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 .
Edited rejection necessitated by claims amendment
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-7, 13,15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Cascante et al (EP 3 406 265 A1) in view of Sharma et al ( Journal of Virology, 2000),Sharma et al (PNAS,1997),Omidi et al ( Journal of drug targeting, 2003), and Pichlmair et al ( Journal of Virology,2007).
Cascante et al disclose complexes of virus-based therapeutic agents encapsulated in poly(beta-amino ester)(PBAEs) modified with at least one oligopeptide. Cascante et al also disclose methods of treatment using these complexes and methods of encapsulating them to form nanoparticles. (See abstract).
Regarding claim 1, Cascante et al teach the use of end-modified PBAEs polymer for the encapsulation and subsequent in vivo delivery of virus-based therapeutics. According to Cascante et al, the polymer of the invention (i.e. end-modified PBAEs ) is preferred over other types of encapsulation reagents because it is composed of biodegradable groups and has a lower toxicity. (See paragraphs [0005-0006]). Cascante et al also disclose that the therapeutic viral particle can be coated with PBAEs that have been end-modified with oligopeptides, this reads on step (a)(ii). (See paragraphs, [0136], [0171-0172], and examples 3, and 3A). Furthermore, Cascante et al disclose that the virus-based therapeutic agent can be any viral vector suitable for use in gene therapy by stating that “The virus-based therapeutic agent may be an adenoviral vector, an adeno-associated viral (AAV) vector, or a retroviral vector such as a lentiviral vector”, this reads on step (a)(i). (See paragraphs [0111-0112]). Cascante et al also disclose parenteral administration of the polymer encapsulated virus-based therapeutics into a subject, this reads on step(b). (See paragraph[0150]). Cascante et al further disclose that the encapsulation of the virus-based therapeutic agent by the nanoparticles (i.e. end-modified PBAEs ) improves the safety profile by reducing the activation of the adaptive immune response when compared to naked uncoated viral particles. (See paragraph [0121]).
Cascante et al do not teach the use of a lentiviral vector lacking a viral fusion protein (i.e. instant claim step (a) (i)).
Sharma et al (2000) teach that generating lentiviral particles lacking the envelope (i.e. the fusion proteins) produce noninfectious particles. This is because the envelope is required to initiate the membrane fusion events required for entry of the viral particles into the cell. (See introduction,1st column, 2nd paragraph, the last 2 lines, and then 2nd column, 1st paragraph, lines 1-4). Sharma et al further demonstrate that these envelope-free particles can be made infectious in vitro by forming complexes with lipofection reagents (i.e. lipofectin: a transfection reagent) or with the G protein of the vesicular stomatitis virus (VSV-G). (See abstract). According to Sharma, mixing noninfectious lentiviral particles with lipofectin produce infective viral particles with an infectivity titer of approximately 103 CFU/ml. (See table 1, page 10791).
Furthermore, Sharma et al (1997), demonstrate that the Moloney murine leukemia (MoML) virus-based retrovirus deficient in viral envelope also become infectious when mixed with lipofection reagents. (See abstract, and Table 2-page 10805). Sharma et al propose that the encapsulation of the retroviral particles with lipofectin “may function simply by replacing the fusogenic function of authentic envelope constituents such as MoML viral env or surrogate envelopes such as VSV-G protein, thereby facilitating fusion of the virus with the plasma or endosomal membranes of the infected cell”. (See the Discussion section-1st paragraph-lines (5-10 ),page 10807).
According to Omidi et al, cationic lipids, such as lipofectin, are one of the most widely used reagent for nucleic acid delivery in both ex vivo and in vivo gene therapy approaches. Omidi et al demonstrate that the use of cationic Lipofection, such as lipofectin and Oligofectamine, to treat A431 cells resulted in 2-fold changes in the expression of 10 and 27 genes, respectively. Omidi et al teach that the functional consequences of cationic lipid-induced gene expression changes resulted in an increased tendency of cells to enter early apoptosis. Omidi et al also suggest considering non-target gene changes when using cationic lipid formulations for gene therapy or gene silencing, as they may potentially mask or interfere with the intended target gene expression. (See abstract).
