Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendments
Applicant’s amendments, corrected specification, Declaration submitted under 37 C.F.R. §1.132 by Eric Tran, Ph.D., IDS, and response filed Mar. 11, 2026 have been received and entered into the case.
Status of the Claims
Claims 1-13 and 15-16 are currently pending.
Claims 1, 4, 5 and 15 are amended.
Claim 14 is cancelled.
Claim 16 is new.
Claims 1-13 and 15-16 have been considered on the merits.
Specification Objections
Specification objections are withdrawn due to amendment.
Claim Objections
The claim objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(a)
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(b)
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment. New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added to address the claim amendments.
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 1-13 and 15-16 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.
In step (I) of claim 1, lines 3-5, the phrase/term “identifying one or more genes in the nucleic acid of a cancer cell of the patient by sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell”, renders the claim and its dependents indefinite, since it is unclear how the sequencing of the whole exome, whole genome or whole transcriptome identifies one or more genes in the cancer cell with a cancer-specific mutation that encodes a mutated amino acid sequence. In other words, simply sequencing a cancer cell does not result in identification of cancer-specific mutations. For the purposes of compact prosecution, the phrase in the claim will be interpreted to mean “identifying one or more genes in the nucleic acid of a cancer cell of the patient
All other claims depend directly or indirectly from rejected claims and are, therefore, also rejected under USC 112 for the reasons set forth above.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Yee (US 2010/0310533 A1) (ref. of record) in view of Hacohen et al. (US 2011/0293637 A1) (ref. of record) and Restifo et al. (Nature Reviews Immunology, 2012) (ref. of record).
With respect to claim 1, Yee teaches a method of treating cancer in a patient by administering a tumor vaccine and by administering adoptive immunotherapy for cancer (abstract, 0004, 0054, and 0062). With respect to step (I) of claim 1, Yee teaches identifying a tumor antigen and introducing genetic material in the T cells genetic material to express a T cell receptor or a chimeric T cell receptor to recognize the target antigen (0005-0009 and 0060-0061). Since a vector containing the sequence of the target antigen is used in this method, it would be understood to involve the identifying of at least one or more genes in the nucleic acid of a cancer cell of the patient which would containing a cancer-specific mutation that encodes a mutated amino acid sequence or the target antigen. With respect to step (II) of claim 1, Yee teaches culturing peripheral blood mononuclear cells (PBMCs) and antigen presenting (APCs) from a subject in the presence of tumor material from the subject and isolating T cell clones for antigen specificity (0005-0009). This would be understood to be inducing autologous antigen presenting cells (APCs) of the patient to present the mutated amino acid sequence. With respect to step (III) of claim 1, Yee teaches co-culturing PBMCs which includes autologous T cells of the subject with autologous APCs that present the tumor antigen (the mutated amino acid sequence) (0005-0009). With respect to step (IV) of claim 1, Yee teaches enriching and cloning the T cell population with antigen specificity for the tumor material or tumor antigens (selecting the autologous T cells that (a) were co-cultured with the autologous APCs that present the mutated amino acid sequence and (b) have antigenic specificity for the mutated amino acid sequence) (abstract and 0005-0009). Since all of the cells and the tumor material are from the subject these steps would be presented in the context of a major histocompatibility complex (MHC) molecule expressed by the patient. With respect to the step (VI) of claim 1, Yee teaches that the PBMCs may be engineered to express a T cell receptor (introducing the nucleotide sequence encoding the TCR, or the antigen- binding portion thereof, into peripheral blood mononuclear cells (PBMC) to obtain an isolated population of cells that express the TCR, or the antigen-binding portion thereof) (0061). With respect to step (VII) of claim 1, Yee teaches administering the autologous T cell population that express the tumor antigen to the subject for adoptive immunotherapy (0005-0009 and 0059). It would be understood that the cells would need to be in a pharmaceutical composition and in an amount effective to treat the cancer in the patient.
Yee does not teach the method including identifying one or more genes in the nucleic acid of a cancer cell comprises sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell as recited in step (I) of claim 1.
