DETAILED ACTION
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 .
Claims 7, 10-14, 18-23, 29-31, 33-36, 46, 51-53, 56, 61, 62, 64, 65, 67-75 and 78 have been canceled. Claims 6, 8, 9, 24-28, 32, 37-44, 47-50, 54, 55, 57-60, 63, 66, 76 and 77 have been amended. Claims 1-6, 8, 9, 15-17, 24-28, 32, 37-45, 47-50, 54, 55, 57-60, 63, 66, 76 and 77 are pending and examined on the merits.
Information Disclosure Statement
NPL reference 209 of the IDS filed 2/22/2024 is lined through because it lacks a publication date.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 24, 25, 27 and 45 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.
(A)It is unclear if the parenthetical information in claim 45 is actually a claim amendment.
(B)Claim 45 contains the trademark/trade names Breyanzie, Tecartus, Kymriah, Yescarta, Abecma and Carvykti. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe recombinant T cells and, accordingly, the identification/description is indefinite.
(C)Claims 24, 25 and 27 are vague and indefinite in the recitation of “not a significant” inhibitor of DGKζ”, “not a significant” inhibitor of DGKα”, and “not a significant inhibitor of other DGKs, respectively. The term “significant” is an objective term, subject to differing interpretations by differing routineers. It is unclear what applicant intends as threshold between “significant” and “not significant”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 37-39, 41 and 42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
(A)Claim 37 requires that the inhibitor of DGKα and/or DGKζ is administered in an amount, at a time, in a duration, and/or at a frequency that is effective to provide an increase in antigen-specific or antigen-receptor -driven activity of the engineered cells. Claim 38 requires that the inhibitor of DGKα and/or DGKζ is administered in an amount, at a time, in a duration, and/or at a frequency that is effective to prevent, inhibit or delay onset of an exhaustion phenotype in the engineered cells. Claim 39 requires that he inhibitor of DGKα and/or DGKζ is administered in an amount, at a time, in a duration, and/or at a frequency that is effective to at least partially reverse an exhaustion phenotype in the engineered cells.
Claim 41 requires that the inhibitor of DGKα and/or DGKζ is administered in amount from about 0.25 to about 250mg. Claim 42 requires that the 0.5mg to about 100mg.
Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In the instant case, the specification provides no reduction to practice for the amount of the inhibitors of DGKα or DGKζ , the administration of the inhibitors of DGKα or DGKζ at a particular time relative to the administration of the engineered T cells expressing the recombinant receptor, the frequency or administration of the inhibitors of DGKα or DGKζ, the duration of the administration of the of the inhibitors of DGKα or DGKζ effective to (i) provide an increase in antigen-specific or antigen-receptor-driven activity of the engineered T-cells; (ii)prevent, inhibit or delay the onset of an exhaustion phenotype in the engineered T cells; or (iii)partially reverse an exhaustion phenotype in the engineered cells.
Further, the specification provides no reduction to practice of the doses of DGKα and/or DGKζ ranging from 0.25mg to 250mg such that the doses in combination with engineered T cells expressing a recombinant receptor provided for a method of treatment in a subject having a disease or condition as required in claim 1.
One of skill in the art would reasonably conclude that applicant was not in possession of the claimed invention at the time of filing.
