So 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/27/2026 has been entered.
Applicant's amendments to the claims and arguments filed on April 27, 2026 have been received and entered. Claims 1, 7, 8, 11 have been amended, while claims 12 and 15 have been canceled. Claims 1-11, 13-14, 16-38 are pending in the instant application.
Election/Restrictions
Applicant's election without traverse of claims 1-27 (group I) in the reply filed on December 12, 2023 was acknowledged.
Claims 28-38 remain withdrawn from further consideration pursuant to 37 CFR l.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Election was made without traverse in the reply filed on December 12, 2023.
Priority
This application is a continuation of PCT/US2019/03 l 743 filed on 05/10/2019, which claims priority from US provisional application no 62/688,084 filed on 06/21/2018 and US provisional 62/670,407 filed on 05/11/2018
Claims 1-11, 13-14, 16-26 and 27 are under consideration.
New-Claim Rejections - 35 USC § 112- scope of enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11, 13-14, 16-26 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
An in vitro method for identifying a T cell receptor (TCR) that targets a PIK3CA antigen, the method comprising:
a) contacting a plurality of lymphocytes with a plurality of antigen presenting cells (APCs), wherein the APCs express a PIK3CA antigen and at least one costimulatory ligand, wherein the PIK3CA antigen comprises an E542K, E545K, H1047R or H1047L mutation as compared to a wild-type PIK3CA sequence, and wherein the PIK3CA antigen and the at least one costimulatory ligand are expressed from a single vector; wherein the lymphocytes and the APCs are autologous (or from a population of peripheral blood mononuclear cells of a single donor).
b) measuring an increase in expression of an inflammatory cytokine IFN-gamma or TNF-alpha by the APC-stimulated lymphocyte from step (a) as compared to expression of the inflammatory cytokine by a control lymphocyte to identify a PIK3CA mutation specific APC-stimulated lymphocyte; wherein the control lymphocyte is a lymphocyte that has not been contacted with an APC, and a lymphocyte that has been contacted with an APC that does not comprise the PIK3CA antigen;
c) isolating the PIK3CA mutation specific T cell clones; and
d) identifying a TCR expressed by the mutation specific APC-stimulated-T cells clone identified in c).
does not reasonably provide enablement for (i) the PIK3CA antigen comprises a mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence’ (ii) wherein the plurality of lymphocytes with a plurality of antigen presenting cells (APCs) are not from single donor but are xenogeneic;(iii) identifying an APC-stimulated lymphocyte by any other way to identify PIK3CA mutation specific lymphocyte or (iv) identifying a TCR expressed by the mutation specific APC-stimulated lymphocyte without isolating PIK3CA mutation specific lymphocyte from plurality of cell population. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
The claims are directed to an in vitro method for identifying a T cell receptor (TCR) that targets a PIK3CA antigen, the method comprising: a) contacting a plurality of lymphocytes with a plurality of antigen presenting cells (APCs), wherein the APCs express a PIK3CA antigen and at least one costimulatory ligand, wherein the PIK3CA antigen comprises a mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence, and wherein the PIK3CA antigen and the at least one costimulatory ligand are expressed from a single vector; b) identifying an APC-stimulated lymphocyte; and c) identifying a TCR expressed by the APC-stimulated lymphocyte identified in b)Dependent claims limit the lymphocytes and the APCs are from a population of peripheral blood mononuclear cells of a single donor and the APC to a mature APC or a monocyte-derived dendritic cell. Dependent claims limit the PIK3CA antigen comprises a mutation comprises an amino acid substitution that comprises E542K, E545K, H1047R or H1047L.
Breadth of the claims:
The breadth of the claimed invention encompasses APCs expressing a PIK3CA antigen comprising any mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence. The mutation at specified position encompass could include deletions, insertions, substitution or silent mutations and therefore claims read on a genus beyond the known hotspot substation E542K, E545K, H1047R or H1047L mutation. The claims further encompass contacting a plurality of lymphocytes isolated from one specie with a plurality of antigen presenting cells (APCs) from another unrelated specie, therefore read on allogenic or xenogeneic contacting of lymphocytes and antigen presenting cells (APCs) to eventually identify and isolate TCR expressed by the APC-stimulated lymphocyte identified in b). The specification further does not enable a method of identifying a TCR expressed by the APC-stimulated lymphocyte identified in b) without isolating the PIK3CA mutation specific lymphocyte (T cell clones) from plurality of APC-stimulated lymphocyte. The disclosure provided by the applicant, in view of prior art, must encompass a wide area of knowledge to a reasonably comprehensive extent. In other word each of these, aspect must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such Artisan.
