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 .
Response to Amendment
Applicant’s remarks and amendments received 07/28/2026 have been acknowledged. Claims 41, 58, 68, and 72 have been amended. Claims 42, 63, 69, 70, 73, and 74 have been canceled.
Claim Objections
Claim 72 recites “wherein the Fab heavy chain is connected to the C-terminus of the scFv via the linker and wherein a polypeptide comprising the scFv, the linker, and the Fab heavy chain polypeptide comprises SEQ ID NO: 22”. SEQ ID NO: 22 comprises the scFv, the Fab light chain connected to the C-terminus of the scFv via a linker (see Table 8 of the Specification).Therefore, it is believed the phrase should read: “wherein the Fab light chain is connected to the C-terminus of the scFv via the linker and wherein a polypeptide comprising the scFv, the linker, and the Fab light chain polypeptide comprises SEQ ID NO: 22.
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.
Claims 41 and 58 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.
Claims 41 and 58 allow CDR sets and variable chains of different anti-PD-L1 Fab clones to be interchanged and paired together, yet there is no evidence that that HCDRs and LCDRs (or VH and VL chains) from different clones can be paired with one another without substantially impacting the ability of the resulting antibody to bind to PD-L1 as it does not appear that each clone is a variant/mutant of a single starting clone. Further, there is no guidance provided in the specification regarding which HCDR sets and LCDR sets (or VH and VL chains) of structurally distinct anti-PD-L1 Fab clones can be interchanged such that binding for PD-L1 is maintained.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or 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 genus (MPEP 2163).
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 at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claims 41 separately lists possible heavy chain CDRs and light chain CDRs present in the PD-L1 binding domain. Because the claim does not expressly require the heavy-and light-chain CDRs to be selected from the same PD-L1 Fab clone, the claim encompasses combinations in which the heavy chain CDR set from one PD-L1 clone is paired with the light chain CDR set from a different PD-L1 clone.
Similarly, claim 58 separately lists possible VH chains and VL chains present in the PD-L1 binding domain. Because the claim does not expressly require the VH and VL chain pair to be selected from the same PD-L1 Fab clone, the claim encompasses combinations in which the VH chain from one PD-L1 clone is paired with the VL chain from a different PD-L1 clone.
While the specification discloses the sequences of different PD-L1-specific Fabs (see Tables 4-6), the specification does not demonstrate or provide evidence that HCDRs and LCDRs (or VH and VL chains) from different clones can be paired with one another without substantially impacting the ability of the resulting antibody to bind to PD-L1. The different PD-L1 Fab clones do not appear to be variants of a single starting clone, so it is not apparent that the HCDRs and LCDRs (or VH and VL chains) from different clones are interchangeable. Nor does the specification provide any guidance for predicting which combination of HCDR and LCDR sets (or VH and VL chains) from different anti-PD-L1 clones would be operable across the claim scope. Without further guidance, artisans could not readily determine which HCDR sets and LCDR sets (or VH and VL chains) of structurally distinct anti-PD-L1 Fab clones can be interchanged such that binding for PD-L1 is maintained.
Therefore, the claimed genus of multispecific antibodies lacks adequate written description because there does not appear to be any correlation between the structure of the claimed PD-L1 binding domains and the function of binding to PD-L1. 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 PD-L1 binding domains at the time the instant application was filed.
Scope of Enablement
Claims 41 and 58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a multispecific antibody comprising a PD-L1-binding domain having compatible HCDR and LCDR sets (or VH and VL chain pairs) does not reasonably provide enablement for multispecific antibody variants comprising a PD-L1 binding domain in which the HCDRs and LCDRs (or VH and VL chains) of different PD-L1 clones are paired together without evidence that the resulting antibody is capable of binding to PD-L1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The nature of the invention relates multispecific CD28 x PD-L1 antibodies that can be used to increase the T cell cytotoxicity of T cell engagers against tumor cells (see Para. 0003 and Para. 0044-0050 of Specification).
Claims 41 separately lists possible heavy chain CDRs and light chain CDRs present in the PD-L1 binding domain. Because the claim does not expressly require the heavy-and light-chain CDRs to be selected from the same PD-L1 Fab clone, the claim encompasses combinations in which the heavy chain CDR set from one PD-L1 clone is paired with the light chain CDR set from a different PD-L1 clone.
