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 .
1. Claims 1-39 as amended on February 14, 2024 are pending and under consideration.
Claim Rejections - 35 USC § 103
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.
2a. Claims 1-3, 5, 6, 8-14, 16-26, and 29-37 are rejected under 35 U.S.C. 103 as being obvious over US 2022/0363761 A1 (Plyte et al. Nov. 17, 2022, filed March 30, 2022), “Plyte-1” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow”.
2b. Claims 1-3, 5, 6, 8-14, 16-26, and 29-37 are rejected under 35 U.S.C. 103 as being obvious over WO 2022/212516 A1 (Plyte et al. Oct. 06, 2022, filed March 30, 2022), “Plyte-2” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow”.
Plyte-1 and Plyte-2 have the same disclosures. Thus, the rejection set forth below applies to both Plyte-1 and Plyte-2. Plyte-1 will be cited in the rejection below, which applies to both Plyte-1 and Plyte-2.
The applied references have a common inventor/applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Plyte-1 teaches bispecific antibodies to PD-1 and LAG-3 for the treatment of cancer in humans. See abstract and ¶¶ 0006-0013.
Plyte-1 teaches the PD-1 heavy chain of SEQ ID NO: 7, which comprises the claimed SEQ ID NOs: 4 and 7-9. See Appendix.
Plyte-1 teaches the LAG-3 heavy chain of SEQ ID NO: 17, which comprises the claimed SEQ ID NOs: 5 and 10-12. See Appendix.
Plyte-1 teaches the PD-1 and LAG-3 common light chain of SEQ ID NO: 24 which comprises SEQ ID NOs: 6 and 13-15. See Appendix.
Plyte-1 teaches a bispecific antibody to PD-1 and LAG-3 comprising SEQ ID NOS: 7, 17 and 24. See ¶¶ 0308-0311.
Plyte-1 teaches a bispecific antibody to PD-1 and LAG-3 comprising SEQ ID NOS: 7, 17 and 24 (antibody 4) inhibits the growth of MDA-MB-231 human breast tumors in mice when administered at 10 mg/kg. See Example 8, ¶ 0369 and Fig. 8B.
Plyte-1 teaches all bispecific PD-1 and LAG-3 antibodies demonstrated better efficacy than the monospecific antibodies as single agent or as a combination. See ¶¶ 0369 and 0420 and Figs. 8A and 8B.
Plyte-1 teaches as set forth above, but does not teach treating the specifically claimed cancers in humans with bispecific PD-1 and LAG-3 antibodies, intravenous administration or the specific doses claimed.
Morrow teaches immune checkpoint inhibitors targeting PD-1/PD-L1 have demonstrated remarkable evidence of antitumor activity. See p. 1-3rd paragraph.
Morrow teaches LAG-3 is a key mediatory of resistance to immune checkpoint inhibitors and co-administration of LAG-3 antibodies can contribute to overcoming that resistance in PD-1/PD-L1 refractory cancer. See all of pp. 3-4.
Morrow teaches dosage regimes for administration for bispecific PD-L1 and LAG-3 antibodies to treat cancers and metastatic cancers in humans. See abstract and p. 4-4th paragraph, p. 34-last paragraph and p. 35-1st paragraph.
Morrow teaches the cancers can be treated with a PD-1 antibody. See p. 30-1st and 2nd paragraphs.
Morrow teaches intravenous administration . See p. 13-last paragraph and p. 35-2nd and 3rd paragraph
Morrow teaches administering various doses of the bispecific PD-L1 and LAG-3 antibodies including at least 100 mg, at least 300 mg, at least 400 mg, at least 900 mg, or at least 1800 mg. See pp. 10-11.
Morrow teaches treating melanoma, head and neck cancer (such as squamous cell carcinoma of the head and neck (SCCHN)), oral cavity, oropharynx, larynx or hypopharynx that is relapsed or metastatic, which can be HPV positive. See pp. 31-3rd paragraph, p. 32 and paragraph bridging pp. 33-34.