However, Hacohen teaches identifying DNA mutations using whole genome or whole exomes or RNA sequencing of tumors (0005). Hacohen teaches this method allows for identifying a plurality of tumor specific mutations in the genome of a subject (0052).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by Yee so that the that the identification of the cancer-specific mutations includes the sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell for the benefit of identifying a plurality of tumor specific mutations in the genome of a subject as taught by Hacohen. It would have been obvious to one of ordinary skill in the art to modify the teachings of Yee so that the identification of the cancer-specific mutations includes sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell, since these methods were known to be effective in methods of identifying cancer-specific mutations in tumors as taught by Hacohen. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by Yee so that the identification of the cancer-specific mutations includes sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell, since Hacohen teaches the successful use of these methods in identifying cancer-specific mutations in tumors.
Although, Yee teaches that PBMCs may be engineered to express a T cell receptor (0061), Yee does not explicitly isolating a nucleotide sequence that encodes an isolated T cell receptor (TCR), or the antigen-binding portion thereof, from the selected autologous T cells, wherein the TCR, or the antigen-binding portion thereof, has antigenic specificity for the mutated amino acid sequence encoded by the cancer-specific mutation as recited in the step (V) of claim 1, and where in the cancer expresses the mutated amino acid sequence for which the TCR, or the antigen-binding portion thereof, has antigenic specificity as recited at the end of claim 1.
However, Restifo teaches genetically-engineered T-cells for treating cancers in patients (abstract). Restifo teaches that if a patient expresses a tumor-associated antigen that is recognized by an available receptor structure, autologous T cells can be genetically engineered to express the receptor (Fig. 2 legend). Restifo reports a variety of T-cell engineering methods including the cloning of T cell receptors that respond to a tumor associated antigen and transfection of autologous T cells from the patient with the isolated nucleic acid sequence so that the cells are engineered to express tumor-specific TCRs for expansion and administration to a patient (Fig. 2). Restifo further teaches tumor-specific T cells, or the cancer expresses the mutated amino acid sequence for which the TCR, or the antigen-binding portion thereof, has antigenic specificity (Fig. 2).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by Yee to include a step of isolating a nucleotide sequence that encodes an isolated T cell receptor (TCR), or the antigen-binding portion thereof, from the selected autologous T cells, wherein the TCR, or the antigen-binding portion thereof, has antigenic specificity for the mutated amino acid sequence encoded by the cancer-specific mutation for the benefit of generating a PBMC or T cell population known to recognize the cancer-specific mutation identified in the patient and which therefor be effective in targeting the particular cancer of the patient as taught by Restifo. One of ordinary skill in the art would have been motivated to do so in order to improve the targeting capability of the therapeutic PBMCs tor T cells towards treating cancer. It would have been obvious to one of ordinary skill in the art to isolate a nucleotide sequence that encodes a TCR from the selected autologous T cell that has been selected for its ability to target a cancer antigen, since one of ordinary skill in the art would understand that selection of such a TCR provide for maximal targeting capability towards the particular cancer antigen as implied in Restifo and Yee. Since all such compositions and methods steps needed to carry out such a modification of the method of Yee were known and described in the cited prior art, one of ordinary skill in the art would have had a reasonable expectation of success in being able to combine these methods.
With respect to claim 2, Yee teaches the cancer is epithelioma (epithelial cancer) (0026). With respect to claim 4, Yee teaches the PBMCs are autologous to the subject or patient (0008 and 0059). With respect to claim 5, Yee teaches the PBMCs are allogenic to the subject or patient (0008 and 0058). With respect to claim 6, Yee teaches the method where autologous dendritic cells were pulsed with the tumor associated self-antigen MART-1/M26 peptide (inducing autologous APCs of the patient to present the mutated amino acid sequence comprises pulsing APCs with peptides comprising the mutated amino acid sequence) (0010, 0069 and 0076). With respect to claim 15, Yee teaches expanding the isolated PBMCs which are co-cultured with tumor material or tumor associated peptides from the patient (expanding the numbers of PBMC that express the TCR, or the antigen-binding portion thereof) (0008 and 0058).
Yee does not teach method where the cancer is cholangiocarcinoma, melanoma, colon cancer, or rectal cancer as recited in claim 3.
However, Hacohen teaches a similar method of adoptive immunotherapy for treating cancer in a patient by identifying one or more genes in the nucleic acid of a cancer cell of the patient. Hacohen teaches the method where the cancer is melanoma or colon cancer (0015).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo including the treating of cholangiocarcinoma, melanoma, colon cancer, or rectal cancer for the benefit treating of treating additional known cancers. It would have been obvious to one of ordinary skill in the art to include the treatment of these additional cancers in the method taught by the combined teachings of Yee and Restifo, since similar treatment methods were known to treat melanoma and colon cancer as taught by Hacohen. It would have been within the purview of one of ordinary skill in the art to include other known cancers such as cholangiocarcinoma and rectal cancer. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to include the claimed cancer, since similar methods of treatment were known to be used for melanoma or colon cancer as taught by Hacohen.
