Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1, 3, 6-10, 22-24, 26, 27 and 31-33 are pending in the Claim Set filed 12/12/2025.
Claims 1, 3, 6 and 31 have been amended.
Claims 2, 4, 5, 11-21, 25 and 28-30 are canceled.
Claims 7-10, 24, 26 and 27 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Herein, claims 1, 3, 6, 22, 23 and 31-33 are for examination.
Maintained Rejections
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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating
obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of claims 1, 3, 6, 22, 23 and 31-33 under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO2020051507, cited in IDS, FOR cite No. 8) [Zhang] in view of Kick et al (Efficient Production of Single-Stranded Phage DNA as Scaffolds for DNA Origami, acs.nanolett, nano lett, p.4672, 2025) [Kick], Wang et al (US 20220227778) [Wang] and Cristillo et al (HIV-1 Env vaccine comprised of electroporated DNA and protein co-administered with Talabostat; Biochemical and Biophysical Research Communications, p.22, 2008) [Cristillo] is maintained.
Regarding claims 1, 3, 6, 13 and 31-33,
Zhang teaches nucleic acid assemblies are suitable as a delivery vehicle for therapeutic, prophylactic and/or diagnostic agents. Since they are nucleic acid based, DNA nucleic acid assemblies are entirely biocompatible and elicit minimal immune response in the host. The automated design of any desired geometry of DNA nucleic acid assembly further allows manipulation of DNA structure tailored for individual drugs, dose, site of target and desired rate of degradation etc. Zhang teaches therapeutic agents can be incorporated into DNA origami nuclei acid assemblies via variety of interactions, non-covalent or covalent. In some forms, the agents to be delivered are simply captures inside the DNA origami nucleic acid assemblies (p. 65, lines 18-33). Further, Zhang teaches prior work has shown that DNA origami as a carrier for anti-cancer drugs such as doxorubicin had increased cellular internalization and increased target cell killing as well as circumvented drug resistance. Small molecules, such the anti-cancer drug doxorubicin, can attach to the DNA origami structures through intercalation (p.66, lns.1-5). Exemplary agents to be delivered include proteins, peptides, carbohydrates, nucleic acid molecules, polymers, small molecules, and combinations thereof. In some forms, the nucleic acid assemblies are used for the delivery of a peptide drug, a dye, an antibody, or antigen-binding fragment of an antibody. Therapeutic agents can include anti-cancer, anti-inflammatories, or more specific drugs for inhibition of the disease or disorder to be treated. These may be administered in combination, for example, a general anti-inflammatory with a specific biological targeted to a particular receptor. For example, one can administer an agent in treatment for ischemia that restores blood flow, such as an anticoagulant, anti-thrombotic or clot dissolving agent such as tissue plasminogen activator, as well as an anti-inflammatory. A chemotherapeutic which selectively kills cancer cells may be administered in combination with an anti-inflammatory that reduces swelling and pain or clotting at the site of the dead and dying tumor cells (p.65, lns.18-33 to p.66, lns.1-18; p.72, lns.29-30). Zhang teaches the terms "scaffolded origami," "origami," or "nucleic acid assembly" are used interchangeably. Moreover, they refer to a long, single strand of polynucleotide (scaffold strand) that is folded into desired shapes on the order of about 10 nm to a micron, or more. In some forms, nucleic acid scaffold sequences are folded into nucleic acid assemblies by hybridization to small nucleic acid "staple sequences." A scaffold or origami composed of DNA (i.e., single stranded DNA) can be referred to as, for example a scaffolded DNA origami or DNA origami, etc. (p.21, lns.11-29). Further, Zhang teaches targeting elements can be added to the staple strands of the DNA assemblies, to enhance targeting of the assemblies to one or more cells, wherein exemplary targeting elements include proteins and peptides. Zhang teaches functional molecules that include targeting molecules that are attached to, incorporated into, and/or contained or encapsulated by nucleic acid assemblies (p.9, lns.1-5; p.60-62, See entire document).
