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 .
Claims 1, 6-13, 17, 18, 26, and 30-34 are pending and under consideration.
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.
The rejection of claims 1, 6-13, 17, 18, 26, 30-34 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 is maintained for reasons of record. 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.
The instant claims are reliant on a generic “nanoparticle” comprising a first two targeting agents binding 4-1BB and either CD16 or CD27, and a second targeting agent that binds a target on a cancer cell surface. The specification teaches unexpected results in that “nanoparticles” containing both CD16 and 4-1BB activating agents result in significantly higher NK cell cytotoxicity than the nanoparticles containing only CD16 and only 4-1BB activating agents (page 34, lines 23-30).
When given the broadest reasonably interpretation “nanoparticles” comprise a genus of particles with different shapes and surface chemistries. Nanoparticles comprising the targeting agents encompass a genus of structures which serve to link or anchor the targeting agents to the surface of the nanoparticle. The specification states:
Types of particles of this invention include, but are not limited to, polymer nanoparticles such as PLGA-based, PLA-based, polysaccharide-based (dextran, cyclodextrin, chitosan, heparin), dendrimer, hydrogel; lipid-based nanoparticles such as lipid nanoparticles, lipid hybrid nanoparticles, liposomes, micelles; inorganics-based nanoparticles such as superparamagnetic iron oxide nanoparticles, metal nanoparticles, platin nanoparticles, calcium phosphate nanoparticles, quantum dots; carbon-based nanoparticles such as fullerenes, carbon nanotubes; and protein-based complexes with nanoscales. Types of microparticles of this invention include but are not limited to particles with sizes at micrometer scale that are polymer microparticles including but not limited to, PLGA-based, PLA-based, polysaccharide-based (dextran, cyclodextrin, chitosan, heparin), dendrimer, hydrogel; lipid-based microparticles such as lipid microparticles, micelles; inorganics-based microparticles such as superparamagnetic iron oxide microparticles, platin microparticles and the like as are known in the art. These particles may be generated and/or have materials be absorbed, encapsulated, or chemically bound through known mechanisms in the art, such as those described in Au et al. 2019 ACS Cent. Sci. 5(1):122-144 and Au et al. 2018 ACS Nano 12(2):1544-1563.
The specification states:
Design of multivalent EGFR-targeted nanoengagers for NK cell-mediated chemoimmunotherapy: Multivalent non-targeted and EGFR-targeted α-CD16- and α-4-1BB-functionalized drug-free and EPI-encapsulated PEG-PLGA NPs (EPI NPs) were engineered via a two-step fabrication method (FIGS. 1B, 1C, 2, and 3; Table 1). The core azide-functionalized drug-free and EPI-encapsulated NPs were first prepared via the nanoprecipitation method (Au et al. 2019 ACS Cent. Sci. 5(1):122-144). Dibenzocyclooctyne (DBCO)-functionalized α-CD16, α-4-1BB, and α-EGFR were then quantitatively conjugated to the azide-functionalized NPs via copper-free azide-cyclooctyne cycloaddition (Au et al. 2018 ACS Nano 12(2):1544-1563). A 1:1 α-CD16 to α-4-1BB molar ratio and a 1:1:1 α-CD16 to α-4-1BB to α-EGFR molar ratio were used for the fabrication of bivalent and trivalent NPs. The EPI NPs were encapsulated with approximately 2.7 wt/wt % of EPI (FIG. 1D).
The specification teaches spatiotemporal co-activation of CD16 and 4-1BB co-stimulatory molecules on NK cells by the nanoparticles prepared by the above method (Figures 7 and 8). The specification provides no evidence that generic nanoparticles, such as those contemplated in the specification, having the targeting agents linked or associated with the nanoparticles by any means at any density, would provide the spatiotemporal co-activation of CD16 and 4-1BB co-stimulatory molecules on NK cells responsible for the superior result.
Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
In the instant case, the trivalent nanoparticles prepared by the methods of Au et al exhibited the increased cytotoxicity attributed to “increased cooperative binding” and more effective clustering to the CD16 and 4-1BB co-stimulatory molecules (page 34, lines 25-27). The functionalized nanoparticles produced by the methods of Au et al do not describe a genus of generic nanoparticles, because the genus is highly variant encompassing different shaped particles in a range of “nano” sizes” having different surface chemistry, having different means for linking the activating agents to the surface and different densities of the activating agents. One of skill in the art could not envisage any other nanoparticle bearing the activating CD16 and 4-1BB agents which would result in increased cooperative binding of the activating agents and more effective clustering of the CD16 and 4-1BB co-stimulatory molecules. One of skill in the art would reasonably conclude that applicant was not in possession of the genus of generic nanoparticles comprising the targeting agent of 4-1BB, the targeting agent of CD16 or CD27 and a targeting agent that binds to a cancer cell at the time of filing.
Applicant argues that there is a presumption that the originally filed description is presumed to be adequate. Applicant relies on In re Marzocchi and in re Wertheim. This has been considered but not found persuasive. Section 2163(I)(A) of the M.P.E.P. states:
However, as discussed in subsection I, supra, issues of adequate written description may arise even for original claims, for example, when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the inventor had possession of the claimed invention at the time of filing.
