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 .
Claims 1-34 and 36-42 are cancelled.
Claims 53-54 are new.
Claims 35, 43-46, 48, and 50-52 are currently amended.
Claims 35 and 43-54 are pending and under examination on the merits.
Priority
This Application is a CON of 16/075,312 and claims benefit of priority to U.S. Provisional Patent Application Nos. 62/291,769, filed February 5, 2016; 62/335,880, filed May 13, 2016; 62/411,805, filed October 24, 2016; 62/291,772, filed February 5, 2016; 62/291,774, filed February 5, 2016; 62/335,965, filed May 13, 2016; 62/291,776, filed February 5, 2016; 62/335,968, filed May 13, 2016; 62/335,979, filed May 13, 2016; 62/336,030, filed May 13, 2016, 62/353,607, filed June 23, 2016; and 62/291,779, filed February 5, 2016.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/31/2026 has been entered.
Maintained-Claim Interpretation
Applicant has amended the claims to recite a fusion protein rather than a chimeric protein. The instant disclosure never provides a clear and closed definition of a chimeric protein. The instant disclosure never provides a clear and closed definition of a fusion protein. The instant disclosure appears to use the terms ‘chimeric protein’ and ‘fusion protein’ interchangeably (see for example, page 143 of the specification). The prior art supports that the terms ‘chimeric protein’ and ‘fusion protein’ are synonymous (see for example, page 861 of Kobe et al (Acta Crystallogr F Struct Biol Commun. 2015 Jul;71(Pt 7):861-9. doi: 10.1107/S2053230X15011061. Epub 2015 Jun 27) and page 1 of GenScript (Chimeric Proteins, Biology Terms Dictionary, obtained from: https://www.genscript.com/biology-glossary/17457/chimeric-proteins; accessed: 02/20/2026)). No other interpretation appears to be sufficiently supported by the instant disclosure.
Maintained-Claim 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 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 35, 43-49, and 51 remain rejected and newly added claims 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Garcin (High efficiency cell-specific targeting of cytokine activity, retrieved from https://www.nature.com/articles/ncomms4016 (Year: 2014)) in view of Rossi et al (Cancer Res (2010) 70 (19): 7600–7609), Lo (WO2000069913A1), and Chang (US 20150231241 A1).
Regarding claim 35, Garcin teaches a chimeric protein (fusion protein; note the claim interpretation section above) comprising mutant IFNα2 having mutations Q124R, R149A, M148A, L153A (see paragraph 2 of column 1 of page 5 and page 7, column 1), wherein the mutant IFNα2 has reduced binding affinity relative to wildtype (WT) IFNα2 (see the last paragraph of the Introduction on page 2, see also the results section).
Garcin teaches that this decreased binding affinity may be restorable through the use of targeting moieties (see abstract and paragraph 2 of column 1 of page 2), wherein the targeting moieties may be a nanobody (note that the instant specification admits that VHHs are commercially available as nanobodies; see Figure 1a, abstract, and paragraph 1 of column 1 of page 2); In the last paragraph of column 1 of page 7, Garcin teaches that one of the targeting moieties may be a VHH or an scFv (see paragraph 1, column 1, of page 2 and the last paragraph of column 1, page 6).
Garcin teaches that while antibody-meditated accumulation of drugs within specific tissues such as tumor tissues has emerged as an effective strategy, this strategy has shown lackluster results in reducing toxic or off-target effects for the delivery of cytokines because this has traditionally been carried out by fusing nanobodies to WT cytokines (such as wild-type, human IFNα2, see for example paragraph 1 of the Results section on pg. 2, right-hand column). Garcin teaches that augmenting the binding affinity of a cytokine does not maximize its potency and that WT cytokines have a saturation effect (see paragraph 2 of the discussion). To allow for targeted use of cytokines, Garcin teaches a generic approach, that is applicable to a range of cytokines and nanobodies (VHHs)/antibodies/scFvs (see paragraph 3 of the discussion; see also paragraph 4 of the discussion showing this approach also was effective for using IL-1 and TNFα (2 structurally unrelated cytokines) and for leptin). Given that this generic approach for therapeutically using cytokines reduced the systemic effects of IFNα2 and, therefore reduces off target effects of IFNα2 (such as leukopenia, see the last paragraph of the results section and Figures 5a-c), this generic approach is presumed to allow for safe and effective use of mutant IFNα2 for a number of applications as determined by the targeting moiety chosen, where moieties for enhancing an anti-proliferative/anti-tumor, antiviral, and for effecting immune cell/regulatory cell functions are known (see paragraph 4 of the discussion; also note that the antitumor effects of IFNs in mice have been clearly shown, see paragraph 3 of the introduction). This approach may also be used to enhance known combination therapies through enhanced targeting and reduction of systemic/off-target toxicities (see paragraph 4 of the discussion of Garcin).
Garcin does not explicitly teach the sequences of the IFNα2.
However, Lo teaches the sequence for human IFNα2 having 100% homology to instantly claimed SEQ ID NO: 336. Absent a showing to the contrary, because Garcin teaches use of a wildtype human IFNα2, it is presumed that the wild type human IFNα2 would have had the sequence taught by Lo. Because Garcin does not mention another base sequence, it is presumed that it is the wild type human IFNα2 that is modified to bear the 149 mutation (supported further by the comparative language employed throughout Garcin to describe attributes/function of fusions using the wild type human IFNα2 and fusions using the 149-mutation-bearing IFNα2).
The combined references do not teach the inclusion of a first targeting moiety binding PD-L1 and a second targeting moiety binding CD8 or CD20 wherein the first and second targeting moieties are in the format of an scFv or VHH.
However, Chang teaches that use of antagonistic antibodies against immune checkpoint proteins such as PD-L1, are known to be effective in treating cancer (see paragraph 0018). Chang further teaches an embodiment for treating tumors/carcinomas (see abstract) wherein a bispecific antibody (which may comprise an scFv, see Chang’s claims 1 and 10) against a leukocyte expressed antigen (such as CD8 or CD20, see Chang’s claim 17) and/or against a target antigen on a tumor or pathogen (such as CD20 or IFNα, see paragraph 0176) is used (see paragraph 0021) wherein the method comprises administering to a subject: (i) an interferon such as IFNα (see Chang’s claims 1 and 2), (ii) a check point inhibitor antibody, such as an anti-PD-L1 antibody (see Chang’s claims 1, 2, and 5), and a second antibody that may bind CD20 or CD8 (see Chang’s claims 12, 17 and 18) and where the bispecific antibody may be conjugated to a therapeutic cytokine (see Chang’s claim 29). Chang additionally teaches that techniques for producing single domain antibodies (DABs or VHH) are also known in the art and the VHH may have potent antigen-binding capacity and can interact with novel epitopes that are inaccessible to conventional VH-VL pairs (see for example paragraphs 0021-0024, 0098, and 0164). Chang further teaches that the person of ordinary skill in the art will realize that other antibodies that bind to leukocyte antigens as well as other antibodies that bind to other disease-associated antigens are known in the art and any such antibody can be used to make F(ab)2, scFv or other antibody fragments using techniques well known in the art. Such alternative antibodies or fragments thereof may be utilized in the instant methods and compositions (see for example paragraph 0359). Chang also teaches that the antibody fragments (VHH and/or scFv may be chimeric (see for example paragraph 0024).
