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, 6-8, 11, 18, 25-31, 33-36, 40, and 41 are pending.
Claims 1, 3, 6-8, 11, 18, 25-31, 33-36, 40, and 41 are under examination on the merits.
Objection to the Drawings
The drawings, dated 07/26/2023, are objected to, because Figures 1-9 are blurry and crossed out. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections
35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 6-8, 11, 18, 25-31, 33-36, 40, and 41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 recites an aAPC that comprises a PLGA or PLA core (PLGA/PLA). The claim is indefinite, because it is unclear whether the core of the aAPC in claim 1 is intended to be a PGLA core, a PLA core, or a PLGA/PLA core. Claims 3, 6-8, 11, 18, 25-31, 33-36, 40, and 41 are included in this rejection, because they do not cure the deficiencies of claim 1 with respect to 35 U.S.C. 112(b).
Regarding claim 30, the term “optionally” renders the claim indefinite because it is unclear whether the limitation(s) following the term are part of the claimed invention. See MPEP § 2173.05(d).
Claim 36 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This claim refers to an IgG4 constant region comprising an unpaired cysteine at “codon 473”. Generally the location of a particular amino acid in a polypeptide is referred to in the art as a “position” or “residue”. As such the skilled artisan would have a reasonable uncertainty as to which IgG4 position (or residue) comprises the claimed unpaired cysteine.
35 U.S.C. 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.
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.
Claims 1, 3, 6-8, 25, 28, 29, 33, 40, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Fahmy et al. (US PG PUB 2010/0284965, publication date: 11/11/2010, IDS) and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010).
Fahmy et al. teach the use of nanoparticles that are artificial antigen-presenting cells (aAPCs) - “Modular aAPCs and methods of their manufacture and use are provided. The modular design of these polymeric aAPCs, which involves flexible addition and subtraction of functional elements including antigen-specific and polymeric T cell receptor activators, co-stimulatory and adhesion molecules, and cytokines allows for exquisite control over the signals provided to T cells by natural APCs… The modular aAPCs are constructed from polymeric nano- or microparticles.” See [0013] and [0014]. At [0015], Fahmy et al. teach that “antigen-presenting molecules can be MHC/HLA class I or class II molecules. The antigen-presenting molecules bind to antigens that can be peptides, polypeptides, proteins, polysaccharides, saccharides, lipids, nucleic acids, haptens or combinations thereof. In preferred embodiments the antigens (or antigenic fragment or epitope) are short peptides about 5-40 amino acids in length. The antigens can be viral antigens, bacterial antigens, parasite antigens, allergens or environmental antigens, tumor antigens…” At [0138], Fahmy et al. recite numerous tumor antigens that may be comprised within aAPCs, and said tumor antigens meet the limitation of a polypeptide ligand for immune cell activation. At [0148] and [0149], Fahmy et al. teach that “[i]n addition to ligation of the T cell receptor, activation and proliferation of lymphocytes are regulated by both positive and negative signals from costimulatory molecules. The most extensively characterized T cell costimulatory pathway is B7-CD28, in which B7-1 (CD80) and B7-2 (CD86) each can engage the stimulatory CD28 receptor and the inhibitory CTLA-4 (CD152) receptor. In conjunction with signaling through the T cell receptor, CD28 ligation increases antigen-specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function, and promotes survival of T cells (Lenshow, et al., Annu. Rev. Immunol., 14:233-258 (1996); Chambers and Allison, Curr. Opin. Immunol., 9:396-404 (1997); and Rathmell and Thompson, Annu. Rev. Immunol., 17:781-828 (1999))… The polymeric aAPCs described herein contain at least one co-stimulatory molecule. Exemplary co-stimulatory molecules, also referred to as ‘co-stimulators’, include, but are not limited to, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2, 4-1BBL, OX40L, inducible co-stimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD2, CD5, CD9, CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, HVEM, an agonist or antibody that binds Toll ligand receptor and a ligand that specifically binds with B7-H3. Other exemplary co-stimulatory molecules that can be used include antibodies that specifically bind with a co-stimulatory molecule present on a T cell, such as, but not limited to, CD27, CD28.”
