DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's reply filed on 10/6/2025 is acknowledged. Claims 44 and 49-68 are pending. Claims 1-43 and 45-48 are canceled. Claim 57 is withdrawn from consideration. Claims 44, 49, 55-56, 58 and 62 have been amended.
3. Claims 44, 49-56 and 58-68 are under examination.
Objection Withdrawn
4. The objection to the disclosure because it contains an embedded hyperlink and/or other form of browser-executable code is withdrawn in view of applicant’s amendments.
Rejection Maintained
Claim Rejections - 35 USC § 112
5. 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.
6. Claims 44, 49-56 and 58-68 remain 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 44 is drawn to a fusion protein that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor, said fusion protein comprising:
(i) one or more heavy chain constant domains, or variants or functional fragments thereof, derived from an Immunoglobulin E (IgE);
(ii) one or more constant domains, or variants or functional fragments thereof, derived from an Immunoglobulin G (IgG), and
(iii) one or more variable domains derived from an immunoglobulin (emphasis added).
Claim 45 is drawn to the fusion protein of claim 44, comprising a C[Symbol font/0x65]3 domain, or a variant or functional fragment thereof.
Claim 46 is drawn to the fusion protein of claim 45, comprising a C[Symbol font/0x65]2 domain, a C[Symbol font/0x65]3 domain, and a C[Symbol font/0x65]4 domain, or variants or functional fragments thereof.
Claim 47 is drawn to the fusion protein of claim 44, comprising a C[Symbol font/0x67]2 domain, or a variant or functional fragment thereof.
Claim 48 is drawn to the fusion protein of claim 47, further comprising a C[Symbol font/0x67]3 domain, or a variant or functional fragment thereof.
Claims 44-48 and their dependent claims are rejected because the specification does not adequately describe all the species encompassed by genus of fragments, variants and derivatives of IgE constant domains (including fragments, variants and derivatives of C[Symbol font/0x65]2 domain, C[Symbol font/0x65]3 domain, and/or C[Symbol font/0x65]4 domain), genus of fragments, variants and derivatives of IgG constant domains (including fragments, variants and derivatives of C[Symbol font/0x67]2 domain and/or C[Symbol font/0x67]3 domain), and genus of fragments, variants and derivatives of variable regions of immunoglobulin, wherein the fragments, variants and derivatives have the claimed function, i.e. binding to an Fc[Symbol font/0x65] receptor, an Fc[Symbol font/0x67] receptor, and an antigen, respectively.
Claim 55 is drawn to the fusion protein of claim 44, comprising an amino acid sequence having at least 85%, 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 5.
Claim 56 is drawn to the fusion protein of claim 44, comprising an amino acid sequence having at least 85%, 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 9, 10, 11, 23, 24, 25, 26, 163-166, 169-172, 174, 175, and 176.
Claim 58 is drawn to the fusion protein of claim 44, comprising: (i) an IgE amino acid sequence having at least 85%, 90%, 95%, or 99% sequence identity with each of SEQ ID NOs: 3, 4, and/or 5; and (ii) an IgG amino acid sequence having at least 85%, 90%, 95%, or 99% sequence identity with: (a) each of SEQ ID NOs: 9, 10, and/or 11; or (b) each of SEQ ID NOs: 174, 175, and 176.
Claim 68 is drawn to the fusion protein of claim 44, comprising a variable domain with an amino acid sequence having at least 85%, 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 1, 160, 161, 162, 177, and 178.
Although claims 55, 56, 58 and 68 limit the fragments variants and derivatives to those having at least 85%, 90%, 95%, or 99% sequence identity to a reference sequence, they are rejected because the specification does not adequately describe which amino acid residues in a reference sequence can be changed such that the fragments, variants and derivatives having at least 85%, 90%, 95%, or 99% sequence identity still have the claimed function, i.e. binding to an Fc[Symbol font/0x65] receptor, an Fc[Symbol font/0x67] receptor, and an antigen, respectively.
The specification discloses amino acid sequences of wild type IgE constant domains (including C[Symbol font/0x65]2 domain, C[Symbol font/0x65]3 domain, and C[Symbol font/0x65]4 domain), wild type IgG constant domains (including C[Symbol font/0x67]2 domain and C[Symbol font/0x67]3 domain), and VH and VL regions of an immunoglobulin, trastuzumab for example. The specification further discloses the following variants of IgE constant domain (Example 1):
IgE containing IgG Fc[Symbol font/0x67]R Loop 1;
IgE containing IgG Fc[Symbol font/0x67]R Loop 2;
IgE containing IgG Fc[Symbol font/0x67]R Loop 3;
IgE containing IgG Fc[Symbol font/0x67]R Loop 1 + Loop 2;
IgE containing IgG Fc[Symbol font/0x67]R Loop 1 + Loop 3;
IgE containing IgG Fc[Symbol font/0x67]R Loop 2+ Loop 3; and
IgE containing IgG Fc[Symbol font/0x67]R Loop 1 + Loop 2+ Loop 3.