Pichlmair et al disclose that the commonly used method for preparing recombinant lentiviral vector carrying the VSV-G type of envelope (i.e. VSV-G pseudotype lentiviral ) results in viral particles contaminated with plasmid-containing vesicles that activate innate immunity. According to Pichlmair, such contamination and the resulting immune response are associated with the presence of the VSV-G envelope. Pichlmair et al demonstrate that lentiviral particles lacking the VSV-G envelope do not stimulate IFN- α production, however, preparations containing the VSV-G envelope are potent at stimulating IFN- α response. (See Fig.2, page 541).
Therefore, it would have been prima facie obvious for one with ordinary skill in the art at the time the invention was filed to combine the teachings of Cascante et al, Sharma (1997), Sharma (2000), Omidi, and Pichlmair to use a composition comprising (OM)-PBAE encapsulated lentiviral vectors lacking fusion protein as a vehicle for the in vivo delivery of a therapeutic agent. Cascante et al teach the use of end-modified PBAEs polymer for the encapsulation and subsequent in vivo delivery of virus-based therapeutic agents. Sharma (1997) and (2000) teach the use of cationic lipids, such as lipofectin, for the encapsulation and in vivo delivery of viral particle devoid of envelope protein. Omidi et al teach using cationic lipid as a reagent for nucleic acid delivery in gene therapy approaches can have cytotoxic effects as they induce apoptosis and produce off-target effects. Pichlmair et al demonstrate that the VSV-G envelope is a potent stimulator of innate immunity. Thus, one would have been motivated to combine prior art teachings to generate OM-PBAE encapsulated lentiviral particles lacking fusion proteins, because OM-PBAE is preferred over other types of reagents due to its biodegradable compositions and low toxicity. Furthermore, one would be motivated to use lentiviral particles lacking the fusion proteins because this preparation provides an improved safety profile by lowering the activation of innate immune response. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
It is noted that Applicants have amended claim 1 to recite that the OM-PBAE coated lentiviral vectors will transduce the cell "through endosomal uptake and/or endosomal escape promoted by said plurality of OM-PBAE molecules". However, such results is an obvious property as it recites functional outcomes. This functional outcome is considered obvious, because the active step of the claims (i.e. contacting cells of a subject with an OM-PBAE coated lentiviral vector lacking a viral fusion protein) is taught by the combined teachings of prior art of record, and there is nothing in applicants' disclosure that shows that these functional outcomes come from something other than the claimed method step. The combined teachings of prior art involve the same active step of instant application. Therefore, the fact that the inventor 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, 227USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding claims 2-5, Cascante et al utilize an OM-PBAE coated adenoviral vector expressing tow reporter genes (i.e. GFP and luciferase) for proof-of principal in vivo experiments. Also, the in vivo studies by Cascante et al involves using two different polymeric coated adenoviruses. (See paragraph [0212]). For example, Cascante et al demonstrate that the in vivo administration of OM-PBAE (i.e.C6Ad) coated adenoviral vector in the tail vein of C57Black mice has a reduced tropism to the liver compared to the naked adenovirus particle, implying that the OM-PBAEs nanoparticles can bypass the uptake by the liver, this reads on claim 5 (See paragraphs [0212],[0222-0223], and Fig.10). However, Cascante et al demonstrate that there was no significant difference in the levels of cytokines following the administration of the naked or coated adenoviral particles. (See paragraph [0237] and Fig.18). Cascante et al also do not teach the coated adenoviral vector show tropism to leukocyte. Yet, as discussed in claim 1 above, the teachings of Cascante et al combined with the recited prior arts render obvious the use of OM-PBAE encapsulated lentiviral particles lacking fusion protein for gene therapy. Hence, the improved safety profile, the lack of cytokines induction, and the gained tropism toward leukocyte, would be considered inherent results, as illustrated in Figs.6, 7, and 9 of instant application.