At [0071] and [0072], Fahmy et al. teach that “the polymer that forms the core of the modular aAPC may be any biodegradable or non-biodegradable synthetic or natural polymer. In a preferred embodiment, the polymer is a biodegradable polymer. Polymeric systems have several features that make them ideal materials for the fabrication of a modular aAPC: 1) control over the size range of fabrication, down to 100 nm or less; 2) reproducible biodegradability without the addition of enzymes or cofactors; 3) capability for sustained release of an encapsulated, protected cytokine or chemokine over a period in the range of days to months by varying factors such as the monomer ratios or polymer size, for example, polylactic acid) (PLA) to poly(glycolic acid) (PGA) copolymer ratios, potentially abrogating the booster requirement (Gupta, et al., Adv. Drug Deliv. Rev., 32(3):225-246 (1998); Kohn, et al., J. Immunol. Methods, 95(1):31-8 (1986); Langer, et al., Adv. Drug Deliv. Rev., 28(1):97-119 (1997); Jiang, et al., Adv. Drug Deliv. Rev., 57(3):391-410)), well-understood fabrication methodologies that offer flexibility over the range of parameters that can be used for fabrication, including choices of the polymer material, solvent, stabilizer, and scale of production; and 5) control over surface properties facilitating the introduction of modular functionalities into the surface… Examples of preferred biodegradable polymers include synthetic polymers that degrade by hydrolysis such as poly(hydroxy acids), such as polymers and copolymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates), and poly(lactide-co-caprolactone).” Therefore Fahmy et al. teach that micro- and nanoparticles of the invention may comprise a polymer core that is a polymer of lactic acid (PLA). Fahmy et al. also teach that micro- and nanoparticles of the invention may comprise a polymer core that is a copolymer of lactic acid and glycolic acid, and absent evidence to the contrary, a copolymer of lactic acid and glycolic acid would meet the limitation of a PLGA, which is known as poly(lactic-co-glycolic) acid. At Figure 1B, Fahmy et al. teach that nanoparticles of the invention may have a size in the range of 20-200 nm.
Therefore Famhy et al. teach an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core; however Famhy et al. do not teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. This deficiency is remedied by Oerlemans et al.
Oerlemans et al. teach that “[m]icelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy.” See Abstract. At p. 270, Oerlemans et al. teach that “[t]his review will focus on micelles as a nanosized drug carrier system for cancer therapy and their modifications for tumor targeting…” At p. 2570, Oerlemans et al. teach that therapeutic micelles may include a hydrophilic shell - “The hydrophilic shell of the micelle provides steric stability and once properly selected avoids rapid uptake by the reticuloendothelial system (RES), resulting in prolonged circulation time in the body (12). Poly(ethylene glycol) (PEG) is the most commonly used hydrophilic polymer. PEG is water soluble, highly hydrated, an efficient steric protector, and biocompatible, and it has low toxicity…” At Fig. 1(b), Oerlemans et al. teach that targeting ligands may be terminally attached to the hydrophilic shell. As such Oerlemans et al. teach that nanosized drug carrier systems may comprise a hydrophilic shell formed of polyethylene glycol (PEG) brushes, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Famhy et al. with the teachings of Oerlemans et al. to develop an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. One of ordinary skill in the art would have been motivated to do so, because Famhy et al. teach an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core. Furthermore Oerlemans et al. teach that nanosized drug carrier systems may comprise a hydrophilic shell formed of polyethylene glycol (PEG) polymers, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. One of ordinary skill in the art would have been motivated to combine the cited references to arrive at the invention of claim 1, because one of ordinary skill in the art would appreciate the by modifying the aAPC of Famhy et al. to comprise a hydrophobic shell formed of PEG polymers, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as a tumor antigen, the resultant invention would be useful in the treatment of cancer.
