DETAILED ACTION
Notice of 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 .
Status of the Claims
The amendments filed 6/22/2026 have been entered.
Response to Arguments
Applicant traverses the rejections of claims under 35 U.S.C. 103(a) as being unpatentable primarily over Baberio et al (ACS Nano 14:11238-11258, 2020; of record) in view of Chen et al (Bioconjug Chem 29:1251-1260, 2018; of record) and Postma et al (JPET 288:114-120, 1999; of record).
Applicant first argues that “[t]he Office Action has not established that a skilled person would have modified the liposomes of Barberio based on Chen and Postma with a reasonable expectation of success in achieving the results of the claimed particles” (Applicant Arguments, Page 10). Applicant additionally argues that “the claimed particles have unexpected properties that could not have been reasonably predicted by one of ordinary skill in the art” (Applicant Arguments, Page 11).
FIRST, regarding Applicant’s argument that “[t]he Office Action has not established that a skilled person would have modified the liposomes of Barberio based on Chen and Postma with a reasonable expectation of success in achieving the results of the claimed particles” (Applicant Arguments, Page 10), it is noted that Applicant provides no reasoning in support of the argument that “that a skilled person would [not] have modified the liposomes of Barberio based on Chen and Postma”. Rather, Applicant’s arguments focus on whether an ordinarily skilled artisan would have modified the liposomes of Barberio et al as proposed “with a reasonable expectation of success”. As argued by Applicant, “the Office Action points to no teaching or suggestion in the cited references indicating that a skilled person would reasonably expect that: (1) a covalently conjugated immunostimulatory agent would remain functionally compatible with an anion/cation layer-by-layer coating as described; (2) the immunostimulatory agent would remain accessible post-conjugation; or (3) the resulting particle would retain the immunostimulatory agent in serum and maintain cell-surface association” (Applicant Arguments, Page 11). Additionally, Applicant argues that “[t]he experimental data in the Application demonstrate... unpredictability and establish that one of ordinary skill in the art would not have... reasonably expected the substitution proposed by the Office Action (i.e., noncovalent for covalent attachment) to yield the results achieved by the claimed particles” (Applicant Arguments, Page 12). And, as to the alleged “results achieved by the claimed particles”, Applicant points to data addressing retention of IL-12 and IL-12 trafficking in vivo (Applicant Arguments, Page 12).
The argument is not found persuasive. At the outset, Applicants are reminded that obviousness does not require absolute predictability, only a reasonable expectation of success of obtaining similar properties (In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988)). In the instant case, it is maintained it would have been prima facie obvious to synthesize the liposomes of Baberio et al utilizing 5% MPB-PE in place of 5% DGS-NTA (Ni) with a reasonable expectation of success. As specifically taught by Barberio et al, “[t]he general design is... easily adaptable to many other conjugation strategies for linking the cytokines to liposomes that can be used to modulate the release rate of the delivered proteins” (Page 11249, Column 1).
Furthermore, it is not necessary that the prior art suggest the combination of references to achieve the same advantage or result discovered by Applicant (i.e., “to achieve the technical effects demonstrated by the claimed particles”). Rather, the reason or motivation to modify a reference to arrive at the claimed invention can be for a different purpose or to solve a different problem (e.g., to avoid the “undesired drawbacks” and potential “regulatory concern[s]” associated with “the noncovalent nature of [DGS-NTA (Ni)] coordination chemistry” and “the adverse biological effects of nickel ions in vivo”) (see In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) - motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention)). The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious (see Ex parte Obiaya, 227 USPQ 58 (Bd. Pat. App. & Inter. 1985)).