(B)Claim 28 is reliant on a genus of DGKα and/or DGKζ inhibitors characterized by formula I, wherein
PNG
media_image1.png
725
581
media_image1.png
Greyscale
PNG
media_image2.png
677
584
media_image2.png
Greyscale
Claim 28 is reliant on a genus of DGKα and/or DGKζ inhibitors characterized by formula II, wherein
PNG
media_image3.png
521
564
media_image3.png
Greyscale
PNG
media_image4.png
754
562
media_image4.png
Greyscale
Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Applicant has disclosed compounds
PNG
media_image5.png
195
155
media_image5.png
Greyscale
PNG
media_image6.png
724
198
media_image6.png
Greyscale
PNG
media_image7.png
722
150
media_image7.png
Greyscale
representing formula I. Applicant has provided a written description of compounds
PNG
media_image8.png
608
535
media_image8.png
Greyscale
representing formula II. The specification provides correlation of the some of the inhibitory compounds with IC50 activity on DGKα and DGKζ (page 295, Table A). However, the description of these compounds fails to adequately describe the genus of inhibitors relied upon in claims 28 and 32 because both genuses as claimed are highly variant encompassing compounds which differ in substituents from the described compounds and it cannot be predicted how these differences will affect the inhibitory activity of the compounds. Given a compound which falls into the category of formula I or II one of skill in the art would not be able to predict if said compound has DGKα and/or DGKζ inhibitory activity as one could do with a well-described genus. One of skill in the art would reasonably conclude that applicant was not in possession of the genus of compounds of claims 28 and 32 at the time of filing.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 3, 4, 5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66, are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Sawa et al (WO2021/130638).
Sawa et al disclose diacylglycerol kinase modulating compounds used in combination with other agents for the treatment of diseases including cancers and solid tumors (abstract) which meets the limitation of cancer in claims 48 and 49. Sawa et al disclose that when a T-cell is under a condition of immunological unresponsiveness, such as anergy, said T cell can exhibit an increased level of DGKα, and thus compounds with an anti-DGKα activity may be used in the treatment of diseases related to a T-cell (paragraph [0005]). Sawa et al disclose that the inhibitory compounds of the invention have selectivity for DGKα, over one or more of the other DGK isoforms including DGKζ (paragraph [0179]) which meets that limitation in claim 24 and 27. Sawa et al disclose that the inhibitory compounds of the invention are combined with one or more additional agents including an inhibitory immune checkpoint blocker, a CAR-T cell or T cell comprising an engineered TCR (paragraph [0246]) which meets the limitations of claims 43, 44 and 63. Sawa et al disclose that co-administered the cellular therapy can entail the administration of cells that are autologous or allogenic to the subject (paragraph [0681]) which meets the limitations of claims 59 and 60. Sawa et al disclose that the co-administered cellular therapy is MART-1 F5 TCR-engineered PBMC which meets the limitation of claim 47 because MSRT-1 is a target antigen expressed on a cell or tissue or the disease or condition. Sawa et al disclose that co-administration of inventive inhibitors with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient. (paragraph [0042]) which meets the limitations of claim 15. Sawa et al disclose exemplary cancers that may be treated with the inventive inhibitors include B-cell lymphoma (paragraph [0045]) which meet the limitation of a B cell malignancy claim 50. Sawa et al disclose that the disease being treated also includes autoimmune, inflammatory or infectious in addition to cancer (paragraph [044]), which meets those limitations in claim 48. Sawa et al disclose an embodiment wherein, a unit dose of the inventive inhibitor is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents and another embodiment wherein a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of an inhibitor of DGKα (paragraph [0042] which meets those limitations in claims 2-5, 16 and 17. Given that that the administration of the inhibitor of DGKα to the subject after therapy with a CAR-t cell or after therapy with the engineered TRC of Sawa et al has the same method steps required in claims 5 and 6, the method of Sawa et al s inherently a method of rescuing engineered T cells from exhaustion and a method for reducing or delaying the onset of T cell exhaustion. See Ex parte Novitski 26 USPQ 1389 (BPAI 1993)..
Sawa et al disclose the co-administration of an inhibitory immune checkpoint blocker (paragraph [0246] including the multispecific inhibitors FPT-155 which is a CTLA4/PD-L1 inhibitor, and the PD-1/CTLA4 inhibitors of PF-06936308, MGD-019, KN0946, MEDI-5852, XmAb-20717 and Ak-104 (paragraph [0853] which meets the limitations of claims 63 and 66.
Sawa et al disclose “Therapeutically effective amount" or “effective amount” is an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.. The effective amount can include a range of amounts and delivered as one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint and an effective amount may be considered in the context of administering one or more therapeutic agents (paragraph [0040]) thus anticipating claim 37.