The written description is not commensurate in scope with the claims which read on any fragments, variants and derivatives comprising substitutions, additions and/or deletions at any positions of wild type C[Symbol font/0x65]2 domain, C[Symbol font/0x65]3 domain, C[Symbol font/0x65]4 domain, C[Symbol font/0x67]2 domain, C[Symbol font/0x67]3 domain, and VH/VL of a reference antibody such as trastuzumab. There is a lack of written description regarding which fragments, variants and derivatives encompassed by the claims are in fact have the claimed functions, i.e. binding to an Fc[Symbol font/0x65] receptor, an Fc[Symbol font/0x67] receptor, and an antigen, respectively.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 claimed genus.
One of ordinary skill in the art would not consider that applicant is in possession of the fragments, variants and derivatives as broadly claimed. The state of art is that there is no sufficient correlation between the structure of the modifications and required function.
Ying et al. (J. Biol. Chem., 2012, 287(23):19399-19408) teaches, “Fc dimerization is mediated mainly by a large hydrophobic interface in its CH3 domain, which involves at least 16 residues in each polypeptide chain that make intermolecular interactions (31, 32). Disruption of this large interaction interface would cause exposure of a hydrophobic surfaces resulting in poor solubility, instability, and/or aggregation" (page 19399, last paragraph). Geczy et al. (J. Boil. Chem., 2012, 287(16):13137-13158) teaches that the combined effect of multiple mutations on the binding affinity cannot be readily predicted based merely on the affinity results of single site mutants (page 13145, column 2, paragraph 3). The combined introduction of all five mutations into [Symbol font/0x64]C1b abolished detectable binding affinity (page 13145, column 2, paragraph 3, and Table 1). National Science Foundation Award Abstract # 1262435 (2012) discloses, “The study of how the effects of individual mutations combine to impact the overall function of a protein is a key question in evolutionary biology. It is also a very difficult question, as the effects multiple protein mutations can combine non-additively. In this case, higher order interactions (beyond pairwise) between mutations need to be considered, and the number of interactions increases exponentially as a function of the total number of protein mutations involved”; and “Specifically, detailed modeling of how protein mutations combine as steps in the evolutionary path of a protein toward new function is currently lacking” (see abstract).
Farrington et al (US 2007/0148164A1, pub. date: 6/28/2007) discloses that Fc point mutations at different positions with different amino acid modifications, even at same positions with different amino acid modifications (for example K288D, K288E and K288M) affect FcRn binding differently (see Figure 7). Lazar et al. (US 2007/0003546A1, pub. date: 1/4/2007) teaches that Fc point mutations at different positions with different amino acid modifications, even at same positions with different amino acid modifications affect Fc[Symbol font/0x67]IIIa binding differently (see pages 71-75, Table 62). Lazar et al. teaches that a principal obstacle to obtaining valuable Fc variants is the difficulty in predicting what amino acid modifications, out of the enormous number of possibilities, will achieve the desired goals (para [0136]). Lazar et al. teaches that Ig domains are small beta sheet structures, the engineering of which has proven extremely demanding; even seemingly harmless substitutions on the surface of a beta sheet can cause severe packing conflicts, dramatically disrupting folding equilibrium; and the determinants of beta sheet stability and specificity are a delicate balance between an extremely large number of subtle interactions (para [0136]). Lazar et al. teaches that an additional obstacle to Fc engineering is the need for active design of correlated or coupled mutations (para [0136]). The effects of individual mutations combine to impact the overall stability and function of a protein is unpredictable.
Thus, the effects of any given mutation or combination of mutations in a variant or a derivative can differ depending on the position(s) modified and the specific mutation implemented at each position. Some mutations may have no discernible effect on the protein function, some may lead to varying degrees of instability or functional impairment, and some may actually improve protein activity or impart other desirable properties, such as improved stability. One skilled in art cannot predict the stability and function of the broadly claimed fragments, variants and derivatives, thus cannot visualize or recognize the members of the genus.
