This office action is issued to replace/vacate the prior Office Action of 10/06/2025 in order to address arguments relating to the declaration of 08/18/2025 that were inadvertently missed.
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
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 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.
Status of the claims
Claims 1-22 are pending and examined on merits in this office action.
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 1-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 as amended is directed to a method of separation of biologically active nanoparticle in a mixture comprising proteins by adsorbing/binding the proteins and the biologically active particles on solid phase of fluid conduit while flowing in a mobile phase and eluting the proteins and the biologically active nanoparticles by salt gradient of high to low salt, wherein the solid phase is non-porous to the nanoparticles.
The biologically active nanoparticles as claimed, encompasses a large number of particles having different binding properties and structures, as for example, a bacteria, a virus particles, whole cells, prions, cellular components such as individual organelles, vacuoles, exosomes and lysosomes, synthetic biologically active nanoparticles such as liposomes and genetically modified virus particles and bacteria for use in plasmid delivery. The solid stationary phase comprising hydrophobic polymer includes a large number of various types of hydrophobic polymer having distinct properties for binding and adsorption of various proteins and biologically active particles and the elution encompasses employing sulfate salts with various types of organic modifies wherein the organic modifier has not been clearly described in the specification, which includes large number of distinct types of compounds, as for example, included but not limited to acetonitrile , various types of polyols (e.g. glycerol) and various types of alcohols.
However, throughout the specification the guidance and examples for separation of biologically active nanoparticle is very limited to separation of exosome that contains lipid bilayer exterior by adsorption through hydrophobic interaction to solid phase surface having polyethylene terephthalate (PET). Example of separation of only of exosome by adsorption to a solid phase surface having polyethylene terephthalate (PET) in a mobile phase containing a sulfate ion (ammonium sulfate) at a certain concentration and elution of the bound exosome after elution of protein with a gradient of decreasing concentration of ammonium salt and acetonitrile organic modifier combination, cannot be considered representative for separation of various types of biologically active nanoparticle such as cells, bacteria and various organelles having surface attached proteins from mixtures of various types of proteins with various types of surfaces having various hydrophobic polymers (as for example, polyethylene glycol, polyepoxy, polyvinyl alcohol of apolycarbonate) for adsorption/binding and elution of various types organic modifier (as for example, glycerol) in combination of sulfate salt gradients. Adsorption of exosome to a solid surface having PET cannot be considered representative of adsorption of virus or various other particles having various proteins on the surface in a mixture of various types of proteins to various hydrophobic surfaces having various hydrophobic polymers (as for example, polyethylene glycol, polyepoxy, polyvinyl alcohol of apolycarbonate) and elution of all the proteins and then elution of the virus, cells or organelles by decreasing concentrations of the sulfate salts with various types of organic modifier as described above. Disclosure of acetonitrile organic modified with ammonium sulfate cannot be considered representative of various types of polyols or glycerol. The disclosure of only of polyethylene terephthalate (PET) cannot be considered as representative of the various distinct hydrophobic polymers for adsorption of various type of biologically active particles. PET is not a representative of polyethylene glycol, polyvinyl alcohol, polyepoxy or apolycarbonate.
Chemistry is generally considered to be unpredictable and/or have unpredictable factors. See, e.g.,In re Carleton, 599 F.2d 1021, 202 USPQ 165, 170 (CCPA 1979) ("Although there is a vast amount of knowledge about general relationships in the chemical arts, chemistry is still largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave.”). The pharmaceutical art, that is the use of a chemical compound to affect a desired physiological activity, is generally considered to be unpredictable and/or have unpredictable factors. See, e.g., In re Fisher, 427 F.2d 833, 839 (CCPA 1970) (“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved (emphasis added); In re Bowden, 183 F.2d 115, 86 USPQ 419, 423 (“chemical reactions frequently are unpredictable”).
Considering the unpredictability found in organic synthesis, exchanging even one substituent for another cannot be considered a foregone conclusion. Accordingly, when a claim presents a genus with substantial variation as that currently presented by Applicant, the disclosure must adequately reflect such variation with a representative number of species. The lack of any disclosure of examples may be considered in determining whether a claimed invention was adequately described. Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011).
