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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 2, 2026 has been entered.
DETAILED ACTION
The amendment filed March 2, 2026 in response to the Office Action of August 28, 2025 is acknowledged and has been entered.
Claim 1 has been amended.
Claims 6, 12-15 and 22-27 have been cancelled.
Claims 28-30 have been added.
Claims 1, 4, 7, 11, 16-21 and 28-30 are pending and under consideration as drawn to the elected invention.
In view of the claim 1 amendments, the Double Patenting rejections over US Patent Nos. 9,402,905, 10,106,611, and 10,793,633 are hereby withdrawn.
NEW REJECTIONS
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 28 and 29 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 28, which depends on claim 1, recites “wherein the HDAC inhibitor is selected from … a benzamide…”. Claim 1 recites “a non-selective pan-HDAC inhibitor”. As evidenced by Li (Li et al., European Journal of Medicinal Chemistry, 100 (2015), 270-276, Publication Date: 06/05/2015), HDACs are divided into 4 classes (I-IV). Benzamide is a class-I selective HDAC inhibitor (paragraphs 1 and 2 of Introduction). Thus claim 28 broaden the scope of claim 1 upon which it depends.
Claim 29, which depends on claim 1, recites “wherein the HDAC inhibitor is selected from … romidepsin…”. Claim 1 recites “a non-selective pan-HDAC inhibitor”. As evidenced by Petrich (Petrich et al., Leukemia & Lymphoma, 2016, Vol. 57, NO. 8, 1755-1765, Publication Year: 2016), HDACs are divided into 4 classes (I-IV). Romidepsin is a class-I selective HDAC inhibitor (paragraphs 2 and 3 of Introduction). Thus claim 29 broaden the scope of claim 1 upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
MAINTAINED/MODIFIED REJECTIONS
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.
Claims 1, 4, 7, 11, 17-20, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Ferrari de Andrade (Ferrari de Andrade et al., Science, 359, 1537-1542, with Suppl. Publication Date: 03/30/2018, cited by IDS of 02/27/2024, of record), in view of Cerwenka (Cerwenka et al., Science, 359, 1460-1461, Publication Date: 03/30/2018, of record), Wucherpfennig (Wucherpfennig et al., US 2016/0046716 A1, Publication Date: 02/18/2016, of record) and Kato (Kato et al., Leukemia, 2007, 21, 2103-2108, Publication Date: 07/12/2007, of record), and as evidenced by WO 2018/217688 A1 (Publication Date: 11/29/2018, of record) and Panobinostat_PubChem (downloaded from: Panobinostat | C21H23N3O2 | CID 6918837 - PubChem on March 9, 2026).
Ferrari de Andrade teaches that MICA and MICB are expressed by many human cancers, enabling elimination of cancer cells by cytotoxic lymphocytes expressing NKG2D receptor. However advanced cancers frequently escape immune mechanism by proteolytic shedding of cell-surface bound MICA and MICB molecules (page 1, col. 1, para. 1).
Ferrari de Andrade teaches that antibodies specifically bind to epitope on the MICA and MICB α3 domain would inhibit MICA and MICB shedding and not interfere with NKG2D binding (page 1, col. 2, para. 1).
Ferrari de Andrade teaches three monoclonal antibodies (7C6, 6F11, and 1C2) that bound to the α3 domain (page 1, col. 2, para. 1). It is noted that 7C6 is the same as the antibody used in Examples of the instant Specification. As evidenced by [0064] and Fig. 21 of WO 2018/217688 A1, antibody 7C6 comprises, a heavy chain CDR sequence SEQ ID NOs: 1-3. SEQ ID NOs: 1-3 are underlined.
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Antibody 7C6 also comprises, a light chain CDR sequence SEQ ID NOs: 4-6. SEQ ID NOs: 4-6 are underlined.
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Ferrari de Andrade teaches that 7C6 mAb enabled strong NK cell-mediated killing of human tumor cells (page 1, col. 3, para. 2).
Ferrari de Andrade teaches that 7C6 antibody inhibit MICA and MICB shedding by human melanoma cells (page 1, col. 3, para. 2; Fig. S8, A to C).
Ferrari de Andrade teaches that treatment with 7C6 antibody strongly reduced the number of lung metastases formed by B16F10-MICA tumor cells (Fig. 2, A and B, and Fig. S10 A and B; page 1, col. 3, para. 3) and CT26-MICA tumor cells (Fig. 2D). It is noted that B16F10 is melanoma cell line.
