DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/10/2026 has been entered.
Applicants’ amendments to the claims and arguments filed on August10, 2026 have been received and entered. Claims 11, 13-14, 23 have been amended, while claims 1-10, 15, 17-19 have been canceled. Claims 11-14, 16, 20-26 and 27 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse claims 14-19 (group V) in the reply filed on July 21, 2025, was acknowledged. The traversal is on the ground(s) that there is no search burden to examine all the claims. This was not found persuasive because the method as claimed could be practiced with other compositions such as one disclosed in Friedman et al (WO/2017/099712, dated 06/15/2017, filed on 12/7/2015). Further, applicants had the opportunity of electing product claims (group I-III) that may have become subject to rejoinder upon their allowability but have elected the method claims instead. Upon further consideration, restriction requirement between invention of group IV and V was withdrawn and claims drawn to invention of group IV were rejoined with elected invention of group V. Applicant’s election with traverse of (i) PI3 kinase inhibitor, (ii) PI3 kinase inhibitor and VIP antagonist and (iii) infectious disease in the reply filed on July 21, 2025, was also acknowledged. Upon further consideration election of species requirement between different species of I and II were withdrawn and all the species of a PI3 kinase inhibitor or a VIP receptor antagonist were rejoined for the generic claims 11-19. Claims drawn to cancer species of cancer treatment are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species. Claims 17-19 are directed to non-elected species (cancer) and therefore claims 17-19 are withdrawn from the examination. Upon the allowance of claim 16, applicant will be entitled to consideration of claims to additional species which depend on or otherwise require all the limitations of an allowable claim. The requirement is still deemed proper and is therefore made FINAL.
Allowable Subject Matter
The following claim 14 is drafted by the examiner and considered to distinguish patentably over the art of record in this application, claim 14 is presented to applicant for consideration:
An in vitro method of proliferating CAR-T cells that are CD28-, said method comprising:
providing purified T cells comprising anergic T cells, wherein the anergic T cells are CD28⁻ CD27- T cells.
transfecting the purified T cells with a CAR to produce CAR-T cells comprising CD28⁻CAR-T cells,
culturing the CD28⁻CAR-T cells from the step (ii) in a medium containing an effective amount of anti-CD3 antibodies, anti-CD28 antibodies and an effective amount of vasoactive intestinal peptide (VIP) receptor antagonist for a sufficient time to produce CD28⁺CD27⁺ replicated CAR-T cells having increased expression of CD28 compared with levels prior to replication.
Priority
This application is a Divisional of 16/092,068 filed on 10/08/2018, which is a 371 of PCT/US2017/026222 filed on 04/05/2017 that claims priority from US provisional application no 62/319,957 filed on 04/08/2016
Claims 11-14, 16, 20-26 and 27 are under consideration.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 11-13 were rejected under 35 U.S.C. 103 as being unpatentable over Friedman et al (WO/2017/099712, dated 06/15/2017, filed on 12/7/2015, IDS), Waller et al (WO/2012/161755, dated 11/29/2012)/Summerbell (Blood (2013) 122 (21): 1041), Li (PLoS One, 2013, 8(5), e63381, 1-14, IDS), Betjes (Transpl Int 2016 Mar; 29(3):274-8, 09/08/2015, IDS) as evidenced by Pearce et al (J Immunol. 2015;195(7):3206-3217, IDS). In view of Applicants’ amendment of base claims 11 and 14, introducing the limitation “CAR-T cells and upon further consideration, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are, however, subject to new rejections over the prior art of record.
Claims 11-14, 16, 20, 23 and 26-27 were rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (WO/2015/164745, 10/29/2015, art of record), Betjes (Transpl Int 2016 Mar;29(3):274-8, 09/08/2015), Perkins et al (Blood (2015) 126 (23): 1893), Pearce et al (J Immunol. 2015;195(7):3206-3217), Waller et al (WO/2012/161755, dated 11/29/2012)/ Summerbell (Blood (2013) 122 (21): 1041) and Li et al (PLoS One, 2013, 8(5), e63381, 1-14, IDS).The rejection is withdrawn for the reasons discussed above.