Sawa et al disclose the administration of 1 mg, 100 mg, about 125 mg, about 150 mg,, about 175 mg,, about 200 mg and about 225 mg of the inventive inhibitor/dose (paragraph [0234]) which meets the limitations of claims 41 and 42.
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.
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 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 54, 55, 59, 60, 63, 66, 76 and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Sawa et al (WO2021/130638) in view of Abate-Daga et al (Molecular Therapy, (May 2012) Vol. 20, No. Suppl. 1, pp. S75) .
Sawa et al teach the limitations of claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 for the reasons set forth above. Sawa et al do not specifically teach
the initiation of administration of the inhibitor 1-28 days after the initial T-cell therapy;
the administration of the inventive inhibitor in initiated within a week of the peak level of the engineered T cells in the blood of the subject;
the dose of cells of the T cell therapy ranges from 105 to 109;
the inventive inhibitor and the checkpoint antagonist is administered for a period of up to three months, or six months after the initial administration of the T cell therapy.
Abate-Daga et al teach that TCR-transduced T cells persist after administration to a patient, but the TCR gene expression decreases due to a global down regulation in gene expression (page 5). It is noted that the vector expressed TCR are at peak levels at the time of infusion, but declines within 1 week to reach a plateau and then further decline after a month, but are still present in the patient.
PNG
media_image9.png
325
591
media_image9.png
Greyscale
Abate-Daga et al teach that the goal is to maintain TCR expression and reactivity throughout the lifetime of the cells in the patient:
PNG
media_image10.png
195
393
media_image10.png
Greyscale
Abate-Daga et al teach that DGKα and DGKζ are overexpressed in the administered cells after infusion into the patient “Post-infusion mTCRb+ vs Infusion”:
Abate-Daga et al teach that the patients were infused with 23.5-68 X 109 cells, and that the higher level of cells expressing the recombinant TCR at 25 and 31 days post infusion was correlated with a response to therapy (“Representative sorting results from patients included in analysis”). The infusion of 23.5-68 X 109 cells meets the limitation of claim 54 requiring “about” 1 X 109 cells.
PNG
media_image11.png
396
278
media_image11.png
Greyscale
It would have been prima facie obvious at the time prior to the effective filing date to (i) initiate the administration of the inhibitor 1-28 days after the initial T-cell therapy or (ii) one week after the initial T-cell therapy thus rendering obvious claims 6 and 9. One of skill in the art would have been motivated to do so in order to preserve the activity of the recombinant TCR which is taught by Abate-Daa et al to persist at an intermediate level for about a week after infusion and for over a month after infusion and because Abate-Daga et al each that response to treatment is a function of the level of recombinant TCR persisting in the patient’s blood. One of skill in the art would understand that the inhibitors of Sawa et al target the DGKa which is overexpressed after infusion of the recombinant cells. One of skill in the art would have been m motivated to keep the recombinant TCR expressing cells active for maximum anti-tumor activity.
It would have been prima facie obvious to (iii)provide a dose of about 109 TCR transduced T cells or about 1 X 105 to about 5 X 108 as a co-administered therapy with the DGKα inhibitor of Sawa et al because Abate-Daga et al teach administration of 25-68 X 109 transduced T cells to patients as a monotherapy without the inventive inhibitor of Sawa et al. Sawa et al further teach that suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects)(paragraph [0040]). Thus, one of skill in the art would understand that lower amount of the TCR transduced T cells in combination with the inhibitors of Sawa et al would provide a therapeutic effect at lower doses such as those in claim 55, and at the same time conserving the recombinant T cells for further administrations to the patient.
