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 .
Applicants’ amendments to the claims and arguments filed on December 29, 2025 have been received and entered. Claims 11-14, 16 have been amended, while claims 1-10, 15, 17-19 have been canceled. Claims 20-27 are newly added. The objection to claim 11 is withdrawn in view of applicant’s amendment to claim 11. It is noted that amendment to claim 11 is no responsive amendment. MPEP714 explicitly states “Each amendment document that includes a change to an existing claim, including the deletion of an existing claim”. In the instant case, claim 11 has been amended from previous claim 11 without changes to previously presented claim. For the sake of compact prosecution, claim 11 has been entered with the amendments to the claims limiting to a VIP receptor antagonist. Claims 11-14, 16, 20-27 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of 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 is not found persuasive because the method as claimed could be practiced with other composition 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 Upon further consideration, restriction requirement between invention of group IV and V was withdrawn and claims drawn to invention of group IV were rejoined with elected invention of group V. Applicant’s election with traverse of (i) PI3 kinase inhibitor, (ii)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 Upon further consideration election of species requirement between different species of I and II were withdrawn and all the species of a PI3 kinase inhibitor or a VIP receptor antagonist were rejoined for the generic claims 11-19. Claims drawn to cancer species of cancer treatment are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species. Claims17-19 are directed to non-elected species (cancer) and therefore claims 17-19 are withdrawn from the examination.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 from or otherwise require all the limitations of an allowable claim. The requirement is still deemed proper and is therefore made FINAL.
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, 20-27 are under consideration.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 11-15 and 16 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Friedman et al (WO/2017/099712, dated 06/15/2017, filed on 12/7/2015). In view of Applicants’ amendment of base claims 11, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained & 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, 13-14, 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, filed on 12/7/2015, IDS), Waller et al (WO/2012/161755, dated 11/29/2012)/Summerbell (Blood (2013) 122 (21): 1041, IDS) 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 T cells and PI3K inhibitor and/or vasoactive intestinal peptide (VIP) receptor antagonist. Claim 11 is interpreted to encompass no operable step. For the sake of compact prosecution, they are interpreted as culturing T cells in presence of VIP receptor antagonist and PI3K antagonist.
With respect to claims 11, 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 expresses 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.), 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 et al cure the deficiency by teaching VIP antagonism enhances cellular immune responses in vivo. VIP antagonism increases the cytotoxic activity of antigen-specific T cells and NK cells. VIP antagonism is predicted to increase the anti-cancer activity of NK cells or antigen-specific T-cells (see para. 45). Waller et al teach administering isolated and purified T cells and a VIP receptor antagonist (see para. 50). Waller et al teach a method of treating a subject with leukemia or lymphoma, said method comprising administering a T-cell in combination with a VIP antagonist to a subject in need thereof (see claims 14-16). Likewise, Summerbell et al teach VIPhyb (a VIP antagonist) increased CD4+ and CD8+ T-cell proliferation as was assessed using flow cytometry (Figure 1). 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).
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 et al/Summerbell, to improve the expansion and therapeutic potential of T cells in the treatment of infectious disease, 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 T cells may become CD28 negative (CD28neg) as a result of repetitive cell divisions, and isolation from elderly patient and therefore may have poor replicative capacity (supra). 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 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. In the instant case the idea of combining them flows logically from their having been taught in the prior art. Thus, it would have only required routine experimentation to modify the composition of Friedman to further include VIP antagonist as disclosed by Waller/Summerbell to use the new composition in a method of expanding T-cells as in Friedman. One of ordinary skill in the 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 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)/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 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).
Claims 11-13, remain 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).
Claim interpretation: Claim 11 is interpreted to be directed to a method reciting an active step of (i) providing a CD28 negative T cells, (ii) culturing the CD28 negative T cells and PI3K inhibitor and/or VIP receptor antagonist, thereby increasing the expansion of CD28 positive T cells.
The teaching of Friedman, Waller/Summerbell, Li have been described above and relied in same manner here. The combination of reference does not explicitly teach starting cell is an isolated T cells that are negative for CD28.