Claims 11-14, 16, 20-25 and 26-27 were rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (WO/2015/164745, EFD 12/7/2015), Betjes (Transpl Int 2016 Mar;29(3):274-8, 09/08/2015), Perkins et al (Blood (2015) 126 (23): 1893) as evidenced by Pearce et al (J Immunol. 2015;195(7):3206-3217), Waller et al (WO/2012/161755, dated 11/29/2012)/ Summerbell (Blood (2013) 122 (21): 1041) and Li et al (PLoS One, 2013, 8(5), e63381, 1-14, IDS) as applied above and further in view of June et al (US20150283178, filed on 4/7/2015)/ Friedman et al (WO/2017/099712, 12/7/2015). The rejection is withdrawn for the reasons discussed above.
\ New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 11-14, 16, 20-27 are rejected under 35 U.S.C. 103 as being unpatentable over Friedman et al (WO/2017/099712, dated 06/15/2017, 12/7/2015, IDS), Waller et al (WO/2012/161755, 11/29/2012) as evidenced by Summerbell (Blood (2013) 122 (21): 1041, IDS), Dotti et al (Immunol. Rev. 2014, 257, 1-35) and Li (PLoS One, 2013, 8(5), e63381, 1-14, IDS).
Claim interpretation: Instant rejection is applied to the active method step and rejoined species of an in vitro cell culture composition comprising culturing purified CAR-T cells and vasoactive intestinal peptide (VIP) receptor antagonist, anti-CD3 antibodies and anti-CD28 antibodies. Further, thereby clause in claim 11 is not given any patentable weight.
With respect to claims 11, 20-21, 23, 26, Friedman teaches a method of contacting T cell with anti-CD3 antibody and Cd28 antibody and PIK3 inhibitor to activate and stimulate the said T cells to proliferate as compared to T cell in absence of PI3K inhibitor (see claims 1-4, page 84, para. 3), wherein said T cells expresses CAR on the surface of the cells (see claim 9, of ‘712). It is further disclosed that the isolated T are contacted with a stimulatory agent and costimulatory agent, such as anti-CD3 and anti-CD28 antibodies, generally attached to a bead or other surface, in a culture medium (see page 31, para. 6). To the extent, Friedman teaches the same active step as claimed, therefore, resulting effect on proliferating T cell including naïve T cells would be inherent. Regarding claim 12, Friedman teaches that the proliferating T cells express CD28 (see page 75, para. 2).
With respect to claim 13, Friedman et al teach the method, wherein prior to proliferating the T cells, the T cells is transduced with a vector having a nucleic acid encoding a chimeric antigen receptor (see page, 12, last para. claims 5-9 of ‘712),
Regarding claims 14, 16, 20, 27, Friedman et al teach a method of treating infectious disease including HIV/ AIDS, diphtheria, hepatitis B, hepatitis C, cholera (see page 20, para. 1, page 77, last para.), said method comprising: said method contacting T cell with anti-CD3 antibody and Cd28 antibody and PIK3 inhibitor to activate and stimulate the said T cells to proliferate as compared to T cell in absence of PI3K inhibitor (see page 12, para. 3, claims 1-4), wherein said proliferating T cells express CD28 (see page 75, para. 2). It is further disclosed that the isolated T are contacted with a stimulatory agent and costimulatory agent, such as anti-CD3 and anti-CD28 antibodies, generally attached to a bead or other surface, in a culture medium (see page 31, para. 6); and administering an effective amount of the replicated T cells to a subject in need, (see page 81, para.3), wherein said T cells express CAR on the surface of the cells (see claim 9, of ‘712).
With respect to claims 20-25, Friedman teaches that the PI3K inhibitor is CAL-101 (also known as idelalisib), IPI-145 (also known as Duvelisib) (see page 36, last para.), and Wortmannin (page 37, para. 5).