Ferrari de Andrade teaches that the therapeutic activity of 7C6 antibody is independent CD8 T cells, and independent IFN-γ (page 2, col. 1, para. 2; Fig. 2F and 2G).
Ferrari de Andrade teaches that 7C6 has activity against established metastases (page 2, the bridging paragraph of cols. 1-2). Ferrari de Andrade teaches that in human A2058 melanoma cells induced tumor model, 7C6 antibody significantly reduce metastases (Fig. 4B).
Ferrari de Andrade teaches that 7C6 antibody has therapeutic activity in T cell deficient tumor model (Rag2-/-Il2rg-/-) (page 3, the bridging paragraph of cols. 2-3; and Fig. 3E).
Ferrari de Andrade teaches that MICA and MICB are widely expressed in human cancers, MICA and MICB antibodies may hold promise for both solid and hematological malignancies. Such antibodies could be used in combination with established therapies that induce or enhance MICA and MICB expression through genomic damage pathways, including local radiation therapy or antibody drug conjugates that deliver toxic payloads to tumor cells. MICA antibodies are also of considerable interest as a combination partner with other immunotherapies to activate NK cells and enhance cytotoxic T cell function for protective antitumor immunity (page 5, col. 3).
Ferrari de Andrade teaches that 7C6 antibody is administered intraperitoneally (pages 13-14 of Suppl., § B16F10 metastasis model in immunocompetent mice).
Ferrari de Andrade teaches that 7C6 antibody was concentrated in Amicon spin column, exchanged into PBS (a pharmaceutically acceptable carrier), and filtered prior to injection (page 4, para. 1 of Suppl.).
Regarding limitation “thereby causing lysis of one or more cancer cells in the subject”, Figure 7F teaches that the 7C6 antibody induces NK cell mediated toxicity in the tumor cells.
Thus, Ferrari de Andrade teaches treating cancer in a subject a therapeutically effective amount of an anti-MICA α3 antibody (7C6) and a pharmaceutically acceptable carrier, thereby reduce tumor size, metastasis. Ferrari de Andrade also teaches that the therapeutic activity of 7C6 is independent of CD8 T cells, or IFN-γ, and 7C6 is functional T-cell deficient tumor model. However, Ferrari de Andrade does not explicitly teach that wherein the cancer is resistant to cytotoxic T cells, or further comprising administering HDAC inhibitor e.g. Panobinostat.
Cerwenka teaches that with great success achieved by interfering with immune checkpoints to unleash antitumor CD8+ T cell responses. There is emerging evidence that cancers develop multiple strategies to escape CD8+ T cell recognition. These tumors can be preferentially attacked by NK cells (page 1460, col. 1, para. 1).
Cerwenka teaches that NK cells express activating receptors, including NKG2D receptor, which recognized ligands displayed on the surface of tumor cells (page 1460, col. 1, para. 1; and the figure on page 1460).
Cerwenka teaches that one major mechanism of tumor escape is the shedding of NKG2D ligands MICA and MICB (page 1460, the bridging paragraph of cols. 1-2).
Cerwenka teaches that these combinations would not only enhance both CD8+ T cell and NK cell activation against cancer cells but, in addition, broaden the spectrum of tumor cells that can be attacked (the bridging paragraph of pages 1460-1461).
Wucherpfennig teaches several antibodies, e.g. mAb CM33322 Ab4 and CM33322 Ab29 binds to alpha-3 domain of human MICA or MICA (Example 10, Example 14, [0358]).
Wucherpfennig teaches that CM33322 Ab29 reduce MICA shedding from tumor cells (Example 13, Fig. 49).
Wucherpfennig teaches that CM33322 Ab29 was administered to B16-MICA tumor bearing mice (Example 12) Fig. 48 shows that treatment with CM33322 Ab29 halts tumor growth.
Wucherpfennig teaches that therapeutic compositions can further include other compounds including HDAC inhibitors, e.g. Panobinostat ([0186], claim 70).
Kato teaches that MICA and MICB expression in various tumor cells is significantly induced by HDAC inhibitor treatment, in vitro and in vivo (Table 2A and Table 2B). MICA and MICB protein expression levels on cell surface were also increased (page 2105, col. 2, para. 2).