SECOND, regarding Applicant’s arguments that “the claimed particles have unexpected properties that could not have been reasonably predicted by one of ordinary skill in the art” (Applicant Arguments, Page 11), Applicant argues that “the Application describes systematic evaluation of four different particle formats: (1) Ni-UL (e.g., noncovalent-unlayered); (2) Ni-LbL (e.g., noncovalent-LbL); (3) Mal-UL (e.g., covalent-unlayered); and (4) Mal-LbL (e.g., covalent-LbL)” all of which “had similar sizes, surface charges, and zeta potential measurements” (Applicant Arguments, Page 11). Significantly, however:
whereas (1)-(3) “all presented similar half-lives of 2-3 hours” in serum-stability studies evaluating immunostimulatory agent retention, “covalent-LbL particles of the present claims exhibited... retention of IL-12 with a half-life of 9 hours” (Applicant Arguments, Page 12);
in “experiments investigating... IL-12 trafficking in vivo... the covalent-LbL particles... achieved the slowest clearance rate from the i.p. cavity” (Applicant Arguments, Page 12); and
in “in vivo mouse therapeutic studies... treatment with free IL-12, noncovalent-unlayered, noncovalent-LbL, and covalent-unlayered particles showed an increase in median survival [from 23 days in untreated tumors] to ~33 days” before “tumors ultimately relapsed and caused death in the vast majority of treated animals” whereas “treatment with covalent-LbL particles... increased median survival to 44 days, with ~30% of the animals eliciting complete responses” (Applicant Arguments, Page 13).
It is well settled that a showing of unexpected results is generally sufficient to overcome a prima facie case of obviousness. In re Albrecht, 514 F.2d 1389 (CCPA 1975). However, as recognized by the court in In re Schulze, 346 F.2d 600 (CCPA 1965), mere arguments are not sufficient to demonstrate unexpected results. Rather, unexpected results must be established by factual evidence by comparing the claimed invention with that of the closest prior art. In re Burckel, 592 F.2d 1175 (CCPA 1979). As discussed by the court in In re De Blauwe, 736 F.2d 699 (Fed. Cir. 1994), “the absence of tests comparing [Applicant’s claimed invention] with those of the closest prior art… constitute mere argument”.
In the instant case, the comparison of Mal-LbL (e.g., covalent-LbL) with Ni-LbL (e.g., noncovalent-LbL) is considered an appropriate comparison of the claimed invention with that of the closest prior art. And, it is found persuasive that instantly claimed particles demonstrate unexpected results when compared to the closest prior art. However, although the evidence establishes unexpected results, Applicant is reminded that “the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support”. In re Clemens, 622 F.2d 1029 (CCPA 1980). In the instant case, the claims are not drafted commensurate in scope with the unexpected results to overcome the prima facie case of obviousness. The unexpected results are limited to particles comprising (a) a liposome comprising 5% MPB-PE, 65% DSPC, 24% cholesterol, and 6% POPG covalently linked to IL-12, and (b) a polymer coating comprising PLR non-covalently associated with the other surface of the liposome and PLE non-covalently associated with the at least one polycation layer.
As such, the rejection of claims under 35 U.S.C. 103(a) has not been overcome. The claims are MAINTAINED rejected.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
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 1-2, 5, 8, 12, 14-15, 20, 22, 24, 27, 30, 56-57, 67 and 72 are MAINTAINED rejected under 35 U.S.C. 103(a) as being unpatentable over Baberio et al (ACS Nano 14:11238-11258, 2020; of record) in view of Chen et al (Bioconjug Chem 29:1251-1260, 2018; of record) and Postma et al (JPET 288:114-120, 1999; of record).
Claims 1-2, 5, 8, 12, 14-15, 20, 22, 24, 27 and 30 are drawn to a particle comprising:
(a) a liposome, wherein the liposome comprises:
(i) at least one first lipid (more specifically, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophneyl)butramide] (MPB-PE) (claim 12)) covalently bonded (more specifically, via maleimide-cysteine conjugation (claim 20)) to at least one immunostimulatory agent (more specifically, a cytokine (claim 27), even more specifically single chain interleukin 12 (scIL-12) (claim 30)), wherein the first lipid forms an outer surface of the liposome;
(ii) a second lipid that is the phospholipid 1.2-distearoyl-sn-glycero-3-phosphocholine (DSPC) (claim 2));
(iii) a third lipid that is the sterol cholesterol (claim 5); and
(iv) a fourth lipid that is the anionic lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1’-rac-glycerol) (POPG) (claim 8);
wherein the liposome comprises 5% MPB-PE, 65% DSPC, 24% cholesterol, and 6% POPG (claims 14-15); and
(b) a polymer coating, wherein the polymer coating comprises:
(i) at least one layer including a polycation (more specifically, poly-L-arginine (PLR) (claim 22)), wherein the polycation is non-covalently associated with the other surface of the liposome; and
(ii) at least one layer including a polyanion (more specifically, poly-L-glutamic acid (PLE) (claim 24)), wherein the polyanion is non-covalently associated with the at least one polycation layer.