Similarly, claim 58 separately lists possible VH chains and VL chains present in the PD-L1 binding domain. Because the claim does not expressly require the VH and VL chain pair to be selected from the same PD-L1 Fab clone, the claim encompasses combinations in which the VH chain from one PD-L1 clone is paired with the VL chain from a different PD-L1 clone.
While the specification discloses the sequences of different PD-L1-specific Fabs (see Tables 4-6), the specification does not demonstrate or provide evidence that HCDRs and LCDRs (or VH and VL chains) from different clones can be paired with one another without substantially impacting the ability of the resulting antibody to bind to PD-L1. The different PD-L1 Fab clones do not appear to be variants of a single starting clone, so it is not apparent that the HCDRs and LCDRs (or VH and VL chains) from different clones are interchangeable. Nor does the specification provide any guidance for predicting which combination of HCDR and LCDR sets (or VH and VL chains) from different anti-PD-L1 clones would be operable across the claim scope.
It is well-known in the art that, in order to bind antigen, a conventional antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6, of record). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chain, and not either alone, that determines the final antigen specificity. The prior art, however, did not establish that HCDRs and LCDRs (or the VH and VL chains) from structurally distinct antibody clones could be paired while retaining antigen binding in the absence of additional experimental testing to confirm that such modified antibodies retained functional activity. As such, artisans would not be able to readily predict which HCDR sets and LCDR sets (or VH and VL chains) of structurally distinct anti-PD-L1 Fab clones can be interchanged such that the resulting antibody retains the ability to bind to PD-L1.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including library construction, mutagenesis, and screening techniques. Even at this high level of skill, however, the effect of combining HCDR sets and LCDR sets (or VH and VL chains) from different anti-PD-L1 Fab clones on antigen binding could not have been readily predicted without additional testing. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement (MPEP 2164.06). Thus, the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus. In the absence of guidance regarding the interchangeability of CDR sets and variable regions across different anti-PD-L1 Fab clones, artisans would necessarily have to engage in undue trial-and-error experimentation to generate and test numerous combinations encompassed by the claim scope to determine which retain binding to PD-L1.
Therefore, the specification is not enabling over the full scope of the claims.
Claim Rejections - 35 USC § 103
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.
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 3, 9, 15, 28, 30, 36, 38, 43, 48, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Ellmark et al (US20180118841A1), hereinafter Ellmark, in view of Rader (Rader, Christoph. "Overview on concepts and applications of Fab antibody fragments." Current protocols in protein science 55.1 (2009): 6-9, of record), Correnti et al (Correnti, Colin E et al. “Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation.” Leukemia vol. 32,5 (2018): 1239-1243. doi:10.1038/s41375-018-0014-3, of record), hereinafter Correnti, and Georges et al (US20200199234A1, of record, published 06/25/2020 prior to the date of the provisional application filed 10/30/2020 and having a different inventive entity), hereinafter Georges.
Ellmark discloses bispecific antibodies comprising first and second antigen binding domains (B1 and B2) capable of binding to different T cell targets (Abstract). CD28 is listed as an exemplary T cell target; as such, one of the binding domains in the bispecific antibody is an CD28 binding domain. Bispecific antibodies targeting two different T cell targets have the potential to specifically activate the immune system in locations where both targets are over-expressed (Para. 0011). The net effects of the bispecific antibodies targeting two T cell receptors thus include 1) a higher degree of immune activation compared to monospecific antibodies, 2) a higher degree of induction of ADCC compared to monospecific binders in combination, and 3) more directed/localized immune activation, which increases the therapeutic window and minimizes toxic side effects (Para. 0013). The B1 and/or B2 antigen-binding domains can be an intact IgG, scFv, Fab, and/or single domain antibody (Para. 0032). In exemplary embodiments, the bispecific antibody is an IgG-scFv format, wherein B1 is an intact IgG and B2 is an scFv attached to the N-terminus of a light or heavy chain of the IgG, or vice versa (Para. 0038). The IgG-scFv can be either in the VH-VL or VL-VH orientation (Para. 0047). As such, either the VH or VL chain of scFv can be attached to the N-terminus of the heavy or light chain of IgG. The B1 and B2 antigen-binding domains (e.g. IgG and scFv) can be joined via a polypeptide linker rich in glycine for flexibility and serine for solubility such as a linker having the amino acid sequence of SEQ ID NO: 144 (GGGGSGGGGSGGGGS), corresponding to SEQ ID NO: 18 of the instant claims (Para. 0048-0049) The polypeptide linker of SEQ ID NO: 4 has the format (GGGGS)n (SEQ ID NO: 60 of the instant claims), wherein n is 3.
