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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/08/2025 has been entered.
Claims 42, 44-51, and 61 are pending.
Claims 42, 44-51, and 61 are under examination on the merits.
Rejections Withdrawn
Nonstatutory Double Patenting
The rejection of claim 50 on the ground of nonstatutory double patenting as being unpatentable over 1, 2, 4, and 5 of U.S. App. No. 17/365,293 (issued as RE50391 on 04/22/2025) in view of Ebens et al. (US PG PUB 2008/0050310, publication date: 02/28/2008), as applied to claims 42-44, 49, 51, and 61, and further in view of Keating (Targ. Oncol., 10: 141-151, Feb 2015) is withdrawn.
Rejections Maintained
35 U.S.C. 103
The rejections of record under 35 U.S.C. 103 have been maintained.
Nonstatutory Double Patenting
The rejection of claims 42, 44, and 49 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 5 of U.S. App. No. 17/365,293 (issued as RE50391 on 04/22/2025) in view of Ebens et al. (US PG PUB 2008/00503 10, publication date: 02/28/2008) is maintained.
The rejection of claims 45-48 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 5 of U.S. App. No. 17/365,293 (issued as RE50391 on 04/22/2025) in view of Ebens et al. (US PG PUB 2008/0050310, publication date: 02/28/2008), as applied to claims 42, 44, and 49, and further in view of Kipps et al. (US PG PUB 2015/0232569, publication date: 08/20/2015) is maintained.
Response to Arguments
With respect to the rejection of the claims on the ground of nonstatutory double patenting over the claims of conflicting U.S. App. No. 17/365,293, in Applicant Arguments, dated 09/08/2025, Applicant asserts that “Ebens is directed to immunoconjugates comprising an anti-CD22 antibody covalently bound to a ‘cytotoxic agent’ payload. Said cytotoxic agent payload can be selected from ‘a toxin, a therapeutic agent, a drug moiety, an antibiotic, a radioactive isotope, and a nucleolytic enzyme.’ (Claim 13 of the ‘293 application). Ebens neither teaches nor suggests using: (a) the specific immunoconjugate that is recited in the instant claims for (b) treating ROR-1 expressing cancers. Ebens only teaches the use of unrelated immunoconjugates for treating CD22 expressing cancers, and while MMAE is mentioned in laundry list of cytotoxic agents, Ebens does not motivate the POSITA to choose MMAE over many of the other cytotoxic agents that are generically and specifically disclosed in the ‘293 application.”
These arguments have been fully considered but are not deemed persuasive, because the teachings of Ebens et al. provide ample motivation to prepare an immunoconjugate comprising MMAE as a cytotoxic payload. For example, at [0134] - [0136], Ebens et al. teach that “[i]n some embodiments, the immunoconjugate comprises an antibody of the invention conjugated to dolastatins or dolostatin peptidic analogs and derivatives, the auristatins (U.S. Pat. Nos. 5,635,483; 5,780,588)… An exemplary auristatin embodiment is MMAE…” At [0933] - [0934], Ebens et al. teach that anti-CD22/MMAE drug conjugates showed potent anti-tumor activity in murine xenograft models. Additionally at Figure 11, Ebens et al. teach that immunoconjugates may be prepared by conjugating an anti-cancer antibody to MMAE using a linker that comprises VC and PAB moieties. Furthermore at [0641] - [0642], Ebens et al. teach that an antibody-drug conjugate (ADC) may be prepared by linking cytotoxic drugs to antibodies via lysine residues. Therefore one of ordinary skill in the art would have been motivated to modify the conflicting immunoconjugate to comprise an MMAE moiety linked to an antibody via a lysine residue, because the resultant immunoconjugate would be useful in delivering MMAE to tumor cells, thereby providing a therapeutic benefit to a cancer patient.