Friedman et al differ from claimed invention by not disclosing use of a vasoactive intestinal peptide (VIP) receptor antagonist alone and/or in combination with phosphatidylinositol-3-kinase inhibitor,
Waller teaches a method comprising purified T cells in presence of anti CD3 and a VIP receptor antagonist (see para. 50) including antibody to VIP receptor (see claim 8 of ‘755). It is further disclosed that T cells are transduced with a vector encoding T cell receptors (TC Rs) that recognize a cancer antigen. Dotti provides explicit motivation to use CAR-T cells over TCR expressing T cells by stating unlike the native TCR, the majority of scFv-based CARs only recognize target antigens expressed on the cell surface, rather than internal antigens that are processed and presented by the cells’ MHC. This limits the detection of a range of tumor specific antigenic epitopes, CARs have the advantage over the classical TCR that they can recognize structures other than protein epitopes, including carbohydrates and glycolipids (see page 4, last para.). Dotti teaches CAR comprises cancer targeting sequence, a transmembrane domain, a T cell costimulatory molecule domain, and a signal-transduction component of a T-cell antigen receptor domain such as CD3-ζ or CD28.ζ or 41BB.ζ signaling domains (see fig,1, see page 4page 6, para. 2). Further the expansion of T cells in presence of VIP receptor antagonist is further evidenced by Summerbell who teaches culturing a population of cells comprising T cells in presence of VIPhyb (a VIP antagonist) that results in increased proliferation of CD4+ and CD8+ T-cell as assessed by flow cytometry (Figure 1). Summerbell teaches increase in VIPhyb dose increases proliferation of both CD4+ and CD8+ T cells (Figure). It is further disclosed that VIPhyb increased early T-cells CD69 expression and abrogated later PD1 upregulation in CD8+ T cells (abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the method of contacting T cells with anti-CD3 antibody and Cd28 antibody in combination with PI3K inhibitor as disclosed in Friedman by substituting and/or further including VIP antagonist to activate and stimulate the said T cells as disclosed in Waller as evidenced by Summerbell, to improve the expansion and therapeutic potential of CAR-T cells in the treatment of infectious disease or cancer, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art explicitly reported that PI3K inhibitor and VIP antagonist composition both are known to expand T cells and commonly used for the treatment of infection/leukemia. It would have been further obvious for one of ordinary skill in the art to combine the teaching of prior art that discloses distinct compositions each of which is taught by the prior art to be useful for the same purpose in order to produce a new composition that is to be used in the method for the very same purpose for expanding T cells or CAR-T cells of Friedman. In the instant case the idea of combining them flows logically from there having been disclosed in prior art. Thus, it would have only required routine experimentation to modify the composition of Friedman to further substitute or include VIP receptor antagonist as disclosed by Waller as suggested by Summerbell to use the new composition in a method of expanding T-cells as in Friedman. One of ordinary skill in art would be motivated to further include a peptide competitive antagonist of VIP that reverses immune suppression caused by native VIP as evident from the teaching of Li (see figure 4, 7 and S2) thereby resulting in favorable effects on expansion of T cells with cytotoxic activity. One of skill in the art would have been expected to have a reasonable expectation of success in improving the expansion of CAR-T cells disclosed in Friedman by substituting and/or further incorporating VIP antagonist because prior art successfully reported VIP antagonism increases the expansion of T cells as evident from the teaching of Waller (see figure 2) and Summerbell (figure 1). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support the finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 11-14, 16, 20, 23 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (WO/2015/164745, 10/29/2015, art of record), Waller et al (WO/2012/161755, dated 11/29/2012) as evidenced by Summerbell (Blood (2013) 122 (21): 1041), Dotti et al (Immunol. Rev. 2014, 257, 1-35), Li et al (PLoS One, 2013, 8(5), e63381, 1-14, IDS) and Perkins et al (Blood (2015) 126 (23): 1893, art of record) .
Claims 11 and 14 are again rejected as an alternative to first obviousness rejection as Friedman reference could be antedated.