Morrow teaches the PD-L1 expression is increased in tumors. See paragraph bridging pp. 2-3 and p. 30-last paragraph.
Morrow teaches treating non-small cell lung cancer (NSCLC). See p. 33-1st and last paragraphs and p. 34-2nd paragraph.
Morrow teaches treating small cell lung cancer. See p. 31-3rd and last paragraph and p. 33-1st paragraph. .
Morrow teaches treating Hodgkin's lymphoma, non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma. See p. 31-3rd paragraph.
Morrow teaches treating mesothelioma. See p. 31-3rd paragraph, p. 32-2nd paragraph, p.68-Table 7 and p. 71-3rd paragraph.
Morrow teaches treating triple negative breast cancer. See p. 33-1st and 2nd paragraph and p. 58-2nd paragraph.
Morrow teaches treating nasopharyngeal cancer, esophageal carcinoma, hepatocellular carcinoma, renal cell carcinoma and bladder urothelial carcinoma. See p. 31-3rd paragraph, paragraph bridging pp. 31-32 and p. 32-2nd and 3rd paragraphs.
Morrow teaches treating clear cell ovarian cancer and MSI-H endometrial cancer. See p. 33-2nd paragraph.
Morrow teaches that the ovarian cancer may be platinum refractory and may have been previously treated with anti-PD-L1 therapy. See p. 34-2nd paragraph.
Morrow teaches that the small cell and non-small lung cancer (SCLC or NSCLC) may have already been treated with, and progressed on, prior anti-PD-1 or anti-PD-L 1 therapy. See p. 34-2nd paragraph.
Morrow teaches treating refractory cancers. See p. 14-2nd paragraph and p. 26-2nd paragraph.
Morrow teaches weekly administration of the bispecific antibody or administration in three week cycles. See pp. 8-10 and p. 13-2nd to last line.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Plyte-1 and Morrow and treat cancer in its various forms and stages as disclosed by Morrow with the bispecific antibody to PD-1 and LAG-3 of Plyte-1 because Plyte-1 teaches treating cancer with the bispecific antibody, Plyte-1 teaches all bispecific PD-1 and LAG-3 antibodies demonstrated better efficacy than the monospecific antibodies as single agent or as a combination and Morrow teaches that a bispecific antibody targeting PD-L1 (the ligand for PD-1) and LAG-3 can be used to treat these various cancers, LAG-3 is a key mediatory of resistance to immune checkpoint inhibitors and co-administration of LAG-3 antibodies can contribute to overcoming that resistance in PD-1/PD-L1 refractory cancer. One would have been motivated to use the bispecific antibody to PD-1 and LAG-3 of Plyte-1 to treat cancer in its various forms and stages to reduce resistance to the therapeutic antibody treatment. One of skill in the would have been motivated to adjust the dose and timing of treatment with the bispecific antibody to PD-1 and LAG-3 of Plyte-1 to optimize the response to treatment.
3a. Claim(s) 1-3, 5-14, 16-26, and 29-37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0363761 A1 (Plyte et al. Nov. 17, 2022, filed March 30, 2022), “Plyte-1” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US 2021/0338813 A1 (Maurer et al. Nov. 4, 2021), “Maurer”.
3b. Claim(s) 1-3, 5-14, 16-26, and 29-37 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/212516 A1 (Plyte et al. Oct. 06, 2022, filed March 30, 2022), “Plyte-2” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US 2021/0338813 A1 (Maurer et al. Nov. 4, 2021), “Maurer”.
Plyte-1 and Plyte-2 have the same disclosures. Thus, the rejection set forth below applies to both Plyte-1 and Plyte-2. Plyte-1 will be cited in the rejection below, which applies to both Plyte-1 and Plyte-2.
Plyte-1 teaches as set forth above, but does not teach treating an unresectable melanoma or a melanoma with a V600-BRAF mutation.