Zhang teaches nucleic acid assemblies i.e., scaffolded origami) are designed by methods that include the placement of all staple sequences. After all the staples are placed, each staple is converted to a vector of numbers, each value corresponding to the scaffold nucleotide to which it is base paired. Then, the input or generated scaffold sequence is used, matching a base identity (A, T, G, or C) to a scaffold number. If no sequence is provided, a segment of M13pm18 is used by default if the required scaffold length is less than 7249 nucleotides, and a sequence is randomly generated if the required length is greater (p.34, lns.8-14). Zhang teaches the number of staple strands varies depending upon the complexity of the structure. For structures with small scaffold strands that are of minimal complexity, such as cubes (i.e., cuboid), the number of staple strands is typically about 5, 10, 50 or more than 50. Number of strands of 50 overlaps with the claimed range of 22-58 nucleotides (p.34, 37) (instant claim 3). A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Further, Zhang teaches the staple strands are oligonucleotides, wherein the assembly is carried out by hybridization of the staples to the scaffold sequence (DNA scaffold) (p.20; lns.29-33; p.53, lns.9-23; p.59; See entire document).
Additionally, Zhang teaches coating the nuclei acid assemblies with PEG or other types of polymers to provide a hydrophilic environment thereby shielding them from immune recognition (p.70, lns.29-32). Zhang teaches that nucleic acid assemblies coated with hydrophilic polymer molecules, such as polyethylene glycol (PEG), can resist serum protein adsorption, prolonging the systemic circulation of the particle. Zhang teaches to enhance half-life of the disclosed nucleic acid assemblies; one may minimize their opsonization and prolong their circulation in vivo. This can be achieved, for example, by coating the nucleic acid assemblies with hydrophilic polymers/surfactants or formulating the nucleic acid assemblies with biodegradable copolymers with hydrophilic characteristics, e.g., PEG, polyethylene oxide, polyoxamer, poloxamine, and polysorbate 80 (Tween 80). (p.71, lns.8-30).
Zhang differs from the claims in that the documents does not teach a scaffolded ssDNA origami of M13mp16 having 7560 oligonucleotides; wherein the small molecule therapeutic is talabostat that is intercalated or electrostatically loaded on the cube (cuboid) without structural changes to the cuboid.
However, Kick, Wang and Cristillo, as a whole, cure the deficiencies.
Kick teaches scaffolded DNA origami enables the fabrication of a variety of complex nanostructures that promise utility in diverse fields of application, ranging from biosensing over advanced therapeutics to metamaterials. The broad applicability of DNA origami as a material beyond the level of proof-of-concept studies critically depends, among other factors, on the availability of large amounts of pure single-stranded (ss) scaffold DNA. Here, we present a method for the efficient production of M13 bacteriophage-derived genomic DNA using high-cell density fermentation of Escherichia coli in stirred-tank bioreactors. (Abstract). Kick teaches single-stranded DNA (ssDNA) can be prepared using variety of enzymatic methods, wherein variants of the ssDNA genome of bacteriophage M13mp18 are commonly used as scaffold material for DNA origami objects (p.4672, left col.; right col.). Particularly, Kick teaches for the scaffolded ssDNA origami method a set of scaffold DNA variants are in use, based on the M13mp18 (7249 b) backbone, for example variants with 7560 and 8064 bases, wherein the variants allow for a higher degree of freedom in design of DNA origami objects (left col. See Table 1, p.4674; yield: 7249b 55%; 7560 60%; 8064 50%), wherein the obtained yield was highest for M13mp18 having 7560 nucleotides (See Table 1). Moreover, Kick teaches the transfer of bacteriophage production from shake flasks to high-cell-density fermentation in a stirred-tank bioreactor allowed us to achieve a fifty-fold increase in maximal phage titer, which enables a process for the efficient production of single-stranded DNA on the gram scale per liter-reaction-volume, thus increasing the efficacy of scaffold DNA production by 2 orders of magnitude compared to previous methods (Conclusion, p.4674). Kick teaches the method we present here allows us to produce large quantities of scaffold DNA, e.g., ssDNA M13mp18 having 7650 nucleotides, that has comparable quality to the scaffold DNA produced from the conventional low yield methods.
Accordingly, one skilled in the art would have been motivated to use ssDNA M13mp18 with 7650 nucleotides to provide scaffolded origami because ssMP13mp18 with 7560 can be produced in large quantities and ssDNA M13mp18 having 7650 nucleotides provided the highest yield compared to the preparation using 7249 b and 8064 b and ssMP13mp18 having 7560 nucleotides origami scaffold has comparable quality to the scaffold DNA produced from the conventional lower yield methods.
