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 .
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, drawn to an activatable proprotein homodimer, in the reply filed on 04/23/2026 is acknowledged. Applicant further elects without traverse the following species: (a) a Fab region that targets PD-1 having the VH and VL pair of SEQ ID NOs: 3 and 4, respectively; (b) a hinge region having the amino acid sequence of SEQ ID NO: 42 as well as the CH2 and CH3 domains of the Fc region having the amino acid sequence of SEQ ID NOs: 57 and 58, respectively; (c) a non-cleavable first linker having the amino acid sequence of SEQ ID NO: 188; (d) an IL-2 amino acid sequence of SEQ ID NO: 85 with R38D/K43E/C125S mutations; (e) a second linker having the amino acid sequence of SEQ ID NO: 93; and (f) an IL-2Ra amino acid sequence of SEQ ID NO: 90 with D6R/E29K mutations.
Claims 34, 36, 37, 38, 40, 41, 42, 43, 52, and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/23/2026.
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 6, 7, and 32 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.
The claims encompass polypeptide chains in which at most 10% of the structure can have random, undefined amino acid mutations across several domains (e.g. IL-2, IL-2Ra, hinge region, CH1 chain, CL chain, cleavable linker, non-cleavable linker, etc.). The specification does not provide guidance for identifying polypeptide chain variants that will predictably yield an activatable proprotein homodimer with preserved structure and function.
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.
The claims are broadly drawn to an activatable proprotein homodimer comprising first and second polypeptides each comprising in the N- to C-terminal direction the VH region, a first linker, an IL-2 protein, a second cleavable linker, and an IL-2Ra protein, wherein the first and second polypeptides comprise an amino acid sequence at least 90% identical to SEQ ID NO: 146. The activatable proprotein homodimer also comprises two of a third polypeptide that associates with the first and second polypeptides to form a Fab region, wherein the third polypeptide comprises an amino acid sequence at least 90% identical to SEQ ID NO: 147.
The specification teaches that in these activatable proprotein homodimers, the binding interaction between IL-2 and IL-2Ra proteins form a biologically-inactive complex by masking the binding sites of the IL-2 proteins that would otherwise bind to an IL-2Rβ/γc chain present on the surface of immune cells. The proprotein homodimer remains inactive or substantially inactive in plasma. The homodimer is targeted to the tumor microenvironment (TME) by the anti-PD-1 Fab The activatable proprotein homodimer is then activated via protease cleavage in the TME, thereby releasing the IL-2Ra proteins and exposing the binding sites of the IL-2 protein that target IL-2Rβ/γc chain present on the surface of immune cells (page 10 and 1st and 2nd paragraphs on page 14 of Specification) and age 10 of Specification). This allows for selective and localized activation of the IL-2 protein in the tumor microenvironment, enhancing tissue penetration and reducing undesirable systemic effects of IL-2 (3rd paragraph on Page 23).
Several exemplary activatable proproteins are disclosed in Table S4 including the P41222037 comprising the claimed polypeptide chains 1 and 2 of SEQ ID NOs: 146 and 147, respectively (see Page 45 to 46). However, as presently written, the claims encompass polypeptide chains in which at most 10% of the structure can have random, undefined amino acid mutations across several domains (e.g. IL-2, IL-2Ra, hinge region, CH1 chain, CL chain, cleavable linker, non-cleavable linker, etc.) that can negatively impact the overall structure and function of the activatable proprotein homodimer. The effect of mutations within these domains is not readily predictable, and such mutations may disrupt essential functions such as masking activity of IL-2/IL-2Ra binding, cleavage of the linker in the tumor microenvironment to release IL-2Ra and allow IL-2a to bind to IL-2Rβ/γc present on immune cells, the ability of first and second polypeptides to dimerize and form the activatable proprotein complex, and binding affinity to PD-1. There is no guidance provided in the specification about which specific amino acids mutations can made in the genus of polypeptide chains such that the overall structure and function of the activatable proprotein homodimer is maintained. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the polypeptide so as not to disrupt the structure and/or activity of the activatable proprotein homodimer.
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 activatable proproteins comprising polypeptide chains having undefined amino acid mutations at the time the instant application was filed.