Maurer teaches treating a previously untreated metastatic or unresectable melanoma . with a combination of a LAG-3 inhibitor and a PD-1 pathway inhibitor, including a bispecific antibody that binds both PD-1 and LAG-3.. See abstract and ¶¶ 0002-0013 and 0167.
Maurer teaches the patient's tumor cells contain a BRAF V600 mutation. See ¶¶ 0013, 0033, 0105 and 0108 and claims 1-4 and 28.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Plyte-1, Morrow and Maurer treat melanoma in its various forms as disclosed by Morrow and Maurer with the bispecific antibody to PD-1 and LAG-3 of Plyte-1 because Plyte-1 teaches treating cancer, Morrow teaches treating melanoma and Maurer teaches treating metastatic or unresectable melanoma with a BRAF V600. with a combination of a LAG-3 inhibitor and a PD-1 pathway inhibitor, including a bispecific antibody that binds both PD-1 and LAG-3. Given that Morrow and Maurer teach that melanoma can be treated with a PD-1/PD-L1 pathway inhibitor and LAG-3 inhibitor, one would been motivated to treat melanoma in its various forms with the bispecific antibody to PD-1 and LAG-3 of Plyte-1.
4a. Claim(s) 1-3, 5, 6, 8-14, and 16-37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0363761 A1 (Plyte et al. Nov. 17, 2022, filed March 30, 2022), “Plyte-1” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US2022/0306743 A1 (O’Neil et al. Sep. 29, 2022, filed Mar. 1, 2022), “O’Neil” and in view of EP 3 533 869 A1 (Izutsu et al. Sep. 4, 2019), “Izutsu”.
4b. Claim(s) 1-3, 5, 6, 8-14, and 16-37 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/212516 A1 (Plyte et al. Oct. 06, 2022, filed March 30, 2022), “Plyte-2” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US2022/0306743 A1 (O’Neil et al. Sep. 29, 2022, filed Mar. 1, 2022), “O’Neil” and in view of EP 3 533 869 A1 (Izutsu et al. Sep. 4, 2019), “Izutsu”.
Plyte-1 and Plyte-2 have the same disclosures. Thus, the rejection set forth below applies to both Plyte-1 and Plyte-2. Plyte-1 will be cited in the rejection below, which applies to both Plyte-1 and Plyte-2.
Plyte-1 teaches as set forth above, but does not teach treating a tumor with a DNA polymerase epsilon mutated solid tumor.
O’Neil teaches treating cancer with CTLA4 binding proteins and PD-1 or PD-L1 inhibitors. See abstract and ¶¶ 0003 and 0007.
O’Neil teaches treating cancers like melanoma, non-small cell lung cancer (NSCLC), small-cell lung carcinoma (SCLC), pleural mesothelioma, kidney cancer, liver cancer, and colorectal cancer. See ¶¶ 0031-0033.
O’Neil teaches that the solid cancers, like pancreatic cancer, ovarian cancer, or cancer of the small intestine, melanoma and colorectal cancer, can comprise a mutation in polymerase epsilon (POLE). . See ¶¶ 0172, 0177-0178, 0182, and 0188.
O’Neil teaches treating POLE mutant cancers with high microsatellite instability status (MSI-H). See ¶¶ 0182-0183.
Izutsu teaches one of the patterns of the genetic mutation in cancer is hypermutation {hypermutated cancer). Hypermutated cancer is distinguished from other forms by higher somatic mutation rates than other forms. Izutsu teaches it is known that cancers that exhibit hypermutation characteristics are found in gastric cancer, breast cancer, colorectal cancer, glioblastoma, uterine carcinoma, and the like. See ¶ 0002.
