Detailed Office 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
Acknowledgement is hereby made of receipt and entry of the communication filed 16 June, 2026. Claims 1, 5, 6, 18, 19, 27, 29, 30, 35-39, 46, 54, 57, and 61-65 are pending in the instant application. Claims 36-39, 46, 54, and 57 stand withdrawn from further consideration by the Examiner, pursuant to 37 C.F.R. § 1.142(b), as being drawn to a non-elected invention.
37 C.F.R. § 1.98
The information disclosure statement filed 16 June, 2026, has been placed in the application file and the information referred to therein has been considered.
Joint Inventors, Common Ownership Presumed
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 at the time any inventions covered therein were effectively filed absent any evidence to the contrary. Applicant is advised of the obligation under 37 C.F.R. § 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned at the time a later invention was effectively filed 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.
35 U.S.C. § 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 of this title, 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.
Claims 1, 5, 6, 18, 19, 27, 29, 30, 35, and 61-65 are rejected under 35 U.S.C. § 103 as being unpatentable over Leen et al. (U.S. Pat. No. 10,385,316 B2, issued 20 August, 2019, and claiming priority to Prov. Appl. No. 61/236,261, filed 24 August, 2009; hereinafter referred to as “Leen et al. (2019)”) in view of Aguayo-Hiraldo et al. (2017), Tzannou et al. (2017), Gerdemann et al. (2012), and Papadopoulou et al. (2014).
The amended claims are directed toward a composition comprising a polyclonal population of cytotoxic T-lymphocytes (CTLs) that recognize a plurality of viral antigens, wherein the plurality of viral antigens comprise the following: a) parainfluenza virus (PIV) M, HN, N, and F antigens; b) respiratory syncytial virus (RSV) N and F antigens; c) influenza virus NP1 and MP1 antigens; and d) human metapneumovirus (hMPV) M, M2-1, F, and N antigens, wherein the CTLs do not significantly lyse uninfected autologous or allogeneic cells. Claim 5 is directed toward PIV-3 antigens. Claims 6, 18, and 19 reference a composition comprising CD4+ and CD8+ T-lymphocytes, CTLs expressing αβ T cell receptors, and/or MHC-restricted CTLs. Claim 27 requires CTL culturing in the presence of IL-7 and IL-4. Claims 29, 30, and 35 are directed toward the properties of the CTL composition (e.g., variability >70%, formulated for IV delivery, capable of lysing viral-antigen expressing cells, etc.). Claim 60 specifies the CTLs are capable of lysing viral antigen-expressing cells. Claims 62-64 reference PIV-, RSV-, Influenza-, and hMVP-reactive CTLs. Claim 65 specifies the multivirus-specific CTL have negligible alloreactivity after stimulation.
As previously set forth Leen et al. (2019) disclose rapid and effective methods of generating antigen-specific CTL that recognize one antigen from two or more different viruses comprising the step of directly stimulating patient PBMCs with pepmixes derived from viral antigens (e.g., parainfluenza, metapneumovirus, RSV and influenza) and culture in cytokine-supplemented conditions (IL-4 and IL-7) (see claims; cols. 27 and 28). Both peptide-pulsed PBMCs and nucleofected dendritic cells (DCs) were utilized to generate CTL (see Example 3). Preferred antigens included RSV F, M, and/or N proteins, Parainfluenza virus (PIV) F, HN, and/or NP proteins (see col. 5). This teaching discloses compositions comprising multivirus-specific CTL and their methods of preparation. The inventors note that multivirus-specific T-cells can be utilized to prevent and treat viral infections, particularly in immunocompromised subjects (cols. 1 and 4). This teaching does not disclose specific PIV3 viral antigens (M, HN, N, and F) or hMPV antigens (M, M2-1, F, and N).
Aguayo-Hiraldo et al. (2017) generated PIV3 pepmixes covering M, HN, N, F, PC, PP, and L (see METHODS, VST Generation, p. 154; RESULTS, Figure 2 and Table 1, p. 156) and used them to stimulate PBMCs from healthy donors. PIV3-specific CD8+ and CD4+ VST were further characterized for cytolytic activity. The authors concluded that PIV3-specific T cells with specificity for M, HN, N, and F support viral control in vivo (see DISCUSSION, p. 160). It was further noted that adoptive transfer of in vitro expanded virus-specific T-cells (VSTs) can effectively treat viral infections in subjects, particularly those receiving stem cell transplants. The authors concluded (see abstract, p. 153) that “Taken together, our findings support the clinical use of PIV3-specific T cells produced with our Good Manufacturing Practice–compliant manufacturing process, in immunocompromised patients with uncontrolled infections.”