The combined references do not explicitly teach a construct comprising an IFNα attached to 2 targeting moieties.
However, Rossi et al teach the viability of a construct comprising one or more IFNα2b copies connected to an anti-HLA moiety and an anti-CD20 moiety (see for example the abstract and Figure 1 and its caption), thus teaching the workability of such a fusion having the required format.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Garcin, Lo, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα (where the particular IFNα may be IFNα2; see example 17 of Chang), anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined/administered in combination to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements (a PDL1-targeting moiety, a CD8 targeting moiety, and an IFNα2 such as the mutant IFNα2 made obvious by the combination of, at least by Garcin in view of Lo) known to treat cancer would be predictably combined into a single construct by known means and formats (there being a finite number of ways to connect the three required components into a single fusion protein) to achieve the same purpose of treating cancer. Likewise, one of ordinary skill in the art would have found it obvious per the cited portion of the MPEP to combine the teachings of Garcin, regarding the use of known mutations for a IFNα2, to incorporate the IFNα2 sequence taught by Lo because it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an therapeutic IFNα2 fusion protein with restorable binding affinity for targeting by activity (see MPEP sections 2143(I)(B) and 2144.06 (II)). The cited prior art provides motivation to combine because Chang teaches that these components ( in combination and individually are useful in treating cancer, as discussed above. The artisan would have been further motivated to modify the IFNα2 (taught by Chang and Lo) according to the generic approach for therapeutically using cytokines taught by Garcin to reduce the systemic/off-target effects of IFNα2 through targeted delivery, as discussed above. Rossi et al teach guidance as to how to build a construct comprising an IFNα2 and 2 additional binding moieties, with motivation to build such a construct with a reasonable expectation of success for the workability of the format resulting in a bispecific fusion protein having the recited limitations. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would therefore meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Garcin further teaches that the targeting moieties may be a nanobody (note that the instant specification admits that VHHs are commercially available as nanobodies (see Figure 1a, abstract, and paragraph 1 of column 1 of page 2)). In the last paragraph of column 1 of page 7, Garcin teaches that one of the targeting moieties may be a VHH or an scFv (see paragraph 1, column 1, of page 2 and the last paragraph of column 1, page 6). Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claim 47, Garcin mentions that many cytokines have anti-cancer properties, but that the use of those cytokines had been limited by systemic toxicity which can be solved by the generic approach to immunocytokine targeting taught in Garcin (see paragraphs 1 and 2 of the Introduction).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Garcin, Lo, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα (where the particular IFNα is not specified any IFNα, such as IFNα2 is presumed to function as taught), anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have been further motivated to modify the IFNα2 (taught by Chang and Lo) according to the generic approach for therapeutically using cytokines taught by Garcin to reduce the systemic/off-target effects of IFNα2 through targeted delivery, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 48-49, as discussed above the combination of Garcin, Lo, Rossi et al, and Chang teach the fusion protein of claim 35. Garcin additionally teaches that HEK293T cells (a host cell) were transiently transfected with a plasmid (recombinant nucleic acid) encoding the Nb-IFNα2 fusion (see p.7 right-hand column).
Thee Examiner believes that it would have been obvious to one of ordinary skill in the art that the chimeric fusion construct described above could be encoded in a similar recombinant nucleic acid composition in a host cell since this is a known, predictable manner of generating such constructs.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Garcin, Lo, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that nucleic acids may be put into host cells to produce the protein (see also Garcin’s teaching of the use of HEK293T host cells, transiently transfected with a plasmid (recombinant nucleic acid) encoding the Nb-IFNα2 fusion) as discussed above. The artisan would have been further motivated to produce the protein construct meeting the limitations of instant claim 35 for treatment of cancer as discussed in the rejections above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 53-54, Garcin teaches the format of a nanobody connected to IFN at Fig 1a,
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50
365
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(see for example, page 3). Additionally, Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1,
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293
705
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(see for example, page 7601).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the generic approach of Garcin in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2 of Garcin. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of Garcin technically reads on the arrangement of both of claims 53 and 54 in light of the present claim drafting, whereby the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 50 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Garcin in view of Rossi et al, Lo, and Chang, as applied to claims 35, 43-49, 51, and 53-54 above, in further view of Clement et al (Anti-CD8 antibodies can trigger CD8+ T cell effector function in the absence of TCR engagement and improve peptide-MHCI tetramer staining. J Immunol. 2011 Jul 15;187(2):654-63).
Regarding claims 50 and 52, Garcin, Lo, Rossi et al, and Chang teach as set forth above.
The combined references do not explicitly teach the function of the second targeting moiety with respect to all functions of CD8.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Garcin, Lo, Rossi et al, Chang, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Maintained Except to address newly added claims 53-54-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 ‘780pplication 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.
Claims 35, 43-49, 51, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 47-66 of copending Application No. 19/226,780 (‘780) in view of Chang and Rossi et al (both as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 35, ‘780’s claim 40 recites a chimeric protein comprising a PD-L1 binding agent (which may be a VHH/nanobody; see claims 47-51 of ‘780) and a modified human IFNα2 (defined in the specification of ‘780 (see for example, pages 33 and 110-112) as having SEQ ID NO: 317 or 318, where SEQ ID NO: 317 of ‘780 is identical to instant SEQ ID NO: 336; see MPEP §2111) having one or more mutations conferring improved safety relative to wild-type IFNα2 wherein the one of more mutations to the modified human IFNα2 may include R149A (see 47-49 of ‘780).
‘780 does not teach the further inclusion of a targeting moiety (VHH or scFv) against CD8 or CD20.
However, Chang teaches that use of antagonistic antibodies against immune checkpoint proteins such as PD-L1, are known to be effective in treating cancer (see paragraph 0018). Chang further teaches an embodiment for treating tumors/carcinomas (see abstract) wherein a bispecific antibody (which may comprise an scFv, see Chang’s claims 1 and 10) against a leukocyte expressed antigen (such as CD8 or CD20, see Chang’s claim 17) and/or against a target antigen on a tumor or pathogen (such as CD20 or IFNα, see paragraph 0176) is used (see paragraph 0021) wherein the method comprises administering to a subject: (i) an interferon such as IFNα (see Chang’s claims 1 and 2), (ii) a check point inhibitor antibody, such as an anti-PD-L1 antibody (see Chang’s claims 1, 2, and 5), and a second antibody that may bind CD20 or CD8 (see Chang’s claims 12, 17 and 18) and where the bispecific antibody may be conjugated to a therapeutic cytokine (see Chang’s claim 29).
Note that the combined references do not explicitly teach a construct comprising an IFNα attached to 2 targeting moieties.