This, it would have been prima facie obvious to modify the teachings of Zhang directed to M13pm18 having less than 7249 nucleotides, since large quantities of ssDNA M13mp18 having 7650 nucleotides can be readily provided and they possess comparable qualities and produce higher yields than when using conventional methods; moreover, variants, such as, ssDNA M13mp18 with 7650 nucleotides, allow for a higher degree of freedom in design of DNA origami objects as taught by Kick. Furthermore, Zhang teaches scaffolded origami in the shape of a cube (cuboid), thus, it would have been well within the skill of one skilled in the art to following the guidance provided by Zhang and Kick, as a whole, to provide scaffolded origami ssDNA M13mp18 with 7650 nucleotides in the shape of a cube (cuboid) having a reasonable expectation of success. Similarly, it would have been obvious to provide a scaffolded origami comprising ssDNA M13mp18 with 7650 nucleotides having the shape of a cube, wherein the cube shaped scaffold has about 50 staple strands of nucleotides attached thereto in view of the cited prior art as a whole. Moreover, the modification of Zhang to provide M13pm18 having 7560 nucleotides would be a predictable variation within the skill and common sense of one of ordinary skill in the art. One of ordinary skill in the art is not an automaton, where a person of ordinary skill in the art would have ordinary creativity and technical skills in the relevant field. Additionally, one of ordinary would have the ability to combine the teachings of the cited prior art and make reasonable inferences and necessarily possess the technical skill for problem solving in their relevant field before the effective filing date of the claimed invention.
Wang teaches therapeutic methods for treating cancer, wherein anticancer agents comprise agents that interact DNA by intercalating with DNA, wherein an anti-cancer therapeutic is talabostat and salts thereof (Abstract; [0276]; [0282; p.95]; methanesulfonic acid [0183[; See entire document). Moreover, it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. BiocrafiLabs, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985). The mere fact that a reference suggests a multitude of possible combinations does not in and of itself make any one of those combinations less obvious, see Merck v. Biocraft, 10 USPQ2d 1843 (Fed Cir 1985). Thus, one skilled in the art would have recognized that talabostat may be intercalated into DNA having a reasonable expectation of success without undue experimentation in view of the teachings of Wang.
Cristillo teaches orally administered talabostat for efficient protein boosting of antibody and T-cell responses primed by DNA. Cristillo teaches that given that DNA can persist at the site of injection for prolonged periods, an immunization strategy in which both antibody and T-cell responses can be primed with relatively low doses of DNA may minimize reactogenicity concerns in humans. Cristillo teaches talabostat provides immunomodulatory effects without reactogenicity or toxicity. Cristillo teaches that talabostat is comparable to QS-21 in augmenting cellular and antibody responses in an electroporated DNA prime/protein boost vaccine strategy, wherein gp120 protein immunization accompanied by orally administered talabostat elicits responses characterized by induction of IFNγ,TNfα, and IL-2, wherein this induction was less pronounced when mice were immunized with gp120/Talab stat alone as compared to when gp120/talabostat was administered to DNA-primed mice. Furthermore, gp120 protein immunization with talabostat either alone (Fig. 2) or in combination with DNA priming (Fig. 3) also demonstrated induction ofTh2 cytokines. Immune responses elicited by this approach were comparable or slightly greater than those noted following protein/QS-21 boost immunization and included a balanced Thl and Th2 cytokine profile, CTL activity and CD4 I-cell help. Cristillo teaches that these results highlight a promising vaccine approach (Abstract; p.23, left col. to right col.; See entire document). Thus, one skilled in the art would have recognized that talabostat can efficiently protein boost antibody and T-cell responses primed by DNA in view of the teachings of Cristillo.
Thus, it would have been obvious to provide talabostat as a small molecule to load onto the scaffolded origami DNA ssMP13mp18 having 7560 nucleotides and 50 staple oligonucleotides shaped into a cuboid before the effective filing date of the claimed invention in the view of the combined teachings of the cited prior art references.