Before the effective filing date of instant invention, it was known that all naïve T cells express CD28, but memory T cells may become CD28 negative (CD28neg) as a result of repetitive cell divisions. This results in accumulation of CD28neg T cells that may constitute >50% of the total circulating T-cell population in the elderly. The frequency of CD28neg T cells is associated with age and CMV infection (see abstract and page 275, col. 1, last para.). It is further disclosed CD28neg T cells can become CD57 positive that is identified as a marker of senescent and T cells as the CD57-positive T cells have the poorest replicative capacity and is frequently used as synonymous with terminal differentiation and/or aged T cells (see Betjes et al page 275, col. 2, last para.).
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 expanding T cell for transplantation purposes to a subject in need thereof as disclosed in Friedman and Waller/Summerbell, wherein more than 15% of the starting isolated T cells are negative for CD28 as suggested by Betjes, 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 conclude that more than 15% of the T cells in the circulating T-cell population in the elderly population undergoing therapy due to cancer or infection would be CD28 negative (supra). One of skill in the art would have been expected to have a reasonable expectation of success in determining the CD28 negative population of T cells contacted with anti-CD3 antibody and Cd28 antibody, PIK3 inhibitor and/or VIP antagonist because that would have blocked the T cell differentiation stimulated with anti-CD3 antibodies in vitro as evident from the teaching of Pearce (see figure 1, page 3215, col. 2, para. 1). 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).
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), 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).
Instant amendments limiting the base claim to a VIP receptor antagonist and dependent claims in combination of PIK inhibitor, necessitated new grounds of rejection that is presented below.
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) more than isolated T cells are negative for CD28 and (ii) the activation and stimulation steps of T- cells is in presence of VIP antagonist.
Before the effective filing date of instant invention, it was known that all naïve T cells express CD28, but memory T cells may become CD28 negative (CD28neg) as a result of repetitive cell divisions, the influence of TNF-alpha, and infection. This results in accumulation of CD28neg T cells, which may constitute >50% of the total circulating T-cell population in the elderly. The frequency of CD28neg T cells is associated with diseases such as cancer (see abstract) (limitation of claims 20 and 26, 30, 31). It is further disclosed that CD28neg T cells can become CD57 positive that is identified as a marker of senescent and T cells as the CD57-positive T cells have the poorest replicative capacity and is frequently used as synonymous with terminal differentiation and/or aged T cells (see page 275, col. 2, last para.). The combination of reference differs from claimed invention by not disclosing activation and stimulation steps of T- cells in presence of VIP antagonist 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). Waller et al cure the deficiency by teaching VIP antagonism enhances cellular immune responses in vivo. VIP antagonism increases the cytotoxic activity of antigen-specific T cells and NK cells. VIP antagonism is predicted to increase the anti-cancer activity of NK cells or antigen-specific T-cells (see para. 45). Waller et al teach administering isolated and purified T cells and a VIP receptor antagonist (see para. 50). Waller et al teach a method of treating a subject with viral infection, said method comprising administering a T-cell in combination with a VIP antagonist to a subject in need thereof (see claims 14-16). Likewise, Summerbell et al teach VIPhyb (a VIP antagonist) increased CD4+ and CD8+ T-cell proliferation as was assessed using flow cytometry (Figure 1). As the VIPhyb dose increased, the percentage of initial splenocytes that underwent proliferation increased in 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 to activate and stimulate the said CAR-T cells as disclosed in Morgan by further incorporating VIP antagonist as suggested by Perkins and Waller/ Summerbell , 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 the 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 patient 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 the 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 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).
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), 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 teaching of Morgan, Betjes, Pearce, Perkins Li and Waller/Summerbell have been described above and relied in same manner. Friedman teach that the effective amount of an expanded modified T cell composition, alone or in combination with one or more therapeutic agents. Thus, the T cell compositions may be administered alone or in combination with other known treatments (see page 76, last para.). 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). Likewise, with respect to claims 21-25, Friedman et al teach that the PI3 kinase inhibitor is CAL-101 (also known as idelalisib), IPI-145 (also known as Duvelisib) (see page 36, last para.), wortmannin (page 37, para. 5).