With respect to claim 3, absent evidence to the contrary, it appears that a PLA polymer core meets the limitation of core of claim 1. As such the limitations of claim 3 are met, because a PLA polymer core would not be expected to comprise glycolic acid.
With respect to claim 6, at [0180], Famhy et al. teach that “[i]n this method, the use of polymers with molecular weights between 3-75,000 daltons is preferred.”
With respect to claims 7 and 8, at [0076], Famhy et al. teach that “[t]he foregoing materials may be used alone, as physical mixtures (blends), or as co-polymers. In a preferred embodiment, the aAPCs are formed of polymers fabricated from polylactides (PLA) and copolymers of lactide and glycolide (PLGA).” Furthermore Fig. 1(b) of Oerlemans et al. demonstrates that targeting ligands may be attached to functional groups of the PEG shell.
With respect to claim 25, at [0070], Fahmy et al. teach that “[a]s used herein, microparticles generally refers to both microparticles in the range of between 0.5 and 1000 microns and nanoparticles in the range of between 50 nm to less than 0.5 nm, preferably having a diameter that is between 1 and 20 microns or having a diameter that is between 50 and 500 nm…”
With respect to claim 28, at [0081], Famhy et al. teach that “[i]n a preferred embodiment, the coupling agent is present in high density on the surface of the aAPC. As used herein, ‘high density’ refers to polymeric aAPCs having a high density of ligands or coupling agents, which is preferably in the range of 1,000 to 10,000,000, more preferably 10,000-1,000.000 ligands per square micron...” A 50 or 500 nm diameter nanoparticle having 10,000-1,000.000 ligands per square micron would yield a nanoparticle with less than 200 ligands per particle.
With respect to claim 29, at [0104], Famhy et al. teach that “[i]n one embodiment, the aAPCs described herein contain antigen-presenting molecules having determinants which match that of a selected subject or which match any known antigen-presenting molecule determinants. The antigen-presenting molecules may be MHC/HLA class I or class II molecules.” Furthermore at [0149], Famhy et al. teach that “[t]he polymeric aAPCs described herein contain at least one co-stimulatory molecule… Other exemplary co-stimulatory molecules that can be used include antibodies that specifically bind with a co-stimulatory molecule present on a T cell, such as, but not limited to, CD27, CD28, 4-IBB…”
With respect to claim 33, at [0106], Famhy et al. teach that “[c]lass I transplantation antigens of the major histocompatibility complex (MHC) or HLA are cell surface glycoproteins which present antigens to cytotoxic T-cells. They are heterodimeric…”
With respect to claims 40 and 41, given that the invention of the prior art comprises a tumor antigen, said invention would be expected to elicit antigen-specific cytotoxic T cell responses, which would provide a therapeutic effect to patients having cancers that express said tumor antigen.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Claims 11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Fahmy et al. (US PG PUB 2010/0284965, publication date: 11/11/2010, IDS) and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010), as applied to claims 1, 3, 6-8, 25, 28, 29, 33, 40, and 41, and further in view of Riley et al. (Langmuir, 19: 8428-8435, 2003, IDS).
The teachings of Fahmy et al. and Oerlemans et al. are detailed above. These references teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. These references do not teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, wherein the PLA portion of the PLA-PEG has a molecular weight of about 10K - 50K (or the PLGA portion of the PLGA-PEG has a molecular weight of about 10K - 50K) and the PEG portion has a molecular weight of about 3K and/or about 5K. These deficiencies are remedied by Riley et al.