Ellmark does not specifically teach that 1) the bispecific antibody is a Fab-scFv (or scFv-Fab) format, wherein the scFv is attached to the N-terminus of the light or heavy chain of the Fab fragment; 2) the different T cell targets are CD28 and PD-L1, or 3) the CD28 binding domain has the CDRs of SEQ ID NOs: 1-6; the VH/VL chains of SEQ ID NOs: 7 and 8; and the full-length amino acid sequence of SEQ ID NO: 9, wherein the linker (G4S)3 is present between the VH and VL chains (see Table 3 of the Specification).
However, Rader teaches that Fab fragments are superior to IgG due to their higher mobility and tissue penetration capability, reduced circulatory half-life, ability to bind antigen monovalently without mediating antibody effector functions, and lower immunogenicity (see Introduction).
Correnti teaches that T-cell coactivation with a PD-L1/CD28 bispecific antibody enhances T-cell activity against PD-L1 positive cancer cells, particularly when paired with a CD3-based bispecific T cell engager (BiTE), and overcomes PD-L1 mediated resistance while minimizing toxic off-target effects (see last paragraph on Page 3 to first two paragraphs on Page 4).
Georges teaches an anti-CD28 antigen binding molecule comprising the VH chain having the amino acid sequence of SEQ ID NO: 42 and a VL chain having the amino acid sequence of SEQ ID NO: 27 (see Para. 0771). The VH chain of SEQ ID NO: 42 corresponds to SEQ ID NO: 7 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 1-3 recited in the instant claims; and the VL chain of SEQ ID NO: 27 corresponds to SEQ ID NO: 8 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 4-6 recited in the instant claims. The antigen binding molecule can be an antibody or fragment thereof such as a single chain variable fragment (scFv) wherein the VH and VL chains are connected via a short linker peptide of 10 to 25 amino acids (Para. 0166-0168, 0176-0177, and 0182). Several peptide linkers are contemplated including the linker (G4S)3 (SEQ ID NO:151) (Para. 0243 and 0245). Taken together, Georges renders obvious the anti-CD28 binding domain present in the multispecific antibodies of the instant claims, wherein the VH and VL chains of the scFv antibody are connected by the peptide linker (G4S)3 to yield SEQ ID NO: 9 of the instant claims.
It would have been obvious to one of ordinary skill in the art to modify the IgG-scFv bispecific antibody such that 1) the IgG arm is replaced with a Fab fragment, wherein the VH or VL of the scFv is attached to the N-terminus of the Fab heavy chain via the linker (G4S)3 (GGGGSGGGGSGGGGS); 2) the T cell targets are CD28 and PD-L1; and 3) the CD28 binding domain is substituted by that disclosed by Georges comprising the VH and VL chains of SEQ ID NOs: 42 and 72, respectively (corresponding to SEQ ID NOs: 7 and 8 of the instant claims), wherein the VH and VL chains are connected via a (G4S)3 linker. One of ordinary skill in the art would have been motivated to do so since Fab fragments have several advantages over full-length IgG, including increased tissue penetration, reduced circulatory half-life, lower immunogenicity, and ability to target antigen monovalently without triggering antibody effector functions as taught by Rader. Moreover, a PD-L1/CD28 bispecific antibody can enhance T-cell activity against PD-L1 positive cancer cells, particularly when paired with a CD3-based BiTE, and overcome PD-L1 mediated tumor resistance while minimizing toxic off-target effects as taught by Correnti. Additionally, it would have been obvious to artisans to substitute CD28-binding domain disclosed by Ellmark with that disclosed by Georges since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Lastly, the binding domains against targets CD28 and PD-L1 can be formatted interchangeably (e.g. scFv targets CD28 and Fab targets PD-L1, or vice versa). Therefore, one of ordinary skill in the art would reasonably expect a scFv-Fab bispecific antibody that binds to the T cell targets CD28 and PD-L1 can effectively treat cancer in a subject.