Although, Yee teaches the method where autologous dendritic cells were pulsed with the tumor associated self-antigen MART-1/M26 peptide (inducing autologous APCs of the patient to present the mutated amino acid sequence comprises pulsing APCs with peptides comprising the mutated amino acid sequence) (0010, 0069 and 0076), Yee does not teach the method where the pulsing is done with a pool of peptides, each peptide in the pool comprising a different mutated amino acid sequence as recited in claim 6.
However, Hacohen teaches stimulating T cells of the sequenced patients and APCs by pulsing with either individual peptides or a peptide pool (0183). Hacohen teaches that the peptides were tumor specific mutated peptides (inducing autologous APCs of the patient to present the mutated amino acid sequence comprises pulsing APCs with peptides comprising the mutated amino acid sequence) (0183).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo so that the inducing of the autologous APCs of the patient is done by pulsing with a pool of peptides, each peptide in the pool comprising a different mutated amino acid sequence for the benefit of inducing the APCS with multiple different peptides with different mutated amino acid sequences that are specific to the cancer of the patient as taught by Hacohen. It would have been obvious to one of ordinary skill in the art so that the induction of the APC is done by pulsing with a pool of peptides with different mutated amnio acid sequences in the method taught by the combined teachings of Yee and Restifo, since similar treatment methods where APC are induced were known to pulse with a pool of peptides with different mutated amnio acid sequences as taught by Hacohen. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to include inducing the APCs by pulsing with a pool of peptides with different mutated amnio acid sequences, since similar methods of treatment were known to pulse with a pool of peptides with different mutated amnio acid sequences as taught by Hacohen and Yee teaches pulsing with a peptides containing a mutated amino acid sequence.
Yee does not teach the method where inducing autologous APCs of the patient to present the mutated amino acid sequence comprises introducing a nucleotide sequence encoding the mutated amino acid sequence into the APCs as recited in claim 7. Similarly, Yee does not teach the method where the nucleotide sequence introduced into the autologous APCs is a tandem minigene (TMG) construct, each minigene comprising a different gene, each gene including a cancer-specific mutation that encodes a mutated amino acid sequence as recited in claim 8.
However, Hacohen teaches inducing APCs of the patient to present the mutated amino acid sequence by introducing a construct encoding the neoantigen peptide into the cells (0133). Hacohen teaches that transducing the cells with expression construct will result in the presentation a peptide and induction of immunity (0133). Hacohen further teaches a preferred method to administer nucleic acids encoding the peptide of the invention is by minigene constructs encoding multiple epitopes and teaches the epitope-encoding DNA sequences are directly adjoined, creating a continuous polypeptide sequence (would be tandem) (0045 and 0154).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo so that the inducing of the autologous APCs of the patient is done by introducing a construct encoding the neoantigen peptide into the cells and where the construct is a tandem minigene (TMG) construct with each minigene containing a different gene and with each gene including a cancer-specific mutation that encodes a mutated amino acid sequence for the benefit of inducing the APCS by the presentation of the peptide as taught by Hacohen. It would have been obvious to one of ordinary skill in the art so that the induction of the APC is done other known means in the art such as by introducing a construct encoding the neoantigen peptide into the cells where the construct is a tandem minigene (TMG) construct with each minigene containing a different gene and with each gene including a cancer-specific mutation that encodes a mutated amino acid sequence as taught by Hacohen. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to so that the induction of the APC is done by introducing a construct encoding the neoantigen peptide into the cells where the construct is a tandem minigene (TMG) construct with each minigene containing a different gene and with each gene including a cancer-specific mutation that encodes a mutated amino acid sequence, since similar methods of treatment were known to successfully use such induction methods for APCs as taught by Hacohen.
Yee does not teach the method where the selected autologous T cells include T cells that have antigenic specificity for a mutated amino acid sequence presented by an MHC Class I molecule and T cells that have antigenic specificity for a mutated amino acid sequence presented by an MHC Class II molecule as recited in claim 16.
However, Restifo teaches that CD4+ T cells (T cells which recognize MHC Class I molecules) are efficient in promoting tumor rejection like CD8+ T cells (T cells which recognize MHC Class II molecules) in part to their ability to secrete IL-2 and recruit and sustain CD8+ cells and be used in cancer immunotherapy (pg. 277 last para.).