Guidance of the Specification and The Existence of Working Examples:
The specification teaches transfecting a construct expressing an antigen of interest to APCs to stimulate a T cell. costimulatory ligands, e.g., 4-1BBL, OX40L, ICOSL, CD40L and CD70 could also be expressed in the APCs to enhance T cells stimulation (see fig. 1). Figure 2 shows an in vitro sensitization (IVS) of donor-derived cells. PBMCs from healthy donors stimulated with autologous mature antigen-presenting cells that are transfected with mRNA encoding a 65 amino acid segment of the PIK3CA gene flanking common hotspot mutations in presence of IL-2. Figure 3 shows high throughput reactivity screen wherein individual in vitro sensitized T cells microwells that are tested for mutation-specific reactivity by incubating with autologous APCs transfected with mRNA encoding either the wild-type (WT) or mutated PIK3CA. It is disclosed that mutation- specific recognition is determined by the preferential upregulation of mRNA transcript of acute inflammatory markers such as IFN-g and TNF-a by high throughput quantitative PCR Figure 4 shows positive microwells that underwent limiting dilution cloning to derive T cell clones of a single specificity. Individual clones are screened for mutation-specific recognition using previously described methodology; molecular sequencing on positive clones to derive the alpha and beta chain sequences of its T cell receptor. Figure 7 depicts identification of mutation-reactive microwells following in vitro sensitization. Figure 8 depicts screening of clones derived from limiting dilution. Growth-positive wells following limiting dilution cloning were screened for PIK3CA mutation-specific recognition by measuring the preferential upregulation of the costimulatory molecule, OX40 (left panel) and/or the release of IFN-g (right panel) in response to the mutated antigen. Figure 8 depicts screening of clones derived from limiting dilution. Figure 9 depicts high throughput screen and identification of PI3KCA-mutation reactive wells of Donor T cells. Figure 10 depicts validation of single-cell sequencing platform to correctly retrieve and quantify paired TCRa/b gene sequences from bulk populations. Figure 10 depicts validation of single-cell sequencing platform to correctly retrieve and quantify paired TCRa/b gene sequences from bulk populations.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The state of the art teaches PIK3CA is one of the two most frequently mutated genes in cancers, occurring in 30–40% of cases. Four frequent ‘hotspot’ PIK3CA mutations (E542K, E545K, H1047R and H1047L) account for 80–90% of all PIK3CA mutations in human malignancies and represent predictive biomarkers (see abstract, Keraite et al Scientific Reports, 2020, 17082, 1-12). The breadth of independent claim encompasses PIK3CA antigen comprising a mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence without specifying the exact amino acid that is substituted for the amino acid at position 542, 545, or 1047. The term a mutation further includes deletions, insertions or substitution mutation. The genus of mutant PIK3CA would 19 possible amino acid substitutions combination of for each of the single position. In view of foregoing recitation of any mutation at position 542, 545, or 1047, there are multiple combination of variant encompassed by the claim. The guidance provided in the specification is limited to a PIK3CA antigen comprising E542K, E545K, H1047R or H1047L mutations. The instant specification and post filing art teaches that the substitution of glutamic acid (E) to lysine (K) or histidine (H) to arginine (R) introduces strongly positively charged, bulky amino acid side chains. These specific mutant PIK3CA peptide could be presented by specific HLA alleles (such as HLA-A*03:01) that effectively recognized by T-cell receptors (TCRs) (see Chandran et al Nature Medicine, 2022, 28, 946-957, page 947, col. 2, para. 2 and page 949, col. 1, fig. 4). The art teaches a subset of all possible amino acid mutations dominate the mutation land scape of cancers, with Glu>Lys and Arg>His mutations being the most prominent features of identified mutation signatures. Charge-changing mutations, whether buried or surface-exposed, can alter protein charge, electrostatics, and conformation. Electrostatics of surface residues have been shown to play a key role in protein-protein interactions (See page 4 last para to page 6, para. 1 of Szpiech et al PLoS ONE, 2017, 12(8): e0183273, 1-12). In view of foregoing teaching of Chandran and Szpiech , it is apparent that only specific amino acid substation (E542K, E545K, H1047R or H1047L) would allow the mutant PIK3CA peptide to be presented by specific HLA-A*03:01 and effectively recognized by T-cell receptors. An artisan would have to perform undue experimentation for the other amino acid substitutions to test as an effective antigen, to make and use the invention, without reasonable expectation of success.
