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 2-5, 7, 9, 11-20, 24, 28, 32-33, 36, and 39-81 are cancelled.
Claims 1, 6, 8, 10, 21-23, 25-27, 29-31, 34-35, and 37-38 are pending.
Claims 21-23, 25-27, 29-31, 34-35, and 37-38 are withdrawn as being drawn to a non-elected invention.
Claims 1, 6, 8, and 10 are under examination on the merits.
Priority
Applicant’s claim of priority to US provisional applications with the serial number 62/618,639, filed January 18, 2018, and the serial number 62/630,182, filed February 13, 2018, is noted.
Withdrawn Rejections
The rejection of claim 8 under 35 USC §112(b) is withdrawn as addressed by the clarifying claim amendments dated 12/23/2025. The rejection of claim 8 under 35 USC §112(d) is withdrawn as addressed by the claim amendments dated 12/23/2025. The rejections of the claims under 35 USC §102 are withdrawn in light of the new claim scope resulting from the claim amendments dated 12/23/2025. The rejections of the claims under 35 USC §103 as presented in the office action dated 09/25/2025 are withdrawn and replaced with the rejections under 35 USC §103 over the same references in order to better account for the new claim scope resultant from the claim amendments dated 12/23/2025.
New Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 1, 6, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015109124A2, hereinafter referred to as Kadmon (as cited on the 02/18/2025 IDS) in view of Liu et al (US20170342119 A1; as cited in the Office Action dated 09/17/2024).
Regarding claims 1, Kadmon teaches fusion molecules comprising PD-L1 binding proteins (which in certain embodiments may be PD-L1 antibody fragments such as an scFv with an Fc from IgG (see for example paragraphs 0047-0048 and reference in its entirety)) constructed with IL15 and an IL15 receptor alpha sushi domain (forming a non-covalent complex; see for example, paragraph 0059) which enhance T cell and NK cell function to increase cell and cytokine mediated immunity for the treatment of various immune dysfunction related disorders including cancers and infectious diseases (see for example paragraph 0001).
Kadmon does not appear to explicitly teach linkage of 2 fusions (which may be identical or merely share elements) via a disulfide bond at the Fc regions.
However, Lui et al teach a soluble fusion protein complex comprising a first soluble fusion protein complex covalently linked to a second soluble fusion protein complex. For example, the soluble fusion protein complexes of the invention are multimerized, e.g., dimerized, trimerized, or otherwise multimerized (e.g., 4 complexes, 5 complexes, etc.). For example, the multimers are homomultimers or heteromultimers. The soluble fusion protein complexes are joined by covalent bonds, e.g., disulfide bonds, chemical cross-linking agents. In some cases, one soluble fusion protein is covalently linked to another soluble fusion protein by a disulfide bond linking the Fc domain of the first soluble fusion protein to the Fc domain of the second soluble fusion protein (see for example, paragraph 0009). Liu et al further teach that the Fc domain or functional fragment thereof includes an Fc domain selected from the group consisting of IgG Fc domain, human IgG1 Fc domain, human IgG2 Fc domain, human IgG3 Fc domain, human IgG4 Fc domain, IgA Fc domain, IgD Fc domain, IgE Fc domain, and IgM Fc domain; or any combination thereof (see for example, paragraph 0010). In some aspects, the first biologically active polypeptide is covalently linked to an IL-15 polypeptide (or functional fragment thereof) by a polypeptide linker sequence. Similarly, the second biologically active polypeptide is covalently linked to an IL-15Rα polypeptide (or functional fragment thereof) by polypeptide linker sequence. Optionally, the IL-15Rα polypeptide (or functional fragment thereof) is covalently linked to the Fc domain (or functional fragment thereof) by polypeptide linker sequence. Each polypeptide linker sequence can be selected independently. Optionally, the polypeptide linker sequences are the same. Alternatively, they are different (see for example, paragraph 0011 and claim 1). Also included in the invention are chimeric antibodies, such as humanized