The disclosure of the only example of separation only of exosome by adsorption to a solid phase surface having polyethylene terephthalate (PET) in a mobile phase containing a sulfate ion (ammonium sulfate) at a certain concentration and elution of the bound exosome after elution of protein with a gradient of decreasing concentration of sulfate salt in combination of acetonitrile, cannot be considered representative for separation of various types of biologically active nanoparticle from mixtures of various types of proteins with various types of hydrophobic surfaces having various hydrophobic polymers for adsorption/binding with various types of mobile phase. Exosome is not representative of a virus, a bacteria and other organelles having surface attached proteins, and as described above and disclosure of adsorption of exosome on PET surface with mobile phase have certain concentration of ammonium sulfate is not representative of adsorption of various distinct types of biologically active nanoparticles on various hydrophobic surface comprising various hydrophobic polymers and elution with gradient of sulfate salt in combination of various types of organic modifiers.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004). Emphasis added.
The term biologically active nanoparticle has not been clearly defined in the specification and have substantial variation within the genus. The “solid phase” is not limited to any particular solid phase and the term encompasses various solid phase having substantial variation within the genus and so does the “mobile phase having the salt”. The gradient elution process is not limited to gradient of sulfate salt (ammonium sulfate or sodium sulfate), but includes combination of various distinct types of organic modifier, thus providing further variations elution conditions for various types of biologically active nanoparticles. Accordingly, it is deemed that the specification fails to provide adequate written description and clear guidance for separation of various biologically active nanoparticles as encompassed by the scope of “biologically active nanoparticle” with various types of mobile phase having various salts for adsorption on various solid phase surfaces provided by various hydrophobic polymers as encompassed by “solid phase” and elution with various decreasing salt gradient wherein all proteins are eluted first followed by the biologically active nanoparticle.
Response to argument
Applicant's arguments and amendments filed 08/18/2025 have been fully considered and are persuasive to overcome the non-statutory double patenting rejection over US Pat. No. 11,596,876 in view of the terminal disclaimer filed and approved on 08/18/2025. However, Applicant’s arguments and the declaration filed 08/18/2025 are not found persuasive to overcome the rejection under 35 USC 112(a) .
Applicant argued that the category of hydrophobic polymers as claimed herein is adequately supported in the description, and that the inventor has possession of the invention as claimed at the time of filing. Applicant argued that the application does not presently claim a stationary phase comprising a hydrophobic polymer generally, but instead claims those hydrophobic polymers having a critical surface tension of about 35 mJ/m2 or greater and a water contact angle of about 85° or less and thus, Applicant is not claiming the totality of the genus of hydrophobic polymers, but instead claiming those polymers having the characteristics as presently required by claim 1.
The above arguments have fully been considered but are not found persuasive. Paragraph [0056] of the specification provides some of the representative examples including polyvinyl alcohol, nylon (e.g., nylon 6; nylon 6,6; nylon 7,7; nylon 8,8; nylon 9,9, nylon 12; nylon 11), polyethylene glycol, polysulfone, polymethyl methacrylate, polyethylene terephthalate, polyepoxies, polyoxymethylene, polyvinylidone chloride, polyphenylene sulfide, acrylonitrile butadiene styrene, polycarbonate, polyvinyl chloride, and polyvinyl acetate, but the hydrophobic polymers are not limited to the disclosed ones only. Thus, the genus of hydrophobic polymer encompasses inordinately a large number of different polymers with distinct structures and properties.