In addition, Zhang teaches a small molecule can attach to the DNA origami structures through intercalation (p.66, lns.1-5). As described above, Wang teaches anticancer agents, e.g., talabostat, that interact with DNA by intercalating with DNA. It well established that intercalation is influenced by electrostatic forces. Instant Claims recite talabostat mesylate (methanesulfonate), so that talabostat mesylate is protonated to provide a positive charge on the nitrogen that is provided from methanesulfonic acid. Therefore, it would necessarily follow that the loading of talabostat mesylate to scaffolded origami DNA ssMP13mp18 having 7560 nucleotides and 50 staple oligonucleotides shaped as a cuboid by intercalation would be influenced by electrostatically forces, thus, providing electrostatically loaded talabostat mesylate thereto. Since intercalation/electrostatically load involves non-covalent interaction of talabostat with the cuboid, it would necessarily follow that talabostat is loaded onto the cuboid without causing structural change to the cuboid.
All the claimed elements herein are known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the claimed invention.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to provide instantly claimed antimicrobial composition and one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the claimed invention as a whole would have been obvious to one of ordinary skill as evidenced by Zhang, Kick, Wang and Cristillo, as a whole.
The rejection of claims 22 and 23 under 35 U.S.C. 103(a) as being unpatentable over Zhang et al (WO2020051507, cited in IDS, FOR cite No. 8) [Zhang] in view of Kick et al (Efficient Production of Single-Stranded Phage DNA as Scaffolds for DNA Origami, acs.nanolett, nano lett, p.4672, 2025) [Kick], Wang et al (US 20220227778) [Wang] and Cristillo et al (Cristillo et al (HIV-1 Env vaccine comprised of electroporated DNA and protein co-administered with Talabostat; Biochemical and Biophysical Research Communications, p.22, 2008) [Cristillo] as applied to claims 1-3, 6, 13 and 31-33 above in further view of Ponnuswamy et al (Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation, Nature Communications, pgs.1-9, 31 May 2017, of record) [Ponnuswamy] is maintained.
The teachings of Zhang, Kick, Wang and Cristillo, as a whole, are described above,
Zhang, Kick, Wang and Cristillo differ from the claim in that the documents do not teach that the nucleic acid nanostructure delivery composition is coated with one or more polymers, wherein the one or more polymers comprise PEG-poly-L-lysine.
However, Ponnuswamy cures the deficiencies.
Ponnuswamy teaches DNA nanostructures have potential therapeutics and diagnostics due to ease and robustness of programming their shapes, site-specific functionalizations and responsive behaviours. However, their utility in biological fluids can be compromised through denaturation induced by physiological salt concentrations and degradation mediated by nucleases. Moreover, Ponnuswamy that DNA nanostructures coated with an oligolysine-PEG copolymer provided enabling up to a 1,000-fold protection against digestion by serum nucleases than when uncoated (abstract). Ponnuswamy teaches that the oligolysine-PEG copolymer is comprised of L-stereoisomer (see Figure 1 on page 2, and on page 3). Ponnuswamy that oligolysine-PEG-stabilized DNA nanostructures survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability, wherein oligolysine-PEG provides low-cost and effective protection of DNA nanostructures for in vivo applications (Abstract; See entire document). Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to coat ssMP13mp18 with 7560 nucleotides origami scaffold with one or more polymers, wherein the one or more polymers comprise PEG-poly-L-lysine, in order to improve the stability of the DNA origami scaffold stability and enhance its protection from digestion by serum nucleases having a reasonable expectation of success in view the teachings of Zhang, Kick, Wang and Cristillo and Ponnuswamy, as a whole.
All the claimed elements herein are known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant argue that they have amended the claims herein to be narrowly tailored a composition comprising talabostat loaded onto an Ml3mpl8 DNA single stranded DNA scaffold that is folded into a cuboid shape. Those skilled in the art recognize that the term "loaded" is a term of art that means the talabostat is bound to the scaffold. As demonstrated by the electrophoretic results presented in Fig. 2A incubation of talabostat with the DNA scaffold increases the mass of the recovered scaffold DNA in a time dependent matter. Thus, the claimed talabostat loaded composition comprises a folded DNA scaffold that is chemically bound to talabostat (i.e., talabostat "loaded" onto the scaffold) and is not merely co-administration of talabostat with a nucleic acid sequence. While Zang (Zhang) describes the use of DNA origami to deliver a small molecule drug (e.g., doxorubicin), those skilled in the art readily recognize that doxorubicin has structures (planar aromatic rings) that suggest doxorubicin will intercalate in DNA. However, unlike doxorubicin, there are no obvious structural features or any suggestion in the literature that talabostat would interact with DNA to allow talabostat to be loaded into a DNA.
