DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Amendment
2. The amendment filed Oct. 27, 2025 has been entered. Claim 29 was amended. Claims 1-28, 30-32, 34-35 and 38-39 are canceled. Claims 29, 33 and 36-37 are under consideration in this Office Action.
Maintained Ground of Rejection
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
3. Claims 29, 33 and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Bazan et al., (WO2006074471 published July 2006; priority to Jan 2006) and Kotha et al., (US 20160230189 published August 2016; priority to Sept 2014) in view of Aparicio et al., (WO2004108141 published Dec 2004; priority to June 2004).
The claims are drawn to a kit for modifying a live cell surface comprising:
a) a dual conjugation cargo molecule with a cationic side chain which forms
non-covalent bonds with the negatively-charged cell surface and a
phosphoric acid containing ligand which facilitates phosphor-ester covalent
bonding with the cell membrane phosphate cargo agent that allows for
concurrently both covalent and non-covalent binding to the live cell surface
which comprises a nontoxic biodegradable polymer with one or more functional
label, wherein at least one of said functional label is adenosine diphosphate which
provides covalent binding to the live cell surface;
wherein said nontoxic biodegradable polymer provides non-covalent binding to
the live cell surface and is an elastin-like polypeptide (ELP) or a cationic
polymer of polylysine, polyarginine or a polyamine having a molecular weight of
about 100,000 Da ~ about 200,000 Da and; b) a medium of pH about 6 to about 8 for conjugation of said cargo agent; and c) instructions for use of the kit materials and conditions for use of the cargo agent as a dual conjugation cargo agent which provides for concurrent covalent and non-covalent interaction with a live cell surface.
Bazan et al., teach a kit comprises a polycationic multichromophore as described herein and one or more substrate-bound unlabeled single-stranded sensor polynucleotides that are complementary to corresponding target ρolynucleotide(s) of interest. In the presence of the target polynucleotide in the sample, the sensor is brought into proximity to the multichromophore upon hybridization to the target, which associates electrostatically with the polycationic multichromophore [KITS]. Bazan et al., teach a conjugation cargo molecule with a cationic side chain, such as a polycationic conjugated polymer. Thereby disclosing the instantly claimed kit of claim 29. The kit comprises an aqueous solution of a polycationic conjugated polymer. The polymers are desirably polycationic, and any or all of the subunits of the polymer may comprise one or more cationic groups. Any suitable cationic groups may be incorporated. Exemplary cationic groups include polyamines groups [THE POLYCATIONIC MULTICHROMOPHORE]. Bazan et al., disclose poly-L-lysine. Thereby disclosing the instantly claimed cationic polymers of claim 29. The multichromophore may interact at least in part electrostatically with the sensor and/or the target, and an increase in energy transfer with the polymer may occur upon binding of the sensor and the target [Abstract]. Thus teaching non-covalent interactions. The terms "polynucleotide," "oligonucleotide," "nucleic acid" and "nucleic acid molecule" are used interchangeably herein to refer to a polymeric form of nucleotides of any length, and may comprise ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. The target nucleotide must have a polyanionic backbone, preferably a sugar-phosphate background, of sufficient negative charge to electrostatically interact with the polycationic multichromophore in the methods described herein, although other forces may additionally participate in the interaction. Other polymers containing a phosphate or other polyanionic backbone, and other synthetic sequence-specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking.
Desirably, the polymers are described herein are soluble in aqueous solutions and other polar solvents, and preferably are soluble in water. By "water-soluble" is meant that the material exhibits solubility in a predominantly aqueous solution, which, although comprising more than 50% by volume of water, does not exclude other substances from that solution, including without limitation buffers, blocking agents, cosolvents, salts, metal ions and detergents [THE POLYCATIONIC MULTICHROMOPHORE]. The polymers may be provided in solution, which may be a predominantly aqueous solution, which may comprise one or more of the additional solution components described herein, including without limitation additional solvents, buffers, biomolecules, polynucleotides, fluorophores, etc [COMPOSITIONS OF MATTER]. For example where a component can be present at a concentration of from 0 to 100%, or where the pH of an aqueous solution can range from 1 to 14, those inherent limits are specifically disclosed [THE POLYCATIONIC MULTICHROMOPHORE]. Figure 2 teach the buffer is 25 mM phosphate buffer, pH = 7.4. Other components may be incorporated into the assay solution, for example one or more buffers suitable for maintaining a pH satisfactory for the biological molecules and their desired properties (e.g., ability to hybridize) [METHODS OF USE]. Thereby disclosing the instantly claimed medium with a pH of about 6 to 8. The conjugated polymers, saturated polymers and dendrimers can be prepared to incorporate multiple cationic species or can be derivatized to render them polycationic after synthesis; semiconductor nanocrystals can be rendered polycationic by addition of cationic species to their surface. In some embodiments, the polycationic multichromophore is not detected by its ability to transfer energy when excited, and thus methods involving such detection schemes do not require the multichromophore to emit or transfer energy [THE POLYCATIONIC MULTICHROMOPHORE]. The angle which the angled linkers are capable of imparting to the polymeric structure is determined as follows. Where the two bonds to other polymeric components are coplanar, the angle can be determined by extending lines representing those bonds to the point at which they intersect, and then measuring the angle between them. Where the two bonds to other polymeric components are not coplanar, the angle can be determined as follows: a first line is drawn between the two ring atoms to which the bonds attach; two bond lines are drawn, one extending from each ring atom in the direction of its respective bond to the other polymeric component to which it is joined; the angle between each bond line and the first line is fixed; and the two ring atoms are then merged into a single point by shrinking the first line to a zero length; the angle then resulting between the two bond lines is the angle the angled linker imparts to the CCP [THE POLYCATIONIC MULTICHROMOPHORE]. The kit for assaying a sample for a target biomolecule comprising: a polycationic conjugated polymer, wherein said polymer can electrostatically interact with a polyanionic target biomolecule; thus teaching covalent interactions.