Riley et al. teach that nanoparticles for use in therapeutic applications may be prepared from PLA–PEG polymer, using a PLA block of between 3 and 45 kDa and a fixed PEG of 5kDa, see Abstract. At p. 8428, Riley et al. teach that “[t]he inherent core-shell structure of micelles and nanoparticles assembled from amphiphilic block copolymers makes them interesting candidates as drug carriers for targeted delivery. Drugs may be incorporated into the core of the assemblies by either covalent or noncovalent bonding, such as hydrophobic or ionic interactions. Poly(ethylene glycol) (PEG) is usually chosen as the hydrophilic buoy block whose role is to provide a hydrated steric barrier… AB block copolymers of PEG with either poly(lactic acid) (PLA−PEG) or poly(lactic acid-co-glycolic acid) (PLGA−PEG) have been extensively investigated as drug delivery vehicles, since the core-forming block is fully biodegradable. By varying the molecular weight ratio of the hydrophobic and hydrophilic blocks, it is possible to control the aggregation behavior of the copolymer.”
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Fahmy et al. and Oerlemans et al. with the teachings of Riley et al. to develop an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, wherein the PLA portion of the PLA-PEG has a molecular weight of about 10K - 50K (or the PLGA portion of the PLGA-PEG has a molecular weight of about 10K - 50K) and the PEG portion has a molecular weight of about 3K and/or about 5K. One of ordinary skill in the art would have been motivated to do so, because Fahmy et al. and Oerlemans et al. teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. Furthermore Riley et al. teach that nanoparticles for use in therapeutic applications may be prepared from PLA–PEG polymer, using a PLA block of between 3 and 45 kDa and a fixed PEG of 5kDa, see Abstract. As such one of ordinary skill in the art would have been motivated to modify the nanoparticle of Fahmy et al. and Oerlemans et al. to include a PLA block of between 3 and 45 kDa and a fixed PEG of 5kDa, because there would have been a reasonable expectation that the resultant invention would be effective in the treatment of cancer. Additionally given that varying the molecular weight ratio of the hydrophobic and hydrophilic blocks allows for the control of aggregation, one of ordinary skill in the art would have been motivated to optimize the molecular weight of the PLGA-PEG component, and absent evidence to the contrary, it is submitted that such an optimization process would lead to the PLGA-PEG molecular weights recited in claim 11.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Claims 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Fahmy et al. (US PG PUB 2010/0284965, publication date: 11/11/2010, IDS) and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010), as applied to claims 1, 3, 6-8, 25, 28, 29, 33, 40, and 41, and further in view of He et al. (Biomaterials, 31: 3657-3666, 2010).
The teachings of Fahmy et al. and Oerlemans et al. are detailed above. These references teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. These references do not teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, wherein the aAPC has a surface charge of about 0 to -20 mV (or about 5 to about -10 mV. These deficiencies are remedied by He et al.
He et al. teach that “to elucidate the effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles (NPs), rhodamine B (RhB) labeled carboxymethyl chitosan grafted NPs (RhB-CMCNP) and chitosan hydrochloride grafted NPs (RhB-CHNP) were developed as the model negatively and positively charged polymeric NPs, respectively. These NPs owned well defined particle sizes (150–500 nm) and Zeta potentials (−40 mV – +35 mV).” See Abstract. At p. 3665, He et al. teach that “[s]olid tumors, along with inflammation and deliberate disruption of endothelia, contributed to an increased leakage which might provide vascular contents with greater access to extravascular targets [11]. The higher distribution percent in tumor for RhB-CMCNP-PS bearing less negative charges might be due to the prolonged blood circulation time. RhB-CHNP-CPT bearing more positive charges exhibited higher distribution percentage in tumor because after reaching the leaky tumor microvasculature, NPs with higher positive charges would be more efficiently to depart from the interstitium and to be internalized by the endothelium or tumor cells contiguous to the endothelium. Smaller particle size was favorable for passive targeting to the tumor owing to the ‘enhanced permeability and retention’ (EPR) effects which resulted in the efficient accumulation in tumor