With respect to claims 11, 13, Morgan et al teach a method of contacting T cell with anti-CD3 antibody and Cd28 antibody to activate and stimulate the said T cells (see claims 1 of ‘745). Morgan further teaches (b) transducing the T cells with a viral vector comprising an engineered T cell receptor (TCR) or a chimeric antigen receptor (CAR) (page 35, lines 23-28); and (c) culturing the transduced T cells to proliferate (page 40, lines 17-19). It is further disclosed that the CAR comprises an extracellular binding domain, including but not limited to an antibody or antigen binding fragment thereof, a tethered ligand, or the extracellular domain of a co-receptor, that specifically binds a target antigen that is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA) (see pages 44-54 and claim 43 of ‘745). Regarding claim 12, Morgan teaches that the T cells express CD28 (see page 14 line 22).
With respect to claims 14-15, Morgan et al teach a method of contacting T cell with anti-CD3 antibody and Cd28 antibody to activate and stimulate the said T cells (see claims 1 of ‘745). Morgan further teaches (b) transducing the T cells with a viral vector comprising an engineered T cell receptor (TCR) or a chimeric antigen receptor (CAR) (page 35, lines 23-28); and (c) culturing the transduced T cells to proliferate (page 40, lines 17-19) and further comprising administering the cells in effective amount to a site of infection (see page 20, lines 15-19, page 86, line 20).
Regarding, claims 26-27, Morgan teaches T cells were activated using (iii) bead bound anti-CD3 and anti-CD28 antibodies, CD3/CD28 Dynabeads were used at a ratio of3 beads to 1 T cell for 20-24 hours (See page 91, lines 2-4).
Morgan differs from claimed invention by not disclosing that (i) the activation and stimulation steps of CAR-T- cells are in presence of VIP antagonist and/or PIK3 inhibitor.
It is further disclosed that T cells are transduced with a vector encoding T cell receptors (TC Rs) that recognize a cancer antigen. Dotti provides explicit motivation to use CAR-T cells over TCR expressing T cells by stating unlike the native TCR, the majority of scFv-based CARs only recognize target antigens expressed on the cell surface, rather than internal antigens that are processed and presented by the cells’ MHC. This limits the detection of a range of tumor specific antigenic epitopes, CARs have the advantage over the classical TCR that they can recognize structures other than protein epitopes, including carbohydrates and glycolipids (see page 4, last para.). Dotti teaches CAR comprises cancer targeting sequence, a transmembrane domain, a T cell costimulatory molecule domain, and a signal-transduction component of a T-cell antigen receptor domain such as CD3-ζ or CD28.ζ or 41BB.ζ signaling domains (see fig,.1, see page 4page 6, para. 2). Further the expansion of T cells in presence of VIP receptor antagonist is further evidenced by Summerbell who teaches culturing a population of cells comprising T cells in presence of VIPhyb (a VIP antagonist) that results in increased proliferation of CD4+ and CD8+ T-cell as assessed by flow cytometry (Figure 1). Summerbell teaches increase in VIPhyb dose increases proliferation of both CD4+ and CD8+ T cells (Figure). It is further disclosed that VIPhyb increased early T-cells CD69 expression and abrogated later PD1 upregulation in CD8+ T cells (abstract).
