DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 26MAY2026 has been entered.
Claim Status
Applicant’s amendments received 26MAY2026 are acknowledged.
Claims 2-11, 14, 18-21, 23-27, 30-43, 46-54, 56-164, and 167-177 have been canceled.
Claims 16-17, 22, and 29 have been amended.
Claims 1, 12-13, 15-17, 22, 28-29, 44-45, 55, 165-166, and 178-178 are pending and under examination on the merits in the instant application (i.e., Claim 1 is independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2020/52764, filed 25SEP2020, which claims the benefit of US Provisional Patent Application No. 62/906447, filed 26SEP2019. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Drawings
Applicant’s arguments, see p 6, Amendments to the drawings section, filed 26MAY2026, with respect to objections to the drawings for minor informalities have been fully considered and said objections to the drawings have been withdrawn in view of new drawings filed as part of said response.
Specification
Applicant’s arguments, see p 6, Amendments to the specification section, filed 26MAY2026, with respect to objections to the specification for minor informalities have been fully considered and said objections to the specification have been withdrawn in view of amendments to the specification filed as part of said response.
Claim Objections
Applicant’s arguments, see p 6, Response to claim objections section, filed 26MAY2026, with respect to objections to of claim 22 for informalities has been fully considered and said objection to claim 22 have been withdrawn in view of claim amendments filed as part of said response.
Withdrawn Rejections
Double Patenting
Applicant’s arguments, see p 6-8, Response to double patenting section, filed 26MAY2026, with respect to the rejection(s) of claim(s) 16-17, 20-21, and 29 (i.e., rejection of claim(s) 20-21 are moot because claims have been cancelled) under non-statutory double patenting have been fully considered and are fully persuasive because of the claim amendments which add limitations not taught in the cited art. As such, said rejections of claim(s) 16-17 and 29 have been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 12-13, 15-17, 22, 29, 44-45, 55, and 179 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus:
Applicant has broadly claimed a multispecific targeting moiety comprising a PD-L1 targeting moiety of SEQ ID NO: 24 (i.e., VHH) and essentially any other recognition domain which recognizes essentially any tumor antigen, any antigen on an immune cell, or any domain which recruits cytotoxic T cells to tumor cells or to the tumor environment (i.e., claims 12-13 and 15); a multifunctional complex comprising a PD-L1 targeting moiety of SEQ ID NO: 24 and essentially any modified human IFNα2 signaling agent which has reduced affinity or activity at the IFNα receptor relative to the wt variant, which is restored by conjugation to the PD-L1 targeting moiety, comprising one or more mutations selected from 8 potential positions of mutations, wherein positions T106, A144, or A145 have unmodified or 2, 5, or 6, amino acid alternatives, respectively (i.e., claims 16-17 and 22); and a Fc-based chimeric complex comprising i) a PD-L1 targeting moiety of SEQ ID NO: 24, ii) essentially any modified human IFNα2 signaling agent which has reduced affinity or activity at the IFNα receptor relative to the wt variant; and iii) essentially any modified Fc domain which has one or more mutations that reduces/eliminates one or more effector functions, promotes Fc chain pairing in the Fc domain, and/or stabilizes the hinge region in the Fc domain, and wherein the complex comprises essentially any one or more linkers, or wherein the Fc domain is selected from IgG, IgA, IgD, IgM, or IgE, or wherein the complex is a homodimer or heterodimer, and a pharmaceutical composition thereof (i.e., claims 29, 44-45, 55, and 179). The broadest claims do not require any of the multispecific, multifunctional, or Fc-based chimeric complexes to have any function apart from binding a second antigen, having reduced affinity or activity with a IFNα2 receptor compared to the wt, or having reduced affinity or activity with a IFNα2 receptor compared to the wt and having reduced/eliminated effector functions, promoted Fc chain pairing in the Fc domain, and/or stabilized hinge region in the Fc domain. No claims recite any specific or particular structure of any of the multispecific, multifunctional, or Fc-based chimeric complexes that gives rise to the specific binding/activity functions apart from claim 22, which provides 4032 alternatives of SEQ ID NOs: 81 or 82.