of NPs with diameter of approximately 150 nm. RhB-CMCNP-PS with lower surface charge and smaller particle size promoted longer blood residence time, thereby contributing to its stronger affinity for tumor endothelial cells and relatively higher accumulation in the tumor vasculature. NPs bearing slight negative charges could contribute more to the elongation of blood circulation time than positively charged NPs with the same particle size (emphasis added).” Based upon the teachings of He et al., one of ordinary skill in the art would have been motivated to prepare relatively small NPs to have a lower (or slightly negative) surface charges, because this would result in NPs having a longer blood residence time, thereby contributing to a strong affinity for endothelial cells and relatively higher accumulation in the tumor vasculature.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Fahmy et al. and Oerlemans et al. with the teachings of Riley et al. to develop an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, wherein the aAPC has a surface charge of about 0 to -20 mV (or about 5 to about -10 mV. One of ordinary skill in the art would have been motivated to do so, because Fahmy et al. and Oerlemans et al. teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. Furthermore based upon the teachings of He et al., one of ordinary skill in the art would have been motivated to prepare relatively small NPs to have a lower (or slightly negative) surface charges, because this would result in NPs having a longer blood residence time, thereby contributing to a strong affinity for endothelial cells and relatively higher accumulation in the tumor vasculature. As such one of ordinary skill in the art would have been motivated to prepare the nanoparticle formulation of Fahmy et al. and Oerlemans et al. to comprise smaller size (approx. 150 mn) nanoparticles with a slight negative charge, as the resultant nanoparticle formulation would be expected to exhibit a strong affinity for endothelial cells and relatively higher accumulation in the tumor vasculature.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Claims 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Fahmy et al. (US PG PUB 2010/0284965, publication date: 11/11/2010, IDS) and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010), as applied to claims 1, 3, 6-8, 25, 29, 33, 35, 40, and 41, and further in view of Vasquez et al. (US PG PUB 2010/0056386, publication date: 03/04/2010).
The teachings of Fahmy et al. and Oerlemans et al. are detailed above. These references teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as an anti-CD28 antibody ligand. These references do not teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as an anti-CD28 antibody ligand having a human IGHV4-59 framework and an IGKV4-01 framework. These deficiencies are remedied by Vasquez et al.
Vasquez et al. teach that antibodies may be prepared with an IGHV4-59 heavy chain framework and an IGKV-04 light chain framework, see [0085] - [0091].
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Fahmy et al. and Oerlemans et al. with the teachings of He et al. to develop an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as an anti-CD28 antibody ligand having a human IGHV4-59 framework and an IGKV4-01 framework. One of ordinary skill in the art would have been motivated to do so, because Fahmy et al. and Oerlemans et al. teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. Furthermore Vasquez et al. teach that antibodies may be prepared with an IGHV4-59 heavy chain framework and an IGKV-04 light chain framework. As such one of ordinary skill in the art would have been motivated to prepare the nanoparticle of Fahmy et al. and Oerlemans et al., which comprises an anti-CD28 antibody ligand, to comprise the framework regions of Vasquez et al., because the resultant nanoparticle would be effective in treating cancer.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Claims 34 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Fahmy et al. (US PG PUB 2010/0284965, publication date: 11/11/2010, IDS) and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010), as applied to claims 1, 3, 6-8, 25, 28, 29, 33, 40, and 41, and further in view of Schütz et al. (Cancer Gene Therapy, 8(9): 655-661, 2001).
The teachings of Fahmy et al. and Oerlemans et al. are detailed above. These references teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as a peptide-HLA ligand. These references do not teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as a peptide-HLA ligand, wherein the HLA is HLA-A*02:01. These deficiencies are remedied by Schütz et al.