Baberio et al teach “liposomes… containing 5% DGS-NTA (Ni), 65% DSPC, 23.9% Cholesterol, and 6.1% POPG by mole” to which “[s]ingle chain IL-12 was added to liposomes” after which the “[p]articles were added to a bath of PLR solution… and allowed to equilibrate” and, “[s]imilarly for terminal layer polyanion [wherein “[f]or the external layer… poly-L-glutamic acid (PLE) [was] chosen” (Page 5)], particles were then added to a bath of polymer” (Page 14, Particle Formulation and Characterization).
Accordingly, Baberio et al teach particles which differ from the instantly claimed particles in that the liposomes of Baberio et al comprise 5% DGS-NTA (Ni) as opposed to 5% MPB-PE.
Yet, as taught by Chen et al, “Ni-chelating liposomes have been widely used as protein carriers… owing to the convenience and versatility of this conjugation chemistry” (Abstract) and, “[a]lthough the use of Ni-NTA coordination chemistry is of great convenience considering the varieties of recombinant proteins that can be purified using hexahistidine technology, the noncovalent nature of this coordination chemistry may give rise to undesired drawbacks” (Page 7, Stability of the Ni-NTA Noncovalent Conjugation Chemistry). In particular, “instability of protein conjugation is an issue intrinsic to the Ni-NTA chelation chemistry… [and] proteins bound on liposomes via Ni-chelation chemistry will dissociate rapidly in the presence of serum” (Page 8, Stability of the Ni-NTA Noncovalent Conjugation Chemistry; see also Page 9, Discussion: “due to its noncovalent nature, the spatial density of proteins is not stable but decreases upon dilution”).
And, as further taught by Chen et al, “substantial studies in the literature have documented the adverse biological effects of nickel ions in vivo, which include tissue inflammation that is correlated with their distributions, allergy, toxicity, and carcinogenicity. Moreover, the hexahistidine tags might also be immunogenic in vivo, which may elicit antibodies targeting histidine repeats and thus represent an off-target effect, whose safety profile remains to be demonstrated. As a result, Ni-chelating liposomes may encounter significant safety challenges toward a final clinical product” (Page 9, Discussion).
As such, Chen et al suggest that an “alternative approach such as maleimide–thiol reaction to conjugate epitopes onto the liposome surface is worth pursuing in the future, and the covalent chemistry may yield a spatial density that is stable over time. Moreover, from the perspective of future applications, the maleimide–thiol conjugation is less likely to be a regulatory concern because several FDA approved drug products contain maleimide–thiol conjugates” (Page 9, Discussion).
Notably, Postma et al (JPET 288:114-120, 1999) teach liposomes comprising the cytokine “rhTNF-α covalently coupled to the outer surface of [the] liposomes” (Abstract) via MPB-PE (Page 287, Figure 1).
Accordingly, it would have been prima facie obvious to synthesize the liposomes of Baberio et al utilizing 5% MPB-PE in place of 5% DGS-NTA (Ni). It would have been obvious to utilize a “maleimide–thiol reaction to conjugate [the peptide] onto the liposome surface” as opposed to the noncovalent DGS-NTA (Ni) linkage in order to avoid the “undesired drawbacks” and potential “regulatory concern[s]” associated with “the noncovalent nature of [DGS-NTA (Ni)] coordination chemistry” and “the adverse biological effects of nickel ions in vivo” as taught by Chen et al. In particular, it would have been obvious to use MPB-PE based further on Postma et al, which specifically teach using MPB-PE to covalently conjugate a cytokine to a liposomal surface, with a reasonable expectation of success.
In view of all of the foregoing, claims 1-2, 5, 8, 12, 14-15, 20, 22, 24, 27 and 30 are rejected as prima facie obvious.