Abate-Daga et al teach that T cells from the subject expressed higher levels of PD-1 post-infusion:
PNG
media_image12.png
227
359
media_image12.png
Greyscale
Thus, it would have been prima facie obvious at the time of the effective filing date to (iv)provide the immune checkpoint antagonists against PD-1 for three to six months after the initial administration of the T cell therapy along with the DGKα inhibitor of Sawa et al to allow for any persisting engineered TCR T-cell to have maximized therapeutic function for the lifetime of the persisting cells in vivo, thus rendering obvious claims 75 and 76.
Claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 58, 59, 60, 63, and 66, are rejected under 35 U.S.C. 103 as being unpatentable over Sawa et al (WO2021/130638) in view of the abstract of Wilson and Welch (Molecular Therapy, 2016, Vol. 24, suppl. 1, page S179).
Sawa et al teach the limitations of claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 for the reasons set forth above. Sawa et al teach that the T cell therapy includes autologous therapy. Sawa et al do not specifically teach that the T cell therapy comprises primary T cells obtained from the subject as required in claim 58.
The abstract of Wilson and Welch teaches a method for the transduction of primary T cells with a CAR-targeting a cancer antigen. The abstract teaches that the method produces CAR-T cells expressing higher levels of CD62L indicative of central memory T cells, and CD25 indicative of active T cells. The abstract teaches that the resulting CAR-T cells demonstrated superior anti-tumor activity when compared to ells maintained under conventional tissue culture plates.
It would have been prima facie obvious at the time prior to the effective filing date to produce autologous CAR-T cells using primary T cells by the method of the abstract of Wilson and Welch. One of skill in the art would have been motivated to od so by the teachings of the abstract regarding the superior anti-tumor activity displayed by the CAR-T cells made from primary T cells using the method of the abstract.
Claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 45, 47-50, 57, 59, 60, 63, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Sawa et al (WO2021/130638) in view of the abstract of Bishop et al (Blood, 2018, vol. 132, suppl. 1 abstract number 2958).
Sawa et al teach the limitations of claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 for the reasons set forth above. Sawa et al do not specifically teach that the CAR-T cell used in the combined therapy with DGKα inhibitor was tisagenlecleucel as required in claim 45, or that the CAR-T cells of the combination therapy were administered parenterally as required in claim 57.
The abstract of Bishop et al teaches that tisagenlecleucel was provided to patients by an infusion which meets the limitation of the T cell therapy being administered parenterally in claim 57 and the particular CAR-T cell in claim 45. The abstract teaches that tisagenlecleucel cells expanded rapidly over the first 28 days in 7 patients and that transgene levels were measurable for up to 400 days after infusion. The abstract teaches that patient who did not have a high degree of expansion and persistence of the infused cells experienced relapse at day 50.
It would have been prima facie obvious at the time of the effective filing date to use tisagenlecleucel a as the T cell therapy in a combination with the DGKα inhibitor of Sawa et al. One of skill in the art would have been motivated to do so in order to prolong the activity of the CAR-T cell. One of skill in the art would understand that evidence of the transgene level for up to 400 days is not necessarily commensurate with the activity of the CAR-T cell, and that the activity can be stimulated by co-administration of the DGKα inhibitor.
Claim 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Sawa et al (WO2021/130638) as applied to claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 above, and further in view of Abate-Daga et al (Blood, 2013, Vol. 12, pp. 1399-1410) and Delgoffe and Powell (Molecular Immunology, 2015, vol. 68, pp. 492-496).
Claim 38 requires that the inhibitor of DGKα is administered in an amount, at a time, in a duration and/or at a frequency that is effective to prevent, inhibit or delay the onset of an exhaustion phenotype in the engineered cells of the method of claim 1.
Claim 39 specifies that the inhibitor of DGKα is administered in an amount, at a time, in a duration and/or at a frequency that is effective to partially reverse an exhausted phenotype in the engineered cells.
Claim 40 requires that the level of exhaustion of the engineered T cells is determined by measuring one or more exhaustion markers on the cell surface of the engineered T cell expressing the recombinant receptor.
Claim 8 specifies that at the time of administration of the inhibitor of DGKα at least 10% of the total recombinant cells in a biological sample from the subject have an exhausted phenotype.