State of the relevant art:
With regards to multispecific sdAb fusion proteins, there are a variety of formats including bivalent dAb/VHH, trivalent dAb/VHH, tetravalent dAb/VHH, VHH2-CH1/CL, Fab-VHH, IgG-[H]-VHH, or IgG-[L]-VHH, with each of them having their pros and cons (Brinkmann, et al., MABS, 2017, 9, 182-212, see Fig 2). In the instance of IgG-[H]-VHH, or IgG-[L]-VHH, Zhong, et al., teach that placement of the VHH on the light chains weakened the IgG HC/LC pairing, placement of the VHH at the C-terminus of the HC reduced cytotoxicity of the parental VHH, and placement of the VHH at the N-terminus of the HC maintained the cytotoxicity of the parental VHH (Zhong, et al., Sci Rep, 2022, 12, 1-11, see entire document, specifically see Fig 1 and Introduction section). Furthermore, Mullins, et al., teach that VHH orientation, position, and flexibility within a VHH bispecific construct can affect binding, potency, and antigen accessibility and that constructing multispecific constructs requires significant optimization of peptide linker lengths and positioning of the VHH elements (Mullins, et al., MAbs, 2024, 16, 1-17, see entire document, specifically see VHH architecture in bispecific antibodies section and p 6, col 2, lines 9-13). Therefore, the literature supports that there are a wide variety of bispecific VHH formats and the orientation of the VHH in the overall structure impacts the efficacy.
Artisans are well aware that a recognition domain is not limited to antibodies or fragments thereof and therefore the breadth of multispecific PD-L1 complexes is expansive. However, even by limiting the recognition domain to antibodies or antibody fragments thereof, knowledge of a given antigen (for instance a tumor antigen, an antigen on an immune cell, or a domain which recruits cytotoxic T cells) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
With regard to the structure and function of the Fc-based chimeric complexes, it is well known in the art that specific point modifications (i.e., mutations/substitutions/deletions) to one or both Fc chains which make up the Fc domain result in improved pairing (e.g., knob-in-hole) (Liu, et al., Front Immunol, 2017, 8, 1-15, see entire document, specifically see Table 1) and/or modulate antibody effector function (Wang, et al., Protein & Cell, 2018, 9, 63-73, see entire document, specifically see Table 1) and therefore require a specific structure (i.e., combination of mutations) to function (i.e., improve pairing, modify effector function, etc.). With regard to mutated IFNα2 signaling agents or signaling molecules, there is considerable variation in the structure and function (i.e., binding affinity to IFNAR). For example, Piehler, et al., teach alanine mutational analysis of IFNα2 resulting in 12 positions (L15, S25, L26, L30, R33, R144, A145, M148, R149, S152, and L153) having at least four-fold decrease in INFAR binding compared to wt IFNα2 (Piehler, et al., JBC, 2000, 275, 40425-40433, see entire document, specifically see Table I); however, it is unclear whether in the instances where binding affinity is significantly reduced compared to the wt variant that the affinity or activity would be restored upon conjugation to a PD-L1 targeting moiety or that combinations of mutations would result in the same decrease in binding affinity. Thus, it is difficult for one to imagine the full breadth of mutant IFNα2 signaling agents having reduced affinity or activity at the IFNAR receptor relative to the wt variant and that the affinity or activity is restored upon conjugation to a PD-L1 targeting moiety. Therefore, the art supports that in a fusion protein that comprises an Fc region, it is specific point mutations in one or both of the Fc chains within the Fc domain, which provides specific pairing results or modulates effector function; and that there is considerable variation in the structure and function of mutant IFNα2 signaling agents.
Accordingly, the skilled artisan would be unable to envisage the multispecific, multifunctional, and/or Fc-based chimeric protein complexes that functions to bind a second antigen, have reduced affinity or activity with a IFNα2 receptor compared to the wt, or have reduced affinity or activity with a IFNα2 receptor compared to the wt and have reduced/eliminated effector functions, promoted Fc chain pairing in the Fc domain, and/or stabilized hinge region in the Fc domain thereof a priori given the current state of the multispecific, multifunctional, and/or Fc-based chimeric protein complex arts.