The multichromophore may interact at least in part electrostatically with the sensor and/or the target, and an increase in energy transfer with the polymer may occur upon binding of the sensor and the target. Also a surface, which can be a sensor, changes its net charge from neutral to cationic by virtue of binding a cationic multichromophore to its surface by binding of a compound to a biomolecule on the substrate [para 133]. Thus teaching the simultaneous binding abilities.
Association of the multichromophore with the sensor can be directly detected or indirectly detected through energy transfer to another species, for example a fluorescent label conjugated to the target and/or a sensor and/or a substrate to which it may be attached, or to or from an intercalating dye that can intercalate with the sensor- target bound complex [KIT]. The kit may optionally contain one or more of the following: one or more labels that can be incorporated into a target; one or more intercalating dyes; one or more sensor biomolecules, one or more substrates which may contain an array, etc [KIT]. In some embodiments, a fluorophore may be employed, for example to receive energy transferred from an excited state of the polycationic multichromophore or vice versa, or to exchange energy with an polynucleotide-specific dye, or in multiple energy transfer schemes. Fluorophores useful in the inventions described herein include any substance which can absorb energy of an appropriate wavelength and emit light. For multiplexed assays, a plurality of different fluorophores can be used with detectably different emission spectra [FLUOROPHORES]. Thereby disclosing the instantly claimed functional fluorophore label of instant claims 36-37. The substrate or a region thereof may be encoded so that the identity of the sensor located in the substrate or region being queried may be determined. Any suitable coding scheme can be used, for example optical codes, RFID tags, magnetic codes, physical codes, fluorescent codes, and combinations of codes [FLUOROPHORES]. Thereby disclosing the instantly claimed functional magnetic moiety label of claim 33 and 37. The substrate can take any form and typically is a plate, bead, pellet, disk, particle, microparticle, or nanoparticle [FLUOROPHORES]. Bazan et al., teach the components of a kit can be retained by a housing. Instructions for using the kit to perform a described method can be provided with the housing, and can be provided in any fixed medium. The instructions may be located inside the housing or outside the housing, and may be printed on the interior or exterior of any surface forming the housing which renders the instructions legible [para 157].
Bazan et al., teach a kit for modifying a live cell surface comprising: a) a dual conjugation cargo molecule with a cationic side chain and a nontoxic biodegradable polymer with one or more functional label, wherein at least one of said functional label is adenosine diphosphate which provides covalent binding to the live cell surface; wherein said nontoxic biodegradable polymer provides non-covalent binding to the live cell surface and is an elastin-like polypeptide (ELP) or a cationic polymer of polylysine, polyarginine or a polyamine and; b) a medium of pH about 6 to about 8 for conjugation of said cargo agent; and c) instructions for use of the kit materials and conditions for use of the cargo agent as a dual conjugation cargo agent which provides for concurrent covalent and non-covalent interaction with a live cell surface; but does not explicitly state the cationic polymer has a molecular weight of about 100,000 Da ~ about 200,000 Da.
