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 05/27/2026 is acknowledged.
Claims 22-24 and 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.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 05/27/2026.
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 1, 6-10, 12-20, and 25 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.
Claim 1 is drawn to an activatable proprotein homodimer comprising first and second polypeptides each comprising in the N- to C-terminal direction a VH region of an antibody that specifically binds to PD-1, a first linker, an IL-2 protein, a second cleavable linker, and an IL-2Ra protein. However, the antigen-binding region of the activatable proproteins can be derived from conventional antibodies having at least six CDRs required for antigen binding. Thus, the VH-only polypeptides present in the activatable proproteins have less than six CDRs required for antigen binding and are thus not expected to bind to PD-1 commensurate in scope of the claims.
Claims 10 and 20 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.
Similarly, claims 15 and 18 encompass IL-2 and IL-2Ra proteins in which at most 10% of the structures can have random, undefined amino acid mutations; yet the specification does not provide guidance for identifying IL-2/IL-2Ra variants having random, undefined amino acid mutations that will predictably yield an activatable proprotein homodimer wherein the masking interaction is preserved until activation in the tumor microenvironment.
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.
Claim 1 is drawn to an activatable proprotein homodimer comprising first and second polypeptides each comprising in the N- to C-terminal direction a VH region of an antibody that specifically binds to PD-1, a first linker, an IL-2 protein, a second cleavable linker, and an IL-2Ra protein. However, the antigen-binding region of the activatable proproteins can be derived from conventional antibodies having at least six CDRs required for antigen binding. Thus, the VH-only polypeptides present in the activatable proproteins have less than six CDRs required for antigen binding and are thus not expected to bind to PD-1 commensurate in scope of the claims.
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). Because CDRs from both VH and VL domains contribute to the antigen- binding site, it is the combination of both the heavy and the light chain, and not either alone, that determines the final antigen specificity. The term “antibody” is not particularly limited in the specification and can thus encompass conventional antibodies that require six CDRs for antigen binding; yet, the claimed activatable proprotein comprise polypeptides having only the VH chain of an anti-PD-1 antibody and thus only three CDRs for antigen binding. However, artisans would not reasonably expect the structure of only a single domain (in this case, a VH chain) of a conventional antibody to have the functional property of binding to the target antigen PD-1. Claims 6-9, 12-19, and 25, which incorporate the limitations of claim 1, do not cure the deficiencies of claim 1 and are thus also rejected.
Claims 10 and 20 are drawn to activatable proprotein homodimers 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.
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. However, there is no guidance provided in the specification about which specific amino acids mutations can made in the 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.
Similarly, claims 15 and 18 encompass activatable proprotein homodimers comprising IL-2 and IL-2Ra proteins having at least 90% sequence identity to SEQ ID NO: 85 and 90, respectively. 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. 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). 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. However, there is no guidance provided in the specification about which other amino acid mutations that can be made in IL-2 and IL-2Ra proteins the masking interaction is preserved while still allowing activation of the construct following cleavage. As such, artisans must engage in additional trial and error experimentation to identify IL-2 and IL-2Ra mutants that will preserve the function 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, including those comprising polypeptide chains or IL-2/IL-2Ra mutants having undefined amino acid mutations at the time the instant application was filed.
Scope of Enablement
Claims 1, 6-10, 12-20, and 25 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.
Claim 1 is drawn to an activatable proprotein homodimer comprising first and second polypeptides each comprising in the N- to C-terminal direction a VH region of an antibody that specifically binds to PD-1, a first linker, an IL-2 protein, a second cleavable linker, and an IL-2Ra protein.
The specification teaches that the activatable proprotein homodimer is targeted to the tumor microenvironment (TME) by the anti-PD-1 Fab region where it is then activated via protease cleavage, 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). Several conventional anti-PD-L1 antibodies comprising a VH/VL chain pair are disclosed in Table P1 beginning on page 28 of the Specification. However, as presently written, claim 1 encompasses activatable proprotein homodimers having only the VH chain of an anti-PD-1 antibody, yet there is no evidence provided in the specification that such constructs can effectively target PD-1 and thus target the activatable proprotein to the tumor microenvironment where it can be activated. Further, the specification provides no guidance for identifying activatable proproteins having only the VH chain of an anti-PD-1 antibody that target PD-1.
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). Because CDRs from both VH and VL domains contribute to the antigen- binding site, it is the combination of both the heavy and the light chain, and not either alone, that determines the final antigen specificity. The term “antibody” is not particularly limited in the specification and can thus encompass conventional antibodies that require six CDRs for antigen binding; yet, the claimed activatable proprotein comprise polypeptides having only the VH chain of an anti-PD-1 antibody and thus only three CDRs for antigen binding. However, artisans would not reasonably expect a single domain (in this case, a VH chain) of a conventional antibody to be capable of binding to the target antigen PD-1 without its cognate VL chain. Claims 6-9, 12-19, and 25, which incorporate the limitations of claim 1, do not cure the deficiencies of claim 1 and are thus also rejected.