Claims 56 and 57, drafted independently, are drawn to a method of delivering an immunostimulatory agent to a target cell (claim 56) and recruiting immune cells to a target cell (claim 57), wherein the methods comprise contacting the target cell with a particle of claim 1 .
Barberio et al teach the “NP to meet the enhanced demands for optimal cytokine delivery” (Abstract), further disclosing “IL-12 delivery against cancer” comprising “localization of NPs on the surface of tumor cells” (Page 4) as well as “deliver[ing] cytokine to immune cells” (Page 6) and “driving immune infiltration and activity in these difficult to treat tumors” (Page 10).
As such, claims 56-57 are also rejected as prima facie obvious.
Claims 67 and 72 are drawn to a method of treating a disease in a subject in need thereof (more specifically, colon cancer, ovarian cancer, etc. (claim 72)), the method comprising administering to the subject an effective amount of a particle of claim 1.
Barberio et al teach “IL-12 delivery from the described NP carrier... to provide antitumor efficacy” in “MC38 colon cancer and... HM-1 ovarian cancer”, specifically demonstrating “improvement in tumor responses.... slower tumor growth and a statistically significant survival benefit” (Page 8, PLE-IL-12-NPs maintain efficacy of IL-12 therapy in multiple tumor models).
As such, claims 67 and 72 are also rejected as prima facie obvious.
Claims 43-44 and 77 are rejected under 35 U.S.C. 103(a) as being unpatentable over Baberio et al (ACS Nano 14:11238-11258, 2020; of record) in view of Chen et al (Bioconjug Chem 29:1251-1260, 2018; of record) and Postma et al (JPET 288:114-120, 1999; of record) as applied to claims 1-2, 5, 8, 12, 14-15, 20, 22, 24, 27, 30, 56-57, 67 and 72 above, in further view of Barberio et al (US 2019/0125895; of record).
Claims 43-44 are drawn to a pharmaceutical composition comprising a plurality of particles of claim 1 and a pharmaceutically acceptable excipient (claim 43) and an additional pharmaceutical agent such as a chemotherapeutic (claim 44).
As discussed above, Baberio et al in view of Chen et al and Postma et al teach particles of claim 1. Additionally, Barberio et al teach a pharmaceutical composition thereof (see Page 17, In vivo toxicity tests: “mice were injected subcutaneously... with... PLE-IL-12-NPs”).
However, the prior art do no explicitly teach a pharmaceutical composition comprising a plurality of particles of claim 1, a pharmaceutically acceptable excipient, and an additional pharmaceutical agent such as a chemotherapeutic.
Yet, Barberio et al ‘895 teach a related “liposomal core nanoparticle with 5% DGS-NTA (Ni)... with an scIL-12 construct... coated with a bilayer of... PLR and a terminal layer of polyanion” (Paragraph 0124) wherein “[i]n certain embodiments, the... particle compris[es] a second lipid... DSPC... a third lipid... POPG.... [and] a fourth lipid... cholesterol” (Paragraphs 0101-0105) as well as “a pharmaceutical formulation comprising a plurality of particles and a pharmaceutically acceptable carrier” (Paragraph 0119) wherein “particles will be formulated by including additional drugs (chemotherapy, synergistic cytokines, etc.)” (Paragraph 0140).
Accordingly, in further view of Barberio et al ‘895, it would have been obvious to formulate the particles of claim 1 and a composition thereof as taught by Baberio et al in view of Chen et al and Postma et al as a pharmaceutical composition comprising a plurality of said particles, a pharmaceutically acceptable excipient, and an additional pharmaceutical agent such as a chemotherapeutic, with a reasonable expectation of success.
As such, claims 43-44 are also rejected as prima facie obvious.
Claim 77 is drawn to a kit comprising a particle of claim 1 and instructions for using the particle.
Barberio et al ‘895 further teach that “[t]he inventions are directed to each individual feature... [and] kit” or “any combination of two or more such features... [or] kits” (Paragraph 0142). Although Barberio et al ‘895 do not disclose instructions for using the particle, as discussed by MPEP 2111.05, to be given patentable weight, printed matter and an associated product must be in a functional relationship. Significantly, as indicated by In re Ngai, 367 F.3d 1336 (Fed. Cir. 2004), discussing a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals so as to exist in a functional relationship.