The independent claims encompass contacting a plurality of lymphocytes isolated from one specie (human) with a plurality of antigen presenting cells (APCs) from another unrelated specie (mouse or porcine), therefore read on xenogeneic contacting of lymphocytes and antigen presenting cells (APCs) to eventually identify and isolate TCR expressed by the APC-stimulated lymphocyte identified in b). The guidance provided in the specification is limited to identifying TCRs specifically targeting mutant PIK3CA, peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with autologous mature antigen-presenting cells transfected with mRNA encoding a 65-amino acid segment of the PIK3CA gene flanking common hotspot mutations (see example 1 of the specification). The prior art teaches extent of interaction between human T-lymphocytes and xenogeneic antigen-presenting cells (APCs) is species-dependent. A successful interaction requires high-affinity receptor-ligand pairing across species and recognition of antigens presented by foreign major histocompatibility complex (MHC). A deficient human T-lymphocyte response to xenogeneic cells is likely the result of a defect in these interactions (see abstract, Diaz et al J Lab Clin Med 2003;142:149-57). The further teaches xenogeneic MHC molecules produce weaker T cell responses. Therefore, T cell allorecognition can be seen as a combination of “mistaken identity” (Yun et al Clin Transplant Res 2024; 38(4): 273-293, page 276, col. 2, para. 2). Van Laethem et al (Trends in Immunology, 2012, 33( 9), 437-441) states “all TCRs that have been structurally analyzed to date were obtained from T cells that had previously undergone selection in the thymus to be MHC-specific” (see page 437, col. 2, para. 2). In view of foregoing, it is apparent that T cell undergoing thymic selection would not effectively form a complex with a xenogeneic APCs expressing PIK3CA antigen that would display foreign surface protein causing a non-specific T cell activation rather than the PIK3CA targeted response required to study the APC's PIK3CA mutation as required by the claim. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
The independent claims recite identifying an APC-stimulated lymphocyte without specifying how to identify and then isolate the PIK3CA mutation specific lymphocyte (T cell clones) from plurality of APC-stimulated lymphocyte before identifying a TCR expressed by the selected PIK3CA mutation specific lymphocyte identified in b). The specification teaches high throughput reactivity screen wherein individual in vitro sensitized T cells that are tested for mutation-specific reactivity by incubating with autologous APCs transfected with mRNA encoding either the wild-type (WT) or mutated PIK3CA (see fig. 3). It is disclosed that mutation- specific recognition is determined by the preferential upregulation of mRNA transcript of acute inflammatory markers such as IFN-g and TNF-a by high throughput quantitative PCR and cloning to derive T cell clones of a single specificity. Individual clones are screened for mutation-specific recognition using previously described methodology (see fig 4). The prior art teaches IFN‐γ is primarily secreted by activated T cells .., and can promote macrophage activation, … enhance antigen presentation (Tau et al Allergy 2001 Dec 24;54(12):1233–1251 and Chandran et al ). The publication teaches method to identify candidate TCR sequences, the ratio of IFNG produced under Mutant and WT stimulation conditions for each clonotype (Fig. 1b) was measured and out of 64 clonotypes, only clonotype 20 significantly upregulated IFNG to Mut PIK3CA (see fig. 1b). In view of foregoing, it is apparent that method must measure inflammatory cytokine such as IFN-gamma or TNF under mutant and wild type stimulation condition to identify and select an isolate T cell clonotype to identify candidate TCR sequence. It is noted that the unpredictability of a particular art area may alone provide reasonable doubt as to the accuracy of the broad statement made in support of enablement of claims. See Ex parte Singh, 17 USPQ2d 1714 (BPAI 1991). It is also well established in case law that the specification must teach those of skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29 USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991). Absent any requirement of identification and isolation of clones expressing TCR, it would require undue experimentation to one of ordinary skill in the art to first establish condition and then test all the clonotype for the expression of TCR to make and use the invention, without reasonable expectation of success.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled commensurate with full scope for the claimed inventions. An artisan of skill would have required undue experimentation to practice the invention, without reasonable expectation of success as supported by the observations in the art record.