Regarding claims 6-7, following the discussion of claim 1 above, the combined teachings of Cascante et al and the recited prior arts render obvious the use of OM-PBAE encapsulated lentiviral particle lacking fusion protein for gene therapy. As a result, the ability of the coated lentiviral particle lacking the fusion protein to transduce T cells within a subject and deliver a transgene (instant claim 6), without the need of any targeting agent or prior activation (instant claim7), would be considered inherent results, as stated in instant specification that the “OM-PBAEs coated lentiviral particle lacking the VSV-G envelope have unexpected tropism for blood cells with the ability to transduce in vivo all leukocyte subpopulations without the need for prior activation of proliferation that is normally needed with lentiviral-mediated gene transfer”. (See Page 26 lines 10-14)
Regarding claim 13, Cascante et al also teach parental administration of OM-PBAEs coated viral vectors by intravenous injection. (See paragraph [0150]).
Regarding claims 15-16, Cascante et al also disclose the synthesis of PBAEs end-modified with oligopeptides, wherein the oligopeptide comprises of CHHH, CKKK, CDDD, or CEEE. (See paragraphs [0172-0177], including examples 3A-3C, page 230).
Regarding claims 17, Cascante et al disclose that the polymer-virus complexes should be prepared and immediately used for subsequent in vitro and in vivo studies. (See page 31 line 31 (i.e. step 8), and line 58 (step 9)). This suggests that Cascante’s teachings implicitly include the use of polymer-virus complexes within four hours prior to administration. Furthermore, it is well recognized that it is prima facie obvious for one with ordinary skill in the art to use routine experimentation to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05.
Regarding claims 18, Cascante et al further disclose a method for preparing polymer-virus complexes that involves mixing a solution containing the OM-PBAEs with a solution containing the viral particle to produce polymer-coated viral particles. (See paragraphs [0210-0211]).
Regarding claim 19, recites a product-by-process limitation, because preparation of polymer-coated complexes can be achieved using different device and does not require specifically the use of the microfluidic device. Also, the use of microfluidic device to perform the mixing between the viral particles and the polymer of the invention (i.e. OM-PBAEs) does not change the inherent properties of the polymer-coated viral particles, and the product as claimed still obvious over the product of the prior art. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Consequently, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Cascante et al in view of Sharma (1997), Sharma (2000), Omidi, and Pichlmair as applied to claims 1-7, 13,15-19 above, and further in view of Kalos et al (Science Translational Medicine,2011).
Regarding claims 8-10, following the discussion of claim 1 above, Cascante et al render obvious the use of OM-PBAEs encapsulated lentiviral vectors for the in vivo delivery of therapeutic agents that is suitable for use in systemic viral gene therapy. Cascante et al do not teach the transduction of T cell with a lentiviral vector encoding CAR specific for CD19.
Kalos et al teach the use of engineered CAR T cells that target CD19 to treat patients with advanced chronic lymphocytic leukemia (CLL). The method of Kalos et al includes the use of lentivirus vectors to transfer CAR19 into patient T cells. Kalos et al state that “CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex–independent approach for the effective treatment of B cell malignancies”. ( See abstract).
Therefore, it would have been prima facie obvious for one with ordinary skill in the art at the time the invention was filed to combine the teachings of Cascante et al and Kalos et al to use a composition comprising (OM)-PBAE encapsulated lentiviral vectors as a vehicle for the in vivo delivery of CD19-specific CAR into T cells. Cascante et al teach the use of end-modified PBAEs polymer for the encapsulation and subsequent in vivo delivery of virus-based therapeutic agents. Kalos et al teach the use of a lentiviral vector carrying CD19-specific CAR to generate engineered CAR T cells to treat patients with advanced chronic lymphocytic leukemia. Thus, one would have been motivated to combine prior art teachings to generate OM-PBAE encapsulated lentiviral particles carrying transgene encoding CAR with specificity to CD19 and use that to produce engineered T cells for use in immunotherapy, because the use of nanoparticle encapsulated lentiviral particles lacking the fusion proteins for the in vivo delivery of a therapeutic agents provides an improved safety profile by lowering the activation of innate immune responses. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Cascante et al in view of Sharma (1997), Sharma (2000), Omidi, and Pichlmair as applied to claims 1-7, 13,15-19 above, and further in view of Fornaguera et al (Advance Science News,2019).