Kotha et al., teach nanoparticle includes a core polyplex and a silica coating on the core polyplex and, optionally, a polymer attached to an outer surface of the silica coating , where the polyplex includes an anionic polymer, a cationic polymer, a cationic polypeptide, and a polynucleotide [abstract]. The conjugates may be attached to the surface of the particles with covalent bonds, or non-covalent interactions [para 147]. A cationic polymer within the polyplex may be a polypeptide containing cationic amino acids and may be, for example, poly(arginine), poly(lysine), poly(histidine), poly(ornithine), poly(citrulline), or a polypeptide that comprises any combination of more than one of the foregoing [para 33]. Thus teaching the polymers of claim 29. In one example, a cationic polymer may comprise a poly(arginine), or poly(L-arginine). A cationic polymer within the polyplex may have a molecular weight of between 1 kDa and 200 kDa. A cationic polymer within the polyplex may also have a molecular weight of between 10 kDa and 100 kDa [para 34]. In another example, a cationic polymer may comprise a D-isomer of poly(arginine) or of any of the foregoing polymers such as polypeptides, which may be particularly advantageous because polymers such as polypeptides containing a D-isomer may be less susceptible to degradation within a cell and therefore have a prolonged effect on influencing payload release and the rate thereof over time [para 34].
Illustrated in FIG. 2A, a cationic polyplex is created, then coated with a silica coating. Polyplex cores of nanoparticles may be created via electrostatic interactions leading to condensation. A solution was created with a cationic polypeptide in water and 30 mM Tris-HCl (pH ˜7.4) in water [para 41]. The solution may be combined via dropwise addition of the cationic solution. After 30 minutes of incubation at room temperature, may have added dropwise to a solution in Tris-HCl (pH=7.4) and allowed to incubate for between 8 and 24 hours at room temperature [para 41]. This method is but one example of manufacturing nanoparticles [para 41]. Thus teaching the claimed pH specific medium.
Thus, Bazan et al., and Kotha et al., have been discussed above; but neither teach the specific type of sugar phosphate is adenosine diphosphate.
Aparicio et al., teach the use of ADP (adenosine diphosphate) or derivatives thereof, in the manufacture of a medicament or pharmaceutical composition [abstract]. Aparicio et al., disclose providing a fluorescent marker labelled ADP molecule [summary]. The ADP ligand can be used for manufacturing diagnostic kits [Detailed Description of the Invention]. Aparicio et al., teach when bound closely together by the ADP:BACH- GPCR complex, the fluorescence emitted upon excitation of the fluorophore will have a different wavelength than that emitted in response to that excitation wavelength when the ADP or a derivative thereof and the BACH-GPCR are not bound or not in sufficiently close juxtaposition, providing for quantitation or bound versus modified interactions by measurement of emission intensity at each wavelength [Fluorescence resonance energy transfer]. This functional assay can be performed in isolated cell membrane fractions or on recombinant cells expressing the BACH-GPCR on their surface [Screening Methods]. Thus Aparicio et al., teach the APD as a phosphoric acid containing ligand.
The formulations comprising the pharmaceutically active ingredient may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient, ADP and the pharmaceutical carriers. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient, ADP with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product [Dosages/Formulations]. In addition, the pharmaceutically active ADP may be incorporated into biodegradable polymers allowing for sustained release of the ingredient, the polymers being implanted in the vicinity of where delivery is desired [Dosage and formulation]. Accordingly, it is contemplated that the pharmaceutically active ADP may be used in conjunction with another pharmaceutically beneficial entity [Dosages/Formulations]. And any instructions or catalogues for any products cited or mentioned in each of the applications and patents and in any of the application cited documents, are hereby incorporated herein by reference. Furthermore, all documents cited in this text, and all documents cited or referenced in documents cited in this text, and any manufacturer's instructions or catalogues for any products cited or mentioned in this text, are hereby incorporated herein by reference.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Aparicio et al’s a phosphoric acid containing ligand which comprises a nontoxic biodegradable polymer with one or more functional label, wherein the functional label is adenosine diphosphate which provides covalent binding to the live cell surface to Bazan et al’s kit comprising: a) a dual conjugation cargo molecule with a cationic side chain capable of concurrently both covalent and non-covalent binding to the live cell surface wherein said nontoxic biodegradable polymer provides non-covalent binding to the live cell surface and is an elastin-like polypeptide (ELP) or a cationic
polymer of polylysine, polyarginine or a polyamine having a molecular weight of
about 100,000 Da ~ about 200,000 Da and; b) a medium of pH about 6 to about 8 for conjugation of said cargo agent; and c) instructions for use of the kit materials and conditions for use of the cargo agent as a dual conjugation cargo agent which provides for concurrent covalent and non-covalent interaction with a live cell surface in order to allow ADP to be incorporated into biodegradable polymers allowing for sustained release of the ingredient.
One of ordinary skill in the art would have a reasonable expectation of success by incorporating ADP to allow for functional fluorophore assays to be performed in isolated cell membrane fractions or on recombinant cells. Finally, it would have been prima facie obvious to combine the invention of Bazan et al., Kotha et al., and Aparicio et al., to advantageously achieve a composition comprising pharmaceutically active ADP may be used in conjunction with a biodegradable cationic polymer with one or more functional labels.