Izutsu teaches P286R and V411L are POLE mutations that cause hypermutation. See ¶¶ 0005.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Plyte-1, Morrow, O’Neil and Izutsu and treat solid tumors with POLE mutations as disclosed by O’Neil and Izutsu with the bispecific antibody to PD-1 and LAG-3 of Plyte-1 because Plyte-1 teaches treating cancer, Morrow teaches treating MSI-H ovarian cancer, and O’Neil teaches treating POLE mutant solid tumor cancers with MSI-H with PD-1 inhibitors and Izutsu teaches P286R and V411L are POLE mutations that cause hypermutation. Given that Morrow and O’Neil teach treating MSI-H cancers with PD-1/PD-L1 and LAG-3 inhibitors and POLE mutants induce MSI-H, one would been motivated to treat solid tumors with POLE mutations with the bispecific antibody to PD-1 and LAG-3 of Plyte-1.
5a. Claim(s) 1-3, 5, 6, 8-26, and 29-37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0363761 A1 (Plyte et al. Nov. 17, 2022, filed March 30, 2022), “Plyte-1” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US 2020/0277378 A1(Sabatos-Peyton Sep. 3, 2020), “Sabatos”
5b. Claim(s) 1-3, 5, 6, 8-26, and 29-37 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/212516 A1 (Plyte et al. Oct. 06, 2022, filed March 30, 2022), “Plyte-2” in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US 2020/0277378 A1 (Sabatos-Peyton Sep. 3, 2020), “Sabatos”
Plyte-1 and Plyte-2 have the same disclosures. Thus, the rejection set forth below applies to both Plyte-1 and Plyte-2. Plyte-1 will be cited in the rejection below, which applies to both Plyte-1 and Plyte-2.
Plyte-1 teaches as set forth above, but does not teach treating a hormone receptor-positive/HER2 negative breast cancer.
Sabatos teaches combination therapies for treating cancer including a combination therapies of three agents which are a PD-1 inhibitor, a LAG-3 inhibitor and (i) an inhibitor of either TGF-beta, TIM-3, C-MET, IL-1b or MEK or (ii) a GITR agonist or (iii) an A2aR antagonist or (iv) a CSF-1/1R binding agent for treating a breast cancer. See abstract and ¶¶ 0011-0015.
Sabatos teaches treating estrogen receptor positive (ER+) and HER2 negative breast cancer. See ¶¶ 0013, 0015, 0982 and 0986.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Plyte-1, Morrow , and Sabatos and treat a hormone receptor-positive/HER2 negative breast cancer with the bispecific antibody to PD-1 and LAG-3 of Plyte-1 because Plyte-1 teaches treating breast cancer, Morrow teaches treating breast cancer (pp. 31-32), and Sabatos teaches treating estrogen receptor positive (ER+) and HER2 negative breast cancer with a combination of a PD-1 inhibitor and a LAG-3 inhibitor. Given that Plyte-1, Morrow , and Sabatos all teach treating breast cancer with a PD-1 inhibitor and a LAG-3 inhibitor, particularly a bispecific antibody to PD-1 and LAG-3 and ER+ and HER2 negative breast cancer, one would been motivated to treat LAG-3 and ER+ and HER2 negative breast cancer with the bispecific antibody to PD-1 and LAG-3 of Plyte-1.
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.
6. Claims 1-3, 5, 6, 8-14, 16-26, and 29-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, 28, 29, 45-48, 50, 57, 58, 63 and 64 of co-pending Application No. 17/708,901 (published as US 2022/0363761 A1) in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow”.
The ‘901 claims are drawn to:
15. A multispecific binding moiety comprising an anti-human PD-1 binding domain and an anti-human LAG-3 binding domain, wherein the anti-human PD-1 binding domain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) of a heavy chain variable region comprising the amino acid sequence selected from any one of SEQ ID NOS: 1-8, and wherein the anti-human PD-1 binding domain comprises a light chain variable region, wherein the light chain variable region comprises a light chain CDR1 (LCDR1) from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 (LCDR2 ) from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24, and a light chain CDR3 (LCDR3) from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24
21. The multispecific binding moiety according to claim 15, wherein the anti-human LAG-3 binding domain comprises . . . g) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 17, and wherein the anti-human LAG-3 binding domain comprises a light chain variable region, wherein the light chain variable region comprises a light chain CDR1 (LCDR1) from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 (LCDR2 ) from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24, and a light chain CDR3 (LCDR3) from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.