Kato teaches that upregulated MICA and MICB expression following HDAC inhibitor treatment enhances the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells (Fig. 3).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancer in a subject a therapeutically effective amount of an activating agent e.g. anti-MICA α3 antibody (7C6) and a pharmaceutically acceptable carrier, as taught by Ferrari de Andrade, and to apply the treatment to cancer resistant to cytotoxic T cells (e.g. CD8+ T cells), as taught by Ferrari de Andrade and Cerwenka, because Ferrari de Andrade teaches 1) 7C6 increase density of MICA/MICB on the tumor cells; 2) the therapeutic activity of 7C6 is independent of CD8 T cells, or IFN-γ; and 3) 7C6 is functional T-cell deficient tumor model; Cerwenka teaches 1) cancers develop multiple strategies to escape CD8+ T cell recognition; 2) one major mechanism of tumor escape is the shedding of NKG2D ligands MICA and MICB. Based on the teachings from Ferrari de Andrade and Cerwenka, one of ordinary skilled in the art would have had a reasonable expectation that 7C6 antibody would have therapeutic activity to cancers resistant to cytotoxic T cells (e.g. CD8+ T cell-resistant cancers). The motivation would have been to develop an effective treatment for this patient population and to broaden the spectrum of tumor cells that can be attacked, as recognized by Cerwenka. In addition, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to further administer an HDAC inhibitor such as Panobinostat in the combination, as taught by Wucherpfennig and Kato, because Wucherpfennig teaches to use MICA α3 domain specific antibody in combination with Panobinostat for cancer treatment and Kato teaches that HDAC inhibitor can increase MICA and MICB expression on tumor cells and enhance cancer cells susceptibility to cytotoxicity of NKG2D-expressing cells. Based on the references, one of ordinary skilled in the art would have had a reasonable expectation that the combination of 7C6 antibody and a HDAC inhibitor would further enhance the therapeutic activity of the 7C6. The motivation would have been to develop an improved combination treatment for cancers resistant to cytotoxic T cell.
Regarding claim 4, Ferrari de Andrade teaches 7C6 is a monoclonal antibodies that bound to the α3 domain (page 1, col. 2, para. 1). It is noted that 7C6 is the same antibody used in the Examples of the instant specification.
Regarding claim 7, Ferrari de Andrade teaches that MICA and MICB α3 domain-specific antibodies strongly inhibited MICA shedding by a diverse panel of human tumor cell lines, resulting a substantial increase in the cell surface density of MICA (Fig. 1, C and D; Fig. S2 A and B; and page 1, col. 2, para. 2). MICA is a ligand for NKG2D.
Cerwenka teaches that it is feasible to combine the MICA-MICB mAb with immune checkpoint inhibitors such as checkpoint inhibitors such as anti-PD1, anti-PD-L1 to further enhance T cell activation (the bridging paragraph of pages 1460-1461).
Regarding claims 17-18, Cerwenka teaches that with great success achieved by interfering with immune checkpoints to unleash antitumor CD8+ T cell responses. There is emerging evidence that cancers develop multiple strategies to escape CD8+ T cell recognition. These tumors can be preferentially attacked by NK cells (page 1460, col. 1, para. 1). As shown in the figure on page1460, anti-PD1/PD-L1 antibodies are involved in inducing tumor cell killing by CD8+ T cells. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use 7C6 antibody to treat cancer resistant to immunotherapy e.g anti-PD1/PD-L1 antibodies, because PD-1/PD-L1 interaction is involved in CD8+ T cell tumor-killing activity. Cancers resistant to anti-PD1/PD-L1 antibodies could be attacked by NK cells-mediated tumor killing. Given that 7C6 antibody enhances NK cell activity and independent of CD8+ T cell, one of ordinary skill in the art would have had a reasonable expectation that 7C6 would be effective to cancers resistant to anti-PD1/anti-PDL1 antibodies.
Regarding claims 19 and 30, Ferrari de Andrade teaches that 7C6 is effective in two melanoma models: B16F10 and A2058.
Regarding claim 28, as evidenced by Panobinostat_Pubchem, Panobinostat is a hydroxamic acid (see § Description).
Regarding claims 20, Ferrari de Andrade teaches that treatment with 7C6 antibody strongly reduced the number of lung metastases formed by B16F10-MICA tumor cells (Fig. 2, A and B, and Fig. S10 A and B; page 1, col. 3, para. 3). In addition, Ferrari de Andrade teaches that in human A2058 melanoma cells induced tumor model, 7C6 antibody significantly reduce metastases (Fig. 4B).
