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 .
Claim Status
2. Applicant's election without traverse of Group I (claims 1-2, 4, 10, 25, 62-67, 69-71, 77, 87-88, 93, 95-96, 104, 112, and 118-120) and species: SEQ ID NO: 11 and G236A/Y300L (GAYL) substitutions in the reply filed on July 20, 2026 is acknowledged. Claims 3, 5-9, 11-24, 26-61, 68, 72-76, 78-86, 89-92, 94, 97-103, 105-111, and 113-117 were canceled by Applicant. Claims 10, 25, 63, 77, 93, and 120 are presently withdrawn by the Examiner for being drawn to non-elected species, e.g., having additional proline substitution at EU position 292. Therefore, claims: 1-2, 4, 10, 25, 62-67, 69-71, 77, 87-88, 93, 95-96, 104, 112, and 118-120 were pending; claims 10, 25, 63, 77, 93, and 120 are presently withdrawn; and claims 1-2, 4, 62, 64-67, 69-71, 87-88, 95-96, 104, 112, and 118-119 are presently subject to examination.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The references should be placed on an information disclosure statement if Applicant would like them considered.
Specification Objections
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “Meso Scale Discovery” at pg. 98), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other improper trademarks and correction is required.
b. There are also what appears to be claims under an additional claims section at pg. 97-119; if they are claims they should be placed on a separate page.
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.
Written Description
6. Claims 1-2, 4, 62, 64-67, 69-71, 87-88, 95-96, 104, 112, and 118-119 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 claims contain 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
No Written Description for the Breath of the Claims: Fc polypeptide or a fragment thereof; Written Description is only present for antibodies comprising the Fc of SEQ ID NO: 11 because of variability in receptor binding.
Claim 1 recites that the polypeptide comprises “fragments” of the Fc or CH2 domain having the GALY substitutions. The claims therefore encompass that the polypeptide may comprise as little as the two amino acids comprising the GALY substitutions.
In contrast, the specification indicates that only antibodies having the full-length Fc of SEQ ID NO: 11 were used. The specification fails to teach any fragments of the Fc polypeptide instantly claimed.
The claims recite functional language of the polypeptide, such as increased binding to human FcγRIIa and FcRn; however, a definition by function does not suffice to define the genus because it is only an indication of what the polypeptide does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the encompassed genus of polypeptides is highly variable (e.g., each polypeptide fragment would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed fragments having increased binding activity towards human FcγRIIa and FcRn have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of polypeptide “fragments” is made herein, which demonstrates the general principle that it is highly unpredictable what biological activity fragments of the instantly claimed polypeptide will have.
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid polypeptide would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a polypeptide sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different polypeptide resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible Fc fragments encompassed the claims. Therefore, without performing the required experiments it is wholly unpredictable which Fc fragments may retain biological activity, let alone have an increased binding to human FcγRIIa and FcRn as instantly claimed.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (emphasis added). That is the case here because only a single operable species of Fc is presently disclosed—specifically, the Fc of SEQ ID NO: 11.
Neither the art nor the specification provides a sufficient representative number of Fc polypeptide fragments and having the claim-recited biding properties to meet the written description requirement for instant claims directed to polypeptides comprising as little as the two amino acids comprising the GALY substitutions.
It is therefore unknown how the instantly claimed genus of polypeptides comprising Fc polypeptide fragments may bind to human FcγRIIa or FcRn. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of polypeptide fragments encompassed by the claims.
No Written Description for the Breath of the Claims: polypeptide comprising minimal structure of a CH2 domain; Written Description is only present for antibodies comprising the Fc of SEQ ID NO: 11 because of variability in receptor binding.
The claims are directed to a polypeptide comprising a variant of: (i) an IgG CH2 polypeptide or (ii) an IgG Fc polypeptide or a fragment thereof, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300. The claims further recite increased binding affinities to human FcγRIIa or FcRn at claims 2, 4, and 62.
The claims therefore broadly encompass polypeptides having as minimal structure as a fragment of a CH2 domain and having substitutions at positions 236 and 300 (GAYL). However, said minimal structure does not correlate with the functions recited in the claims. The specification only sets forth antibodies having the Fc domain of SEQ ID NO: 11 as having the required function. However, SEQ ID NO: 11 is not sufficiently representative of such a broad genus of peptides comprising as minimal structure as a fragment of a CH2 domain as instantly claimed.
The specification discloses binding affinities and assays using antibodies comprising the Fc domain encoded by SEQ ID NO: 11 at FIGs. 7-10, 12, 18-22, 24-26, and 29. The specification does not disclose any other “polypeptides” comprising the Fc of SEQ ID NO: 11, let alone comprising the CH2 domain in isolation.
The claims recite functional language of the polypeptide, such as increased binding to human FcγRIIa and FcRn; however, a definition by function does not suffice to define the genus because it is only an indication of what the polypeptide does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of polypeptides is highly variable (e.g., each polypeptide would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed “polypeptides” having increased binding activity towards human FcγRIIa and FcRn have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of Fc domains is made herein, which shows that the binding activity polypeptides comprising as minimal structure as a CH2 domain will be highly variable.
Ying et al. ("Interactions of IgG1 CH2 and CH3 domains with FcRn." Frontiers in immunology 5 (2014): 146) is a comparative study of the FcRn binding capability of Fc’s CH2 and CH3 domains (see the abstract). FIG 3A of Ying et al. shows that there is a vast difference in the binding activity of monomeric CH2 or CH3 fragments of the Fc domain as comparted to full Fc, and that there is essentially no binding activity for dimeric CH2 or CH3 fragments. Ying et al. FIG 3A is reproduced below for Applicant’s convenience:
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Ying et al. therefore demonstrates that the CH2 domain fragments encompassed by the claims will have significantly impaired binding properties compared to full length Fc (which includes the CH3 domain). Applicant has not demonstrated any CH2 polypeptides in the instant specification, but rather only antibodies comprising the full Fc. Therefore, without actually performing the required experiments, it is wholly unpredictable which members of the instantly claimed genus of polypeptides will bind to human FcγRIIa and FcRn.
Neither the art nor the specification provides a sufficient representative number of CH2 polypeptides and having the claim-recited biding properties to meet the written description requirement for instant claims directed to such polypeptides.
It is therefore unknown how the instantly claimed genus of polypeptides comprising as minimal structure as a fragment of the CH2 domain may bind to human FcγRIIa or FcRn. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of CH2 polypeptides encompassed by the claims.
No Written Description for the Breath of the Claims: IgG Fcs other than Fc of human IgG1; Written Description is only present for human IgG1 because of variability in receptor binding.