New-Claim Rejections - 35 USC § 112-Written description -necessitated by amendments
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10, 13-14, 16-26 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims embrace PIK3CA antigen comprises a mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence intended to stimulate mutation specific T cell.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1117. The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The APCs expressing a PIK3CA antigen comprising any mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence that encompasses a genus of variant that includes deletions, insertions, substitution or silent mutations, other than the known hotspot substation E542K, E545K, H1047R or H1047L mutation., encompassed within the genus of PIK3CA antigen comprising mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA have not been disclosed. Based upon the prior art there is expected to be sequence variation among the species of PIK3CA mutation sequences at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence The genus of mutant PIK3CA would include 19 possible amino acid substitutions combination of for each of the single position. In view of foregoing recitation of any mutation at position 542, 545, or 1047, there are multiple combination of variant encompassed by the claim. The guidance provided in the specification is limited to a PIK3CA antigen comprising E542K, E545K, H1047R or H1047L mutations. The instant specification and post filing art teaches that the substitution of glutamic acid (E) to lysine (K) or histidine (H) to arginine (R) introduces strongly positively charged, bulky amino acid side chains. These specific mutant PIK3CA peptide could be presented by specific HLA alleles (such as HLA-A*03:01) that effectively recognized by T-cell receptors (TCRs) (see Chandran et al Nature Medicine, 2022, 28, 946-957, page 947, col. 2, para. 2 and page 949, col. 1, fig. 4). The art teaches charge-changing mutations, whether buried or surface-exposed, can alter protein charge, electrostatics, and conformation. Electrostatics of surface residues have been shown to play a key role in protein-protein interactions (See page 4 last para to page 6, para. 1 of Szpiech et al PLoS ONE 12(8): e0183273, 1-12). In view of foregoing teaching of Chandran and Szpiech , it is apparent that only specific amino acid substation (E542K, E545K, H1047R or H1047L) would allow the mutant PIK3CA peptide to be presented by specific HLA-A*03:01 and effectively recognized by T-cell receptors. There is no evidence on the record that embraced other mutation with other amino acid substitution would have any known structural relationships to each other; the art indicated that there is variation in electrostatics of surface residues that have been shown to play a key role in protein-protein interactions. The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998).
In the instant case, the claimed embodiments of genus of PIK3CA antigen comprising mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA, other than the PIK3CA antigen comprising E542K, E545K, H1047R or H1047L encompassed within the genus of lack a written description. The specification fails to describe what specific mutation (deletion, insertion or substation) fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed PIK3CA hotspot mutation other than PIK3CA antigen comprising E542K, E545K, H1047R or H1047L, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations, one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of PIK3CA antigen mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence, other than the PIK3CA antigen comprising E542K, E545K, H1047R or H1047L. Moreover, the art has recognized that there would be variation among the species of the genus of PIK3CA antigen mutation.
Therefore, Applicant was not in possession of the genus of egg-directing sequences as encompassed by the claims. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention."
Withdrawn- Claim Rejections - 35 USC § 103
Claims 1-3, 5-11, 13-14, 16-19, 22-26 and 27 were rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016) and Youlin et al (Cancer Letters 293 (2010) 254–262) In view of Applicants’ amendment of base claims 1 and 11, introducing specific mutation, that is not taught by the combination of prior art, the previous rejection is rendered moot and hereby withdrawn. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1, 16-26 and 27 were rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016), Youlin et al (Cancer Letters 293 (2010) 254–262) as applied above for claim 1 and further in view of Sohn et al (J Immunol Methods. 2014; 407: 82–89, art of record). The rejection is withdrawn for the reasons discussed above.
Claims 1, 4, 22-25 and 26 were rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016) and Youlin et al (Cancer Letters 293 (2010) 254–262). as applied above for claim 1, and further in view of Linnemann et al (Nature Medicine, 2013, 19, 1534-1541)/Aflk et al (Nucleic Acids Research, 2017, Vol. 45, No. 16 e148, 1-13). The rejection is withdrawn for the reasons discussed above.
Claims 1, 13-14 were rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016) and Youlin et al (Cancer Letters 293 (2010) 254–262). as applied above for claim 1 and further in view of Watts et al (US 20040209363, dated 10/21/2004)/Sadelain (US20130121960, dated 5/16/2013) and Munks et al (Immunology. 2004 Aug; 112(4): 559–566, art of record). 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 1-3, 5-11, 13-14, 16-19, 22-26 and 27 aree rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016) as evidenced by Nisa et al (Molecular Cancer (2017) 16:93) and Youlin et al (Cancer Letters 293 (2010) 254–262).
Claims ae directed to an in vitro method for identifying a T cell receptor (TCR) that targets a PIK3C antigen, the method comprising:
a) contacting a plurality of lymphocytes with a plurality of antigen presenting cells (APCs), wherein the APCs express a PIK3C antigen and at least one costimulatory ligand, and wherein the PIK3C antigen and the at least one costimulatory ligand are expressed from a single vector;
b) identifying an APC-stimulated lymphocyte; and
c) identifying a TCR expressed by the APC-stimulated lymphocyte identified in b).