However, Rossi et al teach the viability of a construct comprising one or more IFNα2b copies connected to an anti-HLA moiety and an anti-CD20 moiety (see for example the abstract and Figure 1 and its caption).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘780 in view of Chang and Rossi et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Note that the use of the modified IFNα2-anti-PD-L1 VHH construct of ‘780 (where the artisan would have read the generically claimed IFNα2 in light of the specification and therefore would understood the recited IFNα2 to encompass one of either of SEQ ID NO: 317 or 318 of ‘780 (see above)) where the use of either disclosed IFNα2 sequence amounts to the mere use of an equivalent) whereupon adding in a further binding moiety targeting CD8 or CD20 would have been obvious combination for a shared purpose. Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer and would result in a bispecific fusion protein as instantly claimed. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would thereby meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claim 47, ‘780 recites that the anti-PD-L1 antibody may be used to treat cancer (see for example claims 27 and 66 of ‘780; noting that the specification of ‘780 defines cancer cells or tumor cells as including melanoma at page 64 where the artisan, reading the generic recitation of cancer in the claims would look to the specification to determine how cancer was defined (see MPEP §2111)). Therefore, the use of the antibody (as adapted to the format of an scFv or VHH as made obvious by Chang) in combination with other known anti-cancer components as a single construct would have been prima facie obvious combination of components to achieve a shared goal of treating cancer wherein ‘780 guides towards treatment of melanoma.
Regarding claims 48-49, as discussed above the combination of ‘780, Chang, and Rossi et al teach the fusion protein of claim 35.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘780 and Chang because Chang teaches that nucleic acids may be put into host cells to produce the protein. The artisan would have been further motivated to produce the protein construct meeting the limitations of instant claim 35 for treatment of cancer as discussed in the rejections above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 53-54, Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction reproduced above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the fusion protein approach of ‘780 in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 50 and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 47-66 of copending Application No. 19/226,780 (‘780), Chang, and Rossi et al, as applied to claims 35, 43-49, 51, and 53-54 above, in further view of Clement et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 50 and 52, as discussed above, ‘780, Chang, and Rossi et al make obvious the chimeric protein of instant claim 35, but do not explicitly recite/teach the function of the second targeting moiety with respect to all functions of CD8/CD20.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘780, Chang, Rossi et al, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 35, 44-45, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 198, 200, and 210-237 of copending Application No. 17/042,512 (‘512). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 35, 44-45, and 48-49, claim 198 of ‘512 recites an Fc-based chimeric protein comprising a modified human IFNα2 with reduced affinity for IFNαR, wherein the mutation modifying the IFNα2 may be R149A (see claims 198 and 200 of ‘512; noting that SEQ ID NO: 1 of ‘512 is identical to instant SEQ ID NO: 336), wherein the targeting moiety may be a VHH or scFv (see claim 210 of ‘512) wherein there may be 2 targeting moieties which bind a combination of PD-L1 and CD8 or CD20 (see claims 213-214 of ‘512, for example). The artisan would understand that a fusion comprising 2 targeting moieties is a bispecific fusion protein.
‘512 further recites nucleic acids encoding the chimeric protein of claim 218 and a host cell comprising said nucleic acids (see for example claims 218 and 236-237 of ‘512).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of ‘512. Note that the use of the modified IFNα2 of ‘512 would have been the mere use of an equivalent (wherein the IFNα2 of the instant application and ‘512 are at least functional equivalents) Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer (see claim 235 of ‘512). The use of nucleic acids encoding the protein product and a host cell comprising said nucleic acids would have been obvious and desirable so as to produce the protein products recited in the claims of ‘512, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 43, 44-47, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 198, 200, 210, and 235-237 of copending Application No. 17/042,512 (‘512) as applied to claims 35, 44-45, and 48-49 above, in view of Chang (as applied to the claims in the rejections under 35 USC §103 above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
‘512 is held to make obvious the protein of instant claim 35, as set forth above.
Regarding claims 43 and 51, Chang, teaching the combined use of a binding agent against PD-L1, CD8, and CD20 (as discussed in the rejections under 35 USC §103 above), further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would therefore meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘512 and Chang. Note that the use of the modified IFNα2 of ‘512 would have been the mere use of an equivalent (wherein the IFNα2 of the instant application and ‘512 are at least functional equivalents). Note further that because the components of ‘512 and Chang are functional equivalents, combined to treat cancer, combination of the teachings contained in both references would have been obvious and desirable to optimize and use the resulting construct. Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer (see claim 235 of ‘512). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 44 and 45, Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282). The combination of the prior art references of record renders obvious the components (and resulting construct) of these claims, the resulting effects are presumed to be the same. Therefore this chimeric protein would presumably possess/be capable of performing the claimed properties/functions.
Regarding claim 47, ‘512 recites that the antyi-PD-L1 antibody may be used to treat melanoma (see for example claim 235 of ‘512). Therefore, the use of the antibody (as adapted to the format of an scFv or VHH as made obvious by Chang) in combination with other known anti-cancer components as a single construct would have been prima facie obvious combination of components to achieve a shared goal of treating cancer wherein ‘512 guides towards treatment of melanoma.
Claims 50 and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 198, 200, 210, and 235-237 of copending Application No. 17/042,512 (‘512) as applied to claims 35, 44-45, and 48-49 above, in view of Clement et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 50 and 52, as discussed above, ‘512 and makes obvious the chimeric protein of instant claim 35, but do not explicitly recite/teach the function of the second targeting moiety with respect to all functions of CD8/CD20.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘512 and Clement et al. The artisan would have been motivated to make and use the invention as claimed because ‘512 teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer (see for example claim 235 of ‘512). The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 198, 200, 210, and 235-237 of copending Application No. 17/042,512 (‘512) as applied to claims 35, 44-45, and 48-49 above, in view of Garcin and Rossi et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 53-54, Garcin teaches the format of a nanobody connected to IFN at Fig 1a (see for example, page 3 and the depiction reproduced above). Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction reproduced above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the fusion protein approach of ‘512 in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 35, 43-49, and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 11753463B2 (reference C) and Chang (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 35, 44-46, reference C recites a pharmaceutical composition comprising a chimeric protein comprising one or more modified signaling agents with reduced affinity/activity to IFNα2 that is restorable by targeting moieties (which may be human IFNα2 (presumed to be at least a functional equivalent of the IFNα2 instantly claimed; noting that SEQ ID NO: 1 of reference C is identical to instant SEQ ID NO: 336) and having one or more mutations which may be R149A) and one or more targeting moieties which may by a VHH or scFv and may target one or more of PD-L1, CD8, and/or CD20 (see claims 1-8 of reference C), which may be administered to treat melanoma (see for example claims 11-13 of reference C). The artisan would understand that claiming a fusion with two target moieties (encompassed by the claims of reference C, is claiming a bispecific fusion protein.
Regarding claims 48-49, reference C teaches nucleic acids and a host cell comprising said nucleic acids (see claims 9-10 of reference C).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference C and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Note that the use of the modified IFNα2-anti-PD-L1 VHH construct of ‘780 would have been the mere use of an equivalent whereupon adding in a further binding moiety targeting CD8 or CD20 would have been obvious combination for a shared purpose. Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would thereby meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claim 47, reference C recites that the chimeric protein may be used to treat melanoma (see for example claims 1-13 of reference C). Therefore, the use of the antibody (as adapted to the format of an scFv or VHH as made obvious by Chang and reference C) in combination with other known anti-cancer components as a single construct would have been prima facie obvious combination of components to achieve a shared goal of treating cancer wherein reference C guides towards treatment of melanoma.
