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
The amendment filed March 19, 2026 in response to the Office Action of December 11, 2025 is acknowledged and has been entered.
Claims 1, 5, 14, and 24 have been amended.
Claims 2-4, 6, 8, 10, and 22 have been cancelled.
Claims 1, 5, 11, 12, 14, 15, and 17-24 are pending.
Claims 18 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 5, 11, 12, 14, 15, 17, and 20-24 are currently under consideration as drawn to the elected invention.
In view of amendments on Specification, the Specification objection set forth in the Office Action of December 11, 2025 is hereby withdrawn.
In view of cancellation of claim 2, the claim objection set forth in the Office Action of December 11, 2025 is hereby withdrawn.
In view of cancellation of claims 3 and 4, and amendments on claims 5, 14, and 24, the 112(b) rejection set forth in the Office Action of December 11, 2025 is hereby withdrawn.
In view of amendment on claim 14, the 112(d) rejection set forth in the Office Action of December 11, 2025 is hereby withdrawn.
In view of amendment on claims 1 and 14, the 112(a) rejection set forth in the Office Action of December 11, 2025 is hereby withdrawn.
In view of recent claim amendments of Appl. 17/924,982 (April 27, 2026 amendments), the Double Patenting rejections over the Appl. 17/924,982 set forth in the Office Action of December 11, 2025 are hereby withdrawn.
Because the amended claims 1 and 14 incorporate the limitation of the original claim 8, the 103 rejections and other Double Patenting rejections are modified accordingly (see the rejections below).
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim 1, 11, 12, 14, 15, 17, 20, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) in view of Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record) and Tribble (Tribble et al., WO 2017/174824 A1, Publication Date: 12/10/2017, of record).
Moon teaches using engineered TCR T cells to treat various cancers, including melanoma, colon cancer and synovial sarcoma (page 436, col. 2, para. 2).
Moon teaches that the antigens targeted by engineered TCR have included relatively immunogenic antigens derived from spontaneously occurring tumor specific T cells, such as melanoma-associated antigen (MAGE) and New York esophageal squamous cell carcinoma antigen (NY-ESO1) (page 436, col. 2, para. 2).
Moon teaches that there is expression of a set of surface inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and thus prevent autoimmunity (page 437, col. 1, para. 1).
Moon teaches the treatment of a mouse tumor xenograft model with a single injection of 10x 106 Ly95 T cells (T cells engineered to express a NY-ESO1 specific TCR) and injection of 10 mg/Kg anti-PD1 antibody every 5 days (page 438, col. 1, para. 1).
Moon teaches that hypofunctional Ly95 T cells have increased expression of inhibitory receptors (such as PD1, Tim3 and Lag3) compared with cryopreserved Ly95 T cells (the bridging paragraph of cols. 1-2 on page 439; and Fig. 3A); in addition, the TCR expressing T cells have increased expression of inhibitory receptors (such as PD1) compared with non-TCR expressing T cells (the bridging paragraph of pages 439-440; and Fig. 3C).
Moon teaches that the anti-PD1 antibody alone had no effect on tumor growth compared with control, while Ly95 T cells significantly reduced tumor growth. However, tumor-bearing mice that received repeated intraperitoneal injections of PD1 antibody in addition to a single intravenous injection of 10 million Ly95 T cells, demonstrated the slowest rate of tumor growth for 6 weeks from the start of treatment (the bridging paragraph of page 440-441).
Moon teaches administering various agents that affect the tumor microenvironment and/or the T cells themselves, for example an anti-human antibody directed to PD1 in TCR T cell therapy (page 443, col. 2, para. 2).
Moon teaches that manipulation of the tumor microenvironment can be done either prior to T-cell transfer, during T-cell transfer, or after T-cell infiltration to tumor (page 443, col. 2, para. 2).
Moon teaches that these data support using inhibitory receptor (IR) antibodies in combination with human T cell transfer approaches, and IR therapy could also be value in other transgenic TCR approaches (page 445, col. 1, para. 2).
Moon teaches as set forth above. However, Moon does not teach where in the heterologous TCR specifically binds to a MAGE-A4 antigen or peptide antigen thereof; wherein the cancer expresses MAGE-A4 antigen or peptide antigen thereof; or the sequences of alpha chain variable domain and beta chain variable domain.
Sanderson teaches a TCR therapy using MAGE-A4 TCR T cells, which comprises autologous T cells transduced with an affinity-enhanced TCR specific bind to a MAGE-A4 peptide antigen (Abstract). It is noted that the MAGE-A4 TCR used in Sanderson is the TCR T cells used in Example 2 of the instant application (see [0251] of the instant publication).
Sanderson teaches that MAGE-A4 is a member of an extensive family of cancer/testis antigens; its expression is restricted to immune-privileged sites and cancers. In NSCLC, melanoma, bladder, head and neck, and gastroesophageal cancers, MAGE-A4 is highly expressed in up to 50% of cases, and thus MAGE-4A is an attractive target for TCR therapy (the bridging paragraph of pages 1-2).
Sanderson teaches that in vitro assays, MAGE-4A TCR produced strong IFNγ responses to MAGE-A4 expressing tumor cell lines and MAGE-A4 expressing melanoma material (Fig. 1a and Fig. 1b).
Sanderson teaches that in vivo studies, a MAGE-4A TCR was administered as a single intravenous (i.v.) injection to mice bearing either subcutaneous (s.c.) or i.v. xenografted tumors derived from human melanoma cell line (page 2, col. 2, para. 2). MAGE-A4 TCR T cells produce dose-dependent in vivo tumor clearance (Fig. 2a and Fig. 2b).
Sanderson does not teach the TCR comprising the six CDRs recited in claims 1 and 14.
Tribble teaches a TCR which binds to HLA molecules displaying the MAGE A4 peptide GVYDGREHTV (page 2, lines 20-27).
Tribble teaches MAGE-A4 targeting TCR (TCR 4) with the TCR α chain of SEQ ID NO: 8 and the TCR β chain of SEQ ID NO: 9 (see sequences on page 27). As shown below, SEQ ID NO: 8 comprises SEQ ID NOs: 27-28-29 of the instant application; SEQ ID NO: 9 comprises SEQ ID NO: 30-31-32 of the instant specification (CDR regions are boxed):
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Tribble teaches that TCR4 has good specificity to MAGE-A4 (compared to MAGE-B2), see Table on page 20 of Tribble.
Tribble teaches that TCR4 make contact with MAGE-A4 peptide when in complex with HLA-A*0201 on the surface of antigen presenting cells (Example 7).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of treating NY-ESO1 expressing cancers with a combination of a PD-1 axis binding antagonist (e.g. anti-PD1 antibody) and T cells expressing an engineered TCR specifically binds to a NY-ESO1 antigen (e.g. Ly95 T cells) by substituting NY-ESO1 targeting TCR T cells with MAGE-4A targeting TCR T cells for treating MAGE-A4 expressing cancers, as taught by Sanderson. One of ordinary skill in the art would have a reasonable expectation that the combination would improve efficacy for treating MAGE-A4 expressing cancers, because Sanderson teaches that MAGE-A4 TCR expressing T cells show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro. Combining the teachings of Tribble, one of ordinary skill would further modify the method taught by Moon and Sanderson by using the CDRs taught by Tribble for the TCR α chain and TCR β chain, because Tribble teaches that the TCR α chain and TCR β chain comprising these CDRs show good binding activity and specificity to MAGE-A4 on cell surface. One of ordinary skill in the art would have recognized that the TCR α chain and TCR β chain taught by Tribble would be suitable for making TCRs targeting MAGE-A4 antigen and would improve specificity of the MAGR-A4 targeting TCRs used in the combination. One of ordinary skill in the art would have had a reasonable expectation of success because the TCR α chain and TCR β chain have been extensively tested, as evidenced by the examples of Tribble. The motivation would have been to develop a better MAGE-A4 targeting TCR for the combination treatment for MAGE-A4 expressing cancers.