With respect to claims 1-3, Myers teaches an in vitro method for identifying a T cell receptor (TCR) that targets/recognizes an antigen (abstract), comprising:
a) contacting a plurality of lymphocytes with a plurality of antigen presenting cells (APCs), wherein the APC expressing an antigen (breast cancer 5T4) (page 30, 32-33);
b) identifying and isolating lymphocyte that is stimulated by the APC (page 9, lines 20-27, lines 31-32), comprising the T cell receptors which recognizes the breast cancer antigen5T4; and
c) identifying a TCR comprised by the APC-stimulated lymphocyte identified in b) (page 9, lines 20-27, pages)
d) removing and amplifying the nucleic acid encoding said T cell receptor.
With respect to claim 2-3, Myers teaches nucleic acids capable of encoding a peptide epitope of breast cancer antigen (5T4) can be introduced into cells which are used to expand selectively cells which recognize a 5T4 antigen (see page 20, lines 31-33). Myers specifically discloses nucleic acid is capable of encoding a TCR recognizing breast cancer antigen (5T4 )could be introduced into T cells (see page 21, lines 3-4) wherein the coding sequence of nucleic acid may be a DNA or RNA (see page 21, lines 6).
Regarding claim 5, Myers teaches the method of claim 1, wherein the lymphocytes and the APCs are from a population of peripheral blood mononuclear cells of a single donor (page 9, lines32-33, page 22, lines 13-16). It is disclosed that nucleic acids encoding peptide epitopes of breast cancer antigen (5T4) can be used to transfect antigen presenting cells such as autologous dendritic cells which express the peptide epitopes endogenously.).
With respect to claim 6, Myers teaches the method, wherein the APC is a mature APC as APC is capable of expressing an MHC molecule which binds a peptide according to the invention in its peptide binding groove (page 32, lines 17-19, and pages 34, lines 18-19).
With respect to claim 7-10, Myers teaches that the antigen is a tumor associated antigen that is a small polypeptide of a breast cancer antigen 5T4 that is less than 24 amino acid residues (see page 4, lines 5-7, 15, fig. 18 and 29).
With respect to claim 11, Myers teaches that antigen 5T4 peptide may be mutated, by amino acid insertion, deletion or substitution, so long as the MHC binding-specificity of the wild-type 5T4 peptide is retained. In a preferred embodiment the modified epitope has greater affinity for the peptide binding groove. Preferably the peptide contains five or fewer mutations from the wild-type sequence (see page 17, lines 9-12).
Regarding claims 12-14, Myers teaches a method of claim 1, wherein the APC that express an antigen (5T4) further comprises costimulatory ligand that are 4-1BB: and OX40L for enhanced antitumor activity (see page 30, lines 13-15).
Regarding claims 16-19, Myers teaches identifying T cell activation by measuring a T cell proliferation (for example using 3H-thymidine incorporation) or cytokine interferon-gamma production as compared to control using ELISPOT assay (see page 19, lines 1-3).
With respect to claims 22-27, Myers teaches that the method of claim 1, wherein identifying the sequence of the specific cDNAs corresponding to the identified TCR sequences that is subsequently cloned into mammalian expression vectors and transfected into appropriate cell lines that allow expression of a recombined TCR at the cell surface to determine and confirming the binding specificity of the TCR to the antigen (see page 60, lines 4, 12). Myers teaches that the method, wherein the lymphocyte is a T cell (see page 3230, line 27).
The teaching of Myers is supported by Olweus who teaches an in vitro method for identifying a T cell receptor (TCR) that targets an antigen, comprising: (a) contacting a plurality of T cells with a plurality of antigen presenting cells (APCs), wherein the APC expresses an antigen; b) identifying a T-cell that is stimulated by the APC; and c) identifying a TCR comprised in the APC-stimulated T cells (see page 4, lines 22-33, claims 1-2 of ‘763), wherein said candidate foreign antigen is expressed by transfection of a nucleic acid construct encoding said antigens (see claim 6 of ‘763), wherein said nucleic construct is an mRNA construct (see claim 7 of ‘763). It would have been obvious to one of ordinary skill in the art to transfect APC with an DNA or mRNA in view of the teaching of Olweus.