22. The multispecific binding moiety according to claim 21, wherein the anti-human LAG-3 binding domain comprises a heavy chain variable region comprising an amino acid sequence as set forth in any one of SEQ ID NOS: 11-17, or having at least 90% sequence identity thereto.
57. A multispecific binding moiety comprising:
- a PD-1 binding domain comprising heavy chain CDRl (HCDRl ), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 6, and - a LAG-3 binding domain comprising heavy chain CDRl (HCDRl), heavy chain CDR2
(HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 14, wherein the PD-1 binding domain and LAG-3 binding domain comprise light chain
CDRl (LCDRl) comprising the amino acid sequence as set forth in SEQ ID NO: 60, light chain CDR2 (LCDR2) comprising the amino acid sequence as set forth in SEQ ID NO: 61, and light chain CDR3 (LCDR3) comprising the amino acid sequence as set forth in SEQ ID NO: 62.
58. (previously presented) The multispecific binding moiety according to claim 57, comprising: - a PD-1 binding domain comprising a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 6, and - a LAG-3 binding domain comprising a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 14, wherein the PD-1 binding domain and LAG-3 binding domain comprise a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 24.
63. A multispecific binding moiety comprising:- a PD-1 binding domain comprising heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 7, and
- a LAG-3 binding domain comprising heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 17,
wherein the PD-1 binding domain and LAG-3 binding domain comprise light chain CDR1 (LCDR1) comprising the amino acid sequence as set forth in SEQ ID NO: 60, light chain CDR2 (LCDR2) comprising the amino acid sequence as set forth in SEQ ID NO: 61, and light chain CDR3 (LCDR3) comprising the amino acid sequence as set forth in SEQ ID NO: 62.
64. The multispecific binding moiety according to claim 63, comprising: - a PD-1 binding domain comprising a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 7, and - a LAG-3 binding domain comprising a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 17, wherein the PD-1 binding domain and LAG-3 binding domain comprise a light chain 30 variable region comprising the amino acid sequence as set forth in SEQ ID NO: 24.
The ‘901 PD-1 heavy chain of SEQ ID NO: 6 comprises the claimed SEQ ID NOs: 7-9. See Appendix.
The ‘901 PD-1 heavy chain of SEQ ID NO: 7 comprises the claimed SEQ ID NOs: 4 and 7-9. See Appendix.
The ‘901 the LAG-3 heavy chain of SEQ ID NO: 14 comprises the claimed SEQ ID NOs: 10-12. See Appendix.
The ‘901 the LAG-3 heavy chain of SEQ ID NO: 17 comprises the claimed SEQ ID NOs: 5 and 10-12. See Appendix.
The ‘901 PD-1 and LAG-3 common light chain of SEQ ID NO: 24 comprises SEQ ID NOs: 6 and 13-15. See Appendix.
The ‘901 claims teach as set forth above, but do not teach treating cancer with the bispecific anti-PD1 and anti-LAG-3 antibodies.
Morrow teaches as set forth above
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘901 claims and Morrow and treat cancer in its various forms and stages as disclosed by Morrow with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims because Morrow teaches that a bispecific antibody targeting PD-L1 (the ligand for PD-1) and LAG-3 can be used to treat these various cancers, LAG-3 is a key mediatory of resistance to immune checkpoint inhibitors and co-administration of LAG-3 antibodies can contribute to overcoming that resistance in PD-1/PD-L1 refractory cancer. One would have been motivated to use the bispecific antibody to PD-1 and LAG- of the ‘901 claims to treat cancer in its various forms to reduce resistance to the therapeutic antibody treatment. One of skill in the would have been motivated to adjust the dose and timing of treatment with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims to optimize the response to treatment.
This is a provisional nonstatutory double patenting rejection.