Regarding claim 14, the teachings of Moon, Sanderson and Tribble are described above, however, these references do not explicitly teach the steps as recited by claim 14. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Moon, Sanderson, Tribble, and to apply the combination therapy taught by Moon, Sanderson and Tribble to anti-PD-1 antibody treated cancer patients (e.g. NSCLC and Melanoma) who have been determined having stable disease or progressive disease under anti-PD1 single treatment. One of ordinary skill in the art would have had a reasonable expectation of success that the combination therapy would improve the therapeutic activity of the treatment and overcome anti-PD-1 resistance, because Moon shows that cancer cells, which are resistant to anti-PD1 antibody alone, are sensitive to TCR-T cell therapy. In addition, the combination combines two different anti-tumor modular components to enhance therapeutic efficacy and flexibility in treatment. The motivation would have been to apply the combination therapy to a suitable population and to develop a more effective treatment for overcoming resistance to anti-PD1 single treatment.
Regarding claim 11 and 23, Moon teaches that manipulation of the tumor microenvironment can be done either prior to T-cell transfer, during T-cell transfer, or after T-cell infiltration to tumor (page 443, col. 2, para. 2). Thus, one of ordinary skill in the art would have known to administering antibody prior to TCR T cells (separately).
Regarding claims 12 and 24, Moon teaches administering ten million TCR T cells to mice with lung cancer model (A549 model) and anti-PD1 antibody was administered every 5-day (page 438, col. 1, para. 1). Sander teaches administering one million TCR T cells to mice with melanoma cancer model (A375 model) (page 9, col. 2, para. 2). One of ordinary skill in the art would have known to adjust the dosage and administration regimens (based on factors such as the size of the subject, the activity of TCR T cells, the condition of the subject and/or the specific cancer) to reach the claimed dosage range and/or administration regimens. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 15, Moon teaches TCR T cells are administered intravenously (page 438, col. 1, para. 1). Sanderson teaches MAGE-A4 TCR expressing T cells was administered as a single intravenous (i.v.) injection (page 2, col. 2, para. 2).
Regarding claim 17, the mice with tumor model in Moon and Sander’s treatment have not received prior cancer treatment, because these mice were treated immediately after tumor established (see page 438, col. 1, para. 1 of Moon; § In vivo efficacy on page 9 of Sanderson).
Regarding claim 20, Moon teaches that the anti-PD1 antibody alone had no effect on tumor growth compared with control, while Ly95 T cells significantly reduced tumor growth. However, tumor-bearing mice that received repeated intraperitoneal injections of PD1 antibody in addition to a single intravenous injection of 10 million Ly95 T cells, demonstrated the slowest rate of tumor growth for 6 weeks from the start of treatment (the bridging paragraph of page 440-441). Sanderson teaches that MAGE-A4 TCR expressing T cells inhibit the growth of MAGE-A4 expressing A375 tumors, leading to regression and increased survival in xenograft models (Fig. 2). Based on the teachings of Moon and Sanderson, one of ordinary skill in the art would have a reasonable expectation that the combination would be improved response for MAGE-A4 expressing cancers, because Sanderson teaches that MAGE-A4 TCR expressing T cells show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) in view of Sanderson (Sanderson et al., OncoImmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record) and Tribble (Tribble et al., WO 2017/174824 A1, Publication Date: 12/10/2017, of record), as applied to claims 1, 11, 12, 14, 15, 17, 20, 23, and 24 above, and further in view of Keytruda (reference ID: 4003165, Publication Date: 2016/10, of record).
Moon, Sanderson and Tribble teach the method of claim 1 as set forth above. In particular, Moon, Sanderson and Tribble teach the combination of an anti-PD1 antibody and combination of MAGE-A4TCR T cells. However, Moon, Sanderson and Tribble do not teach the anti-PD1 antibody is pembrolizumab (the elected species).
Keytruda teaches that Keytruda (pembrolizumab) is an FDA approved anti-PD1 antibody for treating cancers (page 1, col. 1, para. 2).
Keytruda teaches that Keytruda (pembrolizumab) can be used for treating NSCLC and melanoma, See page 1, § Indications and Usage. Both NSCLC and melanoma are MAGE-A4 expressing cancers, as evidenced by the bridging paragraph of pages 1-2 of Sanderson.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method taught by Moon, Sanderson and Tribble by substituting the anti-PD1 antibody with pembrolizumab with reasonable expectation of success, because Keytruda teaches pembrolizumab is an FDA approved anti-PD1 antibody for NSCLC and melanoma, Sanderson teaches NSCLC and melanoma are MAGE-A4 expressing cancers. Based on the teachings of Moon, Sanderson, Tribble and Keytruda, one of ordinary skill in the art would have recognized that pembrolizumab would be suitable for the claimed combination for treating MAGE-A4 expressing cancers (e.g. NSCLC and melanoma) and would enhance the therapeutic efficacy of the treatment. The motivation would have been to develop a better combination treatment for MAGE-A4 expressing cancers with an approved antibody and to expand applications for pembrolizumab.
Response to Arguments
For the 103 rejection, Applicant first argues the cited references do not teach or suggest the claimed combination, as shown below:
Moon describes combining PD-1 blockade with TCR-engineered T cells targeting NYESO-1. Moon does not disclose or suggest: (1) a TCR that binds MAGE-A4, or (2) the specific TCR a and~ variable domains comprising the aCDRl-3 and ~CDRl-3 sequences recited in claims 1 and 14. Thus, Moon teaches only a different antigen system (NY-ESO-1) using a different TCR construct.
Sanderson does not remedy this deficiency. While Sanderson describes TCR therapy targeting MAGE-A4, Sanderson does not disclose or suggest combining this therapy with PD-1 axis blockade. Sanderson focuses on the activity of ADP-A2M4 T cells alone.
Likewise, while Tribble discloses a MAGE-A4-specific TCR comprising sequences corresponding to the claimed CDR regions, Tribble does not teach or suggest administering a PD-1 axis binding antagonist in combination with TCR-engineered cells.
Therefore, none of the references teach or suggest the claimed treatment regimen comprising both (i) a PD-1 axis binding antagonist and (ii) cells expressing the specific MAGEA4 TCR defined by the claimed CDR sequences.
Applicant’s arguments have been fully considered but they are not persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
It is also noted that, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
As set forth above, Moon teaches: 1) treat cancers with anti-PD-1 antibody and TCR T cells targeting NYESO-1; 2) the therapeutic activity is improved with the combination; 3) T cell therapy induces PD-1 expression and anti-PD-1 antibody can be used to mitigate immunosuppression by PD-1. Sanderson teaches: 1) MAGE-A4 is a good target for some cancers, such as NSCLC and melanoma; 2) TCR T cells targeting MAGE-A4 shows anti-tumor activity to MAGE-A4 expressing cancers. Tribble discloses the MAGE-A4-specific TCR comprising sequences corresponding to the claimed CDR regions which has good specificity to MAGE-4. It would have prima facie been obvious to one of ordinarily skilled in the art to combine the teachings from these references and to develop the specific combination as claimed by substituting NY-ESO1 targeting TCR T cells with MAGE-4A targeting TCR T cells with the CDR sequences cited by the instant claims 1 and 14 for treating MAGE-A4 expressing cancers such as NSCLC and melanoma. One of ordinary skill in the art would have a reasonable expectation that the combination would improve efficacy for treating MAGE-A4 expressing cancers, because Sanderson teaches that MAGE-A4 TCR expressing T cells show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro.
