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 January 28, 2026 in response to the Office Action of September 30, 2025 is acknowledged and has been entered.
Claims 21, 25, 29, 31, 34, 35, and 37 have been amended.
Claims 1-12, 36, 38, 43 and 45 have been cancelled.
Claims 46-54 have been added.
Claims 21-29, 31-35, 37, 39, 41, 42, 44 and 46-54 are pending.
Claims 21-24, 34, 39, 41, 42, 44, 46, 47, 52 and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.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 25-29, 31-33, 35, 37, 48-51, and 54 are currently under consideration as drawn to the elected invention.
In view of cancellation of claims 7, 36, 38 and 37 and the amendment of claim 37, the 112(b) rejections set forth in the previous Office Action of September 30, 2025 are hereby withdrawn.
The amended claims incorporated the limitation of claim 25, thus, the 103 rejections set forth in the previous Office Action of September 30, 2025 are hereby withdrawn.
Similarly, the ODP rejections over Appl. No. 17/786, 239 or Appl. No. 17/785,585 set forth in the previous Office Action of September 30, 2025 are hereby withdrawn in view of the claim amendments.
MAINTAINED/MODIFIED 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.
Claims 25-29, 31-33, 35, 37, 48-51, and 54 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.
Claim 25 is drawn to a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of DGKα and/or DGKζ comprising Formula (II), an antagonist of the PD1/PD-L1 axis, and an antagonist of CTLA4. Given Broadest Reasonable Interpretation (BRI), the claims encompass: 1) a broad genus of cancers, at least including the cancers described in paragraph [0073] of the instant publication US2023/0089255 A1; 2) a broad genus of inhibitors of DGKα and/or DGKζ of Formula (II); and/or 3) a broad genus of antagonists of the PD1/PD-L1 axis which may be any types of molecule, e.g. a protein, nucleic acid or a small molecule (see paragraph [0195] of the instant publication US2023/0089255 A1); and/or 4) a broad genus of antagonists of CTLA4 which may be any types of molecule e.g. a protein, nucleic acid or a small molecule (see paragraph [0217] of the instant publication US2023/0089255 A1); 5) an even bigger number of all possible claimed combinations.
The instant specification provided limited evidence of the effect of a few combinations comprising a DGK inhibitor, and/or antagonist of the PD1/PD-L1 axis and a CTLA antagonist for limited cancers (e.g. melanoma, colorectal cancer):
In Example 2, the inhibition of DGK (note that it is not indicated which compound has been tested) enhances for the combined activity of a specific PD1 antagonist (monoclonal antibody) and a specific CTLA4 antagonist (monoclonal antibody) in the B16 animal tumor model (melanoma). See Figure 2A-H.
Example 3 shows that compound 16 of Formula (I) enhance the activity of an anti-PD1 antibody and/or an anti-CTLA4 antibody in the CT26 animal tumor model (colorectal cancer). The effect of the triple combination appears to be nearly the same as the one of the combination without compound 16 (anti-PD1+anti-CTLA4, Fig. 3H).
Figure 10 (Example 10) shows that a specific compound of Formula (II) (not clear which compound was tested) with anti-PD1 antibody or anti-CTLA antibody provides a stronger efficacy in the MC38 animal model (colorectal cancer).
Figure 12 shows the combination of a specific compound of Formula (II) (not clear which compound was tested) with anti-PD1 antibody and anti-CTLA antibody provides a stronger efficacy relative to combinations with anti-PD1 antibody or anti-CTLA4 in the B16F10 animal model (melanoma).
Taken together, the specification teaches anti-tumor activity for a few combinations comprising a specific DGK inhibitor (undisclosed), a specific antagonist of the PD1/PD-L1 axis (an anti-PD1 antibody) and a specific antagonist of CTLA4 (an anti-CTLA4 antibody) for a few solid cancers (e.g. melanoma, colorectal cancer). Thus, the specification lacks written description support for the broadly claimed methods which encompass unlimited combinations and unlimited cancers.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed".