7. Claims 1-3, 5-14, 16-26, and 29-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, 28, 29, 45-48, 50, 57, 58, 63 and 64 of co-pending Application No. 17/708,901 (published as US 2022/0363761 A1) in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US 2021/0338813 A1 (Maurer et al. Nov. 4, 2021), “Maurer”.
The ‘901 claims and Morrow teach as set forth above, but do not teach treating an unresectable melanoma or a melanoma with a V600-BRAF mutation.
Maurer teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘901 claims, Morrow and Maurer treat melanoma in its various forms as disclosed by Morrow and Maurer with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims because Morrow teaches treating melanoma and Maurer teaches treating metastatic or unresectable melanoma with a BRAF V600. with a combination of a LAG-3 inhibitor and a PD-1 pathway inhibitor, including a bispecific antibody that binds both PD-1 and LAG-3. Given that Morrow and Maurer teach that melanoma can be treated with a PD-1/PD-L1 pathway inhibitor and LAG-3 inhibitor, one would been motivated to treat melanoma in its various forms with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims.
This is a provisional nonstatutory double patenting rejection.
8. Claims 1-3, 5, 6, 8-14, and 16-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, 28, 29, 45-48, 50, 57, 58, 63 and 64 of co-pending Application No. 17/708,901 (published as US 2022/0363761 A1) in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US2022/0306743 A1 (O’Neil et al. Sep. 29, 2022, filed Mar. 1, 2022), “O’Neil” and in view of EP 3 533 869 A1 (Izutsu et al. Sep. 4, 2019), “Izutsu”.
The ‘901 claims and Morrow teach as set forth above, but do not teach treating a tumor with a DNA polymerase epsilon mutated solid tumor.
O’Neil and Izutsu as set forth above
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘901 claims, Morrow , O’Neil and Izutsu and treat solid tumors with POLE mutations as disclosed by O’Neil and Izutsu with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims because Morrow teaches treating MSI-H ovarian cancer, O’Neil teaches treating POLE mutant solid tumor cancers with MSI-H with PD-1 inhibitors and Izutsu teaches P286R and V411L are POLE mutations that cause hypermutation. Given that Morrow and O’Neil teach treating MSI-H cancers with PD-1/PD-L1 and LAG-3 inhibitors and POLE mutants induce MSI-H, one would been motivated to treat solid tumors with POLE mutations with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims.
This is a provisional nonstatutory double patenting rejection.
9. Claims 1-3, 5, 6, 8-26, and 29-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, 28, 29, 45-48, 50, 57, 58, 63 and 64 of co-pending Application No. 17/708,901 (published as US 2022/0363761 A1) in view of WO 2020/229626 A1 (Morrow, M et al. Nov. 19, 2020), “Morrow” as applied to claims 1-3, 5, 6, 8-14, 16-26, and 29-37 above, and further in view of US 2020/0277378 A1(Sabatos-Peyton Sep. 3, 2020), “Sabatos”
The ‘901 claims and Morrow teach as set forth above, but do not teach treating a hormone receptor-positive/HER2 negative breast cancer.
Sabatos teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘901 claims, Morrow , and Sabatos and treat a hormone receptor-positive/HER2 negative breast cancer with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims because Sabatos teaches treating estrogen receptor positive (ER+) and HER2 negative breast cancer with a combination of a PD-1 inhibitor and a LAG-3 inhibitor. Given that Morrow and Sabatos teach treating breast cancer with a PD-1 inhibitor and a LAG-3 inhibitor, particularly bispecific antibody to PD-1 and LAG-3 and ER+ and HER2 negative breast cancer, one would been motivated to treat LAG-3 and ER+ and HER2 negative breast cancer with the bispecific antibody to PD-1 and LAG-3 of the ‘901 claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
10. Claims 1-3 and 5-37 are rejected. Claims 4, 38 and 39 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
11. No claims allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Greg Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment of SEQ ID NOs: 7, 8, 9 with SEQ ID NO: 7 of Plyte
Sequence 7, US/17708901
Publication No. US20220363761A1
GENERAL INFORMATION
APPLICANT: Merus N.V.