The combination of reference differs from claimed invention by not disclosing activation and stimulation steps of CAR-T- cells in presence of PIK3 inhibitor to improve proliferation of T cells
Perkins explored the potential for culture modifications to improve the therapeutic potential of CAR T cells without adding complexity to manufacturing. Perkins tested CAR T cells specific to B cell maturation antigen (BCMA) manufactured using standard IL-2 culture with an inhibitor of PI3K added to the media, or with IL-7 and IL-15 in place of IL-2. Perkin shows that inhibition of PI3K during ex vivo expansion with IL-2 generate a superior anti- BCMA CAR T cell product for clinical use (see abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the method of contacting CAR-T cells with anti-CD3 antibody and Cd28 antibody to activate and stimulate the said CAR-T cells as disclosed in Morgan by further incorporating VIP antagonist as suggested by Waller/ Summerbell and Perkins, to improve the expansion and therapeutic potential of T cells, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in art would be motivated to do so because prior art explicitly reported that T cells may become CD28 negative (CD28neg) as a result of repetitive cell divisions, and isolation from elderly patients and therefore may have poor replicative capacity (supra) . Further, given that VIP antagonist and/or PI3K inhibitor individually were known to expand T cells and commonly used for the treatment of infection, it would have been obvious for one of ordinary skill in the art to combine the two each of which is taught by the prior art to be useful for the same purpose in order to use a new composition that is to be used in the method for the very same purpose of expanding T cells. In the instant case the idea of combining them flows logically from there having been taught in prior art. One of ordinary skill in the art would be motivated to further include a peptide competitive antagonist of VIP that reverse immune suppression caused by native VIP as evident from the teaching of Li (see figure 4) thereby resulting in favorable effects on expansion of T cells with cytotoxic activity. One of skill in the art would have been expected to have a reasonable expectation of success because prior art successfully reported (i) improving the expansion of T cells by contacting said cells in presence of PI3K inhibitor and VIP antagonist as evident from the teaching of Perkins and Waller/Summerbell (ii) block in differentiation T cells stimulated with anti-CD3 antibodies in vitro (see figure 1 of Pearce et al). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support the finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 11-14, 16, 20-25 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (WO/2015/164745, EFD 12/7/2015), Waller et al (WO/2012/161755, dated 11/29/2012) as evidenced by Summerbell (Blood (2013) 122 (21): 1041), Dotti et al (Immunol. Rev. 2014, 257, 1-35), Li et al (PLoS One, 2013, 8(5), e63381, 1-14, IDS) and Perkins et al (Blood (2015) 126 (23): 1893) as applied above and further in view of June et al (US20150283178, filed on 4/7/2015).
The teaching of Morgan, Li and Waller/Summerbell have been described above and relied on in same manner. However, the combination of reference differs from claimed invention by not disclosing administering PIk3inhibitor is idelalisib or Duvelisib or Wortmannin.
However, before effective filing date of instant application, June teaches a method for treating diseases associated with expression of CD19 such as .CLL by administering a recombinant T cell comprising the CAR in combination with a kinase inhibitor (see abstract, para. 8) including in combination with a phosphoinositide 3-kinase (PI3K) inhibitor (e.g., a PI3K inhibitor described idelalisib or Duvelisib) (see para. 551).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the method of administering the expanded modified CAR-T cell in combination of another agent as disclosed in Morgan, Waller/Summerbell by substituting the one PI3K inhibitor with another such as idelalisib, duvelisib or wortmannin as suggested by June to treat conditions in said subject, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art explicitly provide motivation for incorporating kinase inhibitor in combination of T-CAR therapy in subject in need thereof to effectively treat disease (supra). One of skill in the art would have been expected to have a reasonable expectation of success in using recombinant T cell comprising the CAR in combination with a kinase inhibitor because prior art successfully reported (i) using PI3K inhibitor in combination of expanded T-cells (see June). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf),
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejections, they are addressed as follows:
Applicants disagree with the rejection arguing one of ordinary skill in the art would not be motivated to substitute PI3K in an expansion method with a VIP antagonist based on the purported rational provided as the cytotoxicity and cellular immune responses in vivo would have no bearing on the proliferative effect in vitro. These are unrelated events, and the patent office has not provided any grounded basis for which the skilled artisan would make the required substitution. For this reason alone, the claims are not obvious. Applicants’ arguments have been fully considered but are not found persuasive.