Claim 62 encompasses amino acid changes in the CDR regions of a reference antibody. There is a lack of a written description regarding which amino acids within CDRs of a reference antibody can be changed by deletion, addition, substitution and/or combination thereof, such that the resulting antibody maintains the binding specificity of the reference antibody.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column). Murphy et al. (Journal of Immunological Methods, Vol. 463, Pg. 127-133, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystin-leucine-arginine (MC-LR)(Page 130, Section 3.2, paragraph 2) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone (Page 131, Column 1, Paragraph 2). The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR. Thus, the state of the art recognized that it would be highly unpredictable that a specific humanized antibody comprising less than all six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. Thus, the minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed.
The variants disclosed in the specification are not representative for the genus of fragments, variants and derivatives because the genus encompasses modifications at any amino acid positions. The specification does not describe the particular physical or chemical characteristics for the fragments, variants and derivatives of the genus nor does the specification disclose sufficient correlations between a structure and the functions (binding to an Fc[Symbol font/0x65] receptor, an Fc[Symbol font/0x67] receptor, and an antigen).
“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.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997). The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
Therefore, only the variants disclosed in Example 1, and the antibodies comprising all 6 CDRs of a reference antibody, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112 first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
The response states that the amended claims do not recite "variants or functional fragments" or "derivatives" of the recited domains and proteins. Furthermore, claim 55 is amended to recite a "fusion protein ... comprising an amino acid sequence having at least 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs 1 to 5." Claim 56 is amended to recite a "fusion protein comprising ... an amino acid sequence having at least 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 9, 10, 11, 23, 24, 25, 26, 163-166, 169-172, 174, 175, and 176." Claim 58 is amended to recite "an IgE amino acid sequence having at least 90%, 95%, or 99% sequence identity with each of SEQ ID NOs: 3, 4, and/or 5"; and "an IgG amino acid sequence having at least 90%, 95%, or 99% sequence identity with: (a) each of SEQ ID NOs: 9, 10, and/or 11; or (b) each of SEQ ID NOs: 174, 175, and 176." And, claim 62 is amended to recite "a variable domain with an amino acid sequence having at least 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 1, 160, 161, 162, 177, and 178." Applicant notes that these are all dependent claims, depending from claim 44, which recites a fusion protein "that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor" and wherein "wherein the C[Symbol font/0x65]2,C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2, and C[Symbol font/0x67]3 domains provide a binding site for an Fc[Symbol font/0x65] receptor and provide a binding site for an Fc[Symbol font/0x67] receptor."
As recited by the claims, the claimed technology provides a fusion protein "that binds Fc[Symbol font/0x65] receptors and Fc[Symbol font/0x67] receptors." It is the presence of binding sites for both an Fc[Symbol font/0x65] receptor and Fc[Symbol font/0x67] receptor that is the inventive feature of the technology. As noted in the specification at page 4, lines 20-23, the term "binds" refers to binding of the hybrid antibody via one or more constant domains thereof, i.e. "binds" does not refer to specificity of the hybrid antibody binding to target antigen via its variable domains. Accordingly, the specific sequences of the constant domains are not important and neither are the CDR sequences, provided that the fusion protein binds an Fc[Symbol font/0x65] receptor and Fc[Symbol font/0x67] receptor. As long as the constant domains provide binding sites for an Fc[Symbol font/0x65] receptor and Fc[Symbol font/0x67] receptor, one of ordinary skill in the art would understand that amino acids could be substituted and the recited fusion proteins and/or domains would maintain at least 90% sequence identity with the recited sequences. For instance, one of ordinary skill in the art would have knowledge of the functional similarity of amino acids (as also taught in the application as filed at e.g., page 22, lines 19-24). Accordingly, one of ordinary skill in the art would have been able to visualize or recognize the identity of the subject matter purportedly described and thus would have reasonably understood that Applicant had possession of the claimed subject matter at the time of filing the present application.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive.
Although claim 44 has been amended to recite comprising C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains, these domain are not limited to wild-type domains, as evidenced by the following dependent claims:
Claim 55 is drawn to the fusion protein of claim 44, comprising an amino acid sequence having at least 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 5. SEQ ID NOs: 2-5 are human wild type IgE CH1, CH2, CH3 and CH4 domains, respectively (specification, page 33). SEQ ID NO: 1 comprises human wild type IgE constant region (specification, page 32).
Claim 56 is drawn to the fusion protein of claim 44, comprising an amino acid sequence having at least 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 9, 10, 11, 23, 24, 25, 26, 163-166, 169-172, 174, 175, and 176. SEQ ID NOs: 10 and 11, for example are human wild type IgG CH2 and CH3 domains, respectively (specification, page 34).
