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 .
37 C.F.R. § 1.114
A request for continued examination under 37 C.F.R. § 1.114, including the fee set forth in 37 C.F.R. § 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. § 1.114, and the fee set forth in 37 C.F.R. § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. § 1.114.
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 16 March, 2026. Claims 1, 5, 6, 18, 19, 27, 29, 30, 35-39, 46, 54, and 57 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 Claims 36-39, 46, 54, and 57 stand withdrawn from further consideration by the Examiner, pursuant to 37 C.F.R. § 1.142(b), as being drawn to a non-elected invention.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 March, 2026, has been placed in the application file and the information referred to therein has been considered.
35 U.S.C. § 112(b)
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 30 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. Two separate requirements are set forth under this statute: (1) the claims must set forth the subject matter that applicants regard as their invention; and (2) the claims must particularly point out and distinctly define the metes and bounds of the subject matter that will be protected by the patent grant. Claim 30 references the “pepmixes” of claim 1. However, claim 1 is directed toward a polyclonal population of CTLs and fails to mention any type of pepmixes. Accordingly, there is insufficient antecedent basis for this limitation in the claim.
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, and 35, 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), and Gerdemann et al. (2012).
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. 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.).
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).
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.
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.
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 20 March, 2026