Sawa et al teach the limitations of claims 1-5, 15, 16, 17, 24, 27, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 for the reasons set forth above. Sawa et al tach that when a T-cell is under a condition of immunological unresponsiveness, such as anergy, expression of DGKα can be increased, and overexpression of DGKα has been reported to induce anergy (page 2, paragraph [0005]).
Delgoffe and Powel teach that exhaustion is another state of immunological hypo-responsiveness of T cells (page 494, figure 1).
Abate-Daga et al (2013) teach that TCR-transduced T cells persisting in vivo exhibit a phenotype of PD-1+, 2B4+, CD160+and LAG-3- that was similar to that of exhausted HIV-specific CD8+ T lymphocytes suggesting that some aspect of T cell immunity based on adoptively transferred TCR gene-engineered cells may be more similar to an anti-viral response , than to a naturally occurring anti-tumor response (page 1409, second column, lines 1-6). Abate-Daga et al teach that the association between CD160 expression and functional impairment of the infused T cells is indicative of an exhaustion-like process occurring in adoptively transferred gene-engineered T cells (page 1409, second column, lines 13-16).Abata-Daga et al (2013) also teach that the expression of PD-1 at one month post infusion and the sensitivity of these cells to PD-L!-induced inhibition represents an opportunity for therapeutic intervention with blocking antibodies (page 1409, second column, lines 12-15 of the bottom paragraph), thus further rendering obvious claims 76 and 77.
It would have been prima facie obvious at the time of the effective filing ate to measure CD160 expression of the engineered T cell in a biological sample from the patient at the time of administration of the DGKα inhibitor of Sawa et al. One of skill n the art would have been motivated to do so by the teachings of Abate-Daga et al (2013) regarding an exhaustion-like phenotype in post-infusion T cells expressing recombinant receptors which provides the expectation that about 10% or more of the total recombinant receptor-expressing T cells after infusion. One of skill in the art would have been motivated to re-sample the patient’s blood at a later time to determine if the dosage of DGKα inhibitor was effective at reversing or preventing further exhaustion of the administered recombinant T cells.
It would have been prima facie obvious at the time of the effective fling date to use the obtained data regarding the CD160+ expression on post-infusion engineered T cells to determine the amount, time, duration and/or frequency that is effective to prevent, inhibit delay the onset of exhaustion or partially reverse an exhausted phenotype in the engineered T cells, thus rendering obvious claims 38-40.
Claims 1, 2, 3, 4, 5, 15, 16, 17, 24, 26, 28, 32, 37, 41-43, 44, 47-50, 59, 60, 63, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Casarez et al (WO2021/258010, priority to 63/041,771 for compounds 14, 20, 21, 23-4 and 36 of ‘010) in view of Sawa et al (WO2021/130638)..
Casarez et al teach that diacylglycerol kinases are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid which terminated T cell functions propagated through the TCR signaling pathway, thus functioning as an intracellular inhibitory checkpoint (page 1, lines 26-28). Casarez et al teach that inhibition of DGK is expected to enhance T cell signaling pathways and T cell activation (page 1, lines 28-29). Casarez et al teach that knock-out models of DGKα or DGKζ exhibit a hyper-responsive T cell phenotype and an improved anti-tumor response (pages 1-2, bridging sentence). Casarez et al teach that TIL isolated from human renal cell carcinoma patients overexpressed DGKα which resulted in inhibited T cell function (page 2, lines 4-6). Casarez et al teach that compounds which inhibit one or both of DGKα and DGKζ that is safe and effective in the restoration of T cell activation, lowering of the antigen-threshold, enhancing anti-tumor functionality , and overcoming the immunosuppressive effects of PD1, LAG3 and TGFbeta would be a significant advance for the treatment of patients with cancer and viral infections (page 2, lines 17-21). Casarez et al teach the inhibitors of DGK as compounds 14, 20, 21, 23-34 and 36 which meet the limitations of Formula I in claim 28 and formula II in claim 32, wherein compounds 14, 20, 21, 23-28, 31, 33 and 34 bound to DGKα to the exclusion of DGKζ,, compound 29 and 36 which bind to both of DGKα and DGKζ, which meet the limitations of claims 24, and 26.