Claim 58 is drawn to the fusion protein of claim 44, comprising: (i) an IgE amino acid sequence having at least 90%, 95%, or 99% sequence identity with each of SEQ ID NOs: 3, 4, and/or 5; and (ii) an IgG amino acid sequence having at least 90%, 95%, or 99% sequence identity with: (a) each of SEQ ID NOs: 9, 10, and/or 11; or (b) each of SEQ ID NOs: 174, 175, and 176. Claim 58 also encompasses amino acid changes within wild type C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains.
Claim 68 is drawn to the fusion protein of claim 44, comprising a variable domain with an amino acid sequence having at least 90%, 95%, or 99% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 1, 160, 161, 162, 177, and 178. Claim 68 also encompasses amino acid changes within wild type C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains.
As evidenced by claims 55, 56, 58 and 68, the “C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains” in claim 44 encompass a genus of variants that are at least 90%, 95% or 99% identical to wild type human corresponding domains. The specification does not describe which amino acid residues in a wild sequence can be changed such that the variants having at least 90%, 95%, or 99% sequence identity still have the claimed function, i.e. binding to an Fc[Symbol font/0x65] receptor or an Fc[Symbol font/0x67] receptor.
The specification only discloses amino acid sequences of wild type IgE constant domains (including C[Symbol font/0x65]2 domain, C[Symbol font/0x65]3 domain, and C[Symbol font/0x65]4 domain), wild type IgG constant domains (including C[Symbol font/0x67]2 domain and C[Symbol font/0x67]3 domain (Example 1).
Regarding the variable domains, although claim 44 does not require the fusion protein to bind an antigen. Claim 60 does require the fusion protein to bind a cancer antigen. The specification does not disclose any conventional antibodies comprising less than 6 CDRs of a parental antibody, and any domain antibodies comprising less than 3 CDRs of a parental domain antibody which have the function of binding a cancer antigen. Claim 62 encompasses amino acid changes in the CDR regions of a reference antibody. There is a lack of a written description regarding which amino acids within CDRs of a reference antibody can be changed by deletion, addition, substitution and/or combination thereof, such that the resulting antibody maintains the binding specificity of the reference antibody.
Because the specification fails to adequately describe all the species encompassed by the genus, the rejection is deemed proper and is therefore maintained.
Claim Rejections - 35 USC § 102
7. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 44, 49-50, 52-56, 58, 63, 65 and 68 remain rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kimes et al. (WO 2020/172473A1, pub date: 8/27/2020, effectively filed date: 2/20/2019).
Regarding claims 44, 49, 53, 54, and 63, Kimes et al. teaches a chimeric binding agent comprising (ii) one or more of C[Symbol font/0x65]1, C[Symbol font/0x65]2, C[Symbol font/0x65]3, and/or C[Symbol font/0x65]4 domains, and (ii) one or more C[Symbol font/0x67]1, C[Symbol font/0x67]2, C[Symbol font/0x67]3 and/or a hinge region ([0006]), wherein the chimeric binding agent is capable of binding to Fc[Symbol font/0x67]Rs and Fc[Symbol font/0x65]Rs, wherein Fc[Symbol font/0x67]Rs include Fc[Symbol font/0x67]RI, Fc[Symbol font/0x67]RIIA, Fc[Symbol font/0x67]RIIB, Fc[Symbol font/0x67]RIIIA and Fc[Symbol font/0x67]RIIIB, and Fc[Symbol font/0x65]Rs include Fc[Symbol font/0x65]RI and Fc[Symbol font/0x65]RII ([0072]). Kimes et al. teaches that the chimeric binding agent may further comprise a Fab ([0067]). Kimes et al. teaches that the chimeric binding agents may be fused to a molecule (e.g. a small molecule, a peptide, a polypeptide, or a protein) with targeting or homing function for a cell of interest or a target cell (e.g. an immune cell) ([0090]).
Regarding claim 50, Kimes et al. teaches that the chimeric binding agent is a tetramer ([0110]).
Regarding claim 52, Kimes et al. teaches that the one or more C[Symbol font/0x67]1, C[Symbol font/0x67]2, C[Symbol font/0x67]3 and/or a hinge region are from IgG1([0006]).
Regarding claims 55 and 58, Kimes et al. teaches that the one or more of C[Symbol font/0x65]1, C[Symbol font/0x65]2, C[Symbol font/0x65]3, and/or C[Symbol font/0x65]4 domains are from a human or a rodent ([0102]), which inherently comprise the instant SEQ ID NOs: 2-5. Note that SEQ ID NOs: 2-5 are wild type amino acid sequences of C[Symbol font/0x65]1, C[Symbol font/0x65]2, C[Symbol font/0x65]3, and C[Symbol font/0x65]4, respectively (see applicant’s specification page 33).