Scope of Enablement
Claims 6, 7, and 32 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 an activatable proprotein homodimer comprising fully defined polypeptides and their respective domains (e.g. IL-2/IL-2Ra, cleavable linker, non-cleavable linker, CH1, CL, hinge regions, etc.), does not reasonably provide enablement for activatable proprotein homodimer comprising polypeptide chain variants comprising undefined amino acid mutations, wherein the specification provides no data or technical guidance demonstrating that such variants retain functional activity. 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 to an activatable proprotein homodimers composed of two identical polypeptide chains and designed to remain biologically inactive until it reaches the tumor microenvironment where it is cleaved by local proteases to release IL-2Ra proteins and expose binding sites of IL-2 for IL-2Rβ/γc chain present on the surface of immune cells.
The claims are broadly drawn to an activatable proprotein homodimer comprising first and second polypeptides each comprising in the N- to C-terminal direction the VH region, a first linker, an IL-2 protein, a second cleavable linker, and an IL-2Ra protein, wherein the first and second polypeptides comprise an amino acid sequence at least 90% identical to SEQ ID NO: 146. The activatable proprotein homodimer also comprises two of a third polypeptide that associates with the first and second polypeptides to form a Fab region, wherein the third polypeptide comprises an amino acid sequence at least 90% identical to SEQ ID NO: 147.
The specification teaches that in these activatable proprotein homodimers, the binding interaction between IL-2 and IL-2Ra proteins form a biologically-inactive complex by masking the binding sites of the IL-2 proteins that would otherwise bind to an IL-2Rβ/γc chain present on the surface of immune cells. The proprotein homodimer remains inactive or substantially inactive in plasma. The homodimer is targeted to the tumor microenvironment (TME) by the anti-PD-1 Fab The activatable proprotein homodimer is then activated via protease cleavage in the TME, thereby releasing the IL-2Ra proteins and exposing the binding sites of the IL-2 protein that target IL-2Rβ/γc chain present on the surface of immune cells (page 10 and 1st and 2nd paragraphs on page 14 of Specification) and age 10 of Specification). This allows for selective and localized activation of the IL-2 protein in the tumor microenvironment, enhancing tissue penetration and reducing undesirable systemic effects of IL-2 (3rd paragraph on Page 23).
Several exemplary activatable proproteins are disclosed in Table S4 including the P41222037 comprising the claimed polypeptide chains 1 and 2 of SEQ ID NOs: 146 and 147, respectively (see pages 45 to 46). However, as presently written, the claims encompass polypeptide chains in which at most 10% of the structure can have random, undefined amino acid mutations across several domains (e.g. IL-2, IL-2Ra, hinge region, CH1 chain, CL chain, cleavable linker, non-cleavable linker, etc.) that can negatively impact the overall structure and function of the activatable proprotein homodimer. The effect of mutations within these domains is not readily predictable, and such mutations may disrupt essential functions such as masking activity of IL-2/IL-2Ra binding, cleavage of the linker in the tumor microenvironment to release IL-2Ra and allow IL-2a to bind to IL-2Rβ/γc present on immune cells, the ability of first and second polypeptides to dimerize and form the activatable proprotein complex, and binding affinity to PD-1. The specification does not provide sufficient guidance sufficient to establish which amino acid mutations can be in the genus of polypeptide chain variants such that the overall structure and function of the activatable proprotein homodimer is maintained.
The IL-2/IL-2Ra interaction plays an important role in maintain the claimed activatable proprotein homodimer in a masked state until activation within the tumor microenvironment. However, the art recognizes that cytokine-receptor interactions can be modulated by amino acid substitutions at the binding interface. For example, amino acid substitutions in IL-2 have been shown to alter affinity for IL-2Ra, including substitutions that increase receptor affinity (e.g. V69A and Q74P; Rao et al, see Abstract, Page 1083, and Table I) as well as substitutions that reduce receptor affinity (see, e.g. Sun et al, Abstract). These findings demonstrate that the effect of amino acid substitutions on the IL-2/IL-2Ra interaction is not readily predictable. The specification discloses exemplary cysteine substitutions that can be made in IL-2 and IL-2Ra to facilitate formation of disulfide bonds (pages 36-41); yet, the claims as presently written encompass IL-2 and IL-2Ra mutations having random, undefined amino acid mutations. Without further guidance, artisans would be required to generate and screen numerous IL-2 and IL-2Ra variants to determine which maintain sufficient binding to preserve masking while still allowing activation of the construct following cleavage. The same concern extends to other regions of the polypeptide chains in which the undefined amino acid mutations can occur. The cleavable linker, for example, is responsible for release of the masking moiety (IL-2Ra) and exposure of IL-2 following activation. As such, random amino acid mutations within the linker may negatively impact the release of the masking moiety. However, the specification does not provide sufficient guidance for predicting which amino acid mutations will preserve cleavage of the linker and activation of the proprotein commensurate in scope of the claims.