Claim 1 recites that the polypeptide comprises a variant of an IgG Fc or CH2 domain. The claims further recite at claim 87 that the polypeptide may be derived from or comprise isotypes IgG1-4, or human IgG1-4 isotypes. The claims therefore encompass that the polypeptide variant is derived from or comprises any of IgG1-4, and from any species.
In contrast, the specification indicates that only antibodies derived from human IgG1 were used.
The claims recite functional language of the polypeptide comprising IgG variant, such as increased binding to human FcγRIIa and FcRn; however, a definition by function does not suffice to define the genus because it is only an indication of what the polypeptide does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of polypeptides comprising IgG variant is highly variable (e.g., each polypeptide comprising a variant derived from a different IgG would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed peptides comprising “IgG” variants and having increased binding activity towards FcγRIIa or FcRn have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of IgG subclasses is made herein, which shows there is significant variability in FcγRIIa or FcRn binding activity between the IgG subclasses, let alone before introducing the GAYL variants.
Vidarsson et al. ("IgG subclasses and allotypes: from structure to effector functions." Frontiers in immunology 5 (2014): 520) is a review of IgG subclasses. Vidarsson teaches that “[d]ifferences in structure and function of IgG subclasses are summarized in Table1. Although they are more than 90% identical on the amino acid level, each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport.” (see the introduction). Table 1 is reproduced below for Applicant’s convenience:
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Table 1 shows that biding profiles for each of human IgG1-4 is unique for receptors, e.g., FcγRIIa and FcRn. For example, IgG1 binding to FcγRIIaR131 is “+++,” whereas IgG2 binding to FcγRIIaR131 is only “+.” In contrast, Applicant has only demonstrated binding properties of antibodies having a Fc derived from human IgG1, and additionally having the instantly claimed GAYL point mutations.
Applicant has not demonstrated what binding properties said GAYL point mutations will have in an antibody with Fc derived from human IgG2-4, let alone in an antibody having IgG from another species. As shown in the above Table 1, each IgG has unique binding properties. Therefore, without actually performing the required experiments, it is unpredictable which members of the instantly claimed genus of polypeptides comprising IgG variants will sufficiently bind to human FcγRIIa and FcRn.
Neither the art nor the specification provides a sufficient representative number of polypeptides comprising “IgG” variants and having the claim-recited biding properties to meet the written description requirement for instant claims directed to “IgG” variants.
It is therefore unknown how the instantly claimed genus of IgG variants may bind to human FcγRIIa or FcRn. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of peptides comprising “IgG” variants encompassed by the claims.
Regarding claim 67, which further recites that the IgG polypeptide “optionally compris[es] a protuberance in a first Fc of the heterodimer and a corresponding cavity in a second Fc of the heterodimer, and/or comprising one or more mutations that provide or contribute to an opposite charge in each of the two Fc monomers (e.g., a positive charge in a region of a first monomer and a negative charge in a corresponding region of a second monomer), and/or comprising a heterologous amino acid sequence in one or both monomers, to promote dimerization of the two Fc monomers),” e.g., knob-into-hole design: no examples of engineered protuberances and cavities / mutants / heterologous sequences (i.e., dimerization modifications) to promote dimerization in the Fc domains are provided in the specification—said features are not a part of the Fc encoded by the demonstrated and instantly claimed Fc of SEQ ID NO: 11.
The claim recites functional language of the polypeptide, such as promotes dimerization, however a definition by function does not suffice to define the genus because it is only an indication of what the polypeptide does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of polypeptides comprising dimerization modifications is highly variable (e.g., each peptide comprising dimerization modification would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed peptides comprising dimerization modifications have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of dimerization modifications is made herein, which shows that dimerization modifications will necessarily have high variability based on the IgG.
Vidarsson et al., as discussed above, is a review of IgG subclasses. FIG 3 of Vidarsson et al. shows that there is significant variability in the Fc domains (i.e., CH2-CH3) between IgG subclasses, let alone between the IgGs of different species as encompassed by the instant claims. FIG 3 of Vidarsson et al. is reproduced below for Applicant’s convenience:
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Vidarson et al. shows that e.g., only 50% of the IgG1 Fc sequence corresponds to the IgG4 Fc sequence. Vidarsson et al. therefore demonstrates that the features: “a protuberance in a first Fc of the heterodimer and a corresponding cavity in a second Fc of the heterodimer, and/or comprising one or more mutations that provide or contribute to an opposite charge in each of the two Fc monomers (e.g., a positive charge in a region of a first monomer and a negative charge in a corresponding region of a second monomer), and/or comprising a heterologous amino acid sequence in one or both monomers, to promote dimerization of the two Fc monomers” recited in instant claim 67 will necessarily vary from IgG to IgG. On the other hand, Applicant has not demonstrated possession of even a single example of such feature.
Regarding claim 104, which further recites that the polypeptide “comprises an amino acid mutation that (1) inhibits fucosylation as compared to a reference polypeptide, and/or (2) that abrogates a fucosylation site that is present in the reference polypeptide”: no examples of the claimed mutations are demonstrated in the instant specification. The specification only provides chemical means (i.e., 2FF) for achieving afucosylation at Example 3.
The claims recite functional language of the polypeptide, such as inhibits fucosylation, however a definition by function does not suffice to define the genus because it is only an indication of what the polypeptide does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of polypeptides comprising fucosylation mutants is highly variable (e.g., each peptide comprising a fucosylation mutant would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed peptides comprising fucosylation mutants no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of fucosylation mutants is made herein, which shows that the fucoslylation mutants instantly claimed are not known in the art.
Pereira et al. ("The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity." MAbs. Vol. 10. No. 5. Taylor & Francis, 2018) is a review of strategies employed to produce afucosylated antibodies. (see the abstract). Pereria et al. highlights that the known strategies include: Biosynthetic enzymes of GDP-fucose; Fucosyltransferase – FUT8; GDP-fucose transporter (SLC35C1); Generation of bisecting GlcNac; Expression of bacterial RMD in the cytosol of CHO cells to disrupt the GDP-fucose de novo pathway; Biochemical inhibitors of fucosylation; Plant cells as expression platforms; Chemoenzymatic remodeling strategy. Periera et al. at “Strategies to produce afucosylated antibodies.” Pereira et al. therefore indicates that the state of the art is such that mutations to the antibody polypeptide itself are not commonly employed to produce afucosylated antibodies, if it is even possible. Applicant also has not demonstrated even a single mutation that achieves afucolyation.
Neither the art nor the specification provides a sufficient representative number of dimerization modifications or fucosylation mutants to meet the written description requirement for instant claims directed to such subject matter.