As such, claim 77 is also rejected as prima facie obvious.
Claim 47 is rejected under 35 U.S.C. 103(a) as being unpatentable over Baberio et al (ACS Nano 14:11238-11258, 2020; of record) in view of Chen et al (Bioconjug Chem 29:1251-1260, 2018; of record), Postma et al (JPET 288:114-120, 1999; of record), and Barberio et al (US 2019/0125895; of record) as applied to claims 43-44 above, in further view of Makaremi et al (Biomedicines 9:1075, 2021; of record).
Claim 47 is drawn to the pharmaceutical composition of claim 44, wherein the additional pharmaceutical agent is an immune checkpoint therapy such as anti-CTLA-4, PD1, PDL1, LAG-3, TIM-3, etc.
As discussed above, the prior art teach a pharmaceutical composition further comprising an additional pharmaceutical agent, as recited by claim 44.
However, the prior art do not explicitly teach a pharmaceutical composition wherein the additional pharmaceutical agent is an immune checkpoint therapy such as anti-CTLA-4, PD1, PDL1, LAG-3, TIM-3, etc.
Yet, as taught by Barberio et al, the “NPs showed efficacy against tumor challenge in both colorectal and ovarian tumors” (Abstract).
Similarly, Barberio et al ‘895 teach that the the particles are “for the treatment of cancer” (Abstract).
And, as taught by Makaremi et al, “checkpoint-blocking antibodies have shown promising outcomes in CRC [colorectal cancer]”, specifically identifying “immune checkpoint inhibitors (ICIs), such as CTLA-4, PD1, PDL1, LAG-3, TIM-3... for CRC treatment” (Abstract).
Accordingly, in further view of Makaremi et al, it would have been prima facie obvious to select an immune checkpoint therapy such as anti-CTLA-4, PD1, PDL1, LAG-3, TIM-3, etc. as the additional pharmaceutical agent to include in the pharmaceutical composition of Baberio et al in view of Chen et al, Postma et al, and Barberio et al ‘895. As stated in MPEP 2144.06, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846 (CCPA 1980).
As such, claim 47 is also rejected as prima facie obvious.
Claim 78 is rejected under 35 U.S.C. 103(a) as being unpatentable over Baberio et al (ACS Nano 14:11238-11258, 2020; of record) in view of Chen et al (Bioconjug Chem 29:1251-1260, 2018; of record) and Postma et al (JPET 288:114-120, 1999; of record) as applied to claims 1-2, 5, 8, 12, 14-15, 20, 22, 24, 27, 30, 56-57, 67 and 72 above, in further view of Martinez-Jothar et al (J Controlled Release 282:101-109, 2018; of record).
Claim 78 is drawn to the particle of claim 1, wherein the cytokine is scIL-12 comprising a C-terminal cysteine.
As discussed above, Baberio et al in view of Chen et al and Postma et al teach a particle of claim 1, more specifically comprising scIL-12 covalently attached to the liposome via a “maleimide–thiol reaction” and, in particular, via MPB-PE.
However, the prior art do not teach the scIL-12 comprising a C-terminal cysteine.
Yet, Martinez-Jothar et al, discussing “[i]nsights into maleimide-thiol conjugation chemistry” (Title), teach that “this reaction makes use of the thiol group of cysteine residues naturally present in peptides and proteins or that can be easily introduced in these molecules” (Page 102, Column 1), further disclosing “a C-terminal cysteine modified molecule” (Page 102, Column 2).
Accordingly, based further on Martinez-Jothar et al, it would have been prima facie obvious in synthesizing the particles comprising scIL-12 covalently attached to the liposome via a “maleimide–thiol reaction” and, in particular, via MPB-PE, to utilize scIL-12 comprising a C-terminal cysteine, with a reasonable expectation of success.
As such, claim 78 is also rejected as prima facie obvious.
Conclusion
No new ground(s) of rejection are 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 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.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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