Schütz et al. teach that “[t]he effect on immunogenicity of different tumor T cell epitope formulations was evaluated in vitro using nonreplicating recombinant vaccinia vector expressing two forms of the melanoma-associated MART-1/Melan-A antigen. The first recombinant virus expressed a minigene encoding a fusion product between an endoplasmic reticulum (ER)-targeting signal and the HLA-A201 binding 27-35 peptide. The second viral construct encoded the complete MART-1/Melan-A protein. The capacity of HLA-A201 cells infected with either viral construct to generate and to stimulate MART-1/Melan-A 27-35 specific cytotoxic T -lymphocytes (CTL), was comparatively characterized. The results obtained here with a tumor antigen confirmed the capacity of vaccinia virus-encoded ER-minigene to generate a very strong antigenic signal.” See Abstract. At p. 660, Schütz et al. teach that “[w]ithin this frame, our work with psoralen UV-treated vaccinia vector with MART- 1/Melan -A immunogenicity in HLA -A201 context, clearly confirmed the notion that targeted minigenes encoding for immunogenic epitopes represent one of the most effective formulation to generate epitope specific immune responses. In addition, generation of specific CTL found in our current clinical study (manuscript in preparation), seems to support the effectiveness of such rVV-ER -minigene vaccines in vivo.” Based upon the teachings of Schütz et al., one of ordinary skill in the art would appreciate that antigens derived from the MART-1/Melan-A protein may be presented by HLA-A*02:01 to elicit CTL responses directed to melanoma.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Fahmy et al. and Oerlemans et al. with the teachings of Schütz et al. to develop an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as a peptide-HLA ligand, wherein the HLA is HLA-A*02:01. One of ordinary skill in the art would have been motivated to do so, because Fahmy et al. and Oerlemans et al. teach or suggest an aAPC comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising a PLGA or PLA polymer core and a hydrophilic shell formed of PEG, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as a peptide-HLA ligand. Based upon the teachings of Schütz et al., one of ordinary skill in the art would appreciate that antigens derived from the MART-1/Melan-A protein may be presented by HLA-A*02:01 to elicit CTL responses directed to melanoma. As such one of ordinary skill in the art would have been motivated to prepare the nanoparticle of Fahmy et al. and Oerlemans et al. to comprise an HLA-A*02:01 ligand loaded with a MART-1/Melan-A peptide, because there would have been a reasonable expectation that the resultant invention would be effective in treating melanoma.
With respect to claim 35, at [0122], Famhy et al. teach that “[t]he variant MHC/HLA polypeptides disclosed herein may also be coupled to other polypeptides to form fusion proteins. Provided are variant MHC/HLA polypeptides having a first fusion partner comprising all or a part of a MHC/HLA polypeptide fused (i) directly to a second polypeptide or, (ii) optionally, fused to a linker peptide sequence that is fused to the second polypeptide.” As indicated above, at [0149], Famhy et al. teach that “[t]he polymeric aAPCs described herein contain at least one co-stimulatory molecule… Other exemplary co-stimulatory molecules that can be used include antibodies that specifically bind with a co-stimulatory molecule present on a T cell, such as, but not limited to, CD27, CD28, 4-IBB…” In instances where MHC/HLA are fused to a second polypeptide, such as a co-stimulatory anti-CD28 antibody, the resultant HLA fusion would comprise immunoglobulin sequences.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 6-8, 11, 18, 25-29, 33, 35, 36, 40, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 9, 11, 13, 15, 17, and 18 of U.S. Patent No. 11,510,981.
With respect to claims 1, 6, 7, 11, 18, and 25, although the claims at issue are not identical, they are not patentably distinct from each other, because conflicting claim 1 encompasses an artificial antigen presenting cell (aAPC) comprising a polymeric nanoparticle having attached polypeptide ligands suitable for immune system activation, the nanoparticle having a size in the range of 20 to 200 nm, the nanoparticle comprising: a poly(lactic-co-glycolic acid) (PLGA) or polylactic acid (PLA) polymer core (PLGA/PLA), and a hydrophilic shell formed of polyethylene glycol (PEG), wherein the PLGA/PLA portion has a molecular weight of from about 10 kDa to about 30 kDa and the PEG portion has a molecular weight(s) of from about 2 kDa to about 10 kDa, wherein a portion of the PLGA/PLA-PEG polymers have a terminal attachment of a polypeptide ligand.
With respect to claim 3, absent evidence to the contrary, it appears that a PLA polymer core meets the limitation of core of claim 1. As such the limitations of claim 3 are met, because a PLA polymer core would not be expected to comprise glycolic acid.