Applicant further argues that a person of ordinary skill would not have a reasonable expectation of success, as shown below:
TCR therapies depend on numerous variables including antigen affinity, TCR signaling strength, T-cell exhaustion profiles, tumor microenvironment interactions, and immune checkpoint regulation. At the time of the invention, the field recognized that different TCR constructs and different antigens can produce dramatically different functional responses. Accordingly, success with NY-ESO-1-specific TCRs in Moon would not reasonably predict success for MAGE-A4-specific TCRs.
Importantly, MAGE-A4 tumors exhibit distinct biological properties and immuneevasion mechanisms. Sanderson itself demonstrates only that ADP-A2M4 T cells have antitumor activity, but does not suggest that PD-1 blockade would enhance their activity. Thus, the cited art does not provide a reasonable expectation that PD-1 inhibition would beneficially interact with MAGE-A4-specific engineered T cells.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Sanderson teaches that MAGE-A4 TCR expressing T cells show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro. Thus, one of ordinary skill in the art would have had a reasonable expectation that a MAGE-A4 TCR T cell therapy would induce immune suppressor PD1, and anti-PD-1 antibody can block PD1 function and enhance TCR therapeutic activity for treating a MAGE-A4 expressing cancer such as NSCLC and melanoma.
Additionally, in the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed fusion protein. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
Applicant further argues that the specification demonstrates unexpected results, as shown below:
For instance, Example 1 demonstrates antigen-specific induction of PD-1 in the claimed engineered T cells. In particular, Figure 3 shows that modified T cells expressing the heterologous MAGE-A4 TCR upregulate PD-1 expression upon stimulation with MAGE-A4 antigen, whereas non-transduced cells do not do so. This establishes a specific exhaustion mechanism linked to the claimed TCR-antigen interaction.
Example 1 also demonstrates tumor-specific PD-L1 induction following T-cell infiltration. Specifically, biopsy data from treated patients demonstrates that PD-L1 expression in tumors increases after infusion of the claimed modified T cells, indicating an adaptive immune resistance mechanism triggered by the therapy itself. See Figure 1 and Figure 2.
Example 1 further demonstrates that PD-1 blockade rescues exhausted MAGE-A4 TCR T-cell function. Importantly, the data demonstrates that anti-PD-1 antibody restores cytokine production in exhausted engineered T cells, including restoration of IFN-y and granzyme B. See Figure 8. This functional rescue was observed after T cells lost activity following antigen stimulation. The recovery of effector function upon PD-1 blockade demonstrates a synergistic interaction between the specific engineered TCR cells and PD-1 inhibition. Such recovery of exhausted TCR-engineered cells was not predictable from the prior art, which did not demonstrate this effect for MAGE-A4-specific TCR cells.
Applicant’s arguments have been fully considered but they are not persuasive. First, as set forth above, Moon teaches that T cell therapy naturally induce PD-1, Tim 3 and Lag 3 in vivo (see Fig. 3 of Moon). Thus, the immune resistance mechanism triggered by TCR T cel therapy is not unexpected.
Furthermore, Moon also teaches that TILs from the TCR T cells + anti-PD-1 antibody groups demonstrate significantly better killing and IFNγ secretion ability (Fig. 6B). Thus, the results of Example 1 and Figure 8 of the instant specification is not unexpected. It is also noted that the specification does not show results of in vivo treatment with the claimed combination.
In addition, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.)”. MPEP 716.02
In this case, the claims are very broad, encompass a broad genus of PD-1 axis antagonist antibodies and a broad genus of TCR T cells. Only one specific anti-PD-1 antibody (pembrolizumab) and one specific TCR T cell (Spear T cell) combination show activity in in vitro test (Example 1). Accordingly, the data is not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 11,111,301
Claims 1, 11-12, 14, 15, 17, 20, 23 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,111,301 B2 (hereinafter Pat. 301, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) and Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record).
The claims of Pat. 301 teach:
1. A method of treating cancer using immunotherapy, comprising administering to a patient having cancer a population of modified T cells comprising a nucleic acid construct, wherein the cancer expresses one or more tumor antigens selected from NY-ESO1, …, MAGE A4, …; and wherein the nucleic acid construct comprises: (i) a first nucleotide sequence encoding IL 7, (ii) a second nucleotide sequence encoding an antigen receptor, wherein the antigen receptor is …, or a T cell receptor (TCR) that binds to an MHC-displayed peptide fragment of said one or more tumor antigens;
…; and wherein the administration of said modified T cells results in the treatment of the patient's cancer.
9. The method according to claim 1 wherein the TCR comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6 or 11. As shown below, SEQ ID NO: 11 of Pat. 301 (see the sequence on col. 37 of the specification) comprises the CDRs recited by the instant claim 8, CDRs are underlined:
SEQ ID NO: 11
MKKHLTTFLVILWLYFYRGNGKNQVEQSPQSLIILEGKNCTLQCNYTVSPFSNLRWYKQDTGRGPVSL
TILTFSENTKSNGRYTATLDADTKQSSLHITASQLSDSASYICVVSGGTDSWGKLQFGAGTQVVVTPD
IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKS
DFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLR
LWSSGSRAKRSGSGATNFSLLKQAGDVEENPGPRMASLLFFCGAFYLLGTGSMDADVTQTPRNRITKT
GKRIMLECSQTKGHDRMYWYRQDPGLGLRLIYYSFDVKDINKGEISDGYSVSRQAQAKFSLSLESAIP
NQTALYFCATSGQGAYEEQFFGPGTRLTVLEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYP
DHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSEN
DEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKR
KDSRG
Thus, the claims of Pat. 301 teach treating MAGE-A4 expressing cancer by administering a modified immunoresponsive T cells expressing a heterologous TCR specifically binds to a MAGE-A4 antigen. And the TCR comprises the TCR alpha chain and beta chain with recited CDRs of the instant claims. However, the claims of Pat. 301 do not teach in combination with a PD-1 axis bind antagonist, such as anti-PD1 antibody.
Moon and Sanderson teach as set forth above. In particular, Moon and Sanderson teach that anti-PD1 antibody can be used in combination with TCR T cells targeting MAGE-A4 to treat MAGE-A4 expressing cancers. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of treating MAGE-A4 expressing cancer taught by the claims Pat. 301 by adding an anti-PD1 antibody in the treatment, as taught by Moon and Sanderson. One of ordinary skill in the art would have a reasonable expectation that the combination would improve efficacy for MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro. The motivation would have been to expand the method to MAGE-A4 expressing cancers and to develop a more effective cancer treatment.
Regarding claim 14, the teachings of the claims of Pat. 301, Moon, and Sanderson are described above, however, these references do not explicitly teach the steps as recited by claim 14. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of the claims of Pat. 301, Moon, and Sanderson and to apply the combination therapy to anti-PD-1 antibody treated cancer patients (e.g. NSCLC and Melanoma) who have stable disease or progressive disease under anti-PD1 antibody single treatment. One of ordinary skill in the art would have had a reasonable expectation of success that the combination therapy would improve the therapeutic activity (e.g. overcoming resistance) of the treatment, because Moon shows that some cancer cells, which are resistant to anti-PD1 antibody alone, are sensitive to TCR-T cell therapy. In addition, the combination combines multiple anti-tumor modular components which would be able to enhance therapeutic efficacy and flexibility in treatment. The motivation would have been to apply the combination therapy to a suitable population and to develop a more effective treatment for overcoming resistance to anti-PD1 monotherapy.