Accordingly, one of ordinary skill in the art would have been motivated to include both T cells that have antigenic specificity for a mutated amino acid sequence presented by an MHC Class I molecule and T cells that have antigenic specificity for a mutated amino acid sequence presented by an MHC Class II molecule in the method of Yee for the benefit of both cells’ ability to eliminate tumors and the ability of CD 4+ T cells (T cells which present by an MHC Class I molecule ability) to enhance the function of CD8+ T cells (T cells which present by an MHC Class II molecule). It would have been obvious to one of ordinary skill in the art to make such a modification to the method of Yee, since both cell types are known to kill tumors. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Yee teaches treating with isolated T cells that express the tumor antigen to the subject for adoptive immunotherapy and Restifo teaches that both can be used for such purpose.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 9 is rejected under 35 U.S.C. 103(a) as being unpatentable over Yee in view of Hacohen and Restifo (as applied to claims 1-8 and 15-16 above), and further in view of Dudley et al. (Journal of Immunotherapy) (ref. of record).
The teachings of Yee, Hacohen and Restifo can be found in the previous rejection above.
Yee does not teach the method including obtaining multiple fragments of a tumor from the patient, separately co-culturing autologous T cells from each of the multiple fragments with the autologous APCs that present the mutated amino acid sequence, and separately assessing the T cells from each of the multiple fragments for antigenic specificity for the mutated amino acid sequence as recited in claim 9.
However, Dudley teaches a method of generation T lymphocytes with specific reactivity against tumor antigens by using multiple independent TIL (tumor infiltrating lymphocytes) generated from tumor specimens (abstract). Dudley teaches that “the independent initiation and expansion of multiple cultures from a small melanoma specimen enhanced the frequency of generating tumor-reactive cultures” (pg. 333 Col. 1 para. 3). Dudley further teaches cutting the tumor specimen into multiple fragments (pg. 333 Col. 2 last para.). Dudley teaches that independent cultures of TIL isolated from different fragments of tumor from the same patient demonstrated more than 100-fold difference in IFNγ secretion when stimulated with T2 cells as antigen presenting cells, and that the independent TIL cultures exhibited 5-fold differences in recognition of autologous tumor cells (pg. 337 Col. 2 para. 2).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo so that multiple fragments of a tumor from a patient are obtained, separately co-cultured autologous T cells from each fragments with autologous APCs that present the mutated amino acid sequence, and separately assessing the T cells from each of the multiple fragments for antigenic specificity for the mutated amino acid sequence for the benefit increasing the number of potential cancer-specific mutation identified as taught by Dudley. It would have been obvious to one of ordinary skill in the art to make such a modification to the method taught by the combined teachings of Yee and Restifo, since Dudley teaches the advantage of using multiple tumor fragments in increasing the frequency of generating tumor-reactive cultures. One of ordinary skill in the art would recognize that by increasing the pool of T-cells that there will be an increase in the number of T cells presenting a mutated amino acid sequence. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to include the claimed step of obtaining and assessing multiple fragments of tumors from the patient, since Dudley teaches a similar method of identifying autologous T cells that present mutated amino acid sequences that are cancer specific where multiple fragments are used.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 10-13 are rejected under 35 U.S.C. 103(a) as being unpatentable over Yee in view of Hacohen and Restifo (as applied to claims 1-8 and 15-16 above), and further in view of June et al. (US 2004/0101519 A1) (ref. of record).
The teachings of Yee, Hacohen, and Restifo can be found in the previous rejection above.
Yee does not teach the method where selecting the autologous T cells that have antigenic specificity for the mutated amino acid sequence comprises selectively growing the autologous T cells that have antigenic specificity for the mutated amino acid sequence as recited in claim 10.
However, June teaches selectively growing the autologous T cells from cancer patients by enriching a desired T cell population using cell sorting or flow cytometry prior to expanding the cells (0090-0091). In addition, June teaches that the T cells can be from tumor infiltrating lymphocytes from tumor tissue and that the T cells express antigens of interest (have antigen specificity for the mutated amino acid sequence) (0089-0091, 0096). June further teaches that T cells from a tumor can be isolated, expanded and infused into the patient (0106).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo to include the selecting of the autologous T cells that have antigenic specificity for the mutated amino acid sequence by selectively growing the autologous T cells for the benefit increasing the number of autologous T cells with the desired antigenic specificity as taught by June. It would have been obvious to one of ordinary skill in the art to make such a modification to the method taught by the combined teachings of Yee and Restifo, since June teaches the selective isolating of T cells with desired antigenic specificity and expansion of the cells for therapy. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to include the claimed step of selectively growing T cells with the antigenic specificity, since June teaches a similar method of identifying autologous T cells that present mutated amino acid sequences and selectively growing the T cells.