With respect to claim 8, conflicting claim 6 recites that the polypeptide ligands are attached to PEG through primary amines.
With respect to claims 26 and 27, the recited surface charges are recited in conflicting claims 8 and 9.
With respect to claim 28, conflicting claim 11 recites nanoparticles having less than 300 polypeptide ligands per particle.
With respect to claim 29, conflicting claim 13 recites polypeptide ligands that are anti-CD28 antibodies.
With respect to claim 33, conflicting claim 15 recites a dimeric HLA ligand.
With respect to claim 35, conflicting claim 17 recites that the HLA comprises a fusion with immunoglobulin sequences.
With respect to claim 36, conflicting claim 18 recites that the aAPC comprises an anti-CD28 antibody ligand, and each of the HLA immunoglobulin fusion polypeptide ligands and the anti-CD28 antibody ligands have an IgG4 constant region with mutations at codons S241 and L248, and an unpaired cysteine at codon 473.
Claims 30 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, 8, 9, 11, 13, 15, 17, and 18 of U.S. Patent No. 11,510,981, as applied to claims 1, 3, 6-8, 11, 18, 25-29, 33, 35, 36, 40, and 41, and further in view of Vasquez et al. (US PG PUB 2010/0056386, publication date: 03/04/2010).
The teachings of Vasquez et al. are detailed above.
In view of these teachings, one of ordinary skill in the art would have been motivated to modify the conflicting claims to include an anti-CD28 antibody ligand having a human IGHV4-59 framework and an IGKV4-01 framework. Said modification would result in an aAPC that could be used to stimulate T cell responses.
Therefore the instant claims are prima facie obvious over the conflicting claims in view of Vasquez et al.
Claim 34 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, 8, 9, 11, 13, 15, 17, and 18 of U.S. Patent No. 11,510,981, as applied to claims 1, 3, 6-8, 11, 18, 25-29, 33, 35, 36, 40, and 41, and further in view of Schütz et al. (Cancer Gene Therapy, 8(9): 655-661, 2001).
The teachings of Schütz et al. are detailed above.
In view of the teachings of Schütz et al., one of ordinary skill in the art would appreciate that antigens derived from the MART-1/Melan-A protein may be presented by HLA-A*02:01 to elicit CTL responses directed to melanoma. As such one of ordinary skill in the art would have been motivated to modify the conflicting claims to comprise an HLA-A*02:01 ligand loaded with a MART-1/Melan-A peptide, because there would have been a reasonable expectation that the resultant invention would be effective in treating melanoma.
Therefore the instant claims are prima facie obvious over the conflicting claims in view of Schütz et al. et al.
Claims 1, 3, 6-8, 11, 18, 25, 35, 40, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 21 of U.S. Patent No. 10,632,193 in view of Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010).
Claims 1 and 21 of U.S. Patent No. 10,632,193 recite a nano-scale artificial antigen presenting cell (aAPC) comprising: a nanoparticle having an average diameter of less than about 400 nm, comprising a hydrophilic sheath formed from polyethylene glycol (PEG) chains; a population of anti-CD28 T cell costimulatory ligands on the surface of the nanoparticle; and a population of MHC Class I antigen presenting complex ligands on the surface of the nanoparticle, wherein the nanoparticle comprises a PLGA or PLA polymer core and wherein the polymer core is based on 1:0 to 1:1 Lactic Acid:Glycolic Acid ratio.
The teachings of Oerlemans et al. are detailed above.
Oerlemans et al. teach that nanosized drug carrier systems may comprise a hydrophilic shell formed of polyethylene glycol (PEG) polymers, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand. In view of these teachings, one of ordinary skill in the art would have been motivated to modify the conflicting claims to recite a hydrophobic shell formed of PEG polymers, wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand, such as a tumor antigen, because the resultant invention would be useful in the treatment of cancer, thus meeting the limitations of the instant claim 1.
With respect to claim 3, conflicting claim 21 recites that the nanoparticle comprises a PLGA or PLA polymer core and wherein the polymer core is based on 1:0 to 1:1 Lactic Acid:Glycolic Acid ratio.