It is therefore unknown how the genus of dimerization modifications or fucoslylation mutants would promote dimerization or inhibit fucosylation. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of dimerization modifications and fucosylation mutants encompassed by the claims.
Given all of the above, the cited reference therefore demonstrate that Applicant is not in possession of: peptides comprising GAYL Fc/CH2 fragments and the features recited in claims 67 and 104. Applicant is in possession of: human IgG1 antibodies having the GAYL Fc of SEQ ID NO: 11.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
7. Claims 1-2, 4, 62, 64-67, 69-71, 87-88, 95-96, 104, 112, and 118-119 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 antibody comprising the human IgG1 Fc GAYL variant of SEQ ID NO: 11, does not reasonably provide enablement for peptides comprising Fc/CH2 GAYL fragments and features recited in claims 67 (e.g.., knob into hole variants) and 104 (e.g., fucosylation inhibiting mutants). 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 and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to a polypeptide comprising a variant of: (i) an IgG CH2 polypeptide or (ii) an IgG Fc polypeptide or a fragment thereof, wherein the variant comprises the GAYL variant. The claims characterize the polypeptide as having increased binding to a human FcγRIIa at claims 2 and 4, or increased binding to human FcRn at claim 62. The claims further recite that the polypeptide may be comprised in a polypeptide heterodimer optionally comprising e.g., protuberances, cavities, and mutations to promote dimerization at claim 67; or further comprising mutations that e.g., inhibit fucosylation at claim 104.
The claims are therefore broad and encompass that the polypeptide may be as small as a fragment of a CH2 domain comprising the GAYL variant, and that said fragment may be derived from any IgG (e.g., IgG 1-4 from any species). The claim-recited fragments are characterized by increased binding to receptors, improved dimerization, and inhibiting fucosylation.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable how well peptides comprising fragments of CH2 and Fc domains encompassed by the claims will (i) bind to human FcγRIIa or FcRn, (ii) promote dimerization, or (iii) inhibit fucosylation.
It is unpredictable what Fc fragments, let alone CH2 fragments, will having sufficient binding to human FcγRIIa and FcRn
A brief assessment of the state of the art of polypeptide “fragments” is made herein, which demonstrates the general principle that it is highly unpredictable what biological activity fragments of the instantly claimed polypeptide will have.
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid polypeptide would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a polypeptide sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different polypeptide resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible Fc fragments encompassed the claims. Therefore, without performing the required experiments it is wholly unpredictable which Fc fragments may retain biological activity, let alone have an increased binding to human FcγRIIa and FcRn as instantly claimed.
It is unpredictable which CH2 fragments will sufficiently bind to human FcγRIIa and FcRn
Ying et al. ("Interactions of IgG1 CH2 and CH3 domains with FcRn." Frontiers in immunology 5 (2014): 146) is a comparative study of the FcRn binding capability of Fc’s CH2 and CH3 domains (see the abstract). FIG 3A of Ying et al. shows that there is a vast difference in the binding activity of monomeric CH2 or CH3 fragments of the Fc domain as comparted to full Fc, and that there is essentially no binding activity for dimeric CH2 or CH3 fragments. Ying et al. FIG 3A is reproduced below for Applicant’s convenience:
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475
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Ying et al. therefore demonstrates that the CH2 domain fragments encompassed by the claims will have significantly impaired binding properties compared to full length Fc (which includes the CH3 domain). Applicant has not demonstrated any CH2 polypeptides in the instant specification, but rather only antibodies comprising the full Fc. Therefore, without actually performing the required experiments, it is wholly unpredictable which members of the instantly claimed genus of polypeptides will sufficiently bind to human FcγRIIa and FcRn.
It is unpredictable which IgG variants will result in CH2 and Fc fragments having sufficient binding to human FcγRIIa and FcRn
Vidarsson et al. ("IgG subclasses and allotypes: from structure to effector functions." Frontiers in immunology 5 (2014): 520) is a review of IgG subclasses. Vidarsson teaches that “[d]ifferences in structure and function of IgG subclasses are summarized in Table1. Although they are more than 90% identical on the amino acid level, each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport.” (see the introduction). Table 1 is reproduced below for Applicant’s convenience:
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617
872
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Table 1 shows that biding profiles for each of human IgG1-4 is unique for receptors, e.g., FcγRIIa and FcRn. For example, IgG1 binding to FcγRIIaR131 is “+++,” whereas IgG2 binding to FcγRIIaR131 is only “+.” In contrast, Applicant has only demonstrated binding properties of antibodies having a Fc derived from human IgG1, and additionally having the instantly claimed GAYL point mutations.
Applicant has not demonstrated what binding properties said GAYL point mutations will have in an antibody with Fc derived from human IgG2-4, let alone in an antibody having IgG from another species. As shown in the above Table 1, each IgG has unique binding properties. Therefore, without actually performing the required experiments, it is unpredictable which members of the instantly claimed genus of polypeptides comprising IgG variants will sufficiently bind to human FcγRIIa and FcRn.
It is unpredictable how to make and use dimerization modifications (i.e., claim 67)
A brief assessment of the state of the art of dimerization modifications is made herein, which shows that dimerization modifications will necessarily have high variability based on the IgG, and therefore it is unpredictable how to make and use such modifications for “IgG” in general, or for fragments of a Fc or CH2 domain.
Vidarsson et al., as discussed above, is a review of IgG subclasses. FIG 3 of Vidarsson et al. shows that there is significant variability in the Fc domains (i.e., CH2-CH3) between IgG subclasses, let alone between the IgGs of different species as encompassed by the instant claims. FIG 3 of Vidarsson et al. is reproduced below for Applicant’s convenience:
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531
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Vidarson et al. shows that e.g., only 50% of the IgG1 Fc sequence corresponds to the IgG4 Fc sequence. Vidarsson et al. therefore demonstrates that the features: “a protuberance in a first Fc of the heterodimer and a corresponding cavity in a second Fc of the heterodimer, and/or comprising one or more mutations that provide or contribute to an opposite charge in each of the two Fc monomers (e.g., a positive charge in a region of a first monomer and a negative charge in a corresponding region of a second monomer), and/or comprising a heterologous amino acid sequence in one or both monomers, to promote dimerization of the two Fc monomers” recited in instant claim 67 will necessarily vary from IgG to IgG. Therefore, it is unpredictable how to obtain the modifications necessary to promote dimerization as instantly claimed because the structures significantly vary from IgG to IgG.
It is unpredictable how to make and use the instantly claimed fucosylation mutants (i.e., claim 104)
A brief assessment of the state of the art of fucosylation mutants is made herein, which shows that the fucoslylation mutants instantly claimed are not known in the art, and therefore it is unpredictable how to make and use such mutants.