Yee does not teach the method where selecting the autologous T cells that have antigenic specificity for the mutated amino acid sequence comprises selecting the T cells that express any one or more of programmed cell death 1 (PD-1), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), 4-1BB, OX40, and CD107a as recited in claim 11.
However, June teaches selecting T cells expressing CD137 and CD134 using antibodies against CD137 and CD134, also known as 41-BB and OX40, respectively to enrich for the antigen-specific cells (0097). June teaches positively selecting for antigen specific cells prior to expanding the cells by selecting using antibodies specific for T cell activation markers (0097).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo to include the selecting of the autologous T cells selecting T cells expressing one or more of PD-1, LAG-3, TIM-3, 4-1BB, OX40 and CD107 for the benefit selecting the antigen-specific cells as taught by June. It would have been obvious to one of ordinary skill in the art to make such a modification to the method taught by the combined teachings of Yee and Restifo, since June teaches the selective isolating of T cells with desired antigenic specificity by selecting using antibodies against known T cell activation markers and expansion of the cells for therapy. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to include the claimed step of selecting T cells with the antigenic specificity which express the listed markers, since June teaches selecting autologous T cells that present mutated amino acid sequences for the expression of the markers, 41-BB and OX40.
Yee does not teach the method where selecting the autologous T cells that have antigenic specificity for the mutated amino acid sequence comprises selecting the T cells (i) that secrete a greater amount of one or more cytokines upon co-culture with APCs that present the mutated amino acid sequence as compared to the amount of the one or more cytokines secreted by a negative control or (ii) in which at least twice as many of the numbers of T cells secrete one or more cytokines upon co-culture with APCs that present the mutated amino acid sequence as compared to the numbers of negative control T cells that secrete the one or more cytokines as recited in claim 12. Similarly, Yee does not teach the method where the one or more cytokines comprise interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor alpha (TNF-α), granulocyte/monocyte colony stimulating factor (GM-CSF), IL-4, IL-5, IL-9, IL-10, IL-17, and IL-22 as recited in claim 13.
However, June teaches selecting T cells expressing IL-2, IFN-γ, and IL-4 (0097). June teaches positively selecting for antigen specific cells prior to expanding the cells by selecting using antibodies specific for T cell activation markers (0097).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Yee and Restifo to include the selecting of the autologous T cells selecting T cells expressing one or more of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor alpha (TNF-α), granulocyte/monocyte colony stimulating factor (GM-CSF), IL-4, IL-5, IL-9, IL-10, IL-17, and IL-22 for the benefit selecting the antigen-specific cells as taught by June. It would have been obvious to one of ordinary skill in the art to make such a modification to the method taught by the combined teachings of Yee and Restifo, since June teaches the selective isolating of T cells with desired antigenic specificity by selecting using antibodies against known T cell activation markers and expansion of the cells for therapy. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Yee and Restifo to include the claimed step of selecting T cells with the antigenic specificity which express the listed markers, since June teaches selecting autologous T cells that present mutated amino acid sequences for the expression of the markers, IL-2, IFN-γ, and IL-4.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is withdrawn due to the filing of a terminal disclaimer to US Pat. No. 10,973,894.
Response to Arguments
Applicant's arguments filed Mar. 11, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that amended claim 1 now requires in step (I) that the genes containing a cancer-specific mutation that encodes a mutated amino acid sequence have been identified before step III where the autologous T cells of the patient are co-cultured with autologous APCs that present the mutated amino acid sequence and this is not taught by Yee (Remarks pg. 10 para. 2-3). However, this argument was not found to be persuasive, since even though steps have been amended to include roman numerals they do not imply order. The MPEP 2111.01(II) states that it is “improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims [does] not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order,” citing Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003).
Applicant argues that Yee does not teach identifying the cancer-specific mutation before co-culturing autologous T cells with autologous APCs, but instead characterizes the antigen-specificity after the co-culturing (Remarks pg. 10 para. 3). Applicant further argues that the claimed method co-cultures autologous T cells of the patient with the autologous APCs that present the mutated amino acid sequence encoded by the gene containing a cancer-specific mutation already identified (Remarks pg. 10 para. 4). However, this argument was not found to be persuasive, since the mutated amino acid sequence is not required to be identified prior inducing the autologous antigen presenting cells.