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of afunctional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Regarding “treating cancers”, as set forth above, it encompasses treating unlimited number of cancers including all solid cancers (elected species). It is well known that cancer is not a single disease. Dagogo-Jack et al. (Nature Review Clinical Oncology, vol. 15, pp 81-94, February 2018) teach that cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumor might include a diverse collection of cells harboring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumor-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity) (Abstract). No compound (or compound combination) has ever been found that can treat cancers generally even though massive efforts have been directed towards this end. The specification shows a few combinations which have anti-tumor activity to melanoma or colorectal cancer. However, the specification does not provide adequate written description of a method for treating all cancers, e.g. all solid cancers (the elected species) as claimed.
Regarding “an inhibitor of DGKα and/or DGKζ comprising Formula (II)”, the specification discloses and tests 17 compounds of Formula I (Compounds 1-16) or II (Compounds 17-34) which show different activity and specificity to DGKα and DGKζ (see Table A on page 47 of the instant publication US 2023/0089255 A1). For example, compound 1, 2 and 3 have very similar structure, but different inhibiting activity and specificity (see Table A). The specification has not established a relationship between the structure and the functionality (activity/specificity) of these compounds. As evidenced by Racca (Racca et al., Medicinal Research Reviews, 2025, 1-27, of record), DGK inhibitors can have different structures and different specificity to DGKs (Table 5). Thus, compounds 17-34 would not teach other inhibitors of DGKα and/or DGKζ of Formula (II) by the claims, which can be used in combination with an antagonist of the PD1/PD-L1 axis and an antagonist CTLA4 as claimed.
In addition, the claims identify the inhibitors by function only, where the function is to:
inhibit both DGKζ and DGKα (claim 48);
inhibit DGKα and DGKζ but not other DGKs (claim 49).
However, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of inhibitors.
In addition, inhibitors of DGKα and DGKζ (claim 48) would encompass inhibitors which inhibit all DGKs. Given the wide range of physiological and pathological processes involving each DGK isoform, as well as the co-expression of multiple isoforms in cells and tissues, it is clear that isoform-specific DGK inhibitors is essential (page 12, the bridging paragraph of cols 1-2). Furthermore, Wichroski (Wichroski et al., Sci. Transl. Med. 15, easdh1892 (2023), of record) shows that compounds with similar structure could have significantly different activity and specificity to members of DGK family (Fig. 3A and 3B). The specificity of an inhibitor to DGK(s) is important to the therapeutic application for the inhibitor, as taught by Racca. Thus, not knowing structure-function relationship, one of ordinary skill in the art would not be able to readily visualize or recognize which inhibitors would function as the inhibitors tested in the instant examples.
In view of above, the specification shows that compounds 17-34 of Formula (II) have various inhibiting activity to DGKα and/or DGKζ, however, the structures of compounds 17-34 do not teaches structure of other compounds can inhibit DGKα and/or DGKζ of Formula (II). For example, claims 25 and 26 encompass a broad genus of compounds of Formula (II) which may or may not have the required properties for the claimed method. Given that the relationship between structure and inhibitor function has not been established, one of ordinary skill in the art would have not been able to visualize or recognize which compounds of Formula (II) have the required function (e.g. DGKα and/or DGKζ) as claimed.
Moreover, it is unclear whether compounds 17-34 can inhibit DGKα and DGKζ but not other DGKs (see claim 49). Based on a recent review (Racca et al., Medicinal Research Reviews, 2025, 1-27, of record), two inhibitors: BMS-502 and BMS-332 inhibit both DGKα, DGKζ and DGKι, but there is not any inhibitor available with claimed property: inhibits both DGKα and DGKζ but no other DGKs (see Table 5). Thus, the specification does not disclose any compound of Formula (II) with the claimed specificity of claim 49.
