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 .
Status of the Claims
Claims 1,3,9-10,16,18-19,21,23-24 and 33-34 are currently pending in the Application and examined on the merits below.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1,3,9,16,18-19,21,23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al (WO2017019848A1) and further in view of Besin et al (US20180028664) and Corey (WO2018064076A1).
Significantly Applicant amends instant claim 1 to describe a pharmaceutical composition which comprises an RNA molecule encapsulated in a nanoparticle comprising a sequence encoding a chimeric fusion protein wherein the intracellular signalling domain comprises a CD3 zeta and CD89 signalling domain, or just an intracellular domain from CD89.
With respect to instant claims 1, 19, 21 the disclosure of Gill describes modified monocytes/macrophages which express chimeric antigen receptors , equivalent structurally to the instantly claimed “CFP” molecules (abstract). Gill presents chimeric receptor proteins that comprise an extracellular domain comprising an antigen specific scFv molecule, an extracellular “hinge” domain , a transmembrane domain and an intracellular signalling domain derived from the CD3zeta molecule for instance (“CARMA-zeta” figure 1B). The disclosure indicates that monocytes/macrophage may be modified to express the fusion molecules of the invention, such as in-vitro electroporation (p 51, 20-34) of in vitro transcribed RNA molecules which encode the chimeric fusion proteins (p45, 15-24). The disclosure indicates that methods of introducing and expressing exogenous genes into cells are therefore known in the art and the expression vector may be a nucleic acid encoding the desired chimeric receptor molecule, for example mRNA, can be transferred into a host cell by methods such as electroporation for example, or through use of liposome mediated (lipid nanoparticle-chemical) mediated transfection methods (p46, 1-7). Thereby a variety of DNA and RNA nucleic molecules are disclosed as amenable to introduction into myeloid cell of the invention to drive expression of the desired chimeric antigen receptor. With further regards to the nano-particle encapsulation element of the instant claim 1 the disclosure of describes that liposomes (artificial membrane vesicle) are utilized as exemplary non-viral mediated encapsulated nucleic acid delivery devices (p46-47). The methods are described as amenable to in-vitro or in-vivo delivery methods. Pharmaceutical composition of ex-vivo modified cells of the invention are contemplated for formulation/administration to subjects (p59-61). The disclosure of Gill does not explicitly describe composition of lipid nanoparticle formulated for systemic administration. The disclosure of Besin however describes lipid nanoparticle (LNP) composition with improved in-vivo characteristics for delivery of nucleic acid in-vivo (abstract)(0294-0296)(0314). In specific embodiment of Besin, the LNP of the invention may be formulated to encapsulate mRNA molecules that can be utilized to deliver a variety of biologic molecules such as membrane bound therapeutic protein and fusion protein in-vivo (0856-0857)(0874). The disclosure of Besin further specifically describes that pharmaceutical composition of LNP with agent to be delivered which are formulated for systemic delivery through specific parenteral administration such as injection. Therefore it would be obvious to provide a pharmaceutical composition of LNP formulated for systemic delivery to a human subject which is cell free as indicated by Besin for purposes of improved in vivo-delivery of the chimeric fusion protein of Gill to cells of interest. The disclosure of Gill and Besin do not explicitly provide that a CFP may comprise a CD3-zeta + CD89 or simply a CD89 intracellular signalling domain. CD89 is the Fc-alpha receptor (FCAR1). As previously described for claim 16 the disclosure of Corey relates to “chimeric engulfment receptor” molecules which may be preferentially delivered as chimeric fusion proteins which redirect transduced cells to a particular cell type (p2-3). Nucleic acid encoding the fusion protein of the invention may be delivered to a variety of cells including myeloid cells (p62, 1-5), and non-viral lipid based mRNA vectors may be utilized to deliver the coding nucleic acid to host cells in-vitro or in-vivo. (p38, 12-21). Regarding the utilization of CD89 as an intracellular signalling domain the disclosure of Corey describes that intracellular signalling domain of chimeric engulfment receptors may include “proinflammatory” intracellular signalling domains which are derived from FCAR1 (CD89) (p3, 15-30)(p45, 3-13). Likewise the disclosure of Gill describes that costimulatory molecule may include a wide variety of known intracellular signalling moiety which leads to activation of a macrophage for example (p21-p22). It would therefore be obvious to utilize for example a combination of CD3zeta stimulatory domain in combination with an additional co-stimulatory domain (FCAR, CD89) as indicated by Corey for the purposes of providing additional intracellular signalling and activation to a macrophage for example.