Likewise, the undefined amino acid mutations can be present within structural regions of the polypeptide chain’s antigen-binding domain, such as the hinge region and the CH1 and CL chains. The hinge region contributes to flexibility and promote dimerization through interchain interactions (see, e.g. Thompson et al, Abstract, Para. 0007, and Para. 0128-0130) while the CH1 and CL chains are involved in correct immunoglobulin heavy chain folding and assembly (see, e.g. Feige et al, Summary). As such, changes within these regions may disrupt structural integrity and assembly of the activatable proprotein homodimers.
A person of ordinary skill in the art at the time of filing would have had experience in protein engineering, including mutagenesis and screening techniques. Even at this high level of skill, however, the effect of random amino acid mutations across several domains on the structure and functional activity of the activatable proprotein homodimer cannot be 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). By analogy, the claims encompass numerous activatable proprotein variants such that the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus.
Therefore, the specification is not enabling over the full scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7, 9-14, 19-20, 24-26, 30-32, and 39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites an activatable proprotein comprising a VH and VL region of an antibody that specifically binds to PD-1, wherein the activatable proprotein comprises a first and second polypeptide each comprising in the N- to C-terminal direction the VH region, a first linker, an IL-2 protein, a second linker, and an IL-2Ra protein. However, claim 1 does not recite any polypeptide comprising a VL region. Claim 2 (which depends on claim 1) then recites that the proprotein further comprises two additional polypeptides (comprising VH and CL chains, see Tables P1 and S4 of the specification) that associate with the polypeptides of claim 1 to form a Fab comprising the VH and VL chains. Thus, it is unclear whether 1) the VL chain recited in claim 1 is already present in the proprotein of claim 1; 2) the VL chain(s) are first introduced by the additional polypeptides of claim 2 ; or 3) the proprotein comprises additional antigen-binding domains beyond that already required by claim 1. Therefore, the metes and bounds of the patent protection desired. Claims 3-7, 9-14, 19-20, 24-26, 30-32, and 39 depend directly or indirectly from claims 1 or 2 but do not cure the deficiencies of either claim.
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 1-5, 9, 13, 14, 19, 20, 24, 25, 26, 30, 31, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (WO2021055568A1), hereinafter Li in view of Korman (US20090217401A1) and Thompson et al (US20080227958A1), hereinafter Thompson.