Claims 16 and 21 is rejected under 35 U.S.C. 103 as being unpatentable over Ferrari de Andrade (Ferrari de Andrade et al., Science, 359, 1537-1542, Publication Date: 03/30/2018, cited by IDS of 02/27/2024), in view of Cerwenka (Cerwenka et al., Science, 359, 1460-1461, Publication Date: 03/30/2018, of record), Wucherpfennig (Wucherpfennig et al., US 2016/0046716 A1, Publication Date: 02/18/2016, of record) and Kato (Kato et al., Leukemia, 2007, 21, 2103-2108, Publication Date: 07/12/2007, of record) as evidenced by WO 2018/217688 A1 (Publication Date: 11/29/2018, of record) and Panobinostat_PubChem (downloaded from: Panobinostat | C21H23N3O2 | CID 6918837 - PubChem on March 9, 2026), as applied to claims 1, 4, 6, 7, 11 and 17-20 above, and further in view of Friedrich (Friedrich et al., Cancer Immunology, Immunotherapy, 68: 1689-1700, Publication Date: 08/03/2019).
Ferrari de Andrade, Cerwenka, Wucherpfennig and Kato teach method of claim 1 as set forth above. However, Ferrari de Andrade and Cerwenka do not explicitly teach wherein the cancer is an MHC class I deficient cancer or a cancer resistant to IFN gamma, or further comprising a step of testing the cancer for a Jak1 mutation and/or a B2m mutation.
Ferrari de Andrade also teaches that the therapeutic activity of 7C6 antibody is independent of CD8 T cells, and independent of IFN-γ (page 2, col. 1, para. 2; Fig. 2F and 2G).
Friedrich teaches that JAK1 deficiencies melanoma and leukemia cells protect tumor cells from anti-tumor IFN-γ activity, which results in resistance to T-cell responses (page 1695, the bridging paragraph of cols. 1-2).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a cancer (e.g. melanoma) resistant to cytotoxic T cell in a subject a therapeutically effective amount of an activating agent e.g. anti-MICA α3 antibody (7C6), as taught by Ferrari de Andrade, Cerwenka, Wucherpfennig and Kato, and to treat a cancer resistant to IFN gamma and to add a step to identify cancer (e.g. melanoma) with a Jak1 mutation, because the activity of 7C6 is independent of IFN-γ as taught by Ferrari de Andrade and Jak1 mutation in a melanoma would protect tumor cells from IFN-γ activity and be resistant to T-cell response, as taught by Friedrich. Since Ferrari de Andrade and Cerwenka teach that 7C6 based treatment is independent CD8 T cells, and independent IFN-γ, thus, one of ordinary skilled in the art would have had reasonable expectation that the method of claim 1 would be effective to treat melanoma with a Jak1 mutation and to add a step to identify subjects with the melanoma. The motivation would have been to identify a suitable patient population for the treatment.
Response to Arguments
For the rejection under 35 U.S.C. 103, Applicant argues:
Therefore, the scope of claim 1 has been reduced with respect to the antibodies and the HDAC inhibitors. New claims 28 and 29 additionally limit claim 1 with respect to the HDAC inhibitor. New claim 30 limits claim 1 with respect to the cancer that is treated.
Applicant’s arguments have been fully considered but they are not persuasive. The amended claims are still very broad, encompass a broad genus of non-selective pan-HDAC inhibitors and/or a broad genus cancers. In addition, by reciting “a heavy chain CDR sequence SEQ ID NOs: 1-3 and a light chain CDR sequence SEQ ID NOs: 4-6”, given Broadest Reasonable Interpretation (BRI), the claims encompass antibodies comprising partial CDRs of antibody 7C6 which can have different binding property and therapeutic activity compared with antibody 7C6. However, all the data was based on a specific combination: full length antibody 7C6 and Panobinostat.