In response, claim 11 has been amended to recite a method that uses (see indefinite rejection) an in vitro culture comprising a CAT-R cells and VIP receptor antagonist and anti-CD3 antibodies and antic CD28 antibodies. The claimed method is directed to a cell culture that recites transitional phrase comprising . MPEP 2111.03 states “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004. Therefore, claim 11 as amended is not limited to CAR-T cells in presence of VIP receptor antagonist, anti-CD3 antibodies and antic CD28 antibodies but could also include other unrecited agents including PIK3 inhibitor. This is further evidence from dependent claim 20 that requires isolated Tc ells are contacted with all the four PI3K inhibitor, VIP receptor antagonist, anti-CD3 antibodies and antic CD28 antibodies.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have further engaged in selective reading of the teachings of Waller to formulate the grounds for teaching away. It should be noted that Waller explicitly teaches a method comprising purified T cells in presence of anti CD3 and a VIP receptor antagonist (see para. 50) including antibody to VIP receptor (see claim 8 of ‘755) before administering to a subject in need thereof. As previously indicated, it is Summerbell who teaches dose dependent increase in VIPhyb increases proliferation of both CD4+ and CD8+ T cells (Figure). It is further disclosed that VIPhyb increased early T-cells CD69 expression and abrogated later PD1 upregulation in CD8+ T cells (abstract). Thus, contrary to applicants’ argument that there is no motivation prior art explicit provide motivation to substitute an agent that enhances expansion of T cells with another as disclosed in Summerbell.
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To the extent that Summerbell. describe culture of T cells in presence of VIP receptor antagonist to expand T cells, the rejection is applicable to the instant case. Applicants' selective reading of Friedman and Waller ignores the teachings of the Summerbell. There is no requirement for Waller. to teach that which is clearly taught Summerbell. A person of skill in art would be motivated to culture T-cell or CAR-T cells in presence of VIP receptor antagonist and/or PIK3inhinior, because the method would allow T cell or CAR-T cell expansion, with a reasonable expectation of success.
On pages 7-8 of the applicant’s argument, Applicant re-iterates and rely on the previous arguments that have been discussed in preceding sections. The arguments are substantially the same as those addressed in the foregoing response.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Examiner's note: Applicant's representative is requested to contact Examiner to resolve the pending issues to put instant application in condition for allowance.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 11-13, 23-26 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Applicants’ amendments to the claims obviates the basis of the rejection.
Maintained-Obviousness type Double Patenting-in modified form
It is noted that while instant application is a divisional of US patent application no 16092068, however, it is noted that restriction requirement between invention of group IV and V-VI (claims 11-16) drawn to a method of proliferating T cells that are negative for CD28 using an in vitro cell culture purified T cells and a VIP receptor antagonist, VIP degrading enzyme or hosphatidylinositol-3- kinase inhibitor was withdrawn (see notice of allowance mailed on 8/16/2023). There was no election of species requirement between cancer or infectious disease, and therefore, rejection over pending claims 11-16 is appropriate and proper.