Casarez et al teach the combination of the DGK inhibitors with a biologic immune-oncology agent (claim 5 of ‘010). Casarez et al do not teach the combination of the GDK inhibitors with a biologic immuo-oncology agent which is a CAR-T cells or a TCR engineered T-cell.
Sawa et al teach diacylglycerol kinase modulating compounds used in combination with other agents for the treatment of diseases including cancers and solid tumors (abstract) which meets the limitation of cancer in claims 48 and 49. Sawa et al teach that the inhibitory compounds of the invention are combined with one or more additional agents including an inhibitory immune checkpoint blocker, a CAR-T cell or T cell comprising an engineered TCR (paragraph [0246]) which meets the limitations of claims 43, 44 and 63. Sawa et al teach that co-administered the cellular therapy can entail the administration of cells that are autologous or allogenic to the subject (paragraph [0681]) which meets the limitations of claims 59 and 60. Sawa et al teach that the co-administered cellular therapy is MART-1 F5 TCR-engineered PBMC which meets the limitation of claim 47 because MSRT-1 is a target antigen expressed on a cell or tissue or the disease or condition. Sawa et al teach that co-administration of inventive inhibitors with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound taught herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient. (paragraph [0042]) which meets the limitations of claim 15. Sawa et al teach exemplary cancers that may be treated with the inventive inhibitors include B-cell lymphoma (paragraph [0045]) which meet the limitation of a B cell malignancy claim 50. Sawa et al teach that the disease being treated also includes autoimmune, inflammatory or infectious in addition to cancer (paragraph [044]), which meets those limitations in claim 48. Sawa et al teach an embodiment wherein, a unit dose of the inventive inhibitor is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents and another embodiment wherein a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of an inhibitor of DGKα (paragraph [0042] which meets those limitations in claims 2-5, 16 and 17. Given that that the administration of the inhibitor of DGKα to the subject after therapy with a CAR-t cell or after therapy with the engineered TRC of Sawa et al has the same method steps required in claims 5 and 6, the method of Sawa et al s inherently a method of rescuing engineered T cells from exhaustion and a method for reducing or delaying the onset of T cell exhaustion. See Ex parte Novitski 26 USPQ 1389 (BPAI 1993)..
Sawa et al teach the co-administration of an inhibitory immune checkpoint blocker (paragraph [0246] including the multispecific inhibitors FPT-155 which is a CTLA4/PD-L1 inhibitor, and the PD-1/CTLA4 inhibitors of PF-06936308, MGD-019, KN0946, MEDI-5852, XmAb-20717 and Ak-104 (paragraph [0853] which meets the limitations of claims 63 and 66.
Sawa et al teach “Therapeutically effective amount" or “effective amount” is an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.. The effective amount can include a range of amounts and delivered as one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint and an effective amount may be considered in the context of administering one or more therapeutic agents (paragraph [0040]) thus anticipating claim 37.
Sawa et al teach the administration of 1 mg, 100 mg, about 125 mg, about 150 mg,, about 175 mg,, about 200 mg and about 225 mg of the inventive inhibitor/dose (paragraph [0234]) which meets the limitations of claims 41 and 42.
It would have been prima facie obvious at the time of the effective filing date to combine the DGKα inhibitors, or the DGKα and DGKζ inhibitors of Casarez et al with the T cell therapy comprising engineered T cells expressing a recombinant receptor, such as a CAR-T cell therapy or a engineered T cell receptor. One of skill in the art would have been motivated to do so based on the teachings of Sawa et al regarding the analogous combination with other small-molecule inhibitors of DGKα as taught by Sawa et al.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643
Prosecution Insights