reduction in antigen production and a compromised immune response. In contrast to the findings observed with siRNA, the LNP-mRNA formulations of the invention are demonstrated herein to generate enhanced IgG levels, sufficient for prophylactic and therapeutic methods rather than transient IgM responses. With regard to nucleic acid vaccines, Ciaramella et al teach I. NUCLEIC ACID VACCINES (NAVS) [0096] Nucleic Acid Vaccines (NAVs) of the present invention comprise one or more polynucleotides, e.g., polynucleotide constructs, which encode one or more wild type or engineered antigens. Exemplary polynucleotides, e.g., polynucleotide constructs, include antigen-encoding RNA polynucleotides, e.g., mRNAs. In exemplary aspect, polynucleotides of the invention, e.g., antigen-encoding RNA polynucleotides, may include at least one chemical modification. [0097] NAV compositions of the invention may comprise other components including, but not limited to, tolerizing agents or adjuvants. [0100] Adjuvants
[0101] Adjuvants or immune potentiators, may also be administered with or in combination with one or more NAVs.
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Saffie-Siebert et al., Shen et al. and Jung Yuna et al. in order to formulate a nucleic acid vector composition comprising - one or more enzymes and/or one or more fragments thereof; - a nucleic acid; - one or more particles comprising hydrolysable silicon; and - one or more lipids. One would have been motivated to do so, given the suggestion by Saffie-Siebert et al., Shen et al. and Jung Yuna et al. that silicon particles that can include lipids and mRNA or siRNA. There would have been a reasonable expectation of success, given the knowledge that enzymes can be formulated with nanoparticles, which would include fragments of nucleases or polymerases, Yu et al., and also given the knowledge that nucleic acid vaccines can be combined with adjuvants, as taught by Ciaramella et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