Regarding claims 56 and 58, Kimes et al. teaches that the one or more C[Symbol font/0x67]1, C[Symbol font/0x67]2, C[Symbol font/0x67]3 and/or a hinge region are from human or a rodent [0102), which inherently comprise instant SEQ ID NOs: 9-11. Note SEQ ID NOs: 9-11 are wild type amino acid sequences of IgG hinge, C[Symbol font/0x67]2, C[Symbol font/0x67]3, respectively (see applicant’s specification pages 33-34).
Regarding claim 65, Kimes et al. teach that the fusion protein has increased stability ([0115]).
Regarding claim 68, Kimes et al. teaches a pharmaceutical composition comprising the chimeric binding agent, and carrier ([0145]).
Applicant’s Arguments
The response states that the amended claims are novel because Kimes does not disclose all claim features. In particular, Kimes does not disclose the claimed fusion protein that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor, comprises C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains, and comprises one or more variable domains and/or one or more complementarity- determining regions (CDR). As noted by Kimes, the Kimes binding agents "lack ... complementary-determining regions (CDRs)." Kimes at paragraph 63. Accordingly, Kimes does not identically disclose all claim features of amended claim 44. Applicant respectfully asserts that Kimes does not anticipate claim 44. In like manner, because claim 44 is not anticipated by Kimes, claims dependent thereon are likewise not anticipated by Kimes. See, e.g., In re Fine, 837 F.2d 1071 (Fed. Cir. 1988).
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. Kimes et al. teaches a chimeric binding agent comprising (ii) one or more of C[Symbol font/0x65]1, C[Symbol font/0x65]2, C[Symbol font/0x65]3, and/or C[Symbol font/0x65]4 domains, and (ii) one or more C[Symbol font/0x67]1, C[Symbol font/0x67]2, C[Symbol font/0x67]3 and/or a hinge region ([0006]), wherein the chimeric binding agent is capable of binding to Fc[Symbol font/0x67]Rs and Fc[Symbol font/0x65]Rs, ([0072]). Note that one or more of C[Symbol font/0x65]1, C[Symbol font/0x65]2, C[Symbol font/0x65]3, and/or C[Symbol font/0x65]4 domains encompass all of C[Symbol font/0x65]1, C[Symbol font/0x65]2, C[Symbol font/0x65]3, and C[Symbol font/0x65]4 domains, and one or more C[Symbol font/0x67]1, C[Symbol font/0x67]2, C[Symbol font/0x67]3 encompass all of C[Symbol font/0x67]1, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains. Kimes et al. teaches that the chimeric binding agent may further comprise a Fab (which comprises both heavy and light chain variable domains) ([0067]). Therefore, Kimes et al. teaches every limitation of the claims.
Claim Rejections - 35 USC § 103
9. 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.
10. Claims 44, 49-56, 58, 59, 63, 65 and 68 remain rejected under 35 U.S.C. 103 as being unpatentable over Kimes et al. (WO 2020/172473A1, pub date: 8/27/2020, effectively filed date: 2/20/2019), in view of Saxon et al. (US 2006/0171942A1, pub. date: 8/3/2006).
The teachings of Kimes et al. have been set forth above as they apply to claims 44-50, 52-56, 58, 63, 65 and 68.
Regarding claims 51 and 59, Kimes et al. teaches that N-terminus of the IgE-Fc region is linked to a C-terminus of an IgG Fc region, C[Symbol font/0x67]2-C[Symbol font/0x67]3-C[Symbol font/0x65]2-C[Symbol font/0x65]3-C[Symbol font/0x65]4 (Fig. 1C)).
Kimes et al. does not teach that C-terminus of the IgE-Fc region is linked to a N-terminus of an IgG Fc region, C[Symbol font/0x65]2-C[Symbol font/0x65]3-C[Symbol font/0x65]4-C[Symbol font/0x67]2-C[Symbol font/0x67]3.
Saxon et al. teaches a fusion protein comprising C[Symbol font/0x65]2-C[Symbol font/0x65]3-C[Symbol font/0x65]4-hinge-C[Symbol font/0x67]2-C[Symbol font/0x67]3 (claim 14). Saxon et al. teaches that connecting the IgE Fc at its carboxy terminus to an IgG Fc provides a fusion protein with enhanced properties ([0016]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the chimeric binding agent of Kimes to comprise C[Symbol font/0x65]2-C[Symbol font/0x65]3-C[Symbol font/0x65]4-hinge-C[Symbol font/0x67]2-C[Symbol font/0x67]3 (i.e. attaching the C-terminus of the IgE-Fc region to the N-terminus of an IgG Fc region) in view of Saxon et al. One of ordinary skill in the art would have been motivated to do so because Saxon et al. teaches that connecting the IgE Fc at its carboxy terminus to an IgG Fc provides a fusion protein with enhanced properties ([0016]). One of ordinary skill in the art would have had a reasonable expectation of success because Saxon et al. has successfully made a fusion protein by connecting the C-terminus of the IgE-Fc region to the N-terminus of an IgG Fc region.