Claims 41, 58, 68, and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Ellmark in view of Rader, Correnti and Georges, as applied to claims 3, 9, 15, 28, 30, 36, 38, 43, 48, and 53 above, and further in view of Cardarelli et al (US20180179282A1, of record), hereinafter Cardarelli, and Chen et al (Chen, Xiaoying et al. “Fusion protein linkers: property, design and functionality.” Advanced drug delivery reviews vol. 65,10 (2013): 1357-69. doi:10.1016/j.addr.2012.09.039, of record), hereinafter Chen.
The combined teachings of Ellmark in view of Rader, Correnti, and Georges disclose an scFv-Fab bispecific antibody that binds to the T cell targets CD28 and PD-L1, wherein a) the CD28 binding domain has VH and VL chains corresponding to the amino acid sequences of SEQ ID NOs: 7 and 8 of the instant claims and connected via a (G4S)3 linker; and b) the VH or VL chain of the scFv is connected to the N-terminus of the Fab heavy chain via a (G4S)3 linker. However, the teachings of the Ellmark in view of Rader, Correnti, and Georges differ from the instantly claimed invention in that it is not specifically taught that the PD-L1 binding domain has the structure recited in the instant claims nor is it taught that the antigen binding domains of the multispecific antibody are joined by the shorter glycine-serine rich linker GGGGS [or G4S)1] [Note, the multispecific Ab constructs of SEQ ID NOs: 21 and 22 recited in the instant claims have the (G4S)1 between antigen-binding domains, see Table 8 of the Specification].
However, Cardarelli teaches an anti-PD-L1 antibody comprising the light chain having the amino acid sequence of SEQ ID NO: 7 and a heavy chain having the amino acid sequence of SEQ ID NO: 8 (Para. 0072). The light chain of SEQ ID NO: 7 corresponds to SEQ ID NO: 16 or 20 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 13-15 of the instant claims. The heavy chain of SEQ ID NO: 8 corresponds to the amino acid sequence of SEQ ID NO: 17 or 23 of the instant claims and fully comprises the CDRs of SEQ ID NO: 10-12 of the instant claims.
Chen teaches that the most commonly used flexible linkers in multi-domain fusion proteins have sequences consisting primarily of stretches of Gly and Ser residues, particularly (G4S)n. The length of the GS linker can be optimized to achieve appropriate separation of the functional domains, or to maintain necessary inter-domain interactions, by adjusting the copy number “n”. In particular, the flexible GGGGS linker [(G4S)n = 1] has been shown to improve the biological activity of fusion proteins (see Section 3, 3. 1 and Table 3).
It would have been obvious to one of ordinary skill in the art to modify the bispecific CD28 x PD-L1 scFv-Fab antibody taught by combined teachings of the prior art such that the PD-L1 binding domain is substituted with that disclosed by Cardarelli comprising the VH and VL chains of SEQ ID NOs: 42 and 72, respectively. One of ordinary skill in the art would have been motivated to do so since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Further the length of a glycine-serine rich linker joining the functional domains of the multispecific antibody can be determined by routine experimentation and thus encompass specific embodiments of the claimed invention wherein the GS linker is the shorter but flexible GGGGS peptide. Similarly, the orientation of the antigen-binding domains as well as the VH and VL chains present in the scFv can also be determined by routine experimentation. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The combined teachings of the prior art render obvious the multispecific antibody of the instant claims comprising the recited anti-CD28 scFv and anti-PD-L1 Fab domains, wherein the antigen-binding domains are joined by the (G4S)1 linker. Therefore, one of ordinary skill in the art would reasonably expect the scFv-Fab bispecific antibody disclosed by the combined teachings of the prior art to effectively treat cancer in a subject.
Response to Arguments
Applicant's arguments filed 07/28/2026 have been fully considered but they are not persuasive.
With respect to the 35 USC 112(a) rejections, Applicant argues that claims 41 and 58 as amended to incorporate the LCDR2 sets and VL chains of PD-L1 binding domain overcomes the rejection.
In response to Applicant’s arguments, the Examiner notes that claims 41 and 58 (as amended) allow CDR sets and variable chains of different anti-PD-L1 Fab clones to be interchanged and paired together, yet there is no evidence that that HCDRs and LCDRs (or VH and VL chains) from different clones can be paired with one another without substantially impacting the ability of the resulting antibody to bind to PD-L1 as it does not appear that each clone is a variant/mutant of a single starting clone. Further, there is no guidance provided in the specification regarding which HCDR sets and LCDR sets (or VH and VL chains) of structurally distinct anti-PD-L1 Fab clones can be interchanged such that binding for PD-L1 is maintained.