Applicant argues that the claimed method excludes other types of non-neoantigens which do not include an identified mutated amino acid sequence such as oncofetal, oncoviral, overexpressed/accumulated, cancer-testis, lineage-restricted, posttranslationally altered or idiotypic antigens (Remarks pg. 11 para. 1). Similarly, Applicant argues that Yee does not select for TCRs that recognize a mutated amino acid sequence encoded by cancer-specific mutation or neoantigen to the exclusion of other non-mutated cancer antigens (Remarks pg. 11 para. 2). However, these arguments were not found to be persuasive, since the claimed method does not exclude additional non-neoantigens and only requires that at least the antigen present cells (APCs) present a mutated amino acid sequence that is a cancer-specific mutation. The "transitional term "comprising" in step (VII), which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps” (MPEP 2111.03). Additionally, Yee teaches enriching and cloning the T cell population with antigen specificity for the tumor material or tumor antigens (abstract and 0005-0009).
Applicant argues as explained in the Declaration submitted by Dr. Tran, the method of Yee produces non-neoantigen-reactive T cells including T cells reactive to shared antigens and non-tumor antigens which can cause on-target, off tumor toxicity of normal cells that also express the antigen and which dilute the final T-cell product impairing its therapeutic activity (Remarks pg. 11 last para.). However, this argument was not found to be persuasive, since the claimed method does not require the exclusion of non-neoantigen-reactive T cells. The "transitional term "comprising" in step (VII), which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps” (MPEP 2111.03).
Applicant argues that the claimed invention selects for TCRs that recognize a mutated amino acid sequence encoded by a cancer-specific mutation and, since the methods of Yee do not have the claimed sequence of steps the methods do not select for cancer-specific mutations (Remarks pg. 12 para. 1). As explained above, this argument was not found to be persuasive, since even though steps have been amended to include roman numerals they do not imply order. The MPEP 2111.01(II) states that it is “improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims [does] not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order,” citing Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003).
Applicant argues that Yee teaches the desirability of targeting “self” antigens which do not have mutated amino acid sequences and modifying Yee to include neoantigens would be contrary to Yee’s preference of using self-antigens (Remarks pg. 12 para. 2). However, this argument was not found to be persuasive, since the claimed method does not exclude “self” antigens. The "transitional term "comprising" in step (VII), which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps” (MPEP 2111.03). In addition, it appears that Yee uses the term “self” antigens to include normal or non-tumor antigens and tumor antigens (0049). For example in 0004, Yee states, “Induction of a high affinity CDS response against self antigens, which are represented increasingly as potential immune targets in cancer immunotherapy demonstrate a significant role for IL-21 in antigen-specific anti-tumor strategies.” Then in 0049, Yee states “Using peptide-MHC tetramers to track a rare but measurable naive T cell population recognizing a normal self antigen, in the presence ofIL-21, the frequency and absolute numbers of antigen-specific CD8 T cells that could be elicited increased by more than 20-fold compared to cultures grown in the absence of IL-21”. From these statements, it appears that Yee considers the term self-antigens to include both normal antigens and tumor specific antigens, otherwise the immunotherapy would not work.
Applicant argues that Yee is different from the claimed method, since Yee teaches co-culturing T cells with “tumor material” which includes total RNA, lysed tumor cells, necrotic tumor cells, tumor proteins and apoptotic bodies whereas the claimed method requires identified genes containing a cancer-specific mutation that encodes a mutated amino acid sequence before inducing the APCs (step (I) must be completed before step II of the claimed method) (Remarks pg. 12 para. 3). As explained above, this argument was not found to be persuasive, since even though steps have been amended to include roman numerals they do not imply order. The MPEP 2111.01(II) states that it is “improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims [does] not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order,” citing Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003).