Pereira et al. ("The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity." MAbs. Vol. 10. No. 5. Taylor & Francis, 2018) is a review of strategies employed to produce afucosylated antibodies. (see the abstract). Pereria et al. highlights that the known strategies include: Biosynthetic enzymes of GDP-fucose; Fucosyltransferase – FUT8; GDP-fucose transporter (SLC35C1); Generation of bisecting GlcNac; Expression of bacterial RMD in the cytosol of CHO cells to disrupt the GDP-fucose de novo pathway; Biochemical inhibitors of fucosylation; Plant cells as expression platforms; Chemoenzymatic remodeling strategy. Periera et al. at “Strategies to produce afucosylated antibodies.” Pereira et al. therefore indicates that the state of the art is such that mutations to the antibody polypeptide itself are not commonly employed to produce afucosylated antibodies, if it is even possible. Applicant also has not demonstrated even a single mutation that achieves afucolyation.
Therefore, without performing the required experiments, it is wholly unpredictable how well peptides comprising fragments of CH2 and Fc domains encompassed by the claims will (i) bind to human FcγRIIa or FcRn, (ii) dimerize, or (iii) inhibit fucosylation.
6) the amount of direction or guidance provided by the inventor:
The specification only discloses binding affinities and assays using antibodies comprising the Fc domain encoded by SEQ ID NO: 11 (derived from human IgG1) at FIGs. 7-10, 12, 18-22, 24-26, and 29. The specification does not disclose any other “polypeptides” comprising the Fc of SEQ ID NO: 11, let alone comprising the CH2 domain in isolation, fragments of the Fc domain encoded by SEQ ID NO: 11, or derived from IgGs other than human IgG1 as instantly claimed. The specification also fails to disclose any Fc modifications that promote dimerization or fucosylation inhibiting mutants.
Given all of the above, one of skill in the art could not reasonably extrapolate the instant findings regarding binding affinities achieved with antibodies having the Fc domain encoded by SEQ ID NO: 11 to the breadth of the claim-recited polypeptides—having as little as the two amino acids encoded by the GAYL variants and derived from any IgG. It would be undue experimentation to determine which of the encompassed polypeptides could be could: (i) sufficiently bind to human FcγRIIa or FcRn, (ii) promote dimerization, or (iii) inhibit fucosylation.
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because polypeptides comprising fragments of the Fc domain and/or CH2 domain derived from the various IgG subclasses and species and furthermore comprising the GAYL variant would need to synthesized and tested for their ability to (i) bind to human FcγRIIa or FcRn, (ii) promote dimerization, and (iii) inhibit fucosylation. In contrast, applicant has only demonstrated effects achieved using the Fc of SEQ ID NO: 11, which was derived from human IgG1. Applicant furthermore has not demonstrated any dimerization promoting modifications and/or fucosylation mutants. The above-cited references demonstrate that it is unpredictable to achieve each of these features of the claim-recited polypeptide.
In conclusion, the claimed invention does not provide enablement for polypeptides comprising fragments of IgG Fc or CH2 domain, dimerization-promoting modifications, or fucosylation inhibiting mutants. The claimed invention only provides enablement for antibodies comprising the Fc of SEQ ID NO: 11, derived from human IgG1. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
8. 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.
a. Claims 2 and 4 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 2 contains the trademark/trade name “Meso Scale Discovery.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an electrochemiluminescence assay and, accordingly, the identification/description is indefinite.
b. Claims 2 and 4 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 2 recites “wherein the variant, and optionally the polypeptide, has increased binding to human FcγRIIa.” Claim 1, from which claim 2 depends, recites “a polypeptide comprising a [GAYL] variant of: an IgG CH2 polypeptide or (ii) an IgG Fc polypeptide[.]” Since the polypeptide comprises the Fc or CH2 GAYL variant, it is unclear how the Fc or CH2 GAYL variant can exhibit increased binding affinity, but the polypeptide comprising the variant optionally does not. Does comprising a GAYL Fc in a peptide alter the FcγRIIa binding activity of the GAYL Fc? Appropriate clarification and/or correction is requested.
c. Claim 62 is rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 62 recites “further comprises one or more modification that enhances or further enhances binding.” It is unclear if the term “enhances” means “increases” or some other enhancement. For example, would decreased binding be considered enhanced binding? Appropriate clarification and/or correction is requested.
d. Claim 64 is rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 64 recites “the IgG hinge,” however the term lacks antecedent basis in the claims. Appropriate clarification and/or correction is requested.
e. Claims 87-88 is rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 87 recites that the variant is “derived from or comprises” IgG isotypes; Claim 88 recites that the variant is “derived from or comprises” human Fc or human antibody heavy chain. It is unclear if the term “derived from” includes additional features not included by the term “comprises” and if so, what those features may be. Is the term “derived from” of equal scope as “comprises”? Appropriate clarification and/or correction is requested.
f. Claims 96 and 118 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claims 96 and 118 recite that the antibody is “capable of” “specifically binding” to targets. The term “capable of” suggests that the specific binding may or may not be required by the claim; and the term “specifically” is an open-ended term of degree to characterize the binding, and so it is unclear how it differs from “binding.” How specific is “specific binding,” and is specific biding to target required by the claim? Appropriate clarification and/or correction is requested.
g. Claim 104 is rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 104 recites that the mutation “inhibits fucosylation as compared to a reference polypeptide” and/or “abrogates a fucosylation site.” As noted in the 112(a) rejection, the claims encompass polypeptide fragments having minimal structure, and therefore it is unclear what the reference polypeptide is, or what site may be “abrogated” to achieve inhibition of fucosylation. Can either of the GAYL variants instantly claimed be abrogated to achieve inhibition of fucosylation? Appropriate clarification and/or correction is requested.
Claim Rejections - 35 USC § 102
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
10. Claims 1-2, 64-67, 69-71, 87-88, 95-96, 104, 112, and 118 are rejected under 35 U.S.C 102 (a)(2) as anticipated by D’angelo et al. (WO 2011120135 A1; published October 6, 2011).
Claim 1 is directed to a polypeptide comprising a variant of: (i) an IgG CH2 polypeptide or (ii) an IgG Fc polypeptide or a fragment thereof, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300.
Claim 2 is directed to the polypeptide of claim 1, wherein the variant, and optionally the polypeptide, has increased binding to a human FcyRIIa as compared to the binding of a reference polypeptide to the human FcyRIIa, wherein, optionally, binding is as determined using an electrochemiluminescence assay, further optionally Meso Scale Discovery.