Thus, the 35 USC 112(a) rejections are maintained.
With respect to 35 USC 103 rejections, Applicant argues the following:
The result of any obviousness inquiry must, generally, provide a predictable result or have an expectation of success. See MPEP § 2141(III). To have a reasonable expectation of success, "one must be motivated to do more than merely "vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful." Medichem, S.A. V. Roblabo, 327 F.3d 1157, 1165 (Fed. Cir. 2006).
Here, the Office acknowledges that Ellmark does not teach at least two features in the of the claimed invention: 1) a multispecific antibody comprising a CD28 binding domain and a PD- L1 binding domain; and 2) the specific anti-CD28 binding domain CDR sequences. Ellmark teaches multiple specific antibodies binding to two different T-cell targets, and the exemplary T-cell targets includes OX40, CTLA-4, CD137, CD27, GITR, and CD28. Ellmark merely discloses that CD28 can be one of the many T-cell targets and does not provide any indication that CD28 is the optimal choice. Moreover, Ellmark does not disclose PD-L1 as a target. As such, there is no motivation for a person skilled in the art to replace one of the exemplary T-cell targets with PD-L1 to arrive at a multispecific antibody targeting both CD28 and PD-L1.
In addition, a person of ordinary skill in the art would readily recognize that even a single amino acid change in the antibody sequences, especially in the CDR sequences, can dramatically change the function of the antibody. Ellmark does not teach the CD28 binding domain sequences in the claimed invention. The Office alleges that Georges teaches the anti-CD28 CDRs and sequences. However, Georges discloses numerous anti-CD28 sequences (See, e.g., Table B in George). Yet, George does not provide any guidance to select the specific CD28 CDRs as claimed.
In order to arrive at the claimed invention, a person of ordinary skill in the art would have
to i) pick CD28 out of many T-cell targets taught in Ellmark, ii) replace one of the T-cell targets taught by Ellmark with PD-L1, and iii) select the CD28 CDRs out of the many CD28 antibodies disclosed in Georges. As such, when faced with numerous possibilities and unpredictable art, a person of ordinary skill in the art would have no reasonable expectation of success, based on the teachings in Ellmark in view of Rader, Correnti, and Georges, to arrive at the invention in claim 3.
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). The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Ellmark in view of Rader teaches multispecific antibody formats, including scFv-Fabs, for binding to different T cell targets such as CD28. Correnti further teaches that dual targeting of CD28 and PD-L1 by a multispecific antibody enhances T cell activity against cancer cells. Thus, artisans would be motivated to modify the multispecific antibody disclosed by Ellmark to target both CD28 and PD-L1 in order to enhance immune activity against cancer cells. The fact that PD-L1 is not among the T cell targets exemplified in Ellmark does not teach away from the combination. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971) (MPEP 2123). Further, obviousness does require the prior art to identify the claimed embodiment as the “optimal” embodiment.
Moreover, Georges teaches the claimed anti-CD28 antibody sequences. The fact that Georges discloses other anti-CD28 antibodies does not preclude selection of the claimed antibody. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v.Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (MPEP 2144.07). In this case, the artisan had reason to select an anti-CD28 antibody for use in the CD28 x PD-L1 multispecific antibody taught by the combined references, and the claimed antibody was known to target CD28. Georges discloses a finite list of anti-CD28 antibodies. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In reFout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982) (MPEP 2144.06). Applicant has not established that selection of the claimed anti-CD28 antibody from among the other anti-CD28 antibodies disclosed by Georges would have been unpredictable or beyond ordinary skill in the art.
Lastly, the possibility that changes in antibody sequence may affect antibody properties does not establish that the artisan would have lacked a reasonable expectation of success. Obviousness does not require absolute predictability (MPEP 2143.02). The combined teachings of the cited prior art would have provided a reasonable expectation that a CD28 x PD-L1 multispecific antibody incorporating the known anti-CD28 antibody sequences of Georges could be made and used to enhance T cell activity as taught by Correnti. Applicant has not identified evidence of an unexpected result, superior property, or other objective evidence achieved/possessed by the claimed anti-CD28 x PD-L1 multispecific antibody sufficient to rebut the prima facie case of obviousness.
Thus, the 35 USC 103 rejections are maintained.
Conclusion
No claims are allowable.
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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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