With respect to claim 6, conflicting claim 23 recites that the nanoparticle comprises a PLGA or PLA polymer core and the core polymer has a molecular weight of from about 10K to about 50K.
With respect to claims 7 and 8, conflicting claims 24 and 25 recite that 1) the nanoparticle comprises a PLGA or PLA polymer core, and PLGA-PEG and/or PLA-PEG block co-polymers, the PEG portion forming the hydrophilic shell and 2) the polypeptide ligands are attached through functional groups at the PEG terminus.
With respect to claims 11 and 18, conflicting claim 26 recites that the nanoparticle comprises a PLGA or PLA polymer core and wherein the PLA-PEG co-polymer contains a PLA portion having a molecular weight of from about 10K to about 50K, and a PEG portion having molecular weight(s) of from about 2K to about 10K, or wherein the PLGA-PEG co-polymer contains a PLGA portion having molecular weight of from about 10K to about 50K, and a PEG portion having molecular weight(s) of from about 2K to about 10K.
With respect to claim 25, conflicting claim 13 recites that the nanoparticles have a size in the range of about 20 to 200 nm.
With respect to claim 35, conflicting claim 28 recites HLA amino acid sequences fused to immunoglobulin sequences.
With respect to claims 40 and 41, conflicting claim 1 recites a method of treating cancer by administering an aAPC, which would be expected to result in the formation of antigen-specific cytotoxic T cells.
Therefore the instant claims are prima facie obvious over the conflicting claims in view of Oerlemans et al. et al.
Claims 26 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 21 of U.S. Patent No. 10,632,193 and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010), with respect to claims 1, 3, 6-8, 11, 18, 25, 40, and 41, and further in view of He et al. (Biomaterials, 31: 3657-3666, 2010).
The teachings of He et al. are detailed above.
Based upon the teachings of He et al., one of ordinary skill in the art would have been motivated to prepare relatively small NPs to have a lower (or slightly negative) surface charges, because this would result in NPs having a longer blood residence time, thereby contributing to a strong affinity for endothelial cells and relatively higher accumulation in the tumor vasculature. As such one of ordinary skill in the art would have been motivated to prepare the nanoparticle formulation of the conflicting claims to comprise smaller size (approx. 150 mn) nanoparticles with a slight negative charge, as the resultant nanoparticle formulation would be expected to exhibit a strong affinity for endothelial cells and relatively higher accumulation in the tumor vasculature.
Therefore the instant claims are prima facie obvious over the conflicting claims in view of He et al. et al.
Claims 28, 29, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 21 of U.S. Patent No. 10,632,193 and Oerlemans et al. (Pharm Res, 27: 2569-2589, 2010), with respect to claims 1, 3, 6-8, 11, 18, 25, 40, and 41, and further in view of Fahmy et al. (US PG PUB 2010/0284965, publication date: 11/11/2010, IDS).
The teachings of Famhy et al. are detailed above.
With respect to claim 28, at [0070], Fahmy et al. teach that “[a]s used herein, microparticles generally refers to both microparticles in the range of between 0.5 and 1000 microns and nanoparticles in the range of between 50 nm to less than 0.5 nm, preferably having a diameter that is between 1 and 20 microns or having a diameter that is between 50 and 500 nm…” At [0081], Famhy et al. teach that “[i]n a preferred embodiment, the coupling agent is present in high density on the surface of the aAPC. As used herein, ‘high density’ refers to polymeric aAPCs having a high density of ligands or coupling agents, which is preferably in the range of 1,000 to 10,000,000, more preferably 10,000-1,000.000 ligands per square micron...” A 50 or 500 nm diameter nanoparticle having 10,000-1,000.000 ligands per square micron would yield a nanoparticle with less than 200 ligands per particle.
With respect to claim 29, at [0104], Famhy et al. teach that “[i]n one embodiment, the aAPCs described herein contain ant