Claims 11-14, 16, 20-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11859208 in view of Waller et al (WO/2012/161755, dated 11/29/2012),Summerbell (Blood (2013) 122 (21): 1041), Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims are directed to a method of method of proliferating T cells that are negative for CD28. For instance, instant claims are directed to method of proliferating T cells that are negative for CD28 using an in vitro cell culture as provided in claims 1-10 providing replicated T cells. Dependent claims limit the method , wherein the replicated T cells have increased expression of CD28 compared with levels prior to replication and wherein prior to, during, or after proliferating the T cells, the T cells are mixed with a vector having a nucleic acid encoding a chimeric antigen receptor, wherein the chimeric antigen receptor comprises cancer targeting sequence, a transmembrane domain, a T cell costimulatory molecule domain, and a signal-transduction component of a T-cell antigen receptor domain, under conditions such that the cells express the chimeric antigen receptor on the surface of the cells. Claims 14-16 are directed to a method of treating a chronic infection comprising: purifying T cells from a subject providing isolated T cells; mixing the isolated T cells with anti-CD3 antibodies and anti-CD28 antibodies optionally immobilized on a bead or solid surface in combination with a PI3 kinase inhibitor, a VIP receptor antagonist, a VIP degrading enzyme, or combinations thereof; under conditions such that the T cells replicate providing replicated T cells have increased expression ofCD28 compared with levels prior to replication; and administering an effective amount of the replicated T cells to a subject in need thereof. In contrast, claim 1-12 of Patent ‘208 are directed to a n in vitro method of replicating anergic T cells, said method comprising culturing an isolated CD28.sup.−CD27.sup.− anergic T cells in a medium containing an effective amount of anti-CD3 antibodies and anti-CD28 antibodies in combination with a phosphatidylinositol-3-kinase inhibitor and a vasoactive intestinal peptide (VIP) receptor antagonist for a sufficient time to produce CD28.+CD27.sup.+ and/or CD28.+CD27− replicated T cells having increased expression of CD28 compared with levels prior to replication, thereby providing replicated T cells. Dependent claims limit the replicated CD28+CD27+ and the replicated CD28+CD27− T cells express a chimeric antigen receptor on the surface of the cells. Claim 3-4 are directed to a method of treating a cancer in a subject, said method comprising: (i) purifying T cells from the subject providing isolated anergic T cells, wherein the isolated anergic T cells are CD28.−CD27.- T cells; (ii) culturing the isolated CD28. −CD27− anergic T cells in a medium containing an effective amount of anti-CD3 antibodies and anti-CD28 antibodies in combination with a phosphatidylinositol-3-kinase inhibitor and a vasoactive intestinal peptide (VIP) receptor antagonist for a sufficient time to produce CD28.+CD27.+ replicated T cells having increased expression of CD28 compared with levels prior to replication; and (iii) administering an effective amount of the CD28+CD27+ replicated T cells from step (ii) to the subject, thereby treating the cancer, and wherein the cancer is leukemia or lymphoma. Dependent claim limits the method wherein the CD28+CD27+ replicated T cells express a chimeric antigen receptor on the surface of the cells. Claims 6-10 limit the claim to recite different species of PI3K inhibitor. As such, the ‘208 claims 1-2 represent a species of the instant broader T cells claims. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Claims ‘208 differs from claimed method step of claim 14 for not T cell being CAR-T cells or to administering toa subject having infection. Friedman cures deficiency by teaching a method of treating infectious disease including HIV/ AIDS, diphtheria, hepatitis B, hepatitis C, cholera or cancer such as lymphoma (see page 20, para. 1, page 77, last para.), said method comprising: said method contacting T cell with anti-CD3 antibody and Cd28 antibody and PIK3 inhibitor to activate and stimulate the said T cells to proliferate as compared to T cell in absence of PI3K inhibitor, wherein T cells is a CAR-T cells (see page 12, para. 3, claims 1-4), wherein said proliferating T cells express CD28 (see page 75, para. 2). Therefore, it would have been obvious to one of skill in the art, at the time the invention was made, to use the method of ‘208 is a subject having infectious disease as suggested in Friedman.
Claims 11-13, 23-27 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11850263 and Friedman et al (WO/2017/099712, dated 06/15/2017, filed on 12/7/2015, IDS).
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims are directed to a method of method of proliferating T cells that are negative for CD28.