Applicant further argues:
Regarding applicant's previous arguments that the claimed method produced unexpected results, the Office alleged in the August 28 action that synergistic results of the 7C6 antibody and panobinostat were not shown for MHC-I deficient melanoma metastases (e.g., the B2M-KO A375 melanoma cells; see page 15 of the Office action). Applicant points out that, for A375 metastases, synergy of 7C6 and panobinostat is demonstrated in Fig. 7F (left panel). For B2MKO-375 cells, paragraph [000310] of the application recognizes that panobinostat did not enhance the effect of 7C6 in the study shown in Fig. 7F (right panel) but stated that NK cell reconstitution was limited in the experimental model used. Applicant notes that if the model system was limited, the significant effect of 7C6 monotherapy in B2M-KO 375 metastases, which was not present for 7C6 monotherapy in A375 metastases, may have limited detection of a synergistic effect with Panobinostat in the combination.
Applicant’s arguments have been fully considered but they are not persuasive. “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 the instant case, as set forth above, the amended claims are still very broad, encompass a broad genus of antibodies (e.g. only one HCDR and one LCDR sequences of 7C6); a broad genus of non-selective pan-HDAC inhibitors; and/or a broad genus of cancers. However, all the disclosed data was based on a specific combination: antibody 7C6 and Panobinostat. No matter what is the reason for that synergistic results of the 7C6 antibody and panobinostat were not shown for the B2M-KO A375 melanoma model (a MHC-I deficient melanoma model), the results of Fig. 7F (left panel and right panel) indicate the synergistic effect of 7C6 and Panobinostat is context-dependent. Thus, the synergistic results may not be applied for all combinations on all cancers encompassed by the claims. For example, the synergistic effect has not been seen in the treatment for MHC-1 deficient melanoma metastases (Fig. 7F and [0302]). In addition, the synergistic effect has not been seen in any cancer which is resistant to anti-PD1/PD-L1 antibodies as claimed (see claim 18). In addition, as set forth above, HDAC inhibitors Panobinostat (pan-HDAC inhibitor) and romidepsin (HDAC I selective inhibitor) have different specificity to HDAC family members, the combination using romidepsin as the HDAC inhibitor may function differently. Accordingly, the data are not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention.
Applicant further argues:
However, the cited reference combinations do not show, and do not appear to suggest with a reasonable expectation of success, that cancers resistant to cytotoxic T cells, like B2M-KO cancers, could be treated with 7C6 antibody and Panobinostat.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Ferrari de Andrade teaches 1) 7C6 increase density of MICA/MICB on the tumor cells; 2) the therapeutic activity of 7C6 is independent of CD8 T cells, or IFN-γ; and 3) 7C6 is functional in T-cell deficient tumor model; Cerwenka teaches 1) cancers develop multiple strategies to escape CD8+ T cell recognition; 2) one major mechanism of tumor escape is the shedding of NKG2D ligands MICA and MICB. Based on the teachings from Ferrari de Andrade and Cerwenka, one of ordinary skilled in the art would have had a reasonable expectation that 7C6 antibody would have therapeutic activity to cancers resistant to cytotoxic T cells (e.g. CD8+ T cell-resistant cancers which read on “cancer resistant to cytotoxic T cells”).
In addition, 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 reach the claimed combination for treating cancer resistant to cytotoxic T cells. 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.
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.
Patent No. 11,421,032
Claims 1, 4, 7, 11, 17-20, and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,421,032 (hereinafter Pat. 032, corresponding to Appl. 16/612,932, of record), in view of Ferrari de Andrade (Ferrari de Andrade et al., Science, 359, 1537-1542, Publication Date: 03/30/2018, cited by IDS of 02/27/2024, of record) and Cerwenka (Cerwenka et al., Science, 359, 1460-1461, Publication Date: 03/30/2018, of record), as evidenced by WO 2018/217688 A1 (Publication Date: 11/29/2018, of record) and Panobinostat_PubChem (downloaded from: Panobinostat | C21H23N3O2 | CID 6918837 - PubChem on March 9, 2026).
The claims of Pat. 032 teach:
1. A monoclonal antibody, or antigen-binding fragment thereof, wherein the monoclonal antibody comprises: a heavy chain with three CDRs comprising amino acid sequences SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; and a light chain with three CDRs comprising amino acid SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. As evidenced by Table 2 of Pat. 032, SEQ ID NOs: 1-6 of Pat. 032 are identical to SEQ ID NOs: 1-6 of the instant application.