Regarding “antagonist of the PD1/PD-L1 axis”, as set forth above, the claims encompass a broad genus of antagonists of the PD1/PD-L1 axis which may be any types of molecule, e.g. a protein, nucleic acid or a small molecule (see paragraph [0195] of the instant publication US2023/0089255 A1). These compounds could have different structures (antibody, peptide, small molecule, RNA, DNA, etc.), different physical/chemical properties, and function through different mechanisms. Paragraphs [0206-0214] of the instant publication US2023/0089255 A1 teach a number of antibodies to PD1 or PD-L1. However, the antibody antagonists to PD1/PD-L1 axis do not teach the structure of other types of antagonists encompassed by the claims (such as small molecule antagonists). In addition, antibody antagonists to PD1/PD-L1 axis and other types of antagonists have different therapeutic properties, such as specificity, pharmacodynamics. Thus, one of ordinary skill in the art would not be able to readily visualize or recognize other types of antagonists to PD1/PD-L1 axis (other than antibody) in combination with an inhibitor of DGKα and DGKζ would lead to the same outcome as showed in the Examples of the instant specification.
Similarly, Regarding “antagonist of CTLA4”, as set forth above, the claims encompass a broad genus of antagonists of CTLA4 which may be any types of molecule, e.g. a protein, nucleic acid or a small molecule (see paragraph [0217] of the instant publication US2023/0089255 A1). These compounds could have different structures (antibody, peptide, small molecule, RNA, DNA, etc.), different physical/chemical properties, and function through different mechanisms. Paragraphs [0218-02229] of the instant publication US2023/0089255 A1 teach a number of antibodies to CTLA4. However, the antibody antagonists to CTLA4 do not teach the structure of other types of antagonists encompassed by the claims (such as small molecule antagonists). In addition, antibody antagonists to CTLA4 and other types of antagonists have different therapeutic properties, such as specificity, pharmacodynamics. Thus, one of ordinary skill in the art would not be able to readily visualize or recognize other types of antagonists to CTLA4 (other than antibody) in combination with an inhibitor of DGKα and DGKζ would lead to the same outcome as showed in the Examples of the instant specification.
Since claim 25 lacks written description support for each components in the claimed combination, logically, claim 25 lacks written description support for the claimed combinations.
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of§ 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004). Meeting the written description threshold requires showing that the applicant was in "possession" of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning - i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims. Given the claimed broadly class of antibody binding domains, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish "a reasonable structure-function correlation" either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutsch/and GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the "limitations above" and then identifying those that satisfy claim limitations, but mere "wish or plan" for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibody binding domains to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017).
Claims 26-29, 31-33, 35, 37, 48-51, and 54 depend on claim 25 and encompass a broad genus of cancers; and/or a broad genus of inhibitors of DGKα and/or DGKζ; and/or a broad genus of antagonists of the PD1/PD-L1 axis; and/or a broad genus of antagonists of CTLA4. Thus, these claims also lack written description support.
Response to Arguments
For the WRITTEN DESCRIPTION rejection, Applicant argues:
Importantly, while the claimed DGKα/DGKζ inhibitors are novel, the claims are not solely directed to the discovery or generation of new compounds, but rather to the novel use of the novel DGKα/DGKζ inhibitor combined with antagonists of CTLA4 and the PD1/PD-L1axis in a particular therapeutic application (i.e., a method of treating cancer). The description necessary to establish written description for a genus of compounds logically differs from that needed to establish written description for a method of using a genus of compounds to achieve a particular purpose.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, although the claims are drawn to a method, the method encompasses 1) a broad genus of cancers; 2) a broad genus of inhibitors of DGKα and/or DGKζ of Formula (II); 3) a broad genus of antagonists of the PD1/PD-L1 axis; and 4) a broad genus of antagonists of CTLA4. To demonstrate Applicant had the possession of the invention in full scope (the claimed method), the specification would need to have to written description support for the composition (inhibitors of DGKα and/or DGKζ, the antagonist of the PD1-PD-L1 axis and the antagonist of CTLA4) used in the method. Because the components used in the claimed method are defined by functional language, but which otherwise vary materially, structurally and/or functionally, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. In this instance, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; Applicant has not shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; and Applicant has not described distinguishing identifying characteristics sufficient to show that Applicant was in possession of the claimed invention at the time the application was filed.