Claims 50 and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 11753463B2 (reference C) and Chang as applied to claims 35, 43, 44-47, and 51, in further view of Clement et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 50 and 52, as discussed above, Reference C and Chang make obvious the chimeric protein of instant claim 35, but do not explicitly recite/teach the function of the second targeting moiety with respect to all functions of CD8/CD20.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Reference C, Chang, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 53-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 11753463B2 (reference C) and Chang as applied to claims 35, 43-49, and 51 above, in view of Garcin and Rossi et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 53-54, Garcin teaches the format of a nanobody connected to IFN at Fig 1a (see for example, page 3 and the depiction reproduced above). Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction reproduced above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the generic approach of reference C in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 35, 43-46, 48-49, and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of US Patent No. 11661455B2 (reference D) and Chang (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 35 and 43-46, reference D recites a chimeric protein comprising one or more modified signaling agents with reduced affinity/activity to IFNα2 that is restorable by targeting moieties (which may be human IFNα2 (presumed to be at least a functional equivalent of the IFNα2 instantly claimed; noting that SEQ ID NO: 179 of reference D is identical to instant SEQ ID NO: 336) and having one or more mutations which may be R149A) and a targeting moiety that comprises a recognition domain that recognizes and binds to programmed cell death protein 1 ligand 1 (PD-L1), wherein the targeting moiety comprises a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), or a shark heavy-chain-only antibody (VNAR) (see claims 1-6 of reference D).
Reference D does not teach the further inclusion of a targeting moiety (VHH or scFv) against CD8 or CD20.
However, Chang teaches that use of antagonistic antibodies against immune checkpoint proteins such as PD-L1, are known to be effective in treating cancer (see paragraph 0018). Chang further teaches an embodiment for treating tumors/carcinomas (see abstract) wherein a bispecific antibody (which may comprise an scFv, see Chang’s claims 1 and 10) against a leukocyte expressed antigen (such as CD8 or CD20, see Chang’s claim 17) and/or against a target antigen on a tumor or pathogen (such as CD20 or IFNα, see paragraph 0176) is used (see paragraph 0021) wherein the method comprises administering to a subject: (i) an interferon such as IFNα (see Chang’s claims 1 and 2), (ii) a check point inhibitor antibody, such as an anti-PD-L1 antibody (see Chang’s claims 1, 2, and 5), and a second antibody that may bind CD20 or CD8 (see Chang’s claims 12, 17 and 18) and where the bispecific antibody may be conjugated to a therapeutic cytokine (see Chang’s claim 29).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Note that the use of the modified IFNα2-anti-PD-L1 VHH construct of ‘780 would have been the mere use of an equivalent whereupon adding in a further binding moiety targeting CD8 or CD20 would have been obvious combination for a shared purpose. Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would thereby meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claims 48-49, as discussed above the combination of reference D and Chang teach the fusion protein of claim 35.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that nucleic acids may be put into host cells to produce the protein, as discussed above. The artisan would have been further motivated to produce the protein construct meeting the limitations of instant claim 35 for treatment of cancer as discussed in the rejections above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 47 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of US Patent No. 11661455B2 (reference D) and Chang, as applied to claims 35, 43, 44-46, 48-49, and 51, in further view of Garcin (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claim 47, reference D in view of Chang recites the chimeric protein of instant claim 35.
Reference D in view of Chang does not recite treatment of melanoma.
However, Garcin mentions that many cytokines have anti-cancer properties, but that the use of those cytokines had been limited by systemic toxicity which can be solved by the generic approach to immunocytokine targeting taught in Garcin (see paragraphs 1 and 2 of the Introduction).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D, Garcin, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα (where the particular IFNα is not specified any IFNα, such as IFNα2 is presumed to function as taught), anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have been further motivated to modify the IFNα2 (taught by Chang) according to the generic approach for therapeutically using cytokines taught by reference D and/or Garcin to reduce the systemic/off-target effects of IFNα2 through targeted delivery, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 50 and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of US Patent No. 11661455B2 (reference D) and Chang as applied to claims 35, 43, 44-46, 48-49, and 51, in further view of Clement et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 50 and 52, as discussed above, Reference D and Chang make obvious the chimeric protein of instant claim 35, but do not explicitly recite/teach the function of the second targeting moiety with respect to all functions of CD8/CD20.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Reference D, Chang, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 53-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of US Patent No. 11661455B2 (reference D) and Chang as applied to claims 35, 43, 44-46, 48-49, and 51 above, in view of Garcin and Rossi et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 53-54, Garcin teaches the format of a nanobody connected to IFN at Fig 1a (see for example, page 3 and the depiction reproduced above). Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction reproduced above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the fusion protein approach of reference D in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 35, 43-46, 48-49, 51, and 53-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of US Patent No. 10946070B2 (reference E) and Chang and Rossi et al (both as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 35 and 43-46, reference E recites a pharmaceutical composition comprising a chimeric protein comprising a modified IFNα2 with reduced affinity/activity to IFNα2 that is restorable by targeting moieties (which may be human IFNα2 (presumed to be at least a functional equivalent of the IFNα2 instantly claimed) and having one or more mutations which may be R149A) and a targeting moiety comprising an antibody against PD-L2 or CD20 (which may be a VHH), which restored affinity/activity of the IFNα2 (see claims 1-12 of reference E).
Reference E does not explicitly recite the further inclusion of a targeting moiety (VHH or scFv) against CD8 or PD-L1.
However, Chang teaches that use of antagonistic antibodies against immune checkpoint proteins such as PD-L1, are known to be effective in treating cancer (see paragraph 0018). Chang further teaches an embodiment for treating tumors/carcinomas (see abstract) wherein a bispecific antibody (which may comprise an scFv, see Chang’s claims 1 and 10) against a leukocyte expressed antigen (such as CD8 or CD20, see Chang’s claim 17) and/or against a target antigen on a tumor or pathogen (such as CD20 or IFNα, see paragraph 0176) is used (see paragraph 0021) wherein the method comprises administering to a subject: (i) an interferon such as IFNα (see Chang’s claims 1 and 2), (ii) a check point inhibitor antibody, such as an anti-PD-L1 antibody (see Chang’s claims 1, 2, and 5), and a second antibody that may bind CD20 or CD8 (see Chang’s claims 12, 17 and 18) and where the bispecific antibody may be conjugated to a therapeutic cytokine (see Chang’s claim 29).
Note that the combined references do not explicitly teach a construct comprising an IFNα attached to 2 targeting moieties.
However, Rossi et al teach the viability of a construct comprising one or more IFNα2b copies connected to an anti-HLA moiety and an anti-CD20 moiety (see for example the abstract and Figure 1 and its caption).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Note that the use of the modified IFNα2-anti-PD-L1 VHH construct of ‘780 would have been the mere use of an equivalent whereupon adding in a further binding moiety targeting CD8 or CD20 would have been obvious combination for a shared purpose. Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would thereby meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claims 48-49, as discussed above the combination of reference E, Chang, and Rossi et al teach the fusion protein of claim 35.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference E, Chang, and Rossi et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that nucleic acids may be put into host cells to produce the protein, as discussed above. The artisan would have been further motivated to produce the protein construct meeting the limitations of instant claim 35 for treatment of cancer as discussed in the rejections above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 53-54, Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction reproduced above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the fusion protein approach of reference E in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claim 47 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of US Patent No. 10946070B2 (reference E) and Chang, as applied to claims 35, 43, 44-46, 51, and 53-54 in further view of Garcin (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claim 47, reference E in view of Chang recites the chimeric protein of instant claim 35.