Description of representative species in the specification:
MPEP § 2163 states that “a representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
To support such broad claims, the specification teaches six constructs, wherein all six constructs comprise two polypeptide chains, which are paired. The first polypeptide chain comprises in order from N- to C-terminus 2LIGG99-5*GGS linker-Fc3 (i.e., 2LIGG99 = SEQ ID NO: 24 and the whole chain = SEQ ID NO: 171) or 2LIGG99-5*GGS linker-2LIGG99-5*GGS linker-Fc3 (i.e., two anti-PDL1 VHH targeting moieties of SEQ ID NO: 24, wherein the bivalent complex = SEQ ID NO: 173). The second polypeptide chain comprises from N- to C-terminus, Fc4-10*GGS-R149A IFNα2, Fc4-10*GGS-A145G IFNα2, or Fc4-10*GGS-IFNα2 wt (i.e., SEQ ID NOs: 176, 177, or 178, respectively). There are no specific examples, wherein the bivalent construct functions with any length linker or is able to recruit cytotoxic T cells with any IFNα2 mutant without two polypeptide chains, or wherein the mutant IFNα2 is directly linked to the PD-L1 targeting moiety and restores affinity and/or activity, or wherein the Fc-based chimeric protein complex is not very specifically constructed with specific linkers, specific IFNα2 mutants, or specific Fc mutants. Therefore, given the immense breadth of the claims and the depth and diversity of the multispecific, multifunctional, and Fc-based chimeric complex repertoire as described above, such a disclosure would not reasonably be considered representative of the genus, which is only described by its binding target and/or functionality.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). In Amgen v. Sanofi, the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure).
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity to a second antigen, reduction in affinity or activity with a IFNα2 receptor compared to the wt, or have reduced affinity or activity with a IFNα2 receptor compared to the wt and have reduced/eliminated effector functions, promoted Fc chain pairing in the Fc domain, and/or stabilized hinge region in the Fc domain. Although the claims are drawn to a breadth of multispecific, multifunctional, and Fc-based chimeric complexes, the specification discloses six structures, which are able to effectively function and each of those six structures require two polypeptide chains which pair, wherein the first polypeptide chain comprises i) one or two PD-L1 VHH targeting moieties, wherein in the instance of two targeting moieties, there is a specific 5*GGS linker between each targeting moiety, ii) a 5*GGS linker, and iii) a mutated Fc chain; and the second polypeptide chain comprises i) a mutated Fc chain, ii) 10*GGS linker, and iii) a specific mutant of IFNα2.
Claim analysis:
In this instance, the prior art supports that multispecific, multifunctional, and Fc-based chimeric structures require specifically defined structures to effectively function in a biological application. As presently written, the claims define the multispecific, multifunctional, and Fc-based chimeric structures by function. The specification and working examples fail to disclose any data indicating that the breadth of structures (i.e., multispecific, multifunctional, and chimeric complexes) encompassed by the language of the instant claims will have the same function and furthermore would function without all components of the six constructs. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of multispecific, multifunctional, or Fc-based complexes that function to bind a second antigen, recruit cytotoxic t cells, restore affinity and/or activity at a IFNAR, reduce effector function, etc., at the time the instant application was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 12, 28, and 165-166 stand rejected and claims 13 and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,440,943 B2 (Kley, et al.,), herein referred to as “’943.” Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed chimeric construct especially in instant claims 12-13 and 15 are obvious variations of the chimeric protein in claim 1 of the ‘943 patent.
Issued claims of the ‘943 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘943 patent and italics corresponds to the additional claim limitations.
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1. A PD-L1 targeting moiety comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 24.
12. The PD-L1 targeting moiety of claim 1, wherein the targeting moiety further comprises a recognition domain which recognizes a tumor antigen.
13. The PD-L1 targeting moiety of claim 1, wherein the targeting moiety further comprises a recognition domain which recognizes an antigen on an immune cell.
15. The PD-L1 targeting moiety of claim 1, wherein the targeting moiety further comprises a recognition domain which recruits cytotoxic T cells to tumor cells or to the tumor environment.
28. The PD-L1 targeting moiety of claim 1, wherein the PD-L1 targeting moiety binds PD- L1 with improved affinity as compared to a PD-L1 targeting moiety having the amino acid sequence of SEQ ID NO: 1.
165. A recombinant nucleic acid composition encoding the PD-L1 targeting moiety of claim 1.
166. A host cell comprising a nucleic acid of claim 165.
In this instance, because claims 1 and 7 are silent on the species encompassed by the one or more targeting moieties, the specification was consulted to determine the scope of the generic term of one or more targeting moieties directed to a tumor cell or immune cell. Per the specification of the ‘943 patent, SEQ ID NOs: 301 or 303 of Example 8, the targeting moiety or targeting moieties comprise a single PDL1 VHH (i.e., 2LIGG99) linked to an Fc region or two PDL1 VHH (i.e., two 2LIGG99) linked to an Fc region, respectively (i.e., 100% query match to SEQ ID NO: 24 of the instant application) (see OA.APPENDIX); there may be two, three,…or ten or more targeting moieties (col 16, lines 44-47), and illustrative T cell antigens of interest include, CD8, CD3, etc. (col 21, line 60 through col 22, line 21).