With respect to the claim 3 , 9, the disclosure of Gill describes that Her2 is a particular embodiment of antigen binding domain as an scFv for instance (“fragment thereof”) (p2, 24-31) which is of interest to introduce into monocyte/macrophage lineage cells (p24-31) . ScFv for instance are particularly described as desirable antibody fragment suitable for use in the invention of Gill (p18, 1-6). The anti-Her2 CD3 zeta constructs are in examples expressed on the surface of human macrophage cell types (p5 and figure 12A).
With respect to the claim 16 and the inclusion of specifically a CD28 “hinge” domain of in the extracellular portion of a chimeric fusion protein the disclosure of Gill does not specifically describes that CD28 hinge may be utilized , preferring the CD8 hinge sequence instead. However the disclosure of Gill does describe that “a variety of human hinges may be utilized” for construction of the particular chimeric fusion protein of the invention (p36, 15-20). Hinge regions of the “CER” molecules of the invention may be derived from CD8a or additionally CD28, of a small genus of sequences specifically described by the disclosure of Corey (p44, 10-30). Thus it would be obvious to utilize an extracellular hinge domain as derived from CD28 and indicated by the disclosure Corey as a species of the variety of human hinges indicated by the disclosure of Gill for purpose of providing an extracellular spacer domain known functionality in chimeric antigen receptor, CER, CFP constructs for the purpose of for example positioning the binding domain of the CFP away from the from the host cell surface to further enable proper cell/cell contact between target and host cells, allowing for host binding and activation of desirable redirected host cell effector functions (Corey p44, 1-9).
With respect to the claim 18, the disclosure of Gill indicates that the intracellular signalling domain of CD28 is a co-stimulatory molecule (p21, 16-35) , and that in one aspect of the invention may comprise intracellular domain of a co-stimulatory molecule as CD28 for example and a intracellular domain derived from CD3zeta for example as that act in concert to drive and initiate signal transduction in a monocyte , macrophage or dendritic cell of the invention (p36-p37) as such the intracellular domain may comprise “dual” signalling domains derived from the CD28 and CD3zeta molecule (p37, 21-30).
With respect to claims 23 and 24, the disclosure of Besin et al specifically describes that the nanoparticles of the invention may comprise lipid nanoparticles that are of a diameter of ranges that encompass the claimed range of (claim 16) 100nm-300nm (Besin, 0425, 0460, 0480) and may comprise polar (claim 14) (cationic, positive charged, polar) lipids (0485) and non-cationic or neutrally charged (non-polar) (claim 15) lipids at physiological pH (0624). The disclosure of Besin describes that the optimized liposomes of the invention may be administered through for instance an intravenous route of administration (example 29, 1075) and are ideal for this purpose because they avoid potential lipid nanoparticle induced toxicity as described (0294). Therefore, the ordinary artisan at the time the invention was made would have been motivated to use the liposome lipid nanoparticle of Besin as previously disclosed successful systemic delivery nanoparticle with superior in-vivo safety and efficacy profiles.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Gill and Besin and Corey as applied to claim 1 above, and further in view of Powell et al (WO2019199689). The disclosure of Gill does not appear to disclose the exact HER-2 antigen binding domain as indicated in the instant claim 10 for example to SEQ ID Nos 8 and 9. However the disclosure of Powell describes HER2 directed CAR molecules (as such CFP or CER) which comprise scFv redirected antigen binding moiety with sequences identical to that of the instant SEQ ID NO:8 and 9 (see PE2E/Score) as a HER2 directed “4D5” scFv molecule (p93, example 12 SEQ ID NO:26). It would be thus obvious to utilize the antigen binding molecules of Powell as an exemplary HER2 binding domain previously tested and validated in a chimeric antigen receptor construction scheme.
Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gill, Besin and Corey as applied to claim 1 above, and further in view of Dong et al (Int. J. Mol. Sci. 2016, 17, 320).
Claim 33 essentially describes that cells which express the CFP of the invention as in claim 1, express an increased CD86 expression compared to those which do not express the CFP molecule. The disclosure of Gill, Corey and Besin describe the limitation of the instant claimed product of claim 1. The delivery of a stimulatory pro-inflammatory molecule as described to a myeloid cell for example such as a macrophage (Kupffer cell for example of the liver) would inherently result in up-regulation of the CD86 molecule on the surface of the macrophage for example through stimulation of the macrophage through the chimeric fusion protein.