Applicant argues as explained in the Declaration submitted by Dr. Tran, the tumor material used in Yee may negatively impact the ability to detect and expand neoantigen-reactive T cells, if the quality is poor and the generation of tumor cell lines as an alternative is time consuming and may not express all of the neoantigens (Remarks pg. 12-13 bridging para.). Applicant further argues even if the tumor material quality is good, the level of neoantigens in still might be low and not elicit a T-cell response and RNA and protein from normal cells and from housekeeping genes might dilute out the neoantigen RNA or protein (Remarks pg. 13 para. 2). Applicant argues that the advantage of the claimed method is the production of T cells that target neoantigens and avoids the above mention disadvantages of Yee (Remarks pg. 13 para. 3). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., exclusion of additional antigens) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that there is no rationale to modify the method of Yee to identify genes with cancer-specific mutations that encodes a mutated amino acid sequence, since Yee teaches the desirability of targeting “self” antigens (Remarks pg. 13 para. 4). However, this argument was not found to be persuasive, since as explained previously, the self-antigens taught by Yee includes tumor specific antigens and Yee teaches identifying a tumor antigen and introducing genetic material in the T cells genetic material to express a T cell receptor or a chimeric T cell receptor to recognize the target antigen (0005-0009 and 0060-0061). Since a vector containing the sequence of the target antigen is used in this method, it would be understood to involve the identifying of at least one or more genes in the nucleic acid of a cancer cell of the patient which would containing a cancer-specific mutation that encodes a mutated amino acid sequence or the target antigen.
Applicant argues that Restifo, Hacohen, Dudley and June fail to remedy the deficiencies of Yee (Remarks pg. 13 last para.). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Yee were not found to be persuasive as explained above.
Applicant argues that the claimed method produces unexpected results and that the resulting T cells produce a dramatic therapeutic effect (Remarks pg. 14 para. 2-3). Specifically, Applicant argues that Examples 5 and 7 and Fig. 4 demonstrate tumor regression in a patient with metastatic cholangiocarcinoma treated with T cells isolated according to the claimed method (Remarks pg. 14 last para.). However this argument was not found to be persuasive, since Yee also teaches a method of treating cancer in a patient by administering adoptive immunotherapy for cancer and that the method results in anti-tumor effects and tumor regression in a mouse model of ACT (abstract, 0004, 0054, and 0062, Examples 8-9). Furthermore, the Examples in the specification only demonstrate treatment of one patient with tumor regression and based on the tumor regression of the mouse model in Yee these results to not appear to be unexpected.
Similarly, Applicant argues that the reference, Zacharakis, also demonstrates these unexpected results and the reference shows treating a metastatic breast cancer patient that was refractory to chemotherapy with T cells isolated according to the claimed method resolved all of the lesions (Remarks pg. 15 first para.). Additionally, Applicant argues that the reference, Tran, also demonstrates these unexpected results and the reference shows treating a metastatic colorectal patient with T cells isolated according to the claimed method resulted in the regression of lung metastasis (Remarks pg. 15 first para.). However these arguments were not found to be persuasive, since Yee also teaches a method of treating cancer in a patient by administering adoptive immunotherapy for cancer and that the method results in anti-tumor effects and tumor regression in a mouse model of ACT (abstract, 0004, 0054, and 0062, Examples 8-9). Furthermore, the reference, Zacharakis and Tran, each only demonstrate a method of treatment of one patient resulting in tumor regression and based on the tumor regression of the mouse model in Yee these results to not appear to be unexpected. Additionally, it is unclear if the methods disclosed in Zacharakis and Tran are commensurate in scope with the claimed method. For instance, Zacharakis discloses the method included whole exome sequencing and RNA sequencing to identify mutations of a tumor from the patient, then TIL fragments lymphocyte populations derived from pieces of the patient’s tumor were screened against the mutations using pulsed peptide pools or transfected with mRNAs expressing in autologous antigen-present cells (APCS), then they sorted neoantigen-reactive T cell clonotypes, mutant-peptide-reactive cells based on the T cell receptor (TCR)-beta variable (TRBV) region or high expression levels of 4-1BB before administering to the patient (pg. 1 to pg. 3 para. 2). Tran discloses the method included the sequencing of the whole-exome and transcriptome to identify mutations of a tumor from the patient, they generated TIL from multiple tumor fragments, then they evaluated each culture for reactivity against mutant neoepitopes, they selected the culture that recognized mutant KRAS G12D and further selected the culture that showed the highest frequency of CD8+ cells reactive to the G12D mutant, expanded it for treatment and before infusion the patient received nonmyeloablative lymphodepleting chemotherapy regimen (pg. 2256 Col. 1 para. 3 to Col. 2 para. 2).