Regarding claim 11 and 23, Moon teaches that manipulation of the tumor microenvironment can be done either prior to T-cell transfer, during T-cell transfer, or after T-cell infiltration to tumor (page 443, col. 2, para. 2). Thus, one of ordinary skill in the art would have known to administering antibody prior to TCR T cells (separately).
Regarding claims 12 and 24, Moon teaches administering ten million TCR T cells to mice with lung cancer model (A549 model) and anti-PD1 antibody was administered every 5-day (page 438, col. 1, para. 1). Sander teaches administering one million MAGE-A4 TCR T cells to mice with melanoma cancer model (A375 model) (page 9, col. 2, para. 2). One of ordinary skill in the art would have known to adjust the dosage and administration regimen (based on factors such as the size of the subject, the activity of TCR T cells, the condition of the subject and/or the specific cancer) to reach the claimed dosage range and administration regimens. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 15, Moon teaches TCR T cells are administered intravenously (page 438, col. 1, para. 1). Sanderson teaches TCR T cells was administered as a single intravenous (i.v.) injection (page 2, col. 2, para. 2).
Regarding claim 17, the mice with tumor model in Moon and Sander’s treatment have not received prior cancer treatment, because these mice were treated immediately after tumor established (see page 438, col. 1, para. 1 of Moon; § In vivo efficacy on page 9 of Sanderson).
Regarding claim 20, Moon teaches that the anti-PD1 antibody alone had no effect on tumor growth compared with control, while TCR T cells significantly reduced tumor growth. However, tumor-bearing mice that received repeated intraperitoneal injections of PD1 antibody in addition to a single intravenous injection of 10 million TCR T cells, demonstrated the slowest rate of tumor growth for 6 weeks from the start of treatment (the bridging paragraph of page 440-441). Sanderson teaches that MAGE-A4 TCR T cells inhibit the growth of MAGE-A4 expressing A375 tumors, leading to regression and increased survival in xenograft models (Fig. 2). Based on the teachings of Moon and Sanderson, one of ordinary skill in the art would have a reasonable expectation that the combination would be improved response for MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,111,301 B2 (hereinafter Pat. 301, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) and Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record), as applied to claims 1, 11-12, 14, 15, 17, 20, 23 and 24 above, and further in view of Keytruda (reference ID: 4003165, Publication Date: 2016/10).
The claims of Pat. 301, Moon and Sanderson teach the method of claim 1 as set forth above. In particular, the claims of Pat. 301, Moon and Sanderson teach the combination of an anti-PD1 antibody and combination of TCR T cells targeting MAGE-A4. However, the claims of Pat. 301, Moon and Sanderson do not teach the anti-PD1 antibody is pembrolizumab (the elected species).
Keytruda teaches that Keytruda (pembrolizumab) is approved by FDA for treating MAGE-A4 expressing cancers such as NSCLC and melanoma, as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method taught by the claims of Pat. 301, Moon and Sanderson by substituting the anti-PD1 antibody with pembrolizumab with reasonable expectation of success, because Keytruda teaches pembrolizumab is an FDA approved anti-PD1 antibody for NSCLC and melanoma, Sanderson teaches NSCLC and melanoma are MAGE-A4 expressing cancers. Based on the teachings of Moon, Sanderson and Keytruda, one of ordinary skill in the art would have recognized that pembrolizumab would be suitable for the claimed combination for treating MAGE-A4 expressing cancers (e.g. NSCLC and melanoma) and would enhance the therapeutic efficacy of the treatment. The motivation would have been to develop a better combination treatment for MAGE-A4 expressing cancers and to expand applications for pembrolizumab.
Response to Arguments
For this Double Patenting rejection, Applicant argues:
The claims of the present application are patentably distinct from the claims of the '301 patent. In particular, the present claims require a specific treatment regimen that includes administration of modified immunoresponsive cells expressing a heterologous MAGE-A4-specific TCR comprising recited CDR sequences, in combination with a PD-1 axis binding antagonist. In contrast, the claims of the '301 patent require a specific treatment regimen that includes administration of modified immunoresponsive cells expressing a heterologous MAGEA4-specific TCR, in combination with IL-7.
No claim of the present application recites a heterologous co-stimulatory ligand such as IL-7, and no claim of the '301 patent recites a PD-1 axis binding antagonist. Moreover, the therapeutic mechanisms of IL-7 cytokine signaling and PD-1 checkpoint blockade are biologically distinct. In particular, IL-7 promotes T-cell survival, proliferation, and persistence through co-stimulatory signaling pathways (see, e.g., '301 patent at col. 1:52-55), whereas PD-1 blockade restores effector function in exhausted T cells, as demonstrated in the present application (see, e.g., p. 42: 18-25). The present claims, therefore, address checkpoint mediated T-cell exhaustion, a different biological problem from the T-cell persistence addressed by IL-7 therapy in the '301 patent.
Applicant’s arguments have been fully considered but they are not persuasive. Contrary to Applicant’s argument, the TCR of Pat. 301 reads on the TCR of the instant claims because the TCR of Pat. 301 comprising the CDRS as instantly claimed, although the TCR of Pat. 301 further encoding an IL-7 component. Thus, the scope of claims of Pat. 301 overlaps (not distinct) with the scope of the instant claims.
No claims of the present application recites a heterologous co-stimulatory ligand such as IL-7, however, the instant claims do not exclude the TCR further expresses an IL-7, as evidenced by the original claim 10. Similarly, no claim of the Pat. 301 recites a PD-1 axis binding antagonist, however, the Pat. 301 claims do not exclude the treatment further comprising an anti-PD-1 antibody. In addition, combining teachings with Moon and Sanderson, one of ordinary skill in the art would have had a reasonable expectation that an anti-PD-1 antibody would enhance the therapeutic activity of the TCR T cell therapy of Pat. 301.
Accordingly, the claims of the present application and the '301 patent require different therapeutic agents, rely on different immunological mechanisms, and define different therapeutic strategies. The rejection effectively alters the principle of operation of the invention claimed in the '301 patent, rather than identifying an obvious variant of it. The rationale set forth in the Office Action effectively removes the IL-7 co-stimulatory component required by the '301 patent claims and substitutes checkpoint blockade therapy derived from unrelated prior art. Such a modification does not yield an obvious variation of the invention claimed in the '301 patent but instead changes the therapeutic mechanism and on which that invention is based.
Even considering the disclosures of Moon and Sanderson, the modifications proposed in the Office Action require disregarding the IL-7 co-stimulatory ligand feature and substituting checkpoint inhibitor therapy. A proper obviousness-type double-patenting analysis asks whether the later claims are an obvious variation of the invention claimed in the earlier patent, not whether the earlier patent claim could be reconstructed into a different therapy using prior art references.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, the TCR T cells taught by Pat. 301 read on the TCR T cells of the instant claims. Based on teachings of Moon and Sanderson, one of ordinary skilled in the art would have had a reasonable expectation that combining with an anti-PD-1 antibody would be able to enhance the therapeutic activity of the TCR T cell therapy of Pat. 301 (which including IL-7 co-stimulatory component), because the combination would bring three different anti-tumor modular components in the therapy. The combination therapy of an anti-PD1 antibody + the TCR T cell of Pat. 301 would read on the method of instantly claimed. Thus, the claims of Pat. 301, in view of Moon and Sanderson would make the instant claims obvious.
Thus, the rejection is maintained for the reasons of record.
U.S. Patent No. 12,145,990
Claims 1, 11-12, 14, 15, 17, 20, 23 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,145,990 B2 (hereinafter Pat. 990, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) and Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record).