Tzannou et al. (2017) used pepmixes spanning the human metapneumovirus (hMPV) antigens N, P, F, M2-1, M2-2, SH, G, and L to stimulate patient PBMCs (see MATERIALS AND METHODS, VST Generation, Pepmixes, VST Activation, and VST Expansion, p. 679). Polyclonal T-cell populations included both CD8+ and CD4+ T cells (see RESULTS, Amplification of hMPV-Reactive T Cells In Vitro and Functional Characterization of hMPV-Specific T Cells, pp. 681-682). Particularly strong immune responses were noted against F, N, M2-1, and M (see Table 1, p. 682). hMPV-specific T cells are cytolytic and kill virus-infected targets.
Gerdemann et al. (2012) disclose the preparation of polyclonal CTL that recognize a plurality of viral antigens including Influenza MP1 and NP1, as well as, RSV N and F (see Table 1, Clinically relevant viruses and equivalent antigens used for T cell stimulation, p. 1626; RESULTS, Extension to additional viruses, pp. 1627-1628; MATERIALS AND METHODS, CTL generation-peptide stimulation, CTL generation using plasmid-nucleofected DCs, p. 1630). The authors noted that direct stimulation of PBMCs with pepmixes derived from viral antigens (e.g., RSV and influenza) and culture in cytokine-supplemented conditions produced multivirus-specific CTLs that are suitable for clinical trials (see DISCUSSION, p. 1630).
Papadopoulou et al. (2014) demonstrated the feasibility and clinical utility of rapidly generated multivirus-specific T cells (mVSTs) for the treatment of viral infections following hematopoietic stem cell transplantation (HSCT). Polyclonal mVSTs were generated from stem cell donors. These cells recognized multiple antigens from Epstein-Barr virus (EBV), adenovirus (Ad), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV6). These mVSTs were highly effective at treating viral infections in allogeneic transplant recipients. Antiviral specificity was ascertained using interferon-γ (IFN-γ) enzyme-linked immunospot (ELIspot) assay. At least 30 spot-forming cells per 2 x 105 input cells were used to assess viral reactivity for each antigen. There was no evidence of alloreactivity in the mVSTs following a single in vitro stimulation. The authors noted that in all cases, viral clearance was associated with an increase in the frequency of T cells directed against infecting viruses. These mVSTs provided positive clinical responses without toxicity (e.g., GVHD). This teaching does not disclose mVSTs that are reactive with PIV, RSV, Influenza, or hMPV antigens.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a composition comprising a polyclonal population of CTLs, as taught by Leen et al. (2019), directed against the PIV3 M, HN, N, F antigens, as provided by Aguayo-Hiraldo et al. (2017), the hMPV M, M2-1, F, and/or N antigens, as taught by Tzannou et al. (2017), and the influenza MP1 and NP1 antigens and RSV N and F antigens, as disclosed by Gerdemann et al. (2012). The skilled artisan would have reasonably expected these antigens to induce robust virus-specific CTL that would be useful for killing virus in vivo. One of ordinary skill in the art would have also been motivated to produce mVSTs that are reactive with PIV, RSV, Influenza, and hMPV antigens, that do not significantly lyse uninfected autologous or allogeneic cells. This would facilitate their clinical effectiveness and prevent the generation of unwanted immune responses.
Applicant traverses and submits the claimed combination of CTL directed against four specific respiratory viruses (e.g., PIV-3, RSV, influenza, and hMPV) and specific antigens (e.g., PIV-3 M, HN, N, and F; RSV N and F; Influenza NP1 and MP1; and hMPV M, M2-1, F, and N) provided unexpected and superior results, as compared to the teachings of the prior art.
It was argued that the claimed composition could be generated without inducing significant antigenic competition. The specification (see ¶ [0120]) demonstrated that all multi-R-VST lines provided robust activity against all four target viruses. This finding was unexpected considering that Gerdemann et al. (2012) stated that antigenic competition between viral antigens can limit the ability to target multiple viruses simultaneously.