Further supporting the desirable up-regulation of the CD86 molecule (B7-2) the disclosure of Dong et al describes that CD86+ macrophages are a subset of activated/polarized (“M1”) anti-tumor macrophages which may be found in the tumor microenvironment (abstract). The disclosure further indicates that M1 macrophages activate tumor killing mechanism , and likewise amplify beneficial TH1 immunocyte cytotoxic responses (p2, paragraph 2). As the chimeric receptor provides “pro-inflammatory” intracellular signalling sequences (CD3zeta, CD89) for example as disclosed by Corey and Gill, it would be an inherent feature that cells which comprise the receptor would be driven to a beneficial “M1” phenotype in a subject. Alternatively it would be also obvious to provide the targeting molecule (LNP) and RNA encapsulated with mechanism to increase surface expression of the CD89 molecule as a beneficial molecule on polarized anti-cancer M1 macrophages.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Gill, Besin and Corey, as applied to claim 1 above, and further in view of Kowalski et al (Molecular Therapy Vol. 27 No 4 April 2019). The disclosures of Gill, Corey and Besin do not describe that myeloid cells “specifically” express the CFP. However the disclosure make obvious the claimed molecule , therefore the claimed feature appears to be an inherent property of the claimed molecules. However the further disclosure of Kowalski describes that lipid nanoparticles systemically delivered (in-vivo) typically are taken up by the mononuclear phagocytic system of the liver and the spleen (p714, . More particularly the MPS is comprised of Kupffer cells (specialized macrophage, myeloid cells) which retain lipid nanoparticles. It would be obvious therefore to expect that lipid nanoparticles, even those which are not “targeted”, which are systemically administered would preferentially be taken up and expressed by a myeloid cell type such as Kupffer cells of the liver and spleen.
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.
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Claims 1,3,9-10,16,18-19,21,23-24 and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 85, 97, 98, 102 of copending Application No. 18188027 (reference application) of copending Application No. 18188027 in view of Gill, Corey, Besin and alternatively in view of Powell, Dong and Kowalski as applied above. The reference claims describe nucleic acid which such as mRNA molecules which encode proteins that may be incorporated into lipid nanoparticle for example and utilized to transfect macrophage (myeloid cells) for instance in-vivo. It would be obvious to utilize the formulation of the reference patent therefore to create a pharmaceutical composition which comprises a CFP and is directed to HER2 for example as made obvious by the disclosures presented above.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments-Claim Rejections - 35 USC § 103
In initial arguments (i) regarding the rejection of claim 1 over the combined disclosure of Gill Besin and Corey Applicant describes that the references simply do not teach all of the limitations of the instantly amended claims. Particularly Applicant describes that the disclosure of Corey does not reduce to practice and thereby “teach or suggest” CFP which “reduces target cells of a human subject expressing an antigen recognized by the CFP, when the CFP is expressed on the surface of myeloid cells of the human subject” and comprises Fc-alpha-receptor-1 (CD89) as an intracellular signalling domain as indicated in claim 1.
In reply it is found that although the disclosure of Corey may not “reduce to practice” and provide working examples for a chimeric engulfment receptor which comprises an intracellular signalling domain derived from the CD89 molecule, such a “CER” chimeric engulfment receptor is clearly disclosed and explicitly taught by the reference in multiple locations as Applicant may find (claim 13, p133; 24-25, p3). Reduction to practice is not a requirement relevant to prior art teachings and findings of obviousness.
In further arguments regarding the rejection of record, Applicant describes that there would be “no expectation of success” that the claimed invention, as made obvious by the presented references would have resulted in the functional elements presented in claim 1. Applicant appears to indicate that the disclosure of Corey in fact “teaches away” from utilization of CD89 intracellular signalling domains based on the relative effectiveness of CER which incorporate Fc-epsilon-receptor intracellular signalling domains and DAP12 signalling domains. Applicant declares that the CD89 elements are merely comprised as a laundry list of a large number of intracellular signalling domains disclosed.
Regarding the claimed laundry list , as cited above for example the particular claim 13 of the disclosure does not disclose a laundry list of unrelated signalling domains but rather a short curated list of 16 signalling domain derived from desirable domains, with Fc-alpha-receptor 1 included with for example DAP-12 and Fc-receptor-Epsilon-1 as interchangeable components.
Of further Relevance to Applicants argument, “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP2123 II. Therefore as what may be a “nonpreferred embodiment” the disclosure of CD89 intracellular signalling domains and/or CD3 zeta intracellular signalling domains remains a valid disclosed component of the reference of Corey.