Reference E in view of Chang and Rossi et al does not recite treatment of melanoma.
However, Garcin mentions that many cytokines have anti-cancer properties, but that the use of those cytokines had been limited by systemic toxicity which can be solved by the generic approach to immunocytokine targeting taught in Garcin (see paragraphs 1 and 2 of the Introduction).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference E, Garcin, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα (where the particular IFNα is not specified any IFNα, such as IFNα2 is presumed to function as taught), anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have been further motivated to modify the IFNα2 (taught by Chang) according to the generic approach for therapeutically using cytokines taught by reference E and/or Garcin to reduce the systemic/off-target effects of IFNα2 through targeted delivery, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 50 and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of US Patent No. 10946070B2 (reference E), Chang, and Rossi et al, as applied to claims 35, 43, 44-46, 51, and 53-54 in further view of Clement et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
Regarding claims 50 and 52, as discussed above, Reference E, Chang, and Rossi et al make obvious the chimeric protein of instant claim 35, but do not explicitly recite/teach the function of the second targeting moiety with respect to all functions of CD8/CD20.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Reference E, Chang, Rossi et al, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
New-Double Patenting
Please refer to pages 15-16 of this Office Action where the statutory basis for non-statutory double patenting is provided.
Claims 35, 43-49, 51, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-98 of copending Application No. 19/776,180 (‘180) in view of Lo, Chang, and Rossi et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 35, ‘180 claims a chimeric protein comprising: (a) one targeting moiety, said targeting moiety comprising a recognition domain (such as a VHH) which specifically binds to programmed cell death protein 1 ligand 1 (PD-L1); and (b) a modified signaling agent, said modified signaling agent having one or more mutations that confer improved safety as compared to a wild type signaling agent; and wherein the targeting moiety and the modified signaling agent are optionally connected with one or more linkers (see claims 1-2 of ‘180). The modified signaling agent which may be IFNα2 comprises one or more mutations conferring reduced affinity or activity for a receptor relative to a wild type signaling agent, said activity being restorable by attachment to one or more targeting moieties where the mutation may be R149A (see for example, claims 7 and 13-17).
‘180 does not explicitly teach the sequences of the IFNα2.
However, Lo teaches the sequence for human IFNα2 having 100% homology to instantly claimed SEQ ID NO: 336. Absent a showing to the contrary, because ‘180 teaches use of a wildtype human IFNα2, it is presumed that the wild type human IFNα2 would have had the sequence taught by Lo. Because ‘180 does not mention another base sequence, it is presumed that it is the wild type human IFNα2 that is modified to bear the 149 mutation (supported further by the comparative language employed throughout ‘180 to describe attributes/function of fusions using the wild type human IFNα2 and fusions using the 149-mutation-bearing IFNα2).
The combined references do not teach the further inclusion of a targeting moiety (VHH or scFv) against CD8 or CD20.
However, Chang teaches that use of antagonistic antibodies against immune checkpoint proteins such as PD-L1, are known to be effective in treating cancer (see paragraph 0018). Chang further teaches an embodiment for treating tumors/carcinomas (see abstract) wherein a bispecific antibody (which may comprise an scFv, see Chang’s claims 1 and 10) against a leukocyte expressed antigen (such as CD8 or CD20, see Chang’s claim 17) and/or against a target antigen on a tumor or pathogen (such as CD20 or IFNα, see paragraph 0176) is used (see paragraph 0021) wherein the method comprises administering to a subject: (i) an interferon such as IFNα (see Chang’s claims 1 and 2), (ii) a check point inhibitor antibody, such as an anti-PD-L1 antibody (see Chang’s claims 1, 2, and 5), and a second antibody that may bind CD20 or CD8 (see Chang’s claims 12, 17 and 18) and where the bispecific antibody may be conjugated to a therapeutic cytokine (see Chang’s claim 29).
Note that the combined references do not explicitly teach a construct comprising an IFNα attached to 2 targeting moieties.
However, Rossi et al teach the viability of a construct comprising one or more IFNα2b copies connected to an anti-HLA moiety and an anti-CD20 moiety (see for example the abstract and Figure 1 and its caption).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘180 in view of Lo, Chang, and Rossi et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Note that the use of the modified IFNα2-anti-PD-L1 VHH construct of ‘780 (where the artisan would have read the generically claimed IFNα2 in light of the specification and therefore would understood the recited IFNα2 to encompass one of either of SEQ ID NO: 317 or 318 of ‘780 (see above)) where the use of either disclosed IFNα2 sequence amounts to the mere use of an equivalent) whereupon adding in a further binding moiety targeting CD8 or CD20 would have been obvious combination for a shared purpose. Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer and would result in a bispecific fusion protein as instantly claimed. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would thereby meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claim 47, ‘180 recites that fusion protein may be used to treat cancer including melanoma (see for example, claims 90-94 of ‘180). Therefore, the use of the antibody (as adapted to the format of an scFv or VHH as made obvious by Chang) in combination with other known anti-cancer components as a single construct would have been prima facie obvious combination of components to achieve a shared goal of treating cancer wherein ‘180 guides towards treatment of melanoma.
Regarding claims 48-49, as discussed above the combination of ‘180, Chang, and Rossi et al teach the fusion protein of claim 35.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘180 and Chang because Chang teaches that nucleic acids may be put into host cells to produce the protein. The artisan would have been further motivated to produce the protein construct meeting the limitations of instant claim 35 for treatment of cancer as discussed in the rejections above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 53-54, Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction reproduced above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the fusion protein approach of ‘180 in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 50 and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-98 of copending No. 19/776,180 (‘180), Chang, Lo, and Rossi et al, as applied to claims 35, 43-49, 51, and 53-54 above, in further view of Clement et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 50 and 52, as discussed above, ‘180, Lo, Chang, and Rossi et al make obvious the chimeric protein of instant claim 35, but do not explicitly recite/teach the function of the second targeting moiety with respect to all functions of CD8/CD20.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘180, Lo, Chang, Rossi et al, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 35, 43-49, 51, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 19/763,208 (‘208) in view of Garcin, Lo, Chang, and Rossi et al (as cited in the rejections under 35 USC §103, above). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 35, ‘208 claims a fusion protein comprising a cytokine antagonist (that can be a mutant IFNα2) and an targeting moiety consisting of an antibody or antibody-like molecule that can be a nanobody (see for example, claims1-5 of ‘208).
‘208 does not claim that the IFNα2 has the R149A mutation.
However, Garcin teaches a chimeric protein (fusion protein; note the claim interpretation section above) comprising mutant IFNα2 having mutations Q124R, R149A, M148A, L153A (see paragraph 2 of column 1 of page 5 and page 7, column 1), wherein the mutant IFNα2 has reduced binding affinity relative to wildtype (WT) IFNα2 (see the last paragraph of the Introduction on page 2, see also the results section).