11. Claims 44, 49-56, 58, 59, 63-65 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Kimes et al. (WO 2020/172473A1, pub date: 8/27/2020, effectively filed date: 2/20/2019), in view of Saxon et al. (US 2006/0171942A1, pub. date: 8/3/2006), further in view of Timmer et al (US 2017/0015753A1, pub. date: 1/19/2017).
The teachings of Kimes and Saxon et al. have been set forth above as they apply to claims 44-56, 58, 59, 63, 65 and 68.
Regarding claim 64, Kimes and Saxon et al. do not teach that the hinge region in C[Symbol font/0x65]2-C[Symbol font/0x65]3-C[Symbol font/0x65]4-hinge-C[Symbol font/0x67]2-C[Symbol font/0x67]3, for example is a modified IgG hinge region lacking a free cysteine residue.
Timmer et al. teaches making fusion proteins comprising a modified IgG1 hinge having the sequence of EPKSSDKTHTCPPC (SEQ ID NO: 6), where in the Cys220 that forms a disulfide with the C-terminal cysteine of the light chain is mutated to serine, e.g. Cys220Ser (C220S) ([0048]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the modified IgG1 hinge of Timmer et al. in the fusion protein comprising C[Symbol font/0x65]2-C[Symbol font/0x65]3-C[Symbol font/0x65]4-hinge-C[Symbol font/0x67]2-C[Symbol font/0x67]3. One of ordinary skill in the art would have been motivated to do so because Timmer et al. teaches that Cys220 in IgG1 hinge forms a disulfide with the C-terminal cysteine of the light chain and suggested to mutate Cys220 serine ([0048]) and doing so can prevent formation of unwanted disulfide bond. One of ordinary skill in the art would have had a reasonable expectation of success because Timmer et al. teaches making fusion proteins using the modified IgG1 hinge comprising Cys220Ser mutation ([0048]).
12. Claims 44, 49-50, 52-56, 58, 60-63, 65 and 68 remain rejected under 35 U.S.C. 103 as being unpatentable over Kimes et al. (WO 2020/172473A1, pub date: 8/27/2020, effectively filed date: 2/20/2019), in view of Karagiannis et al. (Cancer Immunol Immunother, 2012, 61, 1547-1564, IDS filed on 7/28/2023).
The teachings of Kimes et al. have been set forth above as they apply to claims 44-50, 52-56, 58, 63, 65 and 68.
Regarding claim 60, Kimes et al. does not teach that the chimeric binding agent binds a cancer antigen.
Regarding claim 61, Kimes et al. does not teach that the chimeric binding agent comprises instant SEQ ID NOs: 100-105 (which are 6 CDR sequences of trastuzumab), (see instant specification page 24, Table 1).
Regarding claim 62, Kimes et al. does not teach the chimeric binding agent comprises SEQ ID NOs: 1 and 160 (which are VH and VL sequences of trastuzumab) (see instant specification pages 32 and 33).
Karagiannis et al. teaches that recombinant IgE antibodies including trastuzumab IgE can be used for passive immunotherapy of solid tumors (abstract). Karagiannis et al. teaches that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumors such as ovarian and breast carcinomas (abstract). Karagiannis et al. teaches that with a serum half-life of 21–24 days, compared to a half-life of 2–3 days in tissues, IgG antibodies may be the most effective antibody class to target blood-resident tumors and circulating tumor cells, while their ability to exert tumor surveillance in tissues may be less potent (p1548, last para). Karagiannis et al. teaches that the presence of IgE in the blood is short lived (half-life of 1.5 days), yet the half-life of IgE in tissues (2 weeks) is proportionately longer than that of IgG (2–3 days) (p1550, column 1). The local retention by powerful IgE receptor-expressing resident cells such as mast cells, macrophages and dendritic cells and longer immune surveillance could be beneficial in the context of cancer (p1550, column 1). Karagiannis et al. compared trastuzumab IgE with trastuzumab IgG1 and found that trastuzumab IgE directed monocytic cells to kill tumor cells expressing the HER2/neu antigen by ADCC, a mechanism clearly different from ADCP employed by trastuzumab IgG and monocytic cells (p1555, column 2). The trastuzumab IgE comprises instant SEQ ID NOs 100-105, 1 and 160.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the chimeric binding agent of Kimes to comprise a Fab region of trastuzumab in view of Karagiannis. One of ordinary skill in the art would have been motivated to do so because Karagiannis et al. teaches that trastuzumab IgE directed monocytic cells to kill tumor cells expressing the HER2/neu antigen by ADCC, a mechanism clearly different from ADCP employed by trastuzumab IgG and monocytic cells (p1555, column 2), and the unique properties of IgE, a class of tissue-resident antibodies which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumors such as ovarian and breast carcinomas . One of ordinary skill in the art would have had a reasonable expectation of success because Kimes teaches a chimeric binding agent comprising a Fab, IgG Fc and IgE Fc, Karagiannis et al teaches making trastuzumab IgE and has shown that trastuzumab IgE directed monocytic cells to kill tumor cells expressing the HER2/neu antigen by ADCC, a mechanism clearly different from ADCP employed by trastuzumab IgG and monocytic cells (p1555, column 2).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
In the instant case, both trastuzumab IgE and trastuzumab IgG were used in the prior art for killing cancer cells. It would have been obvious to combine the Fc region of IgE and the Fc region of IgG as suggested by Kimes because such combination would allow the antibody to kill tumor cells by different mechanisms.