Applicant further asserts that “the combination of the ‘293 application in light of Ebens does not render the instant claims patentably indistinct from those of the ‘293 application. As such, the contribution of Kipps does not remedy the deficiencies of the ‘293 patent in light of Ebens. Kipps does no render the instant claims patentably indistinct from the claims of the ‘293 application by simply teaching that a standalone ROR-1 antibody may be useful for treating lymphoma. A standalone antibody and an immunoconjugate are two completely different chemical entities and because a standalone antibody could be useful to treat cancer, does not suggest that employing an anti-ROR-1 antibody as a component of an antibody-drug conjugate (ADC, also known as an immunoconjugate) would make such an ADC more likely to be useful for treating cancer. Applicant points out that the antibody moiety of an immunoconjugate is used a targeting moiety to target specific cancer cells for treatment by the cytotoxic payload of the immunoconjugate. Unlike a therapeutic antibody, the antibody component of an immunoconjugate is not used to treat the cancer. Ebens only teaches the use of unrelated immunoconjugates for treating CD22 expressing cancers, and adding Kipps to Ebens does not motivate the POSITA to use the specific anti-ROR-1 immunoconjugate of the instant claims with for the treatment of a ROR-1 related malignancy.”
These arguments have been fully considered but are not deemed persuasive. Conflicting claims 1 and 2 recite an ADC comprising the same anti-ROR1 antibody as instantly claimed, wherein said anti-ROR1 antibody is linked to an MMAE moiety via a VC/PAB linker. The primary difference between the conflicting claims and the instant claims is that the instant claims recite conjugating a MMAE/VC/PAB drug/linker moiety to said anti-ROR1 antibody at a lysine residue; however at [0641] - [0642], Ebens et al. teach that an antibody-drug conjugate (ADC) may be prepared by linking cytotoxic drugs to antibodies via lysine residues. One of ordinary skill in the art would appreciate that the conflicting ADC may be modified to recite conjugating a MMAE/VC/PAB drug/linker moiety to said anti-ROR1 antibody at a lysine residue, because there would have been a reasonable expectation that the resultant immunoconjugate is effective in treating cancers that express ROR1.
The Office also does not agree with Applicant’s assertion that “[u]nlike a therapeutic antibody, the antibody component of an immunoconjugate is not used to treat the cancer.” The antibody component of an anti-cancer immunoconjugate primarily serves as a targeting agent that helps to concentrate drugs at the site of a tumor; however this would not deter one of ordinary skill in the art from preparing an immunoconjugate that comprises a targeting antibody that also provides a therapeutic benefit. In fact one of ordinary skill in the art would have been particularly motivated to prepare an immunoconjugate that comprises a targeting antibody that also provides a therapeutic benefit, because such an immunoconjugate would be expected to provide a therapeutic benefit by providing multiple anti-cancer medicaments, specifically, 1) a targeting antibody with an anti-cancer effect and 2) a cytotoxic moiety.
Applicant also asserts that “the combination of the ‘293 application in light of Ebens does not render the instant claims patentably indistinct from those of the ‘293 application. As such, the contribution of Keating does not remedy the deficiencies of the ‘293 application in light of Ebens. Keating does not render claim 50 patentably indistinct from the claims of the ‘293 application by simply teaching that idelalisib can be used to treat lymphoma. Instant claim 50 is directed to the use of a combination of: (a) a specific immunoconjugate having a defined antibody joined to a monomethy1 auristatin E (MMAE) payload using a specifically defined chemical linker, wherein said defined antibody is an anti-ROR1 antibody, and (b) a specific additional therapeutic agent selected from ibrutinib, acalabrutinib, venetoclax, everolimus, sapanisertib, and idelalisib. Ebens only teaches the use of unrelated immunoconjugates for treating CD22 expressing cancers, and adding Keating to Ebens does not motivate the POSITA to use the specific immunoconjugate of the instant claims with idelalisib for the treatment of a ROR-1 related malignancy.”
These arguments have been fully considered but are not deemed persuasive. As indicated above, in view of the teachings of Ebens et al., one of ordinary skill in the art would have been motivated to modify the conflicting claims to recite an immunoconjugate comprising a MMAE/VC/PAB drug/linker moiety conjugated to an anti-ROR1 antibody at a lysine residue.