However, throughout the specification the example of separation of biologically active particles are very limited to nanoparticle exosome comprising an envelope that includes a lipid bilayer and the surface for adsorption of the exosomes to surface is very limited to surface comprising hydrophobic polymer of poly(ethylene terephthalate) (PET) (paragraphs [0091-0093]). The disclosure of adsorption and elution only of exosome by adsorption to a solid phase surface having polyethylene terephthalate (PET) in a mobile phase containing a sulfate ion (ammonium sulfate) at a certain concentration and elution of the bound exosome after elution of protein with a gradient of decreasing concentration of salt, cannot be considered representative for separation of various types of biologically active nanoparticle from mixtures of various types of proteins with various types of surfaces with various hydrophobic polymers as encompassed by the genus of hydrophobic polymer for hydrophobic surface. Hydrophobic polymer of polyethylene terephthalate (PET) is not a representative of polyethylene glycol, polysulfone, polymethyl methacrylate, polyepoxies, polyvinylidone chloride, polyphenylene sulfide, acrylonitrile butadiene styrene, polycarbonate, polyvinyl chloride, or polyvinyl acetate. Throughout the specification, there is not a single example, disclosure or guidance of providing a hydrophobic surface having polyethylene glycol having surface tension of about 35 mJ/m2 and water contact angel or about 85⁰ of less, let alone the various other hydrophobic polymer as disclosed above, which the hydrophobic polymers are not limited to the disclosed ones only. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Accordingly, it is deemed that the specification fails to provide adequate written descriptive support and clear guidance of separation of various biologically active nanoparticles as encompassed by the scope of “biologically active nanoparticle” with various types hydrophobic support surface provided by various types of hydrophobic polymers for adsorption of the various biologically active nanoparticles in mobile phase comprising sulfate salt and elution with decreasing salt gradient as encompassed by the claims.
In the declaration filed 08/18/2025, Dr. R. Kenneth Marcus argued that claim 1 incudes, among other things, the feature that the biologically active nanoparticle includes a lipid bilayer and the stationary phase comprises a hydrophobic polymer having a critical surface tension of about 35 mJ/m2 or greater and water contact angle of about 85⁰ or less. Dr. Marcus argued that while we have reduced to practice one example in the originally filed application, we have provided general instruction as to how biologically active nanoparticles comprising an envelope that includes a lipid bilayer can be separated through chromatography with a stationary phase having the above specified characteristics. For support, Dr. Marcus cited a three journal papers, Huang et al. (Analytical and Bioanalytical Chemistry 2021), Pons et al (Analytical Science 2025) and Islam et al (Analitica Chemica Acta 2024).
The above arguments have fully considered but are not found persuasive. As described above, the genus of hydrophobic polymer encompasses inordinately a large number of different polymers with distinct structures and properties and when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Hydrophobic polymer of polyethylene terephthalate (PET) or nylon are not a representative of polyethylene glycol, polysulfone, polymethyl methacrylate, polyepoxies, polyvinylidone chloride, polyphenylene sulfide, acrylonitrile butadiene styrene, polycarbonate, polyvinyl chloride, or polyvinyl acetate. Huang discloses isolation of lentivirus using polyester as hydrophobic polymer and there is no teaching or disclosure regarding the property of surface tension and water contact angle of the polymer. Pons teaches isolation of exosome using Nylon-6 as hydrophobic polymer and there is no teaching or disclosure regarding the property of surface tension and water contact angle of the polymer. Islam discloses isolation of exosomes using polyester as hydrophobic polymer but there is no teaching or disclosure regarding the property of surface tension and water contact angle of the polymer. However, Islam teaches criticality of using Tween-20 as an elution solvent (modifier) for preserving the structural integrity of exosome. Throughout the specification, there is not a single example, disclosure or guidance of providing a hydrophobic surface having polyethylene glycol having surface tension of about 35 mJ/m2 and water contact angel or about 85⁰ of less, let alone the various other hydrophobic polymer as disclosed above, which the hydrophobic polymers are not limited to the disclosed ones only. Disclosing one or two species can not be considered as a representative number of species while there is a substantial variation within the genus of hydrophobic polymer. MPEP clearly says that when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Conclusion
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 extension fee 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 date of this final action.
If Applicants should amend the claims, a complete and responsive reply will clearly identify where support can be found in the disclosure for each amendment. Applicant should point to the page and line numbers of the application corresponding to each amendment, and provide any statements that might help to identify support for the claimed invention (e.g., if the amendment is not supported in ipsis verbis, clarification on the record may be helpful). Should Applicants present new claims, Applicants should clearly identify where support can be found in the disclosure.
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678