For instance, instant claims are directed to a method of proliferating chimeric antigen receptor (CAR) T cells that are negative for CD28 using an in vitro cell culture comprising purified CAR T cells and a VIP receptor antagonist and anti-CD3 antibodies and anti-CD28 antibodies optionally immobilized on a bead or solid surface. Dependent claims limit the method wherein the replicated CAR T cells have increased expression of CD28 compared with levels prior to replication. Claims further limit the cells are isolated from a subject and then mixed with a vector having a nucleic acid encoding the chimeric antigen receptor, wherein the chimeric antigen receptor comprises cancer targeting sequence, a transmembrane domain, a T cell costimulatory molecule domain, and a signal-transduction component of a T-cell antigen receptor domain, under conditions such that the cells express the chimeric antigen receptor on the surface of the isolated T cells. In contrast, claims in 263 are directed to a method of augmenting T-cell activation and ex vivo expansion by co-incubation of human T cells with a nanoparticle containing a small molecule antagonist of VIP signaling, wherein the antagonist of VIP signaling comprises the VIPhyb peptide sequence as set forth in SEQ ID NO: 1, wherein the human T cells are activated with anti-CD3 antibody bound to a plate. The ‘263 differs from claimed invention by not disclosing T cells are CAR T cells and isolated from a subject. Friedman cure the deficiency by teaching a method of contacting T cell with anti-CD3 antibody and Cd28 antibody and PIK3 inhibitor to activate and stimulate the said T cells to proliferate as compared to T cell in absence of PI3K inhibitor (see claims 1-4, page 84, para. 3), wherein said T cells expresses CAR on the surface of the cells (see claim 9, of ‘712). It is further disclosed that the isolated T cells are contacted with a stimulatory agent and costimulatory agent, such as anti-CD3 and anti-CD28 antibodies, generally attached to a bead or other surface, in a culture medium (see page 31, para. 6). To the extent, Friedman teaches the same active step as claimed, therefore, resulting effect on proliferating T cell including naïve T cells would be inherent. Regarding claim 12, Friedman teaches that the proliferating T cells express CD28 (see page 75, para. 2). Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the method of contacting T cells with anti-CD3 antibody and Cd28 antibody in combination with VIP receptor antagonist as disclosed in ‘263 by stimulating the CAR-T cells as disclosed in Friedman, to improve the expansion and therapeutic potential of CAR-T cells in the treatment of diseases, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Further, given that PI3K inhibitor and VIP antagonist composition were known to expand T cells and commonly used for the treatment of infection/leukemia, it would have been further obvious for one of ordinary skill in the art to combine the teaching of prior art that discloses distinct compositions each of which is taught by the prior art to be useful for the same purpose in order to produce a new composition that is to be used in the method for the very same purpose of expanding T cells.
Response to arguments
Applicants argue that the claims have been amended to overcome the rejection of record. Applicants’ arguments have been fully considered but are not found persuasive.
In response, as stated above, the claimed method is directed to a cell culture that recites transitional phrase comprising. MPEP 2111.03 states “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004. Therefore, independent claim as amended is not limited to CAR-T cells in presence of VIP receptor antagonist, anti-CD3 antibodies and antic CD28 antibodies but could also include other unrecited agents including PIK3 inhibitor. This is further evidence from dependent claim 20 that requires isolated T cells are contacted with all the four PI3K inhibitors, VIP receptor antagonist, anti-CD3 antibodies and antic CD28 antibodies. In this context, Friedman teaches a method of contacting T cells with anti-CD3 antibody and Cd28 antibody to improve the expansion and therapeutic potential of T cells including CAR-RT cells in the treatment of infectious disease. A variety of agents suitable for this purpose of expanding T cells are well-known in the art, including VIP receptor antagonist and/or PI3K inhibitor. Summerbell teaches increase in VIPhyb dose increases the percentage of initial splenocytes that underwent proliferation also increased both CD4+ and CD8+ T cells (Figure). It is further disclosed that VIPhyb increased early T-cells CD69 expression and abrogated later PD1 upregulation in CD8+ T cells (abstract). One of ordinary skill in the art seeking to expand T cells would be motivated to modify the method of “028 by including VIP receptor antagonist as suggested in Summerbell/Waller . Applicants' selective reading of ‘028 ignores the teachings of the Summerbell/Waller. There is no requirement for Friedman to teach that which is clearly taught by Summerbell/ Waller. Absent evidence of any unexpected superior result, it would be obvious to one of ordinary skill in the art to use VIP receptor antagonist singularly and/or in combination with PI3K inhibitor because each of these two are known to expand T cells and commonly used for the treatment of infection. One of skill in the art would have been expected to have a reasonable expectation of success in improving the expansion of T cells disclosed in ‘028 by further incorporating VIP antagonist because prior art successfully reported VIP antagonism and/or PIK2 inhibitor increases the expansion of T cells.
Conclusion
No claims allowed.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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