Applicant further argues:
The present claims are not drawn to a genus of compounds, but rather to a new use for known compounds (in combination with a novel DGKα/DGKζ inhibitor) in a particular therapeutic indication (i.e., treatment of cancer). In this regard, the specification provides working evidence and a clear rationale as to why the claimed combination is effective in the treatment of cancer. Moreover, compounds falling within the claimed class of CTLA4 antagonists and the claimed class of PD1/PD-L1 axis antagonists were well known at the relevant filing date and the success of the claimed combination is based, in part, on their combined mode of action (and not solely the compounds themselves). Also see page 25 of the Remarks.
Applicant’s arguments have been fully considered but they are not persuasive. It is acknowledged that antibodies to PD-1, PD-L1 and CTLA4 are well known in the art, and page 41-46 and page 47-49 of the Specification provide more examples of known antibodies to PD-1, PD-L1 and/or CTLA4. However, the claims are not limited to these antibodies (such as nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, or ipilimumab cited by applicant see page 25 para. 2 of the Remarks). As set forth above, antagonists of the PD1/PD-L1 axis which may be any types of molecule, e.g. a protein, nucleic acid or a small molecule and antagonists of CTLA4 which may be any types of molecule e.g. a protein, nucleic acid or a small molecule. Other types of antagonists (i.e. small molecule antagonists) would have different therapeutic properties, such as specificity, pharmacodynamics. Thus, one of ordinary skill in the art would not be able to readily visualize or recognize other types of antagonists to PD1/PD-L1 axis, and/or CTLA4.
Applicant further argues:
It is well established that the written description requirement must be applied in the context of the particular invention and the state of the knowledge in the art. As each field evolves, the balance also evolves between what is known and what is added by each inventive contribution (emphasis added) (Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1085 (Fed. Cir. 2005)). Therefore, given the description in the present specification and the knowledge in the art at the relevant filing date, the skilled artisan would clearly recognize that Applicant was in possession of the claimed methods.
Applicant’s arguments have been fully considered but they are not persuasive. First, as set forth, the claims broadly encompass antagonists to PD1/PD-L1 axis and/or CTLA4 which is not well known and well-tested in the arts.
In addition, for “an inhibitor of DGKα and/or DGKζ comprising Formula (II)”, the claims encompass 1) inhibit both DGKζ and DGKα (claim 48); and inhibit DGKα and DGKζ but not other DGKs (claim 49). However, the instant specification and prior art have not provided a sufficient description about the correlation between the recited functions and the structure of inhibitors. Thus, the claims encompass a broad genus of compounds of Formula (II) which may or may not have the required properties for the claimed method. Given that the relationship between structure and inhibitor function has not been established, one of ordinary skill in the art would have not been able to visualize or recognize which compounds of Formula (II) have the required function as claimed. For example, it is unclear whether compounds 17-34 disclosed in the specification can inhibit other DGKs. As set forth above, prior art does not disclose any inhibitor which inhibits both DGKα and DGKζ but no other DGKs (see Table 5 of Racca et al., Medicinal Research Reviews, 2025, 1-27, of record). Thus, the claims encompass subject matter which are not well-known in the art. Given the description in the present specification and the knowledge in the art, the specification therefore would not reasonably convey to the skilled artisan Applicant’s possession of the claimed invention as of the filing date of the application.
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.