Regarding claims 16-19, Olweus teaches the method wherein said identification comprises identifying reactive T cells by assaying IFN-gamma cytokine production following stimulation of said induced T cells with said antigen presenting cells as compared to control lymphocytes (see claim 16 of ‘763, fig. 2-3, 7). Likewise, Lorenz teaches teach a method for preparing a nucleic acid encoding the TRA and TRB of a TCR construct specific for an epitope from a defined antigen presented on a MHC, comprising (a) stimulating T cells isolated from a donor with professional antigen presenting cells presenting epitopes of said defined antigen, to enrich antigen-specific T cells; and (b) contacting said T cells with a library of cells, wherein each cell expresses a single MHC allele, wherein the library comprises cells expressing all MHC I or MHC II alleles present in the donor, and wherein the cells of said library present epitopes of said defined antigen; and (c) selecting T cells activated by said contact, preferably, based on an activation marker expressed by said activated T cells; and (d) isolating the nucleic acids encoding the TCR alpha and TCR beta chains of the TCR of said T cells (see claim 12). It is further disclosed that APCs are preferably autologous APCs as they are isolated from the same donor as the PBMCs (see page 6, para. 4).
It is relevant to note that while Myers teaches a method, wherein the APC that express an antigen (5T4) further comprises costimulatory ligand that are 4-1BB: and OX40L for enhanced antitumor activity (see page 30, lines 13-15), however, differs from claimed invention by not disclosing APC expressing an antigen is a PIK3CA antigen comprising an amino acid substitution that comprises E542K, E545K, H1047R or H1047L and at least one costimulatory ligand from a single vector.
However, before the effective filing date of instant invention, Cafri teaches targeting of neoantigens may reduce or avoid, for example, one or both of the depletion of high avidity clones directed against the antigen and the loss of T cells bearing high-affinity TCRs for their cognate antigens (see para. 24). It is further disclosed that targeting of neoantigens may provide any one or more of increased cytotoxic capacity, increased persistence in the tumor microenvironment, and decreased susceptibility to immune suppression (see para. 24). Cafri discloses targeting tumor driver gene such as PIK3CA could result in superior results (see para. 94, example 5). It was known in prior art that PIK3CA hotspot mutations lead to increased kinase activity and confer variable oncogenic feature. More specifically, it is disclosed that both PIK3CAE545K and PIK3CA H1047R are tumorigenic (see Nisa , page 2, col. 1, para. 2). Cafri teaches inducing dendritic cells from a patient to present the one or more mutated amino acid sequences; co-culturing T cells from the patient with the dendritic cells; selecting the one or more mutated amino acid sequences for which the T cells have antigenic specificity (see claim 1). It is further disclosed that the peptides of (a) have a length of about 8 to about 19 amino acid residues (see para. 32). Cafri further teaches that the nucleotide sequence(s) is introduced into the dendritic cells so that the dendritic cells express and display the one or more mutated amino acid sequences, bound to an MHC molecule, on the cell membrane. The nucleotide sequence(s) encoding the mutated amino acid may be RNA (see para. 33). The combination of references differs from claimed invention by not disclosing APC expressing a PIK3CA antigen and at least one costimulatory ligand from a single vector.
Youlin teaches transfecting APC with a vector encoding tumor-associated antigen (a truncated human prostate-specific membrane antigen and costimulatory molecule (4-1BBL) (see abstract). Youlin teaches DCs transfected with Ad-tPSMA-IRES-m4-1BBL specifically express high levels of CD80 and CD86 (see fig. 2). It is disclosed that APC (DC) transduced with Ad-tPSMA-IRES-m4-1BBL induced stronger allogeneic T-cell proliferative responses in vitro than untreated DCs (Fig. 4) and a significant increase of IFN-g production was induced by Ad-tPSMA-IRES-m4- 1BBL-transduced DCs (Fig. 5).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method as disclosed Myers, Olweus /Lorenz by substituting the cancer antigen with another cancer PIK3CA neoantigen comprising E542K or E545K as disclosed in Cafri as evidenced by Nisa, as instantly claimed, with a reasonable expectation of success, in a method of identifying TCR that target said antigen, before the effective filing date 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 in order to reduce or avoid the depletion of high avidity clones and the loss of T cells bearing high-affinity TCRs as they are not subject to the same central tolerance mechanisms as self-antigens. It would have been further obvious to one of ordinary skill in the art to modify the method of Myers, Olweus /Lorenz by co-expressing an antigen with a costimulatory molecule from a single vector as disclosed in Youlin, for activating lymphocyte and increasing cytokine IFN-g expression, with a reasonable expectation of success. One of ordinary skill in the art would be motivated to include costimulatory molecule with antigen as signaling through costimulatory ligand 4-1BB L is known to enhances T cell expansion, and augment T cell effector function (see Myers and Youlin). Further, one of ordinary skill in the art would be motivated to co-express antigen and 4-1BB from a single vector as art recognized that genetic manipulation of APCs ( DCs) with viral vectors was considered most efficient with additional advantages of lower cost of preparation and lower levels of toxicity (see page 260, col. 2, para. 1). One of skill in the art would have been expected to have a reasonable expectation of success because prior art successfully reported (i) transfection of APCs with an PIK3C antigen (Cafri) and at least one costimulatory ligand from a single vector (Youlin). 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 1, 16-26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016) as evidenced by Nisa et al (Molecular Cancer (2017) 16:93), Youlin et al (Cancer Letters 293 (2010) 254–262) as applied above for claim 1 and further in view of Sohn et al (J Immunol Methods. 2014; 407: 82–89, art of record).