Additional arguments note that obtaining multi-R-VST compositions with negligible alloreactivity within 10-13 days of culture was unexpected. Gerdemann et al. (2012) suggested that prolonged culture with multiple rounds of stimulation was required. Repetitive stimulation was required to reduce alloreactive T-cells to acceptable levels.
Applicant’s arguments have been carefully considered but are not deemed to be persuasive. First, it should be noted that claim 1 is simply directed toward a composition comprising a polyclonal population of CTLs that recognize a plurality of viral antigens (PIV M, HN, N, and F; RSV N and F; influenza NP1 and MP1; and hMPV M, M2-1, F, and N). The claim does not recite any particular activity or property. Second, Gerdemann et al. (2012) also state (see abstract, p. 1622; emphasis added by the Examiner) that they provided “a system that rapidly generates a single preparation of polyclonal (CD4+ and CD8+) CTLs that is consistently specific for 15 immunodominant and subdominant antigens derived from 7 viruses (EBV, CMV, Adenovirus (Adv), BK, human herpes virus (HHV)-6, respiratory syncytial virus (RSV), and Influenza) that commonly cause post-transplant morbidity and mortality. CTLs can be rapidly produced (10 days) by a single stimulation of donor peripheral blood mononuclear cells (PBMCs) with a peptide mixture spanning the target antigens in the presence of the potent prosurvival cytokines interleukin-4 (IL4) and IL7. This approach reduces the impact of antigenic competition with a consequent increase in the antigenic repertoire and frequency of virus-specific T cells.” The authors further concluded that their “approach can be readily introduced into clinical practice and should be a cost-effective alternative to common antiviral prophylactic agents for allogeneic hematopoietic stem cell transplant (HSCT) recipients.” In the Discussion, it was further stated (see p. 1629; emphasis added by the Examiner) that “we can rapidly generate polyclonal, CD4+ and CD8+ T cells with specificities directed to a wide range of lytic
and latent viruses responsible for infection in the immunocompromised host and after HSCT. These cells were Th1-polarized, had high avidity for a multiplicity of individual viral antigens, produced multiple effector cytokines upon stimulation, and killed virus-infected targets without alloreactivity. Because we generated these T cells using combinations of clinically available peptide libraries and prosurvival cytokines, our approach should be well suited to clinical application.”
Thus, this teaching clearly demonstrates that this approach was able to overcome antigenic competition. It also clearly demonstrates that multi-virus and antigen-specific CTL could be generated rapidly with minimal stimulation and limited alloreactivity. Contrary to Applicant’s arguments, there was a reasonable expectation that antiviral CTLs could be generated against multiple viruses and viral antigens using these methods.
Applicant further argues that additional claim amendments reciting CTLs that do not significantly lyse uninfected autologous or allogeneic target cells distinguishes over the prior art. Applicant further adds that secondary considerations directed toward commercial development and clinical testing support patentability. These arguments have been carefully considered but are not deemed to be persuasive in view of the teachings of Papadopoulou et al. (2014). This teaching clearly demonstrated the feasibility and clinical utility of rapidly generated mVSTs for the treatment of viral infections following HSCT. The authors reported (see last paragraph, p. 9) that a short (10-day) manufacturing process was utilized and that “mVSTs may therefore prove a safe and cost-effective therapeutic alternative for immunocompromised patients with severe viral infections.” Thus, this teaching clearly addresses the new limitations directed toward alloreactivity. This teaching also clearly demonstrates that mVST administration was clinically effective with a 94% response rate. Absent evidence to the contrary, one of ordinary skill in the art would have been motivated to extend this approach to other viruses, particularly common respiratory viruses such as PIV, RSV, Influenza, and hMPV, since Papadopoulou et al. (2014) demonstrate the clinical effectiveness of this approach in treating viral infections, particularly in immunocompromised patients.
Action Is Final
Applicant’s amendment necessitated any and all new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See M.P.E.P. § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. § 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 C.F.R. § 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.
Correspondence
Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the Examiner are unsuccessful, the Examiner's supervisor, Michael Allen, Ph.D., can be reached at (571) 270-3497. Direct general status inquiries to the Technology Center 1600 receptionist at (571) 272-1600.
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Respectfully,
/JEFFREY S PARKIN/Primary Examiner, Art Unit 1671 28 September, 2026