In further reply to previously presented rejection of claim 33 over the combined disclosure of Gill, Besin and Corey and further in view of Dong Applicant traverses. Applicant again provides that claim 1 is not made obvious by the disclosure of Gill, Besin and Corey and that the further disclosure of Dong does not remedy these deficiencies. Applicant describes that therefore the claimed feature cannot be indicated as an inherent feature of the claimed composition. In reply as described above , the disclosure of Gill, Besin and Corey do make obvious the composition of claim 1. The further disclosure of Dong is provided as exemplary and supporting evidence as to why the composition would provide the features of claim 33. Dong clearly indicates that beneficial “proinflammatory” anti-tumor macrophages (M1) are inherently characterized as expressing the CD86 as explained below. The combined disclosure of Gill, Besin and Corey provide the composition which may target a tumor antigen and also provide a proinflammatory signal to the modified macrophages. The disclosure of Gill for example illustrates that properly stimulated CAR modified human macrophages (p75, 20-30)(figure 26A) become M1 polarized and up regulated among other markers, CD89. The up-regulation of the CD86 molecule would thereby naturally flow from the stimulation thereby provided by the chimeric receptor exogenously provided.
In further reply to the previously presented rejection of the instant claim 34, Applicant similarly argues that the claimed feature “specific” expression in myeloid cells is not provided for by the disclosure of Besin, Gill and Corey. Applicant contends that the representative disclosure of Kowalski which indicates that liver macrophages are preferentially targeted by particular mRNA delivery vehicles would not result in a system whereby “target cells of the human subject expressing the antigen are reduced” as in claim 1. However, this appears as a first matter to be incorrect for example in the case of liver cancer, one would logically expect that preferentially targeted liver macrophages may reduce target cells of the human subject expressing the antigen. Furthermore as described above , the disclosure of Gill, Besin and Corey do make obvious the composition of claim 1. The claimed properties of claim 34 for example are results that would naturally flow from the composition as claimed.
In finality Applicant provides in post filing data figures 1 through 3 as evidence of unexpected results, especially in view of the disclosure of Kowalski which provides that particular RNA delivery devices result in preferential delivery to liver macrophages for example as a type of myeloid cell.
As a first issue the Applicant is directed to MPEP 716.01(c) which provides “Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Applicant provides no such declaration or affidavit. Applicant does provide that the information is published as part of WO2025/007059 (figure 1, figure 2), as well as unpublished applications (PCT/US25/33668) (figure 3)
Figure 1 does not specifically show “reduction of target cells” it simply illustrates that potentially, target cells (melanoma cells) are do not proliferate as much when compared to those in vehicle treated mice. Similarly figure 2A and 2B provides that tumor proliferation is potentially reduced in mice which are presented with a trop2-CD89 based (transmembrane-intracellular domain) directed CAR results in lower tumor proliferation particularly at later time points. Figure 3 provides similar data with respect to a GPC3 directed (targeting HepG2) CD89 based CAR molecule. Anti-tumor activity data is not shown therefore “reduction of target cells” as claimed in claim 1 is not established.
Applicant provides that the data presented are commensurate in scope and sufficiently representative of the genus thus claimed. Applicant provides data for 3 antigen binding domains, in combination with as represented a CD89 transmembrane and intracellular signalling domain. This is not what Applicant claims in claim 1. Applicant broadly claims any antigen binding domain, any transmembrane domain in combination with “an” CD3zeta/CD89 or “an” CD89 “intracellular domain”. Data provided only represents for example the complete (?) CD89 intracellular signalling domains. The data proffered to support the unexpected results clearly is not commensurate with the full scope of claim 1.
Finally the results must be actually be unexpected. Evidence provided by the disclosure of Gill for example strongly suggests that macrophages for example which are modified to express a redirecting CAR molecule are capable of providing engulfment of targeted tumor cells (figures 24A-B) . Similar to the representative data presented by Applicant, the disclosure of Gill further exemplifies that mice with HER2(+) xenografts exhibit reduced tumor burden when treated with ex-vivo HER2 directed CAR modified human macrophages (figure 25, A-E, p75). Therefore one of ordinary skill considering the combined disclosure of Gill, Besin and Corey would realize that reduction in tumor burden and/or regulation of tumor proliferation would be an expected result of the composition made obvious.
Conclusion
Summary: No claims are allowed.
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.
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/BRIAN HARTNETT/Examiner, Art Unit 1644
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671