TITLE OF INVENTION: MULTISPECIFIC BINDING MOIETIES COMPRISING NOVEL PD-1 BINDING
TITLE OF INVENTION: DOMAINS
FILE REFERENCE: P129097PC00
CURRENT APPLICATION NUMBER: US/17/708,901
CURRENT FILING DATE: 2022-03-30
PRIOR APPLICATION NUMBER: NL 2027893
PRIOR FILING DATE: 2021-03-31
NUMBER OF SEQ ID NOS: 109
SEQ ID NO 7
LENGTH: 121
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Heavy chain variable region
Query Match 88.0%; Score 180.4; Length 121;
Best Local Similarity 42.5%;
Matches 34; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 YHFWS--------------YIVYSGSYNVNPSLKT------------------------- 21
||||| ||||||||||||||||
Db 31 YHFWSWIRQPPGRGLEWIGYIVYSGSYNVNPSLKTRVTMSVDTSKNQFSLNLRSVTAADT 90
Qy 22 -------GGYTGYGGDWFDP 34
|||||||||||||
Db 91 AVYYCARGGYTGYGGDWFDP 110
Alignment of SEQ ID NOs: 7, 8, 9 with SEQ ID NO: 6 of Plyte
Sequence 6, US/17708901
Publication No. US20220363761A1
GENERAL INFORMATION
APPLICANT: Merus N.V.
TITLE OF INVENTION: MULTISPECIFIC BINDING MOIETIES COMPRISING NOVEL PD-1 BINDING
TITLE OF INVENTION: DOMAINS
FILE REFERENCE: P129097PC00
CURRENT APPLICATION NUMBER: US/17/708,901
CURRENT FILING DATE: 2022-03-30
PRIOR APPLICATION NUMBER: NL 2027893
PRIOR FILING DATE: 2021-03-31
NUMBER OF SEQ ID NOS: 109
SEQ ID NO 6
LENGTH: 121
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Heavy chain variable region
Query Match 88.0%; Score 180.4; Length 121;
Best Local Similarity 42.5%;
Matches 34; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 YHFWS--------------YIVYSGSYNVNPSLKT------------------------- 21
||||| ||||||||||||||||
Db 31 YHFWSWIRQPPGRGLEWIGYIVYSGSYNVNPSLKTRVTMSVDTSKNQFSLNLRSVTAADT 90
Qy 22 -------GGYTGYGGDWFDP 34
|||||||||||||
Db 91 AVYYCARGGYTGYGGDWFDP 110
Alignment of SEQ ID NO: 4 with SEQ ID NO: 7 of Plyte
Sequence 7, US/17708901
Publication No. US20220363761A1
GENERAL INFORMATION
APPLICANT: Merus N.V.
TITLE OF INVENTION: MULTISPECIFIC BINDING MOIETIES COMPRISING NOVEL PD-1 BINDING
TITLE OF INVENTION: DOMAINS
FILE REFERENCE: P129097PC00
CURRENT APPLICATION NUMBER: US/17/708,901
CURRENT FILING DATE: 2022-03-30
PRIOR APPLICATION NUMBER: NL 2027893
PRIOR FILING DATE: 2021-03-31
NUMBER OF SEQ ID NOS: 109
SEQ ID NO 7
LENGTH: 121
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Heavy chain variable region
Query Match 100.0%; Score 657; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSETLSLTCTVSEGSIGYHFWSWIRQPPGRGLEWIGYIVYSGSYNVN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCTVSEGSIGYHFWSWIRQPPGRGLEWIGYIVYSGSYNVN 60
Qy 61 PSLKTRVTMSVDTSKNQFSLNLRSVTAADTAVYYCARGGYTGYGGDWFDPWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PSLKTRVTMSVDTSKNQFSLNLRSVTAADTAVYYCARGGYTGYGGDWFDPWGQGTLVTVS 120
Qy 121 S 121
|
Db 121 S 121
Alignment of SEQ ID NOs: 10, 11, 12 with SEQ ID NO: 17 of Plyte
Sequence 17, US/17708901
Publication No. US20220363761A1
GENERAL INFORMATION
APPLICANT: Merus N.V.