2. The monoclonal antibody, or antigen-binding fragment thereof, of claim 1, wherein (a) …, (c) the monoclonal antibody, or antigen-binding fragment thereof, inhibits the shedding of MICA and/or MICB, (d) the monoclonal antibody, or antigen-binding fragment thereof, increases the cell surface density of MICA and/or MICB, optionally wherein the cell is a cancer cell, (e) …, (f) the monoclonal antibody, or antigen-binding fragment thereof, restores immune activation by stress molecules that activate cytotoxic lymphocytes, optionally the cytotoxic lymphocytes are NK cells or macrophages, (g) the monoclonal antibody, or antigen-binding fragment thereof, enhances the tumor immunity mediated by cytotoxic lymphocytes, optionally the cytotoxic lymphocytes are NK cells or macrophages, (h) the monoclonal antibody, or antigen-binding fragment thereof, enhances the tumor immunity through activation of NKG2D receptor and/or CD16 Fc receptor on cytotoxic lymphocytes, optionally the cytotoxic lymphocytes are NK cells or macrophages, (i) the monoclonal antibody, or antigen-binding fragment thereof, specifically binds MICA α3 domain and/or MICB α3 domain, (j) the monoclonal antibody, or antigen-binding fragment thereof, does not interfere with NKG2D binding to MICA and/or MICB, ...
4. A composition comprising at least one monoclonal antibody, or antigen-binding fragment thereof, according to claim 1, and a carrier.
9. A method of treating a subject afflicted with cancer that expresses MICA and/or MICB comprising administering to the subject at least one monoclonal antibody, or antigen-binding fragment thereof, according to claim 1.
10. The method of claim 9, (b) wherein the at least one monoclonal antibody, or antigen-binding fragment thereof, reduces the number of proliferating cells in the cancer and/or reduces the volume or size of a tumor of the cancer, (c) wherein the at least one monoclonal antibody, or antigen-binding fragment thereof, reduces the metastases of cancer cells, (e) wherein the at least one monoclonal antibody, or antigen-binding fragment thereof, is administered in a pharmaceutically acceptable formulation, (f) further comprising administering to the subject a therapeutic agent or regimen for treating cancer, (g) further comprising administering to the subject an additional therapy selected from the group consisting of immunotherapy, checkpoint blockade, cancer vaccines, chimeric antigen receptors, chemotherapy, radiation, target therapy, and surgery, (h) wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, uterine/cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, …, or recurrent cancer.
11. A method of treating a subject afflicted with cancer that expresses MICA and/or MICB comprising administering to the subject at least one monoclonal antibody, or antigen-binding fragment thereof, according to claim 1, in combination with an agent that enhances MICA and/or MICB expression.
12. The method of claim 11, (b) wherein the agent is selected from the group consisting of radiation therapy, antibody-drug conjugate, HDAC inhibitor, proteasome inhibitor, chemotherapy, alkylating agent, and topoisomerase inhibitor, optionally (i) wherein the HDAC inhibitor can be Panobinostat.
13. An immunoglobulin comprising a variable heavy chain amino acid sequence consisting of SEQ ID NO: 7, and variable light chain amino acid sequence consisting of SEQ ID NO: 8.
As evidenced by Sequence listing of the disclosure of Pat. 032, SEQ ID NO: 7 corresponds to heavy chain of mAb 7C6, SEQ ID NO: 8 corresponds to light chain of mAb 7C6. Thus, taken together the claims of Pat. 032 teach antibody specific to alpha-3 domain of MICA e.g. 7C6 which can inhibits the shedding of MICA and/or MICB, increases the cell surface density of MICA and/or MICB, activate cytotoxic lymphocytes, enhances the tumor immunity through activation of NKG2D receptor and/or CD16 Fc receptor on cytotoxic lymphocytes, and a combination of the antibody with additional anti-cancer therapeutic agent, e.g. Panobinostat, and a method of treating cancers (e.g. skin cancer) comprising administering compositions comprising the antibody. However, the claims of Pat. 032 do not teach a method of treating cancer wherein the cancer in resistant to cytotoxic T cells.