The teaching of Myers, Olweus/Lorenz< Cafri, Nisa and Youlin have been discussed above and relied in same manner here. The combination of reference differs from the claimed invention by not disclosing (i) measuring the cytokine expression comprises quantitative polymerase chain reaction (qPCR) (limitation of claims 20-21).
Sohn teaches it is difficult to assess NKT cell activation by both classic RT-PCR (Figure 3 and 6B) and ELISA (Figure 6C); however, Sohn teaches detection of NKT cell activation by qPCR (see page 6D, last para.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to use qPCR to measure the IFN-gamma expression as disclosed by Sohn, in the method of measuring cytokine expression, as instantly claimed, with a reasonable expectation of success, before the effective filing date 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 as qPCR was shown to be more sensitive in detecting cytokine expression as compared to ELISA (see above). One of skill in the art would have been expected to have a reasonable expectation of success in measuring IFN-g expression using qPCR because prior art teaches the successful detection of IFN-gamma using qPCR. 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 1, 4, 22-25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016) as evidenced by Nisa et al (Molecular Cancer (2017) 16:93) and Youlin et al (Cancer Letters 293 (2010) 254–262). as applied above for claim 1, and further in view of Linnemann et al (Nature Medicine, 2013, 19, 1534-1541)/Aflk et al (Nucleic Acids Research, 2017, Vol. 45, No. 16 e148, 1-13).
The teaching of Myers, Cafri, Olweus/Lorenz, Nisa and Youlin have been discussed above and relied in same manner here. Myers teaches that the method of claim 1, wherein identifying the sequence of the specific cDNAs corresponding to the identified TCR sequences that is subsequently cloned into mammalian expression vectors and transfected into appropriate cell lines that allow expression of a recombined TCR at the cell surface to determine and confirming the binding specificity of the TCR to the antigen (see page 60, lines 4, 12), The combination of references differs from claimed invention by not disclosing (i) performing RNA-sequencing on the lymphocyte and (ii) obtaining mRNA or genomic DNA sequence encoding TCR to validate the binding specificity.
However, before the effective filing date of instant application, it was routine to identify TCR sequences by sequencing of genomic DNA fragments encoding the TCR genes or mRNA encoding TCR. For instance, Linnemann teaches identifying TCR sequence by sequencing the genomic DNA fragments encoding the TCR gene (abstract) and then identifying antigen-specific TCRs in T cell populations (abstract). Linnemann teaches TCR-transduced PBMCs that is contacted with peptide-pulsed APC (T2 cell) that is validated for specificity of antigen binding specificity (see online method section page 1, col. 1, page 1, col. 1, para. 3). Likewise, Aflk reported single cell RNA-sequencing (scRNA-seq) that also allow simultaneous measurement of TCR sequence from a single T cell (see page 4, col. 1, para. 3, fig. 2D, Fig. 4).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Myers, Youlin by identifying the TCR sequences by sequencing of genomic DNA fragments encoding the TCR genes or mRNA encoding TCR as disclosed in Linnemann/ Aflk, as instantly claimed, with a reasonable expectation of success, before the effective filing date 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 in order to assess the TCR repertoire of intertumoral T cell subsets that could be subsequently validated for antigen specificity (see above). One of skill in the art would have been expected to have a reasonable expectation of success because prior art teaches successful identification of TCR sequences by the capture and sequencing of genomic DNA fragments encoding the TCR genes as evident from the teaching of Linnemann. 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 1, 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Myers et al (WO2008/059252, dated 05/22/2008, art of record), Olweus et al (WO2015071763, dated 05/21/2015, art of record)/ Lorenz et al (WO2016146618, dated 09/22/2016), Cafri et al (WO/2018/057447, EFD, 09/23/2016), as evidenced by Nisa et al (Molecular Cancer (2017) 16:93) and Youlin et al (Cancer Letters 293 (2010) 254–262). as applied above for claim 1 and further in view of Watts et al (US 20040209363, dated 10/21/2004)/Sadelain (US20130121960, dated 5/16/2013) and Munks et al (Immunology. 2004 Aug; 112(4): 559–566, art of record).