Regarding claims 11-12, following the discussion of claim 1 above, Cascante et al render obvious the use of OM-PBAEs encapsulated lentiviral vectors for the in vivo delivery of therapeutic agents. Cascante et al do not teach attaching targeting moieties, such as CD3, to nanoparticles. Fornaguera et al utilize OM-PBAE polymers containing retinol as a targeting moiety to direct the nanoparticles to the liver following intravenous administration. Fornaguera et al demonstrate that adding retinol to OM-PBAEs directs the nanoparticles to the liver, as the liver contains many retinol receptors. (See abstract).
Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to combine the teachings of Cascante and Fornaguera and utilize OM-PBAEs containing targeting moiety for the encapsulation of a lentiviral vector to direct the in vivo delivery of therapeutic agents. Because Cascante et al teach the use of end-modified PBAEs polymer for the encapsulation and subsequent in vivo delivery of virus-based therapeutic agents. Fornaguera et al show that adding a liver targeting moiety to the nanoparticle, such as retinol, is sufficient to specifically direct the delivery of the OM-PBAEs to the liver. Thus, one would have been motivated to use OM-PBAEs with a targeting moiety for the directed delivery of the nanoparticles, as disclosed by Fornaguera, because the presence of a targeting moiety would direct tissue specific delivery, allowing the loaded-nanoparticles to be used for the treatment of specific disease. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Cascante et al in view of Sharma (1997), Sharma (2000), Omidi, and Pichlmair as applied to claims 1-7, 13,15-19 above, and further in view of Verheijen et al (Scientific Reports,2019).
Regarding claim 14, The method of Cascante et al for synthesizing OM-PBAE involves initial mixing with DMSO, but the subsequent steps include forming a solid precipitate, which is washed two times with diethyl ether-acetone and dried under vacuum to produce DMSO-free polymers. (See example 3A). It is also well known in the art that the use of solvent, such as DMSO, is well appreciated if it can be avoided in medical application, as demonstrated by Verheijen et al. (See abstract). Verheijen et al demonstrate that DMSO induce changes in cellular processes in both cardiac and hepatic cells, but more severely, induce alterations in miRNA and epigenetic landscape in the 3D maturing cardiac model. (See abstract). Verheijen et al also suggest not to use DMSO within biotechnological applications whenever possible. (See page 9, paragraph 4). Therefore, it would have been prima facie obvious for one with ordinary skill in the art at the time the invention was filed to combine the teachings of Cascante and Verheijen to synthesize OM-PBAE using DMSO-free method for use in medical applications. Cascante et al teach the use of end-modified PBAEs polymer for the encapsulation and subsequent in vivo delivery of virus-based therapeutic agents. Verheijen et al suggest not using DMSO in biotechnological applications whenever possible. Thus, one would have been motivated to synthesize OM-PBAEs using DMSO-free method, because the use of DMSO has been shown to cause significant changes in human cellular processes, miRNA, and epigenetic landscape, indicating that DMSO is not inert. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Response to Arguments
Applicant's arguments filed 08/26/2025 have been fully considered but they are not
persuasive.
Applicants appear to argue that the combined teachings of prior arts of record teach away from the claimed invention. In particular, Applicants argue that the combined teachings of prior arts relies on the use of lipofectamine (Lipofectin™) rather than OM-PBAE to promote cellular entry of the viral vector.