The fusion protein of trastuzumab IgE fused to hinge-C[Symbol font/0x67]2-C[Symbol font/0x67]3 would comprise instant SEQ ID NO:26 (SEQ ID NO:26 is the amino acid sequence of the heavy chain of the trastuzumab IgE plus IgG1 hinge-CH2-CH3, see the instant specification pages 36-37).
13. Claims 44, 49-50, 52-56, 58, 60-63 and 65-68 are rejected under 35 U.S.C. 103 as being unpatentable over Kimes et al. (WO 2020/172473A1, pub date: 8/27/2020, effectively filed date: 2/20/2019), in view of Karagiannis et al. (Cancer Immunol Immunother, 2012, 61, 1547-1564, IDS filed on 7/28/2023), further in view of Kim et al. (Eur J Immunol., 1999, 29: 2819-2825).
The teachings of Kimes et al. and Karagiannis et al. have been set forth above as they apply to claims 44-50, 52-56, 58, 60-63, 65 and 68
Regarding claims 66 and 67, Kimes et al. and Karagiannis et al. do not teach that the chimeric binding agent does not bind FcRn, and comprises a modified IgG CH2 and/or CH3 domain lacking one or more isoleucine or histidine residues associated with FcRn binding.
Kim et al. teaches that Ile253, His310 and His435 in human IgG1 play a central role in regulating serum half-life in mice and Fc-hinge fragments with mutation of Ile253, His310 and His435 have short persistence in the circulation, and also binds with very low affinity, if detectable, to recombinant soluble mouse FcRn (abstract and page 2822, Table 2). Kim et al. teaches that the interaction site of mouse FcRn on human and mouse IgG1 involves the same conserved amino acids located at the CH2-CH3 domain interface of the Ig molecule and the sequence similarities between mouse and human FcRn suggest that these studies have direct relevance to understanding the factors that govern the pharmacokinetics of therapeutic IgG (abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Ile253, His310 and His435 in the IgG1 CH2-CH3 of the chimeric binding agent in view of Karagiannis and Kim. One of ordinary skill in the art would have been motivated to do so because Karagiannis et al. teaches that trastuzumab IgE has shorter serum half-life and longer tissue half-life compared to trastuzumab IgG, and IgE is a class of tissue-resident antibodies which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, and Hinton et al. teaches that Ile253, His310 and His435 play a central role in regulating serum half-life in mice and FC-hinge fragments with mutation of Ile253, His310 and His435 have short persistence in the circulation and bind with very low affinity to FcRn. One of ordinary skill in the art would have had a reasonable expectation of success because Kim et al. has shown that FC-hinge fragments with mutation of Ile253, His310 and His435 have short persistence in the circulation and bind with very low affinity to FcRn.
Applicant’s Arguments for 103 Rejections
The response states that Kimes does not disclose the claimed fusion protein that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor, comprises C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains, and comprises one or more variable domains and/or one or more complementarity- determining regions (CDR). As noted by Kimes, the Kimes binding agents "lack ... complementary-determining regions (CDRs)." Kimes at paragraph 63. Accordingly, Kimes does not identically disclose all claim features of amended claim 44.