Claims 10 and 20 are 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, claims 10 and 20 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 of the activatable proprotein homodimer. For example, the IL-2/IL-2Ra interaction plays an important role in maintaining the claimed activatable proprotein homodimer in a masked state until activation within the tumor microenvironment. The cleavable linker is responsible for release of the masking moiety (IL-2Ra) in the TME and exposure of IL-2 following activation. As such, random amino acid mutations within the IL-2/IL-2Ra proteins or linkers may negatively impact the masking interaction and subsequent activation. 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. The specification, however, does not provide sufficient guidance sufficient to establish which amino acid mutations beyond those disclosed can be made in the genus of polypeptide chain variants such that the overall structure and function of the activatable proprotein homodimer is maintained.
Similarly, claims 15 and 18 encompass activatable proprotein homodimers comprising IL-2 and IL-2Ra proteins having at least 90% sequence identity to SEQ ID NO: 85 and 90, respectively. As stated above, 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. As such, 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.
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 7-8 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 6 recites that the first and second polypeptides of the activatable proprotein homodimer each comprises a CH1, CH2, and CH3 domains.
Claim 7 (which depends on claim 6) recites that the activatable proprotein homodimer further comprises an IgG, IgA, IgD, IgE, or IgM. As presently written, it is unclear whether:
the CH1, CH2, and CH3 domains of claim 6 are derived from one of the recited immunoglobulin classes; or
claim 7 requires the activatable proprotein homodimer to contain additional IgG, IgA, IgD, IgE, or IgE components separate from the CH1, CH2, and CH3 domains already recited.
Claim 8 (which depends on claim 7) recites that the activatable proprotein homodimer further comprises IgG1, IgG2, IgG3, or IgG4. Thus, claim 8 appears to add one of the IgG subclasses as an additional component rather than specifying that the IgG of claim 7 is one of the recited subclasses. Thus, it is unclear whether claim 3:
limits the IgG of claim 7 to a particular IgG subtype; or
requires the presence of an additional IgG1, IgG2, IgG3, or IgG4 component.
Therefore, the metes and bounds of patent protection desired cannot be determined.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7-8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 depends on claim 6, which recites that the activatable proprotein homodimer comprises CH1, CH2, and CH3 domains. Claim 7 further recites the proprotein “further comprising an IgG, IgA, IgD, IgE, or IgM”. As written, claim 7 appears to add additional immunoglobulin components to the proprotein rather than further limiting the CH2, CH2, and CH3 domains of claim 6. Thus, claim 7 improperly broadens claim scope.
Claim 8 depends from claim 7 and recites that the proprotein “further comprising IgG1, IgG2, IgG3, or IgG4”. As written, claim 8 appears to add additional IgG domains to the proprotein rather than limiting the IgG isotype recited in claim 7. Thus, claim 8 further broadens claim scope.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-8, 12-19, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (WO2021055568A1), hereinafter Li in view of Korman (US20090217401A1).
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 CH1 domain, CH2 domain, a CH3 domain, and/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, including the cleavable linker of SEQ ID NO: 112 (PLGLAGSGRSDNQGA) corresponding to SEQ ID NO: 93 (PLGLAGSGRSDNQGA) of the instant claims. 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). 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. 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 VH and VL chains of SEQ ID NO: 4 and 11 would thus necessarily comprise the CDRs present in SEQ ID NOs: 3 and 4 of the instant claims. 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).
It would have been obvious to one of ordinary skill in the art to modify the activatable proprotein homodimer disclosed by Li such that the Fab antigen-binding domain is derived from the anti-PD-1 antibody 5C4. 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. Therefore, one of ordinary skill in the art would reasonably expect that an activatable proprotein homodimer having a Fab antigen-binding domain derived from the anti-PD-1 antibody 5C4 can effectively treat a disease or disorder such as cancer in a subject.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Li in view of Korman, as applied to claims 1-8, 12-19, and 25 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 have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that CH2 comprises the L234A, L235A, and P329A mutations.
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 (Abstract). Thus, Fc variants having mutations that disrupt binding to FcyRs can improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.
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 (LALA-PA). The LALA-PA 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, 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 (LALA-PA) 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 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 1-21 and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19466032 (reference application). 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, wherein each Fab comprise the VH and VL region of the anti-PD-1 antibody (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 and 4), corresponding to SEQ ID NOs: 3 and 4 of the instant claims. The first and second polypeptides further comprises an Fc domain having a CH2, CH3, or CH2CH3 domain of an immunoglobulin, wherein the immunoglobulin is selected from IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, or IgM (co-pending claims 5 and 9). The Fc region comprises the L234A mutation, L235A mutation, P329A mutation, P329G mutation, or a combination thereof according to the EU numbering (co-pending claim 12). 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 6 and 32). The cleavable linker of SEQ ID NO: 93 (PLGLAGSGRSDNQGA) recited in the instant claims is present at positions 75-89 in the polypeptide of SEQ ID NO: 146 according to sequential numbering (see Sequence Listing of either co-pending or instant application). 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 7 and 32). 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 13, 14, and 30). 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 19, 20, and 30). Lastly recited is a pharmaceutical composition comprising the activatable proprotein and a pharmaceutically acceptable carrier (co-pending claim 39). It is noted that the co-pending application 18361357 is the parent of the instant application; 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 parent application.
Thus, the co-pending claims meet the limitations of instant claims 1-21 and 25.
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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