Li discloses an activatable proprotein, comprising a first polypeptide and a second polypeptide with the first and second polypeptides each comprising, in the N-to-C-terminal orientation, a binding moiety, a first linker, an IL-2 protein variant, a second linker, and an IL-2Ra protein; wherein the IL-2 protein variant of the first polypeptide binds to the IL-2 binding protein of the second polypeptide; and the IL-2 binding protein of the first polypeptide binds to the IL-2 protein variant of the second polypeptide; wherein said binding masks a binding site of IL-2 protein variant(s) that otherwise binds to an IL-2Rβ/γc and/or IL-2Rα/ β/γc chain present on the surface of an immune cell in vitro or in vivo; wherein at least one of the first or the second linker is a cleavable linker (Abstract, Claims, Brief Summary of the Invention from Pages 2-3, and and Page 20, Ln. 25-37 to Page 21, Ln. 1-4).). The IL-2 protein variant can comprise an amino acid sequence of SEQ ID NO: 29 corresponding to SEQ ID NO: 85 of the instant claims (human IL-2 mature form with R38D, K43E, and C125S substitution) (Para. 0127-0127 and Table S1 on Page 14 as well as Para. 0139 -0140 showing IL-2 protein variant/IL-2Ra protein variant pairs). The IL-2Ra protein has the amino acid sequence of SEQ ID NO: 53 corresponding to SEQ ID NO: 90 (human IL-2Ra-sushi with D6R and E29K mutations as well as Para. 0139 -0140 showing IL-2 protein variant/IL-2Ra protein variant pairs) of the instant claims (Para. 0134-0135 and Table S2 on Page 17). The binding moieties of the first and second polypeptides dimerize together to further stabilize the activatable proprotein and mask the binding of the IL-2 proteins to their cognate receptors (Page 21, Ln. 30-37 to Page 22, Ln. 1-6; and Page 32, Ln. 18-22). A binding moiety comprises, in an N- to C- terminal orientation: (1) an antigen binding domain of an immunoglobulin (including antigen binding fragments or variants thereof); and (2) an immunoglobulin constant domain (including fragments or variants thereof), wherein the constant domain comprises a CH2 domain, a CH3 domain, or a CH2CH3 domain of an immunoglobulin from the class selected from IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, and IgM (Page 33, Ln. 16-31). In addition, a hinge region can also be present to provide flexibility between different domains of the proprotein (Page 33, Ln. 26-31). The antigen binding domain of the binding moiety can bind to a human antigen (Page 33, Ln. 3-7). Exemplary binding moieties are disclosed in Table M1 on Pages 32-33, including Fab-CH2CH3. In some embodiments, the first linker present in the activatable proprotein is a non-cleavable linker whereas the second linker is a cleavable linker (Page 34, Ln. 9-11). The binding moiety having a Fab region thus comprises not only the VH region of the first and second polypeptides of the instant claims but also the VL region of the third polypeptide of the instant claims. In other words, the third polypeptide is present in the binding moiety. The cleavable linker can comprise at least one protease cleavage site; exemplary cleavable linkers are disclosed in Table S3 on Pages 34 to 35. The non-cleavable linker can have the amino acid sequence of [GGGS]x (SEQ ID NO: 143, wherein in x is 1, corresponding to SEQ ID NO: 188 (GGGS) of the instant claims (Page 36, Ln. 31-37 to Page 37, Ln. 1-5). The non-cleavable linker of SEQ ID NO: 143 is less than 7 amino acids in length. Cleavage of the second linker exposes the binding sites of the first and/or second IL-2 protein variants that bind IL-2Rβ/γc or IL-2Ra/β/γc chain present on the surface of immune cells in vitro or in vivo (Page. 6, Ln. 21-27 and Page 20, Ln. 25-37 to Page 21, Ln. 1-4). Lastly, disclosed are pharmaceutical compositions comprising the activatable proprotein homodimer and a pharmaceutically acceptable carrier (Page 7, Ln. 19-20).
Li does not teach that the Fab antigen binding domain targets PD-1 and comprises CDRs as well as the VH/VL chain pair of SEQ ID NOs: 3 and 4, respectively. Further, Li does not explicitly teach that the hinge domain is present between the Fab and IgG Fc region of the activatable proprotein.
However, Korman teaches human monoclonal antibodies that specifically bind to PD-1 with high affinity as well as methods for using said antibodies to treat hyperproliferative disease, such as cancer (Abstract), wherein, in some embodiments, the anti-PD-1 antibody is 5C4 having the VH and VL chains of SEQ ID NOs: 4 and 11, respectively (Para. 0343) (corresponding to SEQ ID NOs: 3 and 4 of the instant claims, respectively). The anti-PD-1 antibody can be formatted as Fab fragment (a monovalent fragment consisting of the VL, VH, CL, and CH1 domains) (Para. 0128 and Para. 0211).
Thompson teaches binding proteins including antibodies and antibody fragments comprising hinge, CH2, and/or CH3 regions and explains that the hinge is conventionally located between the Fab and Fc portions of the binding protein where it acts a flexible spacer that allows the Fab portion to move freely in space relative to the Fc region and contains cysteine residues that are responsible for forming intrachain disulfide bonds (Abstract, Para. 0007, and Para. 0128-0130).