New Grounds of Rejection
Nonstatutory Double Patenting
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over 1, 2, 4, and 5 of U.S. App. No. 17/365,293 (issued as RE50391 on 04/22/2025) in view of Ebens et al. (US PG PUB 2008/0050310, publication date: 02/28/2008), as applied to claims 42-44, 49, 51, and 61, and further in view of Kipps et al. (US PG PUB 2015/0232569, publication date: 08/20/2015) and Keating (Targ Oncol, 10: 141-151, Feb 2015).
As indicated in the Final Rejection, dated 05/08/2025, based upon the teachings of Ebens et al., one of ordinary skill in the art would have been motivated to modify the immunoconjugate of the conflicting claims to recite the conjugation of MMAE via a lysine residue.
At [0084], Kipps et al. teach that “Applicants have previously discovered expression of full-length ROR1 in numerous cancer cell lines and samples, but not other tissues… The invention therefore provides means to utilize the specificity of ROR-1 expression in cancer cells to treat or prevent cancer.” At [0087], Kipps et al. teach that “[c]ertain embodiments comprise immunopeptides directed against the human ROR1 protein. The immunoglobulin peptides, or antibodies, described herein are shown to bind to the ROR1 protein. The ROR1 binding activity is specific; the observed binding of antibody to ROR1 is not substantially blocked by non-specific reagents. These ROR1 specific antibodies can be used to differentiate between ROR1 cells and normal cells. The ROR1 specific antibodies can also be used in immunotherapy against a ROR1 cancer, to determine the response after therapy for a ROR-1 cancer and to inhibit metastasis.” Kipps et al. teach an anti-ROR1 antibody that comprises the heavy chain variable region of SEQ ID NO: 5 and the light chain variable region of SEQ ID NO: 15. SEQ ID NO(s): 5 and 15 of Kipps et al. share 100% sequence homology with the instant SEQ ID NO(s): 5 and 6, respectively.
At [0123], Kipps et al. teach the “ROR1 antibodies, or antigen-binding fragments, variants, or derivatives thereof of the invention may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions. For example, ROR1-specific antibodies may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides, or toxins.” At [0024], Kipps et al; teach a method for treating lymphoma, a B cell leukemia, AML (acute myeloid lymphoma) or CLL (chronic lymphocytic leukemia), the method comprising administering to the subject an antibody that binds to ROR1.
Keating teaches that idelalisib is a PI3K inhibitor that may be used in the treatment of CLL and NHL, see Abstract. Keating et al. further teach that B-ALL samples were sensitive to idelalisib in vitro, see p. 142, first column. Keating et al. teaches that idelalisib may be used to treat various forms of lymphoma, suchas follicular B cell NHL (Abstract), and small lymphocytic lymphoma (Abstract). At p. 146, first column, Keating teaches that the overall response rate of idelalisib in marginal zone lymphoma patients was 47%. At p. 142, first column, Keating teaches that idelalisib induces apoptosis in diffuse large B cell lymphoma cell lines. Based upon the teachings of Keating, one of ordinary skill in the art would appreciate that idelalisib may be used in the treatment of NHL, CLL, and ALL. One of ordinary skill in the art would appreciate that other forms of B cell lymphomas, including follicular B cell NHL, small lymphocytic lymphoma, marginal zone lymphoma, and diffuse large B cell lymphoma, may also be treated with idelalisib.
Based upon the teachings of Kipps et al. and Keating et al., one of ordinary skill in the art would have been motivated to modify the invention of the conflicting claims and Ebens et al. to comprise the administration of idelalisib, because there would have been a reasonable expectation that the resultant invention is effective in treating various forms of lymphoma, including ROR-1-expressing lymphomas, as taught by Kipps et al.
Claims 50 is therefore prima facie obvious over the conflicting claims in view of Ebens et al. and Keating et al.
Conclusion
No claims are allowed.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642