The teaching of Myers, Olweus/Lorenz, Cafri, and Youlin have been discussed above and relied in same manner here. The Myers/ Olweus differs from claimed invention by not expressing two costimulatory ligands comprising 4-1BBL and OX40L from a single vector.
Watts teaches an antigen presenting cell (APC) comprising at least one costimulatory ligand (claim 1), wherein the costimulatory ligand is selected from the group consisting of 4-1 BBL and OX40L (para (0097). Sadelain provided guidance with respect to cell expressing a vector encoding a co-stimulatory ligand selected from any one or more of CD80, 4-1BBL, OX40L (see para. 7-10). Sadelain teaches use of bicistronic vector (see para. 76). Munkus reported stimulating both 4-1BB and OX40 enhanced the CD8 T-cell response more than 4-1BB alone (abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the APC as disclosed in Myers, Olweus/Lorenz and Youlin by further incorporating OX40L with 4-1 BBL as disclosed in Watts/ Sadelain, as instantly claimed, with a reasonable expectation of success, before the effective filing date 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 reported incorporating co-stimulatory ligand 4-1BB and OX40 to APC enhance the CD8 T-cell response more than one -costimulatory ligand 4-1BB alone (Munkus). Further, use of bicistronic vector to deliver two co-stimulatory ligands would be obvious in view of teaching of Sadelain. One of skill in the art would have been expected to have a reasonable expectation of success in incorporating 4-1BB and OX40 because prior art successfully reported using 4-1BB and OX40 to enhance the CD8 T-cell response. 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 assert that the claim to methods for identifying a T cell receptor (TCR) that targets a PIK3CA antigen is limited to fig. 9-11 of the specification. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, as stated in the previous office action that suggested limiting the scope of the independent claim to a method to identify and quantify PIK3CA TCR gene sequence from the population as disclosed in fig. 9-11 of the specification (emphasis added). In the instant case, claims are not so limited. Please note that instant specification teaches donors cells were stimulated with autologous mature antigen-presenting cells transfected with mRNA encoding a 65-amino acid segment of the PIK3CA gene flanking common hotspot mutations having amino acid substitution that comprises E542K, E545K, H1047R or H1047L. It is disclosed that peripheral blood mononuclear cells (PBMCs) are stimulated with autologous mature antigen-presenting cells transfected with either mRNA encoding the wild-type (WT) PIK3CA antigen or a 65-amino acid segment of the PIK3CA gene flanking common hotspot mutations having amino acid substitution that comprises E542K, E545K, H1047R or H1047L in the presence of low-dose IL- 2 (90 IU/mL) (emphasis added, see scope rejection for xenogeneic cells). The method includes identifying and isolating mutation-specific T cells followed by identifying and selecting a TCR expressed by the APC-stimulated T cells. In the instant case, Claim 1 is broad and embrace contacting a plurality of lymphocytes derived from one donor with a plurality of antigen presenting cells (APCs) from another donor, wherein the APCs express any PIK3CA antigen having mutation at position 542, 545, or 1047 as compared to a wild-type PIK3CA sequence. The independent claims recite mutation at specified position that could include deletion, insertion or substitution mutation (emphasis added). It is emphasized that a PIK3CA hotspot specific mutation is required to detect a TCR because the mutation creates a neoantigen that is not present in wildtype healthy cells that are then processed and presented on the cell surface by human leukocyte antigens (HLAs). The claims as presented embrace in at least one embodiment APCs expressing any PIK3CA antigen containing silent mutation at the specified position as compared to wild type PIK3CA. Absent evidence of any unexpected and/or superior process of identifying TCR that target a generic PIK3CA mutant antigen, it would be obvious for one of ordinary skill the art to modify the prior art of Myers, Olweus/Lorenz to substitute APCs expressing a cancer antigen with another neoantigen (PIK3CA) disclosed in Cafri,as evidence from Nisa with reasonable expectation of success. Applicant has not pointed out how the process for identifying a T cell receptor (TCR) that targets any antigen including PIK3CA antigen disclosed in the instant application is any different form one disclosed in prior art.
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.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 7 and 8 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. Applicant’s amendments to claim 7 and 8 obviates the basis of the rejection.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Grunebach et al Cancer Gene Therapy 12, 749–756 teaches co-transfection of APC with a nucleic acid encoding TAA and costimulatory molecule.
Nisa et al. (Molecular Cancer (2017) 16:93, 1-14) teach PIK3CA hotspot mutations.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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