Application No. 18/280,197
Claims 25, 26, 31-33, 35, 48 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8, 9, 15-17, 24-28, 32, 37-50, 54, 55, 57-60, 63, 66, 76 and 77 of copending Application No. 18/280,197 (hereinafter Appl. 197, US 2024/0108654 A1, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The claims of Appl. 197 teach a method of treatment, the method comprising: (a) administering a T cell therapy to a subject having a disease or condition, wherein the T cell therapy comprises engineered T cells expressing a recombinant receptor; and (b) administering to the subject an inhibitor of DGKα and/or DGKζ (claim 1).
The claims of Appl. 197 teach that the method of claim 1, wherein 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 effect an increase in antigen-specific or antigen receptor-driven activity of the engineered T cells (claim 37); or effective to prevent, inhibit, or delay onset of an exhaustion phenotype in the engineered T cells (claim 38); or effective to at least partially reverse an exhaustion phenotype in the engineered T cells (claim 39).
The claims of Appl. 197 teach that the method of claim 1, wherein the disease or condition is a cancer (claim 49)
The claims of Appl. 197 teach that the method further comprises administering to the subject an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4 (claim 66). Combining claims 1, 49 and 66, the claims of Appl. 197 teach a method of treating a disease (e.g. cancer) with a combination of T cell therapy, an inhibitor of DGKα and/or DGKζ and an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4.
The claims of Appl. 197 teach DGKα and/or DGKζ inhibitor of Formula (II) (claim 32). And the species of claim 32 of Appl. 197 overlap with the species of the instant claim 26.
Taken together, the claims of Appl. 585 reads on the instant claims 25 and 26.
Regarding claim 31-33, which are dependent on the instant claim 1, the combination of T cell therapy, an inhibitor of DGKα and/or DGKζ and an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4 would read on these claims, because administering T cell therapy could be considered as administering one or more other cancer treatments, wherein the other cancer treatment is a biologic drug and the biologic drug that simulates the immune system.
Regarding claims 25 and 26, the claims of Appl. 197 teach DGKα and/or DGKζ inhibitor of Formula (II) (claim 32). This claim of Appl. 585 reads on the instant claim 25. And the species of claim 32 of Appl. 197 overlap with the species of the instant claim 26.
Regarding claim 31-33, which are dependent on the instant claim 1, the combination of T cell therapy, an inhibitor of DGKα and/or DGKζ and an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4 would read on these claims, because administering T cell therapy could be considered as administering one or more other cancer treatments, wherein the other cancer treatment is a biologic drug and the biologic drug that simulates the immune system.
Regarding claim 35, one of ordinary skilled in the art would have expected that the subject has not been treated with an antagonist of the PD1/PD-L1 axis or an antagonist of CTLA-4, would be less likely to be resistant to anti-PD1 or anti-CTLA treatment. Thus, these subjects would be more likely to respond to the treatment with the combination of T cell therapy, an inhibitor of DGKα and/or DGKζ and an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4.
Regarding the instant claim 48, the claims of Appl. 197 teach that the method of claim 1, wherein the inhibitor of DGKα and/or DGKζ is an inhibitor of DGKα and DGKζ (claim 26).
Regarding the instant claim 49, the claims of Appl. 197 teach the method of claim 1, wherein the inhibitor of DGKα and/or DGKζ is not a significant inhibitor of other DGKs (claim 27).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 29, 37, 50, 51 and 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8, 9, 15-17, 24-28, 32, 37-50, 54, 55, 57-60, 63, 66, 76 and 77 of copending Application No. 18/280,197 (hereinafter Appl. 197, US 2024/0108654 A1, of record), as applied to claims 25, 26, 31-33, 35, 48 and 49 above, and further in view of Albelda (Albelda et al., WO 2014/039513, Publication Date: 03/13/2014, of record), Wee (Wee et al., Cancer Res (2019) 79 (13_Supplement): 936, Publication Date: 07/01/2019, cited in IDS of 09/29/2022, of record), and Rotte (Rotte, Journal of Experimental & Clinical Cancer Research, 2019, 38:255, Publication Date: 06/13/2019, cited in IDS of 04/17/2025, of record).