It would have been obvious to one of ordinary skill in the art to modify the activatable proprotein homodimer disclosed by Li such that 1) the Fab antigen-binding domain is derived from the anti-PD-1 antibody 5C4 and 2) the hinge is present between the Fab antigen-binding domain (effector molecule) and the Fc domain of the activable proprotein homodimer. One of ordinary sill in the art would have been motivated to do so since the anti-PD-1 antibody 5C4 or an antigen-binding fragment thereof can be used to treat hyperproliferative disease such as cancer in a subject as taught by Korman. Further, it would have been obvious for artisans to position the hinge region between the Fab and the CH2CH3 domains as taught by Thompson because Thompson explains that the hinge region is conventionally located between the Fab and Fc regions of an antibody and provides flexibility between these domains and is responsible for forming intrachain disulfide bonds. As such, artisans would select this arrangement to achieve similar flexibility between the Fab and Fc domains of the activatable proprotein as well as to facilitate the formation of disulfide bonds between the first and second polypeptides. Therefore, artisans would have reasonably expected that an activatable proprotein homodimer having a Fab antigen-binding domain is derived from the anti-PD-1 antibody 5C4, wherein a hinge region is present between the Fab antigen-binding domain and the Fc domain, can effectively treat a disease or disorder such as cancer in a subject.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Li in view of Korman and Thompson, as applied to claims 1-5, 7, 9, 13, 14, 19, 20, 24, 25, 26, 30, 31, and 39 above, and further in view of Steward et al (WO2000061192A2), hereinafter Steward.
The teachings of Li in view of Korman and Thompson have been discussed above and differ from the instantly claimed invention in that it is not specifically taught the hinge region comprises the amino acid sequence of SEQ ID NO: 42 (IgG1 hinge).
However, Steward discloses fusion proteins having a spacer moiety between functional domains, wherein the spacer moiety comprises the amino acid sequence a human immunoglobulin hinge region such as (from N terminus to C terminus) EPKSCDKTHTCPPCP (SEQ ID NO: 11), corresponding to SEQ ID NO: 4 (EPKSCDKTHTCPPCP) of the instant claims.
It would have been obvious to one of ordinary skill in the art to substitute the hinge region present in the activatable proprotein homodimer disclosed by the prior art with the hinge region having the amino acid sequence EPKSCDKTHTCPPCP (SEQ ID NO: 11) disclosed by Steward. 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 (i.e. as a flexible spacer between functional domains of a fusion protein). 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). Therefore, one of ordinary skill in the art would reasonably expect that the IgG1 hinge region can be effectively used as a spacer between functional domains of the activatable proprotein homodimer, particularly between the Fab and Fc regions.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Li in view of Korman and Thompson, as applied to claims 1-5, 7, 9, 13, 14, 19, 20, 24, 25, 26, 30, 31, and 39 above, and further in view of Wilkinson et al (Wilkinson, Ian et al. “Fc-engineered antibodies with immune effector functions completely abolished.” PloS one vol. 16,12 e0260954. 21 Dec. 2021, doi:10.1371/journal.pone.0260954), hereinafter Wilkinson and Pejchal et al (US20210087271A1), hereinafter Pejchal.
The teachings of Li in view of Korman and Thompson have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the Fc region does not bind or does not substantially bind to FcyR and retains normal or substantially normal binding to FcRn, wherein the Fc region comprises one or a combination of the mutations recited in instant claim 12.
However, Wilkinson teaches that elimination of binding to Fc gamma receptors is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Thus, Fc variants having mutations that disrupt binding to FcyRs can improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins (Abstract).
Pejchal further teaches Fc variants with diminished effector function as a consequence of hinge region and CH2 domain mutations, e.g., L234A, L235A, and P329A/P329H (LALA-PA or LALA-PG). The LALA-PA and LALA-PG mutations significantly reduce affinity to each of FcγRI, FcγRIIA, FcγRIIIA, and C1q as compared to a wildtype human Fc region while maintaining FcRn binding and good developability profiles (Abstract, Para. 0010, Para. 0015, Para. 0016, and Para. 0052).