Claim 64 is directed to the polypeptide of claim 1, wherein the variant does not comprise any additional mutations as compared to the reference IgG Fc polypeptide or fragment thereof, the IgG CH2 polypeptide, the IgG hinge-CH2 polypeptide, or the IgG hinge-Fc polypeptide or fragment thereof, respectively.
Claim 65 is directed to the polypeptide of claim 1, which comprises a Fc polypeptide.
Claim 66 is directed to the polypeptide of claim 1, which is a monomer comprised in a polypeptide dimer (e.g., a Fc dimer).
Claim 67 is directed to the polypeptide of claim 1, i) which is a monomer comprised in a polypeptide homodimer (e.g., a Fc homodimer); or ii) which is a monomer comprised in a polypeptide heterodimer (e.g., a Fc heterodimer, optionally comprising a protuberance in a first Fc of the heterodimer and a corresponding cavity in a second Fc of the heterodimer, and/or comprising one or more mutations that provide or contribute to an opposite charge in each of the two Fc monomers (e.g., a positive charge in a region of a first monomer and a negative charge in a corresponding region of a second monomer), and/or comprising a heterologous amino acid sequence in one or both monomers, to promote dimerization of the two Fc monomers).
Claim 69 is directed to the polypeptide of claim 1, which is comprised in an antibody.
Claim 70 is directed to an antibody comprising the polypeptide of claim 1.
Claim 71 is directed to an antibody comprising a variant of an IgG Fc, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300.
Claim 87 is directed to the polypeptide of claim 1, wherein the variant is derived from or comprises: i) an IgGI isotype, an IgG2 isotype, an IgG3 isotype, or an IgG4 isotype; ii) a human IgGI isotype, a human IgG2 isotype, a human IgG3 isotype, or a human IgG4 isotype; or iii) a human IgGI isotype, optionally comprising a Glm3 allotype, a Glm17 allotype, a Glm3,1 allotype, or a Glm17,1 allotype.
Claim 88 is directed to the polypeptide of claim 1, wherein the variant is derived from or comprises a human Fc or a fragment thereof, or from a human antibody heavy chain or a fragment thereof.
Claim 95 is directed to the antibody of claim 70, wherein the variant does not comprise any additional mutations as compared to a reference wild-type IgG Fc.
Claim 96 is directed to the antibody of claim 69, wherein the antibody is capable of specifically binding to: (i) a target (e.g., an antigen) that is expressed or produced by a pathogen (e.g., virus, bacterium, parasite, fungus) or by a cell infected with the pathogen, wherein, optionally, the pathogen comprises a virus and the virus comprises: a coronavirus; a betacoronavirus; a sarbecovirus; an embecovirus; a nobecovirus; a merbecovirus; a metapneumovirus; a hibecovirus; a SARS-CoV-2; a hepatitis B virus; a hepatitis D virus; an influenza A virus; a cytomegalovirus; a rhinovirus; a hepatitis C virus; an influenza B virus; a human 187559670.1 immunodeficiency virus; a respiratory virus; a respiratory syncytial virus; a zika virus; a rabies virus; a dengue virus; a flavivirus; an ebolavirus; or any combination thereof;(ii) a target (e.g., an antigen) that is expressed by, and/or is expressed on a cell surface of, a tumor cell, optionally a cancer cell or a cell of a proliferative or hyperproliferative disorder;(iii) a target (e.g., an antigen) that is associated with an autoimmune disease;(iv) a target (e.g., an antigen) that is associated with a neurodegenerative disease (v) an immune system signaling molecule, such as a cytokine;(vi) a target (e.g., an antigen) that is associated with inflammation;(vii) a target (e.g., an antigen) that is associated with a non-infectious disease; or (viii) any combination of (i)-(vii).
Claim 104 is directed to the polypeptide of claim 1, wherein the polypetide: i) is afucosylated; has been produced in a host cell that is incapable of fucosylation or that is inhibited in its ability to fucosylate a polypeptide; has been produced under conditions that inhibit fucosylation thereof by a host cell; or any combination thereof; and/or ii) comprises an amino acid mutation that (1) inhibits fucosylation as compared to a reference polypeptide, and/or (2) that abrogates a fucosylation site that is present in the reference polypeptide.
Claim 112 is directed to a composition comprising: the polypeptide of the polypeptide of and a pharmaceutically acceptable carrier, excipient, or diluent.
Claim 118 is directed to the polypeptide of claim 1, wherein the polypeptide is capable of specifically binding to human immunodeficiency virus.
D’angelo et al. discloses polypeptides comprising a variant IgG Fc comprising two variants including the instantly claimed GAYL variant.
D’angelo et al. is directed to polypeptides comprising Fc region mutations at two positions that synergistically make the polypeptides more effective when incorporated in antibody therapeutics than those having wild-type Fc components (see the abstract). D’angelo et al. discloses polypeptides comprising a variant Fc region, wherein said variant Fc region comprises two amino acid modifications relative to a wild-type Fc region, wherein the two amino acid modifications are selected from the group consisting of: L235Y, L235F, G236A, G236D, S239E, S239D, D265E, D270E, D270N, D270L, D270K, S298A, Y300L, 326D, and K326R at para. [0049]. D’angelo et al. discloses the amino acid modifications produce amino acid interactions and dynamics that result in enhanced binding affinity and/or specificity to a FcγRIIa receptor at para. [0043]. D’angelo et al. discloses the Fc region of the parent polypeptide is a human IgG Fc region; and in some embodiments, the human IgG Fc region is a human IgGl, IgG2, IgG3, or IgG4 Fc region at para. [0052]. D’angelo et al. discloses that in some embodiments, the polypeptides described finds use in an antibody or Fc fusion that is a monomer or an oligomer, including a homo- or hetero-oligomer at para. [0169]. D’angelo et al. discloses the polypeptide may target / bind, e.g., HIV proteins at para. [0173]. D’angelo et al. discloses further modification such as afucosylation by cell lines at para. [0171]. Last, D’angelo et al. also discloses comprising the polypeptide in pharmaceutical compositions having pharmaceutically acceptable carriers at para. [0192].
Accordingly, D’angelo et al. anticipates claims 1-2, 64-67, 69-71, 87-88, 95-96, 104, 112, and 118.
11. Claims 1-2, 4, 64-67, 69-71, 87-88, 95, 104, and 112 are rejected under 35 U.S.C 102 (a)(2) as anticipated by Van Dijk et al. (WO 2016196237 A1; published December 8, 2016).
Claim 1 is directed to a polypeptide comprising a variant of: (i) an IgG CH2 polypeptide or (ii) an IgG Fc polypeptide or a fragment thereof, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300.