As set forth above, the claims of Appl. 197 teach the method of instant claim 25. However, the claims of Appl. 197 do not teach: the antagonist of the PD1/PD-L1 axis is an antagonist of PD1 (instant claim 50); the antagonist of PD1 is nivolumab (instant claim 51); the antagonist of CTLA-4 is ipilimumab (instant claim 54), treating solid cancer (instant claim 29) or the subject is resistant or refractory to treatment with an antagonist of the PD1/PD-L1 axis or an antagonist of CTLA-4 (instant claim 37).
Albelda teaches that blockade of DGK isoforms enhances the cytolytic activity and persistence of T cells (page 11, lines 24-29).
Albelda teaches that loss of DGKα, DGKζ or both markedly enhanced the ability of the T cells to kill tumor cells (Figs 4 and 5; page 68, para 1).
Albelda teaches that DGK inhibitors such as R59949 (DGK2 inhibitor) and R59022 (DGK1 inhibitor) can enhance antitumor response to human T cells (the bridging paragraph of pages 79-80, Fig. 21A).
Albelda teaches a composition for enhancing the cytolytic activity of a cell, said composition comprising an inhibitor of diacylglycerol kinase (DGK) (claim 1).
Albelda teaches that the composition inhibits the DGK isoform selected from the group consisting of DGKα and DGKζ (claim 6).
Albelda teaches that the composition inhibits both DGKα and DGKζ (claim 7).
Albelda teaches the DGK inhibitor can be administered to a subject in need thereof (page 59, the bottom paragraph).
Albelda teaches that loss of DGKα, DGKζ or both markedly enhanced the ability of the T cells to kill tumor cells (Figs 4 and 5; page 68, para 1).
Albelda teaches that the method can be used to treat cancers (page 25, the bottom paragraph), the cancer can be solid cancers such as breast cancer, prostate cancer, lung cancer (the bridging paragraph of pages15-16).
Albelda teaches that the inhibitors maybe used in combination with existing therapeutic agents used to treat cancer to enhance the antitumor effect (page 61, paras 2 and 3).
Taken together, Albelda teaches a method of treating cancer in a subject, comprising administering to the subject an inhibitor to DGKα and DGKζ to inhibit DGKα and DGKζ, and in combination with other antitumor agents.
Albelda, Wee and Rotte teach as set forth above. In particular, Albelta teaches that DGK inhibitor can enhance anti-tumor activity of T cells and can be used in treating various solid cancers; Wee teaches the anti-PD1 and DGK-deficiency have additive anti-tumor activity; Rotte further teaches the rationale to combine anti-PD1 and anti-CTLA-1 and nivolumab + ipilimumab combination have been widely tested and approved for treating various solid cancers.
Wee teaches that the combination of DGKζ-deficiency and anti-PD1 were additive in tumor control (Abstract).
Rotte teaches that targeting checkpoints of immune cell activation has been demonstrated to be the most effective approach for activation of anti-tumor immune responses. CTLA-4 and PD-1, both inhibitory checkpoints commonly seen on activated T-cells have been found to be the most reliable targets for the treatment of cancer (Abstract).
Rotte teaches rationale for combination of CTLA-4 and PD-1 blockers. CTLA-4, which is primarily involved in regulation of T-cell activation in lymph nodes/tissues and in suppression of DC activity via Treg cells, would act synergistically with blockade of PD-1 that is mainly involved in inhibition of effector T-cel and NK cell activation in peripheral tissues and in induction of Treg cell differentiation (§ Rationale for combination, on page 4; and Fig. 1).