Applicant’s arguments have been fully considered but they are not persuasive, because the term ‘loaded’ encompasses a vast array of, or diverse set, of interactions. Thus, the term ‘loaded’ represents an all-encompassing, or broad term for various types of interactions between a drug, e.g., tabolastat, and a cuboid shaped ssDNA. Furthermore, the term ‘loaded’ is a common term used in the context of drug delivery systems to describe a process of incorporating a drug in a carrier. In contrast, electrostatically bound emphasizes the physical forces (i.e., attractive charges) holding a drug to a carrier (substrate), such that electrostatically bound is directed to the physical, non-covalent attachment (binding) of a drug to a substrate, of which would also encompass encapsulation (i.e., hydrophobic association) and/or physical trapping (i.e., non-covalent interactions). Moreover, Applicants arguments comparing the structural features of doxorubicin to that tabolastat are not persuasive, since Applicants have failed to demonstrate that molecular structural features dictate binding affinity to a cuboid shaped ssDNA comprising M13mp18 single stranded DNA and a plurality of single stranded oligonucleotide staples. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results and inoperability of the prior art.
Applicants argue that the Examiner has not established a rationale for selecting talabostat other than it is one member of a very broad range of agents (varying widely in structure) (i.e., Wang) that can be used to treat cancer. It is not reasonable to believe that all members of such a broad class of structurally diverse compounds would share all of the same physical properties.
Applicant’s arguments have been fully considered but they are not persuasive, because one skilled in the art would have recognized that DNA origami is an excellent carrier for anti-cancer drugs that provides increased cellular internalization and increased target cell killing as well as circumvented drug resistance as disclosed by Zhang. In addition, Cristillo teaches Talabostat provides immunomodulatory effects without reactogenicity or toxicity, i.e., boost the body’s immune system to help fight diseases like cancer. Moreover, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of the teachings of Zhang, Kick, Wang and Cristillo and Ponnuswamy, as a whole. Furthermore, Wang explicitly teaches therapeutic methods for treating cancer, wherein anticancer agents comprise agents that interact DNA, wherein an anti-cancer therapeutic is talabostat and salts thereof. Moreover, it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. BiocrafiLabs, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985). The mere fact that a reference suggests a multitude of possible combinations does not in and of itself make any one of those combinations less obvious, see Merck v. Biocraft, 10 USPQ2d 1843 (Fed Cir 1985).
Applicants argue that the cited references are devoid of any suggestion of making the claimed combination of the present invention. Applicant has also established the present loaded scaffold compositions have improved efficacy relative to the administration of talabostat alone. Applicant argue that the stable loading of talabostat onto a cuboid folded DNA scaffold was surprising and not predicted by the prior art disclosures. Further, the Examiner has failed to meet his burden of establishing that talabostat was known to be, or was expected to function as, an intercalating agent, or provide any other rationale of why one would expect that talabostat could be loaded onto a DNA scaffold with binding stable enough to be efficacious. Applicants argue that the combined disclosures provided no reasonable expectation that talabostat could be successfully loaded onto a cuboid shaped DNA scaffold as there was no reason to believe that talabostat would function as an intercalating agent. Further, Cristillo discloses the use of DNAs that are intended to induce an immune response which is contrary to the intended use of the DNA scaffolds of Zhang and Kick. Applicants argue that there is no teaching or suggestion within Cristillo that talabostat would bind to a cuboid shaped M13mp18 single stranded DNA.