The claims of Pat. 990 teach:
1. A nucleic acid construct comprising: (i) a first nucleotide sequence encoding IL-7, (ii) a second nucleotide sequence encoding an antigen receptor, wherein the antigen receptor is …, or is a T cell receptor (TCR) that binds to an MHC-displayed peptide fragment of the tumor antigen; ….
2. The nucleic acid construct according to claim 1 wherein the expression from the inducible promoter is induced by the activation of T cells.
9. The nucleic acid construct according to claim 1 wherein the antigen receptor is a T cell receptor (TCR).
10. The nucleic acid construct according to claim 9 wherein the TCR is an affinity enhanced TCR.
11. The nucleic acid construct according to claim 9 wherein the TCR comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6, or 11. As shown below, SEQ ID NO: 11 of Pat. 990 (see sequence on col. 37 of the specification) comprises the CDRs recited by the instant claim 8, CDRs are underlined:
SEQ ID NO: 11
MKKHLTTFLVILWLYFYRGNGKNQVEQSPQSLIILEGKNCTLQCNYTVSPFSNLRWYKQDTGRGPVSL
TILTFSENTKSNGRYTATLDADTKQSSLHITASQLSDSASYICVVSGGTDSWGKLQFGAGTQVVVTPD
IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKS
DFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLR
LWSSGSRAKRSGSGATNFSLLKQAGDVEENPGPRMASLLFFCGAFYLLGTGSMDADVTQTPRNRITKT
GKRIMLECSQTKGHDRMYWYRQDPGLGLRLIYYSFDVKDINKGEISDGYSVSRQAQAKFSLSLESAIP
NQTALYFCATSGQGAYEEQFFGPGTRLTVLEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYP
DHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSEN
DEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKR
KDSRG
Thus, the TCR reads on the TCR of instant claims.
19. The nucleic acid construct according to claim 10 wherein the tumor antigen is NY-ESO1,…, MAGE A4, … or MAGE B2.
17. A population of T cells each comprising a nucleic construct-according to claim 1.
Thus, the claims of Pat. 990 teach a modified immunoresponsive T cells expressing a heterologous TCR specifically binds to a MAGE-A4 antigen and comprising the TCR alpha chain and beta chain with recited CDRs of the instant claims. However, the claims of Pat. 990 do not teach using the TCR T cells in combination with a PD-1 axis bind antagonist, such as anti-PD1 antibody, to treat MAGE-A4 expressing cancers.
Moon and Sanderson teach as set forth above. In particular, Moon and Sanderson teach that anti-PD1 antibody can be used in combination with TCR T cells targeting MAGE-A4 to treat MAGE-A4 expressing cancers. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make the TCR T cells expressing MAGE-A4 targeting TCR and costimulatory ligand as taught by the claims of Pat. 990 and to use the TCR T cells targeting MAGE-A4 expressing cancers in the method of treating MAGE-A4 expressing cancer taught by as taught by Moon and Sanderson. One of ordinary skill in the art would have a reasonable expectation that the combination would improve efficacy for MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 shows anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro. The motivation would have been to expand the method to more cancers e.g. MAGE-A4 expressing cancers and to expand the applications of TCR T cells taught by the claims of Pat. 990.
Regarding claim 14, the teachings of the claims of Pat. 990, Moon, and Sanderson are described above, however, these references do not explicitly teach the steps as recited by claim 14. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of the claims of Pat. 990, Moon, and Sanderson and to apply the combination therapy to anti-PD-1 antibody treated cancer patients (e.g. NSCLC and Melanoma) who have stable disease or progressive disease under anti-PD1 antibody monotherapy. One of ordinary skill in the art would have had a reasonable expectation of success that the combination therapy would improve the therapeutic activity (e.g. overcoming resistance) of the treatment, because Moon shows that some cancer cells, which are resistant to anti-PD1 antibody alone, are sensitive to TCR-T cell therapy. In addition, the combination combines two different anti-tumor modular components to enhance therapeutic efficacy and flexibility in treatment. The motivation would have been to apply the combination therapy to a suitable population and to develop a more effective treatment for overcoming resistance to anti-PD1 single treatment.
Regarding claim 11 and 23, Moon teaches that manipulation of the tumor microenvironment can be done either prior to T-cell transfer, during T-cell transfer, or after T-cell infiltration to tumor (page 443, col. 2, para. 2). Thus, one of ordinary skill in the art would have known to administering antibody prior to TCR T cells (separately).
Regarding claims 12 and 24, Moon teaches administering ten million TCR T cells to mice with lung cancer model (A549 model) and anti-PD1 antibody was administered every 5-day (page 438, col. 1, para. 1). Sanderson teaches administering one million MAGE-A4 TCR T cells to mice with melanoma cancer model (A375 model) (page 9, col. 2, para. 2). One of ordinary skill in the art would have known to adjust the dosage and administration regimen (based on factors such as the size of the subject, the activity of TCR T cells, the condition of the subject and/or the specific cancer) to reach the claimed dosage range and administration regimens. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 15, Moon teaches TCR T cells are administered intravenously (page 438, col. 1, para. 1). Sanderson teaches TCR T cells was administered as a single intravenous (i.v.) injection (page 2, col. 2, para. 2).
Regarding claim 17, the mice with tumor model in Moon and Sander’s treatment have not received prior cancer treatment, because these mice were treated immediately after tumor established (see page 438, col. 1, para. 1 of Moon; § In vivo efficacy on page 9 of Sanderson).
Regarding claim 20, Moon teaches that the anti-PD1 antibody alone had no effect on tumor growth compared with control, while Ly95 T cells significantly reduced tumor growth. However, tumor-bearing mice that received repeated intraperitoneal injections of PD1 antibody in addition to a single intravenous injection of 10 million Ly95 T cells, demonstrated the slowest rate of tumor growth for 6 weeks from the start of treatment (the bridging paragraph of page 440-441). Sanderson teaches that ADP-A2M4 does-dependently inhibit the growth of MAGE-A4 expressing A375 tumors, leading to regression and increased survival in xenograft models (Fig. 2). Based on the teachings of Moon and Sanderson, one of ordinary skill in the art would have a reasonable expectation that the combination would be improved response for MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 shows anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,145,990 B2 (hereinafter Pat. 990, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) and Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record), as applied to claims 1, 11-12, 14, 15, 17, 20, 23 and 24 above, and further in view of Keytruda (reference ID: 4003165, Publication Date: 2016/10, of record).
The claims of Pat. 990, Moon and Sanderson teach the method of claim 4 as set forth above. In particular, the claims of Pat. 990, Moon and Sanderson teach the combination of an anti-PD1 antibody and combination of TCR T cells targeting MAGE-A4. However, the claims of Pat. 990, Moon and Sanderson do not teach the anti-PD1 antibody is pembrolizumab (the elected species).
Keytruda teaches that Keytruda (pembrolizumab) is approved by FDA for treating MAGE-A4 expressing cancers such as NSCLC and melanoma, as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method taught by the claims of Pat. 990, Moon and Sanderson by substituting the anti-PD1 antibody with pembrolizumab with reasonable expectation of success, because Keytruda teaches pembrolizumab is an FDA approved anti-PD1 antibody for NSCLC and melanoma, Sanderson teaches NSCLC and melanoma are MAGE-A4 expressing cancers. Based on the teachings of Moon, Sanderson and Keytruda, one of ordinary skill in the art would have recognized that pembrolizumab would be suitable for the claimed combination for treating MAGE-A4 expressing cancers (e.g. NSCLC and melanoma) and would enhance the therapeutic efficacy of the treatment. The motivation would have been to develop a better combination treatment for MAGE-A4 expressing cancers and to expand applications for pembrolizumab.