It would have been obvious to one of ordinary skill in the art to modify the Fc region of the activatable proprotein homodimer such that it comprising LALA and P329A mutations. One of ordinary skill in the art would have been motivated to do so since elimination of binding to Fc gamma receptors is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins as taught by Wilkinson, and the Fc variants comprising L234A, L235A, and P329A/P329G mutations significantly reduce affinity to each of FcγRI, FcγRIIA, FcγRIIIA, and C1q as compared to a wildtype human Fc region while maintaining FcRn binding and good developability profiles as taught by Pejchal. Therefore, one of ordinary skill in the art would reasonably expect that an activatable proprotein homodimer comprising LALA-PA or LALA-PG Fc mutations that abolish binding to FcyRs and C1q but retains binding to FcRn to more safely and effectively treat a disease or disorder such as cancer in a subject.
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.
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Claims 1-7, 9-14, 19-20, 24-26, 30-32 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19466032 (reference application).as evidenced by Pejchal et al (US20210087271A1), hereinafter Pejchal. Although the claims at issue are not identical, they are not patentably distinct from each other because co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite an activatable proprotein comprising a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide each comprise in an N to C-terminal orientation, a VH chain of an antibody that specifically binds to PD1, a first linker, an IL-2, a second linker, and an IL-2Ra, wherein the IL2 of the first polypeptide binds to the IL-2Ra of the second polypeptide and the IL-2 of the second polypeptide binds to the IL-2Ra of the first polypeptide, wherein the binding between IL-2 and IL2Ra masks a binding site of the IL-2 that otherwise binds to an IL-2RB/yc chain or IL-2Ra/B/yc chain, and wherein the second linker comprises a cleavable linker (co-pending claim 1) and the first linker is a non-cleavable linker of SEQ ID NO: 188 corresponding to SEQ ID NO: 188 of the instant claims (co-pending claims 12 and 13). The activatable proprotein further comprises two of a third polypeptide, wherein the first polypeptide associates with one of the two of the third polypeptide to form a first fragment antigen-binding (Fab) region and the second polypeptide associates with the other of the two of the third polypeptide to form a second Fab region (co-pending claim 2). The first and second Fab regions comprise the VH and VL chains of SEQ ID NOs: 3 and 4, respectively (co-pending claims 3-5), corresponding to SEQ ID NOs: 3 and 4 of the instant claims. The first and second polypeptides each comprises a heavy chain constant domain 1 (CH1), heavy chain constant domain 2 (CH2), and heavy chain constant domain 3 (CH3) (co-pending claim 6) and further comprises IgG, IgA, IgD, IgE, or IgM (co-pending claim 7). The IgG can be of the isotype IgG1, IgG2, IgG3, or IgG4 (co-pending claim 8). The CH2 comprises the L234A, L235A and P329A mutations according to the EU numbering (co-pending claim 9). These mutations are within the lower hinge and the second constant domain (CH2) of IgG1 that comprise the FcγR binding interface and reduce FcyR binding while retaining binding to the neonatal Fc receptor (FcRn) as evidenced by Pejchal (Abstract, Para. 0007, Para. 0010, Para. 0015, Para. 0016, and Para. 0052). The first and second polypeptides each comprises the amino acid sequence of SEQ ID NO: 146, corresponding to SEQ ID NO: 146 of the instant claims (co-pending claims 20 and 21). The third polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 147 corresponding to SEQ ID NO: 147 of the instant claims (co-pending claims 10 and 11). The hinge region of SEQ ID NO: 42 (EPKSCDKTHTCPPCP) is present in the amino acid sequence of SEQ ID NO: 146 (see Sequence Listing of either co-pending or instant application). The IL-2 comprises the R38D, K43E, and CS125 mutations or the amino acid sequence of SEQ ID NO: 85, corresponding to SEQ ID NO: 85 of the instant claims (co-pending claims 14 -16). The IL-2Ra comprises the D6R and E29K mutations or the amino acid sequence of SEQ ID NO: 90, corresponding to SEQ ID NO: 90 of the instant claims (co-pending claims 17-19). Lastly recited is a pharmaceutical composition comprising the activatable proprotein and a pharmaceutically acceptable carrier (co-pending claim 25). It is noted that the instant application 18361357 is the parent of the co-pending application 19466032; thus, the sequences recited in the claims of the instant application correspond to, and are the same as, sequences recited in the claims of the co-pending application.
Thus, the co-pending claims meet the limitations of instant claims
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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