Examiner's Response to Traversal: Applicant's arguments have been carefully
considered but are not found persuasive. The argument that the combined teachings of prior arts relies on the use of lipofectamine (Lipofectin™) rather than OM-PBAE to promote cellular entry of the viral vector is not accurate. Because, as previously discussed, Cascante et al were cited to establish that encapsulating the virus-based therapeutic agent with nanoparticles (i.e. end-modified PBAEs ) improves the safety profile by reducing the activation of the adaptive immune response when compared to naked uncoated viral particles. (See paragraph [0121 ]). Sharma (1997) and (2000) were cited to establish that using cationic lipids, such as lipofectin, for the encapsulation and in vivo delivery of viral particle devoid of envelope protein produce infectious viral particles. Pichlmair et al were cited to establish that the in vivo delivery of viral particles comprising a fusion protein is a potent stimulator of innate immunity. Omidi et al were cited to establish that using cationic lipid as a reagent for nucleic acid delivery in gene therapy approaches can have cytotoxic effects as they induce apoptosis and produce off-target effects. Therefore, after reading Cascante, Sharma (1997), Sharma (2000), and Pichlmair, an ordinary skill in the art would be motivated to use viral particles devoid of fusion protein, since Pichlmair demonstrated that the presence of fusion protein elicits unfavorable immune response. However, after reading Sharma and Sharma , an ordinary skill in the art would know that the viral particle devoid of fusion protein must be coated with a polymer to facilitate its entry into a cell because a viral particle devoid of fusion protein is not infectious. An ordinary skill in the art would also be motivated upon reading Cascante and Omidi to turn away from cationic lipid, such as lipofectamine, since Omidi demonstrated that cationic lipid are toxic, and instead choose OM-PBAE for viral particles coating because OM-PBAE is preferred over other types of reagents due to its biodegradable compositions and low toxicity. It is also noted that Applicants argue that Omidi is cited to teach that the use of cationic lipids such as Lipofectin™ can promote nucleic acid delivery in vitro or in vivo. This is incorrect, because as previously noted, Omidi et al was cited to establish that using cationic lipid, such as lipofectamine, as a reagent for nucleic acid delivery in gene therapy approaches can have cytotoxic effects as they induce apoptosis and produce off-target effects. Therefore, an ordinary skill in the art, upon reading Omidi , will turn away from cationic lipids , since Omidi demonstrated that cationic lipid are toxic. Taken together, Applicants are reminded that ("The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art."); In re Sneed, 710 F.2d 1544, 1550, 218 USPQ 385, 389 (Fed. Cir. 1983) ("[l]t is not necessary that the inventions of the references be physically combinable to render obvious the invention under review."); and In re Nievelt, 482 F.2d 965, 179 USPQ 224, 226 (CCPA 1973) ("Combining the teachings of references does not involve an ability to combine their specific structures").
Applicants further argue that the present invention obtains functional outcomes not contemplated by prior art of record. In particular, Applicants argue that using OM-PBAE polymers to coat the lentiviral vector devoid of fusion protein has the surprising and beneficial effect of allowing the vector to be taken up by target cells via promoting endosomal uptake and/or endosomal escape mechanisms.
Examiner's Response to Traversal: Applicant's arguments have been carefully
considered but are not found persuasive. This is because Applicants have recognized another advantage that would flow naturally from following the suggestion of the prior art, and thus cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicants further appear to argue references individually. In particular, Applicants argue that neither Kalos, nor Fornaguera, or Verheijen cure the deficiency of the combined teachings of of Cascante, Sharma (2000), Sharma (1997), Omidi, and Pichlmair.
Examiner's Response to Traversal: Applicant's arguments have been carefully
considered but are not found persuasive. This is because Applicants appear to attack the secondary references individually. Arguments against a single reference do not obviate a 103 based on multiple references and so these arguments that none of the secondary references teach the entire invention are not persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).
Conclusion
No claim is allowed
Applicant's amendment necessitated the new ground(s) of rejection 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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638