Response to Arguments
For this Double Patenting rejection, Applicant argues:
The claims of the present application are patentably distinct from the claims of the '990 patent. In particular, the present claims require a specific treatment regimen that includes administration of modified immunoresponsive cells expressing a heterologous MAGE-A4-specific TCR comprising recited CDR sequences, in combination with a PD-I axis binding antagonist. In contrast, the claims of the '990 are directed to nucleic acid constructs and engineered T cells comprising a nucleotide sequence encoding a TCR and a nucleotide sequence encoding IL-7.
Applicant’s arguments have been fully considered but they are not persuasive. Contrary to Applicant’s argument, the T cell expressing TCR of Pat. 990 reads on the TCR T cells used by the instant claims because the TCR of Pat. 990 comprising the CDRS as instantly claimed, although the TCR of Pat. 990 further encoding an IL-7 component. Thus, the scope of claims of Pat. 990 overlaps with the scope of the instant claims.
Applicant further reiterates similar arguments set forth above (for Pat. 301). Thus for the reasons set forth above the rejection is maintained.
Application No. 17/297,380
Claims 1, 11-12, 14, 15, 17, 20, 23 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 6, 7, 25, 27, 28, 30-32 of copending Application No. 17/297,380 (hereinafter Appl. 380, US 2024/0050570 A1, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) and Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record).
The claims of Appl. 380 teach an isolated modified T cell or a population of isolated modified T cells comprising a heterologous homodimeric CD8a co-receptor and a heterologous T cell receptor (TCR) that binds MAGE-A4 (claim 1). Given BRI, CD8a co-receptor reads on a co-stimulatory ligand because it can bind to the MHC-I molecule to enhance T cell receptor.
The claims of Appl. 380 teach the modified T cell or the population of modified T cells according to claim 1, wherein the TCR binds a cancer or a tumor antigen or a peptide thereof and/or is an affinity enhanced TCR (claim 4).
The claims of Appl. 380 teach a method of treating cancer in an individual, comprising administering to the individual the modified T cell or the population of modified T cells of claim 1 (claim 25).
The claims of Appl. 380 teach the method of claim 25, further comprising administering to the individual a second therapeutic agent (claim 28).
The claims of Appl. 380 teach the modified T cell or the population of modified T cells according to claim 1, wherein the TCR comprises an a chain variable region (Va) comprising complementarity determining regions (CDRs) Va CDR1, Va CDR2, and Va CDR3 and a chain variable region (V(3) comprising CDRs V(3 CDR1, V3 CDR2, and V3 CDR3, wherein the Va CDR1 comprises the amino acid sequence of SEQ ID NO: 9, the Va CDR2 comprises the amino acid sequence of SEQ ID NO: 10, the Va CDR3 comprises the amino acid sequence of SEQ ID NO: 11, the V(3 CDR1 comprises the amino acid sequence of SEQ ID NO: 12, the V3 CDR2 comprises the amino acid sequence of SEQ ID NO: 13, and the V3 CDR3 comprises the amino acid sequence of SEQ ID NO: 14. Based on the specification, SEQ ID NOs: 9-14 of Appl. 380 (page 26 of US 2024/0050570) are the same as the SEQ ID NO: 27-32 of the instant application. The SEQ ID NOs: 9-14 of Appl. 380 shown below:
PNG
media_image2.png
126
428
media_image2.png
Greyscale
Thus, the claims of Appl. 380 teach treating cancers by administering a modified immunoresponsive T cells expressing a heterologous TCR specifically binds to a MAGE-A4 antigen and a heterologous co-stimulatory ligand (CD8a co-receptor). And the TCR comprises the TCR alpha chain and beta chain with recited CDRs of the instant claim 8. The claims of Appl. 380 also teach using the TCR T cells in combination with another composition. However, the claims of Appl. 380 do not teach in combination with a PD-1 axis bind antagonist, such as anti-PD1 antibody, or the cancer is MAGE-A4 expressing cancers.
Moon and Sanderson teach as set forth above. In particular, Moon and Sanderson teach that anti-PD1 antibody can be used in combination with TCR T cells targeting MAGE-A4 to treat MAGE-A4 expressing cancers. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of treating MAGE-A4 expressing cancer taught by the claims Appl. 380 by adding an anti-PD1 antibody to treat MAGE-A4 expressing cancers, as taught by Moon and Sanderson. One of ordinary skill in the art would have a reasonable expectation that the combination would improve efficacy for treating MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 (e.g. ADP-A2M4) shows anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro. The motivation would have been to expand the method to more cancers e.g. MAGE-A4 expressing cancers and to expand the applications of the TCR T cells of Appl. 380.
Regarding claim 14, the teachings of the claims of Appl. 380, Moon, and Sanderson are described above, however, these references do not explicitly teach the steps as recited by claim 14. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of the claims of Appl. 380, Moon, and Sanderson and to apply the combination therapy to anti-PD-1 antibody treated cancer patients (e.g. NSCLC and Melanoma) who have stable disease or progressive disease under anti-PD1 antibody single treatment. One of ordinary skill in the art would have had a reasonable expectation of success that the combination therapy would improve the therapeutic activity (e.g. overcoming resistance) of the treatment, because Moon shows that some cancer cells, which are resistant to anti-PD1 antibody alone, are sensitive to TCR-T cell therapy. In addition, the combination combines two different anti-tumor modular components to enhance therapeutic efficacy and flexibility in treatment. The motivation would have been to apply the combination therapy to a suitable population and to develop a more effective treatment for overcoming resistance to anti-PD1 single treatment.
Regarding claim 11 and 23, Moon teaches that manipulation of the tumor microenvironment can be done either prior to T-cell transfer, during T-cell transfer, or after T-cell infiltration to tumor (page 443, col. 2, para. 2). Thus, one of ordinary skill in the art would have known to administering antibody prior to TCR T cells (separately).
Regarding claims 12 and 24, Moon teaches administering ten million TCR T cells to mice with lung cancer model (A549 model) and anti-PD1 antibody was administered every 5-day (page 438, col. 1, para. 1). Sander teaches administering one million MAGE-A4 TCR T cells to mice with melanoma cancer model (A375 model) (page 9, col. 2, para. 2). One of ordinary skill in the art would have known to adjust the dosage and administration regimens (based on factors such as the size of the subject, the activity of TCR T cells, the condition of the subject and/or the specific cancer) to reach the claimed dosage range and administration regimens. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 15, Moon teaches TCR T cells are administered intravenously (page 438, col. 1, para. 1). Sanderson teaches TCR T cells was administered as a single intravenous (i.v.) injection (page 2, col. 2, para. 2).
Regarding claim 17, the mice with tumor model in Moon and Sander’s treatment have not received prior cancer treatment, because these mice were treated immediately after tumor established (see page 438, col. 1, para. 1 of Moon; § In vivo efficacy on page 9 of Sanderson).
Regarding claim 20, Moon teaches that the anti-PD1 antibody alone had no effect on tumor growth compared with control, while Ly95 T cells significantly reduced tumor growth. However, tumor-bearing mice that received repeated intraperitoneal injections of PD1 antibody in addition to a single intravenous injection of 10 million TCR T cells, demonstrated the slowest rate of tumor growth for 6 weeks from the start of treatment (the bridging paragraph of page 440-441). Sanderson teaches that ADP-A2M4 does-dependently inhibit the growth of MAGE-A4 expressing A375 tumors, leading to regression and increased survival in xenograft models (Fig. 2). Based on the teachings of Moon and Sanderson, one of ordinary skill in the art would have a reasonable expectation that the combination would be improved response for MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 (such as ADP-A2M4) show anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro.
This is a provisional nonstatutory double patenting rejection.