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, Perkin and Waller/Summerbell by substituting the one PI3K inhibitor with another such as idelalisib, duvelisib or wortmannin as suggested by June/Friedman 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
Applicant disagree with the rejection arguing Friedman et al. cannot account for any VIP antagonist let alone the use of a VIP antagonist with without any other agent for expanding CAR T cells (claims 11) or the treatment of an infectious disease using said expanded CAR T cells of the presently amended claims. Applicant assert that the person of ordinary skill in the art would not be motivated by the teachings of Waller et al., Summerbell, and Li to substitute the PI3K inhibitor of Friedman for the VIP antagonist presently claims. Applicant continue to argue that one would not be motivated to substitute PI3K in an expansion method with a VIP antagonist based on the purported rational provided by the patent office 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. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that claim 11 has been amended to recite a method that uses (see indefinite rejection) an in vitro culture comprising a CAT-T 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 CAT-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 argument that there is no motivation to contact substitute the PI3K inhibitor of Friedman for the VIP antagonist, it should be noted that the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Friedman/Morgan 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 . Waller teaches VIP antagonism enhances cellular immune responses in vivo. Waller et al teach administering isolated and purified T cells and a VIP receptor antagonist (see para. 50). Likewise, Summerbell et al teach VIPhyb (a VIP antagonist) increased CD4+ and CD8+ T-cell proliferation as was assessed using flow cytometry (Figure 1) (emphasis added). 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 Friedman by including VIP receptor antagonist as suggested in Summerbell/Waller . Applicants' selective reading of Friedman et al. 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 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. It is relevant to note that each of these are taught by the prior art to be useful for the same purpose and it would be obvious to combine both 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 the prior art. 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 Friedman by further incorporating VIP antagonist because prior art successfully reported VIP antagonism and/or PIK2 inhibitor increases the expansion of T cells.
On page 7 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.
New & Maintained-Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-13, 23-26 are 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.
Claims 11 is vague and indefinite because method fails to recite any operable step. It is unclear as how to use the in vitro cell culture provided by claims 1-10. Is the use pertaining to culturing the composition or administering the composition a subject or something else? An active operable step in the claim such as (i) providing a T cell that is negative for CD28, (ii) culturing/contacting the T cells in presence of PI3K inhibitor and/or VIP receptor antagonist and anti-CD3 antibodies and anti-CD28 antibodies would obviate the basis of the rejection. Claims 12-13, 23-26 are included in the rejection because they directly or indirectly depend on the rejected base claim. Appropriate correction is required.
Claim 12 recites the limitation "the replicated CAR T cels have increased expression of CD28”" in line 1. It is noted that there is no recitation of any replicated T cells in base claim 11. There is insufficient antecedent basis for this limitation in the claim. Appropriate correction is needed.
Response to arguments
Applicant disagree with the rejection arguing claim 11 has been amended to overcome the rejection of record. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that claim 11 continue to recite the only operably step of using in vitro cell culture. However, it is unclear as to use pertain to culturing the composition or administering the composition a subject or something else? It is suggested that applicant should consider amending the claim to operable step such as culturing/contacting the T cells in presence of VIP receptor antagonist and anti-CD3 antibodies and anti-CD28 antibodies to over come the rejection of record.
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 administering the T cell to a subject having infection. Friedman cure the 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 (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, 23-26 are 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 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. 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. 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 argues 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 recite 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 inhibitor, 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 . Waller teaches VIP antagonism enhances cellular immune responses in vivo. Likewise, 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 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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. June et al (USPGPUB 20150283178, dated 10/08/2015, filed on 4/7/2015) teaches a method for treating diseases associated with expression of CD19 such as .CLL by administering a recombinant T cell comprising the CD19 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).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
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 by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
Prosecution Insights