Saxon teaches a fusion molecule comprising an Fc[Symbol font/0x65] fragment functionally connected at the carboxy end of the Fc[Symbol font/0x65] fragment to an Fc[Symbol font/0x67] fragment. See Saxon at paragraph 115. Saxon describes that the fusion molecules crosslink Fc[Symbol font/0x67]receptors with Fc[Symbol font/0x65] receptors and block FCE receptor-mediated biological activities. See Saxon at paragraph 15 and id at paragraph 113. Saxon does not teach or suggest the claimed fusion protein that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67]receptor, comprises C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains, and comprises one or more variable domains and/or one or more complementarity-determining regions (CDR).
Timmer teaches proteins that bind to death receptor 5 (DR5). Timmer at paragraph 74. In particular, the DR5-targeting proteins comprise at least one copy of a single-domain antibody sequence that specifically binds DR5. Timmer at paragraph 74. As taught by Timmer, a single-domain antibody consists of an antibody variable domain that is specific for an antigen. Timmer at paragraph 76. Accordingly, the Timmer proteins do not comprise C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains, and comprises one or more variable domains and/or one or more complementarity-determining regions (CDR).
Karagiannis describes IgE antibodies that are engineered to have variable domains specific for particular antigens, e.g., by fusing antigen-specific variable domains from an IgG to human IgE-derived (e) constant regions. Karagiannis at page 1552, left column (chimeric anti-FRα antibody MOv18 IgE). Id at page 1555, right column (anti-HER2/neu antibody trastuzumab IgE). The Karagiannis antibodies are specifically designed to interact with target antigens via their variable domains in accordance with conventional antibody-antigen binding. Indeed, Karagiannis discusses at length the importance of carefully choosing antigens to be targeted by the Karagiannis IgE hybrid antibodies. See Karagiannis at page 1557 to 1561, describing safety concerns and metrics relating to types of antigens and epitopes in targets. For instance, "an antigen that is not shed in a multivalent form into the circulation must be chosen." Karagiannis at page 1557, top of column 1557. Thus, Karagiannis teaches modulating a therapeutic effect of conventional variable domain binding to its antigen by replacing an IgG constant domain with an IgE constant domain. See Karagiannis at Abstract. In contrast, the claimed technology provides a first-in-class fusion protein that exerts its function through binding of the constant domains to an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor. As described by Applicant, "the hybrid antibody is capable of binding to and activating both an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor, thereby transducing receptor signaling and effector functions in cells of immune system in which these receptors are expressed." Application at page 4, lines 27-30. In particular, as described by the application, the term "binds" (and related words such as "binding") refers to binding of the hybrid antibody via one or more constant domains thereof i.e. "binds" does not refer to specificity of the hybrid antibody binding to target antigen via its variable domains. Karagiannis does not teach or suggest fusion protein that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67] receptor, said fusion protein comprising C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains; and one or more variable domains and/or one or more complementarity-determining regions (CDR), wherein the C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains provide a binding site for an Fcα receptor and provide a binding site for an Fc[Symbol font/0x67] receptor. In particular, Karagiannis does not teach or suggest binding of constant domains to targets to provide a therapeutic effect.
Kim describes three amino acids at the CH2-CH3 domain interface (Ile253, His310 and His435) in play a central role in the control of serum half-life of IgG. Kim does not teach or suggest does not teach or suggest a fusion protein that binds an Fc[Symbol font/0x65] receptor and an Fc[Symbol font/0x67]receptor, said fusion protein comprising C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains; and one or more variable domains and/or one or more complementarity-determining regions (CDR), wherein the C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains provide a binding site for an Fce receptor and provide a binding site for an Fc[Symbol font/0x67] receptor.
Kimes, Saxon, Timmer, Karagiannis, and Kim, alone or in combination, do not teach or suggest binding of constant domains to targets to provide a therapeutic effect. Kimes, Saxon, Timmer, Karagiannis, and Kim, alone or in combination, do not teach or suggest a fusion protein that binds an Fc[Symbol font/0x65]receptor and an Fc[Symbol font/0x67] receptor, said fusion protein comprising C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains; and one or more variable domains and/or one or more complementarity-determining regions (CDR), wherein the C[Symbol font/0x65]2, C[Symbol font/0x65]3, C[Symbol font/0x65]4, C[Symbol font/0x67]2 and C[Symbol font/0x67]3 domains provide a binding site for an Fce receptor and provide a binding site for an Fcy receptor. Accordingly, Applicant respectfully asserts that the cited references fail to render claim 44 prima facie obvious. In like manner, because claim 44 is not obvious, claims dependent thereon are likewise nonobvious. See, e.g., In re Fne, 837 F.2d 1071 (Fed. Cir. 1988).
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive for the same reasons as discussed in the 102(a)(2) rejection.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
14. The following is a quotation of 35 U.S.C. 1