Ferrari de Andrade and Cerwenka teach as set forth above, for example, antibodies specifically bind to epitope on the MICA and MICB α3 domain would inhibit MICA and MICB shedding and not interfere with NKG2D binding; antibody specific to MICA alpha-3 domain can strongly inhibited MICA shedding by a diverse panel of human tumor cell lines (including melanoma) and can be used to treat cancers resistant to cytotoxic T cells. In addition, Ferrari de Andrade teaches that 7C6 is effective in two melanoma models: B16F10 and A2058, e.g. in human A2058 melanoma cells induced tumor model, 7C6 antibody significantly reduce metastases (Fig. 4B).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to generate antibody specific to MICA alpha-3 domain (e.g. 7C6) and a pharmaceutical composition comprising the antibody or a combination of the antibody and Panobinostat, as taught by the claims of Pat. 032, and to use the pharmaceutical composition to treat cancers (such as melanoma) and cancers resistant to cytotoxic T cells, as taught by Ferrari de Andrade and Cerwenka, because the antibody specific to MICA alpha-3 domain provides an anti-tumor mechanism independent of CD8+ T cells and IFNγ. One of ordinary skill in the art would have a reasonable expectation that compositions taught by the claims of Pat. 032 would be effective in treating the claimed cancers. The motivation would be to expand applications of the composition and to develop new pharmaceutical composition for cancer treatment.
Regarding claim 28, as evidenced by Panobinostat_Pubchem, Panobinostat is a hydroxamic acid (see § Description).
Claims 16 and 21 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,421,032 (hereinafter Pat. 032, corresponding to Appl. 16/612,932, of record), in view of Ferrari de Andrade (Ferrari de Andrade et al., Science, 359, 1537-1542, Publication Date: 03/30/2018, cited by IDS of 02/27/2024, of record) and Cerwenka (Cerwenka et al., Science, 359, 1460-1461, Publication Date: 03/30/2018, of record), as evidenced by WO 2018/217688 A1 (Publication Date: 11/29/2018, of record) and Panobinostat_PubChem (downloaded from: Panobinostat | C21H23N3O2 | CID 6918837 - PubChem on March 9, 2026), as applied to claims 1, 4, 6, 7, 11 and 17-20 above, and further in view of Friedrich (Friedrich et al., Cancer Immunology, Immunotherapy, 68: 1689-1700, Publication Date: 08/03/2019, of record).
The claims of Pat. 032, Ferrari de Andrade and Cerwenka teach method of claim 1 as set forth above. However, the claims of Pat. 032, Ferrari de Andrade and Cerwenka do not teach wherein the cancer is an MHC class I deficient cancer or a cancer resistant to IFN gamma, or further comprising a step of testing the cancer for a Jak1 mutation and/or a B2m mutation.
Ferrari de Andrade also teaches that the therapeutic activity of 7C6 antibody is independent CD8 T cells, and independent IFN-γ (page 2, col. 1, para. 2; Fig. 2F and 2G).
Friedrich teaches that JAK1 deficiencies melanoma and leukemia cells protect tumor cells from anti-tumor IFN-γ activity, which results in resistance to T-cell responses (page 1695, the bridging paragraph of cols. 1-2).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a cancer (e.g. melanoma) resistant to cytotoxic T cell in a subject a therapeutically effective amount of an activating agent e.g. anti-MICA α3 antibody (e.g. 7C6), as taught by the claims of Pat. 032, Ferrari de Andrade and Cerwenka, to treat an MHC class I deficient cancer or a cancer resistant to IFN gamma, and to add a step to identify cancer (e.g. melanoma) with a Jak1 mutation, because Jak1 mutation in a melanoma would protect tumor cells from IFN-γ activity and be resistant to T-cell response, as taught by Friedrich. Since Ferrari de Andrade and Cerwenka 7C6 based treatment is independent CD8 T cells, and independent IFN-γ, thus, one of ordinary skilled in the art would have had reasonable expectation that 7C6 would be effective to treat melanoma with a Jak1 mutation and to add a step to identify subjects with the melanoma. The motivation would have been to identify a suitable patient population for the treatment.
Response to Arguments
For the Double Patenting rejections, Applicant argues:
Considering the amendments to claim 1 and the above discussions related to the obviousness rejections, applicant contends that the amended claims are not obvious in light of US Patent Nos. 9,402,905, 10,106,611, 10,793,633 or 11,421,032. Applicant respectfully requests reconsideration of the double patenting rejections.
Applicant’s arguments have been fully considered but they are only partially persuasive. In view of the claim amendments, the rejections over US Patent Nos. 9,402,905, 10,106,611, and 10,793,633 are hereby withdrawn. However, the instant claims are still obvious in light of Pat. 11,421,032 as set forth above. Thus, for the reasons set forth above the rejection is maintained.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642