Rotte teaches treating cancers with various combinations, including nivolumab + ipilimumab for melanoma (page 5, col. 1, para. 2), renal cell carcinoma (page 5, the bridging paragraph of cols. 1-2), colorectal cancer (the bridging paragraph of pages 5-6), NSCLC (the bridging paragraph of pages 6-7), SCLC (page 7, col. 2, para. 1), etc. And the combination has been approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancers (Abstract).
Regarding claim 29, the claims of Appl. 197 teach treating a cancer with a combination of T cell therapy, an inhibitor of DGKα and/or DGKζ and an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4. Albelta teaches that DGK inhibitor can enhance anti-tumor activity of T cells and can be used in treating various solid cancers; Wee teaches the anti-PD1 and DGK-deficiency have additive anti-tumor activity; Rotte further teaches the rationale to combine anti-PD1 and anti-CTLA-1 and nivolumab + ipilimumab combination have been widely tested and approved for treating various solid cancers. Based on the teachings, one of ordinary skill in the art would have a reasonable expectation that the combination would be effective for treating solid cancer.
Regarding claim 37, Rotte teaches that anti-PD1 or anti-CTLA-4 drugs when administered as monotherapy had more than 50% of patients failed to respond to the treatment (resistant to anti-PD1 or anti-CTLA-4). Combination of CTLA-4 and PD-1 blockers can increase the response rates in patients (which implies that some resistant patients respond to the combination treatment). Rotte also teaches anti-PD1 and anti-CTLA-4 target different immune cells. Thus, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to recognize that the combination taught by the claims of Appl. 197, would be able to treat cancers resistant to anti-PD1 or anti-CTLA-1 monotherapy.
Regarding instant claims 50, 51 and 54, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the compounds of Formula (II) taught by the claims of Appl. 197 to treat a disease (e.g. cancer) with a combination of T cell therapy, an inhibitor of DGKα and/or DGKζ and an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA-4; and to use an antagonist of PD-1 (e.g. nivolumab) and an antagonist of CTLA-4 (e.g. ipilimumab) based on the combined teachings from Albelda, Wee and Rotte, because Wee teaches that anti-PD-1 and DGKζ-deficiency combination has enhanced anti-tumor activity, Rotte teaches that anti-PD-1 and anti-CTLA-4 can further enhance anti-tumor T cell activity and nivolumab + ipilimumab have been tested in treating various solid cancers. Thus, one of ordinary in the art would have a reasonable expectation that the combination would have further enhanced anti-tumor T cell activity and stronger therapeutic activity. Given that nivolumab and ipilimumab are well known in the art, have been well tested in clinical trials and have been approved for treating various solid cancers, as evidenced by Rotte, one of ordinary skill in the art would have a reasonable expectation of success to use nivolumab and ipilimumab in the inhibitor taught by the claims of Appl. 197. The motivation would have been to develop a more effective treatment and expand the applications of nivolumab and ipilimumab.
Regarding claims 37 and 38, Rotte teaches that anti-PD1 or anti-CTLA-4 drugs when administered as monotherapy had more than 50% of patients failed to respond to the treatment (resistant to anti-PD1 or anti-CTLA-4). Combination of CTLA-4 and PD-1 blockers can increase the response rates in patients (which implies that some resistant patients respond to the combination treatment). Rotte also teaches anti-PD1 and anti-CTLA-4 target different immune cells. Thus, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to recognize that the combination taught by the claims of Appl. 197, would be able to treat cancers resistant to anti-PD1 or anti-CTLA-1 monotherapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
For the rejection under Double Patenting, applicant requests that each of the foregoing rejections be held in abeyance until the pending claims are indicated otherwise allowable, at which time Applicant will consider submitting a terminal disclaimer complying with 37 C.F.R. §1.321 (b) and (c).
Applicants’ arguments have been considered, but have not been found persuasive because the claims of the instant application are still obvious in view of the co-pending claims and a terminal disclaimer has not been filed. MPEP 804 I-B states: “The “provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in at least one of the applications.” Thus, the rejection is maintained because it is not the only rejection remaining.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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