Claim 2 is directed to the polypeptide of claim 1, wherein the variant, and optionally the polypeptide, has increased binding to a human FcyRIIa as compared to the binding of a reference polypeptide to the human FcyRIIa, wherein, optionally, binding is as determined using an electrochemiluminescence assay, further optionally Meso Scale Discovery.
Claim 4 is directed to the polypeptide of claim 2, wherein the human FcyRIIa comprises: i) H131 and, optionally, the increased binding to the human FcyRIIa H131 comprises at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, or at least 18-fold greater binding to the human FcyRIIa H131 as compared to the binding of a reference polypeptide comprising a wild-type human IgG Fc polypeptide or a fragment thereof to the human FcyRIIa H131; or ii) R131 and, optionally, the increased binding to the human FcyRIIa R131 comprises at least 4-fold greater binding to the human FcyRIIa R131 as compared to the binding of a reference polypeptide comprising a wild-type human IgG Fc polypeptide or a fragment thereof to the human FeyRIIa R131.
Claim 64 is directed to the polypeptide of claim 1, wherein the variant does not comprise any additional mutations as compared to the reference IgG Fc polypeptide or fragment thereof, the IgG CH2 polypeptide, the IgG hinge-CH2 polypeptide, or the IgG hinge-Fc polypeptide or fragment thereof, respectively.
Claim 65 is directed to the polypeptide of claim 1, which comprises a Fc polypeptide.
Claim 66 is directed to the polypeptide of claim 1, which is a monomer comprised in a polypeptide dimer (e.g., a Fc dimer).
Claim 67 is directed to the polypeptide of claim 1, i) which is a monomer comprised in a polypeptide homodimer (e.g., a Fc homodimer); or ii) which is a monomer comprised in a polypeptide heterodimer (e.g., a Fc heterodimer, optionally comprising a protuberance in a first Fc of the heterodimer and a corresponding cavity in a second Fc of the heterodimer, and/or comprising one or more mutations that provide or contribute to an opposite charge in each of the two Fc monomers (e.g., a positive charge in a region of a first monomer and a negative charge in a corresponding region of a second monomer), and/or comprising a heterologous amino acid sequence in one or both monomers, to promote dimerization of the two Fc monomers).
Claim 69 is directed to the polypeptide of claim 1, which is comprised in an antibody.
Claim 70 is directed to an antibody comprising the polypeptide of claim 1.
Claim 71 is directed to an antibody comprising a variant of an IgG Fc, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300.
Claim 87 is directed to the polypeptide of claim 1, wherein the variant is derived from or comprises: i) an IgGI isotype, an IgG2 isotype, an IgG3 isotype, or an IgG4 isotype; ii) a human IgGI isotype, a human IgG2 isotype, a human IgG3 isotype, or a human IgG4 isotype; or iii) a human IgGI isotype, optionally comprising a Glm3 allotype, a Glm17 allotype, a Glm3,1 allotype, or a Glm17,1 allotype.
Claim 88 is directed to the polypeptide of claim 1, wherein the variant is derived from or comprises a human Fc or a fragment thereof, or from a human antibody heavy chain or a fragment thereof.
Claim 95 is directed to the antibody of claim 70, wherein the variant does not comprise any additional mutations as compared to a reference wild-type IgG Fc.
Claim 104 is directed to the polypeptide of claim 1, wherein the polypetide: i) is afucosylated; has been produced in a host cell that is incapable of fucosylation or that is inhibited in its ability to fucosylate a polypeptide; has been produced under conditions that inhibit fucosylation thereof by a host cell; or any combination thereof; and/or ii) comprises an amino acid mutation that (1) inhibits fucosylation as compared to a reference polypeptide, and/or (2) that abrogates a fucosylation site that is present in the reference polypeptide.
Claim 112 is directed to a composition comprising: the polypeptide of the polypeptide of and a pharmaceutically acceptable carrier, excipient, or diluent.
Van Dijk et al. discloses antibodies (i.e., polypeptides) comprising an IgG heavy chain constant region (i.e., including Fc domain) and having one or more variants including the instantly claimed GA and YL variants.
Van Dijk et al. is directed to antibodies that specifically bind to human CTLA-4 (see the abstract). Van Dijk et al. discloses the antibody comprises a human IgG heavy chain constant region that is a variant of a wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human Fc gamma receptors with higher affinity than the wild type human IgG heavy chain constant region binds to the human Fc gamma receptors; that the human Fc gamma receptor is selected from the group consisting of FcγRIIIA, FcγRIIA, and FcγRI; and that the variant human IgG heavy chain constant region comprises one or more of the following amino acid mutations, according to the EU numbering system: G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305I, A330L, I332E, E333A, K334A, A339T, and P396L at para. [0024]. Figure 8 discloses binding curves of the antibodies to H131 FcγRIIA variant. Van Djik et al. discuss dimerization of the antibody at para. [0089] (and dimerization necessarily must be homodimer or heterodimer); and that the antibody can be human IgG1-4 at para. [0089]. Van Djik et al. discloses afucosylated Fc region at para. [0024]. Last, Van Djik et al. also discloses comprising the polypeptide in pharmaceutical compositions having pharmaceutically acceptable carriers at para. [0031].
Accordingly, Van Djik et al. anticipates claims 1-2, 4, 64-67, 69-71, 87-88, 95, 104, and 112.
12. Claims 1-2, 62, 64-67, 69-71, 87-88, 95, 104, 112 are rejected under 35 U.S.C 102 (a)(2) as anticipated by Lazar et al. (WO 2005056606 A2; published June 23, 2025).
Claim 1 is directed to a polypeptide comprising a variant of: (i) an IgG CH2 polypeptide or (ii) an IgG Fc polypeptide or a fragment thereof, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300.
Claim 2 is directed to the polypeptide of claim 1, wherein the variant, and optionally the polypeptide, has increased binding to a human FcyRIIa as compared to the binding of a reference polypeptide to the human FcyRIIa, wherein, optionally, binding is as determined using an electrochemiluminescence assay, further optionally Meso Scale Discovery.
Claim 62 is directed to the polypeptide of claim 1, wherein the variant further comprises one or more modification that enhances or further enhances binding to a human FcRn as compared to (1) a reference polypeptide that comprises a wild-type human IgGIFc polypeptide and/or to (2) the polypeptide claim 1 without the one or more modification.
Claim 64 is directed to the polypeptide of claim 1, wherein the variant does not comprise any additional mutations as compared to the reference IgG Fc polypeptide or fragment thereof, the IgG CH2 polypeptide, the IgG hinge-CH2 polypeptide, or the IgG hinge-Fc polypeptide or fragment thereof, respectively.
Claim 65 is directed to the polypeptide of claim 1, which comprises a Fc polypeptide.