Applicant argues that the invention has receive extensive media coverage as evidenced by article metrics of Zacharakis which show it is the 16th most visible article, was published in a high impact journal, and had a commentary; the article metrics for Tran shows the article’s high impact; and the claimed method receive coverage in the lay press, The New York Times (Remarks pg. 15 para. 2 to pg. 16 para. 2). However, these secondary considerations were not found to be persuasive, since the combined teachings of Yee, Hacohen, and Restifo teach the claim method. Additionally, the method referred to in The New York Times article appears to be different from the claimed invention. For instance, the method cited in the Times involves extracting T cells from the tumors and culturing the cells, using chemotherapy to wipe out the immune system of the patient and then administered the cultured T cells (pg. 3 para. 3). It is unclear if the method used for this article is commensurate in scope with the claimed method.
Applicant argues that the claimed methods rapidly assess a large number of mutations restricted by all of the patient’s MHC molecules at once allowing for the identification of the full repertoire of the mutation-reactive T cells in the patient (Remarks pg. 16 para. 2). Applicant further argues that MHC Class II epitopes are difficult to predict because the prediction algorithms are only useful for a few MHC class I alleles and are constrained by the limited available reagents used to select mutation-reactive T cells, the MHC Class II molecules have binding motifs that are not readily discernible and there are thousands of MHC II alleles in humans (Remarks pg. 16 last para.). Applicant argues that that these constraints in predicting MHC Class II demonstrate that it was unexpected that a large number of cancer-specific, mutated amino acid sequences not restricted to MHC molecules could be rapidly assessed in a patient at one time and may identify the entire repertoire of cancer-specific mutations recognized by the patient’s T cells (Remarks pg. 17 first para.). However, these arguments were not found to be persuasive, since these features upon which applicant relies (i.e. rapid assessment of a large number of mutations restricted by all of the patient’s MHC molecules) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Eric Tran, Ph.D. filed on Mar. 11, 2026 under 37 CFR §1.132 has been considered but is ineffective to overcome the rejections of claims under 35 U.S.C. §103.
Dr. Tran explains the claimed method requires the identification of the genes containing cancer-specific mutations that encode mutated amino acid sequences prior to inducing the APCs (Declaration para. 3). Additionally, Dr. Tran states that Yee discloses preparing a T cell population by culturing T cells with tumor material in the presence IL-21 and APCs and Yee does not teaches identifying the genes containing a cancer-specific mutation (Declaration para. 4-5). However, these arguments were not found to be persuasive as explained above in the response to the arguments, since even though steps have been amended to include roman numerals they do not imply order. The MPEP 2111.01(II) states that it is “improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims [does] not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order,” citing Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003). Further, Yee teaches identifying a tumor antigen and introducing genetic material in the T cells genetic material to express a T cell receptor or a chimeric T cell receptor to recognize the target antigen (0005-0009 and 0060-0061). Since a vector containing the sequence of the target antigen is used in this method, it would be understood to involve the identifying of at least one or more genes in the nucleic acid of a cancer cell of the patient which would containing a cancer-specific mutation that encodes a mutated amino acid sequence or the target antigen.
Dr. Tran states that the claimed method produces T cells with only target neoantigens by the selection of TCRs that recognize a mutated amino acid sequence encoded by a cancer specific mutation or neoantigen and which may be missed in the method of Yee (Declaration para. 6). Dr. Tran explains that the method of Yee can produce non-neoantigen-reactive T cells including T cells reactive against shared antigens and non-tumor antigens and these T cells may cause on-target, off-tumor toxicity of normal cells and dilute the final T cell product by decreasing the frequency of tumor-reactive T cells (Declaration para. 7). Dr. Tran explains that the tumor material used in Yee may negatively impact the ability to detect and expand neoantigen-reactive T cells, if the quality is poor and the generation of tumor cell lines as an alternative is time consuming and may not express all of the neoantigens (Declaration para. 8). Dr. Tran explains that even if the tumor material quality is good, the level of neoantigens in still might be low and not elicit a T-cell response and RNA and protein from normal cells and from housekeeping genes might dilute out the neoantigen RNA or protein (Declaration para. 9). Dr. Tran explains that the advantage of the claimed method is the production of T cells that target neoantigens and avoids the above mention disadvantages of Yee (Declaration para. 10). However, these arguments were not found to be persuasive, since the claimed method does not require the exclusion of non-neoantigen-reactive T cells. Furthermore, the "transitional term "comprising" in step (VII), which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps” (MPEP 2111.03).
Conclusion
No claims are allowed.
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.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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