Applicant’s arguments have been fully considered but they are not persuasive, because Zhang teaches nucleic acid assemblies, e.g., DNA origami scaffolds, are suitable as a delivery vehicle for therapeutic, prophylactic and/or diagnostic agents, where the DNA nucleic acid assemblies are entirely biocompatible and elicit minimal immune response in the host. Further, Zhang stresses that the design of any desired geometry of DNA nucleic acid assembly, e.g., cuboid, that advantageously allows manipulation of DNA structure tailored for individual drugs, dose, site of target and desired rate of degradation etc., wherein a therapeutic agent can be efficiency captured, e.g., covalently or non-covalently, inside the DNA origami nucleic acid assemblies. Thus, given the known advantages of Zhang’s DNA carrier to deliver small molecules, one skilled in the art would have readily adapted it for the non-viral delivery of talabostat having a reasonable expectation of success especially in view of Zhang teaching that DNA nucleic acid assembly allows manipulation of DNA structure tailored for individual drugs, dose, site of target and desired rate of degradation. Moreover, Cristillo discloses the benefits of utilizing DNA as a carrier for administration of talabostat, moreover, Zhang teaches DNA nucleic acid assemblies are entirely biocompatible and elicit minimal immune response in the host. Additionally, Wang teaches providing varied therapeutic agents capable of loading onto DNA, of which includes talabostat methane sulfonate (mesylate). Thus, one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the claimed invention. Furthermore, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." That is, the present loaded scaffold compositions having improved efficacy relative to the administration of talabostat alone that generated said alleged unexpected results are not commensurate in scope with talabostat that is ‘loaded on’ the DNA cuboid, because the term ‘loaded’ represents an all-encompassing, or broad term for a vast array of various types of interactions. In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Furthermore, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results over the entire claimed range were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). In the instant case, Applicants have failed to provide evidence showing there was no reasonable expectation of success. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Additionally, obviousness only requires a reasonable expectation of success, not absolute predictability.
Applicants argue that Examples 4-7 in the specification and the accompanying data presented in Figs. 4 and 6. Figs. 4A - 4E show that DNAO-TLBST (an origami DNA in combination with talabostat) induces cytotoxicity and concomitant IL- 1β, IL-18, and IFNβ release in murine macrophages. Figs. 6A - 6D show that DNAO-TLBST induces cytotoxicity and concomitant IL- Iβ, IL-18, and IFNβ~ release in human macrophages. In all panels of Figs. 4 and 6, the left-most bar is media, the second bar from the left is a DNAO control, the third bar from the left is free TLBST, and the right-most bar is DNAO-TLBST. With the exception of Fig. 6B, the data demonstrate the synergistic effect of administering DNA origami combined with talabostat, relative to administration of only the DNA, or the free drug. As it was unknown whether talabostat would even interact with nucleic acids, the synergistic effect resulting from the combination was surprising and not suggested by the prior art.
Applicant’s arguments have been fully considered but they are not persuasive, because, the Examiner is not persuaded by the argument regarding unexpected results because the data presented (Examples 4-7; Figs. 4 and 6. Figs. 4A - 4E) are not commensurate in scope with the claims because data does not show unexpected results over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
MPEP 716.02(d) Unexpected Results Commensurate in Scope with Claimed Invention [R-08.2012].
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Applicant’s arguments regarding the claims are closely aligned with the exemplified embodiments is not persuasive. As discussed above, the results must be over the entire claimed range (i.e., not merely closely aligned)
The scope of the showing must be commensurate with the scope of claims to consider evidence probative of unexpected results, for example. In re Dill, 202 USPQ 805 (CCPA, 1979), In re Lindner 173 USPQ 356 (CCPA 1972), In re Hyson, 172 USPQ 399 (CCPA 1972), In re Boesch, 205 USPQ 215, (CCPA 1980), In re Grasselli, 218 USPQ 769 (Fed. Cir. 1983), In re Clemens, 206 USPQ 289 (CCPA 1980). It should be clear that the probative value of the data is not commensurate in scope with the degree of protection sought by the claim. That is, the composition comprising a non-viral delivery vehicle that generated said alleged unexpected results are not commensurate in scope comprising a non-viral delivery vehicle composition comprising talabostat that is loaded onto a cuboid which is presently claimed where the term loaded is a broad term for various types of interactions that would encompass covalent and non-covalent interactions, such as encapsulation (i.e., hydrophobic association) and/or physical trapping (i.e., non-covalent interactions). Furthermore, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results over the entire claimed range were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991).