Garcin teaches that this decreased binding affinity may be restorable through the use of targeting moieties (see abstract and paragraph 2 of column 1 of page 2), wherein the targeting moieties may be a nanobody (note that the instant specification admits that VHHs are commercially available as nanobodies; see Figure 1a, abstract, and paragraph 1 of column 1 of page 2); In the last paragraph of column 1 of page 7, Garcin teaches that one of the targeting moieties may be a VHH or an scFv (see paragraph 1, column 1, of page 2 and the last paragraph of column 1, page 6).
Garcin teaches that while antibody-meditated accumulation of drugs within specific tissues such as tumor tissues has emerged as an effective strategy, this strategy has shown lackluster results in reducing toxic or off-target effects for the delivery of cytokines because this has traditionally been carried out by fusing nanobodies to WT cytokines (such as wild-type, human IFNα2, see for example paragraph 1 of the Results section on pg. 2, right-hand column). Garcin teaches that augmenting the binding affinity of a cytokine does not maximize its potency and that WT cytokines have a saturation effect (see paragraph 2 of the discussion). To allow for targeted use of cytokines, Garcin teaches a generic approach, that is applicable to a range of cytokines and nanobodies (VHHs)/antibodies/scFvs (see paragraph 3 of the discussion; see also paragraph 4 of the discussion showing this approach also was effective for using IL-1 and TNFα (2 structurally unrelated cytokines) and for leptin). Given that this generic approach for therapeutically using cytokines reduced the systemic effects of IFNα2 and, therefore reduces off target effects of IFNα2 (such as leukopenia, see the last paragraph of the results section and Figures 5a-c), this generic approach is presumed to allow for safe and effective use of mutant IFNα2 for a number of applications as determined by the targeting moiety chosen, where moieties for enhancing an anti-proliferative/anti-tumor, antiviral, and for effecting immune cell/regulatory cell functions are known (see paragraph 4 of the discussion; also note that the antitumor effects of IFNs in mice have been clearly shown, see paragraph 3 of the introduction). This approach may also be used to enhance known combination therapies through enhanced targeting and reduction of systemic/off-target toxicities (see paragraph 4 of the discussion of Garcin).
Garcin does not explicitly teach the sequences of the IFNα2.
However, Lo teaches the sequence for human IFNα2 having 100% homology to instantly claimed SEQ ID NO: 336. Absent a showing to the contrary, because Garcin teaches use of a wildtype human IFNα2, it is presumed that the wild type human IFNα2 would have had the sequence taught by Lo. Because Garcin does not mention another base sequence, it is presumed that it is the wild type human IFNα2 that is modified to bear the 149 mutation (supported further by the comparative language employed throughout Garcin to describe attributes/function of fusions using the wild type human IFNα2 and fusions using the 149-mutation-bearing IFNα2).
The combined references do not teach the inclusion of a first targeting moiety binding PD-L1 and a second targeting moiety binding CD8 or CD20 wherein the first and second targeting moieties are in the format of an scFv or VHH.
However, Chang teaches that use of antagonistic antibodies against immune checkpoint proteins such as PD-L1, are known to be effective in treating cancer (see paragraph 0018). Chang further teaches an embodiment for treating tumors/carcinomas (see abstract) wherein a bispecific antibody (which may comprise an scFv, see Chang’s claims 1 and 10) against a leukocyte expressed antigen (such as CD8 or CD20, see Chang’s claim 17) and/or against a target antigen on a tumor or pathogen (such as CD20 or IFNα, see paragraph 0176) is used (see paragraph 0021) wherein the method comprises administering to a subject: (i) an interferon such as IFNα (see Chang’s claims 1 and 2), (ii) a check point inhibitor antibody, such as an anti-PD-L1 antibody (see Chang’s claims 1, 2, and 5), and a second antibody that may bind CD20 or CD8 (see Chang’s claims 12, 17 and 18) and where the bispecific antibody may be conjugated to a therapeutic cytokine (see Chang’s claim 29). Chang additionally teaches that techniques for producing single domain antibodies (DABs or VHH) are also known in the art and the VHH may have potent antigen-binding capacity and can interact with novel epitopes that are inaccessible to conventional VH-VL pairs (see for example paragraphs 0021-0024, 0098, and 0164). Chang further teaches that the person of ordinary skill in the art will realize that other antibodies that bind to leukocyte antigens as well as other antibodies that bind to other disease-associated antigens are known in the art and any such antibody can be used to make F(ab)2, scFv or other antibody fragments using techniques well known in the art. Such alternative antibodies or fragments thereof may be utilized in the instant methods and compositions (see for example paragraph 0359). Chang also teaches that the antibody fragments (VHH and/or scFv may be chimeric (see for example paragraph 0024).
The combined references do not explicitly teach a construct comprising an IFNα attached to 2 targeting moieties.
However, Rossi et al teach the viability of a construct comprising one or more IFNα2b copies connected to an anti-HLA moiety and an anti-CD20 moiety (see for example the abstract and Figure 1 and its caption), thus teaching the workability of such a fusion having the required format.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘208, Garcin, Lo, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα (where the particular IFNα may be IFNα2; see example 17 of Chang), anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined/administered in combination to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements (a PDL1-targeting moiety, a CD8 targeting moiety, and an IFNα2 such as the mutant IFNα2 made obvious by the combination of, at least by Garcin in view of Lo) known to treat cancer would be predictably combined into a single construct by known means and formats (there being a finite number of ways to connect the three required components into a single fusion protein) to achieve the same purpose of treating cancer. Likewise, one of ordinary skill in the art would have found it obvious per the cited portion of the MPEP to combine the teachings of Garcin, regarding the use of known mutations for a IFNα2, to incorporate the IFNα2 sequence taught by Lo because it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an therapeutic IFNα2 fusion protein with restorable binding affinity for targeting by activity (see MPEP sections 2143(I)(B) and 2144.06 (II)). The cited prior art provides motivation to combine because Chang teaches that these components ( in combination and individually are useful in treating cancer, as discussed above. The artisan would have been further motivated to modify the IFNα2 (taught by Chang and Lo) according to the generic approach for therapeutically using cytokines taught by Garcin to reduce the systemic/off-target effects of IFNα2 through targeted delivery, as discussed above. Rossi et al teach guidance as to how to build a construct comprising an IFNα2 and 2 additional binding moieties, with motivation to build such a construct with a reasonable expectation of success for the workability of the format resulting in a bispecific fusion protein having the recited limitations. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Regarding claims 43 and 51, Chang further teaches that:
“[i]t is now clear that tumors can escape immune surveillance by co-opting certain immune-checkpoint pathways, particularly in T cells that are specific for tumor antigens (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Because many such immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies against the ligands and/or their receptors (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Although checkpoint inhibitor antibodies against CTLA4, PD1 and PD-L1 are the most clinically advanced…Programmed cell death 1 ligand 1 (PD-L1, also known as CD274 and B7-H1) is a ligand for PD1, found on activated T cells, B cells, myeloid cells and macrophages. Although there are two endogenous ligands for PD1—PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1 antibodies. The complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer et al., 2012, N Eng J Med 366:2455-65),”
(see paragraphs 0130 and 0134 of Chang). Thus, one of ordinary skill in the art would understand from the teachings of Chang that an activity of PD-L1 is binding PD-1, resulting in inhibition of CD8+ T cell proliferation, and would thus understand that the anti-PD-L1 antibodies of Chang would block PD-1/PD-L1 complex formation (binding) which would then block inhibition of T cell proliferation, thereby functionally modulating an activity of PD-L1.
