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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/21/2026 has been entered.
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),Ramsey et al ( Journal of Controlled Release, 2010), Pichlmair et al, and Segovia et al ( Acta Biomaterlia,2014).
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]). Moreover, Cascante et al teach assessing liver injury following intravenous administration of viral therapeutic agents by measuring serum aspartate aminotransferase (AST) and alanine aminotransferase ( ALT) level seven days after administration. Cascante et al report that the level of AST and ALT were elevated in mice receiving a high dose of naked adenovirus, whereas the same effect was not observed in mice receiving the corresponding polymer-coated formulation. ( See example 17B, [0232-0234]). Accordingly, Cascante et al teach the use of serum AST and ALT as biomarkers for evaluating liver injury following administration of a viral therapeutic agent and teach their use in comparing the safety of polymer coated and uncoated viral formulation, this reads on step (c).
It is submitted that 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) supplement Cascante et al by teaching that lentiviral particles lacking the envelope (i.e. the fusion proteins) produce noninfectious particles. According to Sharma, the loss of infectivity 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). Accordingly, Sharam et al provide an ordinary skill in the art with the knowledge that retroviral particle lacking its normal envelope proteins can be modified using external delivery component to facilitate entry into target cells.
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 I FN- a production, however, preparations containing
the VSV-G envelope are potent at stimulating IFN- a response. (See Fig.2, page 541). Accordingly, Pichlmair et al demonstrate that the presence of fusion protein elicits unfavorable immune response.
Ramsey et al, further supplement the cited prior arts by generating hybrid nanoparticulate vectors formed by complexing non-infectious retrovirus-like particles lacking a viral envelope protein with synthetic polymer including poly-L-lysine (PLL) or polyethylenimine (PEI). Ramsey et al report that the polymers replace the function of the viral envelope protein and interact with the target cell membrane, initiate cellular uptake and facilitate escape from endocytic vesicles. (See abstract). Ramsey et al also expressly state that “ We have shown that it is possible to construct hybrid vectors in which viral proteins are replaced with polymers that can provide the complementary function”. ( See 2nd column-2nd pargraph on page 44). Accordingly, Ramsey et al provide a more specific teaching that a synthetic polymer can also be used to facilitate gene delivery from envelope -deficient retrovirus-like particle.
It is submitted that neither Sharma nor Ramsey suggest the use of OM PBAE shell recited in instant claim.
Segovia et al supplement Sharma and Ramsey by teaching that OM-PBAE can be used for gene-delivery nanoparticles containing nucleic acid. More specifically, Segovia et al report that gene-delivery performance and cellular compatibility depends on the oligopeptide composition formulation. Accordingly, Segovia et al identify that OM-PBAE as a known and suitable class of gene-delivery materials whose properties can be tuned through polymer design and formulation. ( See abstract).
Taken together, 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), Ramsey, Pichlmair, and Segovia 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, and expressly teach that the polymer encapsulation can provide safety related benefit, including lower hepatotoxicity. 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. Ramsey et al teach that synthetic polymers can be used with envelope-deficient retrovirus-like particle to facilitate cellular uptake ad intracellular delivery. Thus, identify a polymer-based approach addressing the entry problem discussed by Sharma. Pichlmair et al demonstrate that the VSV-G envelope is a potent stimulator of innate immunity. While Segovia et al identify OM-PBAEs as gene-delivery material with formulation dependent delivery. 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. Accordingly, instant claim merely amount to combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
It is noted that claim 1 recites 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), Ramsey, Pichlmair , and Segovia 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 in view of the cited prior arts 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 the cited prior arts 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 in view of the cited prior arts 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), Ramsey, Pichlmair, and Segovia 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 in view of the cited prior arts 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 the cited prior arts 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 in view of the cited prior arts 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), Ramsey, Pichlmair, and Segovia 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 in view of the cited prior arts 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. Thus, instant claim merely amounts to combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Response to Arguments
Applicant's arguments filed 09/21/2026 have been fully considered but they are not
persuasive.
Applicant argue that the additional limitation reciting the step of measuring a biomarker for hepatotoxicity or presence of the lentiviral vector particles or nucleic acid in spleen, bone marrow, or liver tissue is neither disclosed nor suggested by any of the cited references.
Examiner's Response to Traversal: Applicant's arguments have been carefully
considered but are not found persuasive. Because as discussed in the rejection above, Cascante et al teach the use of serum AST and ALT as biomarkers for evaluating liver injury following administration of a viral therapeutic agent and teach their use in comparing the safety of polymer coated and uncoated viral formulation. Accordingly, Cascante et al teach the first alternative feature namely “measuring a biomarker for hepatotoxicity”.
Applicants further argue that the claimed OM-PBAE-encapsulated fusion-protein-deficient lentiviral vector exhibits unexpected results, including lack of tropism of the OM-PBAE-coated lentiviral vector particles toward spleen, bone marrow or liver, lack of the presence of viral vector nucleic acids in those tissues, and a lack of hepatotoxicity, compared to VSV-G+ pseudotyped lentiviral vectors.
Examiner's Response to Traversal: Applicant's arguments have been carefully
considered but are not found persuasive. This is because as discussed in the rejection above, Cascante et al teach polymer encapsulation of viral therapeutic agents and describe reduced liver tropism and improved safety related outcomes associated with polymer coating. Accordingly, the general proposition that polymer encapsulation can modify viral tropism and improve certain safety outcomes is suggested by the prior art. Although, Cascante et al do not by itself disclose the specific combination of OM-PBAE shell and fusion-protein-deficient lentiviral vector; however, Sharma; Ramsey; Pichlmair; and Segovia collectively provide teachings concerning envelope-deficient viral particles, polymer assisted delivery, and OM-PBAEs gene-delivery materials. Thus, evidence of reduced hepatic toxicity and lack of tropism toward liver, bone marrow, and spleen is persuasive only to the extent that the Applicant provide comparative data that demonstrate an actual improvement over the relevant prior art under comparable experimental condition. Accordingly, Applicants argument have been considered but do not overcome the rejection.
According to the MPEP “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e.”
Conclusion
No claim is allowed
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