antibodies (see for example, paragraph 0035). In certain embodiments, the antigen for the antigen-specific binding domain comprises a cell surface receptor or ligand. In a further embodiment, the antigen comprises a CD antigen, cytokine or chemokine receptor or ligand, growth factor receptor or ligand, tissue factor, cell adhesion molecule, MHC/MHC-like molecules, Fc receptor, Toll-like receptor, NK receptor, TCR, BCR, positive/negative co-stimulatory receptor or ligand, death receptor or ligand, tumor associated antigen, or virus encoded antigen (see for example, paragraph 0094). Additionally, preferred binding domains of the invention may include various other tumor-specific antibody domains known in the art. The antibodies and their respective targets for treatment of cancer include but are not limited to MPDL3280A (anti-PD-L1) and pidilizumab (anti-PD-1) (se paragraph 0096). In other embodiments, the binding domain is specific to an immune checkpoint molecule or its ligand and acts as an inhibitor of immune checkpoint suppressive activity or as an agonist of immune checkpoint stimulatory activity. Such immune checkpoint molecules and ligands include PD1, PDL1, PDL2, CTLA4, CD28, CD80, CD86, B7-H3, B7-H4, B7-H5, ICOS-L, ICOS, BTLA, CD137L, CD137, HVEM, KIR, 4-1BB, OX4OL, CD70, CD27, OX40, GITR, IDO, TIM3, GALS, VISTA, CD155, TIGIT, LIGHT, LAIR-1, Siglecs and A2aR (citing Pardoll D M. 2012. Nature Rev Cancer 12:252-264, Thaventhiran T, et al. 2012. J Clin Cell Immunol S12:004) (see for example, paragraph 0099). Note that Lui et al teach that the fusions may be different (one having an anti-PD-L1 antibody and the other having an anti-CD3 antibody/binder (see for example, claim 1) wherein the two fusions may share something as simple as a linker or amino acid to fulfill the limitation that the second fusion comprises features of the first fusion where a feature, as instantly recited, is considered to be functional or may be deemed to comprise features of binding (as both fusions have a binding feature which is a functional feature). Under either interpretation, both of which are deemed reasonable in light of the failure of the specification to provide a definition of such feature, the recited limitations of the claims are deemed to be made obvious over Kadmon and Lui et al where Kadmon guides one of ordinary skill in the art to the anti-PDL1 antibody/fragment thereof/scFv and where Lui et al teach the success and means of making and using such an arrangement of fusion proteins. Lui et al are held to teach and make obvious a single polypeptide having from N to C terminus an PD-L1 binding motif, an IL-15Rα and an Fc portion of an IgG antibody (see for example, figure 1 of Lui et al in combination with the teachings of Lui et al cited 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 Kadmon and Liu et al. The artisan would have been motivated to make and use the invention as claimed because Kadmon and Liu et al both teach the use of fusions comprising overlapping components (anti-PD-L1 antibody, IL15/superagonist and IL15Rα) where Liu et al teach that this arrangement is functional and that this arrangement may be used to create heteromers that bind disease antigen (such as PDL1) and a domain targeting CD3 on T cells for killing tumor cells (see for example, paragraph 0004 and claims 1, 17, and 18). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 6 and 10, note that paragraph 0017 of the instant specification provides that an immune competent cell is preferably a CD4+ T-cell, CD8+ T-cell, or NK cell. Kadmon teaches that the invention provides molecules, such as fusion proteins that bind PD-L1 that, apart from reducing or inhibiting immunosuppression by binding to PD-L1, also promote one or more immune responses by interaction with other ligands or receptors. In an embodiment of the invention, the molecule binds to PD-L1 on target cells, and also stimulates a cell-mediated immune response, for example, by promoting proliferation of T cells and/or NK cells (see for example paragraph 0009). Thereby, the construct of Kadmon is deemed to be bound, at least at some point and for a period of time, to an immune competent cell as claimed in instant claim 6, as presently drafted.
