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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/23/26 has been entered.
Claims 1-7, 9, 13, 15-21, 24, 26, 29, 32, and 42 are pending and are currently under consideration.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 recites “…wherein the IgG1 heavy chains comprise….” There is insufficient antecedent basis for “the IgG1 heavy chains” in the claim.
Claim Rejections - 35 USC § 103
Claims 1, 15, 17-19, 29, and 32 are rejected under 35 U.S.C. 103(a) as being unpatentable over Saha et al (US 2016/0145355 A1; 5/26/16) in view of Larkin et al (NEJM, 2015, 373(1): 23-34), Jin et al (Bispecific Antibodies, 2011, Chapter 9, pages 151-169), and Dimasi et al (JMB, 2009, 393: 672-692).
Saha et al teaches metastatic melanoma cancer patients benefit from being administered the anti-CTLA-4 antibody ipilimumab (which, as evidenced by Table 3 of Engelhardt et al (US 10196445 B1; 2/5/19), comprises HC, LC, and CDRs of instant SEQ ID NOs: 4, 92, 94, and 141-146) and anti-PD-1 antibodies have demonstrated therapeutic benefit when administered to cancer patients ([0004], in particular). Saha et al further teaches nivolumab as an anti-PD-1 antibody ([0083], in particular). Saha et al teaches that a bispecific anti-CTLA-4 and anti-PD-1 antibody would be expected to exhibit efficacy superior to anti-CTLA-4 and anti-PD-1 antibodies administered separately or in combination for treatment of cancer ([0007], in particular). Saha et al further teaches bispecific antibodies are made by expressing vectors comprising nucleic acids encoding the bispecific antibodies in host cells, such as HEK293T cells, and culturing the host cells ([0143]-[0153], in particular). Saha et al further teaches a method of treating cancer comprising administering bispecific antibodies that specifically bind CTLA-4 and PD-1 ([0020], in particular). Saha et al further teaches said method wherein the bispecific antibodies are in a composition comprising pharmaceutically acceptable carrier ([0129], in particular). Saha et al further teaches said method wherein the bispecific antibodies are recombinant “scFv-IgG” or “IgG-scFv” antibodies ([0070], in particular).
Saha et al does not specifically demonstrate generating “scFv-IgG” or “IgG-scFv” bispecific antibodies encompassed by the claims. However, these deficiencies are made up in the teachings of Larkin et al, Jin et al, and Dimasi et al.
Larkin et al teaches metastatic melanoma patients administered a combination of nivolumab plus ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone (Abstract, in particular). Larkin et al further teaches both PD-L1 positive-tumor and PD-L1 negative-tumor metastatic melanoma patients benefit from being administered a combination of nivolumab plus ipilimumab (page 28, in particular).
Jin et al teaches bispecific “scFv-IgG” and “IgG-scFv” antibodies comprise heavy chains and light chains, and two scFv components being connected to either C terminal of the heavy chains (in the case of IgG-scFv) or N terminal of the light chains (in the case of scFv-IgG) (Fig 9.1, in particular).
Dimasi et al illustrates “scFv-IgG” and “IgG-scFv” antibodies wherein the IgG domains have binding specificity to a first antigen and the scFv components have binding specificity to a second antigen (see Bs1Ab and Bs3Ab of Fig. 1, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer to metastatic melanoma patients (including metastatic melanoma patients with cancer cells expressing PD-L1 and those with cancer cells not expressing PD-L1) a pharmaceutical composition comprising “scFv-IgG” and “IgG-scFv” bispecific antibodies specific for PD-L1 and CTLA-4 and a pharmaceutical carrier wherein the bispecific antibodies are generated by performing a combined method comprising culturing host cells (such as such as HEK293T cells of Saha et al) expressing vectors comprising polynucleotides encoding sequences of nivolumab and ipilimumab formatted in “scFv-IgG” and “IgG-scFv” structures such that the IgG domains have binding specificity to a first antigen (either PD-1 or CTLA-4) and the scFv components have binding specificity to a second antigen (either PD-1 or CTLA-4) because Larkin et al teaches metastatic melanoma patients administered a combination of nivolumab (anti-PD-1 antibody) plus ipilimumab (anti-CTLA-4 antibody) resulted in significantly longer progression-free survival than ipilimumab alone, Larkin et al further teaches both PD-L1 positive-tumor and PD-L1 negative-tumor metastatic melanoma patients benefit from being administered a combination of nivolumab plus ipilimumab, Saha et al teaches that a bispecific anti-CTLA-4 and anti-PD-1 antibody would be expected to exhibit efficacy superior to anti-CTLA-4 and anti-PD-1 antibodies administered separately or in combination for treatment of cancer, Saha et al further teaches a method of treating cancer comprising administering bispecific antibodies that specifically bind CTLA-4 and PD-1, Saha et al further teaches said method wherein the bispecific antibodies are in a composition comprising pharmaceutically acceptable carrier, Saha et al further teaches said method wherein the bispecific antibodies are “scFv-IgG” or “IgG-scFv”, and Dimasi et al illustrates “scFv-IgG” and “IgG-scFv” antibodies wherein the IgG domains have binding specificity to a first antigen and the scFv components have binding specificity to a second antigen. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 13, 15, 17-19, 29, and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Saha et al (US 2016/0145355 A1; 5/26/16) in view of Larkin et al (NEJM, 2015, 373(1): 23-34), Jin et al (Bispecific Antibodies, 2011, Chapter 9, pages 151-169), and Dimasi et al (JMB, 2009, 393: 672-692) as applied to claims 1, 15, 17-19, 29, and 32 above, and as further evidenced by He et al (Oncotarget, 2017, 8(40): 67129-67139) and Fessa et al (Seminars in Oncology, 2017, 44: 136-140).
Teachings of Saha et al, Larkin et al, Jin et al, and Dimasi et al are discussed above.
Saha et al, Larkin et al, Jin et al, and Dimasi et al do not specifically teach Kd values of bispecific antibodies of the combined method. However, these deficiencies are made up in the teachings of He et al and Fessa et al.
He et al teaches binding affinity of ipilimumab is 18.2 nM (left column on page 67135, in particular).
Fessa et al teaches binding affinity of nivolumab is 3.06 pM (Table 1).
The binding of affinity of the bispecific antibody of the combined method, generated using ipilimumab and nivolumab sequences, to both CTLA-4 and PD-1 is predictably less than 70 nM because He et al teaches binding affinity of ipilimumab is 18.2 nM and Fessa et al teaches binding affinity of nivolumab is 3.06 pM – both binding affinities that are significantly less than 70 nM.
Allowable Subject Matter
Claims 2-7, 9, and 42 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.
Claims 20, 21, 24, and 26 are allowed.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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