Applicants argue that claim 1 has been amended to specify that the DNA scaffold comprises an M13mp18 single stranded DNA and a plurality of single stranded oligonucleotide staples, that fold the scaffold into a cuboid shape. Thus, the claims subject matter closely matches the structure of the compounds tested in Examples 4-7 and is commensurate with the unexpected properties.
Applicant’s arguments have been fully considered but they are not persuasive, because the results must be over the entire claimed range (i.e., not merely closely aligned), whereas, the termed ‘loaded’ encompasses a vast array of, or diverse set of, interactions. Furthermore, Examples 4-7 fail to disclose the claimed DNA, which comprises a plurality of single stranded oligonucleotide staples required by instant claims., i.e., the examples are silent regarding the essential feature of single-stranded oligonucleotide staples: DNAO structure is un-stapled.
Applicants argue that Zang (Zhang) discloses that various targeting moieties can be used that specifically targets the nucleic acid assembly to one or more types of cells, tissues, organs, or microenvironments. Zang fails to teach that a cell targeting peptide can be conjugated to a protein nucleic acid, wherein the peptide nucleic acid comprises a sequence of nucleic acid bases complementary to a nucleic acid sequence of the non-viral delivery vehicle. Applicants argue that Ponnuswamy is cited for disclosing that DNA nanostructures coated with an oligolysine-PEG copolymer survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability. However, Ponnuswamy fails to supplement the inadequacies of the Zhang, Kick et and Wang et al references in regard to the selection of talabostat for combination with a single-stranded DNA delivery vehicle wherein the talabostat is loaded and stably bound to single-stranded DNA delivery vehicle.
Applicant’s arguments have been fully considered but they are not persuasive, because Zhang teaches targeting elements can be added to the staple strands of the DNA assemblies, to enhance targeting of the assemblies to one or more cells, wherein exemplary targeting elements include proteins and peptides. Zhang teaches functional molecules that include targeting molecules that are attached to, incorporated into, and/or contained or encapsulated by nucleic acid assemblies. Thus, it would have been well within those skilled in the art to provide targeting agents comprising a sequence of nucleic acid bases complementary to a nucleic acid sequence of the non-viral delivery vehicle having a reasonable expectation of success. Furthermore, Ponnuswamy teaches that DNA nanostructures coated with an oligolysine-PEG copolymer provided enabling up to a 1,000-fold protection against digestion by serum nucleases than when uncoated. Ponnuswamy teaches that oligolysine-PEG-stabilized DNA nanostructures survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability, wherein oligolysine-PEG provides low-cost and effective protection of DNA nanostructures for in vivo applications. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to provide a targeting agent comprising complimentary nuclei acid sequence to attached to and/or incorporate into the non-viral delivery DNA vehicle and further coat ssMP13mp18 with 7560 nucleotides origami scaffold with one or more polymers, wherein the one or more polymers comprise PEG-poly-L-lysine, in order to improve the cell targeting and stability of the DNA origami scaffold stability and enhance its protection from digestion by serum nucleases having a reasonable expectation of success in view the teachings of Zhang, Kick, Wang and Cristillo and Ponnuswamy, as a whole. Further, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, Zhang is directed to nucleic acid assemblies that are suitable as a delivery vehicle for therapeutic, prophylactic and/or diagnostic agents. Since they are nucleic acid based, DNA nucleic acid assemblies are entirely biocompatible and elicit minimal immune response in the host. Moreover, Zhang teaches DNA nucleic acid assemblies are entirely biocompatible and elicit minimal immune response in the host and the DNA structure can be tailored for the delivery of individual drugs, dose, site of target and desired rate of degradation. Zhang teaches DNA origami as a carrier for anti-cancer drugs increased cellular internalization and increased target cell killing as well as circumvented drug resistance. The issue is whether one of ordinary skill in the art would have been motivated to load talabostat to a non-viral delivery vehicle, e,g., cuboid ssDNA M13mp18 having 7650 nucleotides. The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). It would have been prima facie obvious to provide talabostat loaded onto a non-viral delivery vehicle in order to enhance its cellular delivery for improved cancer therapy by targeting it to specific cells, promoting controlled and prolonged release in order to concentrate talabostat at a tumor site and further enabling talabostat in combination therapies having a reasonable expectation of success.
Conclusions
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/T.W./ Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619