Claim 66 is directed to the polypeptide of claim 1, which is a monomer comprised in a polypeptide dimer (e.g., a Fc dimer).
Claim 67 is directed to the polypeptide of claim 1, i) which is a monomer comprised in a polypeptide homodimer (e.g., a Fc homodimer); or ii) which is a monomer comprised in a polypeptide heterodimer (e.g., a Fc heterodimer, optionally comprising a protuberance in a first Fc of the heterodimer and a corresponding cavity in a second Fc of the heterodimer, and/or comprising one or more mutations that provide or contribute to an opposite charge in each of the two Fc monomers (e.g., a positive charge in a region of a first monomer and a negative charge in a corresponding region of a second monomer), and/or comprising a heterologous amino acid sequence in one or both monomers, to promote dimerization of the two Fc monomers).
Claim 69 is directed to the polypeptide of claim 1, which is comprised in an antibody.
Claim 70 is directed to an antibody comprising the polypeptide of claim 1.
Claim 71 is directed to an antibody comprising a variant of an IgG Fc, wherein the variant comprises an alanine (A) at EU position 236 and a leucine (L) at EU position 300.
Claim 87 is directed to the polypeptide of claim 1, wherein the variant is derived from or comprises: i) an IgGI isotype, an IgG2 isotype, an IgG3 isotype, or an IgG4 isotype; ii) a human IgGI isotype, a human IgG2 isotype, a human IgG3 isotype, or a human IgG4 isotype; or iii) a human IgGI isotype, optionally comprising a Glm3 allotype, a Glm17 allotype, a Glm3,1 allotype, or a Glm17,1 allotype.
Claim 88 is directed to the polypeptide of claim 1, wherein the variant is derived from or comprises a human Fc or a fragment thereof, or from a human antibody heavy chain or a fragment thereof.
Claim 95 is directed to the antibody of claim 70, wherein the variant does not comprise any additional mutations as compared to a reference wild-type IgG Fc.
Claim 104 is directed to the polypeptide of claim 1, wherein the polypetide: i) is afucosylated; has been produced in a host cell that is incapable of fucosylation or that is inhibited in its ability to fucosylate a polypeptide; has been produced under conditions that inhibit fucosylation thereof by a host cell; or any combination thereof; and/or ii) comprises an amino acid mutation that (1) inhibits fucosylation as compared to a reference polypeptide, and/or (2) that abrogates a fucosylation site that is present in the reference polypeptide.
Claim 112 is directed to a composition comprising: the polypeptide of the polypeptide of and a pharmaceutically acceptable carrier, excipient, or diluent.
Lazar et al. discloses antibodies (i.e., polypeptides) having IgG1 constant regions (i.e., including Fc domains) and having variants selected from a list including the instantly claimed GA and YL variants.
Lazar et al. is directed to optimized antibodies that target the EGFR (see the title). Lazar et al. discloses preferred embodiments of the invention where the EGFR targeting proteins of the present invention may be optimized to possess enhanced affinity for a human activating FCYR, preferably FcyRI, FcγRlla, FcγRllc, FcγRllla, and FcγRlllb at para. [0090]. Lazar et al. discloses EGFR targeting proteins of the invention may comprise modifications that modulate interaction with Fc ligands other than FcγRs, including but not limited to complement proteins, FcRn, and Fc receptor homologs (FcRHs) at para. [0094]. Lazar et al. discloses human IgG1 is the most commonly used constant region at para. [0214].
[para 0020] recites: [I]n some embodiments, variant proteins comprising an immunoglobulin constant chain, and amino acid modification selected from the group consisting of: P230A, E233D, L234D, L234E, L234N, L234Q, L234T, L234H, L234Y, L234I, L234V, L234F, L235D, L235S, L235N, L235Q, L235T, L235H, L235Y, L235I, L235V, L235F, S239D, S239E, S239N, S239Q, S239F, S239T, S239H, S239Y, V240I, V240A, V240T, V240M, F241W, F241L, F241Y, F241E, F241R, F243W, F243L F243Y, F243R, F243Q, P244H, P245A, P247V, P247G, V262I, V262A, V262T, V262E, V263I, V263A, V263T, V263M, V264L, V264I, V264W, V264T, V264R, V264F, V264M, V264Y, V264E, D265G, D265N, D265Q, D265Y, D265F, D265V, D265I, D265L, D265H, D265T, V266I, V266A, V266T, V266M, S267Q, S267L, S267T, S267H, S267D, S267N, E269H, E269Y, E269F, E269R, E269T, E269L, E269N, D270Q, D270T, D270H, E272S, E272K, E272I, E272Y, V273I, K274T, K274E, K274R, K274L, K274Y, F275W, N276S, N276E, N276R, N276L, N276Y, Y278T, Y278E, Y278K, Y278W, E283R, Y296E, Y296Q, Y296D, Y296N, Y296S, Y296T, Y296L, Y296I, Y296H, N297S, N297D, N297E, A298H, T299I, T299L, T299A, T299S, T299V, T299H, T299F, T299E, V302I, W313F, E318R, K320T, K320D, K320I, K322T, K322H, V323I, S324T, S324D, S324R, S324I, S324V, S324L, S324Y, N325Q, N325L, N325I, N325D, N325E, N325A, N325T, N325V, N325H, K326L, K326I, K326T, A327N, A327L, A327D, A327T, L328M, L328D, L328E, L328N, L328Q, L328F, L328I, L328V, L328T, L328H, L328A, P329F, A330L, A330Y, A330V, A330I, A330F, A330R, A330H, A330S, A330W, A330M, P331V, P331H, I332D, I332E, I332N, I332Q, I332T, I332H, I332Y, I332A, E333T, E333H, E333I, E333Y, K334I, K334T, K334F, T335D, T335R, T335Y, D221K, D221Y, K222E, K222Y, T223E, T223K, H224E, H224Y, T225E, T225, T225K, T225W, P227E, P227K, P227Y, P227G, P228E, P228K, P228Y, P228G, P230E, P230Y, P230G, A231E, A231K