However, ‘the activity’ is never sufficiently defined. For example, it is unclear whether a single activity being modulated/unmodulated is sufficient to meet the claim or whether all activity must be modulated/unmodulated. Therefore, it is possible that the anti-PD-L1 antibodies of Chang, while inhibiting binding of PD-L1 to PD-1 may not functionally modulate all other activities of PD-L1 and would therefore meet the limitations of both claims 43 and 51. Chang is silent as to the whether the antibodies functionally modulate all PD-L1 activities.
Regarding claims 44 and 45, Garcin further teaches that the targeting moieties may be a nanobody (note that the instant specification admits that VHHs are commercially available as nanobodies (see Figure 1a, abstract, and paragraph 1 of column 1 of page 2)). In the last paragraph of column 1 of page 7, Garcin teaches that one of the targeting moieties may be a VHH or an scFv (see paragraph 1, column 1, of page 2 and the last paragraph of column 1, page 6). Chang additionally teaches that the use of a VHH or scFv format for an antigen, such as PD-L1, CD8, or CD20, would have been obvious to one of ordinary skill in the art for use in the method of Chang, as discussed above.
Regarding claim 46, Chang teaches that the combinations (including a combination of a bispecific antibody and an immunomodulator which can be an IFNα) are for pharmaceutically useful compositions with a pharmaceutically acceptable excipient (see for example paragraph 0282).
Regarding claim 47, Garcin mentions that many cytokines have anti-cancer properties, but that the use of those cytokines had been limited by systemic toxicity which can be solved by the generic approach to immunocytokine targeting taught in Garcin (see paragraphs 1 and 2 of the Introduction).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘208, Garcin, Lo, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα (where the particular IFNα is not specified any IFNα, such as IFNα2 is presumed to function as taught), anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. The artisan would have been further motivated to modify the IFNα2 (taught by Chang and Lo) according to the generic approach for therapeutically using cytokines taught by Garcin to reduce the systemic/off-target effects of IFNα2 through targeted delivery, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 48-49, as discussed above the combination of ‘208, Garcin, Lo, Rossi et al, and Chang teach the fusion protein of claim 35. Garcin additionally teaches that HEK293T cells (a host cell) were transiently transfected with a plasmid (recombinant nucleic acid) encoding the Nb-IFNα2 fusion (see p.7 right-hand column).
Thee Examiner believes that it would have been obvious to one of ordinary skill in the art that the chimeric fusion construct described above could be encoded in a similar recombinant nucleic acid composition in a host cell since this is a known, predictable manner of generating such constructs.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘208, Garcin, Lo, Rossi et al, and Chang. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that nucleic acids may be put into host cells to produce the protein (see also Garcin’s teaching of the use of HEK293T host cells, transiently transfected with a plasmid (recombinant nucleic acid) encoding the Nb-IFNα2 fusion) as discussed above. The artisan would have been further motivated to produce the protein construct meeting the limitations of instant claim 35 for treatment of cancer as discussed in the rejections above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 53-54, Garcin teaches the format of a nanobody connected to IFN at Fig 1a (see for example, page 3 and the depiction above). Additionally, Rossi et al teach that the first and second targeting moieties are attached to one another, with one of the targeting moieties being attached to the IFN2αb at figure 1 (see for example, page 7601 and the depiction above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the cited prior art references in combination. The artisan, using the generic approach of ‘208 and Garcin in light of the additional cited references would have found it obvious to similarly attach one or more nanobodies to the modified INFα2 of Garcin. There are a finite number of arrangements for the ordered connection of the recited limitations (the first targeting moiety, the second targeting moiety, and the modified signaling agent). There being a finite order of attachments (first targeting moiety-second targeting moiety-modified signaling agent; first targeting moiety-modified signaling agent-second targeting moiety; second targeting moiety-modified signaling agent-first targeting moiety; second targeting moiety-first targeting moiety-modified signaling agent; modified signaling agent-second targeting moiety-first targeting moiety; modified signaling agent-first targeting moiety-second targeting moiety), the particular order chosen is deemed to be no more than a result effective variable for routine optimization with any of the arrangements being reasonably expected to function reliably, yielding no more than predictable results. Note that the arrangement of Garcin technically reads on the arrangement of both of claims 53 and 54 in light of the present claim drafting, whereby the arrangement of claim 53 is encompassed within the scope of arrangements encompassed by claim 54. The artisan would have been motivated to make such a construct for reasons iterated above in the rejection of claim 35 which reviews the benefits of the resulting fusion protein for treating cancer.
Claims 50 and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 19/763,208 (‘208) in view of Garcin, Lo, Chang, and Rossi et al (as cited in the rejections under 35 USC §103, above), as applied to claims 35, 43-49, 51, and 53-54 above, in further view of Clement et al (Anti-CD8 antibodies can trigger CD8+ T cell effector function in the absence of TCR engagement and improve peptide-MHCI tetramer staining. J Immunol. 2011 Jul 15;187(2):654-63). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim a chimeric protein comprising the same components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 50 and 52, Garcin, Lo, Rossi et al, and Chang teach as set forth above.
The combined references do not explicitly teach the function of the second targeting moiety with respect to all functions of CD8.
However, Clement et al teach findings from evaluation of a panel of anti-human CD8 antibodies that comprised six anti-CD8α antibodies (OKT8, SK1, MCD8, 32/M4, C8/144B and DK25) and one anti-CD8β antibody (2ST8.5H7). Six out of seven anti-human CD8 antibodies from the panel (SK1, MCD8, 32/M4, C8/144B, DK25 and 2ST8.5H7) did not elicit any chemokine production when incubated with four different HLA A*0201-restricted CD8+ T-cell clones (ILA1, ALF3, MEL5 and MEL187.c5) with a total of three different specificities in the absence of specific pMHCI antigen. The panel of seven anti-human CD8 antibodies was further tested in cytotoxicity assays with 4 different CD8+ T-cell clones (MEL187.c5, ALF3, LC13 and SB10). Anti-human CD8 antibodies that were incapable of inducing chemokine release failed to elicit cytotoxic activity in any of these four CD8+ T-cell clones (see Figure 3). In contrast, SB10 CD8+ T-cells exhibited substantial cytotoxicity in response to stimulation with OKT8; lower levels of specific lysis were also induced in the CD8+ T-cell clones LC13 (3.18%), ALF3 (5.1%) and MEL187.c5 (3.8%) (see Figure 3 and data not shown). These results are consistent with a previous study that described a mouse anti-CD8 antibody, KT112, capable of inducing cytotoxicity. Collectively, these data indicate that considerable heterogeneity exists in the ability of anti-CD8 antibodies to activate CD8+ T-cells (see the Results section).
Therefore, Clement et al clearly teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells, by way of inducing chemokine production leading to cytotoxic activity, and anti-CD8 antibodies that do not functionally modulate, by way of inducing chemokine production leading to cytotoxic activity or any other indicated way, CD8 on CD8+ T cells.