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, (i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter), if new is unobvious. In this instance, it would be obvious to one of ordinary skill in the art that the targeting moiety of a fusion protein of the ‘943 patent would have a lower binding affinity than the targeting moiety alone as instantly claimed. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Furthermore, although the ‘943 patent is silent with regard to the PDL1 targeting moiety of SEQ ID NO: 24 (i.e., the targeting moiety of SEQ ID NO: 301 of the ‘943 patent) having improved binding affinity as compared to SEQ ID NO: 1 in claim 28, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the VHH anti-PDL1 antibody taught by the ‘943 patent would have the claimed properties recited in claim 28.
In this instance, because
the targeting moiety of the chimeric protein complex of claim 1 of the ‘943 patent encompasses SEQ ID NOs: 301 or 303, which are 100% query match to SEQ ID NO: 24 (i.e., anti-PDL1 VHH or anti-PDL1 VHH-linker-anti-PDL1 VHH, respectively) of the instant application (i.e., a PDL1 targeting moiety of SEQ ID NO: 24, which further comprises a recognition domain which recognizes a tumor of instant claims 1 and 12);
the targeting moiety of the chimeric protein complex of claims 1 and 7 of the ‘943 patent encompasses T cell antigens (i.e., a PDL1 targeting moiety of SEQ ID NO: 24, which further comprises a recognition domain which recognizes an antigen on an immune cell of instant claim 13); and
because the IFNα1 is able to recruit T cells via signaling cascades which is targeted to a tumor via the PDL1 targeting moiety (i.e., a PDL1 targeting moiety of SEQ ID NO: 24, which further comprises a recognition domain which recruits T cells to a tumor of instant claim 15), there is no clear difference in the scope between the products of the instant application and the ’943 patent.
Applicant argues that the PDL1 VHH of SEQ ID NO: 24 of claim 1 of the instant application provides unexpected and superior results on its own in comparison to in a chimeric protein complex as encompassed in the ‘943 patent.
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
In response to applicant's argument and as discussed supra, it is expected that a VHH alone would have superior performance (i.e., binding affinity) without being encumbered by additional building blocks of a chimeric protein complex as the orientation, positioning, etc. within the chimeric protein complex can interfere with binding affinity according to Mullins, et al., MAbs, 2024, 16, 1-17.
Claims 16-17, 22, 29, 44-45, 55, and 178-179 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,440,943 B2 (Kley, et al.,) herein referred to as “’943” as applied to claims 1, 12-13, 15, 28, and 165-166 in view of Piehler, et al., (Immunol Rev, 2012, 250, 317-334), herein referred to as “Piehler” and US 2019/0144553 A1 (Kley, et al., effectively filed 11NOV2016), herein referred to as “’553.”
The issued claims of the ‘943 patent are listed supra.
However, they do not claim: wherein the targeting moiety further comprises a modified IFNα2 that has reduced affinity or activity at the IFNAR2; or wherein the targeting moiety restores the affinity or activity at the IFNAR2; or wherein the IFNα2 comprises one or more mutations selected from R33A,... and L153A with respect to the amino acid sequence of SEQ ID NO: 81 or 82; or pharmaceutical compositions comprising the targeting moiety and a pharmaceutically acceptable carrier, an Fc-based chimeric complex comprising: i) the targeting moiety comprising SEQ ID NO: 24, ii) a modified IFNα2 that has reduced affinity or activity at the IFNAR2, and iii) a mutated Fc domain having one or more mutations that reduces or eliminates one or more effector functions, etc.; or wherein the Fc-based chimeric complex further comprised one or more linkers; is selected from IgG, IgA, etc.; or wherein the Fc-based chimeric protein complex is a homodimer or heterodimer; or a pharmaceutical composition comprising the Fc-based chimeric complex and a pharmaceutically acceptable carrier.
Nevertheless, Piehler teaches the varied binding affinities of IFNs to IFNAR1 and IFNAR2 (see entire document). Specifically, Piehler shows that muteins of IFNα2 when compared to relative binding affinity to IFNAR1 and IFNAR2 and anti-viral or anti-proliferative effects, resulted in a linear correlation between relative binding affinity and anti-proliferative potency and that only low binding affinities correlates with anti-viral activity (see Fig 8A). Fig 8A shows that by increasing binding to IFNAR1 while decreasing binding to IFNAR2 results in reduced anti-proliferative effects and at the low end of relative binding also reduces anti-viral effects. Furthermore, Piehler teaches that the low activity of IFNα1 is consistent with its low receptor binding affinity in comparison to IFNα2 (see Fig 8B and 8C).