, A231Y, A231P, A231G, P232E, P232K, P232Y, P232G, E233N, E233Q, E233K, E233R, E233S, E233T, E233H, E233A, E233V, E233L, E233I, E233F, E233M, E233Y, E233W, E233G, L234K, L234R, L234S, L234A, L234M, L234W, L234P, L234G, L235E, L235K, L235R, L235A, L235M, L235W, L235P, L235G, G236D, G236E, G236N, G236Q, G236K, G236R, G236S, G236T, G236H, G236A, G236V, G236L, G236I, G236F, G236M, G236Y, G236W, G236P, G237D, G237E, G237N, G237Q, G237K, G237R, G237S, G237T, G237H, G237V, G237L, G237I, G237F, G237M, G237Y, G237W, G237P, P238D, P238E, P238N, P238Q, P238K, P238R, P238S, P238T, P238H, P238V, P238L, P238I, P238F, P238M, P238Y, P238W, P238G, S239Q, S239K, S239R, S239V, S239L, S239I, S239M, S239W, S239P, S239G, F241D, F241E, F241Y, F243E, K246D, K246E, K246H, K246Y, D249Q, D249H, D249Y, R255E, R255Y, E258S, E258H, E258Y, T260D, T260E, T260H, T260Y, V262E, V262F, V264D, V264E, V264N, V264Q, V264K, V264R, V264S, V264H, V264W, V264P, V264G, D265Q, D265K, D265R, D265S, D265T, D265H, D265V, D265L, D265I, D265F, D265M, D265Y, D265W, D265P, S267E, S267Q, S267K, S267R, S267V, S267L, S267I, S267F, S267M, S267Y, S267W, S267P, H268D, H268E, H268Q, H268K, H268R, H268T, H268V, H268L, H268I, H268F, H268M, H268W, H268P, H268G, E269K, E269S, E269V, E269I, E269M, E269W, E269P, E269G, D270R, D270S, D270L, D270I, D270F, D270M, D270Y, D270W, D270P, D270G, P271D, P271E, P271N, P271Q, P271K, P271R, P271S, P271T, P271H, P271A, P271V, P271L, P271I, P271F, P271M, P271Y, P271W, P271G, E272D, E272R, E272T, E272H, E272V, E272L, E272F, E272M, E272W, E272P, E272G, K274D, K274N, K274S, K274H, K274V, K274I, K274F, K274M, K274W, K274P, K274G, F275L, N276D, N276T, N276H, N276V, N276I, N276F, N276M, N276W, N276P, N276G, Y278D, Y278N, Y278Q, Y278R, Y278S, Y278H, Y278V, Y278L, Y278I, Y278M, Y278P, Y278G, D280K, D280L, D280W, D280P, D280G, G281D, G281K, G281Y, G281P, V282E, V282K, V282Y, V282P, V282G, E283K, E283H, E283L, E283Y, E283P, E283G, V284E, V284N, V284T, V284L, V284Y, H285D, H285E, H285Q, H285K, H285Y, H285W, N286E, N286Y, N286P, N286G, K288D, K288E, K288Y, K290D, K290N, K290H, K290L, K290W, P291D, P291E, P291Q, P291T, P291H, P291I, P291G, R292D, R292E, R292T, R292Y, E293N, E293R, E293S, E293T, E293H, E293V, E293L, E293I, E293F, E293M, E293Y, E293W, E293P, E293G, E294K, E294R, E294S, E294T, E294H, E294V, E294L, E294I, E294F, E294M, E294Y, E294W, E294P, E294G, Q295D, Q295E, Q295N, Q295R, Q295S, Q295T, Q295H, Q295V, Q295I, Q295F, Q295M, Q295Y, Q295W, Q295P, Q295G, Y296K, Y296R, Y296A, Y296V, Y296M, Y296G, N297Q, N297K, N297R, N297T, N297H, N297V, N297L, N297I, N297F, N297M, N297Y, N297W, N297P, N297G, S298D, S298E, S298Q, S298K, S298R, S298I, S298F, S298M, S298Y, S298W, T299D, T299E, T299N, T299Q, T299K, T299R, T299L, T299F, T299M, T299Y, T299W, T299P, T299G, Y300D, Y300E, Y300N, Y300Q, Y300K, Y300R, Y300S, Y300T, Y300H, Y300A, Y300V, Y300M, Y300W, Y300P, Y300G, R301D, R301E, R301H, R301Y, V303D, V303E, V303Y, S304D, S304N, S304T, S304H, S304L, V305E, V305T, V305Y, K317E, K317Q, E318Q, E318H, E318L, E318Y, K320N, K320S, K320H, K320V, K320L, K320F, K320Y, K320W, K320P, K320G, K322D, K322S, K322V, K322I, K322F, K322Y, K322W, K322P, K322G, S324H, S324F, S324M, S324W, S324P, S324G, N325K, N325R, N325S, N325F, N325M, N325Y, N325W, N325P, N325G, K326P, A327E, A327K, A327R, A327H, A327V, A327I, A327F, A327M, A327Y, A327W, A327P, L328D, L328Q, L328K, L328R, L328S, L328T, L328V, L328I, L328Y, L328W, L328P, L328G, P329D, P329E, P329N, P329Q, P329K, P329R, P329S, P329T, P329H, P329V, P329L, P329I, P329M, P329Y, P329W, P329G, A330E, A330N, A330T, A330P, A330G, P331D, P331Q, P331R, P331T, P331L, P331I, P331F, P331M, P331Y, P331W, I332K, I332R, I332S, I332V, I332L, I332F, I332M, I332W, I332P, I332G, E333L, E333F, E333M, E333P, K334P, T335N, T335S, T335H, T335V, T335L, T335I, T335F, T335M, T335W, T335P, T335G, I336E, I336K, I336Y, S337E, S337N, and S337H, are provided using the methods described herein (wherein numbering is according to the EU index as in Kabat). One or more additional substitutions can be selected from the group consisting of S298A, K326A, K326S, K326N, K326Q, K326D, K325E, K326W, K326Y, E333A, E333S, K334A, K334E, Y300I, Y300L, Q295K, E294N, S298N, S298V, S298D, D280H, K290S, D280Q, D280Y, K290G, K290T, K290Y, T250Q, T250E, M428L, and M428F.
Note: an antibody is a polypeptide that comprises Fc polypeptide (Claims 1-2, 62, 64-65, 69-71, 87-88, 95).
Lazar et al. further discuses comprising dimers at para. [0110]; further modification such as afucosylation by cell lines at para. [0114]; and comprising the polypeptide in pharmaceutical compositions having pharmaceutically acceptable carriers at para. [0164]. (Claims 66-67, 104, 112).
Accordingly, Lazar et al. anticipates claims 1-2, 62, 64-67, 69-71, 87-88, 95, 104, 112.
Pertinent Art
13. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure:
Richards et al. ("Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells." Molecular cancer therapeutics 7.8 (2008): 2517-2527)—teaches Fc polypeptide having G236A substitution and benefits on ADCC.
Stavenhagen et al. ("Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcγ receptors." Cancer research 67.18 (2007): 8882-8890)—teaches Fc polypeptide havingY330L substitution and benefits on ADCC.
Conclusion
14. No claim is allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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