Applicant argues that the examiner’s burden of “proving” lack of written description has not been met. Based on the presumption of an adequate disclosure. This has been considered but not found persuasive. Applicant argues that the examiner’s statement that the “specification provides no evidence that the generic nanoparticle having targeting agent linked or associated with the nanoparticles by any means and t any density would provide the spatiotemporal co-activation of CD16 and 4-1BB costimulatory molecules on NK responsible for the superior result” is nothing but the shifting of the burden of proof onto applicant. This has been considered but not found persuasive. As stated in the M.P.E.P, above, issues of adequate written description may arise even for original claims, for example, when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the inventor had possession of the claimed invention at the time of filing. Applicant further argues that vague statements about the breadth of the genus do not rise to the level of evidence sufficient to overcome the presumption of adequate written description. This has been considered but not found persuasive. Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus.
Clearly the instant specification fails to describe or provide a reduction to practice of a representative number of species of generic nanoparticle sufficient to describe the genus relied upon in the claims. Applicant argues that it is not required to disclose every single species within the claimed genus where the invention in question is in a predictable field of the art and that that the disclosure of a single-species can satisfy the requirement for a representative number of species in a predictable field of the art.
This has been considered but not found persuasive. The instant invention is not in a predictable field of the art. Applicant argues in the response of 2/26/2026:
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Thus, “unexpected results” would not be expected in a predictable field of art.
Regarding the requirement for a description of species sufficient to describe the claimed genus, the genus can be described by coupling a particular structural feature with a particular function. However, this has not been done.
Applicant argues that the specification discloses that a nanoparticle describes a polymeric particle or sphere in the nanometer size range. This has been considered but not found persuasive. A ‘description” of a polymeric particle or sphere within the appropriate size range (specification, parge 17, lines 13-15) is exemplary rather than a limiting definition for the nanoparticles. The specification further states that both types of particles or spheres can be used as drug carriers into which drugs, imaging agents and/or antigens may be incorporated in the form of solid solutions or solid dispersions or onto which these materials may be absorbed , encapsulated or chemically bound.
Applicant argues that the specification details five classes of nanoparticles: polymer, lipid-based, inorganics-based, carbon-based and protein based complexes and a9 specific types of nanoparticles within these classes on page 18. Applicant concludes that the specification thus provides structural features common to the genus of nanoparticles claimed so that one of skill in the art could readily envisage members of the genus. This has been considered but not found persuasive.. the genus of nanoparticles is not the isolated nanoparticle per se, but the nanoparticle comprising the targeting agents that bind to 4-1BB and CD16 or 4-1BB and CD27 such that such that a simultaneous activation of the two cognate ligands on NK cells results in increased co-operative binding and more effective ligation of the co-stimulatory ligand on the same nanoparticle.
Applicant argues that the specification exemplifies the advantageous effects of PEG-PLGA nanoparticles comprising both alpha-CD16 and alpha-4-1BB n the manner claimed. This has been considered but not found persuasive. None of the claims are limited to PEG-PLGA nanoparticles and neither is mention made of the particular anti-CD116 and anti-4-1BB referred to as α-CD16 and α-4-1BB in the specification. . Applicant points out that NK cells contacted with a nanoparticles comprising both α-CD16 and α-4-1BB results in significantly greater cell cytotoxicity. It is noted in particular that the specification teaches that PEG-PLGA nanoparticles are functionalized with the α-CD16 and α-4-1BB. Applicant maintains that the functionalization of one nanoparticle with two types of targeting agent would provide the same advantageous effect, irrespective of the type of nanoparticle used. This has been considered but not found persuasive. The unexpected property of attributed to “increased cooperative binding” and more effective clustering to the CD16 and 4-1BB co-stimulatory molecules cannot be assumed in other nanoparticles with different surface chemistries and different linkages of the antibody to the surface because the nanoparticle field in relation to biology is not predictable. . Applicant argues that the high surface to volume ratio of the nanoparticles offers the advantage to manipulate their dimensions ad functionalize their surface with multivalent targeting moieties. This has been considered but not found persuasive because functionalization can occur at different densities providing different spatial relationships between the two antibodies .
Applicant argues that Kosmides describes iron-dextran nanoparticles containing anti-PD-L1 and anti-4-1BB which block the PD-L1 while activating 4-1BB, this has been considered but not found persuasive. The functionalized iron dextran particles of Kosmides do not provide a description of the nanoparticles of the claims. Applicant argues that Loftus describes the ability of a graphene oxide nanocluster to bind and activate CD16 on a NK cell surface. This has been considered but not found persuasive. The nanocluster of Loftus et al do not describe the nanoparticles of the instant claim.
Wu et al describes magnetic nanoparticles comprising EGFR and MICA/MICB which triggered expression of NKG2D, NKp30, NKp44, NKp46 and CD69 in NK cells. Park et al, Ye et al and Wu et al are all a post-filing reference and cannot suffice to describe the instant nanoparticles of the claims.
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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