Additionally, ‘553 teaches targeted chimeric proteins which comprise a PDL1 targeting moiety, a IFNα2 signaling agent, and an Fc-domain and pharmaceutical compositions thereof (see entire document, specifically see abstract, ¶0058-0059, and ¶0172). The IFNα2 signaling agent comprises SEQ ID NO: 1, which is 100% query match for SEQ ID NO: 8 of the instant application and mutants thereof, wherein the mutations are inclusive of L153A, R149A, and M148A (see ¶0063), which has reduced affinity and/or activity at IFNAR2 (¶0059), but is restorable upon attachment to a targeting moiety (¶0008).
It would have been obvious to artisans to modify the issued Fc-based fusion protein, comprising an anti-PDL1 targeting moiety, a modified human IFNα1, and an Fc domain as claimed by the ‘943 patent to include a modified IFNα2, as taught by Piehler and ‘553. This is because Piehler teaches that IFNα2 with increased binding affinity to IFNAR2 compared to IFNAR2 results in improved anti-proliferation and anti-viral effects and ‘553 teaches that fusing mutants of IFNα2, which have reduced affinity for IFNAR2, with a PDL1 targeting moiety results in restoration of binding affinity and/or activity at IFNAR2. One would have been motivated to do so, given the direction by Piehler that the utilization of IFNα1 vs IFNα2 results in significantly different anti-proliferation and anti-viral outcomes. There would have been a reasonable expectation of success, given the knowledge that by modifying the chimeric protein comprising a PDL1 targeting moiety, a modified IFNα1, and Fc domain taught by the ‘943 patent to substitute the modified IFNα2 would lead to a more biologically effective construct as taught by Piehler and ‘553.
Claims 1, 15, 28, and 165-166 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,583,898 B2 (Kley, et al., Application No. 17/813985), herein referred to as “’898.” Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed chimeric construct especially in instant claims 12-13 and 15 are obvious variations of the chimeric protein in claim 1 of the ‘898 patent.
Issued claims of the ‘898 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘898 patent and italics corresponds to the additional claim limitations.
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1. A PD-L1 targeting moiety comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 24.
15. The PD-L1 targeting moiety of claim 1, wherein the targeting moiety further comprises a recognition domain which recruits cytotoxic T cells to tumor cells or to the tumor environment.
28. The PD-L1 targeting moiety of claim 1, wherein the PD-L1 targeting moiety binds PD- L1 with improved affinity as compared to a PD-L1 targeting moiety having the amino acid sequence of SEQ ID NO: 1.
165. A recombinant nucleic acid composition encoding the PD-L1 targeting moiety of claim 1.
166. A host cell comprising a nucleic acid of claim 165.
In this instance, because claims 1 is silent on the species encompassed by the VHH targeting moiety that specifically binds to PDL1, the specification was consulted to determine the scope of the generic term of targeting moiety comprising a recombinant VHH that binds PDL1. Per the specification of the ‘898 patent, SEQ ID NO: 301 of Example 8, the PDL1 targeting moiety comprises a single PDL1 VHH (i.e., 2LIGG99) linked to an Fc region (i.e., 100% query match to SEQ ID NO: 24 of the instant application) (see OA.APPENDIX).
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, (i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter), if new is unobvious. In this instance, it would be obvious to one of ordinary skill in the art that the targeting moiety of a fusion protein of the ‘898 patent would have a lower binding affinity than the targeting moiety alone as instantly claimed. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Furthermore, although the ‘898 patent is silent with regard to the PDL1 targeting moiety of SEQ ID NO: 24 (i.e., the targeting moiety of SEQ ID NO: 301 of the ‘898 patent) having improved binding affinity as compared to SEQ ID NO: 1 in claim 28, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the VHH anti-PDL1 antibody taught by the ‘898 patent would have the claimed properties recited in claim 28.
In this instance, because
the targeting moiety of the chimeric protein complex of claim 1 of the ‘898 patent encompasses SEQ ID NO: 301, which is 100% query match to SEQ ID NO: 24 (i.e., anti-PDL1 VHH) of the instant application (i.e., a PDL1 targeting moiety of SEQ ID NO: 24 of instant claim 1); and
because the IFNα1 is able to recruit T cells via signaling cascades which is targeted to a tumor via the PDL1 targeting moiety (i.e., a PDL1 targeting moiety of SEQ ID NO: 24, which further comprises a recognition domain which recruits T cells to a tumor of instant claim 15), there is no clear difference in the scope between the products of the instant application and the ’898 patent.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