TITLE OF INVENTION: MULTISPECIFIC BINDING MOIETIES COMPRISING NOVEL PD-1 BINDING
TITLE OF INVENTION: DOMAINS
FILE REFERENCE: P129097PC00
CURRENT APPLICATION NUMBER: US/17/708,901
CURRENT FILING DATE: 2022-03-30
PRIOR APPLICATION NUMBER: NL 2027893
PRIOR FILING DATE: 2021-03-31
NUMBER OF SEQ ID NOS: 109
SEQ ID NO 17
LENGTH: 119
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Heavy chain variable region
Query Match 87.1%; Score 166.4; Length 119;
Best Local Similarity 41.0%;
Matches 32; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 TNALN--------------WINTHTGNPTYAQGFIG------------------------ 22
||||| |||||||||||||||||
Db 31 TNALNWVRQAPGQGLEWMGWINTHTGNPTYAQGFIGRFVFSLDTSVSTAYLQIRSLKAED 90
Qy 23 --------EPNWGVYFDY 32
||||||||||
Db 91 TAVYYCAREPNWGVYFDY 108
Alignment of SEQ ID NOs: 10, 11, 12 with SEQ ID NO: 14 of Plyte
ALIGNMENT:
Query Match 87.1%; Score 166.4; Length 119;
Best Local Similarity 41.0%;
Matches 32; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 TNALN--------------WINTHTGNPTYAQGFIG------------------------ 22
||||| |||||||||||||||||
Db 31 TNALNWVRQAPGQGLEWMGWINTHTGNPTYAQGFIGRFVFSLDTSVSTAYLQIRSLKAED 90
Qy 23 --------EPNWGVYFDY 32
||||||||||
Db 91 TAVYYCAREPNWGVYFDY 108
Alignment of SEQ ID NO: 5 with SEQ ID NO: 17 of Plyte
Sequence 17, US/17708901
Publication No. US20220363761A1
GENERAL INFORMATION
APPLICANT: Merus N.V.
TITLE OF INVENTION: MULTISPECIFIC BINDING MOIETIES COMPRISING NOVEL PD-1 BINDING
TITLE OF INVENTION: DOMAINS
FILE REFERENCE: P129097PC00
CURRENT APPLICATION NUMBER: US/17/708,901
CURRENT FILING DATE: 2022-03-30
PRIOR APPLICATION NUMBER: NL 2027893
PRIOR FILING DATE: 2021-03-31
NUMBER OF SEQ ID NOS: 109
SEQ ID NO 17
LENGTH: 119
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Heavy chain variable region
Query Match 100.0%; Score 641; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTTNALNWVRQAPGQGLEWMGWINTHTGNPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTTNALNWVRQAPGQGLEWMGWINTHTGNPTY 60
Qy 61 AQGFIGRFVFSLDTSVSTAYLQIRSLKAEDTAVYYCAREPNWGVYFDYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQGFIGRFVFSLDTSVSTAYLQIRSLKAEDTAVYYCAREPNWGVYFDYWGQGTLVTVSS 119
Alignment of SEQ ID NOs: 13, 14, 15 with SEQ ID NO: 24 of Plyte
ALIGNMENT:
Query Match 80.9%; Score 104.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RASQSISSYLN---------------AASSLQS--------------------------- 18
||||||||||| |||||||
Db 24 RASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDF 83
Qy 19 -----QQSYSTPPT 27
|||||||||
Db 84 ATYYCQQSYSTPPT 97
Alignment of SEQ ID NO: 6 with SEQ ID NO: 24 of Plyte
ALIGNMENT:
Query Match 100.0%; Score 549; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK 107