Claims 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 6, 7, 25, 27, 28, 30-32 of copending Application No. 17/297,380 (hereinafter Appl. 380, US 2024/0050570 A1, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) and Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record) as applied to claims 1, 11-12, 14, 15, 17, 20, 23 and 24 above, and further in view of Keytruda (reference ID: 4003165, Publication Date: 2016/10, of record).
The claims of Appl. 380, Moon and Sanderson teach the method of claim 1 as set forth above. In particular, the claims of Appl. 380, Moon and Sanderson teach the combination of an anti-PD1 antibody and combination of TCR T cells targeting MAGE-A4. However, the claims of Appl. 380, Moon and Sanderson do not teach the anti-PD1 antibody is pembrolizumab (the elected species).
Keytruda teaches that Keytruda (pembrolizumab) is approved by FDA for treating MAGE-A4 expressing cancers such as NSCLC and melanoma, as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method taught by the claims of Appl. 380, Moon and Sanderson by substituting the anti-PD1 antibody with pembrolizumab with reasonable expectation of success, because Keytruda teaches pembrolizumab is an FDA approved anti-PD1 antibody for NSCLC and melanoma, Sanderson teaches NSCLC and melanoma are MAGE-A4 expressing cancers. Based on the teachings of Moon, Sanderson and Keytruda, one of ordinary skill in the art would have recognized that pembrolizumab would be suitable for the claimed combination for treating MAGE-A4 expressing cancers (e.g. NSCLC and melanoma) and would enhance the therapeutic efficacy of the treatment. The motivation would have been to develop a better combination treatment for MAGE-A4 expressing cancers and to expand applications for pembrolizumab.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For this Double Patenting rejection, Applicant argues:
The present claims are directed to a specific therapeutic method requiring combination therapy with a PD-1 axis binding antagonist and a population of modified immunoresponsive cells expressing the recited MAGE-A4-specific TCR. In contrast, the claims. of the '380 application are directed to modified T cells comprising a heterologous homodimeric CD8a co-receptor and a heterologous TCR that binds MAGE-A4.
No claim of the present application is directed to modified T cells and no claim of the '380 application is directed to a method of treating cancer or of preventing or delaying the progression of cancer. Indeed, the Examiner of the '151 application stated that method-of treatment claims were patentably distinct from the T-cell claims.3 In addition, no claim of the present application recites a heterologous homodimeric CD8a co-receptor, and no claim of the '380 application recites a PD-1 axis binding antagonist.
Applicant’s arguments have been fully considered but they are not persuasive. Contrary to Applicant’s argument, the claims of Appl. 380 teach a method of treating cancer in an individual, comprising administering to the individual the modified T cell or the population of modified T cells of claim 1 (claim 25). The claims of Appl. 380 teach the method of claim 25, further comprising administering to the individual a second therapeutic agent (claim 28). In addition, the TCR of Appl. 380 reads on the TCR of the instant claims because the TCR comprising the CDRS as instantly claimed, although the TCR of Appl. 380 further encoding a CD8α co-receptor. Thus, the scope of claims of Appl. 380 overlaps with the scope of the instant claims.
No claims of the present application recites a heterologous co-stimulatory ligand such as CD8α co-receptor, however, the instant claims do not exclude the TCR further expresses an CD8α co-receptor. Similarly, no claim of the Appl. 380 recites a PD-1 axis binding antagonist, however, the Appl. 380 claims do not exclude the treatment further comprising an anti-PD-1 antibody (as evidenced by claim 28). In addition, combining teachings with Moon and Sanderson, one of ordinary skill in the art would have had a reasonable expectation that an anti-PD-1 antibody would enhance the therapeutic activity of the TCR T cell therapy of Appl. 380.
Applicant further argues that CD8α co-receptor and anti-PD-1 antibody function through different mechanism. However, this would not have stopped one of ordinary skilled in the art to combine an anti-PD-1 antibody and a TCR-T cell of Appl. 380. Because the combination would bring three different anti-tumor modular components in the treatment, one of ordinary skill in the art would have a reasonable expectation that the combination would have enhanced therapeutic activity. The combination therapy of anti-PD-1 antibody and the TCR T cells of Appl. 380 would read on the methods of instant claimed. Accordingly, the claims of Appl. 380 in view of Moon and Sanderson would make the instant claim obvious.
Thus, the rejection is maintained for the reasons of record.
Application No. 18/912,151
Claims 1, 11-12, 14, 15, 17, 20, 23 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/912,151 (hereinafter Appl. 151, US 2025/0043011 A1, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record), Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record) and Tribble (Tribble et al., WO 2017/174824 A1, Publication Date: 12/10/2017).
The claims of Appl. 151 teach a T cell comprising a constitutively expressed antigen receptor and an inducible expressed IL-7 molecule, wherein the antigen receptor is …, or is a T cell receptor (TCR) that binds to an MHC-displayed peptide fragment of the tumor antigen (claim 1); wherein the antigen receptor is a TCR (claim 9); wherein the tumor antigen is NY-ESO1, …, MAGE A4, … or MAGE B2 (claim 13).
The claims of Appl. 151 teach a method of treating cancer comprising administering to a patient having cancer the T cell according to claim 1, wherein the cancer expresses the tumor antigen (claim 15), wherein the tumor antigen can be MAGE-A4 (claim 16).
The claims of Appl. 151 teach a method of treating cancer comprising administering to a patient having cancer the T cell according to claim 1, wherein the cancer expresses the tumor antigen (claim 15), wherein the tumor antigen can be MAGE-A4 (claim 16).
Thus, the claims of Appl. 151 teach treating MAGE-A4 expressing cancers by administering a modified immunoresponsive T cells expressing a heterologous TCR specifically binds to a MAGE-A4 antigen. However, the claims of Appl. 151 do not teach in combination with a PD-1 axis bind antagonist, such as anti-PD1 antibody, or the TCR comprising the six CDRs recited.
Moon, Sanderson and Tribble teach as set forth above. In particular, Moon and Sanderson teach that anti-PD1 antibody can be used in combination with TCR T cells targeting MAGE-A4 to treat MAGE-A4 expressing cancers. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of treating MAGE-A4 expressing cancer taught by the claims Appl. 151 by adding an anti-PD1 antibody in the treatment, as taught by Moon and Sanderson. One of ordinary skill in the art would have a reasonable expectation that the combination would improve efficacy for MAGE-A4 expressing cancers, because Sanderson teaches that TCR T cells targeting MAGE-A4 antigen shows anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro. The motivation would have been to expand the method to more cancers e.g. MAGE-A4 expressing cancers and to expand the applications of the TCR T cells taught by the Appl. 151.
Tribble further teaches a TCR targeting MAGE-A4 antigen which comprises six CDRs recited, as set forth above. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method taught by the claims of Appl. 151, Moon and Sanderson by using the CDRs taught by Tribble for the TCR α chain and TCR β chain, because Tribble teaches that the TCR α chain and TCR β chain comprising these CDRs show good binding activity and specificity to MAGE-A4. One of ordinary skill in the art would have recognized that the TCR α chain and TCR β chain taught by Tribble would be suitable for making TCRs targeting MAGE-A4 antigen and would improve specificity of the MAGR-A4 targeting TCRs used in the combination. One of ordinary skill in the art would have had a reasonable expectation of success because the TCR α chain and TCR β chain have been extensively tested, as evidenced by the examples of Tribble. The motivation would have been to develop a better MAGE-A4 targeting TCR for the combination treatment for MAGE-A4 expressing cancers.