Where Kadmon teaches compositions meeting the instant claim recitations, the claims are deemed to be made obvious by the combination of Kadmon and Liu et al.
Regarding claim 8, as discussed above, Kadmon and Liu et al are deemed to make obvious instant claim 1. Based upon paragraph 0011 of the instant specification, the anti-PDL1 scFv/antibody/antibody fragment is considered to be the recited (and elected species) of the affinity portion wherein covalent linkage is understood to read upon the recitation of being covalently bound (in the interest of advancing prosecution). Kadmon does not explicitly teach that the PD-L1 binder (scFv) is covalently bound to at least one of the cytokine receptor (IL15R) or cytokine/cytokine analog (IL15/IL15 superagonist). However, Kadmon teaches that the invention provides a PD-L1-binding domain is linked to an IL15R stimulatory domain, which IL15R stimulatory domain comprises the sushi domain of the IL15R alpha chain or a variant thereof and IL15 or a variant thereof (see paragraph 0059, for example).
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 Kadmon. The artisan would have been motivated to make and use the invention as claimed because Kadmon teaches that the invention provides a PD-L1-binding domain is linked to an IL15R stimulatory domain, which IL15R stimulatory domain comprises the sushi domain of the IL15R alpha chain or a variant thereof and IL15 or a variant thereof (see paragraph 0059, for example). There are ultimately 2 options of said linkage: covalent or non-covalent. There being only 2 options, it would have been a routine matter of optimization to choose between the two options (see MPEP 2144.05(I and II) and MPEP 2143) wherein, absent evidence to the contrary, either means of linkage (covalent or noncovalent) would presumably function such that the means of linking would appear to be a matter of obvious choice yielding no more than predictable results. As part of determining obviousness, it is to be considered that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 may bar its patentability. When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions,” (see MPEP 2141. I.)). The artisan would have been motivated to make a fusion comprising the components of Kadmon to treat neoplastic disease (see for example the abstract). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Response
A. Applicant argues that the prior art cited does not teach the specific molecule claimed.
Response: Applicant fails to address the arguments combining the teachings of Kadmon and Liu et al made in the office action dated 09/25/2025. Applicant instead attacks the references individually and then asserts that the combined references fail to make obvious the claims fusion. First, 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, the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). Third, Kadmon does teach bispecific fusion molecules comprising PD-L1-binding proteins constructed with IL15 and an IL15 receptor alpha sushi domain, nucleic acid molecules encoding the same, and therapeutic compositions thereof (see for example, paragraph 0001). Applicant argues difficulties of combining the claimed elements into a single construct. This ignores the teachings of Lui et al which teach a format comprising the claimed elements in the claimed arrangement where the artisan would have found it obvious to modify the components of Kadmon to conform to the arrangement of Lui et al for reasons iterated in the rejection above, with a reasonable expectation of success. Applicant argues Liu et al do not teach IL-15 or IL-15Rα domains or PD-L1 binding domains or the claimed structure. The Examiner points to the portions of Liu et al cited in the rejections under 35 USC §103 above to show where Liu et al do in fact teach these elements. Likewise, the motivation to modify Kadmon according to Liu et al may be found in the rejections of the claims under 35 USC §103 presented above. Modification of the teachings of Kadmon et al according to Liu et al would have been obvious to the artisan who would have been motivated to make and use the invention as claimed because Kadmon and Liu et al both teach the use of fusions comprising overlapping components (anti-PD-L1 antibody, IL15/superagonist and IL15Rα) where Liu et al teach that this arrangement is functional and that this arrangement may be used to create heteromers that bind disease antigen (such as PDL1) and a domain targeting CD3 on T cells for killing tumor cells (see for example, paragraph 0004 and claims 1, 17, and 18).
The arguments presented in the remarks dated 12/23/2025 are deemed unpersuasive to overcome the rejections of record for the claims as presently drafted.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
JP 2017184750 A (note that the English translation is being relied upon) is further deemed relevant to the claimed subject matter.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678