Therefore, one of ordinary skill in the art would have understood Clement et al to teach anti-CD8 antibodies that functionally modulate CD8 on CD8+ T cells and anti-CD8 antibodies that do not functionally modulate CD8 on CD8+ T cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Garcin, Lo, Rossi et al, Chang, and Clement et al. The artisan would have been motivated to make and use the invention as claimed because Chang teaches that an IFNα2, anti-PDL1 scFv and an scFv targeting CD8 or CD20 are known and may be combined to treat cancer. The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Chang teaches that these components in combination and individually are useful in treating cancer, as discussed above. One of ordinary skill in the art would have found it obvious to use the antibodies of Clement as art recognized equivalents because these antibodies are known in the art to bind CD8 (See MPEP section 2143(I)(B) regarding simple substitution of one known element for another to obtain predictable results). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
Applicant argues for withdrawal of the rejections under 35 USC §103 alleging a. Garcin alone does not provide proper basis for rejection of the claimed bispecific on the grounds of nonobvious of for rebuttal of surprising results (see pages 4-5 of the 08/31/2026 remarks), b. the results disclosed at the specification at pages 146-147, Fig. 15d-e, and Fig. 8a-c provide evidence of surprising results (see for example, pages 5-6 of the 08/31/2026 remarks), and c. the motivation to combine is improper (see for example, page 6 of the 08/31/2026 remarks).
Response: These argument are unpersuasive. First, Applicant’s argument’s related to the rejections over Garcin only discuss the teachings of Garcin in isolation. Garcin is cited as but one of a combination of references. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Second, Applicant points to the specification at pages 146-147and Figure 15 (panels D-E) as showing that IFNα2 having the R149A mutation, when targeted to the cell with a VHH that targets a cell-surface expressed antigen, has significantly greater (restored) IFN signaling as measured by STAT1 phosphorylation (see panels 15 B and C showing that the mutated IFNα2-antiCD8VHH shows significantly increased STAT1 phosphorylation in CD8+ cells, but not CD8- cells, panels B and C respectively; see panels 15 D-F showing that the mutated IFNα2-antiCD8VHH-antiPD-L1VHH shows significantly increased STAT1 phosphorylation in CD8+ cells, but not CD8- cells, panels E and F respectively). However, the effect that Applicant alleges is surprising (increased IFN signaling as measured by increased STAT1 phosphorylation where the mutant IFNα2 is targeted) is not surprising/unexpected or even unpredictable in light of the prior art. Garcin (as cited in the rejections under 35 USC §103 above) teaches a generic approach to increase by several orders of magnitude the targeting efficiency of immunocytokines (see for example, column 1 of page 2 and column 2 of page 3). Garcin tested an anti-PD-L2VHH-IFNα2R124R fusion and found that the targeted fusion had increased (restored) IFN signaling (as measured by STAT1 phosphorylation) in PD-L2 expressing cells (see for example, pages 5-6). Garcin teaches that they demonstrated that mutated IFN immunocytokine is up to almost 1,000-fold more potent on cells expressing a selected target at their surface and show that their targeting strategy delivers activity only to the selected cells when injected intravenously in mice. Garcin teaches that such an exceptionally high in vivo targeting efficiency is due to an increased cell surface binding achieved by VHH-mediated interaction that compensates the reduced mutant IFN activity specifically on cells expressing the VHH target protein. As a result, the IFN is virtually inactive while ‘en route’ and is activated only upon binding to the desired target (see for example, page 7 at column 1). Applicant seems to take issue with the fact that Garcin does not reduce to practice Applicant’s exact invention. That is not the standard for non-obviousness nor by which surprising results are evaluated. Garcin teaches that targeting of the modified IFNα2 results in the increased potency on cells expressing a selected target, where the approach of Garcin is notably taught to be generic (such that different targeting moieties could be used to target the mutant IFNα2 to different cells for different purposes. The prior art steps in to provide the motivation for arriving at a fusion comprising a first targeting moiety binding PDL1, a second targeting moiety binding CD8, and a mutant IFNα2 having 95% or more identity to instant SEQ ID NO: 336 with an R149A mutation. None of Applicant’s presented data allow for a determination to be made regarding whether the results Applicant continues to allege as surprising are merely additive or reflective of unexpected synergy because the effect of the mutant IFNα2, the PDL1-targeting moiety, and the CD8-targeting moiety cannot be individually ascertained. It is understood in the art that the effects of combining two or more structures known individually to accomplish the same purpose is at least additive and is prima facie obvious (see for example, MPEP §§2143(I)(A) and (G)). Additionally, as explained at pages 20-21 of the Non-Final Office Action dated 01/18/2024, the state of the art acknowledges that bispecifics tend to be more efficacious than their monospecific components administered separately or co-administered. For example, Kontermann (Dual targeting strategies with bispecific antibodies. MAbs. 2012 Mar-Apr;4(2):182-97. doi: 10.4161/mabs.4.2.19000. Epub 2012 Mar 1), teaches that a bispecific against EGFR/IGF-1R is more effective than the parental components co-administered for tumor reduction/management and that for some indications bispecifics generally are more effective than the combination of the parents as monotherapies. Kontermann, analyzing a number of examples concludes that, results from these studies demonstrate that, in general, bispecific antibodies outperform treatment with monospecific antibodies, but are similar to the combination of parental antibodies, although for some indications increased potency was described. The examples clearly show that bispecific antibodies targeting different disease modulators are capable of improving standard therapy (see paragraph 3 of the Dual Targeting of 2 receptors in Cancer Therapy section; and the Conclusion section). Therefore, the results claimed to be surprising so as to overcome the 103 rejections of record are not surprising because the asserted enhanced efficacy of the bispecific would have been expected and therefore remains obvious in light of the teachings of Kontermann, as discussed above.
Third, the motivation to swap the PDL2 binding moiety of Garcin for the PDL1-binding moiety of Chang is clearly articulated in the rejection of claim 35, in summary, because Chang teaches that the combination of a target moiety binding PDL1, a target moiety binding CD8, and an IFNα is effective for treating cancer. The motivation is to treat cancer.
The rejections are therefore maintained at this time.
B. Applicant requests withdrawal of the rejections for double patenting pointing to substantially the same points relied upon for the requested withdrawal of the rejections of the claims for obviousness in point A above (see pages 6-9 of the 08/31/2026 remarks).
Response: The response to point A above is considered to sufficiently rebut the points repeated in the argument for withdrawal of the rejections for double patenting.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon continues to be considered pertinent to applicant's disclosure.
US9492562B2 teaches a construct comprising human IFNα2 with a R149A mutation having reduced affinity compared to wildtype and further comprising a targeting moiety binding PD-L2 wherein CD20 is taught to be another biomarker to target for treating cancer. Kermer et al (Mol Cancer Ther (2014) 13 (1): 112–121) teach a trifunctional fusion comprising a tumor-specific recombinant antibody (may be an scFv), IL-15 linked to a fragment of the IL-15Rα chain (RD; a cytokine like IFNα2) and the extracellular domain of 4-1BBL(may be an scFv).
Xuan et al (Blood (2010) 115 (14): 2864–2871) teach fusion proteins consisting of anti-CD20 and murine or human IFNα for use in treating B-cell malignancies.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