Response to Arguments
4. Applicant's arguments filed Oct. 27, 2025 have been fully considered but they are not persuasive.
Applicants point to the amendment reciting “ …a dual conjugation cargo molecule with a cationic side chain which forms non-covalent bonds with the negatively-charged cell surface and a phosphoric acid containing ligand which facilitates phosphor-ester covalent bonding with the cell membrane phosphate…” as a limitation not taught by the prior art. However, the cargo agent must have a cationic side chain and Bazen et al., teaches a cargo agent with a cationic or lysine/polylysine side chain. It is noted that the cell surface is not a component within the kit, rather the ability to form non-covalent bonds with the negatively-charged cell surface is directed to the intended use of the side chain. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Similarly, the language of “… cargo agent that allows for
concurrently both covalent and non-covalent binding to the live cell surface…” refers to the intended use of the cargo agent and does not further limit that structure of the cargo agent.
With respect to the cargo agent comprises a nontoxic biodegradable polymer with one or more functional label, wherein at least one of said functional label is adenosine diphosphate; Bazan et al., teach the sugar phosphate (where ADP specific type of sugar phosphate is adenosine diphosphate) combined with a medium of pH about 6 to about 8 for conjugation of said cargo agent. It is noted that the instant specification under physiological condition where the pH is 6 to 8 allowing for naturally occurring covalent binding. Furthermore, Bazan et al., clearly teach covalent bonding for the functional labels. Aparico et al., teach ADP as a functional label because ADP once it is incorporated into biodegradable polymers it allows for sustained release of the ingredient. Aparico et al., teach ADP on the cell surface. Therefore, this limitation is taught by the prior art.
With regard to the kit instructions, Bazan et al., teach the components of a kit can be retained by a housing. Instructions for using the kit to perform a described method can be provided with the housing, and can be provided in any fixed medium. The instructions may be located inside the housing or outside the housing, and may be printed on the interior or exterior of any surface forming the housing which renders the instructions legible [para 157]. Thus teaching kit instructions just as instantly claimed.
Additionally, Applicants attention is directed to MPEP 2115.05 To be given patentable weight, the printed matter and associated product must be in a functional relationship. A functional relationship can be found where the printed matter performs some function with respect to the product to which it is associated. See Lowry, 32 F.3d at 1584, 32 USPQ2d at 1035 (citing Gulack, 703 F.2d at 1386, 217 USPQ at 404). For instance, indicia on a measuring cup perform the function of indicating volume within that measuring cup. See In re Miller, 418 F.2d 1392, 1396, 164 USPQ 46, 49 (CCPA 1969). A functional relationship can also be found where the product performs some function with respect to the printed matter to which it is associated. For instance, where a hatband places a string of numbers in a certain physical relationship to each other such that a claimed algorithm is satisfied due to the physical structure of the hatband, the hatband performs a function with respect to the string of numbers. See Gulack, 703 F.2d at 1386-87, 217 USPQ at 405.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have a reasonable expectation of success by incorporating ADP to allow for functional fluorophore assays to be performed in isolated cell membrane fractions or on recombinant cells. Finally, it would have been prima facie obvious to combine the invention of Bazan et al., Kotha et al., and Aparicio et al., to advantageously achieve a composition comprising pharmaceutically active ADP may be used in conjunction with a biodegradable cationic polymer with one or more functional labels.
Thus none of the arguments are not found persuasive and the rejection is maintained.
Pertinent Art
5. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. WO2017136652 teach active agent such as a therapeutic, prophylactic, or diagnostic agent attached to a targeting moiety via a linker, and particles comprising such conjugates have been designed which can provide improved temporospatial delivery of the active agent and/or improved biodistribution. The conjugates are part of or a component of the particle and may be attached to the surface of the particles with covalent bonds, or non-covalent interactions; the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and/or polyarginine and ADP.
AU2017378431 (priority to 2017-12-14) teach a cationic polymer within the core can have a molecular weight in a range of from 1-200 kDa (e.g., from 1-150, 1-100, 5-200, 5-150, 5-100, 10-200, 10-150, 10-100, 15-200, 15-150, 15-100).
KR100862973 published Oct. 2008; priority to June 2007)
KR100862973 disclose a magnetic nanocomposite is provided to be stable in an aqueous solution, show excellent magnetic characteristic and be used as a target magnetic drug delivery with improved cell target efficiency due to be surface-modified by cation, thereby being used as contrast media by comprising pharmaceutically acceptable media. The magnetic nanocomposite comprises: a magnetic nanoparticle; a pharmaceutically active ingredient, an anionic polymer layer surrounding the magnetic nanoparticle; and a cationic polymer layer surrounding the anionic polymer layer wherein the cationic polymer is at least one selected from the group consisting of polylysine, and polyvinylamine.
All pertinent art references available on Google Patents.
Conclusion
6. No claims allowed.
7. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Dan Kolker, can be reached on 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645