Regarding claim 14, the teachings of the claims of Appl. 151, Moon, and Sanderson are described above, however, these references do not explicitly teach the steps as recited by claim 14. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of the claims of Appl. 151, Moon, and Sanderson and to apply the combination therapy to anti-PD-1 antibody treated cancer patients (e.g. NSCLC and Melanoma) who have stable disease or progressive disease under anti-PD1 antibody single treatment. One of ordinary skill in the art would have had a reasonable expectation of success that the combination therapy would improve the therapeutic activity (e.g. overcoming resistance) of the treatment, because Moon shows that some cancer cells, which are resistant to anti-PD1 antibody alone, are sensitive to TCR-T cell therapy. In addition, the combination combines multiple different anti-tumor modular components to enhance therapeutic efficacy and flexibility in treatment. The motivation would have been to apply the combination therapy to a suitable population and to develop a more effective treatment for overcoming resistance to anti-PD1 single treatment.
Regarding claim 11 and 23, Moon teaches that manipulation of the tumor microenvironment can be done either prior to T-cell transfer, during T-cell transfer, or after T-cell infiltration to tumor (page 443, col. 2, para. 2). Thus, one of ordinary skill in the art would have known to administering antibody prior to TCR T cells (separately).
Regarding claims 12 and 24, Moon teaches administering ten million TCR T cells to mice with lung cancer model (A549 model) and anti-PD1 antibody was administered every 5-day (page 438, col. 1, para. 1). Sander teaches administering one million TCR T cells to mice with melanoma cancer model (A375 model) (page 9, col. 2, para. 2). One of ordinary skill in the art would have known to adjust the dosage and administration regimens (based on factors such as the size of the subject, the activity of TCR T cells, the condition of the subject and/or the specific cancer) to reach the claimed dosage range and administration regimens. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 15, Moon teaches TCR T cells are administered intravenously (page 438, col. 1, para. 1). Sanderson teaches TCR T cells was administered as a single intravenous (i.v.) injection (page 2, col. 2, para. 2).
Regarding claim 17, the mice with tumor model in Moon and Sander’s treatment have not received prior cancer treatment, because these mice were treated immediately after tumor established (see page 438, col. 1, para. 1 of Moon; § In vivo efficacy on page 9 of Sanderson).
Regarding claim 20, Moon teaches that the anti-PD1 antibody alone had no effect on tumor growth compared with control, while Ly95 TCR T cells significantly reduced tumor growth. However, tumor-bearing mice that received repeated intraperitoneal injections of PD1 antibody in addition to a single intravenous injection of 10 million Ly95 TCR T cells, demonstrated the slowest rate of tumor growth for 6 weeks from the start of treatment (the bridging paragraph of page 440-441). Sanderson teaches that ADP-A2M4 does-dependently inhibit the growth of MAGE-A4 expressing A375 tumors, leading to regression and increased survival in xenograft models (Fig. 2). Based on the teachings of Moon and Sanderson, one of ordinary skill in the art would have a reasonable expectation that the combination would be improved response for MAGE-A4 expressing cancers, because Sanderson teaches that ADP-A2M4 shows anti-tumor activity in vitro and in vivo for MAGE-A4 expressing cancers; Moon teaches that inhibitory receptors (such as PD1) that are naturally upregulated after TCR engagement to block continued activation and anti-PD1 antibody can enhance TCR therapeutic activity in vivo and in vitro.
This is a provisional nonstatutory double patenting rejection.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/912,151 (hereinafter Appl. 151, US 2025/0043011 A1, of record) in view of Moon (Moon et al., Clin Cancer Res; 22(2), 436-447, Publication Date: 08/31/2015, cited in IDS of 08/17/2022, of record) Sanderson (Sanderson et al., Oncoimmunology, Vol. 9, No. 1, e1682381, Publication Date: 11/24/2019, cited in IDS of 08/17/2022, of record) and Tribble (Tribble et al., WO 2017/174824 A1, Publication Date: 12/10/2017, of record), as applied to claims 1, 11-12, 14, 15, 17, 20, 23 and 24 above, and further in view of Keytruda (reference ID: 4003165, Publication Date: 2016/10, of record).
The claims of Appl. 151, Moon, Sanderson and Tribble teach the method of claim 1 as set forth above. In particular, the claims of Appl. 151, Moon, Sanderson and Tribble teach the combination of an anti-PD1 antibody and combination of TCR T cells targeting MAGE-A4. However, the claims of Appl. 151, Moon, Sanderson and Tribble do not teach the anti-PD1 antibody is pembrolizumab (the elected species).
Keytruda teaches that Keytruda (pembrolizumab) is approved by FDA for treating MAGE-A4 expressing cancers such as NSCLC and melanoma, as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method taught by the claims of Appl. 151, Moon and Sanderson by substituting the anti-PD1 antibody with pembrolizumab with reasonable expectation of success, because Keytruda teaches pembrolizumab is an FDA approved anti-PD1 antibody for NSCLC and melanoma, Sanderson teaches NSCLC and melanoma are MAGE-A4 expressing cancers. Based on the teachings of Moon, Sanderson and Keytruda, one of ordinary skill in the art would have recognized that pembrolizumab would be suitable for the claimed combination for treating MAGE-A4 expressing cancers (e.g. NSCLC and melanoma) and would enhance the therapeutic efficacy of the treatment. The motivation would have been to develop a better combination treatment for MAGE-A4 expressing cancers and to expand applications for pembrolizumab.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For this Double Patenting rejection, Applicant argues:
The claims of the present application are patentably distinct from the claims of the '151 application. The present claims require a specific treatment regimen that includes administration of modified immunoresponsive cells expressing a heterologous MAGE-A4-specific TCR comprising recited CDR sequences, in combination with a PD-1 axis binding antagonist. In contrast, the claims of the '151 application are directed to engineered T cells comprising a constitutively expressed antigen receptor together with an inducibly expressed IL-7 molecule and their use in methods of treating cancer.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, the T cell expressing TCR of Appl. 151 overlap the TCR T cells of the instant claims because the TCR of Appl. 151 can be MAGE-A4 targeted TCR T cells, although the TCR of Appl. 151 further encoding an IL-7 component. Thus, the scope of claims of Appl. 151 overlaps with the scope of the instant claims.
In addition, as set forth above, the claims of Appl. 151, Moon, Sanderson and Tribble teaches that combining an anti-PD-1 antibody may enhance the MAGE-A4 TCR T cell therapy (see 103 rejection and response above). The combination therapy of anti-PD-1 antibody and the TCR T cells of Appl. 151 would read on the methods of instant claimed. Accordingly, the claims of Appl. 151 in view of Moon and Sanderson would make the instant claim obvious.
Applicant further reiterates similar arguments set forth above. Thus for the reasons set forth above the rejection is maintained.
NEW REJECTION
Claim Rejections - 35 USC § 112
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.
Claim 21 is 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. This is a NEW MATTER rejection.
Claim 21 depends on claim 1, which was amended after filing date. The limitation combination of claim 1 and claim 21 (the TCR comprising the 6 CDRS and binding to the amino acid sequence of SEQ ID NO: 18) has no clear support in the specification as originally filed. Applicants argue that the support for the amended claims can be found throughout the Specification and in the original claims. It is acknowledged that original claim 8 discloses the CDRs of amended claim 1. However, no TCR comprising the recited CDRs AND binding to the amino acid sequence of SEQ ID NO: 8 is disclosed in either original claims or in the original specification. Thus, the original disclosure does not provide support for the amended claim 21. The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See MPEP 2163.05 (II). See also In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (“Whatever may be the viability of an inductive-deductive approach to arriving at a claimed subgenus, it cannot be said that such a subgenus is necessarily described by a genus encompassing it and a species upon which it reads.”) Thus the limitation of amended claim 21 is new matter because it is not supported by the as-filed disclosure.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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